BENZAMIDE CGRP RECEPTOR ANTAGONISTS

BACKGROUND OF THE INVENTION CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively. CGRP-alpha and CGRP -beta display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to the CGRP receptor which is a heterodimer consisting of the G-protein coupled calcitonin-like receptor (CLR) in association with the single transmembrane protein known as receptor activity modifying protein 1 (RAMPi). CGRP receptors are predominantly coupled to the activation of adenylyl cyclase and have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.

CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache. In clinical studies, elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al. (1990) Ann. Neurol. 28, 183-187), salivary levels of CGRP are elevated in migraine subjects between (Bellamy et al. (2006) Headache 46, 24-33) and during attacks (Cady et al. (2009) Headache 49, 1258-1266), and CGRP itself has been shown to trigger migrainous headache (Lassen et al. (2002) Cephalalgia 22, 54-61). In clinical trials, the CGRP receptor antagonist BIBN4096BS has been shown to be effective in treating acute attacks of migraine (Olesen et al. (2004) New Engl. J. Med. 350, 1 104-1 1 10) and was able to prevent headache induced by CGRP infusion in a control group (Petersen et al. (2005) Clin. Pharmacol. Ther. 77, 202-213). The orally bioavailable CGRP receptor antagonist telcagepant has also shown antimigraine effectiveness in phase III clinical trials (Ho et al. (2008) Lancet 372, 21 15-2123; Connor et al. (2009) Neurology 73, 970-977).

CGRP-mediated activation of the trigeminovascular system may play a key role in migraine pathogenesis. Additionally, CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle meningeal arteiy, the principal artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP. Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al. (1988) Ann. Neurol. 23, 193-196). Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP receptor antagonist (Williamson et al. (1997) Cephalalgia 17, 525-531). Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al. (1995) Brain Res. 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP receptor antagonist BIBN4096BS (Doods et al. (2000) Br. J. Pharmacol. 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP receptor antagonist.

CGRP -mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distention of dural blood vessels during migraine headache may sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extra- cranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et al. (2000) Ann. Neurol. 47, 614-624). A CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRP receptor antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans. Such disorders may include migraine and cluster headache (Doods (2001) Curr. Opin. Invest. Drugs 2, 1261 -1268; Edvinsson et al. (1994) Cephalalgia 14, 320-327); chronic tension type headache (Ashina et al. (2000) Neurology 14, 1335-1340); pain (Yu et al. (1998) Eur. J. Pharmacol. 347, 275-282); chronic pain (Hulsebosch et al. (2000) Pain 86, 163-175); neurogenic inflammation and inflammatory pain (Holzer (1988) Neuroscience 24, 739-768; Delay-Goyet et al. (1992) Acta Physiol. Scanda. 146, 537-538;

Salmon et al. (2001) Nature Neurosci. 4, 357-358); eye pain (May et al. (2002) Cephalalgia 22, 195-196), tooth pain (Awawdeh et al. (2002) Int. Endocrin. J. 35, 30-36), non-insulin dependent diabetes mellitus (Molina et al. (1990) Diabetes 39, 260-265); vascular disorders; inflammation (Zhang et al. (2001) Pain 89, 265); arthritis, bronchial hyperreactivity, asthma, (Foster et al. (1992) Ann. NY Acad. Sci. 657, 397-404; Schini et al. (1994) Am. J. Physiol. 267, H2483-H2490; Zheng et al. (1993) J. Virol. 67, 5786-5791); shock, sepsis (Beer et al. (2002) Crit. Care Med. 30, 1794-1798); opiate withdrawal syndrome (Salmon et al. (2001) Nature Neurosci. 4, 357- 358); morphine tolerance (Menard et al. (1996) J. Neurosci. 16, 2342-2351); hot flashes in men and women (Chen et al. (1993) Lancet 342, 49; Spetz et al. (2001) J. Urology 166, 1720-1723); allergic dermatitis (Wallengren (2000) Contact Dermatitis 43, 137-143); psoriasis; encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al. (1999) Neurobiol. Dis. 6, 1 -34); skin diseases (Geppetti and Holzer, Eds., Neurogenic

Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al. (2002) J. Membr. Biol. 189, 225); obesity (Walker et al. (2010) Endocrinology 151, 4257-4269); inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al. (2002) Scand. J. Gastroenterol. 37, 414-422) and cystitis. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.

SUMMARY OF THE INVENTION

The present invention is directed to benzamide compounds which are potent antagonists of CGRP receptors and may be useful in the treatment or prevention of diseases in which the CGRP receptor is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of Formula I:

G ¹ isCR ³ orN; _,

G ² is CR ¹ orN;

G ³ is CR ² orN;

G ⁴ is CR ³ orN;

G ⁵ is CR ³ orN;

Yis O, CR ⁵ R ⁶ , NR ^b or SO _m;

V is CR ⁵ R ⁶ , C=0, O, NR ^b or SO _m;

E ¹ is N or CH;

A ¹ is CHR ⁶ , C=0;

A ² is CR ⁶ R ⁷ , C=0 or NR ⁴ ;

A ³ is CR ⁶ R ⁷ , C=0, NR ⁴ , O or S;

A ⁴ is a bond, CR ⁶ R ⁷ , O, S or NR ⁴ ;

E ² is N or C;

A ⁵ is CR ⁶ orN;

A ⁶ is CR ⁷ , C=0,NorNR ⁴ ;

A ⁷ is CR ⁶ , CR ⁷ , N, NR ⁴ or C=0;

A ⁸ is a bond, CR ⁷ , O, N or NR ⁴ ;

Z ¹ is CR ^a or N;

Z ² is CR ^a orN;

Z ³ is CR ^a ;

W ¹ is

a) hydrogen, b) Ci-6 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo, R ⁸ , (C=0)OR ⁵ , OR ⁴ , (C=0)NR ^b R ^c , SO _m R ^d and NR ^b R ^c ,

c) heterocyclyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo, R ⁴ , R ⁸ , (C]. ₆ alkyl)R ⁸ , OR ⁴ , (C=0)OR ⁵ , (C=0)R ⁸ , (C=0)NR ^b R ^c and SO _m R ^d ,

d) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, R ⁴ , R ⁸ , (Ci-6 alkyl)R ⁸ , OR ⁴ , (C=0)OR ⁵ , (C=0)NR ^b R ^c and SO _m R ^d ,

e) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, C _1-6 alkyl, OR ⁴ , (Ci^ alkyfjR ⁸ , (C=0)OR ⁵ , (C=0)NR ^b R ^c and SO _m R ^d , or

f) C3-8 cycloalkyl, which is optionally substituted with one to three substituents

4 8 8 independently selected from the group consisting of halo, oxo, R", R°, (C _1-6 a]kyl)R ⁰ , (C=0)OR ⁵ , OR ⁴ , (C=0)NR ^b R ^c and SO _m R ^d ;

W ² is

a) hydrogen,

b) Ci-6 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo and hydroxyl, or

c) C3-6 cycloalkyl, which is optionally substituted with one to four substituents

independently selected from the group consisting of halo, oxo and hydroxyl;

R ¹ is hydrogen, halo, Ci _-6 alkyl, 0(Ci_6 alkyl) or NR ^b R°, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;

R ² is

a) hydrogen,

b) halo,

c) cyano,

d) Ci-6 alkyl or C3.6 cycloalkyl, which may be optionally substituted with one to four

substituents independently selected from the group consisting of halo, hydroxyl, NR ^b R ^c and (C=0)NR ^b R ^c ;

e) 0(Ci_ alkyl), which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;

f) (C=0)NR ^b R ^c , g) (C=0)OR ⁴ ,

h) (C=0)OR ⁸ ,

i) (C=0)R ^s ,

j) NR ^b R ^c ,

k) SO _m R ^d ,

1) phenyl, which optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, R ⁴ , R ⁸ , OR ⁴ , NR ^b R ^c , (C=0)NR ^b R ^c , and SO _m R ^d ,

m) heterocyclyl, which optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, R ⁴ , R ⁸ , OR ⁴ , NR ^b R ^c , (C=0)NR ^b R ^c , and SO _m R ^d , or

n) heteroaryl, which optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, R ⁴ , R ⁸ , OR ⁴ , NR ^b R ^c , (C=0)NR ^b R ^c and SO _m R ^d ;

1 2

or R and R can be taken together with the carbon atom to which they are attached to form a C ₃ . cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to two substituents independently selected from the group consisting of cyano, R ⁴ , R ⁸ , halo, oxo and OR ⁴ ;

R is hydrogen, halo, hydroxyl, cyano or C| _-6 alkyl;

R ⁴ is hydrogen or Q.6 alkyl, wherein said alkyl group is optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, cyano, SO _m R ^d , OR ⁵ , NR ^b R ^c , (C=0)NR ^b R ^c and R ⁸ ;

R ⁵ is hydrogen, Ci. ₆ alkyl, heterocyclyl, or C ₃ „ ₈ cycloalkyl, which is optionally substituted with one to three halo;

R ⁶ is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl or NR ^b R ^c ;

R ⁷ is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl, 0(Ci_6 alkyl), NR ^b R°, C _3-6 cycloalkyl, heterocyclyl, heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl groups are optionally substituted with one to three substituents independently selected form the group consisting of halo, hydroxyl, R ⁸ , R ⁵ , and OR ⁵ ; or R° and R' can be taken together with the carbon atom or atoms to which they are attached to form a C ₃ . ₈ cycloalkyl, C ₃ . ₈ cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, oxo, R ⁵ , OR ⁵ , C3-6 cycloalkyl and heterocyclyl;

R ⁸ is phenyl, heteroaryl, heterocyclyl or C3.8 cycloalkyl, wherein said phenyl, heteroaryl, heterocyclyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, hydroxy., cyano, R ⁵ , NR ^b R ^c , OR ⁵ and SO _m R ⁹ ;

R ⁹ is hydrogen, Ci _-6 alkyl, C ₃ . ₈ cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and OR ⁵ ;

or two R ⁴ groups or an R ⁴ and R ⁸ group can be taken together with the atom to which they are attached to form a C ₃ . ₈ cycloalkyl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, NR ^b R°, OR ⁵ , C ₃ _6 cycloalkyl, and heterocyclyl wherein said alkyl, cycloalkyl and heterocyclyl rings are optionally substituted with one to four substituents independently selected from the group consisting of oxo, Ci-6 alkyl, halo and hydroxyl;

R ^a is selected from the group consisting of hydrogen, halo, cyano, Ci_6 alkyl and OR ⁵ , wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;

R ^b is hydrogen, Ci_ ₆ alkyl, (C=0)R ⁵ , (C=0)R ⁸ , SO _m R ⁹ , C ₃ . ₆ cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said alkyl, phenyl, heteroaryl, and heterocyclyl groups are optionally substituted with R , halo, hydroxyl, cyano, Ci _-6 alkyl, OR and SO _m R ;

R° is hydrogen or Ci_ ₆ alkyl, which is optionally substituted with one to three subsitituents independently selected from the group consisting of halo, OR ⁵ and hydroxyl; or R ^b and R ^c can be taken together with the atom to which they are attached to form a heterocyclyl ring which is optionally substituted with one to three substituents independently selected from the group consisting of R ⁵ , halo, oxo, hydroxyl, OR ⁵ and heterocyclyl;

R ^d is C,. ₆ alkyl, C ₃ - ₆ cycloalkyl and NR ^b R ^c ;

m is an integer from zero to two;

or a pharmaceutically acceptable salt thereof. In a class of the invention In another class of

the invention is

In a class of the invention, G is CR ³ . In a subclass of the invention, G ¹ is CH. In another class of the invention, G is N.

In a class of the invention, G is CR . In a subclass of the invention, G ² is CH. In another class of the invention, G

In a class of the invention, G ³ is CR ² . In another class of the invention, G ³ is N. In a class of the invention, G ⁴ is CR ³ . In a subclass of the invention, G ⁴ is CH. In another class of the invention, G is N.

In a class of the invention, G ⁵ is CR ³ . In a subclass of the invention, G ⁵ is CH. In another class of the invention, G ⁵ is N.

In a class of the invention, Y is O. In another class of the invention, Y is CR ⁵ R ⁶ . In another class of the invention, Y is NR ^b . In another class of the invention, Y is SO _m .

In a class of the invention, V is CR ⁵ R ⁶ . In a subclass of the invention, V is CH ₂ . In a class of the invention, V is C=0. In a class of the invention, V is O. In a class of the invention, V is NR ^b . In another class of the invention, V is SO _m .

In a class of the invention, E ¹ is CH. In another class of the invention, E ¹ is N.

In a class of the invention, E ² is C. In another class of the invention, E ² is N.

In a class of the invention, A ¹ is CHR ⁶ . In a subclass of the invention, A ¹ is CH ₂ .

In another class of the invention, A ¹ is C=0

In a class of the invention, A ^z is CR ⁶ R ⁷ . In another class of the invention, A ² 2 i ·s

C=0. In another class of the invention, A is NR .

In a class of the invention, A ^J is CR ⁶ R ⁷ . In a subclass of the invention, A ⁵ is CH ₂ . In another class of the invention, A ³ is C=0. In another class of the invention, A ³ is NR ⁴ . In another class of the invention, A ³ is O. In another class of the invention, A ³ is S. In a class of the invention, A ⁴ is CR ⁶ R ⁷ . In another class of the invention, A ⁴ is S. In another class of the invention, A ⁴ is NR ⁴ . In another class of the invention, A ⁴ is O. In another class of the invention, A ⁴ is a bond.

In a class of the invention, A ⁵ is CR ⁶ . In a subclass of the invention, A ⁵ is CH. In another class of the invention, A ⁵ is N.

In a class of the invention, A ⁶ is CR ⁷ . In another class of the invention, A ⁶ is C=0. In another class of the invention, A ⁶ is NR ⁴ .

In a class of the invention, A ⁷ is CR ⁶ . In another class of the invention, A ⁷ is CR ⁷ . In a subclass of the invention, A ⁷ is CH. In another class of the invention, A ⁷ is C-O. In another class of the invention, A ⁷ is NR ⁴ .

In a class of the invention, A ⁸ is CR ⁷ . In a subclass of the invention, A ⁸ is CH. In another class of the invention, A ⁸ is NR ⁴ . In another class of the invention, A ⁸ is O. In another class of the invention, A is a bond.

In a class of the invention, Z ¹ is CR ^a . hi a subclass of the invention, Z ¹ is CH. In another class of the invention, Z ¹ is N.

In a class of the invention, Z ² is CR ^a . In another class of the invention, Z ² is N.

In a class of the invention, Z ³ is CR ^a . In a subclass of the invention, Z ³ is CH.

In a class of the invention, W ¹ is:

a) Cj.6 alkyl, which is optionally substituted with one to four substituents

8 5 independently selected from the group consisting of halo, oxo, R , (C=0)OR ,

OR ⁴ , (C=0)NR ^b R ^c , SO _m R ^d and NR ^b R ^c ,

b) heterocyclyl, which is optionally substituted with one to three substituents

independently selected from the group consisting of halo, oxo, R ⁴ , R ⁸ , (C,.6 alkyl)R ⁸ , OR ⁴ , (C=0)OR ⁵ , (C=0)R ⁸ , (C=0)NR ^b R ^c and SO _m R ^d , c) heteroaryl, which is optionally substituted with one to three substituents

independently selected from the group consisting of halo, oxo, C] _-6 alkyl, OR ⁴ , (Ci. ₆ alkyl)R ⁸ , (C=0)OR ⁵ , (C=0)NR ^b R ^c and SO _m R ^d ; or

d) C3.8 cycloalkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, R ⁴ , R ⁸ , (Ci-6 alkyl)R ⁸ , (C=0)OR ⁵ , OR ⁴ , (C=0)NR ^b R ^c and SO _m R ^d .

In a subclass of the invention, W ¹ is:

a) heterocyclyl, which is optionally substituted with one to three substituents

4 8

independently selected from the group consisting of halo, oxo, R R°, (Cj.6 alkyl)R ⁸ , OR ⁴ , (C=0)OR ⁵ , (C=0)R ⁸ , (C=0)NR ^b R ^c and SO _m R ^d , or b) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, Ci _-6 alkyl, OR ⁴ , (C-6 alkyl)R ⁸ , (C=0)OR ⁵ , (C=0)NR ^b R° and SO _m R ^d .

In a further subclass of the invention, W ¹ is heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, R ⁴ , OR ⁴ and R ⁸ .

In a class of the invention, W is hydrogen.

In a class of the invention, R ¹ is hydrogen.

In a class of the invention, R ² is heteroaryl, which is optionally substituted with one substituent selected from the group consisting of Ci _-6 alkyl, heterocyclyl and C3.6 cycloalkyl.

In a class of the invention, R ³ is hydrogen.

In a class of the invention, R ^a is hydrogen or halo.

In a class of the invention, R ^b is hydrogen or Ci _-6 alkyl.

In a class of the invention, R° is hydrogen or Ci _-6 alkyl.

In a class of the invention, R ^d is Ci. ₆ alkyl.

Reference to the preferred classes and subclasses set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise.

Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 397, or pharmaceutically acceptable salts thereof.

The invention also encompasses a pharmaceutical composition which comprises an inert carrier and the compound of Formula I, or a pharmaceutically acceptable salt thereof.

The invention also encompasses a potential method of treating headache in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In a specific embodiment of the invention, the headache is migraine headache.

The invention also encompasses the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the potential treatment of headache. In a specific embodiment of the invention, the headache is migraine headache.

The invention is also directed to medicaments or pharmaceutical compositions for treating diseases or disorders in which CGRP is involved, such as migraine, which comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention is also directed to the use of a compound of Formula I for treating diseases or disorders in which CGRP is involved, such as migraine.

The invention is further directed to a method for the manufacture of a medicament or a composition for treating diseases or disorders in which CGRP is involved, such as migraine, comprising combining a compound of Formula I with one or more pharmaceutically acceptable earners.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers,

diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. In addition, the absolute configuration may be determined by use of vibrational circular dichroism (VCD) spectoscopy in conjuction with computational chemistry.

If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

In the compounds of Formula I, the atoms may exhibit their natural iso topic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (lH) and deuterium (^H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.

Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Tautomers of compounds defined in Formula I are also included within the scope of the present invention. For example, compounds including carbonyl -Ο¾0(0)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both keto and enol forms are included within the scope of the present invention.

When any variable (e.g. R.4, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.

It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5: 1 188-1 198; Showell, G.A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinaiy skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase

"optionally substituted with one or more substituents" should be understood as meaning that the group in question is either unsubstituted or may be substituted with one or more substituents.

As used herein, "alkyl" is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds. Thus, Ci -4-alkyl is defined to identify the group as having 1 , 2, 3 or 4 carbons in a linear or branched arrangement, such that Ci -4-alkyl specifically includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert- butyl.

The term "cycloalkyl" means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.

As appreciated by those of skill in the art, "halo" or "halogen" as used herein is intended to include chloro (CI), fluoro (F), bromo (Br) and iodo (I).

The term "cycloalkyl" or "carbocycle" shall mean cyclic rings of alkanes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

If no number of carbon atoms is specified, the term "alkenyl" refers to a non- aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon double bond. Preferably 1 carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C2-C6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. The term "cycloalkenyl" or shall mean cyclic rings of alkenes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e.,

cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl).

As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring.

The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyridinonyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl,

tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl,

dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

The term "heterocycle" or "heterocyclyl" as used herein is intended to mean a 4- to 10-membered nonaromatic ring, unless otherwise specified, containing from 1 to 4

heteroatoms selected from the group consisting of O, N, S, SO, or S0 ₂ and includes bicyclic or spirocyclic groups. "Heterocyclyl" therefore includes, but is not limited to the following:

piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl, oxetanyl, azetidinyl, pyrrolidonyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also emcompassed by this definition. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. In one aspect of the invention the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in the

Examples and herein. Specific compounds within the present invention include a compound which may be selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof. The subject compounds are useful in a method of antagonism of CGRP receptors in a patient such as a mammal in need of such antagonism comprising the administration of an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.

Another embodiment of the present invention is directed to a method for the treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable earner. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the terms "administration of or "administering a" compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.

The ability of the compounds of the present invention to act as CGRP receptor antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention may have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; obesity; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.

The subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.

The subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also include therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with an an anti- migraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5-HTJB/ID agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HTID agonist such as PNU-142633 and a 5-HTi _F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective

cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone,

oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine and the like; or

glucocorticoids. Similarly, the instant compounds may be administered with an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with an interleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1 receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine Al receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyn e B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT ₂ receptor antagonists; opiod agonists such as codeine, hydrocodone, tramadol, dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist or potentiator; a GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; an antidepressant, for example amitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene antagonist, for example montelukast or zafirlukast; an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide.

Also, the present compounds may be used in conjunction with gap junction inhibitors; neuronal calcium channel blockers such as civamide; AMPA/KA antagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-a-ergocryptine, dihydro-P-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, a-ergocryptine, β-ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin or divalproex sodium; an anti-hypertensive such as an angiotensin II antagonist, for example losartan, irbesartin, valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartan and candesartan cilexetil, an angiotensin I antagonist, an angiotensin converting enzyme inhibitor such as lisinopril, enalapril, captopril, benazepril, quinapril, perindopril, ramipril and trandolapril; or botulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non-sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine, phenylpropanolamine, or pseudoephedrine. The present compounds also may be used in conjunction with anti-emetics.

In an embodiment of the invention the present compounds may be used in conjunction with an anti-migraine agent, such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HTIB/ID agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, and other serotonin agonists; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the compound of the present invention to the other active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, or from about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s), and via the same or different routes of administration.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals the compounds of the invention are effective for use in humans.

The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceiyl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example

heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the laiown art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3 -butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions and the like, containing the compounds of the present invention are employed. Similarly, transdermal patches may also be used for topical administration. The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require antagonism of CGRP receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing the risk of headache, migraine, cluster headache, or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The utility of the compounds in accordance with the present invention as antagonists of CGRP receptor activity may be demonstrated by methodology known in the art. Inhibition of the binding of ^{l 25} I-CGRP to receptors and functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ^{, 25} I-CGRP to receptors in SK-N-MC cell membranes was carried out essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, membranes (25 μg) were incubated in 1 mL of binding buffer [ 10 mM HEPES, pH 7.4, 5 mM MgCl ₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM ¹²⁵ I-CGRP and antagonist. After incubation at room temperature for 3 h, the assay was terminated by filtration through GFB glass fibre filter plates (PerkinElmer) that had been blocked with 0.5% polyethyleneimine for 3 h. The filters were washed three times with ice- cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCl ₂ ), then the plates were air dried.

Scintillation fluid (50 xL) was added and the radioactivity was counted on a Topcount (Packard Instrument). Data analysis was carried out by using Prism and the K was determined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108).

RECOMBINANT RECEPTOR: Human CL receptor (Genbank accession number L76380) was subcloned into the expression vector pIREShyg2 (BD Biosciences

Clontech) as a 5'NheI and 3' Pmel fragment. Human RAMP1 (Genbank accession number AJ001014) was subcloned into the expression vector pIRESpuro2 (BD Biosciences Clontech) as a 5'NheI and 3'NotI fragment. HEK 293 cells (human embryonic kidney cells; ATCC #CRL- 1573) were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 μg mL streptomycin, and maintained at 37 °C and 95% humidity. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS. Stable cell line generation was accomplished by co-transfecting 10 μg of DNA with 30 μg Lipofectamine 2000 (Invitrogen) in 75 cm ² flasks. CL receptor and RAMPl expression constructs were co-transfected in equal amounts. Twenty-four hours after transfection the cells were diluted and selective medium (growth medium + 300 μg/mL hygromycin and 1 μg/mL puromycin) was added the following day. A clonal cell line was generated by single cell deposition utilizing a FACS Vantage SE (Becton Dickinson). Growth medium was adjusted to 150 μg mL hygromycin and 0.5 μg/mL puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY (ASSAY A): Cells expressing recombinant human CL receptor/RAMP 1 were washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA and Complete™ protease inhibitors (Roche). The cell suspension was disrupted with a laboratory homogenizer and centrifuged at 48,000 g to isolate membranes. The pellets were resuspended in harvest buffer plus 250 mM sucrose and stored at -70°C. For binding assays, 20 μg of membranes were incubated in 1 raL binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCl ₂ , and 0.2% BSA) for 3 h at room temperature containing 10 pM ¹²⁵ I-hCGRP (GE Healthcare) and antagonist. The assay was terminated by filtration through 96-well GFB glass fiber filter plates (PerkinElmer) that had been blocked with 0.05% polyethyleneimine. The filters were washed 3 times with ice-cold assay buffer (10 mM HEPES, pH 7.4, and 5 mM MgCl ₂ ). Scintillation fluid was added and the plates were counted on a Topcount (Packard). Non-specific binding was determined and the data analysis was carried out with the apparent dissociation constant (Κϊ) determined by using a nonlinear least squares fitting the bound CPM data to the equation below:

Yobsd = (Y™, - Yn,inX%I _mm . -% _mi n / 100) + Yjnin + fYmav - . Yn ¥100-%W10<»

1 + ([Drug] / Ki (l + [Radiolabel] / Κ _ά ) ^nH

Where Y is observed CPM bound, Y _max is total bound counts, Y _m j _n is non specific bound counts, (Ymax - Ymin) is specific bound counts, % I _max is the maximum percent inhibition, % I min is the minimum percent inhibition, radiolabel is the probe, and the Ki is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY (ASSAY B): Cells were resuspended in DMEM/F12 (Hyclone) supplemented with 1 g/L BSA and 300 μΜ isobutyl- methylxanthine. Cells were then plated in a 384-well plate (Proxiplate Plus 384; 509052761 ; Perkin-Elmer) at a density of 2,000 cells/well and incubated with antagonist for 30 min at 37 °C. Human a-CGRP was then added to the cells at a final concentration of 1.2 nM and incubated an additional 20 min at 37 °C. Following agonist stimulation, the cells were processed for cAMP determination using the two-step procedure according to the manufacturer's recommended protocol (HTRF cAMP dynamic 2 assay kit; 62AM4PEC; Cisbio). Raw data were transformed into concentration of cAMP using a standard curve then dose response curves were plotted and IC50 values were determined.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY (ASSAY C): Cells were resuspended in DMEM/F12 (Hyclone) supplemented with 1 g/L BSA and 300 μΜ isobutyl- methylxanthine. Cells were then plated in a 384-well plate (Proxiplate Plus 384; 509052761 ; Perkin-Elmer) at a density of 3,500 cells/well and incubated with antagonist for 30 min at 37 °C. Human a-CGRP was then added to the cells at a final concentration of 1 nM and incubated an additional 20 min at 37 °C. Following agonist stimulation, the cells were processed for cAMP determination using the two-step procedure according to the manufacturer's recommended protocol (HTRF cAMP dynamic 2 assay kit; 62AM4PEC; Cisbio). Raw data were transformed into concentration of cAMP using a standard curve then dose response curves were plotted and IC50 values were determined.

Representative K _\ or IC50 values in the recombinant receptor assays for exemplaiy compounds of the invention are provided in the table below:

Example Assay Ki or IC50 (nM)

1 A 770

2 A 180

3 B 15

4 B 0.18

5 B 0.69

6 B 0.13

7 B 0.08

8 B 0.45

9 B 53

10 B 1.2

1 1 A 140

12 B 0.20

13 B 1.6

14 B 63

15 B 0.24

16 B 0.10

17 B 1 1

18 B 0.22

19 B 0.17

20 B 0.59

21 B 0.10

22 B 0.14

23 B 0.99

24 B 1.9

25 B 2.0

26 B 0.18

27 B 0.27

28 B 0.35

29 B 2.1

30 B 0.25

31 B 0.66 32 B 0.32

33 B 19

34 B 1.0

35 B 0.14

36 B 2.7

37 B 1.6

38 B 0.98

39 B 0.56

40 B 0.15

41 B 0.32

42 B 0.27

43 C 120

44 B 0.01

45 B 0.17

46 B 0.22

47 B 1.0

48 B 0.13

49 C 2.1

50 B 0.13

51 B 0.17

52 B 0.04

53 B 0.11

54 C 1.3

55 B 0.24

56 B 0.09

57 B 0.06

58 C 0.33

59 B 0.45

60 C 13

61 B 9.2

62 B 0.14

63 B 7.1

64 B 0.23

65 B 0.35

66 B 0.84

67 B 0.17

68 C 0.71 69 C 0.30

70 C 1.5

71 B 0.05

72 B 1.3

73 B 1.5

74 C 1.3

75 B 1.6

76 B 0.75

77 B 0.19

78 C 0.27

79 B 0.37

80 B 660

81 B 18

82 B 0.08

83 B 0.14

84 A 89

85 B 5.0

86 B 0.63

87 B 13

88 A 190

89 B 15

90 B 25

91 B 11

92 B 19

93 B 27

94 B 3.8

95 B 13

96 B 26

97 B 52

98 B 4.4

99 B 15

100 B 3.1

101 B 15

102 B 63

103 B 33

104 B 35

105 B 8.4 106 B 73

107 B 28

108 B 17

109 B 38

110 B 10

1 11 A 440

1 12 A 2500

113 A 150

114 A 190

1 15 B 5.3

1 16 B 68

1 17 B 1.4

118 B 5.4

119 B 17

120 A 700

121 B 0.41

122 A 71

123 A 180

124 B 0.97

125 B 40

126 B 0.30

127 B 3.6

128 B 44

129 B 10

130 A 46

131 B 37

132 B 1.4

133 B 3.1

134 B 3.1

135 B 53

136 B 0.79

137 B 1600

138 C 8.8

139 B 0.08

140 B 2.0

141 B 0.49

142 B 0.31 143 A 62

144 A 57

145 A 630

146 B 2.0

147 B 3.5

148 B 67

149 B 2.8

150 B 50

151 B 6.8

152 B 4.2

153 B 1.7

154 B 54

155 B 34

156 B 33

157 B 8.7

158 B 2.6

159 B 0.99

160 B 28

161 B 62

162 B 0.62

163 B 7.9

164 B 0.40

165 B 0.98

166 B 0.20

167 A 2400

168 A 570

169 A 2700

170 A 1600

171 A 210

172 B 140

173 A 100

174 A 180

175 A 800

176 A 350

177 A 420

178 A 1300

179 A 1500 180 A 840

181 A 970

182 B 240

183 A 1 10

184 B 64

185 A 190

186 A 1 10

187 A 1200

188 B 260

189 A 1600

190 A 1000

191 A 1800

192 A 380

193 B 41

194 B 7.5

195 B 2.9

196 B 0.56

197 A 83

198 B 5.1

199 A 190

200 B 0.73

201 B 0.88

202 B 6.0

203 B 3.3

204 B 2.0

205 A 160

206 B 27

207 B 0.96

208 B 1.6

209 B 7.0

210 C 3.1

211 B 0.25

212 C 0.13

213 A 150

214 A 300

215 A 670

216 A 1 100 217 B 0.17

218 B 1.9

219 B 0.26

220 B 42

221 B 200

222 A 360

223 B 10

224 A 120

225 A 35

226 B 3.3

227 B 3.9

228 B 13

229 B 87

230 B 8.0

231 B 560

232 B 970

233 B 0.16

234 B 5000

235 B 0.94

236 B 4.9

237 B 710

238 B 0.28

239 B 0.97

240 B 0.14

241 B 0.94

242 B 0.43

243 B 1.4

244 B 0.47

245 B 1.9

246 B 1.6

247 B 0.12

248 B 0.24

249 B 0.35

250 B 0.13

251 B 0.39

252 B 27

253 B 1.0 254 B 1.5

255 B 0.36

256 B 1.3

257 B 0.20

258 B 0.22

259 B 11

260 B 2.1

261 B 3.2

262 B 0.24

263 B 2.7

264 B 0.30

265 B 0.13

266 B 0.31

267 B 0.21

268 B 0.48

269 A 0.04

270 B 0.44

271 C 2.1

272 C 2.3

273 C 7.1

274 B 0.65

275 C 170

276 C 0.24

277 C 0.41

278 C 4.2

279 C 1.40

280 C 1.1

281 c 0.98

282 c 1.2

283 c 1.9

284 c 0.15

285 c 0.88

286 B 0.19

287 C 8.3

288 B 0.62

289 C 0.15

290 C 0.30 291 C 1.2

292 C 0.1 1

293 c 0.43

294 c 0.11

295 B 5.7

296 B 83

297 A 140

298 B 8.0

299 B 2.0

300 B 0.20

301 B 1.3

302 B 0.94

303 B 2.0

304 B 1.8

305 B 2.0

306 B 39

307 B 1.9

308 B 2.7

309 B 0.23

310 C 0.51

311 B 2.2

312 B 1.0

313 B 0.22

314 B 0.37

315 C 0.24

316 B 0.36

317 C 0.39

318 C 2.4

319 C 2.6

320 B 430

321 B 1.2

322 B 18

323 B 0.55

324 B 0.55

325 B 0.85

326 C 2.5

327 B 0.46 328 C 1.7

329 C 0.66

330 c 0.26

331 c 1.7

332 c 0.38

333 c 3.0

334 c 1.2

335 c 0.40

336 c 0.37

337 c 0.31

338 c 1.3

339 c 0.08

340 c 0.74

341 c 0.09

342 B 40

343 B 170

344 B 1 10

345 B 7.3

346 B 27

347 B 3.4

348 B 13

349 B 0.99

350 B 0.78

351 B 5.2

352 C 2.4

353 C 38

354 C 12

355 C 10

356 B 1.5

357 C 1.3

358 C 0.10

359 B 31

360 B 0.81

361 B 0.28

362 B 0.68

363 C 0.71 365 B 0.02

366 C 0.40

367 B 7.0

368 B 22

369 B 35

370 C 1.1

371 C 4.5

372 C 2.9

373 C 3.0

374 C 0.57

375 C 1.0

376 C 5.0

377 C 3.5

378 C 7.6

379 C 27

380 C 44

381 C 45

382 C 520

383 C 2.4

384 B 0.23

385 B 0.03

386 B 0.03

387 B 0.06

388 B 0.13

389 B 0.18

390 B 0.08

391 B 0.07

392 B 0.09

393 B 0.1 1

394 B 0.24

395 B 0.56

396 B 0.23

397 B 0.28

The following abbreviations are used throughout the text: Ac acetyl

AIBN 2,2'-azobisisobutyronitrile

aq ^Ί aqueous

Ar aryl

B ₂ (Pin) ₂ bis(pinacolato)diboron

BINAP 2,2' -bis (diphenylphosphino)- 1 , 1 '-binaphthalene

Bn benzyl

Boc fcrf-butoxycarbonyl

(benzotriazol- 1 -yloxy)ira(dimemylamino)phosphonium

BOP

hexafluorophosphate

br broad

BSA bovine serum albumin

Bu butyl

ca circa (approximately)

CAN ammonium cerium(IV) nitrate

Cbz carboxybenzyl

CDI 1 , 1 '-carbonyldiimidazole

d doublet

DABCO diazabicyclo [2.2.2] octane

DAST (diethylamino)sulfur trifluoride

dba dibenzylideneacetone

DBU l ,8-diazabicyclo[5.4.0]undec-7-ene

DCE 1 ,2-dichloroethane

dd doublet of doublets

DIBAL diisobutylaluminum hydride

DIEA NN-diisopropylethylamine

DIPEA N,N-diisopropylethylamine

DMA NN-dimethylacetamide

DMAc N,N-dimethylacetamide

DMAP 4-(dimethylamino)pyridine

DMEM: Dulbecco's Modified Eagle Medium (High Glucose)

DMF NN-dimethylformamide

DMPU N,N'-dimethylpropyleneurea

DMSO dimethylsulfoxide

DPBF 1 ,3-diphenylisobenzofuran

dppf 1 , 1 '-&z ^' s(diphenylphosphino)ferrocene

EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

EDTA ethylenediaminetetraacetic acid

eq equivalents

ESI electrospray ionization

Et ethyl

FBS fetal bovine serum

h hours 0(7-azabenzotriazol- 1 -yl)-N,N,N'N'-tetramethyluronium

HATU

hexafluorophosphate

HEPES N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)

HMDS hexamethyldisilazane

HMTA hexamethylenetetramine

HOAt 1 -hydroxy-7-azabenzotriazole

HOBt 1 -hydroxybenzotriazole

HPLC high performance liquid chromatography

Hz hertz

imid imidazole

/-Pr isopropyl

J coupling constant

LCMS liquid chromatography-mass spectrometry

LDA lithium diisopropylamide

m/z mass to charge ratio

m multiplet

mCPBA 3-chloroperbenzoic acid

Me methyl

min minutes

MP macroporous polystyrene

Ms methanesulfonyl

MTBE methyl teri-butyl ether

MW molecular weight

NBS N-bromosuccinimide

n-BuLi «-butyllithium

M-HexLi fl-hexyllithium

NMM N-methyl morpholine

NMP 1 -methyl-2-pyrrolidinone

NMR nuclear magnetic resonance

OAc acetate

P pentet

PBPB pyridinium bromide perbromide

PBS phosphate-buffered saline

Pd/C palladium on carbon

Ph phenyl

PMBC1 4-methoxybenzyl chloride

psi pounds per square inch

p-Ts 4-toluenesulfonyl

Py pyridyl

PYBOP benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate

PyCIU chlorodipyrrolidinocarbenium

q quartet

rt room temperature s singlet

SEM 2-trimethylsilylethoxymethyl

SEMC1 2-trimethylsilylethoxymethyl chloride

SFC supercritical fluid chromatography

SM starting material

t triplet

T3P 2,4,6-tripropyl-l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide

TBAF »-tetrabutylammonium fluoride

TBDPS /eri-butyldiphenylsilyl

TBDPSC1 teri-butyldiphenylsilyl chloride

t-B tert-butyl

TCCA trichloroisocyanuric acid

TEA triethylamine

TFA trifluoroacetic acid

TCFH tetramethylchloroformamidinium hexafluorophosphate

THF tetrahydrofuran

trisyl 2,4,6-triisopropylbenzenesulfonyl

V/V volume to volume

X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein.

The compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves loiown to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

REACTION SCHEMES The compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.

Scheme 1 illustrates the general strategy for preparing the compounds of the present invention by coupling of a carboxylic acid intermediate (1.1) to an amine (1.2) to give the desired product amide 1.3. Various carboxylic acid intermediates, such as those described herein {vide infra), may be coupled to a variety of amines to give the compounds of the present invention. There are many known strategies for effecting such coupling chemistry, including use of coupling reagents, such as EDC with HOBt, PyBOP, HATU, CDI and the like. Alternatively, the carboxylic acid 1.1 may be activated as an acid chloride or anhydride, for example, to facilitate reaction with the amine of interest. Activation of the amine 1.2, for example with trimethylaluminum, followed by treatment with an ester derivative of carboxylic acid 1.1, may also be a useful strategy in cases where the amine is relatively unreactive. In some cases, various protecting group strategies familiar to one skilled in the art of organic synthesis may be employed to allow preparation of a particular compound of the present invention. In some cases, if the final product 1.3 is a mixture of stereoisomers, including enantiomers or diastereoisomers, SFC or normal phase or reverse-phase chromatography (employing a chiral or achiral stationary phase) may provide single isomers. Additionally, intermediates such as ester 4.8 in Scheme 4, can be resolved using similar conditions and the individual stereoisomers may be elaborated to prepare the final compounds of interest. SCHEME 1

1-1 1.3

Another general approach for the preparation of compounds of the present invention is illustrated in Scheme 2. This methodology relies on a palladium-catalyzed arylation of intermediate 2.1 with a boronic acid (2.2). In some cases, it may be advantageous to use alternative conditions that utilize a different catalyst, base, ligand or solvent system as known to one skilled in the art. The aryl boronic acid 2.2 may be replaced by a similar reactant, such as the corresponding aryl stananne or trifluoroboronate salt and the aryl bromide 2.1 may be replaced with the corresponding chloride or iodide to effect the formation of similar biaryl products. Alternatively, aryl bromide 2.1 may be converted to the boronic acid via treatment with bis(pinacolato)diboron in the presence of a suitable palladium catalyst, ligand, and base (e.g., Pd ₂ (dba)3, X-phos and KOAc) and subsequently coupled with a suitable aryl or heteroaryl halide to afford target 2.3.

Scheme 3 describes a number of methods in which the amide from Scheme 1 may be alkylated or acylated to afford derivatives such as 3.3. The Boc group (or other suitable protecting group) from intermediate 3.1 is removed under acidic conditions to provide amine 3.2, which may then be treated with a base (e.g. NaH) and an alkylating agent (R ⁴ -X) to afford the substituted amine 3.3. Amine 3.2 may alternatively undergo reductive amination with a ketone or aldehyde under standard conditions to afford 3.3. Reaction of amine 3.2 with an epoxide in the presence of a mild base (TEA) may afford amine 3.3. Alternatively, treating 3.2 with an acylating agent in the presence of a base (TEA or other) may afford an amide variant of 3.3. Other functionalization of the amine may include sulphonylation, urea or carbamate formation, and N-arylation.

SCHEME 3

In most cases, intermediate acids of the type 1.1 may be prepared using well- precedented methodology and several such intermediates are described herein {vide infra). Variations of these approaches, familiar to one skilled in the art of organic synthesis, may be employed to produce a variety of related intermediates. Scheme 4 describes one such method wherein acid 4.1 is esterified, followed by treatment of 4.2 with NBS and a radical initiator (AIBN or benzoyl peroxide) in a suitable solvent to afford benzyl bromide 4.3. Treatment of this bromide with the anion of 4.4 may be used to provide the alkylated product 4.5. To prepare intermediates where E = N, a base such as NaH may be employed; and when E = CH, a stronger base (e.g. LiHMDS) may be required. The methyl ether of 4.5 is cleaved with BBr ₃ or HBr, followed by re-esterification of the carboxylic acid product, if required. The resulting phenol 4.6 is then treated with aryl iodide (or bromide) 4.7 in the presence of a copper source, a suitable base, and a ligand to afford the ether 4.8. If 4.7 is a heteroaryl bromide (or fluoride) or aryl fluoride, then treatment of phenol 4.6 with NaH or Cs ₂ C0 ₃ in DMF followed by reaction with 4.7 may afford the corresponding ether as well. If ether 4.8 is a mixture of isomers, it may be convenient to separate the isomers at this stage using SFC or reverse or normal phase chromatography employing an achiral or chiral stationary phase, prior to saponification of the ester to afford acid 4.9. SCHEME 4

4.8 4.9

An alternative method to prepare acid intermediate of the type 5.11 is illustrated in Scheme 5. Base-catalyzed S _N Ar reaction of aryl fluoride 5.2 with phenol 5.1 affords ether 5.3, which is then brominated with NBS to provide benzyl bromide 5.4. The bromide may then be used to alkylate a suitable nucleophile such as the anion of 5.5 to afford ester 5.6. Reduction of the nitro group with iron in ethanolic ammonium chloride, or other suitable reducing conditions, is followed by conversion of the amino group to the boronate ester 5.8 using teri-butyl nitrite and benzoyl peroxide, followed by B ₂ (Pin)2. Palladium-catalyzed cross-coupling of boronate 5.8 with a variety of aryl/heteroaryl halides, such as 5.9, under Suzuki conditions affords the ether 5.10, which is subsequently hydrolyzed to provide acid 5.11.

Acid intermediates of type 6.6 may be prepared as shown in Scheme 6, using similar methodology to that described in Scheme 4. Phenol 5.1 is transformed into ether 6.2 under Ullmann or direct displacement conditions, depending upon the nature of halide 6.1. Bromination of the tolyl group in 6.2 followed by alkylation as described {vide supra), and ester hydrolysis affords intermediate 6.6.

SCHEME 6

Another variation of this methodology is illustrated in Scheme 7, which describes a synthetic route to acid intermediates of the type 7.6. Chloride 6.2 is converted to boronate 7.1 using standard conditions (Pd ₂ (dba)3, X-Phos, KOAc, B ₂ (Pin) ₂ ) and then subsequent bromination affords bromide 7.2. Alkylation of a suitable substrate, such as pyrazinone 7.3, with bromide 7.2 is followed by Suzuki coupling and hydroylsis to afford acid 7.6.

SCHEME 7

Alternatively, acid intermediates represented by 8.9 can by synthesized by the route described in Scheme 8. Ullmann coupling of phenol 5.1 with iodoester 8.1 affords ether 8.2. Alternatively, if a heteroaryl 8.1 is used, then base catalyzed displacement may also afford ether 8.2. Bromination, alkylation, and deprotection of the terf-butyl ester under acidic conditions affords acid 8.5. Coupling of the acid with the substituted amide oxime 8.6 under EDC or other coupling conditions, followed by cyclization with 2,4,6-tripropyl-l,3, 5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (T3P) or TBAF, affords oxadiazole 8.8, which is subsequently hydrolyzed to afford acid 8.9.

SCHEME 8

A synthetic route to acid intermediate 9.15 is depicted in Scheme 9. Following standard protectioning group chemistry, silyl ether 9.3 is brominated with excess NBS to afford 9.4, which can undergo silver mediated hydrolysis to provide aldehyde 9.5. Fluoride mediated removal of the silyl group is followed by heating of 9.6 with trimethylorthoformate in the presence of acid to form acetal 9.7. Coupling of the phenol with aryl iodide 9.8 under Ullmann conditions, followed by acidic deprotection of the acetal and reduction of the subsequent aldehyde with a reducing agent such as sodium tnacetoxyborohydride affords alcohol 9.11. The alcohol can be converted to the benzyl bromide 9.12 through treatment with carbon tetrabromide and triphenylphosphine, and then used to alkylate an agent such as pyrimidinone 9.13 to afford, after saponification, acid 9.15. SCHEME 9

9.14 9.15

Scheme 10 illustrates the preparation of acid intermediate 10.4. Benzyl bromide 9.12 can undergo a palladium-mediated coupling with boronic acid 10.1, for example, to fonn ester 10.2. The methyl ether is cleaved with HBr in water with heat and then saponification of the ester affords acid 10.4.

Scheme 1 1 depicts a synthetic route to acid intermediate 11.5, which begins by palladium catalyzed cross-coupling of benzyl bromide 4.3 with boronic acid 10.1. Removal of the methyl ethers is effected by treatment with HBr in water. Ullmann coupling of phenol 11.2 with iodide 11.3, followed by saponification, affords 11.5.

11.4 11.5 Scheme 12 describes the preparation of pyridazinone acid intermediate 12.2 condensation of aldehyde 9.10 with dihydropyridazinone 12.1 under basic conditions.

SCHEME 12

Scheme 13 describes the preparation of urea containing intermediate 13.2 via alkylation of benzyl bromide 9.12 with a diamine such as 13.1, followed by cyclization with CDI and ester hydrolysis.

SCHEME 13

Scheme 14 illustrates a method to install a benzylic methyl group to afford intermediates such as 14.6. Bromide 14.1 is treated with vinylpyrrolidinone 14.2 under Heck coupling conditions (Pd(OAc) ₂ , X-Phos, dicyclohexylmethylamine) to afford 14.3. The benzyl ether is removed under hydrogenolysis conditions (H ₂ , Pd/C) to afford phenol 14.4. Ullmann coupling followed by saponification, affords the acid 14.6.

14.5 14.6

The preparation of some specific types of aryl/heteroaryl halides for use in, but not limited to, the Ullmann coupling reaction as described in the preceding Schemes, are shown in Schemes 15-17. Scheme 15 illustrates a method to prepare substituted thiadiazoles of the type 15.4. lodoacid 15.1 is coupled with the substituted acylhydrazide 15.2 using EDC/HOAt to give intermediate 15.3, which is subsequently heated with Lawesson's reagent to afford thiadiazole 15.4.

SCHEME 15

Acid 15.1 may also be transformed into an oxadiazole as shown in Scheme 16, starting with the coupling of N-hydroxyamidine 16.1 to give intermediate 16.2. This intermediate may be heated with 2,4,6-tripropyl-l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), or isolated and treated with TBAF, to afford oxadiazole 16.3. SCHEME 16

The synthesis of pyridazine 17.4 is outlined in Scheme 17. Palladium catalyzed cross-coupling between chloropyridazine 17.1 and pinacol boronate 17.2 affords aminobiaryl 17.3. The amino group is then converted into an iodide under Sandmeyer conditions to afford iodide 17.4.

Schemes 18-20 illustrate methods to prepare substituted amines that are useful for the preparation of compounds of the present invention. In Scheme 18, piperidinyl amine 18.1 is bisalkylated with benzyl bromide to afford 18.2. Standard removal of the Boc group gives 18.3, which can then undergo reductive alkylation with an aldehyde or ketone (18.4) to afford 18.5. At this stage, if product 18.5 is a mixture of stereoisomers, they may be separated utilizing techniques such as chiral SFC or reverse or normal phase chromatography prior to removal of the benzyl groups under hydrogenolysis conditions to afford 18.7a and 18.7b.

SCHEME 18

Intermediates of type 19.6 can be prepared as described in Scheme 19. Standard protecting group manipulations yield amine 19.3, which is alkylated with epoxide 19.4 in the presence of a base such as triethylamine to afford alcohol 19.5. If product 19.5 is a mixture of stereoisomers, they may be separated using standard techniques at this stage, followed by removal of the Cbz group to afford 19.6.

SCHEME 19

A method to prepare substituted amines of the type 20.10 is outlined in Scheme 20. 1,4-Addition of amine 20.1 to ethyl 4,4,4-trifiuorobut-2-enoate 20.2 affords amine 20.3. Other unsaturated esters may be used as alternatives to 20.2 to provide other products. Acylation with 20.4 in the presence of base provides diester 20.5, which may be cyclized and then decarboxylated by sequential treatments with base and then acid, respectively, to give ketone 20.6. The ketone may undergo reductive amination with benzylamine, and the resulting piperidinone 20.7 can be reduced with LAH to provide amine 20.8. At this stage, the stereoisomers may be separated using SFC or reverse or normal phase chromatography

(employing a chiral or achiral stationary phase) and then the benzyl group removed to afford isomers 20.10a-d.

SCHEME 20

In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. Additionally, various protecting group strategies may be employed to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. Wherein a racemic mixture is produced, the enantiomers may be separated using SFC reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies may also be employed in the synthesis of these key intermediates. Asymmetric methodologies (e.g. chiral catalysis, auxiliaries) may be used where possible and appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions, depends upon the nature of the intended product.

N-(3-Fluoropyridin-2-vI)-4-iodobenzamide

Oxalyl chloride (508 mg, 4.00 mmol) was added dropwise to a solution of 4- iodobenzoic acid (500 mg, 2.0 mmol) in CH2CI2 (5 mL) at 0 °C containing 3 drops of DMF. The mixture was stirred at 0 °C for 1 h and warmed up to 23 °C and stirred for 2 h. The CH ₂ C1 ₂ was then removed, and the residue was dissolved in 6 mL dry pyridine. The freshly prepared acid chloride in pyridine was then added to a solution of 2-amino-3-fluoropyridine (448 mg, 4.00 mmol) in pyridine (4 mL) and mixture was stirred at 0 °C for 2 h and ambient temperature for 10 h. After removal of the solvent, the residue was partitioned between saturated NaHC0 ₃ and EtOAc (30 mL x 3); the combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3% EtOAc in petroleum ether, grading to 25% EtOAc in petroleum ether, to give the title compound. Ή NMR (400 MHz, CD ₃ OD): δ 7.96-7.93 (m, 1H), 7.78-7.77 (d, J = 2.0 Hz, 2H), 7.76-7.74 (m, 3H), 7.44-7.40 (m, 1H).

INTERMEDIATE A2

4-BiOmo-N-cyclobutylbenzamide

To a solution of 4-bromobenzoic acid (600 mg, 2.56 mmol) in anhydrous DMF (20 mL) was added cyclobutylamine (218 mg, 9.60 mmol), HATU (1.17 g, 3.07 mmol), TEA (1.5 mL) and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water (100 mL) and then extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of 10% to 30% ethyl acetate in petroleum ether) to give the title compound. MS m/z = 253.9 [M+l]. Ή NMR (400 MHz, CDC1 ₃ ): δ 7.62 (d, J = 4.8 Hz, 2 H), 7.55 (d, J = 4.8 Hz, 2 H), 6.22 (s, 1 H), 4.62-4.52 (m, 1 H), 2.47-2.40 (m, 2 H), 2.01-1.91 (m, 2 H), 1.81-1,75 (m, 2 H).

I 3

2-(4-Iodophenyl)-5-methyl-l ,3,4-thiadiazole

Step A: N'-Acetyl-4-iodobenzohvdrazide

N-Methylmorpholine (17.7 mL, 161 mmol) was added to a stirring solution of 4- iodobenzoic acid (10.0 g, 40.3 mmol), acetylhydrazide (3.00 g, 40.3 mmol), EDC (13.5 g, 70.6 mmol), and HOAt (2.70 g, 20.2 mmol) in DMF (81 mL). The resulting mixture was stirred at 50 °C for 30 min. The mixture was cooled to ambient temperature, and excess water was added. The resulting solids were filtered, washed with water, and dried under high vacuum to give the title compound. LC-MS m/z found = 305.1 [M+l].

Ste B: 2-(4-Iodophenyl)-5-methyl-l ,3 _< 4-thiadiazole

Lawesson's Reagent (21.2 g, 52.5 mmol) was added to a stirring solution of Ν'- acetyl-4-iodobenzohydrazide (12.0 g, 39.5 mmol) in THF (395 mL) and the resulting mixture was stirred at 50 °C for 2 h. The mixture was concentrated to dryness. Purification of the crude mixture by silica gel chromatography (100→ 50% Hexanes/EtOAc) and recrystallization from EtOAc gave the title compound. LC-MS m/z found = 303.1 [M+l]; Ή NMR (400 MHz, DMSO): δ 2.78 (s, 3 H); 7.72-7.71 (m, 2 H); 7.92-7.91 (m, 2 H).

2-Cyclopropyl-5-(4-iodophenyl)-l,3,4-thiadiazole

Step A: N'-(Cvclopropanecarbonyl)-4-iodobenzohvdrazide

N-Methylmorpholine (21.3 mL, 194 mmol) was added to a solution of 4- iodobenzoic acid (12.0 g, 48.4 mmol), cyclopropanecarbohydrazide (6.10 g, 60.5 mmol), EDC (16.2 g, 85.0 mmol), and HOAt (3.30 g, 24.2 mmol) in DMF (16 mL). The resulting mixture was stirred at 50 °C for 1 h. The reaction was cooled to ambient temperature and excess water was added. The resulting solids were filtered, washed with water, and dried under high vacuum to give the title compound. LC-MS m/z found = 331.2 [M+l].

Step B: 2-Cyclopropyl-5-(4-iodophenyl)-L3,4-thiadiazole

Lawesson's Reagent (25.4 g, 62.8 mmol) was added to a solution of N- (cyclopropanecarbonyl)-4-iodobenzohydrazide (15.6 g, 47.3 mmol) in THF (475 mL) and the resulting mixture was stirred at 50 °C for 2 h. The mixture was concentrated to dryness.

Purification of the crude mixture by silica gel chromatography (100→ 50% Hexanes/ EtOAc) provided the title compound. LC-MS m/z found = 329.1 (M+l); Ή NMR (400 MHz, DMSO): δ 1.08-1.07 (m, 2 H); 1.18 (t, J = 7.1 Hz, 1 H); 1.25-1.24 (m, 2 H); 7.69-7.68 (m, 2 H); 7.91-7.90 (m, 2 H).

2-(4-Iodophenyl)-5-(tetrahvdro-2H-pyran-4-yl)-l,3,4-thiadiaz ole

2,4,6-Tripropyl-l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (5.88 mL, 50% in DMF, 10.1 mmol) was added to a vial containing 4-iodobenzoic acid (1.00 g, 4.03 mmol), tetrahydro-2H-pyran-4-carbohydrazide (0.640 g, 4.44 mmol), and TEA (1.69 mL, 12.1 mmol) in EtOAc (4 mL). The vial was sealed and the resulting mixture was heated at 80 °C for 18 h. The reaction was concentrated. The residue was taken up in THF (37 mL), Lawesson's Reagent (1.89 g, 4.68 mmol) was added, and the resulting mixture was heated at reflux for 1 h. The reaction mixture was concentrated to dryness. Purification of the crude mixture by silica gel chromatography (100→ 75% CH ₂ Cl ₂ /EtOAc) gave the title compound. LC-MS m/z = 373.1 [M + 1].

INTERMEDIATE A6

2-(2-Fluoro-4-iodophenylV5-isopropyl-L3,4-thiadiazole

Step A: 2-Fluoi -4-iodo-N'-isobutvi lbenzohvdrazide

N-Methylmorpholine (1.65 mL, 15.0 mmol) was added to a solution of 2-f uoro- 4-iodobenzoic acid (1.0 g, 3.7 mmol), isobutyrohydrazide, (0.44 g, 4.3 mmol), EDC (1.3 g, 6.6 mmol), and HO At (0.26 g, 1.9 mmol) in DMF (7.5 mL). The resulting mixture was stirred at 23 °C for 1 h. Excess ice water was added. The resulting solids were filtered, washed with water, then diethyl ether, and dried under high vacuum to give the title compound. MS m/z = 351.0 (M+l).

Step B: 2-(2-Fluoro-4-iodophenyl)-5-isopropyl-l,3,4-thiadiazole

Lawesson's Reagent (2.3 g, 5.7 mmol) was added to a solution of 2-fluoro-4-iodo-N- isobutyrylbenzohydrazide (1.4 g, 4.0 mmol) in THF (30 mL) and the resulting mixture was stirred at 65 °C for 2 h. Lawesson's Reagent (1.0 g, 2.5 mmol) was added again to the solution, and heating was continued for 18 h. The mixture was cooled to 23 °C and then concentrated to dryness. The residue was adsorbed onto 10 g of silica gel which was then loaded onto a column of silica gel. Elution using a gradient of heptanes/ethyl acetate (95/5 to 35/65) gave the title compound. MS: m/z = 349.0 (M+l)

2-(5-(4-Bromo-2-fluorophenyl)-L3,4-thiadiazol-2-yl)propan -2-ol

AIBN (0.055 g, 0.33 mmol) and l-hydroxypyrrolidine-2,5-dione (0.096 g, 0.83 mmol) were added to a solution of 2-(4-bromo-2-fluorophenyl)-5-isopropyl-l ,3,4-thiadiazole (1.00 g, 3.32 mmol) in MeCN (1 1 mL). The resulting solution was heated at reflux, and air was bubbled through the reaction mixture. After heating at reflux for 4 h, a second portion of AIBN (0.055 g, 0.33 mmol) and 1 -hydro ypyrrolidine-2,5-dione (0.096 g, 0.83 mmol) were added, and the reaction was heated at reflux for 18 h. The reaction was cooled to ambient temperature and triphenylphosphine (2.61 g, 9.96 mmol) was added. The resulting mixture was stirred at ambient temperature for 1 h. The mixture was then concentrated. Purification of the crude mixture by silica gel chromatography (100→ 90% CH ₂ C1 ₂ / MeOH) followed reverse phase HPLC (C-18, 95 → 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. LC-MS m/z = 317.1 [M+l]. 'H NMR (400 MHz, DMSO): 6 1.62 (s, 6 H); 6.37 (s, 1 H); 7.65 (dd, J = 8.5, 1.9 Hz, 1 H); 7.88 (dd, J = 10.6, 1.9 Hz, 1 H); 8.16 (t, J = 8.2 Hz, 1 H).

3-(2-Fluoro-4-iodophenyl)-6-isopropylpyridazine

Step A: 3-Fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline

To a solution of 4-bromo-3-fluoroaniline (5.00 g, 26.4 mmol) in dioxane (80 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l ,3,2-dioxaborolane) (7.30 g, 28.9 mmol), Pd (dppf)Cl ₂ (962 mg, 1.32 mmol), dppf (730 mg, 1.32 mmol) and KOAc (7.70 g, 78.9 mmol). The mixture was deoxygenated and then stirred at 80 °C under N ₂ atmosphere for 16 h. The reaction mixture was filtered. The filtrate was concentrated and purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 20: 1) to give the title compound as a light yellow solid. Ή NMR (300 MHz, CDC1 ₃ ): 8 7.51 (dd, J = 7.5, 7.5 Hz, 1H), 6.34 (dd, J = 2.1, 8.1 Hz, 1H), 6.23 (dd, J = 1.8, 11.4 Hz, 1H), 3.96 (br s, 2H), 1.33 (s, 12H).

Step B: 3-Fluoro-4-(6-isopropylpyridazin-3-yl)aniline

To a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.2 mmol) in toluene (40 mL) and water (8 mL) was added 3-chloro-6- isopropylpyridazine (560 mg, 3.56 mmol), Pd (dppf)Cl ₂ . CH ₂ C1 ₂ (580 mg, 0.71 mmol), and Κ ₃ Ρ0 ₄ ·3Η ₂ 0 (2.1 g, 8.9 mmol). The reaction mixture was deoxygenated and then heated at reflux under N ₂ atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 1 : 1) to give the title compound as a yellow solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 8.08 (dd, J = 8.8, 8.8 Hz, 1H), 7.82 (dd, J = 1.6, 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 2.4, 8.4 Hz, 1H), 6.45 (dd, J = 2.0, 13.2 Hz, 1H), 3.98 (br s, 2H), 3.36-3.29 (m, 1H), 1.40 (d, J = 7.2 Hz, 6H). Step C: 3-(2-Fluoro-4-iodophenyl)-6-isopropylpyridazine

To a suspension of 3-fluoro-4-(6-isopropylpyridazin-3-yl)aniline (740 mg, 3.2 mmol) in aq. HC1 (IN, 8 mL) at 0 °C was added dropwise aqueous 4N NaN0 ₂ solution (0.95 mL, 3.8 mmol). After addition, the reaction mixture was stirred at 0 °C for 1 h and then aqueous 6N KI solution (1.07 mL, 6.4 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for another 0.5 h and then at 23 °C for 18 h. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with water (20 mL x 2), dried over Na ₂ S0 ₄ , and concentrated to give the title compound as a brown solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 7.95 (dd, J = 8.0, 8.0Hz, 1H), 7.89 (dd, J = 2.0, 8.8 Hz, 1H), 7.67 (dd, J - 1.6, 8.4 Hz, 1H), 7.58 (dd, J = 1.6, 10.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 3.42-3.35 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

3-Ethyl-6-(4-iodophenyl)pyridazine

Step A: 4-(6-Ethylpyridazin-3-yl)anilme

To a solution of 3-chloro-6-ethylpyridazine (4.6 g, 32 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (8.5 g, 39 mmol), Pd(dppf)Cl ₂ (2.6 g, 3.2 mmol) in toluene (80 mL) was added Κ ₃ Ρ0 ₄ ·3Η ₂ 0 (17.2 g, 64.8 mol) and water (15 mL). The reaction mixture was stirred at 90 °C for 18 h and then concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc = 5: 1 to 1 : 1) to give the title compound. MS: m/z = 200.1 (M + 1). Ή NMR (300 MHz, CDC1 ₃ ): δ 7.84 (dd, 7 = 1.8, 6.9 Hz, 2H), 7.60 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.71 (dd, J = 2.1 , 6.9 Hz, 2H), 3.84 (br s, 2H), 2.94 (q, J = 7.5 Hz, 2H), 1.32 (d, J = 7.5 Hz, 3H).

Step B: 3-Ethyl-6-(4-iodophenyl)pyridazine

To a suspension of 4-(6-ethylpyridazin-3-yl)aniline (4.6 g, 23 mmol) in aq. HC1 (IN, 70 mL) at 0 °C was added dropwise aq. NaN0 ₂ (2.0 g in 7 mL of H ₂ 0, 28 mmol). After addition, the reaction mixture was stirred at 0 °C for 1 h, and then a solution of KI (7.8 g, 46.2 mol) in H ₂ 0 (7.8 mL) was added dropwise. The resulting mixture was stirred at 0 °C for another 5 h and then extracted with EtOAc (80 mL x 5). The combined organic phase was washed with aqueous Na ₂ S0 ₃ (100 mL x 2) and brine (100 mL), dried over Na ₂ S0 ₄ , and concentrated to give the title compound as a yellow solid. MS: m/z = 310.8 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.87-7.81 (m, 4H), 7.76 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.07 (q, J = 7.6 Hz, 2H), 1.42 (t, J = 7.6 Hz, 3H).

INTERMEDIATE A10

=\ N=N

6-(4-BiOmophenyl)-3-methyl-l,2,4-triazine

Step A: 2-Amino-l-(4-bromophenyl)ethanone hydrobromide

To a solution of 2-bromo-l-(4-bromophenyl)ethanone (5.0 g, 18 mmol) in CHCI3

(100 mL) was added HMTA (2.5 g, 18 mmol) and the solution was stirred at 23 °C for 5h. The precipitate was collected by filtration, the residue dissolved in MeOH (150 mL), and then a solution of aqueous HBr 40% (30 mL) was added. The resulting mixture was stirred at 45 °C for 16 h and then concentrated. The residue was recrystallized from water to give the title compound as a white solid. MS: m/z = 213.9 (M + 1). Ή NMR (400 MHz, DMSO-c¾): δ 8.22 (br s, 3H), 7.94 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 4.60 (s, 2H).

Step B: N-(2-(4-Bromophenyl)-2-oxoethyl)acetamide

To a solution of 2-amino-l-(4-bromophenyl)ethanone hydrobromide (3.80 g, 12.9 mmol) in dry CH ₂ C1 ₂ (100 mL) was added Et ₃ N (3.90 g, 38.7 mmol) followed by AcCl (1.20 g, 15.5 mmol) dropwise at 0 °C. The resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with CH ₂ CI ₂ (100 mL x 3). The combined organic phase was washed with water (100 mL x 2), dried over Na ₂ SC>4, and concentrated to give the title compound as a white solid. MS: m/z = 255.8 (M + 1). *H NMR (400 MHz, CDCI ₃ ): δ 7.79-7.78 (d, J = 8.8 Hz, 2H), 7.60-7.58 (d, J = 8.8 Hz, 2H), 6.44 (br s, 1H), 4.66 (d, J = 4.0 Hz, 2H), 2.04 (s, 3H).

Step C: 6-(4-Bromophenyl)-3-methyl-4,5-dihydro-L2,4-triazine

To a solution ofN-(2-(4-bromophenyl)-2-oxoethyl)acetamide (3.1 g, 12 mmol) in EtOH (100 mL) was added ΝΗ ₂ ΝΗ ₂ · H ₂ 0 (85%, 0.72 g, 12 mmol) and concentrated HC1 (2 mL). The resulting mixture was heated at reflux for 18 h. After cooling to 23 °C, the pH of the reaction mixture was adjusted to 8 with aqueous ΝΗ ₃ , and then water (200 mL) was added with stirring. The precipitate was collected by filtration, washed with water (100 mL), and dried to give the title compound as a yellow solid. MS: m/z = 251.9 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 7.89 (br s, 1H), 7.56-7.50 (m, 4H), 4.19 (s, 2H), 2.06 (s, 3H).

Step D: 6-(4-Bromophenyl)-3-m ethyl- 1 ,2,4-triazine

To a solution of 6-(4-bromophenyl)-3-methyl-4,5-dihydro-l ,2,4-triazine (1.0 g,

4.0 mmol) in acetone (100 mL) was added KMn0 ₄ (1.9 g, 12 mmol) in one portion at 23 °C The reaction mixture was stirred at 23 °C for 18 h and then filtered. The filtrate was concentrated, the residue was suspended in water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , and concentrated to give the title compound as a white solid. MS: m/z = 267.9 (M+19). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.90 (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 2.94 (s, 3H).

3-(4-Iodophenyl)-6-isopropylpyridazine

Step A: 3-Chloro-6-(prop-l-en-2-yl)pyridazine

A mixture of 3,6-dichloropyridazine (35 g, 0.24 mol), 4,4,5,5-tetramethyl-2- (prop-l-en-2-yl)-l ,3,2-dioxaborolane (40 g, 0.24 mol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (19.6 g, 0.0240 mol), Κ ₃ Ρ0 ₄ ·3Η ₂ 0 (127 g, 0.480 mol) in toluene (350 mL) and H ₂ 0 (75 mL) was heated at reflux under N ₂ atmosphere for 16 h. After cooling to 23 °C, the reaction mixture was filtered. The filtrate was washed with water (100 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether to petroleum ether: EtOAc = 20: 1) to afford 3-chloro-6-(prop-l-en-2-yl)pyridazine. MS: m/z = 154.9 (M+l). Ή NMR (300 MHz, CDCI ₃ ): δ 7.67 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 5.86 (d, J = 0.6 Hz, 1H), 5.53 (d, J = 0.6 Hz, 1H), 2.33 (s, 3H).

Step B: 3-Chloro-6-isopropylpyridazine

A mixture of 3-chloro-6-(prop-l-en-2-yl)pyridazine (6.0 g, 39 mmol),

Rh(PPh ₃ ) ₃ Cl (2.5 g, 2.7 mmol) in MeOH (250 mL) was shaken under H ₂ atmosphere (15 psi) at ambient temperature for 16 h. The reaction mixture was filtered and the filtrate concentrated to afford 3-chloi -6-isopropylpyridazine. Ή NMR (300 MHz, CDC1 ₃ ): δ 7.43 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 3.38-3.25 (m, 1H), 1.35 (d, J = 6.9 Hz, 6H).

Step C: 4-(6-Isopi pylpyridazin-3-yl)aniline

To a solution of 3-chloro-6-isopropylpyridazine (10.0 g, 63.9 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (16.8 g, 76.7 mmol), and Pd(dppf)Cl ₂ (9.30 g,12.8 mmol) in toluene (100 mL) was added K ₃ PO ₄ (27.1 g, 0.130 mol) and water (20 mL). The reaction mixture was stirred at 90 °C for 18 h and then concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography

(Si0 _2> petroleum ether: EtOAc = 5: 1 to 1 : 1) to give the title compound. MS: m/z = 213.9 (M+l). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.92 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 3.91 (br, 2H), 3.47-3.15 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H). Step D: 3-(4-Iodophenyl)-6-isopropylpyridazine

To a suspension of 4-(6-isopropylpyridazin-3-yl)aniline (1 1.6 g, 54.5 mmol) in aq. HC1 (IN, 150 mL) at 0 °C was added dropwise aq. NaN0 ₂ (4.50 g in 15 mL of H ₂ 0, 65.9 mmol). After the addition, the reaction mixture was stirred at 0 °C for 1 h, and then a solution of KI (18.1 g, 0.1 10 mol) in H ₂ 0 ( 18 mL) was added dropwise. The resulting mixture was stirred at 0 °C for another 5 h and then extracted with EtOAc (120 mL x 6). The combined organic phase was washed with aqueous Na ₂ S0 ₃ (200 mL x 2) and brine (200 mL), dried over Na ₂ S0 ₄ , and concentrated to give the title compound as a yellow solid. MS: m/z = 324.9 (Μ+1).Ή NMR (400 MHz, CDCI ₃ ): δ 7.84 (m, 4H), 7.66 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.38-3.31 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H).

3-(2,6-Difluoro-4-iodophenyl)-6-isopropylpyridazine

Step A: 3,5-Difluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline

A mixture of 4-bromo-3,5-difluoroaniline (23.0 g, 110 mmol), 4,4,4',4 ^, ,5,5,5',5'- octamethyl-2,2'-bi(l ,3,2-dioxaborolane) (30.9 g, 122 mmol), dppf (3.0 g, 5.5 mmol), Pd(dppf)Cl ₂ (4.5 g, 5.5 mmol) and KOAc (32.0 g, 331 mmol) in dioxane (230 mL) was heated at 80 °C under N ₂ atmosphere for 18 h. The reaction mixture was cooled and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc = 20: 1) to give the title compound as a light yellow solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 6.13-6.11 (m, 2H), 4.04 (br s, 2H), 1.35 (s, 12H).

Step B: 3,5-Difluoro-4-(6-isopropylpwidazin-3-yl)aniline

A mixture of 3,5-difluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline (3.00 g, 11.8 mmol), 3-chloro-6-isopropylpyridazine (1.5 g, 9.8 mmol), DPBF-PdCl ₂ (639 mg, 0.980 mmol) and K ₃ P0 ₄ (4.20 g, 19.6 mmol) in THF (90 mL) and water (17 mL) was heated at reflux under N ₂ atmosphere for 16 h. Upon cooling to 23 °C, the reaction mixture was filtered. The filtrate was concentrated and the residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 2:1) to give the title compound as an orange oil. Ή NMR (400 MHz, CDCI ₃ ): 5 7.11 (dd, J = 1.2, 7.2Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.33-6.28 (m, 2H), 4.15-4.09 (m, 2H), 3.40-3.33 (m, 1H), 1.41 (d, J = 7.2 Hz, 6H).

6H).

Step C: 3-(2,6-Difluoro-4-iodophenylV6-isopropylpyridazine

To a mixture of 3,5-difluoro-4-(6-isopropylpyridazin-3-yl)aniline (2.26 g, 9.07 mmol) in water (18 mL) was added aqueous 6N HC1 solution (4.53 mL, 27.2 mmol) at room temperature. The resulting solution was cooled to 0 °C and aqueous 4N NaN0 ₂ solution (2.72 mL, 10.9 mmol in H ₂ 0) was added dropwise. After addition, the mixture was stirred at 0 °C for 1 h, and then aqueous 6N KI solution (3.02 mL, 18.1 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h and then at 23 °C for another 4 h. The reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over Na ₂ S0 ₄ , and concentrated to give the title compound as a brown oil. Ή NMR (300 MHz, CDCI3): δ 7.57-7.54 (m, 1H), 7.48-7.42 (m, 3H), 3.45-3.36 (m, 1H), 1.43 (d, J = 6.9 Hz, 6H).

2-(4-Bromophenyl)-5-isopropyl-l,3,4-thiadiazole

Step A: 4-Bromo-N'-isobutyrylbenzohvdrazide To a solution of 4-bromobenzoic acid (20.1 g, 100 mmol) in DMF (150 mL) was added HOBt (14.9 g, 1 10 mmol), EDC (21.1 g, 1 10 mmol) and Et ₃ N (20.9 mL, 150 mmol). The mixture was stirred at 25 °C for 0.5 h, and then isopropylhydrazide (1 1.2 g, 1 10 mmol) was added. The reaction mixture was stirred at 25 °C for 14 h, and then diluted with EtOAc (300 mL) and washed with H ₂ 0 (100 mL x 2). The organic phase was dried over Na ₂ S0 ₄ , and concentrated. The residue was washed with CH ₂ C1 ₂ (20 mL x 3) and dried to afford the title compound as a white solid. MS (ESI) m/z = 285.0, 287.0 [M + 1 ]. Ή NMR (300 MHz, DMSO- d6): 8 10.41 (s, 1H), 9.87 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 2.46-2.50 (m, 1H), 1.07 (d, J = 6.9 Hz, 6H).

Step B: 2-(4-Bromophenyl)-5-isopropyl-l ,3,4-thiadiazole

To a solution of 4-bromo-N'-isobutyrylbenzohydrazide (1.0 g, 3.5 mmol) in THF (10 mL) was added Lawesson's reagent (1.4 g, 3.5 mmol) under N ₂ atmosphere. The reaction mixture was heated in the microwave at 120 °C for 25 min. The mixture was concentrated and the residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 50: 1 to 20: 1) to afford title compound as a white solid. MS (ESI) m/z = 282.0, 284.0 [M + 1]. Ή NMR (400 MHz, CDC1 ₃ ): δ 7.91 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 3.26-3.24 (m, 1H), 1.46 (d, J = 6.9 Hz, 6H).

I 4

4-(5-Cvclopropyl- 1 ,3 ,4-thiadiazol-2-yl)phenol

Diisopropylamine (1.4 mL, 9.8 mmol) was added to a mixture of 2-bromo-5-cyclopropyl- 1 ,3,4-thiadiazole (1.0 g, 4.9 mmol), 4-hydroxyphenyl)boronic acid (0.81 g, 5.9 mmol), palladium(II) acetate (0.055 g, 0.24 mmol), and 3,3',3"-phosphinidynetris

(benzenesufonic acid) trisodium salt (310 mg, 0.49 mmol) in DMF (18 mL) and water (6.1 mL). The resulting mixture was heated at 90 °C for 2 h in a sealed vial. Saturated aqueous ammonium chloride solution was added and organics were extracted using EtOAc (3x). The combined organics were washed with brine, dried over MgS0 ₄ , filtered, and concentrated. Purification of the crude mixture by silica gel chromatography (100→ 90% (¾(¾/ MeOH) gave the title compound. MS m/z = 219.2 [M+l]. Ή NMR (400 MHz, DMSO): δ 1.03-1.02 (m, 2 H); 1.24- 1.23 (m, 3 H); 6.89-6.88 (m, 2 H); 7.72-7.71 (m, 2 H).

(2R, R)-2-methyl- 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine and (2R, S)-2-methyl- 1 - (tetrahydro-2H-pyran-4-yl)piperidin-4-amine and (2S, R)-2-methyl- 1 -(tetrahvdro-2H-pyran-4- vDpiperidin-4-amine and (2S, S)-2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-amine Step A: Methyl 3-((tetrahydro-2H-pyran-4-yl)amino)butanoate

To a solution of tetrahydro-2H-pyran-4-amine (5.00 g, 49.4 mmol) in MeOH (40 mL) was added (£)-methyl but-2-enoate (14.8 g, 148 mmol). The reaction mixture was stirred at 65 °C under N ₂ atmosphere for 30 h and then concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 10: 1) to give the title compound as colorless oil. Ή NMR (400 MHz, CD ₃ OD): δ 3.96-3.94 (bm, 2H), 3.69 (s, 3H), 3.44-3.43 (m, 2H), 3.30- 2.88 (m, 1H), 2.83-2.79 (m, 1H), 2.54-2.50 (m, 1H), 2.38-2.33 (dd, J = 15.6, 6.8Hz, 1H), 1.85- 1.84 (m, 2H), 1.41-1.38 (m, 2H), 1.12 (d, J = 6.4Hz, 3H).

Step B: Methyl 3-(3-ethoxy-3-oxo- N-(tetrahydro-2H-pyran-4-yl)propanamido)butanoate

To a stirred solution of ethyl 3-chloro-3-oxopropanoate (3.6 g, 24 mmol) in CH ₂ C1 (20 mL), was added dropwise a solution of methyl 3-((tetrahydro-2H-pyran-4- yl)amino)butanoate (4.0 g, 20 mmol) and Et ₃ N (2.4 g, 24 mmol) in dry CH ₂ C1 ₂ (20 mL) at 23 °C After the addition, the mixture was stirred at 23 °C for another 5 h, and then quenched with water (50 mL). The organic phase was washed with aq. Na ₂ C0 ₃ (2 x 20 mL), dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography (SiC½, petroleum ether: EtOAc = 10: 1 , 5: 1 , 1 : 1) to give the title compound as a light yellow liquid. MS: mlz = 315.9 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 4.22-4.17 (m, 2H), 4.05-4.02 (m, 2H), 3.75-3.70 (m, 1H), 3.67 (s, 3H), 3.61-3.55 (m, 1H), 3.45-3.35 (m, 4H), 3.19-3.15 (m, 1H), 2.74-2.69 (m, 1H), 1.96-1.93 (m, 2H), 1.67-1.59 (m, 2H), 1.42 (d, J = 6.8 Hz, 3H), 1.30-1.26 (t, J = 7.2 Hz, 3H).

Step B: 6-Methyl-l-(tetrahvdro-2H-pyran-4-yl)piperidine-2,4-dione

To a solution of methyl 3-(3-ethoxy-3-oxo- N-(tetrahydro-2H-pyran-4- yl)propanamido)butanoate (5.0 g, 15 mmol) in dry THF (50 mL) was added sodium methoxide (0.97 g, 18 mmol). The reaction mixture was heated at reflux for 3 h and then concentrated. The residue was dissolved in aq. HC1 (30 mL, 6N) and heated at reflux for 5 h. After cooling to 23 °C, the mixture was neutralized with aqueous Na ₂ CC>3 (10%) and extracted with C¾C1 ₂ (50 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated to give the title compound as an off-white solid. Ή NMR (400 MHz, CD ₃ OD): δ 4.61 -4.58 (m, 1H), 4.06-3.99 (m, 4H), 3.51-3.46 (m, 2H), 2.75-2.71 (m, 1H), 2.52-2.47 (m, 1H), 2.01-1.94 (m, 3H),1.75-1.58 (m, 2H), 1.29 (m, 3H).

Step C: 4-((4-Methoxybenzyl)amino)-6-methyl-l-(tetrahvdro-2H-pyran-4 -yl)piperidin-2-one

To a solution of 6-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidine-2,4-dione (6.00 g, 28.4 mmol) in THF (150 mL) was added (4-methoxyphenyl)methanamine (7.79 g, 56.8 mmol) and AcOH (2.05 g, 34.1 mmol). The reaction mixture was stirred at 25 °C for 2 h and then NaB¾CN (5.35 g, 85.2 mmol) was added. The reaction mixture was heated at reflux for 20 h, diluted with water (150 mL), and then extracted with EtOAc (200 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V) : acetonitrile to give the title compound as white solid. MS: mlz = 333.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.42-7.38 (m, 2H), 7.00-6.97 (m, 2H), 4.13-4.10 (m, 2H), 4.00-3.96 (m, 3H), 3.80 (s, 3H), 3.77-3.75 (m, 1H), 3.46-3.43 (m, 3H), 2.95-2.75 (m, 1H), 2.51-2.05 (m, 4H), 1.80-1.56 (m, 3H), 1.40-1.31 (m, 3H).

Step D: N-(4-methoxybenzyl)-2 -methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

To a suspension of LiAlHLt (0.40 g, 11 mmol) in THF (50 mL) was added dropwise a solution of 4-((4-methoxybenzyl)amino)-6-methyl-l-(tetrahydro-2H-pyran-4 - yl)piperidin-2-one (1.8 g, 5.4 mmol) in THF (50 mL) at 0 °C. The reaction mixture was heated at 50 °C for 12 h. After cooling to 0 °C, the reaction mixture was quenched by adding water (0.4 mL), then aq. NaOH (15%, 0.4 mL) and water (1.2 mL). The resulting mixture was filtered, the filtrate was dried over Na ₂ S0 ₄ , and then concentrated to give the title compound as a brown oil. MS: 77¾/z = 319.1 (M + 1). Step E: Benzyl 4-methoxybenzyl(2-methyl-l-(tetrahvdro-2H-pyran-4-yl piperidin-4-yl)carbamate

To a mixture solution ofN-(4-methoxybenzyl)-2-methyl-l -(tetrahydro-2H-pyran- 4-yl)piperidin-4-amine (6.50 g, 20.4 mmol) and Na ₂ C0 ₃ (4.40 g, 40.8 mmol) in THF (50 mL) was added CbzCl (4.20 g, 24.5 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 3 h and then concentrated. The residue was diluted with EtOAc (50 mL). The organic phase was washed with water (50 mL), dried over Na ₂ S04, and concentrated to give the title compound as an oil. MS: mlz = 453.1 (M + l). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.31-7.15 (m, 7H), 6.85-6.83 (m, 2H), 5.22-5.17 (m, 2H), 4.71-4.68 (m, 2H), 4.46-4.28 (m, 3H), 4.02-3.92 (m, 2H), 3.78 (s, 3H), 3.43-3.25 (m, 3H), 2.81-2.55 (m, 1H), 1.85-1.41 (m, 8H), 1.00 (m, 3H).

Step F: (2R, R)-N-Benzyl-2 -methyl- l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine and (2R.4S)- N-benzyl (2-methyl-l -(tetrahvdro-2H-pyran-4-yl)piperidin-4-vncarbamate and (2S,4R)-N-benzyl (2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbama te and (2S,4S)-N-benzyl (2- methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbamate

To a solution of benzyl 4-methoxybenzyl(2 -methyl- 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)carbamate (7.00 g, 15.8 mmol) in CH ₃ CN (80 mL) and H ₂ 0 (20 mL) was added CAN (17.0 g, 30.9 mmol) at 20 °C. The reaction mixture was stirred at ambient temperature for 12 h, and then diluted with water (80 mL) and extracted with EtOAc (150 mL). The combined organic phase was washed with aq. Na ₂ C0 ₃ (50 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (with 0.05% ammonia) : acetonitrile to give the title compound as a mixture of four isomers (yellow solid).

The four isomers were separated by SFC (Column: Chiralpak AD; C0 ₂ /EtOH (0.1%)NH ₄ OH = 80/20) to give benzyl (2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)carbamate (isomer 1), benzyl (2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)carbamate (isomer 4), and a mixture of isomers 2 and 3. The mixture of isomers 2 and 3 was separated by SFC (Chiralcel OJ column; eluting with C0 ₂ /EtOH (0.1%) NH ₄ OH = 90/10) to give benzyl (2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbama te (isomer 2) and benzyl (2 -methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbamate (isomer 3).

Benzyl (2-methyl-l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)carbama te (isomer 1): MS: mlz = 332.9 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 8 7.42-7.26 (m, 5H), 5.10 (s, 2H), 4.14-4.03 (m, 2H), 3.92-3.68 (m, 2H), 3.65-3.45 (m, 4H), 3.09 (t, J = 12.0Hz, 1H), 2.32-2.18 (m, 2H), 2.05 (m, 1H), 1.92-1.59 (m, 5H), 1.44 (d, J = 6.8 Hz, 3H).

Benzyl (2-methyl-l -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)carbamate (isomer 2): MS: mlz = 332.9 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.42-7.28 (m, 5H), 5.1 1 (s, 2H), 4.16-4.02 (m, 3H), 4.00-3.60 (m, 2H), 3.59-3.38 (m, 3H), 3.26-3.09 (m, 1H), 2.28-1 .78 (m, 6H), 1.73-1.56 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H).

Benzyl (2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbama te (isomer 3): MS: mlz - 332.9 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.37-7.31 (m, 5H), 5.09 (s, 2H), 4.04-4.00 (m, 3H), 3.88-3.75 (m, 1 H), 3.48-3.39 (m, 3H), 3.09-2.93 (m, 1H), 2.02-1.42 (m, 9H), 1.21 (d, J = 6.4 Hz, 3H).

Benzyl ( ^" 2-methyl-l-(tetrahvdro-2h-pyran-4-yl)piperidin-4-yl)ca rbamate (isomer 4): MS: mlz = 332.9 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.44-7.24 (m, 5H), 5.19-5.04 (m, 2H), 4.14-4.01 (m, 2H), 3.91-3.80 (m, 1H), 3.79-3.68 (m, 1H), 3.62-3.46 (m, 4H), 3.09 (t, J = 12.4 Hz, 1H), 2.26-2.22 (m, 2H), 2.10-1.97 (m, 1H), 1.92-1.61 (m, 5H), 1.44 (d, J = 6.4 Hz, 3H).

Step G: (2R,^R)-2-Methyl-l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-ami ne and (2R,4S)-2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-amine and (2S, R)-2-methyl- 1 -(tetrahvdro-2H-pyran-4- yl)piperidin-4-amine and (2S, S)-2-methyl- 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine

A mixture of benzyl (2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)carbamate (isomer 1, 80 mg, 0.24 mmol) and catalytic 10% Pd/C (15 mg) in MeOH (15 mL) was shaken at 25 °C under H ₂ atmosphere (50 psi) for 4 h. The reaction mixture was filtered, and the filtrate was concentrated to give 2-methyl-l-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (peak 1) as colorless oil. Isomer 1 : (400 MHz, CDC ): δ 4.07-3.95 (m, 2H), 3.48-3.38 (m, 1H), 3.36-3.26 (m, 1H), 3.17-2.91 (m, 4H), 2.75-2.62 (m, 1H), 2.57-2.44 (m, 1H), 2.19-2.16 (m, 1H), 1.93-1.76 (m, 2H), 1.58-1.45 (m, 2H), 1.39-1.22 (m, 2H), 1.15-1.08 (m, 3H).

Isomers 2 through 4 were hydrogenated using catalytic Pd C in MeOH as described above to give the title compounds:

Isomer 2: Ή NMR (400 MHz, CD ₃ OD): δ 4.20-4.09 (m, 3H), 3.80-3.74 (m, 2H), 3.46 (m, 3H), 3.25-3.21 (m, 1H), 2.39-1.90 (m, 6H), 1.88-1.67 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H).

Isomer 3: Ή NMR (400 MHz, CD ₃ OD): δ 4.04-3.95 (m, 2H), 3.49-3.36 (m, 3H), 3.16-3.06 (m, 1H), 2.93-2.81 (m, 1H), 2.74-2.70 (m, 1H), 2.62-2.50 (m, 1H), 1.92-1.80 (m, 3H), 1.80-1.72 (m, 1H), 1.67-1.41 (m, 4H), 1.09 (d, J = 6.8 Hz, 3H).

Isomer 4: Ή NMR (400 MHz, CD ₃ OD): δ 4.07-4.00 (m, 2H), 3.91-3.82 (m, 1H), 3.75-3.65 (m, 1 H), 3.60-3.45 (m, 4 H), 3.12-3.03 (m, 1H), 2.40-2.27 (m, 2H), 2.09-1.75 (m, 6H), 1.48 (d, J = 6.4 Hz, 3 H).

(2S, R)-l -(Tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl piperidin-4-amine and (25, ^S)-l - (tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4-am ine and (2R, S)-l-(tetrahydro-2H- pyran-4-yl)-2-(trifluoromethyl)piperidin-4-amine and (2R, R)-l-(tetrahvdro-2H-pyran-4-yl)-2- (trifluoromethyl)piperidin-4-amine

Step A: Ethyl 4,4,4-trifluoro-3-((tetrahvdro-2H-pyran-4-yl)amino)butanoate

To a solution of tetrahydro-2H-pyran-4-amine (5.9 g, 59 mmol) in MeOH (150 mL) was added (Z)-ethyl 4,4,4-trifluorobut-2-enoate (19.7 g, 117 mmol). The reaction mixture was heated at reflux for 18 h and then concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether/EtOAc = 100/1 to 20/1) to give ethyl 4,4,4-trifluoro-3- ((tetrahydro-2H-pyran-4-yl)amino)butanoate as yellow oil. 'H NMR (400 MHz, CDC1 ₃ ): δ 4.15- 4.13 (m, 2H), 3.90-3.86 (m, 2H), 3.70-3.65 (m, 1H), 3.35-3.33 (m, 2H), 2.91-2.82 (m, 2H), 2.68- 2.63 (m, 1H), 2.40-2.36 (m, 1H), 1.79-1.70 (m, 2H), 1.33-1.18 (m, 5H).

Step B: Ethyl 3-(3-ethoxy-3-oxo- N-(tetrahvdro-2H-pyran-4-yl)propanamido)-4A4- trifluorobutanoate

To a solution of ethyl 3-chloro-3-oxopropanoate (8.9 g, 59 mmol) in CH ₂ C1 ₂ (80 mL), was added dropwise a solution of ethyl 4,4,4-trifluoro-3-((tetrahydro-2H-pyran-4- yl)amino)butanoate (13.3 g, 49.4 mmol) and triethylamine (8.3 mL, 59 mmol) in CH ₂ C1 ₂ (130 mL) at 0 °C. After the addition, the reaction mixture was stirred at 23 °C for 18 h, washed with saturated aqueous NaHC0 ₃ (80 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether/EtOAc = 100/1 to 50/1) to give ethyl 3-(3-ethoxy-3-oxo- N-(tetrahydro-2H-pyran-4-yl)propanamido)-4,4,4-trifluorobuta noate as yellow oil. MS: m/z = 384.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 4.73-4.70 (m, 1H), 4.23- 4.18 (m, 4H), 4.12-3.95 (m, 2H), 3.77-3.49 (m, 2H), 3.39-3.26 (m, 2H), 3.22-3.07 (m, 1H), 2.93- 2.79 (m, 2H), 2.00-1.47 (m, 4H), 1.33-1.20 (m, 6H).

Step C: 1 -(Tetrahvdro-2H-pyran-4-yl)-6-(trifluoromethyl)piperidine-2, 4-dione

To a suspension of sodium methoxide (2.70 g, 50.2 mmol) in THF (80 mL) was added ethyl 3-(3-ethoxy-3-oxo- N-(tetrahydro-2H-pyran-4-yl)propanamido)-4,4,4- trifluorobutanoate (16.0 g, 41.8 mmol). The reaction mixture was heated at reflux for 2 h and then concentrated. The residue was diluted with aqueous 6Ν HC1 solution (48 mL) and heated at reflux for another 2 h. After cooling to 23 °C, the mixture was diluted with CH2CI2 (200 mL) and H ₂ 0 (50 mL) and neutralized with aqueous NaHC0 ₃ . The CH ₂ C1 ₂ phase was dried over Na ₂ S0 ₄ , concentrated, and the residue purified by column

chromatography (Si0 ₂ , CH ₂ Cl ₂ /MeOH = 100/1) to give 1 -(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)piperidine-2,4-dione as brown oil. MS: m/z = 265.9 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 4.56-4.46 (m, 1H), 4.31-4.18 (m, 1H), 4.06 (m, 2H), 3.60-3.50 (m, 2H), 3.38-3.28 (m, 1H), 3.03-2.94 (m, 1H), 2.71 -2.60 (m, 1H), 2.01 -1.89 (m, 2H), 1.88- 1.80 (m, 1H), 1.70-1.59 (ra, 1H).

Step D: 4-(Benzylamino)-l -(tetrahvdro-2H-pyran-4-yl)-6-(trifluoromethyl)piperidin-2-o ne

To a solution of 1 -(tetrahydro-2H-pyran-4-yl)-6-

(trifluoromethyl)piperidine-2,4-dione (8.7 g, 33 mmol) in THF (100 niL) was added BnNH ₂ (5.7 mL, 53 mmol) and HOAc (1.9 mL, 33 mmol). The reaction mixture was stirred at 23 °C for 1 h, and then NaBH ₃ CN (10.4 g, 165 mmol) was added. The mixture was heated at reflux for 18 h and then concentrated. The residue was dissolved in CH ₂ CI ₂ (100 mL), washed with saturated aqueous NaHC0 ₃ (50 mL) and H ₂ 0 (50 mL), concentrated and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (with 0.05% ammonia) : acetonitrile to give 4-(benzylamino)-l- (tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)piperidin-2-on e as yellow oil. MS: mlz - 357.0 (M + 1). Ή NMR (400 MHz, DMSO-i/ ₆ ): δ 9.16 (s, 1H), 7.50-7.41 (m, 5H), 4.82- 4.68 (m, 1H), 4.23 (s, 2H), 3.87-3.76 (m, 3H), 3.69-3.48 (m, 3H), 3.34-3.18 (m, 2H), 3.03- 2.93 (m, 1H), 2.83-2.72 (m, 1H), 2.63-2.54 (m, 1H), 2.38-2.17 (m, 1H), 2.12-1.89 (m, 2H), 1.65-1.41 (m, 2H).

Step E: (2S, R)-N-Benzyl- 1 -(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4- amine and (2R.^R)-N-benzyl-l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluorome thyl)piperidin-4- amine and (2R, S)-N-benzyl- 1 -(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4- amine and (2S, S)-N-benzyl- 1 -(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4- amine

To a suspension of L1AIH ₄ (0.41 g, 1 1 mmol) in THF (50 mL) was added dropwise a solution of 4-(benzylamino)-l -(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)piperidin-2-one (1.9 g, 5.4 mmol) in THF (50 mL) at 23 °C. The reaction mixture was heated at 50 °C for 12 h. After cooling to 0 °C, the reaction mixture was quenched by adding water (0.4 mL), and then aq. NaOH (15%, 0.4 mL) and water (1.2 mL). The resulting mixture was filtered, and the filtrate was dried over Na ₂ S0 ₄ and concentrated to give the title compound as a mixture of isomers (brown oil). The isomers were separated by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V) : acetonitrile to give two sets of isomers. The isomers of peak 1 were further separated by SFC (Chiralpak AD column) eluting with CO ₂ /IPA (0.1%NH ₄ OH) = 85/15 to give N-benzyl-l -(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)piperidin-4-amine (isomer 1) and N-benzyl-l -(tetrahydro-2H-pyran-4-yl)- 2-(trifluoromethyl)piperidin-4-amine (isomer 2).

N-Benzyl-l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)pip eridin-4- amine (isomer 1): MS: mlz = 343.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.45-7.24 (m, 5H), 4.00 (dd, J = 4.0, 11.2Hz, 2H), 3.86 (s, 2H), 3.48-3.38 (m, 1H), 3.36-3.32 (m,

1H), 3.18-3.07 (m, 1H), 3.07-2.96 (m, 1H), 2.77-2.65 (m, 1H), 2.48-2.36 (m, 1H), 2.28- 2.18 (m, 1H), 2.11-2.00 (m, 1H), 1.89-1.77 (m, 1H), 1.76-1.67 (m, 1H), 1.64-1.53 (m, 2H), 1.52-1.42 (m, 1H), 1.41-1.30 (m, 1H), 1.17 (d, J = 6.0 Hz, 1H).

N-Benzyl-l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)pip eridin-4- amine (isomer 2) : MS: mlz = 343.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.45-7.24 (m, 5H), 4.00 (dd, J = 4.0, 1 1.2Hz, 2H), 3.86 (s, 2H), 3.48-3.38 (m, 1H), 3.36-3.32 (m,

1H), 3.18-3.07 (m, 1H), 3.07-2.96 (m, 1H), 2.77-2.65 (m, 1H), 2.48-2.36 (m, 1H), 2.28- 2.18 (m, 1H), 2.11-2.00 (m, 1H), 1.89-1.77 (m, 1H), 1.76-1.67 (m, 1H), 1.64-1.53 (m, 2H), 1.52-1.42 (m, 1H), 1.41-1.30 (m, 1H), 1.17 (d, J = 6.0 Hz, 1H).

The isomers of peak 2 were further separated by SFC (Chiralpak AD column) eluting with C0 ₂ /MeOH (0.1%NH ₄ OH) = 85/15 to give N-benzyl-l-(tetrahydro- 2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4-amine (isomer 3) and N-benzyl-1- (tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4-am ine (isomer 4).

N-Benzyl-l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)pip eridin-4- amine (isomer 3 ^s ): MS: mlz = 343.1 (M + 1). ^] H NMR (400 MHz, CD ₃ OD): δ 7.39-7.24

(m, 5H), 3.99-3.91 (m, 2H), 3.84 (s, 2H), 3.76-3.65 (m, 1H), 3.43-3.35 (m, 2H), 3.08-2.98 (m, 1H), 2.95-2.79 (m, 3H), 2.24-2.22 (m, 1H), 1.93-1.85 (m, 1H), 1.84-1.77 (m, 1H),

1.76-1.67 (m, 1H), 1.64-1.46 (m, 3H), 1.35-1.22 (m, 1H).

N-Benzyl-l-(tetrahvdro-2H-pyran-4-yn-2-(trifluoromethyl)pipe ridin-4- amine (isomer 4 ^s ): MS: mlz = 343.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.39-7.24

(m, 5H), 3.99-3.91 (m, 2H), 3.84 (s, 2H), 3.76-3.65 (m, 1H), 3.43-3.35 (m, 2H), 3.08-2.98 (m, 1H), 2.95-2.79 (m, 3H), 2.24-2.22 (m, 1H), 1.93-1.85 (m, 1H), 1.84-1.77 (m, 1H),

1.76-1.67 (m, 1H), 1.64-1.46 (m, 3H), 1.35-1.22 (m, 1H).

Step F: (2S, R)-l-(Tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin -4-amine and (2S, ^S)-l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidi n-4-amine and (2R, ^S)-l-

(tetrahvdro-2H-pyran-4-yl -2-(trifluoromethyl)piperidin-4-amine and (2R, 4R)- 1 -(tetrahydro-2H- pyran-4-yl)-2-(trifluoromethyl)piperidin-4-amine

A mixture of compound N-benzyl-l -(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)piperidin-4-amine (isomer 1) (150 mg, 0.44 mmol) and catalytic 10% Pd/C (25 mg) in MeOH (15 mL) was shaken at 25 °C under ¾ atmosphere (15 Psi) for 4 h. The reaction mixture was filtered, and the filtrate was concentrated to give 1 -(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)piperidin-4-amine (isomer 1) as colorless oil, which was used without purification.

l -(Tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl ^' )piperidin-4-amine

(isomer 1) : MS: mlz = 252.8 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 4.02 (dd, J = 3.2, 1 1.2Hz, 2H), 3.46-3.41 (m, IH), 3.31 -3.27(m, IH), 3.20-3.10 (m, IH), 3.10-2.97 (m, 2H), 2.78-2.71 (m, IH), 2.35-2.25 (m, IH), 2.15-2.05 (m, IH), 1.91-1.77 (m, 2H), 1.69-1.51 (m, 3H), 1.41-1.37 (m, IH), 1.34-1.23 (m, IH).

Isomers 2 through 4 were hydrogenated using catalytic Pd/C in MeOH as described above to give the title compounds:

1 -(TetrahvdiO-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4-a mine (isomer 2): MS: mlz = 252.8 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 4.02 (dd, J = 3.2, 11.2Hz, 2H), 3.46- 3.41(m, IH), 3.40-3.27 (m, IH), 3.21-3.04 (m, 3H), 2.76-2.68 (m, IH), 2.35-2.25 (m, IH), 2.15- 2.05 (m, IH), 1.91-1.77 (m, 2H), 1.69-1.51 (m, 3H), 1.42-1.22 (m, 2H).

1 -(Tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)piperidin-4-a mine (isomer 3): MS: mlz = 252.8 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 3.99 (dd, J = 2.4, 1 1.2Hz, 2H), 3.60- 3.46 (m, IH), 3.39-3.33 (m, 2H), 3.10-2.88 (m, 3H), 2.83-2.77 (m, IH), 2.13-2.08 (m, IH), 1.84- 1.76 (m, 2H), 1.70-1.52 (m, 3H), 1.45-1.33 (m, IH), 1.26-1.14 (m, IH).

1 -(Tetrahvdro-2H-pyran-4-yl ^" )-2-(trifluoromethyl)piperidin-4-amine (isomer 4);

MS: mlz = 252.8 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 3.99 (dd, J = 2.4, 1 1.2Hz, 2H), 3.60- 3.46 (m, IH), 3.39-3.33 (m, 2H), 3.10-2.83 (m, 4H), 2.13-2.08 (m, IH), 1.84-1.76 (m, 2H), 1.70- 1.52 (m, 3H), 1.45-1.33 (m, IH), 1.26-1.14 (m, IH).

(R)-4-Amino-l-cvclopropylpyrrolidin-2-one and (S)-4-Amino-l-cvclopro ylpyrrolidin-2-one Step A: Benzyl (l -cvclopropyl-5-oxopyrrolidin-3-yl)carbamate

Benzyl chloroformate (0.90 mL, 6.3 mmol) was added to a suspension of 4- amino- l -cyclopropyl-2-pyiTolidinone hydrochloride (1.00 g, 5.66 mmol) and K ₂ CO ₃ (4.75 g, 34.4 mmol) in THF (1 15 mL) at 0 °C and the reaction mixture was stirred for 4 h. Benzyl chloroformate (0.90 mL, 6.3 mmol) was added and the reaction mixture was stirred for 18 h. Water (1 mL) was added, the reaction was filtered, and the filtrate was concentrated. The residue was purified by column chromatography eluting with MeOH:CH ₂ Cl2 (0-5%) to afford the racemic title compound as a light yellow viscous liquid. The enantiomers were separated on a Chiralcel OD-H column, eluting with supercritical carbon dioxide/ethanol (70/30) containing 0.1% diethylamine. First eluting enantiomer: MS: m/z - 275.3 (M + 1). Second eluting enantiomer: MS: m/z = 275.3 (M + 1).

Step B: (R)-4-Amino- 1 -cvclopropylpyrrolidin-2-one and (S)-4-amino-l-cvclopropylpyrrolidin-2- one

Palladium hydroxide on carbon (0.15 g, 0.22 mmol) was added to a solution of (R)-benzyl(l-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (1.13 g, 4.12 mmol) in MeOH (80 mL) at 25 °C and the reaction mixture was stirred under H ₂ (balloon) for 2 h. The reaction mixture was filtered through a pad of Celite ^® , and the filtrate was concentrated to afford the title compound. MS: mlz ~ 163.3 (M + 23). (S)-Benzyl(l-cyclopropyl-5-oxopyrrolidin-3- yl)carbamate was hydrogenated using Pd(OH) ₂ in MeOH to afford (S)-4-Amino-l - cyclopropylpyrrolidin-2-one, as described above. MS: m/z = 163.3 (M + 23).

l-(4,4-Difluorocyclohexyl)piperidin-4-amine

Step A: /erf-Butyl (l-(4,4-difluorocvclohexyl)piperidin-4-yl)carbamate

4,4-Difluorocyclohexanone (500 mg, 3.70 mmol) was added to a solution of tert- butylpiperidin-4-ylcarbamate (1.5 g, 7.5 mmol) and HOAc (0.21 mL, 3.7 mmol) in THF (20 mL) and the reaction mixture was stirred at 50 °C for 2 h. NaBH(OAc) ₃ (2.40 g, 1 1.2 mmol) was added and the reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was diluted with aqueous NaHC0 ₃ (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by prep-HPLC (Phenomenex Gemini column) eluting with 5-95% acetonitrile in water (with 0.05% ammonia) to give tert-bvXy\ (l -(4,4-difluorocyclohexyl)piperidin-4-yl)carbamate. MS: m/z: 319.1 [M+l]. Ή NMR (400 MHz, CDC1 ₃ ): δ 4.41-4.38 (m, IH), 3.91-3.87 (m, IH), 3.63-3.58 (m, IH), 3.25- 3.19 (m, IH), 3.03-3.00 (m, IH), 2.86-2.80 (m, IH), 2.50-2.44 (m, IH), 1.96-1.87 (m, 5H), 1.80- 1.77 (m, IH), 1.68-1.65 (m, IH), 1.62-1.59 (m, 10H), 1.57-1.41 (m, 3H). Step B: l -(4 ₁ 4-Difluorocvclohexyl)piperidin-4-amine

ieri-Butyl(l-(4,4-difluoiOcyclohexyl)piperidin-4-yl)carbamat e (1.2 g, 3.8 mmol) in a solution of HC1 in MeOH (4 N, 15 niL) was stirred at 23 °C for 2 h. The reaction mixture was concentrated to give l-(4,4-difluorocyclohexyl)piperidin-4-amine (2HC1 salt) as a yellow oil. Ή NMR (400 MHz, CD ₃ OD): 5 4.64-4.54 (m, 1H), 4.07-3.97 (m, 1H), 3.73-3.61 (m, 1H), 3.55- 3.37 (m, 2H), 3.27-3.10 (m, 2H), 2.79-2.64 (m, 1H), 2.37-2.18 (m, 4H), 2.08-1.77 (m, 4H), 1.64- 1.37 (m, 2H).

l-(2-Methylcvclohexyl piperidin-4-amine

Step A: ter -Butyl (l -(2-methylcvclohexyl)piperidin-4-yl)carbamate

2-Methyl-cyclohexanone (4.0 g, 0.036 mol) was added to a solution of tert- butylpiperidin-4-ylcarbamate (4.8 g, 0.024 mol) and AcOH (2.1 mL, 0.036 mol) in DCE (60 mL) and the reaction mixture was stirred at 23 °C for 1 h. NaBH(OAc) ₃ (10 g, 0.048 mol) was added and the mixture was stirred at 23 °C for 18 h. The reaction was diluted with aqueous NaHC0 ₃ (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography (petroleum ethenEtOAc = 5: 1 to EtOAc) to give teri-butyl(l-(2-methylcyclohexyl)piperidin-4-yl)carbamate as a brown solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 4.57-4.47 (m, 3H), 3.48 (s, 1H), 3.21-3.09 (m, 2H), 2.25-2.15 (m, 4H), 1.95-1.92 (m, 2H), 1.79-1.76 (m, 2H), 1.60-1.57 (m, 2H), 1.46-1.43 (m, 1 1H), 1.40-1.36 (m, 2H), 0.96-0.94 (m, 3H).

Step B: l -(2-Methylcyclohexyl)piperidin-4-amine

teri-Butyl(l-(2-methylcyclohexyl)piperidin-4-yl)carbamate (1.8 g, 6.1 mmol) in a solution of HC1 in MeOH (4N, 30 mL) was stirred at 23 °C for 2 h. The reaction mixture was concentrated to give l-(2-methylcyclohexyl)piperidin-4-amine as a brown solid. Ή NMR (400 MHz, CD ₃ OD): δ 3.93-3.80 (m, 2H), 3.54-3.50 (m, 1H), 3.28-3.23 (m, 1H), 3.18-3.09 (m, 2H), 2.56-2.55 (m, 1H), 2.36-2.29 (m, 2H), 2.24-2.17 (m, 1H), 2.13-2.04 (m, 2H), 1.97-1.94 (m, 1H), 1.78-1.60 (m, 3H), 1.53-1.37 (m, 3H), 1.16-1.10 (m, 3H).

Step C: Benzyl ( 1 -(2-methylcyclohexyl)piperidin-4-yl)carbamate Benzyl chloroformate (2.50 g, 14.5 mmol) was added dropwise to a solution of 1- (2-methylcyclohexyl)piperidin-4-amine (1.3 g, 4.8 mmol) and Na ₂ C0 ₃ (3.1 g, 29 mmol) in THF (25 mL) and water (5 mL) at 0 °C. The reaction mixture was warmed to 23 °C and stirred for 18 h. The reaction was concentrated, the residue was diluted with water (30 mL), and then extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na ₂ S04, and concentrated. The residue was purified by column chromatography (petroleum ether: EtOAc = 10: 1 to 1 : 1) to give benzyl (l-(2-methylcyclohexyl)piperidin-4-yl)carbamate as a mixture of isomers (white solid). The isomers were separated by SFC (Chiralpak AD column) eluting with C0 ₂ / EtOH (0.2% NH ₄ OH) = 60/40, to afford isomer 1 and isomer 2 of the title compound. Isomer 1 : Ή NMR (400 MHz, CDC1 ₃ ): δ 7.37-7.32 (m, 5H), 5.08 (s, 2H), 4.70-4.58 (m, 1H), 3.54-3.48 (m, 1H), 3.10-2.91(m, 2H), 2.19-2.17 (m, 1H), 2.05-2.02 (m, 3H), 1.95-1.93 (m, 2H), 1.76-1.74 (m, 3H), 1.62-1.56 (m, 3H), 1.48-1.29 (m, 3H), 0.89-0.92 (m, 3H). Isomer 2: Ή NMR (400 MHz, CD ₃ OD,): δ 7.55-7.53 (m, 5H), 5.08 (s, 2H), 3.46-3.43 (m, 1H), 3.16-3.12 (m, 2H), 2.27-2.26 (m, 1H), 2.14-2.10 (m, 3H), 1.92-1.82 (m, 4H), 1.64-1.31 (m, 8H), 0.96 (d, J = 7.2 Hz, 3H).

Step C: l-(2-Methylcvclohexyl)piperidin-4-amine (Isomers 1 and 2)

Catalytic 10% Pd/C (30 mg) was added to a solution of benzyl (l-(2- methylcyclohexyl)piperidin-4-yl)carbamate (isomer 1) (230 mg, 0.70 mmol) in MeOH (10 mL) and the reaction mixture was shaken at 23 °C for 6 h under H ₂ atmosphere (15 psi). The mixture was filtered through a pad of Celite ^® and the filtrate was concentrated to give l-(2- methylcyclohexyl)piperidin-4-amine as a brown oil. Isomer 1 : Ή NMR (400 MHz, CDC1 ₃ ): δ 3.08-3.00 (m, 2H), 2.62-2.61 (m, 1H), 2.20-2.18 (m, 1H), 2.04-1.91 (m, 3H), 1.81-1.73 (m, 4H), 1.59-1.43 (m, 5H), 1.41-1.33 (m, 2H), 1.32-1.21 (m, 1H), 0.91 (d, J = 7.2 Hz, 3H). Isomer 2 was also hydrogenated with catalytic Pd/C in MeOH as described above.

(7S,2S)-2-(4-Aminopiperidin-l-yl)cyclohexanol and (7R,2R)-2-(4-aminopiperidin-l- vDcvclohexanol

Step A: /er/-Butyl 4-(((benzyloxy)carbonyl)amino)piperidine-l -carboxylate

Benzyl chloroformate (28 g, 0.17 mol) was added to a solution of ieri-butyl-4- aminopiperidine-l-carboxylate (30 g, 0.15 mol) and K ₂ C0 ₃ (41 g, 0.30 mol) in THF (250 mL) and H ₂ 0 (125 mL) and the resulting mixture was stirred at 23 °C for 18 h. The THF was removed and the resulting aqueous phase was extracted with EtOAc (70 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated to give /er -butyl-4- (((benzyloxy)carbonyl)amino)piperidine-l-carboxylate as a yellow solid. Ή NMR (400 MHz, CD ₃ OD): δ 7.41-7.32 (m, 5H), 5.08 (s, 2H), 4.02-3.98 (m, 2H), 3.62-3.57 (m, 1H), 2.94-2.87 (m, 2H), 1.86 (dd, J = 2.8,13.2 Hz, 2H), 1.46 (s, 9H), 1.41-1.27 (m, 2H).

Step B: Benzyl piperidin-4-ylcarbamate hydrochloride

/er -Butyl 4-(((benzyloxy)carbonyl)amino)piperidine-l-carboxylate (49.0 g, 0.147 mol) in a solution of HC1 in MeOH (4N, 400 mL) was stirred at 23 °C for 2 h. The reaction mixture was concentrated to give benzyl piperidin-4-ylcarbamate hydrochloride as a yellow solid. 'H NMR (400 MHz, CD ₃ OD): δ 7.37- 7.31 (m, 5H), 5.10 (s, 2H), 3.74 -3.71 (m, 1H), 3.43-3.39 (m, 2H), 3.10- 3.07 (m, 2H), 2.15- 2.10 (m, 2H), 1.75 (dd, J = 10.4, 22 Hz, 2H). Step C: Benzyl (l-(i/R,2R)-2-hydroxycvclohexyl)piperidin-4-yl)carbamate and benzyl (1 - ((7S,2S)-2-hydroxycyclohexyl)piperidin-4-yl)carbamate

7-Oxabicyclo [4.1.0] heptane (2.0 g, 20 mmol) was added to a solution of benzyl piperidin-4-ylcarbamate hydrochloride (5.4 g, 20 mmol) and Et ₃ N (2.8 mL, 20 mmol) in EtOH (40 mL) and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography (Si0 _2, petroleum ether: EtOAc = 2: 1 to 1 :2) to give benzyl (l-(2-hydroxycyclohexyl)piperidin-4-yl)carbamate as a mixture of isomers (yellow oil). The isomers were separated by SFC (Chiralcel OJ column, eluting with C0 ₂ / EtOH (0.2% NH ₄ OH) =85/15) to give benzyl (l-(2- hydroxycyclohexyl)piperidin-4-yl)carbamate (isomer 1) and benzyl (l -(2- hydroxycyclohexyl)piperidin-4-yl)carbamate (isomer 2). Isomer 1 : MS: m/z = 333.2 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 7.34 -7.27 (m, 5H), 5.06 (s, 2H), 3.45-3.43 (m, 2H), 2.88-2.25 (m, 1H), 2.68-2.66 (m, 2H), 2.34-2.28 (m, 2H), 2.03- 2.01 (m, 1H), 1.89-1.76 (m, 5H), 1.68-1.55 (m, 2H), 1.34-1.22 (m, 4H). Isomer 2: MS: m/z = 333.2 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 7.34 -7.27 (m, 5H), 5.06 (s, 2H), 3.45-3.43 (m, 2H), 2.88-2.25 (m, 1H), 2.68-2.66 (m, 2H), 2.34- 2.28 (m, 2H), 2.03- 2.01 (m, 1H), 1.89-1.76 (m, 5H), 1.68-1.55 (m, 2H), 1.34-1.22 (m, 4H). Step C: (7S,2S)-2-(4-Aminopiperidin-l -yl)cyclohexanol and (7R,2R)-2-(4-aminopiperidin-l - yDcyclohexanol

A mixture of benzyl ( 1 -(2-hydroxycyclohexyl)piperidin-4-yl)carbamate (isomer 1) (500 mg, 1.51 mmol) and catalytic 10% Pd/C (50 mg) in MeOH (10 mL) was shaken at 23 °C under H ₂ atmosphere (15 psi) for 16 h. The mixture was filtered through a pad of Celite® and the filtrate was concentrated to give 2-(4-aminopiperidin-l -yl)cyclohexanol (isomer 1 ) as a yellow solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 3.37-3.31 (m, 1H), 2.83-2.79 (m, 1H), 2.68-2.56 (m, 2H), 2.23-2.09 (m, 3H), 1.86-1.69 (m, 5H), 1.46-1.35 (m, 2H), 1.32- 1.09 (m, 5H). Isomer 2 was also hydrogenated with catalytic Pd/C in MeOH to afford the title compound.

(R)- 1 -(Tetrahvdrofuran-3-yl)piperidin-4-amine and (S)- 1 -(tetrahvdrofuran-3-yl)piperidin-4-amine Step A: (R -N-Benzyl-l-(tetrahvdrofuran-3-yl)piperidin-4-amine and (S)-N-benzyl-l- (tetrahydrofuran-3-yl)piperidin-4-amine

To a solution of benzyl piperidin-4-ylcarbamate hydrochloride (5.0 g, 18 mmol) in DCE (50 mL) was added Et ₃ N (2.6 mL, 18 mmol) and dihydrofuran-3(2H)-one (1.6 g, 18 mmol). The reaction mixture was stirred at 23 °C for 1 h and then NaBH(OAc) ₃ (7.9 g, 37 mmol) was added. The mixture was stirred at ambient temperature for 18 h, diluted with aqueous NaHC0 ₃ (40 mL), and then extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (50 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc = 5: 1 to EtOAc) to give benzyl (1 - (tetrahydrofuran-3-yl)piperidin-4-yl)carbamate as a racemic mixture (white solid). The enantiomers were separated by SFC (Chiralpak AD column, eluting with C0 ₂ / EtOH (0.1% NH4OH) =75/25) to give benzyl (l -(tetrahydrofuran-3-yl)piperidin-4-yl)carbamate (isomer 1) and benzyl (l -(tetrahydrofuran-3-yl)piperidin-4-yl)carbamate (isomer 2). Isomer 1 : MS (ESI) m/z: 304.9 [M + 1 ]. Ή NMR (400 MHz, CD ₃ OD): δ 7.36-7.30 (m, 5H), 5.08 (s, 2H), 3.95-3.86 (m, 2H), 3.77-3.76 (m, 1 H), 3.65-3.55 (m, 1H), 3.51 -3.40 (m, 1 H), 3.09 - 2.96 (m, 2H), 2.88 - 2.76 (m, 1H), 2.34 - 2.20 (m, 2H), 2.18 - 2.07 (m, 1H), 1.96 - 1.88 (m, 3H), 1.56-1.53 (m, 2H). Isomer 2: MS (ESI) m/z: 304.9 [M + 1 ]. Ή NMR (400 MHz, CD ₃ OD): δ 7.36-7.30 (m, 5H), 5.08 (s, 2H), 3.95-3.86 (m, 2H), 3.77-3.76 (m, 1H), 3.65-3.55 (m, 1H), 3.51 -3.40 (m, 1H), 3.09 - 2.96 (m, 2H), 2.88 - 2.76 (m, 1 H), 2.34 - 2.20 (m, 2H), 2.18 - 2.07 (m, 1 H), 1.96 - 1.88 (m, 3H), 1.56-1.53 (m, 2H).

Step B: (R)-l -(Tetrahydroraran-3-yl)piperidin-4-amine and (S)- l -(tetrahydrofuran-3-yl)piperidin- 4-amine

A mixture of benzyl ( l -(tetrahydrofuran-3-yl)piperidin-4-yl)carbamate (isomer 1) (1.1 g, 3.6 mmol) and catalytic 10% Pd/C (200 mg) in MeOH (20 mL) was shaken at 23 °C under H ₂ atmosphere (15 psi) for 2 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to give l -(tetrahydiOfuran-3-yl)piperidin-4-amine (isomerl) as yellow oil. Ή NMR (400 MHz, CD ₃ OD): δ 3.94-3.87 (m, 2H), 3.77-3.76 (m, IH), 3.63-3.60 (m, I H), 3.02-2.98 (m, 2H), 2.84-2.77 (m, I H), 2.76-2.67 (m, IH), 2.17-2.14 (m, 3H), 1.91 -1.87 (m, 3H), 1.50-1.44 (m, 2H). Isomer 2 was also hydrogenated using catalytic Pd/C in MeOH to afford the title compound.

7-Aminohexahydroindolizin-3(2H)-one

Step A: (iT)-7-(Hvdroxyimino)hexahydroindolizin-3(2H)-one

A mixture of hexahydroindolizine-3,7-dione (70 mg, 0.46 mmol), ΝΗ ₂ ΟΗ·ΗΟ (41 mg, 0.50 mmol), and AcONa (35 mg, 0.50 mmol) in water (2 mL) and EtOH (10 mL) was stirred at 23 °C for 18 h. The reaction mixture was concentrated to give (E)-7- (hydroxyimino)hexahydroindolizin-3(2H)-one as a white solid. Ή NMR (400 MHz, CD ₃ OD): δ 4.19-4.09 (m, 2H), 3.72-3.63 (m, 2H), 3.57-3.52 (m, IH), 3.42-3.36 (m, IH), 2.94-2.87 (m, IH), 2.81-2.74 (m, IH), 2.60-2.56 (m, IH), 2.47-2.43 (m, 4H), 2.41 -2.21 (m, 4H), 2.14-2.08 (m, IH), 1.90-1.71 (m, 4H). Step B: 7-Aminohexahvdroindolizin-3(2H)-one

A mixture of (£)-7-(hydroxyimino)hexahydroindolizin-3(2H)-one (66 mg, 0.46 mmol) and catalytic 10% Pd/C (20 mg) in MeOH (10 mL) was shaken at 23 °C under H ₂ atmosphere (15 psi) for 18 h. The mixture was filtered through a pad of Celite® and the filtrate was concentrated to give racemic 7-aminohexahydroindolizin-3(2H)-one as a yellow oil. Ή NMR (400 MHz , CD ₃ OD): δ 4.06-4.01 (m, I H), 3.64-3.57 (m, I H), 2.94-2.89 (m, IH), 2.77- 2.71 (m, I H), 2.40-2.33 (m, 2H), 2.30-2.21 (m, I H), 2.07-2.01 (m, I H), 1.90-1.87 (m, I H), 1.69- 1.60 (m, I H), 1.24-1.03 (m, 2H).

INTERMEDIATE B9

(3R, 4S)-3 -Fluoro- 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine and (3S, 4R)-3 -fluoro- 1 - (tetrahydro-2H-pyran-4-yl)piperidin-4-amine

Step A: (3S,4R)-tert-Bu yl 4-(((benzyloxy)carbonyl)amino)-3-fluoiOpiperidine-l-carboxyl ate and

Benzyl chloroformate (8.50 mL, 59.6 mmol) was added dropwise to a solution of (3R,4S and 3S,4R)-/er^butyl-4-amino-3-fluoropiperidine-l-carboxylate (10 g, 46 mmol) and DIEA (24.0 mL, 137 mmol) in CH ₂ C1 ₂ (100 mL) at 0 °C and the reaction was stirred for 18 h at 23 °C. The reaction was diluted with water (50 mL) and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl2 (2 x 30 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes/ethyl acetate (100/0 to 70/30). The enantiomers were separated by SFC (IC column, eluting with 30% isopropyl alcohol:70% C0 ₂ , with 0.1% DEA) to afford the title compounds. Isomer 1 (first eluting) (3R,4S): MS: mlz = 375.2 (M + 23); Isomer 2 (second eluting) (3S,4R): MS: mlz = 375.2 (M + 23).

Step B: Benzyl ((3R, S)-3-fluoropiperidin-4-yl)carbamate hydrochloride and

benzyl ((3S, R)-3-fluoropiperidin-4-yl)carbamate hydrochloride

A solution of 4-(((benzyloxy)carbonyl)amino)-3- fluoropiperidine-l-carboxylate (isomer 1) (5.34 g, 15.2 mmol) in EtOAc (30 mL) at 0 °C was saturated with HC1 gas and then stirred for 2 h. The mixture was concentrated to yield the title compound (isomer 1). MS: mlz = 253.1 (M + 1).

A solution of (3S,4R)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3- fluoropiperidine-l-carboxylate (isomer 2) (2.02 g, 5.73 mmol) in EtOAc (30 mL) at 0 °C was saturated with HC1 gas and then stirred for 2 h. The mixture was concentrated to yield the title compound (isomer 2). MS: mlz = 253.1 (M + 1).

Step C: Benzyl ((3R,4S)-3 -fluoro- l -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)carbamate and benzyl ((3S,4R)-3 -fluoro- l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbamate A solution of tetrahydro-4H-pyran-4-one (1.62 g, 16.2 mmol) and benzyl ((3R,4S)-3-fluoropiperidin-4-yl)carbamate hydrochloride (4.68 g, 16.2 mmol) in DCE (150 mL) was stin-ed at 23 °C for 1.5 h. Sodium triacetoxyborohydride (8.59 g, 40.5 mmol) was added and the reaction was stirred for 18 h. The reaction mixture was diluted with water (50 mL) and basified with aqueous NaHC0 ₃ solution. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of CH ₂ Cl ₂ /MeOH (100/0 to 95/5) to give title compound. MS: mlz = 337.1 (M + 1).

A solution of tetrahydro-4H-pyran-4-one (0.57 g, 5.7 mmol) and benzyl ((3S,4R)-

3-fluoropiperidin-4-yl)carbamate hydrochloride (1.64 g, 5.68 mmol) in DCE (150 mL) was stirred at 23 °C for 1.5 h. Sodium triacetoxyborohydride (3.61 g, 17.0 mmol) was added and the reaction was stirred for 18 h. The reaction mixture was diluted with water (50 mL) and basified with aqueous NaHC0 ₃ solution. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of CH ₂ Cl ₂ /MeOH (100/0 to 95/5) to give title compound. MS: mlz = 337.1 (M + 1). Step D: (3R.^S)-3-Fluoro-l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-ami ne and (3S, R)-3-fluoro- l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-amine

A mixture of 10% Pd C (180 mg, 1.69 mmol) and benzyl ((JR,4S)-3-fluoro-l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbamate (3.66 g, 10.8 mmol) in MeOH (8 mL) and H ₂ 0 (0.5 mL) was stirred under H ₂ (balloon) at 23 °C for 3 h. The mixture was filtered through a pad of Celite ^® and the filtrate was concentrated to yield the title compound. MS: mlz = 203.2 (M + 1).

A mixture of 10% Pd/C (180 mg, 1.69 mmol) and benzyl ((3S,4R)-3-fluoro-l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)carbamate (2.28 g, 6.78 mmol) in MeOH (8 mL) and H ₂ 0 (0.5 mL) was stirred under H ₂ (balloon) at 23 °C for 3 h. The mixture was filtered through a pad of Celite ^® and the filtrate was concentrated to yield the title compound. MS: mlz = 203.2 (M + 1)·

INTERMEDIATE B10

3-fluoro-l-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-ami ne

Step A: fc -butyl (3-fluoropiperidin-4-yl)carbamate

Palladium on carbon (10% w/w loading, 2.144 g, 2.015 mmol) was added to a room temperature mixture of benzyl 4-((ieri-butoxycarbonyl)amino)-3 -fluoropiperidine- 1 - carboxylate (7.1 g, 20.15 mmol) in MeOH (2 ml) and the mixture was placed under an atmosphere of hydrogen (balloon) and allowed to stir for 14 h. The mixture was filtered, washing with methanol, and the solvent was evaporated under reduced pressure to give the title compound. MS: mlz = 219.17 (M + 1). Step B: tert-butyl (3-fluoro-l-(3-fluorotetrahvdro-2H-pyran-4-yl)piperidin-4-yl ]carbamate

Acetic acid (0.283 ml, 4.95 mmol) was added to a stirred, room temperature mixture of 3-fluorodihydro-2H-pyran-4(3H)-one (1.169 g, 9.90 mmol) and tert-butyl (3- fluoropiperidin-4-yl)carbamate (1.08 g, 4.95 mmol) in DCE (49.5 ml). The reaction mixture was stirred at room temperature for 14 h. Sodium triacetoxyborohydride (3.15 g, 14.84 mmol) was added and the mixture continued to stir at room temperature for 2 h. The mixture was purified by column chromatography on silica gel, eluting with EtOAc/isohexane, to give the title compound. MS: mlz = 321.10 (M + 1).

Step C: 3-fluoro-l-(3-fluorotetrahvdro-2H-pyran-4-yl)piperidin-4-ami ne Hydrochloric acid (11.71 mL, 46.8 mmol) was added to a stirred, room temperature mixture of tert-butyl (3-fluoro-l -(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4- yl)carbamate (1.50 g, 4.68 mmol) in dichloromethane (5 mL). The mixture was allowed to stir at room temperature for 90 min. The mixture was concentrated under reduced pressure to give the title compound. MS: mlz = 221.08 (M + 1).

Step D: benzyl (3-fluoro-l-(3-fluorotetrahvdro-2H-pyran-4-yl)piperidin-4-yl )carbamate Ν,Ν-diisopropylethylamine (2.53 ml, 14.53 mmol) and benzyl chloro formate (0.83 mL, 5.81 mmol) was added to a stirred, room temperature mixture of 3-fluoro-l-(3- fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride (1.42 g, 4.84 mmol) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 45 min. The mixture was diluted with dichloromethane (50 mL), washed with water (1 x 30 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (0-20% then 40%) to give benzyl (3-fluoiO-l-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-yl )carbamate as a mixture of isomers. MS: mlz = 355.09 (M + 1). The mixture of isomers was resolved by SFC (IA column, MeOH/DEA/C0 ₂ ). The solvent was evaporated under reduced pressure to give isomer 1 (first eluting) and isomer 2 (second eluting) of the title compound.

Step E: 3-fluoro-l-(3-fluorotetrahvdro-2H-pyran-4-yl)piperidin-4-ami ne (isomers 1 and 2)

Palladium on carbon (10% w/w, 75 mg, 0.071 mmol) was added to a room temperature mixture of benzyl (3 -fluoro- 1 -(3 -fluorotetrahydro-2H-pyran-4-yl)piperidin-4- yl)carbamate (isomer 2) (250 mg, 0.705 mmol) in MeOH (5 ml). The mixture was placed under an atmosphere of hydrogen (balloon) and allowed to stir for 2 h. The mixture was filtered, washing with methanol, and the solvent was evaporated under reduced pressure to give the title compound. Isomer 2: MS: mlz =221.23 (M + 1). Isomer 1 was also hydrogenated with catalytic Pd/C in MeOH as described above.

r-cvclopropyl-3-fluoro-( ^" L4'-bipiperidin1-4-amine

Step A: benzyl 4-((tert-butoxycarbonyl)amino)-3-fluoropiperidine-l -carboxylate

Benzyl chloro formate (21.19 mL, 148 mmol) was added to a stirred, room temperature mixture of tert-butyl (3-fluoropiperidin-4-yl)carbamate (27 g, 124 mmol) and N,N- diisopropylethylamine (43.2 mL, 247 mmol) in dichloromethane (300 mL) and the mixture was allowed to stir for 14 h. The reaction mixture was diluted with dichloromethane (300 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1 x 200 mL), dried (MgS0 ₄ ), filtered and the solvent evaporated under reduced pressure. The resultant solid was washed with ethyl acetate (2 x 40 mL) to give the racemic title compound. The racemic mixture was resolved by SFC (Chiral Cel OJ column, ethanol/CC> ₂ (30/70)) to give the title compounds as isomer 1 (first eluting) and isomer 2 (second eluting). MS: mlz =375.2 (M + 23).

Step B: tert-butyl (3-fluoiOpiperidin-4-yl)carbamate

Palladium on carbon (10% w/w, 2.144 g, 2.015 mmol) was added to a room temperature mixture of benzyl 4-((tert-butoxycarbonyl)amino)-3-fluoropiperidine-l-carboxyl ate (isomer 2) (7.1 g, 20.15 mmol) in MeOH (20 ml) and the mixture was placed under an atmosphere of hydrogen (balloon) and allowed to stir for 14 h. The mixture was filtered, washing with methanol, and the solvent was evaporated under reduced pressure to give the title compound. MS: mlz =219.17 (M + 1).

Step C: tert-butyl (r-cvclopropyl-3-fluoro- l,4'-bipiperidin1-4-yl)carbamate

Acetic acid (glacial, 406 μΐ, 7.09 mmol) was added to a stirred, room temperature mixture of 1 -cyclopropylpiperidin-4-one (987 mg, 7.09 mmol) and tert-butyl (3-fluoropiperidin- 4-yl)carbamate (619.0 mg, 2.84 mmol) in DCE (28 mL) and the mixture was allowed to stir for 14 h. Sodium triacetoxyborohydride (1.803 g, 8.51 mmol) was added and the mixture was allowed to stir for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with CH ₂ Cl ₂ /MeOH/NH ₃ (aq.) to give the title compound. MS: mlz =342.17 (M + 1).

Step D: -cvclopropyl-3-fluoro-[l ,4'-bipiperidinl-4-amine

Hydrochloric acid (4 N in dioxane, 7.36 mL, 29.4 mmol) was added to a stirred, room temperature mixture of tert-butyl ( -cyclopropyl-3-fluoro-[l,4'-bipiperidin]-4-yl)carbamate (670 mg, 1.962 mmol) in dichloromethane (5 mL) and the mixture was stirred at room temperature for 14 h. The mixture was concentrated under redued pressure to give the title compound. MS: mlz = 242.14 (M + 1).

3-((6-(Methylsulfonyl)pyridin-3-yl)oxy)-4-((2-oxopyiTolidin- l-yl)methyl)benzoic acid

Step A: Methyl 3-inethoxy-4-((2-oxopyiTolidin-l -yl)methyl)benzoate

A solution of 2-pyrrolidinone (8.60 g, 101 mmol) in DMF (150 mL) was added to a stirred slurry of NaH (4.60 g, 60% dispersion in mineral oil, 1 16 mmol) in DMF (150 mL) at 0 °C. The mixture was stirred for 15 min at 0 °C and a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (25 g, 96 mmol) in DMF (150 mL) was added. The resulting mixture was slowly allowed to warm to ambient temperature and stirred for 1 h. The mixture was cooled to 0 °C and saturated aqueous ammonium chloride was added. The organic phase was extracted using EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS04, filtered, and concentrated. Purification of the residue by silica gel chromatography (75→ 100% Hexanes/EtOAc) gave the title compound. LC-MS m/z = 264.3 [M+l].

Steps B: Methyl 3-hvdroxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate

A solution of boron tribromide in CH ₂ C1 ₂ (270 mL, 270 mmol) was carefully added to a stirred solution of methyl 3-methoxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate (23.7 g, 90.0 mmol) at 0 °C in CH ₂ C1 ₂ (450 mL) and the mixture was stirred at 0 °C for 4 h. The mixture was warmed to ambient temperature and was stirred for 1 h. The mixture was then cooled to 0 °C and was quenched carefully with MeOH. The resulting mixture was

concentrated. The residue was reesterified by dilution with MeOH and concentration (2x). The residue was diluted with CH ₂ C1 ₂ and saturated aqueous sodium bicarbonate. The organic phase was extracted with CH ₂ C1 ₂ (3x), dried over MgS0 ₄ , filtered, and concentrated to give the title compound. LC-MS m/z = 250.2 [M+l].

Step C: Methyl 3-((6-(methylsulfonyl)pyridin-3-yl)oxy)-4-((2-oxopyrrolidin- l- vDmethvDbenzoate

Cesium carbonate (3.92 g, 12.0 mmol) was added to a stirred solution of 5-bromo- 2-methanesulfonyl-pyridine (2.84 g, 12.0 mmol) and methyl 3-hydroxy-4-((2-oxopyrrolidin-l - yl)methyl)benzoate (2.00 g, 8.02 mmol) in DMF (27 mL) in a sealed tube. The resulting mixture was stirred at 1 10 °C for 4 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS0 ₄ , filtered, and concentrated. Purification of the residue by silica gel chromatography (100→ 90% CH ₂ C1 ₂ / MeOH) gave the title compound. LC-MS m/z = 405.2 [M+l ].

Step D: 3-((6-(Methylsulfonyl)pyridin-3-yl)oxy)-4-((2-oxopyrrolidin- l -yl)methyl)benzoic acid NaOH (0.69 mL, 0.69 mmol) was added to a solution of methyl 3-((6- (methylsulfonyl)pyi-idin-3-yl)oxy)-4-((2-oxopyrrolidin-l -yl)methyl)benzoate (96 mg, 0.23 mmol) in THF (2.2 mL) at 25 °C and the reaction mixture was stirred for 18 h. The reaction was quenched by addition of HCl (0.69 mL, 0.69 mmol), and the solvent evaporated to afford a white solid. LC-MS m/z = 391.1 [M+l].

INTERMEDIATE C2

3-(4-(Ethylcarbamoyl)phenoxy)-4-((2-oxopiperidin- 1 -vDmethyDbenzoic acid

Step A: Methyl 3-methoxy-4-((2-oxopiperidin-l-yl)methyl)benzoate

A solution of 2-piperidinone (2.2 g, 22 mmol) in DMF (30 mL) was added to a stirred slurry of NaH (0.90 g, 60% dispersion in mineral oil, 23 mmol) in DMF (30 mL) at 0 °C. The mixture was stirred for 15 min at 0 °C and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (5.0 g, 19 mmol) in DMF (30 mL) was added. The resulting mixture was stirred at 0 °C for 4 h and was then slowly allowed to warm to ambient temperature. The mixture was stirred for 1 h. The mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution was added and the mixture was extracted using EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS04, filtered, and concentrated.

Purification of the concentrate by silica gel chromatography (100→ 90% CH2CI2/ MeOH) gave the title compound. LC-MS m/z = 278.3 [M+l].

Step B: Methyl 3-hydroxy-4-((2-oxopiperidin-l-yl)methyl)benzoate

A solution of boron tribromide in CH2CI2 (50.4 mL, 50.4 mmol) was carefully added to a stirred solution of methyl 3-methoxy-4-((2-oxopiperidin-l -yl)methyl)benzoate (4.7 g, 17 mmol) in CH2CI2 (85 mL) at 0 °C. The mixture was stirred at 0 °C for 4 h and was then stored for 2 days in a -20 °C freezer. The mixture was warmed to 0 °C and was then quenched carefully with excess MeOH. The resulting mixture was concentrated. The residue was re- esterified by dilution with MeOH and concentration (2x). The residue was diluted with CH2CI2 and saturated aqueous sodium bicarbonate solution. The organic phase was extracted with CH2CI2 (3x), dried over MgSC>4, filtered, and concentrated to give the title compound. LC-MS m/z = 264.3 [M+l].

Step C: Methyl 3-(4-(ethylcarbamoyl)phenoxy)-4-((2-oxopiperidin-l-yl)methyl )benzoate

2,2,6,6-Tetramethyl-3,5-heptanedione (0.19 g, 1.0 mmol) was added to a stirred slurry of methyl 3-hydroxy-4-((2-oxopiperidin-l-yl)methyl)benzoate (0.50 g, 2.0 mmol), copper (I) chloride (0.20 g, 2.0 mmol), 4-bromo-N-ethylbenzamide (0.57 g, 2.5 mmol), and cesium carbonate (1.96 g, 6.02 mmol) in ΝΜΡ (7 mL). The mixture was flushed with argon and heated at 80 °C for 5 h. The mixture was cooled to ambient temperature, aqueous saturated ammonium chloride solution was added and the mixture was extracted using EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS0 , filtered, and concentrated.

Purification of the crude mixture by silica gel chromatography (100→ 90% CH2CI2/ MeOH) gave the title compound. LC-MS m/z = 397.4 [M+l]. Step D: 3-(4-(Ethylcarbamoyl)phenoxy)-4-((2-oxopiperidin-l-yl)methyl )benzoic acid

Aqueous NaOH solution (IN, 1.75 mL, 1.75 mmol) was added to a stirred solution of methyl 3-(4-(ethylcarbamoyl)phenoxy)-4-((2-oxopiperidin-l-yl)methyl )benzoate (240 mg, 0.58 mmol) in MeOH (6 mL) and the mixture was stirred for 1 h at 50 °C. Aqueous HC1 solution (6N, 0.290 mL, 1.75 mmol) was added to the cooled reaction mixture, and the mixture was concentrated to dryness to afford the title compound. LC-MS m/z - 397.3 [M+l].

INTERMEDIATE C3

3-(4-(Cyclopropylcarbamoyl)phenoxy)-4-((2-oxopyrrolidin-l -yl)methyl)ben2oic acid

Step A: Methyl 3-(4-(cyclopropylcarbamoyl)phenoxy)-4-((2-oxopyrrolidin-l-yl )methyl)benzoate

To a mixture of methyl 3-hydroxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate (1.50 g, 6.02 mmol), 4-bromo-N-cyclopropylbenzamide (2.02 g, 8.42 mmol), cesium carbonate (3.92 g, 12.0 mmol) was added a solution of 2,2,6,6-tetramethyl-3,5-heptanedione (0.630 mL, 3.01 mmol) and copper(I) chloride (0.600 g, 6.02 mmol) in anhydrous, deoxygenated ΝΜΡ (60 mL). The mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to ambient temperature. Saturated aqueous NH ₄ C1 solution was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with water (3x), brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of CH ₂ Cl ₂ :MeOH - 100:0 to 95:5, to give the title compound. MS: mlz = 409.2 (M + 1).

Step B: 3-(4-(Cyclopropylcarbamoyl ^' )phenoxy ^' )-4-(f2-oxopyrrolidin-l-yl ^' )methyl)benzoic acid

To a solution of methyl 3-(4-(cyclopropylcarbamoyl)phenoxy)-4-((2- oxopyrrolidin-l-yl)methyl)benzoate (1.4 g, 3.4 mmol) in THF (11 mL) and MeOH (6 mL) was added aqueous NaOH (1M, 10.3 mL, 10.3 mmol). The mixture was stirred at ambient temperature for 15 min. Aqueous HC1 solution (IN) was added drop wise until pH = 7 and the mixture was concentrated. The crude solid was azeotroped with acetonitrile (2x) and dried to give the title compound and 3 equivalents of sodium chloride. MS: mlz = 395.2 (M + 1).

4-(5-((l-Benzyl-5-oxopyrrolidin-3-yl)carbamoyl)-2-f(2-oxoimi dazolidin-l- yl)methyl)phenoxy)benzoic acid

Step A: Methyl 3-hydroxy-4-methylbenzoate

To a solution of methyl 3-methoxy-4-methylbenzoate (50 g, 0.28 mol) in anhydrous CH ₂ C1 ₂ (300 mL) was added dropwise BBr ₃ (144 g, 0.560 mol) at -20 °C. After addition, the reaction mixture was stirred at 0 °C for 3 h, quenched with MeOH (100 mL), and then concentrated. The residue was diluted with EtOAc (300 mL), washed with brine (100 mL x

3), dried over Na ₂ S0 ₄ , and concentrated. The crude product was washed MTBE (50 mL x 2) to give methyl 3-hydroxy-4-methylbenzoate as a yellow solid. Ή NMR (300 MHz, CDC1 ₃ ): δ 7.40

(d, J = 2.7 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.91-6.88 (m, 1H), 3.87 (s, 3H), 2.49 (s, 3H).

Step B: 3-Hydroxy-4-methylbenzoic acid

To a solution of methyl 3-hydroxy-4-methylbenzoate (15.0 g, 90.5 mmol) in methanol (50 mL) was added aqueous LiOH (6.5 g in 50 mL of water, 0.27 mol) and the mixture was stirred at 23 °C for 16 h. The reaction mixture was acidified with aqueous HCl (IN) to pH 4 and then concentrated. The residue was washed with water (25 mL x 2) and dried to give 3- hydroxy-4-methylbenzoic acid as a white solid. Ή NMR (400 MHz, CD ₃ OD): δ 7.43-7.41 (m, 2H), 7.17-7.15 (m, 1 H), 2.25 (s, 3H).

Step C: ferf -Butyl 3-hydroxy-4-methylbenzoate

A mixture of 3-hydroxy-4-methylbenzoic acid (10.0 g, 65.8 mmol) and 1,1-di- ieri-butoxy-NN-dimethylmethanamine (63 mL, 0.26 mmol) in THF (200 mL) was heated at reflux for 4 h and then concentrated. The residue was purified by chromatography column (Si0 ₂ , petroleum ether:ethyl acetate = 100: 1) to give tert-butyl 3-hydroxy-4-methylbenzoate as a yellow solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 7.47-7.44 (m, 2H), 7.15-7.12 (m, 1H), 5.41 (s, 1H), 2.27 (s, 3H), 1.57 (s, 9H).

Step D: ferf -Butyl 3-(4-(ethoxycarbonyl phenoxy)-4-methylbenzoate

To a solution of tert-butyl 3-hydroxy-4-methylbenzoate (15.0 g, 72.1 mmol) in DMSO (150 mL) was added ethyl 4-iodobenzoate (21.6 g, 78.7 mmol), pyridine-2-carboxylic acid (1.80 g, 14.4 mmol), Cul (1.4 g, 7.2 mmol) and K ₃ P0 ₄ (30.6 g, 0.140 mol). The reaction mixture was stirred at 120 °C for 18 h, then cooled to 23 °C, and diluted with water (300 mL). The resulting mixture was extracted with ethyl acetate (150 mL x 3) and the combined organic phase was washed with brine (150 mL x 3), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: ethyl acetate = 100: 1) to give tert-butyl 3-(4-(ethoxycarbonyl)phenoxy)-4-methylbenzoate as a yellow solid. Ή NMR (400

MHz, CDC1 ₃ ): δ 8.01-7.97 (m, 2H), 7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6.90-6.86 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.56 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H).

Step E: tert-Butyl 4-(bromomethyl)-3-(4-(ethoxycarbonyl)phenoxy)benzoate

To a solution of tert-butyl 3-(4-(ethoxycarbonyl)phenoxy)-4-methylbenzoate

(7.50 g, 21.9 mmol) in PhCl (100 mL) was added NBS (4.30 g, 24.1 mmol) and benzoyl peroxide (1.1 g, 4.4 mmol). The reaction mixture was heated at reflux for 2 h, cooled to ambient temperature, and then quenched with saturated aqueous Na ₂ S0 ₃ solution (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic phase was washed with water (150 mL x 2) and brine (150 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenethyl acetate = 100: 1 to 50: 1) to give tert-butyl 4-(bromomethyl)-3-(4-(ethoxycarbonyl)phenoxy)benzoate as a yellow solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 8.12 (d, J = 8.8 Hz, 2H), 7.77 (dd, J = 1.2, 8.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.52 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.56 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H).

Step F: fe -Butyl 3-( ^' 4-(edioxycarbonvnphenoxy ^' )-4-((2-oxoimidazolidin-l-yl)mediyl)benzoate

To a solution of imidazolidin-2-one (1.20 g, 13.8 mmol) in DMF (10 mL) was added NaH (600 mg, 15.2 minol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then teri-butyl 4-(bromomethyl)-3-(4-(ethoxycarbonyl)phenoxy)benzoate (2.0 g, 4.6 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH ₄ CI solution (10 mL), diluted with water (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 5: 1 to 1 : 2) to give /er/-butyl 3-(4-(ethoxycarbonyl)phenoxy)-4-((2-oxoimidazolidin-l- yl)methyl)benzoate as a yellow solid. MS: m/z = 441.2 (M + 1). ^! H NMR (400 MHz, CDC1 ₃ ) : δ

8.01 (d, J = 8.8 Hz, 2H), 7.81 (dd, J = 1.2, 8.0 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 4.46 (s, 1H), 4.40 (s, 2H), 4.34 (t, J = 7.2 Hz, 2H), 3.36-3.30 (m, 4H),

1.55 (s, 9H), 1.38 (t, J = 7.2 Hz, 3H).

Step G: 3-(4-(Ethoxycarbonyl)phenoxy)-4-((2-oxoimidazolidin-l-yl)met hyl)benzoic acid

A solution of teri-butyl 3-(4-(ethoxycarbonyl)phenoxy)-4-((2-oxoimidazolidin-l- yl)methyl)benzoate (1.27 g, 2.88 mmol) in TFA/CH ₂ C1 ₂ (24 mL, V/V = 1 :5) was stirred at 23 °C for 18 h. The reaction mixture was concentrated to give 3-(4-(ethoxycarbonyl)phenoxy)-4-((2- oxoimidazolidin-l-yl)methyl)benzoic acid as a brown oil. MS: m/z = 385.1 (M + 1). Ή NMR (300 MHz, CDCI ₃ ): δ 8.02 (d, J = 8.7 Hz, 2H), 7.92-7.85 (m, 1H), 7.66 (s, 1H), 7.61 (d, J = 6.6 Hz, 1H), 6.96-6.88 (m, 2H), 4.47 (s, 2H), 4.35 (t, J = 7.2 Hz, 2H), 3.49-3.38 (m, 4H), 1.37 (t, J =

7.2 Hz, 3H).

Step H: Ethyl 4-(5-((l -benzyl-5-oxopyrrolidin-3-yl)carbamoyl)-2-((2-oxoimidazolidi n-l - yl)methyl)phenoxy)benzoate

To a solution of crude 3-(4-(ethoxycarbonyl)phenoxy)-4-((2-oxoimidazolidin-l- yl)methyl)benzoic acid (200 mg, 0.52 mmol) in DMF (10 mL) was added Et ₃ N (0.218 mL, 1.56 mmol), HATU (240 mg, 0.62 mmol) and 4-amino-l -benzylpyrrolidin-2-one (120 mg, 0.62 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V) : acetonitrile, to give ethyl 4-(5-((l-benzyl-5- oxopyrrolidin-3-yl)carbamoyl)-2-((2-oxoimidazolidin-l -yl)methyl)phenoxy)benzoate as a white solid. MS: m/z = 557.5(M + 1). Step I: 4-(5-((l-Benzyl-5-oxopyiTolidin-3-yl ^' )carbamoyl)-2-((2-oxoimidazolidin-l- yl)methyl)phenoxy)benzoic acid

To a solution of ethyl 4-(5-((l -benzyl-5-oxopyiTolidin-3-yl)carbamoyl)-2-((2- oxoimidazolidin-l -yl)methyl)phenoxy)benzoate (150 mg, 0.27 mmol) in MeOH (5 mL) was added a solution of LiOH (19.4 mg, 0.81 mmol) in H ₂ 0 (5 mL). The reaction mixture was stirred at 20 °C for 16 h and then concentrated. The residue was diluted with water (10 mL) and the pH value was adjusted to ~4 with aq. HCl (IN). The resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated to give racemic 4-(5-((l-benzyl-5-oxopyrrolidin-3-yl)carbamoyl)-2-((2-oxoimi dazolidin-l- yl)methyl)phenoxy)benzoic acid as a white solid. MS: m/z = 529.5 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.01 (d, J = 8.4 Hz, 2H), 7.68 (dd, J = 1.6, 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.30-7.21 (m, 5H), 6.98 (d, J = 8.8 Hz, 2H), 4.63-4.57 (m, 1H), 4.51-4.41 (m, 2H), 4.38 (s, 2H), 3.70-3.66 (m, 1H), 3.42-3.23 (m, 5H), 2.56-2.51 (m, 1H), 2.14- 2.00 (m, 1H).

4- { [Y S)-2-Oxo-4-phenylpyiTOlidin- 1 -yllmethyl) -3-[4-(tetrahydro-2H-pyran-4- ylcarbamoyl)phenoxy ^" ]benzoic acid

Step A: (SVMethyl 3-methoxy-4-((2-oxo-4-phenylpyrrolidin-l-yl)methyl)benzoate

To a stirred slurry of NaH (0.280 g, 6.95 mmol) in DMF (10 mL) at 0 °C was added (S)-4-phenylpyrrolidin-2-one (0.980 g, 6.08 mmol) in DMF (10 mL). The mixture was stirred for 5 min and then Methyl 4-(bromomethyl)-3-methoxybenzoate (1.50 g, 5.79 mmol) was added in DMF (10 mL). The resulting mixture was slowly allowed to come to ambient temperature and was then stirred for lh. The mixture was cooled to 0 °C and was carefully quenched with saturated aqueous ammonium chloride solution. The organic phase was extracted with EtOAc (3x). The combined organic phase was washed with brine (3x), dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography (50-100% EtOAc / Hexanes) afforded the title compound as a tan solid. MS: m/z = 340.2 (M + 1). Step B: 3-Hydroxy-4-{ (^S)-2-oxo-4-phenylpyiTolidin-l -yllmethyl|benzoate

A solution of boron tribromide in CH2CI2 (14.2 mL, 14.2 mmol) was carefully added to a 0 °C solution of (S)-methyl 3-methoxy-4-((2-oxo-4-phenylpyrrolidin-l-yl)methyl)benzoate (1.61g, 4.74 mmol) in CH ₂ C1 ₂ (16 mL). The mixture was stirred for 18 h at 0 °C and then warmed to 23 °C. The mixture was quenched with MeOH and concentrated to dryness. The residue was purified by silica gel chromatography (gradiating from 0 to 10% MeOH / CH2CI2) to afford the title compound as an off-white solid. MS: m/z = 326.2 (M + 1).

Step C: Methyl 4-{[(^S)-2-oxo-4-phenylpyrrolidin-l-yllmethyl|-3-r4-(tetrahy dro-2H-pyran-4- ylcarbamoyl)phenoxy]benzoate

To a stirred mixture of methyl 3-hydroxy-4- {[(4S)-2-oxo-4-phenylpyrrolidin-l- yl] methyl }benzoate (35 mg, 0.1 1 mmol) and 4-iodo-N-(tetrahydro-2H-pyran-4-yl)benzamide (53 mg, 0.16 mmol) in deoxygenated ΝΜΡ (500 uL) was added Cs ₂ C0 ₃ (70 mg, 0.22 mmol), CuCl (530 mg, 5.4 umol) and 2,2,6,6-tetramethyl-3,4-heptanedione (2.0 mg, 11 umol). The reaction mixture was heated at 120 °C for 3 h in a sealed vial. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and then washed with saturated aqueous ammonium chloride solution (3x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified via reverse-phase HPLC, eluting with 5% acetonitrile in water (0.05% ΝΗ ₄ ΟΗ used as a modifier) initially, grading to 95% acetonitrile in water to give the title compound. MS: mlz = 529.2 (M + 1).

ylcarbamoyl)phenoxy]benzoic acid

To a solution of methyl 4-{[(^S)-2-oxo-4-phenylpyrrolidin-l-yl]methyl}-3-[4- (tetrahydro-2H-pyran-4-ylcarbamoyl)phenoxy]benzoate (27 mg, 0.051 mmol) in a 1 : 1 mixture of THF/MeOH (1 mL) was added 2.8 M aqueous NaOH solution (0.055 mL, 0.153 mmol). The resulting mixture was stirred at 50 °C for 3 h. A solution of 2N HC1 in ether was then added to the mixture until pH ~ 3 and the reaction mixture was concentrated. The title compound was used without purification. MS: mlz = 515.2 (M + 1).

INTERMEDIATE C6

4- { [Y S)-2-Oxo-4-phenylpyrrolidin- 1 -yl ^" |methyl| -3-[4-(tetrahydro-2H-pyran-4- ylcarbamoyDphenoxylbenzoic acid

Step A: 3-r4-(ter^-Butoxycarbonyl)phenoxy]-4-{ (4S)-2-oxo-4-phenylpyrrolidin-l - yl]methyl} benzoate

To a solution of methyl 3-hydroxy-4-{[(4S)-2-oxo-4-phenylpyrrolidin-l- yl]methyl}benzoate (200 mg, 0.615 mmol) in deoxygenated NMP (4 mL) was added 4-tert- butylbromo benzoate (158 mg, 0.615 mmol), CuCl (61 mg, 0.62 mmol), 2,2,6,6-tetramethyl-3,5- heptane dione (113 mg, 0.615 mmol), and CS2CO3 (400 mg, 1.23 mmol). The reaction mixture was heated at 120 °C for 2 h. The mixture was cooled to ambient temperature, diluted with

EtOAc, and washed with aqueous ammonium chloride (3x) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography (0% to 80% EtOAc/hexanes) afforded the title compound. MS: mlz = 502.2 (M+l).

Step B: 4-[5-(Methoxycarbonyl)-2-{r(4S)-2-oxo-4-phenylpyrrolidin-l- yl]methyl}phenoxy ^" lbenzoic acid

To a solution of methyl 3-[4-(teri-butoxycarbonyl)phenoxy]-4-{[(4S)-2-oxo-4- phenylpyrrolidin-l-yl]methyl}benzoate (207 mg, 0.413 mmol) in CH2CI2 (5 mL) was added TFA (0.32 mL, 4.1 mmol) and the reaction mixture was stirred for 3 h at ambient temperature.

Another portion of TFA (0.32 mL) was added and the mixture was stirred at ambient temperature for 2 h. The reaction was then concentrated to afford the title compound. MS: mlz = 446.1 (M+l).

INTERMEDIATE C7

Step A: Methyl 4-((2-oxopyrrolidin-l-yl)methyl)-3-(4-(5-(tetrahvdro-2H-pyra n-4-yl)-l ,3,4- thiadiazol-2-yl)phenoxy)benzoate

2,2,6,6-Tetramethyl-3,5-heptanedione (102 mg, 0.552 mmol) was added to a stirred solution of methyl 3-hydroxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate (250 mg, 1.00 mmol), 2-(4-iodophenyl)-5-(tetrahydro-2H-pyi-an-4-yl)-l,3,4-thiadia zole (467 mg, 1.25 mmol), copper(I) chloride (109 mg, 1.10 mmol) and cesium carbonate (980 mg, 3.01 mmol) in NMP (3.3 mL). The mixture was flushed with argon and heated at 80 °C for 2 h. The mixture was cooled, diluted with aqueous saturated ammonium chloride solution, and then extracted with EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS0 ₄ , filtered, and concentrated. The crude mixture was purified by silica gel chromatography (100→ 90% CH ₂ C1 ₂ / MeOH) followed by a second purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) to afford the TFA salt of the title compound. The residue was diluted with aqueous Na ₂ C0 ₃ , extracted with CH ₂ C1 (3x), dried over MgS0 ₄ , filtered, and concentrated gave the title compound. LC-MS m/z found = 494.3[M+1].

Step B: 4-( (2-Oxopyrrolidin-l -yl)methyl)-3-(4-( 5-(tetrahydro-2H-pyran-4-yl)-l ,3,4-thiadiazol-2- yl)phenoxy)benzoic acid

An aqueous solution of NaOH (1M, 2.33 mL, 2.33 mmol) was added to a stirred solution of methyl 4-((2-oxopyrrolidin- 1 -yl)methyl)-3 -(4-(5-(tetrahydro-2H-pyran-4-yl)- 1 ,3,4- thiadiazol-2-yl)phenoxy)benzoate (384 mg, 0.778 mmol) in MeOH (0.8 mL). The resulting mixture was heated at 50 °C for 1 h. The mixture was cooled to ambient temperature, an aqueous solution of HC1 (6M, 0.389 mL, 2.33 mmol) was added, and the mixture was concentrated to give the title compound and three equivalents of NaCl. LC-MS m/z found = 480.3 [M+l].

INTERMEDIATE C8

3-(4-(5-Methylpyrazin-2-yl)phenoxy)-4-((2-oxopy olidin-l -yl)methyl)benzoic acid

Step A: 4-Methyl-3-(4-nitrophenoxy)benzoate

A mixture of methyl 3-hydroxy-4-methylbenzoate (40.0 g, 0.240 mol), l-fiuoro-4- nitrobenzene (37.4 g, 0.265 mol) and K ₂ C0 ₃ (66.5 g, 0.480 mol) in DMF (350 mL) was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was diluted with water (700 mL) and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with water (300 mL x 2) and brine (300 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 40: 1 to 15: 1) to give methyl 4-methyl-3-(4-nitrophenoxy)benzoate. MS: mlz = 288.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.21 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 9.2 Hz, 2H), 3.89 (s, 3H), 2.25 (s, 3H).

Step B: Methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate

To a solution of methyl 4-methyl-3-(4-nitrophenoxy)benzoate (59.6 g, 0.210 mol) and NBS (39.7 g, 0.230 mol) in chlorobenzene (500 mL) was added benzoyl peroxide (10.8 g, 40.0 mmol) and the resulting mixture was stirred at 130 °C for 16 h. The reaction mixture was concentrated to remove most of the chlorobenzene, and the residue was treated with aqueous 10% Na ₂ S0 ₃ solution (300 mL). The resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic phase was washed with water (200 mL x 2) and brine (200 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 50: 1 to 10: 1) to give methyl 4-(bromomethyl)-3-(4- nitrophenoxy)benzoate as a yellow solid. MS: mlz = 365.8 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): 5 8.25 (d, J = 9.2 Hz, 2H), 7.90 (dd, J = 1.6, 8.0 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 9.2 Hz, 2H), 4.52 (s, 2H), 3.90 (s, 3H).

Step C: Methyl 3-(4-nitrophenoxy)-4-((2-oxopyrrolidin-l -yl)methyl)benzoate

To a solution of pyrrolidin-2-one (1 1.6 g, 0.140 mol) in DMF (200 mL) was added NaH (4.9 g, 0.13 mol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate (41 g, 0.1 1 mol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at 23 °C for 4 h and then quenched with saturated aqueous NH ₄ C1 solution (50 mL). The resulting mixture was diluted with water (300 niL) and extracted with EtOAc (300 niL x 3). The combined organic phase was washed with H ₂ 0 (300 raL x 2) and brine (300 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 15: 1 to 5: 1) to give methyl 3 -(4-nitrophenoxy)-4-((2-oxopyrrolidin-l -yl)methyl)benzoate. MS: mlz = 371.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.22 (d, J = 9.2 Hz, 2H), 7.91 (dd, 7 = 1.6, 8.0 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 9.6 Hz, 2H), 4.50 (s, 2H), 3.90 (s, 3H), 3.28 (t, J = 7.2 Hz, 2H), 2.35 (t, J = 8.0 Hz„ 2H), 1.98-1.94 (m, 2H).

Step D: Methyl 3-(4-aminophenoxy)-4-((2-oxopyrrolidin-l-yl)methyl)benzoate

To a mixture of methyl 3-(4-mtrophenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoate (35 g, 0.10 mol) and Fe powder (28 g, 0.50 mol) in EtOH (200 mL) was added a solution of NH ₄ C1 (27 g, 0.50 mol) in water (80 mL) and the resulting mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated, diluted with H ₂ 0 (300 mL), and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with H ₂ 0 (300 mL) and brine (300 mL), dried over Na ₂ S0 ₄ , and concentrated to give methyl 3-(4- aminophenoxy)-4-((2-oxopyrrolidin-l-yl)methyl)benzoate. MS: m/z = 340.7 (M + 1). Ή (400 MHz, CDC1 ₃ ): δ 7.67 (dd, J = 1.6, 8.0 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 4.62 (s, 2H), 3.83 (s, 3H), 3.38 (t, J = 7.2 Hz, 2H), 2.43 (t, J = 8.0 Hz, 2H), 2.04-1.99 (m, 2H).

Step E: Methyl 4-( ^' (2-oxopyrrolidin-l-yl)methyl)-3-(4-(4,4,5,5-tetramethy l-L3,2-dioxaborolan-2- yl)phenoxy)benzoate

A solution of B ₂ (Pin) ₂ (27.9 g, 109 mmol) and benzoyl peroxide (1.14 g, 4.70 mmol) in MeCN (300 mL) was stirred at ambient temperature for 5 min and then methyl 3-(4- aminophenoxy)-4-((2-oxopyrrolidin-l-yl)methyl)benzoate (31.0 g, 91.8 mmol) was added. The resulting mixture was stirred at 30 °C for 10 min before te i-BuONO (14.1 g, 1 19 mmol) was added dropwise. After addition, the reaction mixture was stirred at 30 °C for 18 h. Acetonitrile was removed and the residue was dissolved in EtOAc (300 mL) and washed with NH ₄ OH (5% aqueous solution, 100 mL x 3), then brine (100 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 50: 1 to 5: 1) to give methyl 4-((2-oxopyrrolidin-l-yl)methyl)-3-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenoxy)benzoate as a solid. MS: m/z = 452.2 (M + 1). Ή NMR (300 MHz, CDC1 ₃ ): 8 7.80- 7.75 (m, 3H), 7.56 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 4.53 (s, 2H), 3.84 (s, 3H), 3.29 (t, J = 6.9 Hz, 2H), 2.38 (t, J = 8.1 Hz, 2H), 1.98-1.90 (m, 2H), 1.33 (s, 12H).

Step F: Methyl 3-(4-(5-methylpyrazin-2-yl)phenoxy)-4-((2-oxopyrrolidin-l -yl)methyl)benzoate A mixture of methyl 4-((2-oxopyrrolidin-l-yl)methyl)-3-(4-(4,4,5 _> 5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate (500 mg, 1.10 mmol), 2-bromo-5-methylpyrazihe (192 mg, 1.20 mmol), Pd(PPh ₃ ) ₄ (190 mg, 0.165 mmol) and Na ₂ C0 ₃ (233 mg in 0.8 mL of H ₂ 0, 2.2 mmol) in DMF (8 mL) was heated at 100 °C under N ₂ atmosphere for 16 h. The reaction mixture was cooled to 23 °C, diluted with H ₂ 0 (15 mL), and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with H ₂ 0 (20 mL) and brine (20 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 1 : 1) to give methyl 3-(4-(5-methylpyrazin-2-yl)phenoxy)-4-((2- oxopyrrolidin-l-yl)methyl)benzoate. MS: m/z = 418.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): 5 8.81 (s, 1H), 8.42 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 4.53 (s, 2H), 3.80 (s, 3H), 3.30 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 2.33 (t, J = 8.0 Hz, 2H), 1.94-1.91 (m, 2H).

Step G: 3-(4-(5-Methylpyrazin-2-yl)phenoxy -4-((2-oxopyrrolidin-l-yl)methvnbenzoic acid

A mixture of methyl 3-(4-(5-methylpyrazin-2-yl)phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoate (100 mg, 0.240 mmol) and LiOH (27 mg, 0.96 mmol) in MeOH (5 mL) and H ₂ 0 (5 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated, diluted with H ₂ 0 (8 mL), and the pH adjusted to 4 with aqueous HC1 (2 N) solution. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over Na ₂ S0 ₄ , and concentrated to give the title compound. MS: m/z = 405.2 (M + 1).

INTERMEDIATE C9

3-(4-(3-Cvclobutyl-L2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxopyr rolidin-l -vDmethvDbenzoic acid Step A: Methyl 3-(4-(3-cvclobutyl-l ,2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxopyrrolidin-l- vDmethvDbenzoate

N-Methylmorpholine (0.30 mL, 2.7 mmol) was added to a stirred solution of 4-(5- (methoxycarbonyl)-2-((2-oxopyrrolidin-l-yl)methyl)phenoxy)be nzoic acid (0.20 g, 0.54 mmol), (Z)-N-hydroxycyclobutanecarboximidamide (0.120 g, 1.08 mmol), EDC (0.18 g, 0.95 mmol), and HOAt (0.040 g, 0.27 mmol) in toluene (5 mL) and DMF (0.5 mL). The resulting mixture was heated at 80 °C for 18 h. The mixture was cooled to ambient temperature. 2,4,6-tripropyl- l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.71 mL, 50% in DMF, 0.81 mmol) was added and the resulting mixture was stirred for 1 h at 50 °C. The mixture was concentrated and the residue was purified by reverse phase HPLC (C- 18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) to afford the title compound as the TFA salt. The residue was diluted with aqueous Na ₂ CC>3, extracted with CH ₂ C1 ₂ , dried over Na ₂ S0 ₄ , and concentrated to give the title compound. LC-MS m/z found = 466.3 [M+l].

Step B : 3 -(4-(3 -Cvclobutyl- 1 ,2,4-oxadiazol-5-vDphenoxy)-4-((2-oxopyrrolidin- 1 - vDmethvDbenzoic acid

Methyl 3-(4-(3-cyclobutyl-l ,2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoate (36 mg, 0.080 mmol) and NaOH (241 μΐ, 0.241 mmol) were stirred at 50 °C for 1 h. The reaction was cooled to 23 °C and HC1 (40.2 μΐ, 0.241 mmol) was added. The mixture was concentrated to dryness. MS m/z found = 434.3 [M+l].

INTERMEDIATE CIO

3 -(4-Chloro-3-fluorophenoxy)-4-((2-oxopyrrolidin-l -vDmethvDbenzoic acid

Step A: Methyl 3-(4-chloro-3-fluorophenoxy)-4-methylbenzoate

A mixture of methyl 3-hydroxy-4-methylbenzoate (2.7 g, 0.016 mol), 4-bromo-l- chloro-2-fiuorobenzene (3.4 g, 0.016 mmol), 2,2,6,6-tetramethyl-3,5- heptanedione (1.6 g, 9.0 mmol), CuCl (1.74 g, 18.0 mmol) and Cs ₂ C0 ₃ (15.6 g, 48.0 mmol) in NMP (35 mL) was stirred at 80 °C under N ₂ atmosphere for 18 h. After cooling to 23 °C, the reaction mixture was filtered, the filtrate was diluted with EtOAc (100 mL), and washed with water (50 mL x 3) and brine (50 mL). The organic phase was dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 100: 1 to 50: 1) to give methyl 3-(4- chloiO-3-fluorophenoxy)-4-methylbenzoate. MS: m/z = 295.2 (M+l). Ή NMR (300 MHz CDC1 ₃ ): δ 7.81 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.37-7.28 (m, 2H), 6.73-6.56 (m, 2H), 3.90 (s, 3H), 2.89 (s, 3H). Step B: Methyl 4-(bromometlwl)-3-(4-chloro-3-fluorophenoxy)benzoate

A mixture of methyl 3-(4-chloro-3-fluorophenoxy)-4-methylbenzoate (2.7 g, 9.2 mmol), NBS (1.6 g, 9.2 mmol) and benzoyl peroxide (0.45 g, 1.8 mmol) in chlorobenzene (35 mL) was heated at 130 °C for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 100: 1 to 10: 1) to give methyl 4-(bromomethyl)-3-(4-chloro-3-fluorophenoxy)benzoate. Ή NMR (300 MHz, CDC1 ₃ ): 5 7.74 (dd, J = 1.5, 7.8 Hz, 1H), 7.48-7.44 (m, 2H), 7.30 (t, J = 8.4 Hz, 1H), 6.80-6.70 (m, 2H), 4.48 (s, 2H), 3.82 (s, 3H). Step C: Methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxopyrrolidin-l-yl)methyl )benzoate

To a solution of 2-pyrrolidinone (0.55 g, 6.5 mmol) in DMF (10 mL) at 0 °C was added NaH (0.26 g, 6.5 mmol, 60% in mineral oil). The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-3-(4-chloro-3-fluorophenoxy)benzoate (2.0 g, 5.4 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was stirred at 23 °C for 18 h and then quenched with saturated aqueous NH ₄ CI solution (10 mL). The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with H ₂ 0 (20 mL x 2) and brine (20 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum

ethenEtOAc = 10: 1 to 1 : 2) to give methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxopyrrolidin-l - yl)methyl)benzoate. MS: m/z = 377.9 (M+l). Ή NMR (CDC1 ₃ , 300 MHz): δ 7.86 (dd, J = 1.5, 7.8 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.43-7.33 (m, 2H), 6.79-6.69 (m, 2H), 4.55 (s, 2H), 3.91 (s, 3H), 3.32 (t, J = 7.2 Hz, 2H), 2.42 (t, J = 8.1 Hz, 2H), 2.04-1.99 (m, 2H).

Step D: 3-(4-Chloro-3-fluorophenoxy)-4-((2-oxopyrrolidin-l -yl)methyl)benzoic acid

A mixture of methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoate (1.2 g, 3.2 mmol) and LiOH (0.40 g in 5 mL of H ₂ 0, 16 mmol) in MeOH (10 mL) was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (15 mL) and the pH was adjusted to 4 with aqueous HC1 (IN). The resulting mixture was extracted with EtOAc (15 mL x 2). The combined organic phase was washed with brine (15 mL x 2), dried over Na ₂ S0 ₄ , and concentrated to give 3-(4-chloro-3-fluorophenoxy)-4-((2-oxopyrrolidin-l - yl)methyl)benzoic acid. MS: m/z 363.9 (M+l). Ή NMR (CDC1 ₃ , 300 MHz): δ 7.88 (dd, J = 1.5, 7.8 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 7.45-7.34 (m, 2H), 6.82-6.71 (m, 2H), 4.57 (s, 2H), 3.36 (t, J = 7.2 Hz, 2H), 2.46 (t, 7 = 8.1 Hz, 2H), 2.09-1.99 (m, 2H).

INTERMEDIATE CI 1

2-Fluoro-4-{| ^" ( S or ^R)-4-(4-methoxyphenyl)-2-oxopyrrolidin-l-yllmethyl)-5-[4-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)phenoxy ^" |benzoic acid

Step A: Methyl 4-(bromomethyl)-5-(4-( ^' fer^-butoxycarbonyl)phenoxy)-2-fluorobenzoate

To a solution of methyl 5-(4-(teri-butoxycarbonyl)phenoxy)-2-fluoro-4- methylbenzoate (130 mg, 0.36 mmol) in benzene (10 mL) was added NBS (96 mg, 0.54 mmol) and AIBN (30 mg, 0.18 mmol). The reaction was heated at reflux for 18 h and then quenched with 10% aqueous NaHS0 ₃ solution. The reaction mixture was then diluted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes-.EtOAc - 100:0 to 65:35, to give the title compound. MS: m/z 462.9, 464.8 (M+23).

Step B: Methyl 5- 4-(ter -butoxycarbonyl)phenoxyl-2-fluoro-4-([ ^' (^S or 4R)-4-(4- methoxyphenyl)-2-oxopyiTolidin-l-yllmethyllbenzoate

To a solution of (4S or ^R-4-(4-methoxyphenyl))pyiTolidin-2-one (86.0 mg, 0.196 mmol) in DMF (2 mL) was added NaH (60% dispersion, 10 mg, 0.26 mmol). The reaction was stirred at ambient temperature for 10 min before addition of a solution of methyl 4- (bromomethyl)-5-(4-(/eri-butoxycarbonyl)phenoxy)-2-fluoroben zoate (86.0 mg, 0.196 mmol) in DMF (2 mL). The reaction was stirred at ambient temperature for 1 h and then quenched with water. The reaction mixture was diluted with ethyl acetate and washed with water (3x) and brine. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified via reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound. MS: m/z = 550.2 (M + 1). Step C: 4-[4-Fluoro-5-(methoxycarbonyl)-2-{| ^~ (' _l S' or R)-4-(4-methoxyphenyl)-2-oxopyrrolidin- 1 -yllmethvDphenoxylbenzoic acid

To a stirred solution of methyl 5-[4-(teri-butoxycarbonyl)phenoxy]-2-fluoro-4- {[(4S or ^R))-4-(4-methoxyphenyl)-2-oxopyiTolidin-l-yl]methyl}benzoat e (30 mg, 0.055 mmol) was added TFA (0.1 10 mL, 1.37 mmol). The reaction was stirred for 18 h at ambient temperature and then concentrated to afford the title compound which was used without purification. MS: mlz = 494.1 (M + 1).

Step D: Methyl 2-fluoro-4-i[( SOr ^)-4-(4-methoxyphenyl)-2-oxopyrrolidin-l-yl1methyll-5- [4-(3 -methyl- L2,4-oxadiazol-5-yl)phenoxy1benzoate

To a stirred solution of 4-[4-fluoro-5-(methoxycarbonyl)-2-{[(4S or 4R)-4-(4- methoxyphenyl)-2-oxopyrrolidin-l -yl]methyl}phenoxy]benzoic acid (26 mg, 0.053 mmol) in DMF (2 mL) was added (£)-N'-hydroxyacetimidamide (12 mg, 0.16 mmol), EDC (30 mg, 0.16 mmol), HOAt (22 mg, 0.16 mmol), and TEA (0.037 mL, 0.26 mmol). The reaction was heated at 60 °C for 3 h. 2,4,6-TripiOpyl-l ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 50% solution in DMF, 202 mg, 0.316 mmol) was then added and the mixture heated at 80 °C for 12 h. The reaction mixture was cooled to ambient temperature, filtered, and purified via reverse-phase HPLC, eluting with 5% acetonitrile in water (0.05% NH ₄ OH used as a modifier) initially, grading to 95% acetonitrile in water, to give the title compound. MS: mlz = 532.2 (M + 1).

Step E: 2-Fluoro-4-{[ ^" ( S or ^R)-4-(4-methoxyphenyl)-2-oxopyrrolidin-l-yllmethyl|-5-[ ^" 4-(3- methyl-l ^^-oxadiazol-S-vDphenoxylbenzoic acid

To a stirred solution of methyl 2-fluoro-4-{[(4S or 4R)-4-(4-methoxyphenyl)-2- oxopyrrolidin-l-yl]methyl}-5-[4-(3-methyl-l ,2,4-oxadiazol-5-yl)phenoxy]benzoate

(1 1 mg, 0.021 mmol) in a mixture of 1 : 1 THF/MeOH (1 mL) was added 2.8 M aqueous NaOH solution (0.022 mL, 0.062 mmol). The resulting mixture was stirred at 50 °C for 1 h. A solution of 2N HC1 in ether was added to the mixture until pH ~ 3 and the reaction mixture was concentrate to afford the title compound, which was used without purification. MS: mlz = 518.2 (M + l).

INTERMEDIATE CI 2

3-(4-(5-Methyl-l ^-miadiazol-2-yl)phenoxy)-4-f(2-oxo-4-(trifluoromethyl)pyrro lidin-l- yl)methyl)benzoic acid

Step A: Methyl 3-methoxy-4-((2-oxo-4-(trifluoromethyl)pyrrolidin-l-yl)methy l)benzoate

A solution of 4-(trifluoromethyl)pyrrolidin-2-one (4.96 g, 32.4 mmol) in DMF (50 mL) was added to a slurry of NaH (1.35 g, 60% dispersion in mineral oil, 33.8 mmol) in DMF (50 mL) at 0 °C. This mixture was stirred at 0 °C for 5 min before a solution of methyl 4- (bromomethyl)-3-methoxybenzoate (7.0 g, 27 mmol) in DMF (50 mL) was added, and the solution was stirred at 0 °C for 15 min. The mixture was quenched with saturated aqueous ammonium chloride solution and then extracted with EtOAc (3x). The combined organic phase was washed with brine, dried over MgS0 ₄ , filtered, and concentrated. Purification of the residue by silica gel chromatography (100→ 0% Hexanes/EtOAc) gave the title compound. LC-MS m/z found = 332.2 [M+l]. Step B: Methyl 3-hvdroxy-4-((2-oxo-4-(trifluoromethyl)pyrrolidin-l-yl)methy l)benzoate

A solution of boron tribromide in CH ₂ C1 ₂ (1M, 18.1 mL, 18.1 mmol) was carefully added to a solution of methyl 3-methoxy-4-((2-oxo-4-(trifluoromethyl)pyrrolidin-l- yl)methyl)benzoate (2.00 g, 6.04 mmol) in CH ₂ C1 ₂ (20 mL) at 0 °C. The mixture was stirred at 0 °C for 3 h and then at -20 °C for 18 h. The mixture was warmed to 0 °C and quenched carefully with excess MeOH. The resulting mixture was concentrated from MeOH (2x). Purification of the residue by silica gel chromatography (100→ 90% CH2CI2/ MeOH) gave the title compound. LC-MS m/z found = 318.3 [M+l].

Step C: Methyl 3-(4-(5-methyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxo-4- (trifluoromethyl)pyrrolidin- 1 -yl)methyl)benzoate

2,2,6,6-Tetramethyl-3,5-heptanedione (0.080 g, 0.43 mmol) was added to a solution of methyl 3-hydroxy-4-((2-oxo-4-(trifluoromethyl)pyrrolidin-l -yl)methyl)benzoate (0.25 g, 0.79 mmol), 2-(4-iodophenyl)-5-methyl-l ,3,4-thiadiazole (476 mg, 1.58 mmol), copper(I) chloride (0.086 g, 0.87 mmol), and cesium carbonate (0.77 g, 2.4 mmol) in NMP (7.5 mL). The mixture was flushed with argon and heated at 80 °C for 18 h. The cooled reaction was filtered through a syringe filter washing with DMF (4 mL). Purification of the residue by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) afforded the title compound as the TFA salt. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound. LC-MS m/z found = 492.2[M+1].

Step D: 3-(4-(5-Methyl-1 ,4-thiadiazol-2-yl)phenoxy -4-((2-oxo-4-( ^" trifluoromethyl)pyrrolidin- 1 -yl)methyl)benzoic acid

Aqueous NaOH (1M, 2.2 mL, 2.2 mmol) was added to a solution of methyl 3-(4-(5- methyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-4-((2-oxo-4-(trifluoromethyl)pyr rolidin- 1 - yl)methyl)benzoate (355 mg, 0.722 mmol) in MeOH (7.2 mL) and the mixture was heated at 50 °C for 2 h. The mixture was cooled to ambient temperature and aqueous 6M HC1 solution (361 μΐ, 2.17 mmol) was added. The resulting mixture was concentrated to give the racemic title compound and three equivalents of NaCl. LC-MS m/z found = 478.1 [M+l].

INTERMEDIATE CI 3

3-((6-(3-Methyl-L2^-oxadiazol-5-yl)pyridin-3-yl)oxy)-4-(( 2-oxopyn-olidin-l-yl)methyl)benzoic acid

Step A: tert-Butyl 5-bromopicolinate

l,l-Di-ier/-butoxy-N,N-dimethylmethanamine (36 mL, 15 mmol) was added dropwise to a solution of 5-bromopicolinic acid (6.0 g, 3.0 mmol) in anhydrous THF (150 mL) at reflux. The resulting mixture was heated at reflux for 18 h, cooled, and then concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 100: 1 to 4: 1) to give /er -butyl 5-bromopicolinate. MS: mlz = 279.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.79 (d, J = 1.2 Hz, 1H), 7.94-7.93 (m, 2H), 1.62 (s, 9H).

Step B: tert-Butyl 5-(5-(methoxycarbonyl)-2-((2-oxopyrrolidin-l-yl)methyl)pheno xy)picolinate To a solution of tert-butyl 5-bromopicolinate (3.50 g, 13.6 mmol) in NMP (70 mL) was added methyl 3-hydroxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate (2.80 g, 1 1.3 mmol), 2,2,6,6-tetramethyl-heptane-3,5-dione (1.4 mL, 6.2 mmol), CuCl (1.20 g, 12.5 mmol) and CS2CO3 (7.40 g, 22.6 mmol). The reaction mixture was heated at 80 °C under N ₂ atmosphere for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic phase was washed with water (80 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 4: 1 to EtOAc) to give tert-butyl 5-(5-(methoxycarbonyl)-2-((2- oxopyiTolidin-l-yl)methyl)phenoxy)picolinate. MS: mlz = 449.0 (M + 23). Ή NMR (400 MHz, CDCI ₃ ): δ 8.45 (s, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.88 (dd, J = 1.2, 8.0 Hz, 1 H), 7.59 (d, J = 1.2 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.29 (d, J = 1.4 Hz, 1 H), 4.54 (s, 2 H), 3.88 (s, 3 H), 3.30 (t, J = 7.2 Hz, 2 H), 2.38 (d, J = 8.0 Hz, 2 H), 2.06-1.95 (m, 2 H), 1.64 (s, 9 H).

Step C: 5-(5-(Methoxycarbonyl)-2-((2-oxopyrrolidin-l-yl)methyl)pheno xy)picolinic acid

A solution of tert-butyl 5-(5-(memoxycarbonyl)-2-((2-oxopyrrolidin-l- yl)methyl)phenoxy)picolinate (3.1 g, 7.2 mmol) in TFA (10 mL) and CH ₂ C1 ₂ (50 mL) was stirred at 23 °C for 18 h. The reaction mixture was concentrated, the residue was dissolved in CH ₂ C1 ₂ (30 mL), and washed with H ₂ 0 (15 mL x 2). The organic phase was dried over Na ₂ S0 ₄ and concentrated to give 5-(5-(methoxycarbonyl)-2-((2-oxopyrrolidin-l-yl)methyl)pheno xy)picolinic acid. MS: mlz = 371.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 9.74 (br, 3 H), 7.96 (m, 7.6 Hz, 1 H), 7.70 (s, 1 H), 7.79-7.44 (m, 2 H), 4.58 (s, 2 H), 3.92 (s, 3 H), 3.40 (t, J = 7.2 Hz, 2 H), 2.52 (t, J = 8.0 Hz, 2 H), 2.04 (d, J = 8.0 Hz, 2H).

Step D: Methyl 3-((6-(3-methyl-l ,2,4-oxadiazol-5-yl)pyridin-3-yl ^' )oxy)-4-((2-oxopynOlidin-l- yl)methyl)benzoate

To a solution of 5-(5-(methoxycarbonyl)-2-((2-oxopyrrolidin-l- yl)methyl)phenoxy)picolinic acid (3.0 g, 8.1 mmol) in toluene (100 mL) was added N'- hydroxyacetimidamide (1.20 g, 16.2 mmol), EDC (2.70 g, 14.1 mmol), HOBt (548 mg, 4.10 mmol) and N-methylmorpholine (6.2 mL, 41 mmol). The resulting mixture was heated at 50 °C for 20 h and then 2,4,6-tripropyl-[ 1 ,3, 5,2,4,6] trioxatriphosphinane 2,4,6-trioxide (T3P, 5.3 mL, 12 mmol) was added. The reaction mixture was stirred at 60 °C for 20 h and then concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with water (50 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 4: 1 to EtOAc) to give methyl 3-((6-(3-methyl-l,2,4-oxadiazol-5-yl)pyridin-3-yl)oxy)-4- ((2-oxopyrrolidin-l-yl)methyl)benzoate. MS: mlz = 431.1 (M + 23). Ή NMR (400 MHz, CDCI ₃ ): δ 8.52 (d, J = 2.8 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.93-7.91 (m, 1 H), 7.66 (d, J = 1.6 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.36 (dd, J = 2.8, 8.8 Hz, 1 H), 4.55 (s, 2 H), 3.90 (s, 3 H), 3.31 (t, J = 7.2 Hz, 2 H), 2.51 (s, 3 H), 2.37 (t, J = 8.0 Hz, 2 H), 2.06-1.96 (m, 2 H).

Step E: 3-((6-(3-Methyl-l,2,4-oxadiazol-5-yl)pyi-idin-3-yl)oxy)-4-(( 2-oxopyrrolidin-l- yl)methyl)benzoic acid

A mixture of methyl 3-((6-(3-methyl-l,2,4-oxadiazol-5-yl)pyiidin-3-yl)oxy)-4- ((2-oxopyrrolidin-l-yl)methyl)benzoate (970 mg, 2.38 mmol) and LiOH (114 mg in 5 mL of water, 4.8 mmol) in THF (15 mL) was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 2). The pH of the aqueous phase was adjusted to 4 with aqueous HC1 (IN), and then extracted with EtOAc (20 mL x 5). The combined organic phase was washed with brine, dried over Na ₂ S0 ₄ , and concentrated to dryness to give 3-((6-(3-methyl-l,2,4-oxadiazol-5-yl)pyridin-3-yl)oxy)-4-((2 -oxopyrrolidin-l- yl)methyl)benzoic acid. MS: m/z = 395.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.54 (d, J = 2.8 Hz, 1 H), 8.16 (d, J = 8.8 Hz, 1 H), 7.93 (dd, J = 1.6, 8.0 Hz, 1 H), 7.69 (d, J = 1.2 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.39 (dd, J = 2.8, 8.8 Hz, 1 H), 4.58 (s, 2 H), 3.35 (t, J = 6.8 Hz, 2 H), 2.51 (s, 3 H), 2.41 (t, J = 8.0 Hz, 2 H), 2.05-1.98 (m, 2 H).

INTERMEDIATE C14

(S)-3-(4-(3-Methyl-L2,4-oxadiazol-5-yI)phenoxy)-4-( (2-oxo-4-phenylpynOlidin-l - yl)methyl)benzoic acid

Step A: (SVMethyl 3-(4-(3-methyl-L2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxo-4-phen ylpyrrolidin- 1 -vDmethvDbenzoate

Ι ,Ι'-Carbonyldiimidazole (0.400 g, 2.46 mmol) was added to a solution (S)-4-(5- (methoxycarbonyl)-2-((2-oxo-4-phenylpyrrolidin-l -yl)methyl)phenoxy)benzoic acid (1.0 g, 2.2 mmol) in 2-methyl THF (10 mL) at 23 °C and the reaction mixture was stirred for 2 h. N- hydroxyacetamidine (0.166 g, 2.24 mmol) was added and the reaction was stirred for an additional 1 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with CH ₂ Cl ₂ /MeOH (0/100 to 10/90) to afford the intermediate (S)-methyl 3-(4- ((acetimidamidooxy)carbonyl)phenoxy)-4-((2-oxo-4-phenylpyrro lidin-l-yl)methyl)benzoate. n-Tetrabutylammonium fluoride (1.95 mL, 1.95 mmol) was added to a solution of (S)-methyl 3-(4-((acetimidamidooxy)carbonyl)phenoxy)-4-((2-oxo-4-phenyl pyrrolidin-l- yl)methyl)benzoate (0.977 g, 1.95 mmol) in 2-MeTHF (10 mL) and the mixture was stirred at 23 °C for 4 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of hexanes/ethyl acetate (80/20 to 20/80), to give the title compound. MS: mlz = 484.1 (M + 1).

Step B: (S)-3-(4-(3-Methyl-l,2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxo-4 -phenylpyrrolidin-l- vDmethvDbenzoic acid

Aqueous IN NaOH (3.0 mL, 3.0 mmol) was added to a solution of (S)-methyl 3- (4-(3-mefhyl- 1 ,2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxo-4-phenylpyrrolidin- 1 -yl)methyl)benzoate (0.723 g, 1.49 mmol) in MeOH (5 mL) at 23 °C. The reaction mixture was warmed to 55 °C and stirred for 12 h. The mixture was cooled to 23 °C, quenched with aqueous IN HCl (3.0 mL, 3.0 mmol), and concentrated to yield the title compound. MS: mlz = 470.1 (M + 1).

(S)-3-(4-(6-Methylpyridazin-3-yl)phenoxy)-4-((2-oxo-4-phe nylpyrrolidin-l -yl)methyl)benzoic acid

Step A: (S)-4-Phenyl-pyrrolidin-2-one 4-Phenyl-pyiTolidin-2-one (commercial) was separated by SFC (Chiralpak AD column; eluting with C0 ₂ /MeOH (0.2% NH ₄ OH) =75/25)) to afford the title compound as the second eluting isomer.

Step B: (SVMethyl 3-(4-nitrophenoxy)-4-((2-oxo-4-phenylpyiTolidin-l-yl)methyl) benzoate

Sodium hydride (60% in mineral oil, 0.60 g, 15 mmol) was added to a solution of

(S)-4-phenyl-pyn-olidin-2-one (2.65 g, 16.4 mmol) in DMF (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-3-(4- nitrophenoxy)benzoate (5.00 g, 13.7 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 18 h and then quenched with aqueous NH ₄ CI solution (10 mL). The resulting mixture was diluted with water (50 mL) and extracted with

EtOAc (50 mL x 3). The combined organic phase was washed with H ₂ 0 (50 mL x 3) and brine (50 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column

chromatography (Si0 ₂ , petroleum ether: EtOAc = 10: 1 to 1 : 1) to give title compound as a yellow solid. MS: mlz = 446.9 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.21 (d, J = 8.8 Hz, 2H), 7.92 (dd, J = 1.6, 8.0 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.34-7.25 (m, 3H), 7.16 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.57 (dd, J = 15.2, 15.2 Hz, 2H), 3.90 (s, 3H), 3.66 (dd, J = 8.4, 9.2 Hz, 1H), 3.56-3.48 (m, 1H), 3.29 (dd, J = 7.2, 9.6 Hz, 1H), 2.80 (dd, J = 8.8, 16.8 Hz, 1H), 2.55 (dd, J = 8.4, 16.8 Hz, 1H). Step C: (SVMethyl 3-(4-aminophenoxy)-4-((2-oxo-4-phenylpyrrolidin-l-yl)methyl) benzoate

A mixture of (S)-methyl 3-(4-nitrophenoxy)-4-((2-oxo-4-phenylpyrrolidin-l- yl)methyl)benzoate (4.3 g, 9.6 mmol) and catalytic 10% Pd/C (430 mg) in MeOH (60 mL) was shaken under H ₂ ( 15 psi) for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a brown solid. MS: mlz = 416.9 (M + 1). ^! H NMR (300 MHz, CDCI ₃ ): δ 7.71 (d, J = 8.7 Hz, 1H), 7.42-7.20 (m, 7H), 6.81 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.7 Hz, 2H), 4.70 (dd, J = 15.3, 15.3 Hz, 2H), 3.86 (s, 3H), 3.80-3.74 (m, 1H), 3.60-3.34 (m, 2H), 2.87 (dd, J = 9.0, 16.8 Hz, 1H), 2.63 (dd, J = 8.7, 17.1 Hz, 1H).

Step D: (SVMethyl 4-((2-oxo-4-phenylpyrrolidin-l -yl)methyl)-3-(4-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenoxy)benzoate

A solution of B ₂ (Pin) ₂ (2.60 g, 10.1 mmol) and benzoyl peroxide (105 mg, 0.420 mmol) in MeCN (60 mL) was stirred at ambient temperature for 5 min, and then (S)-methyl 3-(4- aminophenoxy)-4-((2-oxo-4-phenylpyrrolidin-l-yl)methyl)benzo ate (3.50 g, 8.42 mmol) was added. The resulting mixture was stiired at 40 °C for 10 min before teri-BuONO (1.30 g, 12.6 mmol) was added dropwise. After addition, the reaction mixture was stirred at 40 °C for 18 h and then concentrated. The residue was dissolved in EtOAc (100 mL), washed with NH ₄ OH (5% aqueous solution, 30 mL x 3) and brine (30 mL), dried over Na ₂ S04, and concentrated. The residue was purified by column chromatography (S1O2, petroleum ether:EtOAc = 20: 1 to 2: 1) to give the title compound as a yellow solid. MS: mlz = 527.9 (M + 1). Ή NMR (300 MHz, CDCI ₃ ): δ 7.85-7.79 (m, 2H), 7.60-7.59 (m, 1H), 7.48-7.45 (m, 1H), 7.39-7.15 (m, 6H), 6.97- 6.92 (m, 2H), 4.69-4.56 (m, 2H), 3.88 (s, 3H), 3.72-3.66 (m, 1H), 3.53-3.40 (m, 1H), 3.37-3.31 (m, 1H), 2.87-2.78 (m, 1H), 2.61-2.53 (m, 1H), 1.36 (s, 9H), 1.30-1.26 (m, 3H). Step E: (SVMethyl 3-(4-(6-methylpyridazin-3-yl)phenoxy)-4-((2-oxo-4-phenylpyrr olidin-l- yl)methyl)benzoate

To a deoxygenated solution of (S)-methyl 4-((2-oxo-4-phenylpyrrolidin-l- yl)methyl)-3-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate (1.0 g, 1.9 mmol) in THF (15 mL) and H ₂ 0 (3 mL) was added 3-chloro-6-methylpyridazine (295 mg, 2.30 mmol), Pd(PPh ₃ ) ₄ (440 mg, 0.38 mmol), and Na ₂ C0 ₃ (402 mg, 3.80 mmol). The mixture was heated at 80 °C under N ₂ atmosphere for 16 h. The reaction was cooled and concentrated, and the residue was diluted with EtOAc (25 mL), and washed with H ₂ 0 (15 mL x 2). The organic phase was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column

chromatography (Si0 ₂ , petroleum ether: EtOAc = petroleum ether: EtOAc = 10: 1 to EtOAc) to give the title compound as a yellow solid. MS: mlz = 493.9 (M + 1). Ή NMR (300 MHz, CDC1 ₃ ): δ 7.99 (d, J = 9.0 Hz, 2H), 7.76 (d, J - 8.1 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.41-7.40 (m, 3H), 7.32 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 7.2 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.58 (dd, J = 15.0, 15.0Hz, 2H), 4.05 (dd, J = 7.2, 14.4Hz, lH), 3.81 (s, 3H), 3.66- 3.61 (m,lH), 3.47-3.43 (m, 1H), 3.29 (dd, J = 7.5, 9.3Hz, 1H), 2.69 (s, 3H), 2.49 (dd, J = 8.7, 17.1Hz, 1H).

Step F: (S)-3-(4-(6-Methylpyridazin-3-yl)phenoxy)-4-((2-oxo-4-phenyl pyrrolidin-l- vDmethvDbenzoic acid

LiOH (140 mg in 3 mL of H ₂ 0, 5.84 mmol) was added to a solution of (S)-m ethyl 3-(4-(6-methylpyridazin-3-yl)phenoxy)-4-((2-oxo-4-phenylpyrr olidin-l-yl)methyl)benzoate (600 mg, 1.17 mmol) in MeOH (6 mL) and the reaction was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (8 mL) and the pH adjusted to 4 with aqueous HC1 (IN) and the resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried over Na ₂ S0 ₄ , and concentrated to dryness to give the title compound as a yellow oil. MS: mlz = 479.9 (M + 1). Ή NMR (300 MHz, CDC1 ₃ ): δ 7.9-7.90 (m, 2H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.68-7.34 (m, 5H), 7.25-7.07 (m, 4H), 7.00 (d, J = 9.0 Hz, 2H), 4.59 (dd, J = 15.0, 15.0 Hz, 2H), 3.67-3.62 (m, 1H), 3.51-3.40 (m, 1H), 3.29 (dd, J = 7.2, 9.3Hz, 1H), 2.81-2.75 (m, 1H), 2.71 (s, 3H), 2.53 (dd, J = 8.7, 16.8 Hz, 1H).

3-(4-Chloro-3-fluorophenoxy)-4-((2-oxo-4-phenylimidazolid in-l-yl)methyl)benzoic acid Step A: Methyl 4-{((2-amino-2-phenylethyl)amino ^' )methyl|-3-(4-chloro-3- fluorophenoxy)benzoate and methyl 4- {((2-amino-l-phenylethyl)amino)methyl|-3-(4-chloro-3- fluorophenoxy)benzoate

To a solution of methyl 4-(bromomethyl)-3-(4-chloro-3-fluorophenoxy)benzoate

(1.0 g, 2.7 mmol) in THF (15 mL) was added l -phenylethane-l,2-diamine dihydrochloride (2.2 g, 10.7 mmol) and DIEA (2.0 mL, 13.4 mmol) at 23 °C. The resulting solution was stirred at 23

°C for 1 h and then concentrated to give a mixture of methyl 4-{((2-amino-2- phenylethyl)amino)methyl}-3-(4-chloro-3-fluorophenoxy)benzoa te and methyl 4-{((2-amino-l- phenylethyI)amino)methyl}-3-(4-chloro-3-fluorophenoxy)benzoa te as yellow oil, which was used directly without further purification. MS: mlz = 429.1 (M + 1).

Step B: Methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-4-phenylimidazolidin- l- yl)methyl)benzoate and methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-5-phenylimidazolidin- l- yl)methyl)benzoate

To a mixture of methyl 4-{((2-amino-2-phenylethyl)amino)methyl}-3-(4-chloro- 3-fluorophenoxy)benzoate and methyl 4-{((2-amino-l -phenylethyl)amino)methyl}-3-(4-chloro- 3-fluorophenoxy)benzoate (4.2 g, 9.8 mmol) in 1 ,4-dioxane (40 mL) was added CDI (2.60 g, 16.1 mmol) at 23 °C. The reaction mixture was heated at 80 °C for 12 h and then concentrated. The residue was diluted with H ₂ 0 (80 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 5: 1 to 1 :5) to give a mixture of methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-4- phenylimidazolidin-l-yl)methyl)benzoate and methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-5- phenylimidazolidin-l-yl)methyl)benzoate, which was separated by SFC (Chiralpak AS column, eluting with C0 ₂ /EtOH (0.2% NH ₄ OH) = 70/30) to give: Isomer 1 (regioisomer) methyl 3-(4- chloro-3-fluorophenoxy)-4-((2-oxo-5-phenylimidazolidin-l-yl) methyl)benzoate; Isomer 2 (title compound) methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-4-phenylimidazolidin- l- yl)methyl)benzoate, Isomer 3 (title compound) methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo- 4-phenylimidazolidin-l-yl)methyl)benzoate, and Isomer 4 (regioisomer) methyl 3-(4-chloro-3- fluorophenoxy)-4-((2-oxo-5-phenylimidazolidin-l-yl)methyl)be nzoate.

Isomer 2: MS: mlz = 455.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.84 (d J = 7.6 Hz, 1H), 7.60-7.49. (m, 2H), 7.39-7.26 (m, 6H), 6.73-6.65 (m, 2H), 4. 95 (s, 1H), 4.76-4.72 (m, 1H), 4.54 (d, J = 15.6 Hz, 1H), 4.42 (d, J = 15.6 Hz, lH), 3.88 (s, 3H), 3.75-3.70 (m, 1H), 3.17-3.14 (m, 1H). Step B: 3-(4-Chloro-3-fluorophenoxy)-4-((2-oxo-4-phenylimidazolidin- l-yl)methyl)benzoic acid

A solution of methyl 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-4- phenylimidazolidin-l-yl)methyl)benzoate (isomer 2) (50 mg, 0.28 mmol) and LiOH (17 mg, in 3 mL of water, 0.33 mmol) in MeOH (3 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was then adjusted to 4 with aqueous HC1 (IN). The resulting mixture was concentrated to give a mixture of 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-4- phenylimidazolidin-l-yl)methyl)benzoic acid and LiCl as a white solid. MS: mlz = 441.0 (M +

1).

INTERMEDIATE CI 7

(S)-3-(4-(5-IsopiOpyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)benzoic acid

Step A: (SVMethyl 3-methoxy-4-((4-methyl-2-oxopyrrolidin-l -yl)methyl)benzoate

To a solution of 4-methylpyrrolidin-2-one (574 mg, 5.79 mmol) in dry DMF (15 mL) was added NaH (255 mg, 6.37 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (1.50 g, 5.79 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 14 h and then quenched with saturated aqueous NH ₄ CI (10 mL). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with H ₂ 0 (30 mL x 3) and brine (30 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column

chromatography (Si0 ₂ , petroleum ether: EtOAc = 20: 1 to 3: 1) to give the title compound as a racemate, which was separated by SFC (Chiralpak AD column; eluting with C0 ₂ /MeOH (0.2% NH ₄ OH) = 75/25) to give the title compound as the first eluting isomer. MS (ESI) m/z: 278.1 [M + 1]. Ή NMR (400 MHz CDC1 ₃ ): δ 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.51 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.42-3.38 (m, 1H), 2.86-2.84 (m, 1H), 2.63- 2.57 (m, 1H), 2.47-2.38 (m, 1H), 2.10-2.04 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H).

Step B: (SVMethyl 3-hvdroxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate

A solution of BBr ₃ (0.65 mL, 6.9 mmol) in CH ₂ C1 ₂ (5 mL) was carefully added dropwise to a solution of (S)-methyl 3-methoxy-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate (637 mg, 2.30 mmol) in CH ₂ C1 ₂ (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 4 h, and then warmed to ambient temperature and stirred for 18 h. The reaction mixture was quenched carefully with MeOH (5 mL) and concentrated to dryness. The residue was dissolved in MeOH (20 mL) and heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, and then concentrated. The residue was diluted with CH ₂ C1 ₂ (25 mL), and washed with saturated aqueous NaHC0 ₃ (15 mL) and water (15 mL). The organic phase was dried over Na ₂ S0 ₄ and concentrated to give the title compound as a yellow oil. MS (ESI) m/z = 263.9 [M + 1]. Ή NMR (400 MHz CDC1 ₃ ): δ 9.35 (br s, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.49 (dd, J = 1.6, 8.0 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 4.35 (s, 2H), 3.88 (s, 3H), 3.60 (dd, J = 8.0, 9.6 Hz, 1H), 3.05 (dd, J = 6.0, 9.6 Hz, 1H), 2.61 (dd, J = 8.8, 16.8 Hz, 1H), 2.53-2.44 (m, 1H), 2.05 (dd, J = 6.8, 17.2 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H).

Step C: (SVMethyl 3-(4-( ^' 5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyiTolidin- 1 -yl)m ethyl )benzoate

To a solution of (S)-methyl 3-hydroxy-4-((4-methyl-2-oxopyiTolidin-l - yl)methyl)benzoate (600 mg, 2.28 mmol) in NMP (20 mL) was added 2-(4-bromophenyl)-5- isopropyl-l ,3,4-thiadiazole (774 mg, 2.73 mmol), 2,2,6, 6-tetramethyl-heptane-3, 5-dione (231 mg, 1.25 mmol), CuCl (248 mg, 2.51 mmol) and Cs ₂ C0 ₃ (2.23 g, 6.84 mmol). The reaction

- I l l - mixture was stin-ed at 80 °C under N ₂ atmosphere for 16 h. The mixture was cooled, diluted with water (40 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over Na ₂ S04, and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 50: 1 to 10: 1) to give the title compound as a yellow solid. MS (ESI) m/z: 466.1 [M + 1], Ή NMR (400 MHz, CD ₃ OD): δ 8.00 (d, J = 6.8 Hz, 2H), 7.90 (dd, J = 1.6, 8.0Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 6.8 Hz, 2H), 4.61 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 3.89 (s, 3H), 3.56-3.49 (m, 2H), 2.97 (m, 1H), 2.52-2.40 (m, 2H), 1.98 (dd, J = 6.4, 16.0Hz, 1H), 1.50 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 3H).

Step 4: (S)-3-(4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-

1 -vDmethypbenzoic acid

A solution of (S)-methyl 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-

4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (700 mg, 1.50 mmol) and LiOH (1 10 mg, in 15 mL of water, 4.5 mmol) in MeOH (45 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was then adjusted to 4 with aqueous HC1

(IN). The mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL x 3).

The combined organic phase was dried over Na ₂ S0 ₄ and concentrated to give the title compound as a yellow solid. MS (ESI) m/z: 452.0 [M + 1]. Ή NMR (400 MHz

CD ₃ OD): δ 8.00 (d, J = 6.8 Hz, 2H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 6.8 Hz, 2H), 4.61 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 3.58-3.48 (m, 2H), 2.97 (m, 1H), 2.52-2.39 (m, 2H), 2.00 (dd, J = 7.2, 17.2Hz, 1H), 1.50 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 3H).

(S)-3-(4-(5-Methyl-L3,4-thiadiazol-2-yl)phenoxy)-4-((4-me thyl-2-oxopyrrolidin-l- yl)methyl)benzoic acid Step A: ( S)-M ethyl 3 -(4-( 5-methyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyn lidin- 1 -yl methyl)benzoate

To a solution of (S)-methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)benzoate (600 mg, 2.28 mmol) in NMP (20 mL) was added 2-(4-bromophenyl)- 5-methyl-l ,3,4-thiadiazole (868 mg, 3.42 mmol), 2,2,6,6-tetramethyl-heptane-3,5-dione (0.260 mL, 1.25 mmol), CuCl (248 mg, 2.51 mmol) and Cs ₂ C0 ₃ (2.23 g, 6.84 mmol). The reaction mixture was heated at 80 °C under N ₂ atmosphere for 16 h. The mixture was cooled to ambient temperature, diluted with water (40 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over

Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 50: 1 to 10: 1) to give the title compound as a yellow oil. MS:

mlz = 438.0 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.95 (d, J = 7.2 Hz, 2H), 7.87 (dd, J = 1.6, 8.0 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 6.8

Hz, 2H), 4.57 (d, J = 15.2 Hz, 1H), 4.52 (d, J = 15.2 Hz, 1H), 3.86 (s, 3H), 3.48 (dd, J = 7.6, 9.6 Hz, lH), 2.94 (m, 1H), 2.80 (s, 3H), 2.50-2.36 (m, 2H), 1.95 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H).

Step B: (S)-3-(4-(5-Methyl-l,3,4-thiadiazol-2-vnphenoxy)-4-((4-methy l-2-oxopyrrolidin-l- vDmethvDbenzoic acid

A solution of (S)-methyl 3-(4-(5-methyl-l,3,4-thiadiazol-2-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (770 mg, 1.76 mmol) and LiOH (127 mg, in 15 mL of water, 5.28 mmol) in MeOH (30 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated, and the pH was then adjusted to 4 with aqueous HC1 (IN). The resulting mixture was concentrated to dryness to give the title compound as a yellow solid. MS: mlz = 424.0 (M + l ).

INTERMEDIATE C19

3-(4-(5-lsopropyl-l ,4-thiadiazol-2-yl)phenoxy)-4-(f2-oxopyrrolidin-l -yl)methyl)benzoic acid Step A: Methyl 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxopyrrolidin-l- vDmethvDbenzoate

2-(4-Iodophenyl)-5-isopropyl-l ,3,4-thiadiazole (3.5 g, 1 1 mmol) was added to a mixture of methyl 3-hydroxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate, (2.6 g, 1 1 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (1.2 mL, 5.8 mmol), and CS2CO3 (10.3 g, 31.8 mmol) in N- methyl-2-pyrrolidinone (40 mL). Copper(I) chloride (0.11 g, 1.06 mmol) was added and the reaction was heated at 80 °C and stirred for 3 h. The reaction was cooled to 23 °C, diluted with water (30 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography, eluting with a gradient of hexanes/ethyl acetate (100/0 to 40/60) to afford the title compound. MS: mlz = 452.1 (M + 1).

Step B: 3-(4-(5-Isopropyl-L3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxopyr rolidin-l- yl)methyl)benzoic acid

Aqueous NaOH (1M, 20.2 mL, 20.2 mmol) was added to a solution of methyl 3-(4-(5- isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxopyrrolidin-l-yl)methy l)benzoate (3.1 g, 6.8 mmol) in methanol (20 mL) and the resulting mixture was heated at 65 °C for 3 h. The reaction was cooled to 23 °C, aqueous IN HC1 (20.2 mL, 20.2 mmol) was added, and the mixture was concentrated. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford the title compound. MS: mlz = 438.1 (M + 1).

INTERMEDIATE C20

3-(4-(3-Methyl-l ,2,4-triazin-6-yl)phenoxy)-4-((2-oxopyrrolidin-l-yl)methyl)b enzoic acid Step A: Methyl 3-(4-(3-methyl-L2 ₁ 4-triazin-6-yl)phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoate

To a solution of 6-(4-bromophenyl)-3-methyl-l,2,4-triazine (0.78 g, 3.1 mmol) and methyl 3-hydroxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate (0.78 g, 3.1 mmol) in NMP

(100 mL) was added 2,2,6,6-tetramethylheptane-3,5-dione (0.32 g, 1.7 mmol), CuCl (0.34 g, 3.4 mmol) and CS2CO3 (3.1 g, 9.4 mmol). The resulting mixture was stirred at 90 °C for 18 h, and then cooled to 23 °C and filtered. The filtrate was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over Na ₂ S04, and concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V) : acetonitrile to give methyl 3-(4-(3- methyl-l ,2,4-triazin-6-yl)phenoxy)-4-((2-oxopyrrolidin-l-yl)methyl)b enzoate as a yellow solid. MS: m/z = 419.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 9.21 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.89 (dd, J = 1.6, 8.0Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 4.61 (s, 2H), 3.89 (s, 3H), 3.41 (t, J = 6.8 Hz, 2H),

Step B: 3-(4-(3-Methyl-L2^-triazin-6-yl)phenoxy)-4-((2-oxopyrrolidin -l-yl)methyl)benzoic acid

A mixture of methyl 3 -(4-(3 -methyl- 1, 2,4-triazin-6-yl)phenoxy)-4-((2- oxopyrrolidin-l-yl)methyl)benzoate (200 mg, 0.48 mmol) and LiOH (57 mg in 4 mL of water, 2.4 mmol) in MeOH (20 mL) was stirred at 23 °C for 18 h. The pH was then adjusted to 5 with aqueous HCl (2N) and then concentrated to afford 3 -(4-(3 -methyl- 1 , 2,4-triazin-6-yl)phenoxy)-4- ((2-oxopyrrolidin-l-yl)methyl)benzoic acid as a white solid. MS: m/z = 405.1 (M + 1).

INTERMEDIATE C21

(R)-3-(4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxoimidazolidin -l- yl)methyl)benzoic acid

Step A: Methyl 4-(((2-aminopropyl)amino)methyl)-3-methoxybenzoate

To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (30.0 g, 0.120 mol) in THF (360 mL) was added propane- 1 ,2-diamine (34.3 g, 0.460 mol) and DIEA (84.0 mL, 0.580 mol) at 23 °C. The resulting mixture was stirred at 23 °C for 1 h and then concentrated to give crude methyl 4-(((2-aminopropyl)amino)methyl)-3-methoxybenzoate as a yellow oil.

Step B: (R)-Methyl 3-methoxy-4-((4-methyl-2-oxoimidazolidin-l -yl)methyl)benzoate

To a solution of crude methyl 4-(((2-aminopropyl)amino)methyl)-3- methoxybenzoate (51 g) in dioxane (350 mL) was added CDI (108 g, 0.670 mol) at 23 °C. The resulting mixture was heated at 80 °C for 12 h and then concentrated. The residue was diluted with H ₂ 0 (600 mL) and extracted with EtOAc (400 mL x 3). The combined organic phase was washed with water (300 mL x 2), dried over Na?S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 5: 1 to 1 :5) to give racemic methyl 3-methoxy-4-((4-methyl-2-oxoimidazolidin-l -yl)methyl)benzoate (as well as the regioisomers), which was separated by SFC (Chiralpak AD column; eluting with C0 ₂ /MeOH (0.2% NH ₄ OH) = 75/30) to give (R)-methyl 3-methoxy-4-((4-methyl-2-oxoimidazolidin-l-yl)methyl)benzoat e (isomer 1) and (S)-methyl 3-methoxy-4-((4-methyl-2-oxoimidazolidin-l-yl)methyl)benzoat e (isomer 4). Isomer 1 : MS: m/z = 278.9 (M+l). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.63 (dd, J = 1.2, 7.8 Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 4.81 (s, 1H), 4.47 (d, J = 15.9 Hz, 1H), 4.40 (d, J = 15.9 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.83-3.74 (m, 1H), 3.47 (dd, J = 8.7, 8.7 Hz, 1H), 2.94-2.89 (m, 1H), 1.24 (d, J = 6.0 Hz, 3H).

Step C: (R)-Methyl 3-hvdroxy-4-((4-methyl-2-oxoimidazolidin-l-yl)methyl)benzoat e

To a solution of (R)-methyl 3-methoxy-4-((4-methyl-2-oxoimidazolidin-l - yl)methyl)benzoate (isomer 1, 2.3 g, 8.3 mmol) in CH ₂ C1 ₂ (30 mL) was added BBr ₃ (2.4 mL, 24.8 mmol) at -10 °C. The reaction mixture was stirred at 0 °C for 3 h and then quenched by adding MeOH (6 mL) dropwise. The resulting mixture was concentrated, the residue dissolved in MeOH (30 mL) and heated at reflux for 3 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc (30 mL). The organic phase was washed with aqueous NaHC0 ₃ (15 mL x 2) and brine (15 mL), dried over Na ₂ S0 ₄ , and concentrated to give (R)-methyl 3- hydroxy-4-((4-methyl-2-oxoimidazolidin-l-yl)methyl)benzoate as a white solid. MS: m/z =

264.9 (M+l). Ή NMR (300 MHz, CDC1 ₃ ): δ 9.34 (s, 1H), 7.53 (d, J - 1.5 Hz, 1H), 7.42 (dd, J = 1.2, 7.5Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 4.95 (s, 1H), 4.25 (d, J = 15.3 Hz, 1H), 4.18 (d, J = 15.3 Hz, 1H), 3.84 (s, 3H), 3.82-3.75 (m, 1H), 3.59-3.52 (m, 1H), 3.01-2.96 (m, 1H), 1.16 (d, J = 6.3 Hz, 3H).

Step D: (RVMethyl 3-(4-(5-isopropyl-1.3.4-thiadiazol-2-vnphenoxy)-4-((4-methyl -2- oxoimidazolidin- 1 -yl)methyl)benzoate

To a solution of (R)-methyl 3-hydroxy-4-((4-methyl-2-oxoimidazolidin-l - yl)methyl)benzoate (isomer 1 , 1.00 g, 3.78 mmol), 2-(4-bromophenyl)-5-isopropyl- 1 ,3,4- thiadiazole (1.29 g, 4.54 mmol), 2,2,6,6-tetramethyl-heptane-3, 5-dione (380 mg, 2.08 mmol), Cs ₂ C0 ₃ (2.47 g, 7.57 mmol) in NMP (20 mL) was added CuCl (450 mg, 4.54 mmol). The reaction mixture was stirred at 80 °C under N ₂ atmosphere for 16 h, cooled, and then diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 3: 1 to 1 : 1 to EtOAc) to give the title compound as yellow oil. MS: m/z = 467.1 (M + 1). 'HNMR (300 MHz, CD ₃ OD): δ 7.98 (d, J = 9.0 Hz, 2H), 7.89 (dd, J = 1.5, 7.8 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 9.0 Hz, 2H), 4.50 (d, J = 15.9 Hz, 1H), 4.38 (d, J = 15.9 Hz, 1H), 3.88 (s, 3H), 3.75-3.70 (m, 1H), 3.55-3.43 (m, 2H), 2.95 (dd, J = 6.6, 8.7 Hz, 1H), 1.49 (d, J = 6.9 Hz, 6H), 1.18 (d, J = 6.3 Hz, 3H).

Step E: (R)-3-(4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl ^' )phenoxy)-4-((4-methyl-2-oxoiniidazolidin-l- vDmethvDbenzoic acid

A mixture of (R)-m ethyl 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4- methyl-2-oxoimidazolidin-l-yl)methyl)benzoate (1.10 g, 2.36 mmol) and LiOH (170 mg, 7.07 mmol, in 5 mL of H ₂ 0) in MeOH (15 mL) was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (20 mL), concentrated, and the pH was adjusted to 4 with aqueous HC1 (IN). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated to give the title compound as a yellow solid. MS: m/z = 453.0 (M + 1). 'HNMR (300 MHz, CD ₃ OD): δ 7.99 (d, / = 8.7 Hz, 2H), 7.90 (dd, J = 1.5, 8.1Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 4.50 (d, J = 15.9 Hz, lH), 4.38 (d, J = 15.9 Hz, 1H), 3.77-3.68 (m, 1H), 3.56-3.46 (m, 2H), 2.95 (dd, J = 6.6, 8.7 Hz, 1H), 1.48 (d, J = 6.9 Hz, 6H), 1.18 (d, J = 6.0 Hz, 3H).

INTERMEDIATE C22

4-((5-Methyl-2-oxopyi-idin-l(2H)-yl)methyl)-3-(4-(6-methylpy ridazin-3-yl)phenoxy)benzoic acid Step 1 : Methyl 3-methoxy-4-((5-methyl-2-oxopyridin-l (2H)-yl)methyl)benzoate

To a solution of 5-methylpyridin-2(lH)-one (460 mg, 4.25 mmol) in DMF (10 mL) was added NaH (170 mg, 4.25 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (1.00 g, 3.86 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was stirred at 23 °C for 16 h and then quenched with saturated aqueous NH ₄ C1 (10 mL). The resulting mixture was diluted with water (30 mL) and extracted EtOAc (30 mL x 3). The combined organic phase was washed brine (50 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 _2> petroleum ethenEtOAc = 5: 1 to 1 :2) to give methyl 3-methoxy-4-((5-methyl-2-oxopyridin-l (2H)-yl)methyl)benzoate as a solid. MS: m/z = 287.9 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.59 (dd, J - 1.6, 8.0 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 2.8, 9.2 Hz, 1H), 7.10 (s, 1H), 6.55 (d, J = 9.2 Hz, 1H), 5.14 (s, 2H), 3.91 (d, J = 8.0 Hz, 6H), 2.05 (s, 3H).

Step 2: Methyl 3-hydroxy-4-((5-methyl-2-oxopyridin-l (2H)-yl)methyl)benzoate

To a solution of methyl 3-methoxy-4-((5-methyl-2-oxopyridin-l (2H)- yl)methyl)benzoate (840 mg, 2.92 mmol) in CH ₂ C1 ₂ (20 mL) was added BBr ₃ (2.20 g, 8.77 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 18 h, and then quenched by adding MeOH (10 mL) dropwise at 0 °C. The resulting mixture was concentrated, and the residue was dissolved in MeOH and heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature and concentrated. The residue was dissolved in EtOAc (50 mL), washed with NaHC0 ₃ (30 mL) and water (30 mL), dried over Na ₂ S0 ₄ , and concentrated to give methyl 3-hydroxy-4-((5-methyl-2-oxopyridin-l(2H)-yl)methyl)benzoate as a yellow solid. 1H NMR (400 MHz, CD ₃ OD): δ 7.56 (s, 1H), 7.44-7.41 (m, 3H), 7.19 (d, J = 10.8 Hz, 1H), 6.52 (d, J = 12.4 Hz, 1H), 5.15 (s, 2H), 3.85 (s, 3H), 2.10 (s, 3H).

Step 3: Methyl 4-( ^, r5-methyl-2-oxopyridin-l(2H)-yl)methyl)-3-(4-(6-methyl pyridazin-3- yl)phenoxy)benzoate

To a solution of methyl 3-hydroxy-4-((5-methyl-2-oxopyridin-l(2H)- yl)methyl)benzoate (730 mg, 2.67 mmol) in NMP (10 mL) was added 3-(4-iodophenyl)-6- methylpyridazine (950 mg, 3.21 mmol), 2,2,6,6-tetramethyl-heptane-3, 5-dione (270 mg, 1.47 mmol), CuCl (290 mg, 2.94 mmol) and Cs ₂ C0 ₃ (2.61 g, 8.01 mmol). The reaction mixture was heated at 90 °C under N ₂ atmosphere for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc = 5: 1 to 1 : 1) to give methyl 4-((5-methyl-2- oxopyridin-l (2H)-yl)methyl)-3-(4-(6-methylpyridazin-3-yl)phenoxy)benzoat e. MS: m/z = 442.1 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 8.06 (dd, J = 2.0, 6.8 Hz, 2H), 7.80 (dd, J = 2.4, 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.50 (d, J - 8.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.15 (dd, J = 2.4, 9.2 Hz, 1H), 7.13-7.12 (m, 1H), 7.08 (dd, J = 2.0, 6.8 Hz, 2H), 6.52 (d, J = 8.8 Hz, 1H), 5.21 (s, 2H), 3.85 (s, 3H), 2.77 (s, 3H), 1.96 (s, 3H).

Step 4: 4-( (5-Methyl-2-oxopyridin- 1 ( 2H)-yl)methyl)-3 -(4-( 6-methylpyridazin-3 - yl)phenoxV)benzoic acid A mixture of methyl 4-((5-methyl-2-oxopyi-idin-l (2H)-yl)methyl)-3-(4-(6- methylpyridazin-3-yl)phenoxy)benzoate (540 mg, 1.22 mmol) and LiOH (88.0 mg, 3.67 mmol, in 5 mL of H ₂ 0) in MeOH (5 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was adjusted to ~4 with aqueous HCl (IN). The resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic phase was dried over Na ₂ S04 and concentrated to give 4-((5-methyl-2-oxopyridin-l (2H)-yl)methyl)-3-(4-(6-methylpyridazin-3- yl)phenoxy)benzoic acid as a white solid. MS: m/z = 428.1 (M + 1).

INTERMEDIATE C23

3-(4-Carboxyphenoxy)-4-[(2-oxopyrrolidin-l-yl)methyl benzoic acid

Step A: Methyl 3-| ^" 4-(methoxycarbonyl)phenoxy1-4-[ ^' (2-oxopyrrolidin-l-yl)methyl]benzoate

To a solution of methyl 3-hydroxy-4-[(2-oxopyrrolidin-l-yl)methyl]benzoate (400 mg, 1.61 mmol) in NMP (4 mL, deoxygenated with N ₂ ) was added methyl 4-iodobenzoate (631 mg, 2.41 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (163 mg, 0.880 mmol), cesium carbonate (1.57 g, 4.81 mmol), and copper(I) chloride (175 mg, 1.77 mmol). The reaction mixture was heated at 80 °C for 3 h. The reaction was cooled and partitioned between 1 M aqueous NH ₄ CI solution (25 mL) and EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 x 25 mL), dried by MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes: EtOAc - 100:0 to 0: 100, to give the title compound. MS: m/z = 384.1 (M+l).

Step B: 3-(4-Carboxyphenoxy)-4-r(2-oxopyrrolidin-l-yl)methyllbenzoic acid

Aqueous NaOH (5M, 1.2 mL, 6.0 mmol) was added to a solution of methyl 3-[4- (methoxycarbonyl)phenoxy]-4-[(2-oxopyrrolidin-l-yl)methyl]be nzoate (360 mg, 0.95 mmol) in a mixture of THF (2 mL), methanol (1.2 mL), and water (1 mL). The reaction mixture was stirred at 23 °C for 3 h. Aqueous HCl (1M, 6.00 mL, 6.00 mmol) was added to adjust the pH to 4, the mixture was diluted with water (25 mL) and extracted with CH ₂ C1 ₂ (2 x 25 mL). The combined organic layers were dried by MgS0 ₄ , filtered, and concentrated to give the title compound. MS: m/z = 356.1 (M+l). INTERMEDIATE C24

(S)-3-(4-(6-(Difluoromethyl)pyridazin-3-yl)phenoxy)-4-(^^

vDmethvDbenzoic acid

Step A: 3-Chloro-6-vinylpyridazine

A mixture of 3,6-dichloropyridazine (70 g, 470 mmol), vinylboronic acid pinacol ester (72.4 g, 470 mmol), Pd(dppf)Cl ₂ (34 g, 47 mmol), and K ₂ C0 ₃ (193 g, 1.40 mol) in dioxane (700 mL) and water (280 mL) was heated at 80 °C under N ₂ atmosphere for 18 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (600 mL) and filtered. The filtrate was washed with brine (200 mL x 3), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether 100% ) to give 3-chloro-6- vinylpyridazine as a yellow oil. Ή NMR: (400 MHz, CDC1 ₃ ): δ 7.5 (d, J = 12 Hz, 1H), 7.35- 7.45 (m, 1H), 6.97 (dd, J = 17.6, 10.8 Hz, 1H), 6.17 (d, J = 17.6 Hz 1H) , 5.67 (d, J = 11 Hz, 1H).

Step B: 6-Chloropyridazine-3-carbaldehvde

Ozone was bubbled through a solution of 3-chloro-6-vinylpyridazine (10.9 g, 77.3 mmol) in dry CH ₂ C1 ₂ (200 mL) and MeOH (200 mL) at -78 °C until the reaction mixture turned blue. Oxygen was then bubbled into the mixture at -78 °C until the solution turned colorless.

The resulting mixture was carefully quenched by adding PPh ₃ (40.6 g, 155 mmol) in portions at 0

°C and then the mixture was stirred at 23 °C for 18 h. The reaction mixture was concentrated and the residue was purified by column chromatography (Si0 , petroleum ether: EtOAc = 100:

1) to give 6-chloropyridazine-3-carbaldehyde as a yellow solid. ^J H NMR: (400 MHz, CDC1 ₃ ): 5

10.29 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.1 1 (d, J = 8.6 Hz , 1H).

Step C: 3-Chloro-6-(difluoromethyl)pyridazine To a solution of 6-chloropyridazine-3-carbaldehyde (0.50 g, 3.5 mmol) in CH2CI2 (31 mL) was added DAST (0.55 mL, 4.5 mmol) at -20 °C. The reaction mixture warmed to 23 °C and stirred for 18 h. The reaction mixture was quenched with water (2 mL) at 0 °C, washed with brine (15 mL x 3), dried over Na ₂ S0 ₄ , and concentrated to give 3-chloro-6- (difluoromethyl)pyridazine as a yellow solid. Ή NMR: (400 MHz, CDC1 ₃ ): δ 7.74 (d, J = 12 Hz, 1H), 7.64 (d, J = 12 Hz, 1H), 6.70-7.00 (m, 1H).

Step D: (SVMethyl 4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-nitrophenoxy) benzoate

A mixture of (S)-methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate (3.3 g, 0.010 mol), 4-fluoro nitrobenzene (1.9 g, 0.010 mol) and K ₂ C0 ₃ (12.5 g, 0.100 mol) in DMF (20 mL) was stirred at 50 °C for 16 h. The reaction mixture was diluted with H ₂ 0 (60 mL) and extracted with EtOAc (60 mL x 2). The combined organic phase was washed with ¾0 (60 mL) and brine (60 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 40: 1, 10: 1, 8: 1) to give (S)-methyl 4-((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-3 -(4-nitrophenoxy)benzoate as a yellow solid. MS: m/z = 385.0 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.22 (d, J = 6.4 Hz, 2H), 7.91 (dd, J = 1.2, 8.0 Hz, 1H), 7.67 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 2H), 4.52 (d, J = 15.6 Hz, 1H), 4.44 (d, J = 15.6 Hz, 1H), 3.89 (s, 3H), 3.40-3.35 (m, 1H), 2.87-2.82 (m, 1H), 2.54-2.48 (m, 1H), 2.42-2.33 (m, 1H), 2.02-1.96 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H).

Step E: (SVMethyl 3-(4-aminophenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl) benzoate

A mixture of (S)-methyl 4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4- nitrophenoxy)benzoate (4.20 g, 10.9 mmol) and catalytic 10% Pd/C (300 mg) in methanol (50 mL) was shaken under H ₂ (15 psi) at 23 °C for 6 h. The reaction mixture was filtered and the filtrate was concentrated to give (S)-m ethyl 3-(4-aminophenoxy)-4-((4-methyl-2-oxopyrrolidin- l -yl)methyl)benzoate as colorless oil. MS: m/z = 354.9 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 8 7.67 (dd, J = 1.6, 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 6.84-6.76 (m, 4H), 4.60 (s, 2H), 3.82 (s, 3H), 3.55 (dd, J = 8.0, 9.6Hz, 1H), 3.02-2.86 (m, 1H), 2.62-2.53 (m, 1H), 2.47 (m, 1H), 2.05 (dd, J = 6.4, 16.4Hz, 1H), 1.10 (d, J = 6.8 Hz, 3H).

Step F: (SVMethyl 4-((4-methyl-2-oxopynOlidin-l -yl)methyl)-3-(4-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenoxy)benzoate

A solution of B ₂ (pin)2 (4.30 g, 16.9 mmol) and benzoyl peroxide (17 mg, 0.71 mmol) in MeCN (50 mL) was stirred at ambient temperature for 5 min and then (SVinethyl 3-(4- aminophenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzo ate (5.00 g, 14.1 mmol) was added. The resulting mixture was stirred at 30 °C for 10 min and then fcr/-BuONO (2.20 g, 21.6 mmol) was added dropwise. After addition, the reaction mixture was stirred at 30 °C for 18 h. The mixture was concentrated and the residue was dissolved in EtOAc (50 mL), washed with NH ₄ OH (5% aqueous solution, 20 mL x 3) and brine (30 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 5: 1 to 1 :2) to give (S)-methyl 4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate as colorless oil. MS: mix = 466.3 (M + 1). Ή NMR (300 MHz, CDCI ₃ ): 8 7.75-7.69 (m, 2H), 7.50-7.47 (m, 1H), 7.34-7.28 (m, 2H), 6.89-6.83 (m, 2H), 4.51-4.45 (m, 2H), 3.78 (s, 3H), 3.39-3.31 (m, 1H), 2.85-2.77 (m, 1H), 2.52- 2.44 (m, 1H), 2.35-2.30 (m, 1H), 1.99-1.91 (m, 1H), 1.27 (s, 12H), 1.00 (d, J = 6.8 Hz, 3H).

Step G: (SVMethyl 3-(4-(6-(difluoromethyl)pyridazin-3-yl)phenoxy)-4-((4-methyl -2- oxopyrrolidin- 1 -yl)methyl)benzoate

A mixture of (S)-methyl 4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)benzoate (700 mg, 1.1 mmol), 3-chloro-6- (difluoromethyl)pyridazine (210 mg, 1.26 mmol), Pd(PPh ₃ ) ₄ (180 mg, 0.16 mmol), and Na ₂ C0 ₃ (335 mg in 5 mL of H ₂ 0, 3.16 mmol) in THF (35 mL) was stirred at 80 °C under N ₂ atmosphere for 3 h. The reaction mixture was cooled, diluted with water (40 mL), and extracted with EtOAc (40 mL x 3). The combined organic phase was washed with water (50 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc = 5: 1 to 1 :3) to give (S)-methyl 3-(4-(6-(difluoromethyl)pyridazin-3- yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoat e as colorless oil. MS: m/z = 468.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.12 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 1H), 7.87-7.84 (m, 2H), 7.57-7.53 (m, 2H), 7.1 1-7.08 (m, 3H), 4.59 (d, J = 15.2 Hz, 1H), 4.53 (d, J = 15.6 Hz, 1H), 3.88 (s, 3H), 3.43 (dd, J = 8.0, 9.6 Hz, 1H), 2.90 (dd, J = 6.4, 9.6 Hz, 1H), 2.55 (dd, J = 8.4, 16.4 Hz, 1H), 2.43-2.39 (m, 1H), 2.05-2.01 (m, 1H), 1.08 (d, J - 6.8 Hz, 3H).

Step H: (S)-3-(4-(6-(Difluoromethyl)pyridazin-3-yl)phenoxy)-4-((4-me thyl-2-oxopyrrolidin-l - vPmethvPbenzoic acid

A mixture of (S)-methyl 3-(4-(6-(difluoromethyl)pyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l -yl)methyl)benzoate (220 mg, 0.47 mmol) and LiOH (34 mg in 2 mL of water, 1.41 mmol) in THF (6 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and then the pH was adjusted to 4 with aqueous HC1 (IN). The resulting mixture was diluted with EtOAc (10 mL), washed with water (5 mL x 3), dried over Na ₂ S0 ₄ , and concentrated to give (S)-3-(4-(6-(difluoromethyl)pyridazin-3-yl)phenoxy)-4-((4-me thyl-2- oxopyrrolidin-l-yl)methyl)benzoic acid as a white solid. MS: m/z = 454.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.34 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 1.6, 8.0Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.06 (t, J = 54.4 Hz, 1H), 4.62 (d, J = 15.2 Hz, 1H), 4.55 (d, J = 15.2 Hz, 1H), 3.51 (dd, J = 7.6, 9.6 Hz, 1H), 2.98-2.94 (m, 1H), 2.51-2.37 (m, 2H), 2.01-1.94 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H).

INTERMEDIATE C25

( _l S ^f )-4-((4-Methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(6-me thylpyridazin-3-yl)phenoxy)benzoic acid

Step A: (SVMethyl 4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(6-methylpyri dazin-3- yl)phenoxy)benzoate

A mixture of (S)-methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate (10.0 g, 38.0 mmol), 3-(4-iodophenyl)-6-methylpyridazine (13.5 g, 45.6 mmol), 2,2,6,6-tetramethyl-heptane-3, 5-dione (3.9 g, 21 mmol), Cs ₂ C0 ₃ (24.8 g, 76.0 mmol) and CuCl (4.5 g, 46 mmol) in NMP (200 mL) was stirred at 80 °C under N ₂ atmosphere for 16 h. After cooling to 23 °C, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , concentrated and the residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 3 : 1 to 1 : 1 to EtOAc) to give the title compound as a yellow solid. MS: m/z = 432.1 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 8.06 (dd, J = 2.0, 6.8 Hz, 2H), 7.83 (dd, J = 1.6, 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.42-7.38 (m, 2H), 7.07 (dd, J = 2.4, 7.2 Hz, 2H), 4.59 (d, J = 15.6 Hz, 1H), 4.53 (d, J = 15.6 Hz, 1H), 3.87 (s, 3H), 3.44 (dd, J = 8.0, 9.6 Hz, 1H), 2.90 (dd, J = 6.4, 9.6 Hz, 1H), 2.75 (s, 3H), 2.54 (dd, J = 8.4, 16.4 Hz, 1H), 2.45-2.36 (m, 1H), 2.05-1.99 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H). Step B: (S)-4-((4-Methyl-2-oxopyiTOlidin-l -yl)methvD-3-(4-( 6-methylpyridazin-3- yl~)phenoxy)benzoic acid

A mixture of (S)-Methyl 4-((4-methyl-2-oxopyiTolidin-l-yl)methyl)-3-(4-(6- methylpyridazin-3-yl)phenoxy)benzoate (3.20 g, 7.42 mmol) and LiOH (530 mg in 10 mL of H ₂ 0, 22.2 mmol) in MeOH (40 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was adjusted to 4 with aqueous HC1 (IN). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated to give the title compound. MS: m/z = 418.1 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 8.02 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.62 (d, J = 15.2 Hz, 1H), 4.55 (d, J = 15.2 Hz, 1H), 3.50-3.43 (m, 1H), 2.92 (dd, J = 6.4, 16.8 Hz, 1H), 2.78 (s, 3H), 2.60-2.54 (m, 1H), 2.46-2.38 (m, 1H), 2.08-2.02 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H).

INTERMEDIATE C26

2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxop yrrolidin-l-yl)methyl)benzoic acid Step A: Methyl 2-fluoro-5-methoxy-4-methylbenzoate

A suspension of 2-fluoro-5-methoxy-4-methylbenzoic acid (20 g, 1 10 mmol) and Amberlyst® 15 (5.0 g) in methanol (540 mL) was heated at 90 °C and stirred for 16 h. A catalytic amount of concentrated sulfuric acid (1 mL) was added to the mixture and heating was continued for 24 h. The mixture was cooled to 0 °C and excess solid sodium bicarbonate was added. The resulting suspension was stirred for 30 min and then filtered through a pad of Celite®. The filter cake was washed thoroughly with methanol (2 ^χ 200 mL). The filtrate was concentrated. The residue was diluted with water (200 mL) and the aqueous phase was extracted with ethyl ether (600 mL). The organic layer was washed with brine, dried over MgS0 ₄ , and concentrated to give the title compound. MS: m/z = 199.1. (M + 1).

Step B: Methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate

NBS (20.3 g, 1 14 mmol) and AIBN (1.70 g, 10.3 mmol) were added to a solution of methyl 2-fluoro-5-methoxy-4-methylbenzoate (20.5 g, 103 mmol) in benzene (500 mL). The resulting mixture was heated at reflux for 16 h, and then cooled to ambient temperature and concentrated. The residue was suspended in ethyl ether (500 mL) and filtered. The filtrate was concentrated, and the residue was reciystallized from ethyl acetate to give the title compound. MS: mlz = 277.0 (M + 1).

Step C: (S)-M ethyl 2-fluoro-5-methoxy-4-((4-methyl-2-oxopyrrolidin-l- vDmethyDbenzoate

To a solution of (S)-4-methylpyrrolidin-2-one (3.30 g, 33.4 mmol) in DMF (100 mL) was added NaH (1.20 g, 30.6 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-2- fluoro-5-methoxybenzoate (7.70 g, 27.8 mmol) in DMF (30 mL) was added dropwise.

The reaction mixture was stirred at 23 °C for 4 h and then quenched with saturated

aqueous NH ₄ C1 solution (50 mL). The resulting mixture was diluted with water (100 mL) and extracted EtOAc (100 mL x 3). The combined organic phase was washed with H ₂ 0 (100 mL x 2) and brine ( 100 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 10: 1 to 1 : 1) to give the title compound. MS: m/z = 296.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.36 (d, J = 5.6 Hz, 1H), 6.93 (d, J = 10.4 Hz, 1H), 4.51-4.45 (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.42 (dd, J = 8.0, 9.6 Hz, 1H), 2.88 (dd, J = 6.0, 10.0 Hz, 1H), 2.61 (dd, J = 8.8, 16.8 Hz, 1H), 2.48-2.43 (m, 1H), 2.08 (dd, J = 6.8, 16.4 Hz, 1H), 1.1 1 (d, J = 6.4 Hz, 3H).

Step D: (SVMethyl 2-fluoro-5-hvdroxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl) benzoate

To a solution of (S)-methyl 2-fluoro-5-methoxy-4-((4-methyl-2- oxopyrrolidin-l-yl)methyl)benzoate (5.6 g, 19 mmol) in CH ₂ C1 ₂ (50 mL) was added BBr ₃ (5.5 mL, 57 mmol) at -10 °C. The reaction mixture was stirred at 0 °C for 3 h and then quenched by dropwise addition of MeOH (10 mL) at 0 °C. The resulting mixture was concentrated, the residue dissolved in MeOH (50 mL), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated, the residue dissolved in EtOAc (80 mL), and the organic phase washed with aqueous NaHC0 ₃ (40 mL x 2) and brine (40 mL). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated to give the title compound as a white solid. MS: m/z = 282.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.46 (d, J = 6.4 Hz, 1H), 6.87 (d, J = 10.0 Hz, 1H), 4.35-4.27 (m, 2H), 3.90 (s, 3H), 3.61 (dd, J = 8.0, 9.6 Hz, 1H),. 3.07 (dd, J = 6.0, 9.6 Hz, 1H), 2.61 (dd, J = 8.8, 16.8 Hz, 1H), 2.57-2.44 (m, 1H), 2.08 (dd, J = 6.8, 16.8 Hz, lH), 1.1 1 (d, J = 6.8 Hz, 3H). Step E: (SVMethyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-meth yl-2- oxopyrrolidin- 1 -yPmethvDbenzoate

To a solution of (S)-methyl 2-fluoro-5-hydroxy-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)benzoate (2.5 g, 8.9 mmol), 3-(4-iodophenyl)-6-isopropylpyridazine (3.46 g, 10.7 mmol), 2,2,6,6-tetramethyl-heptane-3,5-dione (0.90 g, 4.9 mmol), and CS2CO3 (5.8 g, 18 mmol) in NMP (40 mL) was added CuCl (1.06 g, 10.7 mmol). The reaction mixture was stirred at 80 °C under N ₂ atmosphere for 16 h. The mixture was cooled to ambient temperature, diluted with water (100 mL), and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , concentrated, and purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 3: 1 to 1 : 1 to EtOAc) to give the title compound as a yellow solid. MS: m/z = 478.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.02 (d, J= 8.8 Hz, 2H), 7.72 (d, J= 8.8 Hz, 1H), 7.50 (d, J= 6.0 Hz, 1H), 7.37 (br s, 1H), 7.07 (d, J= 10.4 Hz, 1H), 6.98 (d, J= 8.8 Hz, 2H), 4.49 (d, J= 15.6 Hz, 1H), 4.42 (d, J= 15.6 Hz, 1H), 3.82 (s, 3H), 3.39 (dd, J= 8.0, 9.6 Hz, 1H), 3.34-3.30 (m, 1H), 2.86 (dd, J= 6.0, 9.6 Hz, 1H), 2.49 (m, 1H), 2.38-2.36 (m, 1H), 2.00-1.95 (m, 1H), 1.35 (d, J= 6.8 Hz, 6H), 1.04 (d, J= 6.8 Hz, 3H).

Step F: (S)-2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoic acid

A mixture of (S)-methyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-

((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (3.0 g, 6.3 mmol) and LiOH (451 mg in 10 mL of water, 18.9 mmol) in MeOH (30 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was adjusted to 4 with aqueous HCl (IN). The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined EtOAc phase was washed with water (40 mL x 2) and brine (40 mL), dried over Na ₂ S0 , and concentrated to give the title compound as a yellow oil. MS: m/z = 464.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.10-8.06 (m, 3H), 7.70 (d, J= 9.2 Hz, 1H), 7.53 (d, J= 6.4 Hz, 1H), 7.22 (d, J= 10.4 Hz, 1H), 7.1 1 (d, J= 8.8 Hz, 2H), 4.56 (d, J= 15.2 Hz, 1H), 4.48 (d, J= 15.6 Hz, 1H), 3.51 (dd, 7= 7.6, 9.6 Hz, 1H), 3.35-3.31 (m, 1H), 2.97 (dd, J= 6.0, 9.6 Hz, 1H), 2.50- 2.39 (m, 2H), 2.06-2.03 (m, 1H), 1.39 (d, J= 6.8 Hz, 6H), 1.06 (d, J = 6.8 Hz, 3H).

INTERMEDIATE C27

(S)-2-Fluoro-5-(4-(5-isopropyl-l J^ hiadiazol-2-yl ^" )phenoxy)-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoic acid

Step A: (SVMethyl 2-fluoro-5-(4-(5-isopropyl-l,3,4-thiadiazol-2-yl)phenoxy -4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate

Copper(I) chloride (0.030 g, 0.32 mmol) was added to a mixture of 2-(4-iodophenyl)-5- isopropyl-l ,3,4-thiadiazole, (1.2 g, 3.5 mmol), (S)-methyl 2-fluoro-5-hydroxy-4-((4-methyl-2- oxopyrrolidin-l-yl)methyl)benzoate, (0.90 g, 3.2 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione, (0.40 mL, 1.8 mmol), and Cs ₂ C03 _; (5.2 g, 16 mmol) in N-methyl-2-pyrrolidinone (15 mL) under N ₂ and the reaction mixture was heated at 90 °C for 3 h. The mixture was cooled to 23 °C and acidified with aqueous IN HCl. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with ice water (2 x 20 mL), and brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was dissolved in acetonitrile (10 mL) and K ₂ C0 ₃ (0.40 g, 2.9 mmol) and Mel (1.0 mL, 16 mmol) were added. The mixture was stirred for 3 days, concentrated, diluted with water (30 mL) and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column

chromatography, eluting with a gradient of hexanes/ethyl acetate (100/0 to 0/100) to give the title compound. MS: mlz = 484.2 (M + 1).

Step B: (S)-2-Fluoro-5-(4-(5-isopropyl-L3,4-thiadiazol-2-yl)phenoxy) -4-((4-methyl-2- oxopyrrolidin-1 -yl)methyl)benzoic acid

A mixture of aqueous NaOH (1M, 8.82 mL, 8.82 mmol) and (S)-methyl 2-fluoro- 5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)benzoate (1.06 g, 2.21 mmol) in methanol (10 mL) was stirred at 65 °C for 3 h. The mixture was cooled to 23 °C, aqueous HCl (1M, 8.82 mL, 8.82 mmol) was added, and then the mixture was concentrated. The reaction mixture was diluted with water (25 mL), and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford the title compound. MS: mlz = 470.2 (M + 1). INTERMEDIATE C28

2-Fluoro-5-(4-(5-isopiOpyl-L3,4-thiadiazol-2-yl)phenoxy)-4-( (2-oxopyridin-l(2H)- yl)methyl)benzoic acid

Step A: Methyl 2-fluoro-5-methoxy-4-((2-oxopyridin-K2H ^' )-yl ^' )methyl)benzoate

A solution of 2-hydroxypyridine (1.89 g, 19.8 mmol) in DMF (10 mL) was added to a suspension of sodium hydride (0.938 g, 23.5 mmol) in DMF (10 mL) at 0 °C. After 10 minutes, methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate, (5.0 g, 18 mmol) was added and the reaction was stirred for 2 h. The reaction was quenched with saturated aqueous ammonium chloride, diluted with water and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with ice water (3 x 20 mL) and brine (1 x 20 mL), dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of hexanes/ethyl acetate (85/15 to 0/100) to yield the title compound. MS: mlz = 292.1 (M + 1).

Step B: Methyl 2-fluoro-5-hvdroxy-4-((2-oxopyridin-l(2H ^' )-yl)methyl benzoate

Boron tribromide (34.0 mL, 34.0 mmol, 1M in CH ₂ CI ₂ ) was added to a solution of methyl 2-fluoro-5-methoxy-4-((2-oxopyridin-l(2H)-yl)methyl)benzoate (3.29 g, 1 1.3 mmol) in CH ₂ C1 ₂ (100 mL) at 0 °C. After 3 h, the reaction mixture was quenched with methanol (30 mL) at 0°C, and allowed to warm to 23 °C and stir for 18 h. The mixture was concentrated, diluted with water (30 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate to afford the title compound. MS: mlz = 278.1 (M + 1).

Step C: Methyl 2-fluoro-5-(4-(5-isopropyl-L3,4-thiadiazol-2-yl)phenoxy)-4-( (2-oxopyridin- 1 (2H)-yl)methyl)benzoate

Copper(I) chloride (0.090 g, 0.91 mmol) was added to a mixture of 2-(4-iodophenyl)-5- isopropyl-l,3,4-thiadiazole, (3.01 g, 9.13 mmol), methyl 2-fluoro-5-hydroxy-4-((2-oxopyridin- 1 (2H)-yl)methyl)benzoate, (2.53 g, 9.13 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (1.05 mL, 5.02 mmol), and Cs ₂ C0 ₃ (8.92 g, 27.4 mmol) in N-methyl-2-pyrrolidinone (50 mL). The reaction mixture was heated at 80 °C and stirred for 6 h. The mixture was cooled to 23 °C, diluted with water (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with ice water (2 x 20 mL) and brine (1x20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of hexanes/ethyl acetate (100/0 to 0/100) to yield the title compound. MS: mlz = 480.1 (M + 1). Step D: 2-Fluoro-5-(4-(5-isopropyl-L3,4-thiadiazol-2-yl)phenoxy)-4-( (2-oxopyridin-l(2H)- yl)mefhyl)benzoic acid

A mixture of aqueous NaOH (IN, 10.1 mL, 10.1 mmol) and methyl 2-fluoro-5-(4- (5-isopropyl-l,3,4-thiadiazol-2-yl)phenoxy)-4-((2-0xopyridin -l(2H)-yl)methyl)benzoate (1.62 g, 3.38 mmol) in MeOH (10 mL) was stirred at 65 °C for 2 h. The mixture was cooled to 23 °C, and the reaction was acidified with aqueous 1M HC1 (10.1 mL, 10.1 mmol) and concentrated. The residue was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford the title compound. MS: mlz = 466.1 (M + 1). INTERMEDIATE C29

4-((2,4-Dioxo-3,4-dihvdropyrimidin-l(2H)-yl)methyl)-3-(4-(6- methylpyridazin-3- yl)phenoxy)benzoic acid

Step A: Methyl 4-((2,4-dioxo-3,4-dihvdropyrimidin-l (2H)-yl)methyl)-3-methoxybenzoate

To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (1.5 g, 5.8 mmol) and pyrimidine-2,4(lH,3H)-dione (0.78 g, 6.9 mmol) in DMF (30 mL) was added K ₂ C0 ₃ (1.60 g, 1 1.6 mmol). The reaction mixture was stirred at 50 °C for 18 h, diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with water (50 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V) :

acetonitrile to give methyl 4-((2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)methyl)-3- methoxybenzoate as a white solid. MS (ESI) m/z: 290.8 [M + 1 ]. Ή NMR (400 MHz, DMSO- d6): δ 1 1.33 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 1.2, 7.6 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 5.90 (dd, J = 2.4, 8.0 Hz, 1H), 4.84 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H).

Step B: Methyl 4-((2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-3-hydrox ybenzoate

A solution of methyl 4-((2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-3- methoxybenzoate (0.90 g, 3.1 mmol) in a solution of aqueous 48% HBr (40 mL) was stirred at 100 °C for 40 h. The mixture was concentrated, the residue was dissolved in MeOH (25 mL), and then heated at reflux for 18 h. The reaction mixture was cooled and then concentrated to give methyl 4-((2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-3-hydrox ybenzoate as colorless oil. MS (ESI) m/z = 277.1 [M + 1]. Ή NMR (400 MHz, DMSO-d ₆ ): δ 1 1.30 (s, 1H), 10.29 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 1.6, 8.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 5.58 (dd, J = 2.4, 8.0 Hz, 1H), 4.81 (s, 2H), 3.80 (s, 3H).

Step C: Methyl 4-((2,4-dioxo-3,4-dihvdropyrimidin-l(2H -yl)methyl)-3-(4-(6-methylpyridazin-3- yl)phenoxy)benzoate

To a solution of methyl 4-((2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-3- hydroxybenzoate (180 mg, 0.65 mmol) in NMP (10 mL) was added 3-(4-iodophenyl)-6- methylpyridazine (347 mg, 1.17 mmol), 2,2,6,6-tetramethyl-heptane-3,5-dione (79 uL, 0.36 mmol), CuCl (71 mg, 0.72 mmol) and Cs ₂ C0 ₃ (640 mg, 1.95 mmol). The reaction mixture was heated at 80 °C under N ₂ atmosphere for 16 h. The reaction mixture was cooled, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with water (20 mL x 2), dried over Na ₂ S04, and concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V) : acetonitrile to give methyl 4-((2,4-dioxo-3,4-dihydropyrimidin-l (2H)- yl)methyl)-3-(4-(6-methylpyridazin-3-yl)phenoxy)benzoate as white solid. MS: m/z = 445.1 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 8.77 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.88 (dd, J = 1.6, 8.0 Hz, 1H), 7.62-7.57 (m, 3H), 7.17 (d, J = 8.8 Hz, 2H), 5.53 (d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 3.85 (s, 3H), 2.89 (s, 3H). Step D: 4-((2^-Dioxo-3,4-dihvdropyrimidin- l (2H)-yl)methyl)-3-f4-(6-methylpyridazin-3- yl)phenoxy)benzoic acid

A mixture of methyl 4-((2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)methyl)-3-(4- (6-memylpyridazin-3-yl)phenoxy)benzoate (60 mg, 0.13 mmol) in MeOH (10 mL) and aqueous LiOH (9.0 mg in 5 mL of water, 0.39 mmol) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was adjusted to 4 with aqueous HC1 (IN). The resulting mixture was concentrated to give 4-((2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)methyl)-3-(4-(6- methylpyridazin-3-yl)phenoxy)benzoic acid as a white solid.

4-(((S)-4-methyl-2-oxopyn-olidin-l -yl)methyl)-3-(4-(6-(2,2,2-trifluoro-l-hydroxyethyl)pyridazi n- 3-yl)phenoxy)benzoic acid

Step A: l-(6-Chloropyridazin-3-yl)-2,2,2-trifluoroethanol

To a solution of 6-chloropyridazine-3-carbaldehyde (2.50 g, 17.5 mmol) in THF (50 mL) was added dropwise TMSCF ₃ (3.74 g, 26.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then Bu ₄ NF (1 1.4 g, 43.8 mmol) in THF (25 mL) was added. The resulting mixture was stirred at 23 °C for 18 h, diluted with water (120 mL), and extracted with CH2CI2 (80 mL x 2). The combined organic phase was washed with brine (80 mL x 2), dried over Na ₂ S04, and concentrated. The residue was purified by column chromatography to give 1 - (6-chloropyridazin-3-yl)-2,2,2-trifluoroethanol as a yellow solid. Ή NMR: (400 MHz, CDC1 ₃ ): δ 7.45-7.70 (m, 2H), 5.17-5.35 (m, 1H), 4.81 (d, J = 7.2 Hz, 1 H). Step B: Methyl 4-(((S)-4-methyl-2-oxopyrrolidin-l -yl)methyl)-3-(4-(6-(2,2,2-trifluoro-l- hvdroxyethyl)pyridazin-3-yl)phenoxy)benzoate

A mixture of (S)-methyl 4-((4-methyl-2-oxopyrrolidin-l -yl)methyl)-3-(4-(4,4,5,5- tetramethyl- l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate (300 mg, 0.644 mmol), l -(6- chloropyridazin-3-yl)-2,2,2-trifluoroethanol ( 164 mg, 0.774 mmol), Pd(PPh ₃ ) ₄ (38 mg, 0.032 mmol), and aqueous Na ₂ C0 ₃ (137 mg in 3 mL of H ₂ 0, 1 .29 mmol) in THF ( 10 mL) was stirred at 80 °C under N ₂ atmosphere for 3 h. The reaction mixture was cooled, diluted with water (25 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 5: 1 to 1 :3, EtOAc) to give methyl 4-(((S)-4- methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(6-(2,2,2 rifluoro-l-hydroxyethyl)pyridazin-3- yl)phenoxy)benzoate as colorless oil. MS: m/z = 538.1 (M + 23). Ή NMR (400 MHz, CD ₃ OD): δ 8.27 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 1.6, 8.0 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 5.44 (q, J = 6.8 Hz, 1H), 4.63 (d, J = 15.2 Hz, 1H), 4.56 (d, J = 15.2 Hz, 1H), 3.88 (s, 3H), 3.52 (dd, J = 8.0, 10.0 Hz, 1H), 3.01 -2.96 (m, 1H), 2.53-2.38 (m, 2H), 2.02-1.96 (m, 1H), 1.08 (d, J = 6.4 Hz, 3H).

Step C : 4-( ((S)-4-Methyl-2-oxopyrrolidin- 1 -yl)methyl)-3 -i4-(6-(2.2.2-trifluoro- 1 - hvdroxyethyl)pyridazin-3 -yl)phenoxy)benzoic acid

A mixture of methyl 4-(((S)-4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(6-

(2,2,2-trifluoro-l-hydroxyethyl)pyridazin-3-yl)phenoxy)be nzoate (70 mg, 0.14 mmol) and LiOH (10 mg in 2 mL of water, 0.40 mmol) in THF (6 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was adjusted to 4 with aqueous HC1 (IN). The mixture was extracted with EtOAc (3 x 10 mL), and the combined organic phase was washed with brine, dried, and concentrated to give racemic 4-(((S)-4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(6- (2,2,2-trifluoro-l-hydroxyethyl)pyridazin-3-yl)phenoxy)benzo ic acid as a white solid. MS: m/z = 502.1 (M + 1).

INTERMEDIATE C31

3-(4-(6-Isopropylpyridazin-3-yl)phenoxy)-4-((2-oxo-L2-dihvdr opyridin-3-yl)methyl)benzoic acid

Step A: Methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate

To a solution of methyl 4-methyl-3-(4-nitrophenoxy)benzoate (10.0 g, 34.8 mmol) in chlorobenzene (100 mL) was added NBS (6.8 g, 38 mmol) and benzoyl peroxide (168 mg, 0.700 mmol). The resulting mixture was heated at 120 °C for 3 h, cooled, and then concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc = 75: 1 to 30: 1) to give methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate as a white solid. Ή NMR (400 MHz, CDClj _, ): δ 8.27-8.23 (m, 2H), 7.90 (dd, J = 1.6, 8.0 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.10-7.07 (m, 2H), 4.52 (s, 2H), 3.90 (s, 3H).

Step B: Methyl 4-((2-methoxypyridin-3-yl)methyl)-3-f4-nitrophenoxy)benzoate

A mixture of methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate (5.3 g, 15 mmol), (2-methoxypyridin-3-yl) boronic acid (2.7 g, 17 mmol), Pd(PPh ₃ ) ₄ (0.84 g, 0.73 mmol) and K ₂ C0 ₃ (6.0 g in 20 mL of water, 44 mmol) in dioxane (100 mL) was heated at 80 °C under N ₂ atmosphere for 18 h. The reaction mixture was cooled, concentrated, diluted with water (80 mL), and extracted with EtOAc (80 mL x 2). The combined organic phase was dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (S1O ₂ , petroleum ether: EtOAc = 50: 1 to 10: 1) to give methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4- nitrophenoxy)benzoate as a white solid. MS: m/z = 395.1 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 8.23-8.20 (m, 2H), 7.94 (dd, J = 1.6, 4.8 Hz, 1H), 7.90 (dd, J = 1.6, 8.0 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.42 (dd, J = 1.6, 7.2 Hz, 1H), 6.98-6.96 (m, 2H), 6.81 (dd, J = 5.2, 7.2 Hz, 1H), 3.98 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).

Step C: Methyl 3-(4-aminophenoxy)-4-((2-methoxypyridin-3-yl)methyl)benzoate

A mixture of methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4- nitrophenoxy)benzoate (4.9 g, 12.4 mmol) and catalytic 10% Pd/C (0.4 g) in EtOAc (100 mL) was shaken at 23 °C under H ₂ (15 psi) for 18 h. The reaction mixture was filtered through a pad of Celite ^® and the filtrate was concentrated to give methyl 3-(4-aminophenoxy)-4-((2- methoxypyridin-3-yl)methyl)benzoate as a white solid. MS: m/z = 365.2 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 7.98 (dd, J = 1.6, 4.8 Hz, 1H), 7.60 (dd, J = 1.6, 8.0 Hz, 1H), 7.44 (dd, J = 2.0, 7.2 Hz, 1H), 7.28-7.26 (m, 2H), 6.86 (dd, J = 5.2, 7.2 Hz, 1H), 6.76-6.69 (m, 4H), 4.02 (s, 2H), 3.91 (s, 3H), 3.80 (s, 3H).

Step D: Methyl 4-((2-methoxypyridin-3-yl methyl)-3-(4-(4.4.5,5-tetramethyl-l ,3,2-dioxaborolan- 2-yl)phenoxy)benzoate

To a solution of B ₂ Pin ₂ (3.10 g, 12.2 mmol) and benzoyl peroxide (123 mg, 0.510 mmol) in MeCN (100 mL) was added methyl 3-(4-aminophenoxy)-4-((2-methoxypyridin-3- yl)methyl)benzoate (3.70 g, 10.2 mmol). The reaction mixture was stirred at 23 °C for 10 min and then ieri-BuONO (1.60 g, 15.2 mmol) was added dropwise. After addition, the reaction mixture was stirred at 40 °C for 18 h. The mixture was concentrated and the residue was diluted with EtOAc (150 mL), washed with NH ₄ OH (5% aqueous solution, 80 mL x 3) and brine (80 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc = 50: 1 to 20: 1) to give methyl 4-((2-methoxypyridin-3-yl)methyl)- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)be nzoate as a white solid. MS (ESI) m/z: 476.2 [M + 1]. Ή NMR (400 MHz, CD ₃ OD): δ 7.97 (dd, J = 2.0, 4.8 Hz, 1H), 7.78 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (d, J - 8.4 Hz, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.43 (dd, J = 1.6, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.87-6.83 (m, 3H), 3.99 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 1.36 (s, 12H).

Step E: Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-methoxypyridi n-3- vDmethvDbenzoate

A mixture of methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)benzoate (1.0 g, 2.1 mmol), 3-chloro-6- isopropylpyridazine (0.50 g, 3.2 mmol), Pd(dppf)Cl ₂ (170 mg, 0.21 mmol) and K ₃ P0 ₄ -3H ₂ 0 (1.7 g, 6.3 mmol, in 5 mL water) in toluene (50 mL) was stirred at 70 °C under N ₂ atmosphere for 18 h. Then the reaction mixture was cooled, diluted with water (80 mL), and extracted with EtOAc (80 mL x 2). The combined organic phase was dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc = 10: 1 to 3: 1) to give methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-methoxypyridi n-3- yl)methyl)benzoate as a white solid. MS: m/z = 470.2 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 8.10-8.06 (m, 3H), 7.97 (dd, J = 1.6, 5.2 Hz, 1H), 7.81 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.47 (dd, J - 1.6, 7.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.05- 7.03 (m, 2H), 8.86 (dd, J = 5.2, 7.2 Hz, 1H), 4.04 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.34-3.33 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H).

Step F: Methyl 3-(4-(6-isopropylpyridazin-3-yl ^" )phenoxy)-4-((2-oxo-l,2-dihydropyridin-3- vDmethvDbenzoate

Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-methoxypyridi n-3- yl)methyl)benzoate (0.63 g, 1.3 mmol) was added to a solution of 48% aqueous HBr (50 mL) and the mixture was heated at reflux for 4 h. The mixture was cooled and concentrated. The residue was dissolved in MeOH (50 mL), heated at reflux for 18 h, cooled, and concentrated. The residue was diluted with aqueous NaHC0 ₃ (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , and concentrated to give methyl 3-(4-(6- isopiOpylpyridazin-3-yl)phenoxy)-4-((2-oxo-l ,2-dihydropyridin-3-yl)methyl)benzoate as a white solid. MS: m/z = 456.2 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 8.10-8.06 (m, 3H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.29 (dd, J = 1.6, 6.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.29 (dd, J = 6.8, 6.8 Hz, 1H ), 3.96 (s, 2H), 3.87 (s, 3H), 3.34-3.33 (m, 1H), 1.43 (d, J = 7.2 Hz, 6H).

Step G: 3-(4-f6-Isopropylpyridazin-3-yl)phenoxy)-4-f(2-oxo-l ,2-dihydropyridin-3- yl)methyl)benzoic acid

A mixture of methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxo-l ,2- dihydropyridin-3-yl)methyl)benzoate (100 mg, 0.22 mmol) and LiOH (26 mg, 1.1 mmol in 2 mL water) in MeOH (10 mL) was stirred at 23 °C for 18 h. The mixture was concentrated, and diluted with water (15 mL). The resulting mixture was acidified with aqueous HC1 (2N) to pH 5 and then extracted with EtOAc (20 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , and concentrated to give 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxo-l,2- dihydropyridin-3-yl)methyl)benzoic acid as a white solid. MS (ESI) m/z = 442.1 [M + 1]. Ή NMR (400 MHz, CD ₃ OD): δ 8.10-8.05 (m, 3H), 7.83 (dd, J - 1.6, 8.0 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.29 (dd, J = 2.0, 6.4 Hz, 1H), 7.1 1 -7.07 (m, 2H), 6.29 (dd, J = 6.8, 6.8 Hz, 1H ), 3.96 (s, 2H), 3.36-3.33 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

INTERMEDIATE C32

3-(4-(6-Isopropylpyridazin-3-yl)phenoxy)-4-((l-methyl-2-o xo-l ,2-dihvdropyridin-3- yl)methyl)benzoic acid

Step A: Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((l -methyl-2-oxo-l ,2- dihvdropyridin-3-yl)methyl)benzoate

To a solution of methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxo-l ,2- dihydropyridin-3-yl)methyl)benzoate (50 mg, 0.1 1 mmol) in DMF (5 mL) was added NaH (5.0 mg, 0.13 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min and then Mel (20 mg, 0.13 mmol) was added. The resulting mixture was stirred at 23 °C for 18 h, quenched with aqueous NH ₄ CI solution (15 mL), and extracted with EtOAc (10 mL x 2). The combined organic phase was dried over Na ₂ S04 and concentrate to give methyl 3-(4-(6- isopropylpyridazin-3-yl)phenoxy)-4-((l-methyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)benzoate as a yellow solid. MS: m/z = 470.1 (M+l). Ή NMR (400 MHz, CD ₃ OD): δ 8.07-8.03 (m, 3H), 7.80 (dd, J = 1.6, 8.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 2.0, 6.8 Hz, 1H), 7.26 (d, J = 6.8 Hz, 1H), 7.05-7.03 (m, 2H), 6.23 (dd, J = 6.8, 6.8 Hz, 1H ), 3.95 (s, 2H), 3.84 (s, 3H), 3.52 (s, 3H), 3.34-3.33 (m, 1H), 1.40 (d, J = 7.2 Hz, 6H).

Step B: 3-(4-(6-Isopropylpyridazin-3-yl)phenoxy)-4-((l-methyl-2-oxo- L2-dihvdropyridin-3- vDmethvDbenzoic acid

Methyl 3-(4-(6-isopropylpyridazin-3 -yl)phenoxy)-4-(( 1 -methyl-2-oxo- 1 ,2- dihydropyridin-3-yl)methyl)benzoate was treated with LiOH to afford the title compound as described above.

INTERMEDIATE C33

(S)-5-(4-(6-Ethylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-m ethyl-2-oxopyn'olidin-l- vDmethvDbenzoic acid

Step 1 : (S)-Methyl 5-(4-(6-ethylpyridazin-3-yl)phenoxy)-2-fluoi -4- ((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)benzoate

To a solution of 3-ethyl-6-(4-iodophenyl)pyridazine (1.0 g, 3.6 mmol), (S)-methyl 2-fluoro-5-hydroxy-4-((4-methyl-2-oxopyiToIidin-l -yl)methyl)benzoate (1.7 g, 5.4 mmol), 2,2,6,6-tetramethyl-heptane-3, 5-dione (0.40 mL, 2.0 mmol), Cs ₂ C0 ₃ (2.3 g, 7.2 mmol) in NMP (20 mL) was added CuCl (380 mg, 3.9 mmol). The reaction mixture was heated at 80 °C under N ₂ atmosphere for 16 h. The reaction was cooled, diluted with water (40 mL), and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ , concentrated and purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc = 3: 1 to EtOAc) to give (S)-methyl 5-(4-(6-ethylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-methyl-2 - oxopyiTolidin-l-yl)methyl)benzoate as a yellow solid. MS: m/z = 486.2 (M + 23). 'H NMR (300 MHz, CDC1 ₃ ): δ 8.00 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 6.3 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 10.5 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 4.51-4.37 (m, 2H), 3.81 (s, 3H), 3.41 -3.29 (m, 1H), 3.00 (q, J = 7.5 Hz, 2H), 2.84 (dd, J = 6.0, 9.6 Hz, 1H), 2.50 (dd, J = 8.7, 16.2 Hz, 1H), 2.42-2.28 (m, 1H), 2.02-1.93 (m, 1H), 1.35 (t, J = 7.5 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H).

Step 4: (S -5-(4-(6-Ethylpwidazin-3-yl)phenoxy)-2-fluoro-4-((4-methyl-2 -oxopyrrolidin-l- yl)methyl)benzoic acid

A mixture of (S)-methyl 5-(4-(6-ethylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (700 mg, 1.50 mmol) and LiOH (73 mg in 3 mL of water, 3.0 mmol) in THF (9 mL) was stirred at 20 °C for 16 h. The reaction mixture was acidified with aqueous HC1 (IN) until the pH was 4. The resulting mixture was concentrated to give (S)-5-(4-(6-ethylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-meth yl-2-oxopyrrolidin-l- yl)methyl)benzoic acid as a white solid. MS: m/z = 450.0 (M+l). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.03 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 10.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.59-4.47 (m, 2H), 3.48-3.44 (m, 1H), 3.11 (q, J = 7.6 Hz, 2H), 2.94-2.91 (m, 1H), 2.60-2.56 (m,lH), 2.49-2.38 (m, 1H), 2.10- 2.00 (m, 1H), 1.42 (t, J = 7.6 Hz, 3H), 1.10 (d, J = 7.6 Hz, 3H).

INTERMEDIATE C34

2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxop yrrolidin-l -yl)methyl ^' )benzoic acid Step A: Methyl 2-fluoro-5-methoxy-4-methylbenzoate

A suspension of 2-fluoro-5-methoxy-4-methylbenzoic acid (20 g, 1 10 mmol) and

Amberlyst® 15 (5.0 g) in methanol (540 mL) was heated at 90 °C for 16 h. A catalytic amount of concentrated sulfuric acid (1 mL) was added to the mixture and heating was continued for 24 h. The mixture was cooled to 0 °C and excess solid sodium bicarbonate added. The resulting suspension was stirred for 30 min then filtered through a pad of Celite®. The filter cake was washed thoroughly with methanol (2 x 200 mL). The filtrate was concentrated and the residue was diluted with water (200 mL) and extracted with ethyl ether (600 mL). The organic layer was washed with brine, dried over MgS0 ₄ , and concentrated to give the title compound. MS: mlz = 199.1 (M + 1). Step B: Methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate

NBS (20.3 g, 1 14 mmol) and AIBN (1.7 g, 10 mmol) were added to a solution of methyl 2-fluoro-5-methoxy-4-methylbenzoate (20.5 g, 103 mmol) in benzene (500 mL). The resulting mixture was heated at reflux and stirred for 16 h. The reaction mixture was cooled to 23 °C and concentrated. The residue was suspended in ethyl ether (500 mL) and filtered. The filtrate was concentrated and the residue recrystallized from ethyl acetate to give the title compound. MS: mlz = 277.0 (M + 1).

Step C: Methyl 2-fluoro-5-methoxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate

Sodium hydride (60% dispersion in mineral oil, 245 mg, 6.14 mmol) was added to a solution of 2-pyrrolidone (0.40 mL, 5.4 mmol) in THF (6 mL) at 0 °C. The resulting suspension was stirred at 0 °C for 25 min before a solution of methyl 4-(bromomethyl)-2-fluoro- 5-methoxybenzoate (1.00 g, 3.61 mmol) in THF (6 mL) was added. The resulting mixture was warmed to 23 °C, diluted with saturated aqueous sodium bicarbonate (120 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexanes initially, grading to 100% EtOAc) to give the title compound. MS: mlz = 282.1 (M + 1).

Step D: Methyl 2-fluoro-5-hvdiOxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate

Boron tribromide (0.33 mL, 3.5 mmol) was added to a solution of methyl 2- fluoro-5-methoxy-4-((2-oxopyrrolidin-l-yl)methyl)benzoate (495 mg, 1.76 mmol) in dichloroethane (18 mL) and the resulting mixture was stirred at 23 °C for 16 h. The mixture was quenched slowly with methanol (10 mL). The resulting acidic mixture was heated at 60 °C for 30 min then concentrated. The residue was diluted saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound as an off-white solid. MS: mlz = 268.1 (M + 1). Step E: Methyl 2-fluoro-5-(4-(6-isopiOpylpyridazin-3-yl)phenoxy)-4-((2-oxop yriOlidin-l- yl)methyl)benzoate

A mixture of copper(I) chloride (122 mg, 1.24 mmol), methyl 2-fluoro-5-hydroxy- 4-((2-oxopyiTOlidin-l-yl)methyl)benzoate (300 mg, 1.12 mmol), 3-(4-iodophenyl)-6- isopropylpyridazine (546 mg, 1.68 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.13 mL, 0.62 mmol), and cesium carbonate (841 mg, 2.58 mmol) in deoxygenated NMP (6 mL) was heated at 80 °C under argon for 36 h. The mixture was cooled to 23 °C and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexanes initially, grading to 100% EtOAc) to give the title compound. MS: mlz = 464.2 (M + 1).

Step F: 2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoic acid

A mixture of methyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2- oxopyrrolidin-l-yl)methyl)benzoate (270 mg, 0.59 mmol) and lithium hydroxide (28 mg, 1.2 mmol) in methanol (5 mL) was heated at 65 °C for 14 h. The mixture was cooled to 23 °C, neutralized with a solution of HC1 in ethyl ether (2 M, 0.60 mL, 1.2 mmol), and concentrated to afford the title compound. MS: mlz = 450.2 (M + 1).

INTERMEDIATE C35

2-Fluoro-5-(4-(5-isopropyl-L3 ₁ 4-thiadiazol-2-yl)phenoxy)-4-((2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)methyl)benzoic acid

Step A: Methyl 4-(dibromomethyl)-2-fluoro-5-methoxybenzoate

To a solution of methyl 2-fluoro-5-methoxy-4-methylbenzoate (15.0 g, 65.6 mmol) and NBS (33.6 g, 190 mmol) in chlorobenzene (200 mL) was added benzoyl peroxide (916 mg, 3.80 mmol) at 23 °C. The resulting mixture was heated at 130 °C for 7 h. The reaction mixture was concentrated, the residue was diluted with aqueous Na ₂ S0 ₃ (10%, 300 mL), and extracted with EtOAc (150 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography on silica gel (petroleum ethenEtOAc, 100: 1) to give the title compound as a yellow solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 7.64 (d, J = 10.8 Hz, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.01 (s, 1H), 3.93 (d, J = 6.4 Hz, 6H).

Step B: Methyl 2-fluoro-4-formyl-5-methoxybenzoate

To a solution of methyl 4-(dibromomethyl)-2-fluoro-5-methoxybenzoate (25.0 g, 70.2 mmol) in HOAc (200 mL) and H ₂ 0 (40 mL) was added KOAc (34.5 g, 0.350 mol). The resulting mixture was stirred at 70 °C for 16 h and then concentrated. The residue was diluted with EtOAc (200 mL), washed with saturated NaHC0 ₃ (100 mL x 2) and saturated aqueous sodium chloride solution (100 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc, 100: 1 to 50: 1) to give the title compound as a yellow solid. MS: m/z = 213.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 10.45 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 10.0 Hz, 1H), 7.53 (d, J = 5.2 Hz, 1H), 3.97 (d, J = 1.6 Hz, 6H).

Step C: Methyl 2-fluoro-4-formyl-5-hvdroxybenzoate

To a solution of methyl 2-fluoro-4-formyl-5-methoxybenzoate (10.0 g, 47.1 mmol) in anhydrous CH ₂ C1 ₂ (150 mL) was added BBr ₃ (9.00 mL, 94.3 mmol) dropwise at 0 °C. After addition, the reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was quenched by adding MeOH (20 mL) dropwise at 0 °C and concentrated. The residue was dissolved in MeOH (100 mL) and heated at reflux for 5 h. The mixture was concentrated, and the residue was diluted with EtOAc (200 mL), washed with saturated NaHC0 ₃ (100 mL x 2) and saturated aqueous sodium chloride solution (100 mL), dried over Na ₂ S0 ₄ , and concentrated to give the title compound as a yellow solid. MS: m/z = 199.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): 5 10.60 (br. s, 1H), 9.92 (s, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H).

Step D: Methyl 4-(dimethoxymethyl)-2-fluoro-5-hvdroxybenzoate

To a solution of methyl 2-fluoro-4-formyl-5-hydroxybenzoate (7.00 g, 35.3 mmol) in MeOH (100 mL) was added concentrated H S0 ₄ (113 uL, 2.10 mmol) and

trimethoxymethane (1 1.3 g, 0.1 10 mol). The reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 0 °C, poured into ice cold saturated aqueous NaHC0 ₃ solution (100 mL), and extracted with CH ₂ CI ₂ (80 mL x 3). The combined organic layer was washed with saturated aqueous sodium chloride solution (100 mL), dried over Na ₂ S04, and concentrated to give the title compound as a brown oil. MS: mlz = 245.1 (M + 1). 'NMR (400 MHz, CDC1 ₃ ): δ 7.90 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 14.8 Hz, 1H), 5.59 (s, 1H), 3.94 (s, 3H), 3.41 (s, 6H).

Step E: Methyl 4-(dimethoxymethyl)-2-fluoro-5-(4-(5-isopropyl-L3,4-thiadiaz ol-2- yl)phenoxy)benzoate

A mixture of methyl 4-(dimethoxymethyl)-2-fluoro-5-hydroxybenzoate (7.00 g, 28.7 mmol), 2-(4-iodophenyl)-5-isopropyl-l,3,4-thiadiazole (11.4 g, 34.4 mmol), 2,2,6,6- tetramethyl-heptane-3,5-dione (3.40 mL, 15.8 mmol), Cs ₂ C0 ₃ (18.7 g, 57.3 mmol), and CuCl (3.10 g, 31.5 mmol) in NMP (150 mL) was heated at 80 °C under N ₂ atmosphere for 16 h. The reaction mixture was cooled to 23 °C, diluted with water (200 mL), and extracted with EtOAc (150 mL x 3). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc, 10: 1 to 5: 1) to give the title compound as a brown oil. MS: mlz = 447.0 (M + 1). 1H NMR (400 MHz, CDCI ₃ ): δ 7.92 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 6.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 5.56 (s, 1H), 3.90 (s, 3H), 3.52-3.501 (m, 1H), 3.34 (s, 6H), 1.58 (s, 6H).

Step F: Methyl 2-fluoro-4-formyl-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)benzoate

To a solution of methyl 4-(dimethoxymethyl)-2-fluoro-5-(4-(5-isopropyl- 1,3,4- thiadiazol-2-yl)phenoxy)benzoate (8.60 g, 19.3 mmol) in acetone (90 mL) and H ₂ 0 (30 mL) was added 4-methylbenzenesulfonic acid (1.1 g, 5.8 mmol). The resulting mixture was stirred at 50 °C for 16 h and then concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with saturated aqueous NaHC0 ₃ (50 mL) and brine (50 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column cluomatography on silica gel (petroleum ether: EtOAc, 10: 1 to 5: 1) to give the title compound as a yellow solid. MS: mlz = 401.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 10.42 (d, J = 2.8 Hz, 1H), 7.99 (dd, J = 2.0, 7.2 Hz, 2H), 7.71 (d, J = 10.0 Hz, 1 H), 7.57 (d, J = 5.6 Hz, 1 H), 7.13 (dd, J = 2.0, 6.8 Hz, 2H), 3.92 (s, 3H), 3.55-3.48 (m, 1H), 1.49 (d, J = 6.8 Hz, 6H). Step G: Methyl 2-fluoro-4-(hvdroxymethyl)-5-(4-(5-isopropyl-l ₁ 3,4-thiadiazol-2- yl)phenoxy)benzoate

To a solution of methyl 2-fluoro-4-formyl-5-(4-(5-isopropyl-l,3,4-thiadiazol-2- yl)phenoxy)benzoate (7.00 g, 17.5 mmol) in anhydrous THF (100 mL) was added NaBH ₄ (661 mg, 17.5 mmol) at -10 °C. The reaction mixture was stirred at -10 °C for 1 h, poured into ice- water (100 mL), and extracted with EtOAc (80 mL x 3). The combined organic phase was washed with brine (80 mL), dried over Na ₂ SC>4, and concentrated to give the title compound. MS: mlz = 403.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.92 (d, J = 11.2 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 1 1.2 Hz, 2H), 4.77 (s, 2H), 3.90 (s, 3H), 3.53- 3.45 (m, 1H), 1.50 (d, J = 9.2 Hz, 6H).

Step H: Methyl 4-(bromomethyl)-2-fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2- yt)phenoxy)benzoate

To a solution of methyl 2-fluoro-4-(hydroxymethyl)-5-(4-(5-isopropyl-l,3,4- thiadiazol-2-yl)phenoxy)benzoate (800 mg, 2.0 mmol) in anhydrous CH ₂ C1 ₂ (30 mL) was added CBr ₄ (1.3 g, 5.0 mmol) and PPh ₃ (1.7 g, 5.0 mmol) at 0 °C. The reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with CH ₂ C1 ₂ (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over Na ₂ S0 ₄ , and concentrated to give the title compound. MS: mlz = 466.9 (M + 1). 1H NMR (400 MHz, CDC1 ₃ ): 5 7.94 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 6.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.07 (d, J = 8.0 Hz, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 3.52-3.47 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H).

Step I: Methyl 2-fluoro-5-(4-(5-isopropyl-l,3,4-thiadiazol-2-yl)phenoxy)-4- ((2-oxo-2,3-dihydro- 1 H-benzo| ^" d ^" |imidazol- 1 -vDmethvDbenzoate

Cesium carbonate (84 mg, 0.26 mmol) was added to a solution of 1H- benzo[d]imidazol-2(3H)-one (28 mg, 0.21 mmol) in DMF (1.7 mL) and the resulting mixture was stirred at 23 °C for 30 min. Methyl 4-(bromomethyl)-2-fluoro-5-(4-(5-isopr0pyl- 1 ,3,4- thiadiazol-2-yl)phenoxy)benzoate (80 mg, 0.17 mmol) was added and the mixture was heated at 60 °C for 2.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (70 mL). The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: mlz = 519.2 (M + 1).

Step J: 2-Fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxo-2,3-dihvdro-lH- benzordlimidazol-1 -vDmethvDbenzoic acid A mixture of methyl 2-fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4- ((2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l -yl)methyl)benzoate (85.0 mg, 0.164 mmol) and NaOH (1 M, 0.245 mL, 0.245 mmol) in methanol (1.50 mL) was stirred at 50 °C for 2 h. The reaction mixture was cooled to 23 °C, neutralized with aqueous HC1 (1 M, 0.145 mL,

0.145 mmol), and concentrated to yield the title compound. MS: mlz = 505.1 (M + 1).

INTERMEDIATE C36

Me

3 -(4-(5-Isopropyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-4-( 1 -(2-oxopyrrolidin- 1 -vDethvDbenzoic acid

Step A: Methyl 3-(benzyloxy)-4-(l-(2-oxopyrrolidin-l-yl)vinyl)benzoate

A mixture of methyl 3-(benzyloxy)-4-bromobenzoate (0.61 g, 1.9 mmol), N-vinyl- 2-pyrrolidone (2.0 mL, 19 mmol), X-Phos (90 mg, 0.19 mmol), N,N-dicyclohexylmethylamine (0.85 mL, 4.0 mmol), and palladium(II) acetate (19 mg, 0.090 mmol) in dioxane (16 mL) was heated at 100 °C under argon for 16 h. Additional X-Phos (75 mg, 0.16 mmol) and palladium(II) acetate (20 mg, 0.09 mmol) were added and the reaction was heated at 100 °C for 2 h. The reaction mixture was cooled to 23 °C, diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexanes initially, grading to 50% EtOAc in hexanes) to give the title compound. MS: mlz = 352.2 (M + 1).

Step B: Methyl 3 -hydro y-4-(l -(2-oxopyrrolidin- 1 -vDethvDbenzoate

A mixture of methyl 3-(benzyloxy)-4-(l -(2-oxopyrrolidin-l -yl)vinyl)benzoate (0.17 g, 0.40 mmol) and catalytic 10% Pd/C (0.1 1 g, 0.1 1 mmol) in methanol (10 mL) was stirred under ¾ (balloon) at 23 °C for 1 h. The reaction mixture was filtered through a pad of Celite and the filter cake was washed thoroughly with methanol. The filtrate was concentrated and the residue purified by silica gel chromatography (hexanes initially, grading to 100% EtOAc) to give the title compound. MS: m/z - 264.1 (M + 1). Step C: Methyl 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-( ^' l -( ^' 2-oxopyrrolidin-l - yl)ethyl)benzoate

A mixture of methyl 3-hydroxy-4-(l -(2-oxopynOlidin-l -yl)ethyl)benzoate (124 mg, 0.471 mmol), 2-(4-iodophenyl)-5-isopropyl-l ,3,4-thiadiazole (233 mg, 0.706 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (50 \iL, 0.26 mmol), cesium carbonate (353 mg, 1.08 mmol), and copper(I) chloride ( 1 mg, 0.52 mmol) in deoxygenated NMP (2.4 mL) was heated at 80 °C under argon for 48 h. The reaction mixture was cooled to 23 °C, and diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexanes initially, grading to 100% EtOAc, then 20% methanol in EtOAc) to give the title compound. MS: mlz = 466.2 (M + 1).

Step D: 3-(4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-f l-(2-oxopyrrolidin-l - yl)ethyl)benzoic acid

A mixture of methyl 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-(l -(2- oxopynOlidin-l -yl)ethyl)benzoate (140 mg, 0.30 mmol) and lithium hydroxide (21 mg,

0.90 mmol) in methanol (3 mL) was heated at 50 °C for 18 h. The reaction mixture was cooled to 23 °C, neutralized with a solution of HC1 in dioxane (4 M, 240 xL, 0.96 mmol), and concentrated to give the title compound. MS: m/z = 452.2 (M + 1).

INTERMEDIATE C37

2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxo- L2-dihvdiOpyridin-3- yl)methyl)benzoic acid Step A: Methyl 5-((/er -butyldiphenylsilyl)oxy)-2-fluoro-4-methylbenzoate ier<-Butylchlorodiphenylsilane (32.1 mL, 125 mmol) was added to a solution of methyl 2- fluoro-5-hydroxy-4-methylbenzoate (23.0 g, 125 mmol) and imidazole (17 g, 250 mmol) in dichloromethane (620 mL). The resulting mixture was stirred at 23 °C for 16 h. Additional tert- butylchlorodiphenylsilane (1.0 mL, 3.9 mmol) was added and the reaction mixture stirred for 2 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (300 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:EtOAc, 100:0 to 60:40, to give the title compound. MS: mlz = 423.2 (M + 1). Step B: Methyl 4-(bromomethyl)-5-((ter^-butyldiphenylsilyl)oxy)-2-fluoroben zoate

NBS (48.0 g, 270 mmol) and AIBN (2.20 g, 13.5 mmol) were added to a solution of methyl 5-((teri-butyldiphenylsilyl)oxy)-2-fluoro-4-methylbenzoate (38.0 g, 90.0 mmol) in benzene (450 mL). The resulting mixture was heated at reflux for 16 h. The reaction mixture was cooled to 23 °C and additional NBS, AIBN, and benzene were added. The reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled to 23 °C and concentrated to half its volume. The mixture was basified with 1M aqueous NaOH to pH 8. The mixture was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:EtOAc, 95:5 to 35:65, to give the title compound. MS: mlz = 501.0 (M + 1).

Step C: Methyl 5-((fer^-butyldiphenylsilyl)oxy)-2-fluoro-4-((2-methoxypyrid in-3- vDmethvDbenzoate

A solution of methyl 4-(bromomethyl)-5-((ieri-butyldiphenylsilyl)oxy)-2- fluorobenzoate (4.31 g, 8.60 mmol), (2-methoxypyridin-3-yl)boronic acid (1.58 g, 10.3 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l ,l ^, -biphenyl)[2-(2'-amino-l, - biphenyl)]palladium(II) (680 mg, 0.86 mmol), and aqueous potassium phosphate tribasic (2M, 8.60 mL, 17.2 mmol) in deoxygenated THF (22 mL) and water (2.2 mL) was heated at 60 °C in a sealed vessel for 2.5 h. The reaction mixture was cooled to 23 °C and partitioned between saturated aqueous ammonium chloride (50 mL) and ethyl acetate (500 mL). The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and

concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:EtOAc, 99: 1 to 65:35, to give the title compound. MS: mlz = 530.2 (M + 1). Step D: Methyl 2-fluoro-5-hvdroxy-4-((2-methoxypyridin-3-yl)methyl)benzoate

A solution of tetrabutylammonium fluoride in THF (1M, 5.89 mL, 5.89 mmol) was added dropwise to a solution of methyl 5-((ter/-butyldiphenylsilyl)oxy)-2-fluoro-4-((2- methoxypyridin-3-yl)methyl)benzoate (3.12 g, 5.89 mmol) in THF (39 mL) at 0 °C. The reaction mixture was allowed to warm to 23 °C over 1 h. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:EtOAc, 95:5 to 30:70, to give the title compound. MS: ml 2 = 292.0 (M + 1).

Step E: Methyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-meth oxypyridin-3- vDmethvDbenzoate

A mixture of copper(I) chloride (122 mg, 1.24 mmol), methyl 2-fluoro-5- hydroxy-4-((2-methoxypyridin-3-yl)methyl)benzoate (220 mg, 0.755 mmol), 3-(4-iodophenyl)-6- isopropylpyridazine (490 mg, 1.51 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (70.0 μί, 0.378 mmol), and cesium carbonate (738 mg, 2.26 mmol) in deoxygenated NMP (2 mL) was heated at 80 °C in a sealed vessel for 4 h. The mixture was cooled to 23 °C, diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:EtOAc, 98:2 to 35:65, to give the title compound. MS: ml 2 = 488.2 (M + 1).

Step F: 2-Fluoro-4-((2-hvdroxypyridin-3-yl)methyl)-5-(4-(6-isopropyl pyridazin-3- yl)phenoxy)benzoic acid

Methyl 2-fluoro-5-(4-(6-isopiOpylpyridazin-3-yl)phenoxy)-4-((2-meth oxypyridin-

3-yl)methyl)benzoate (84.0 mg, 0.172 mmol) was dissolved in aqueous HBr (48%, 0.195 mL, 1.72 mmol) and water (0.4 mL). The reaction mixture was heated at 100 °C for 4 h. The reaction mixture was cooled to 23 °C, neutralized with aqueous 3 M NaOH, and concentrated to provide the title compound. MS: ml 2 = 460.2 (M + 1).

INTERMEDIATE C38

2-Fluoro-5-(4-( ^' 5-isopropyl-l ,3,4-thiadiazol-2-yl ^> )phenoxy)-4-((6-methyl-3-oxo-2,3- dihvdropyridazin-4-yl)methyl)benzoic acid

To a solution of methyl 2-fluoro-4-fonnyl-5-(4-(5-isopropyl-l,3,4-thiadiazol-2- yl)phenoxy)benzoate (250 mg, 0.62 mmol) and 6-methyl-4,5-dihydropyridazin-3(2H)-one (74 mg, 0.66 mmol) in ethanol (6 mL) was added aqueous sodium hydroxide (3 M, 0.52 mL, 1.5 mmol). The reaction mixture was stirred at 23 °C for 16 h. The mixture was neutralized with an aqueous solution of HQ (3 M, 0.52 mL, 1.56 mmol) and concentrated to give the title compound as a yellow solid. MS: m/z = 481.1 (M + 1).

INTERMEDIATE C39

2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxop iperidin-l-yl)methyl)benzoic acid Step A: Methyl 2-fluoro-5-methoxy-4-((2-oxopiperidin-l-yl)methylbenzoate

To a solution of piperidin-2-one (72 mg, 0.72 mmol) in DMSO (4 mL) was added NaH (60% dispersion, 37 mg, 0.94 mmol). The reaction mixture was stirred at 23 °C for 10 min before addition of methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate (200 mg, 0.20 mmol) dissolved in DMSO (4 mL). The reaction mixture was stirred at 23 °C for 1 h and then excess Mel was added. After 30 min of stirring at 23 °C, the reaction mixture was quenched with water. The reaction mixture was then diluted with ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water (3x) and saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc, 100:0 to 10:90, to give the title compound. MS: mlz = 296.1 (M +

1)· Step B: Methyl 2-fluoro-5-hvdroxy-4-((2-oxopiperidin-l-yl)methylbenzoate

Methyl 2-fluoro-5-methoxy-4-((2-oxopiperidin-l-yl)methylbenzoate (60 mg, 0.20 mmol) was suspended in a solution of 36% HBr in AcOH (1.5 n L) in a sealed vial. The reaction was heated at 90 °C for 18 h and then cooled to 23 °C. The reaction mixture was then quenched with MeOH and concentrated. The residue was dissolved in MeOH (5 niL). Concentrated

H2SO4 (10 uL) was added and the mixture was heated at reflux for 18 h. After cooling to 23 °C, the mixture was concentrated. The residue was purified via reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: mlz - 282.1 (M+l).

Step C: Methyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxop iperidin-l- vDmethvDbenzoate

To a solution of methyl 2-fluoro-5-hydroxy-4-((2-oxopiperidin-l- yl)methylbenzoate (29 mg, 0.10 mmol) in deoxygenated NMP (2 mL) was added 3-(4- iodophenyl)-6-isopropylpyridazine (50 mg, 0.16 mmol), CuCl (11 mg, 0.1 1 mmol), 2,2,6,6- tetramethyl-3,5-heptanedione (15 mg, 0.080 mmol), and Cs ₂ C0 ₃ (170 mg, 0.52 mmol). The reaction mixture was heated at 90 °C for 18 h in a sealed vessel and then cooled to 23 °C. The reaction mixture was then diluted with ethyl acetate and the organic phase washed with saturated ammonium chloride (3x) and brine. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified via reverse-phase HPLC, eluting with 10% acetonitrile in water (0.05% NH ₄ OH used as a modifier) initially, grading to 95% acetonitrile in water to give the title compound. MS: mlz = 478.2 (M+l).

Step D: 2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxop iperidin-l- yl)methyl)benzoic acid

To a solution of methyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2- oxopiperidin-l-yl)methyl)benzoate (20 mg, 0.04 mmol) in 1 : 1 2-MeTHF/MeOH (1 mL) was added 2.8 M aqueous NaOH (0.02 mL, 0.06 mmol). The resulting mixture was stirred at 23 °C for 1 h, acidified with a solution of 2N HC1 in ether until pH ~ 3 and then the reaction mixture was concentrated to afford the title compound. MS: mlz = 464.2 (M + 1).

INTERMEDIATE C40

4-(Difluoro(2-oxo-l ,2-dihvdrop idin-3-yl)methyl)-3-(4-(6-isopropylpyridazin-3

yl)phenoxy)benzoic acid Step A: Methyl 4-methyl-3-(4-nitrophenoxy)benzoate

A mixture of methyl 3-hydroxy-4-methylbenzoate (40 g, 0.24 mol), l-fluoro-4- nitrobenzene (37.4 g, 0.270 mol), and K ₂ C0 ₃ (66.5 g, 0.480 mol) in DMF (350 mL) was stirred at 20 °C for 16 h. The mixture was filtered, the filtrate diluted with water (700 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (300 mL x 2) and saturated aqueous sodium chloride solution (300 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum

ether:EtOAc, 40: 1 to 15: 1) to give methyl 4-methyl-3-(4-nitrophenoxy)benzoate. MS: mlz = 288.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.21 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 9.2 Hz, 2H), 3.89 (s, 3H), 2.25 (s, 3H).

Step B: Methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate

To a solution of methyl 4-methyl-3-(4-nitrophenoxy)benzoate (59.6 g, 0.210 mol) and NBS (39.7 g, 0.230 mol) in chlorobenzene (500 mL) was added benzoyl peroxide (1 1 g, 0.040 mol). The resulting mixture was stirred at 130 °C for 16 h. The mixture was concentrated, the residue diluted with aqueous Na ₂ S0 ₃ (10%, 300 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (200 mL x 2) and saturated aqueous sodium chloride solution (200 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether: EtOAc, 50: 1 to 10: 1) to give methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate as a yellow solid. MS: mlz = 365.8 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.25 (d, J = 9.2 Hz, 2H), 7.90 (dd, J = 1.6, 8.0 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 9.2 Hz, 2H), 4.52 (s, 2H), 3.90 (s, 3H).

Step C: Methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4-nitrophenoxy)benzoate

A mixture of methyl 4-(bromomethyl)-3-(4-nitrophenoxy)benzoate (5.30 g, 14.5 mmol), (2-methoxypyridin-3-yl) boronic acid (2.70 g, 17.4 mmol), Pd(PPh ₃ ) ₄ (0.84 g, 0.73 mmol), and aqueous K2CO3 (6.00 g in 20 mL of water, 43.5 mmol) in dioxane (100 mL) was heated at 80 °C for 16 h. The mixture was concentrated, diluted with water (80 mL), and extracted with EtOAc (80 mL x 2). The combined organic layers were dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (SiO , petroleum

ethenEtOAc, 50: 1 to 10: 1) to give methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4- nitrophenoxy)benzoate as a white solid. MS: mlz = 395.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.23-8.20 (m, 2H), 7.94 (dd, J = 1.6, 4.8 Hz, 1H), 7.90 (dd, J = 1.6, 8.0 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.42 (dd, J = 1.6, 7.2 Hz, 1H), 6.98-6.96 (m, 2H), 6.81 (dd, J = 5.2, 7.2Hz, 1H), 3.98 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).

Step D: Methyl 3-(4-aminophenoxy -4-((2-methoxypyridin-3-yl)methyl)benzoate

A mixture of methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4- nitrophenoxy)benzoate (4.90 g, 12.4 mmol) and catalytic 10% Pd/C (0.4 g) in EtOAc (100 mL) was shaken at 23 °C under H ₂ (15 psi) for 16 h. The mixture was filtered through a pad of Celite ^® and the filtrate was concentrated to give methyl 3-(4-aminophenoxy)-4-((2- methoxypyridin-3-yl)methyl)benzoate as a white solid. MS: mlz = 365.2 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.98 (dd, J = 1.6, 4.8 Hz, 1H), 7.60 (dd, J = 1.6, 8.0 Hz, 1H), 7.44 (dd, J = 2.0, 7.2 Hz, 1H), 7.28-7.26 (m, 2H), 6.86 (dd, J = 5.2, 7.2 Hz, 1H), 6.76-6.69 (m, 4H), 4.02 (s, 2H), 3.91 (s, 3H), 3.80 (s, 3H).

Step E: Methyl 3-(4-iodophenoxy)-4-((2-methoxypyridin-3-yl)methyl)benzoate

To a suspension of methyl 3-(4-aminophenoxy)-4-((2-methoxypyridin-3- yl)methyl)benzoate (0.50 g, 1.4 mmol) in aqueous HC1 (IN, 8 mL) at 0 °C was added NaN0 ₂ (1 15 mg in 0.4 mL of H 0, 1.67 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h and before a solution of KI (0.46 g, 2.8 mmol) in H ₂ 0 (0.4 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 5 h and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated aqueous Na ₂ S0 ₃ (20 mL x 2) and saturated aqueous sodium chloride solution (20 mL), dried over Na ₂ S0 ₄ , and concentrated to give methyl 3-(4-iodophenoxy)-4-((2-methoxypyridin-3-yl)methyl)benzoate as a yellow oil. MS: mlz = 476.0 (M + 1). Ή NMR (300 MHz, CDCI ₃ ): δ 7.95 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 6.6 Hz, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 1.5 Hz, 1H), 7.23-7.20 (m, 2H), 6.71 -6.68 (m, 1H), 6.58 (d, J = 9.0 Hz, 2H), 3.87 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H).

Step F: Methyl 3-(4-iodophenoxy)-4-(2-methoxynicotinoyl)benzoate To a solution of methyl 3-(4-iodophenoxy)-4-((2-methoxypyridin-3- yl)methyl)benzoate (600 mg, 1.26 mmol) in acetone (30 raL) was added Mn0 ₄ (2.00 g, 12.6 mmol). The suspension was heated at reflux for 2 d and then filtered. The filtrate was concentrated and the residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc, 20: 1 to 3: 1) to give methyl 3-(4-iodophenoxy)-4-(2-methoxynicotinoyl)benzoate as colorless oil. MS: mlz = 490.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.24-8.23 (m, 1H), 7.89 (dd, J = 1.6, 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 6.8 Hz, 2H), 6.91 (dd, J = 4.8, 7.6 Hz, 1H), 6.43 (d, J = 6.8 Hz, 2H), 3.91 (s, 3H), 3.76 (s, 3H).

Step G: Methyl 4-(difluoro(2-methoxypyridin-3-yl methyl)-3-(4-iodophenoxy)benzoate

A mixture of methyl 3-(4-iodophenoxy)-4-(2-methoxynicotinoyl)benzoate (301 mg, 0.615 mmol) in excess DAST (5 mL) was heated at 50 °C for 2 d. The reaction mixture was cooled to 23 °C and added dropwise to ice-water (30 mL). The mixture was basified with saturated aqueous Na ₂ C0 ₃ solution to pH -10 and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with aqueous HC1 (2N, 30 mL) and water (30 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc, 20: 1 to 10: 1) to give methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)- 3-(4-iodophenoxy)benzoate as brown oil. MS: mlz = 512.0 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.13 (d, J = 4.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.92-7.90 (m, 2H), 7.50 (dd, J = 2.0, 6.8 Hz, 2H), 7.45 (s, 1H), 6.85-6.83 (m, 1H), 6.39 (dd, J = 2.0, 6.4 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 3H).

Step H: Methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)-3-(4-(4,4,5,5-tetr amethyl-L3,2- dioxaborolan-2-yl)phenoxy)benzoate

A mixture of methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)-3-(4- iodophenoxy)benzoate (150 mg, 0.29 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi( 1 ,3,2- dioxaborolane) (220 mg, 0.88 mmol), KOAc (86 mg, 0.88 mmol), and Pd(dppf)Cl ₂ (50 mg, 0.06 mmol) in DMSO (8 mL) was heated at 80 °C under N ₂ atmosphere for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and the residue purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc, 5: 1) to give methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)-3-(4- (4,4,5, 5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate as colorless oil. MS: mlz = 512.2 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.09 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92-7.91 (m, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.47 (s, 1H), 6.82 (dd, J = 4.8, 7.6 Hz, 1H), 6.60 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.77 (s, 3H), 1.33 (s, 12H).

Step I: Methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)-3-(4-(6-isopropylp yridazin-3- yl)phenoxy)benzoate

To a solution of methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)benzoate (110 mg, 0.22 mmol) in THF/H ₂ 0 (4: 1, 10 mL) was added 3-chloro-6-isopropylpyridazine (40 mg, 0.26 mmol), Na ₂ C0 ₃ (46 mg, 0.43 mmol), and Pd(PPh ₃ ) ₄ (30 mg, 0.02 mmol). The resulting solution was heated at reflux under N ₂ atmosphere for 12 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc, 10: 1 to 5: 1) to give methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)-3-(4-(6-isopropylp yridazin-3- yl)phenoxy)benzoate as colorless oil. MS: mlz = 506.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.10 (d, J = 4.0 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.95-7.93 (m, 4H), 7.71 (d, J = 9.2 Hz, 1H), 7.55 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.83-6.81 (m, 1H), 6.73 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.38-3.32 (m, 1H), 1.41 (d, J = 7.2 Hz, 6H).

Step J: 4-(Difluoro(2-oxo-L2-dihvdropyridin-3-yl)methyl ^' )-3-(4-(6-isopropylpyridazin-3- yl)phenoxy)benzoic acid

A mixture of methyl 4-(difluoro(2-methoxypyridin-3-yl)methyl)-3-(4-(6- isopropylpyridazin-3-yl)phenoxy)benzoate (70 mg, 0.14 mmol) in aqueous 48% HBr (3 mL) was stirred at 23 °C for 20 h. The reaction mixture was concentrated and the residue purified by prep-HPLC (Column: Phenomenex Synergi max-RP; 95:5 to 5:95 water (0.075% TFA, V/V):acetonitrile) to give 4-(difluoro(2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3-(4-(6- isopropylpyridazin-3-yl)phenoxy)benzoic acid as colorless oil. MS: mlz = 478.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.46 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 8.06-7.97 (m, 4H), 7.94 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.34 (d, J = 5.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.28 (dd, J = 6.8, 6.8 Hz, 1H ), 3.44-3.34 (m, 1H), 1.45 (d, J = 6.8 Hz, 6H).

INTERMEDIATE C41

(»SV5-(4-(6-Cvclopentylpyridazin-3-yl)phenox

yl)methyl)benzoic acid Step A : 3-Chloro-6-(cvclopent-l-en-l-yl)pyridazine

A mixture of 2-(cyclopent-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborol ane (1.04 g, 5.37 mmol), 3,6-dichloropyridazine (800 mg, 5.37 mmol), Pd(dppf)Cl ₂ (440 mg, 0.54 mmol) and Κ ₃ Ρ0 ·3Η ₂ 0 (2.86 g, 10.7 mmol) in toluene/H ₂ 0 (10: 1, 22 mL) was stirred at 100 °C under N ₂ atmosphere for 16 h. The reaction mixture was cooled to 23 °C, diluted with H ₂ 0 (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with H ₂ 0 (30 mL) and saturated aqueous sodium chloride solution (30 mL), dried over Na ₂ S0 , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc, 20: 1) to give 3-chloro-6-(cyclopent-l-en-l-yl)pyridazine as yellow solid. MS: m/z = 180.9 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.58 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.69-6.68 (m, 1H), 2.94-2.92 (m, 2H), 2.64-2.63 (m, 2H), 2.11 -2.07 (m, 2H).

Step B : 3-Chloro-6-cvclopentylpyridazine

A mixture of 3-chloro-6-(cyclopent-l-en-l-yl)pyridazine (600 mg, 3.32 mmol) and Rh(PPh ₃ )Cl (180 mg, 0.19 mmol) in MeOH (400 mL) was stirred under H ₂ (balloon) at 30 °C for 18 h. The reaction mixture was filtered and the filtrate concentrated to give 3-chloro-6- cyclopentylpyridazine as yellow solid. MS: m/z = 182.9 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 7.41 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 3.41-3.34 (m, 1H), 2.21-2.1 1 (m, 2H), 1.89- 1.70 (m, 6H). Step C : (SVMethyl 5-(4-(6-cvclopentylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-me thyl-2- oxopyrrolidin-l -yl)methyl)benzoate

A mixture of (S)-methyl 2-fluoro-4-((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-5-(4- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate (400 mg, 0.83 mmol), 3-chloro- 6-cyclopentylpyridazine (181 mg, 0.990 mmol), Pd(PPh ₃ ) ₄ (143 mg, 0.120 mmol) and Na ₂ C0 ₃ (219 mg, 2.07 mmol) in 5: 1 THF/H ₂ 0 (30 mL) was heated at reflux under N ₂ atmosphere for 18 h. The reaction mixture was cooled to 23 °C, diluted with H ₂ 0 (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with H ₂ 0 (30 mL) and saturated aqueous sodium chloride solution (30 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc, 5: 1 to 1 : 1) to give (S)- methyl 5-(4-(6-cyclopentylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-me thyl-2-oxopyrrolidin-l- yl)methyl)benzoate as off-white solid. MS: m/z = 504.1(M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.10-8.06 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.59-7.53 (m, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 10.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.56 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 3.90 (s, 3H), 3.48-3.40 (m, 2H), 2.92 (dd, J = 6.0, 9.6 Hz, 1H), 2.57 (dd, J = 8.8, 16.6 Hz, 1H), 2.44 (m, 1H), 2.25-2.16 (m, 2H), 2.08 (m, 1H), 1.96 - 1.84 (m, 4H), 1.83 - 1.76 (m, 2H), 1.1 1 (d, J = 6.8 Hz, 3H).

Step D : (S)-5-(4-(6-Cyclopentylpyridazin-3-yl ^' )phenoxy)-2-fluoro-4-((4-methyl-2-oxopyrrolidin- l-yf)methyl)benzoic acid

A mixture of (S)-methyl 5-(4-(6-cyclopentylpyridazin-3-yl)phenoxy)-2-fluoro-4-

((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (200 mg, 0.40 mmol) and LiOH (28.5 mg in 5 mL of H ₂ 0, 1.20 mmol) in MeOH (5 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH adjusted to 4 with aqueous HCl (1 N). The resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated to give (S)-5-(4-(6-cyclopentylpyridazin-3-yl)phenoxy)-2-fluoro-4-(( 4-methyl-2- oxopyrrolidin-l-yl)methyl)benzoic acid as a white solid. MS: m/z = 490.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.16-8.08 (m, 3H), 7.73 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 6.0 Hz, 1H), 7.25 (d, J = 10.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 4.59 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 15.6 Hz, 1H), 3.56-3.45 (m, 2H), 3.02 (m, 1H), 2.51-2.47 (m, 2H), 2.21 (m, 1H), 2.03-1.84 (m, 8H), 1.25 (d, J = 7.2Hz, 3H).

INTERMEDIATE C42

(S)-2-Fluoro-5-(4-(6-(2-fluoropropan-2-yl)pyridazin-3-yl)phe noxy)-4-((4-methyl-2- oxopyrrolidin- 1 -vDmethyl)benzoic acid Step A: Methyl 5-(4-chlorophenoxy)-2-fluoro-4-methylbenzoate

To a solution of methyl 2-fluoro-5-hydroxy-4-methylbenzoate (16.5 g, 89.6 mmol) and 1 -chloro-4-iodobenzene (25.6 g, 107 mmol) in NMP (300 mL) was added 2,2,6,6- tetramethylheptane-3,5-dione (9.10 g, 49.3 mmol), CuCl (9.70 g, 98.5 mmol), and Cs ₂ C0 ₃ (58.4 g, 179 mmol). The resulting mixture was heated at 90 °C under N ₂ atmosphere for 16 h, cooled to 23 °C, and filtered. The filtrate was concentrated. The residue was diluted with EtOAc (150 mL), the organic phase washed with H ₂ 0 (100 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography silica gel (petroleum ethenEtOAc, 100: 1 then 50: 1 then 10: 1) to give methyl 5-(4-chlorophenoxy)-2-fluoro-4-methylbenzoate as oil. MS: m/z = 294.9 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.45 (d J = 6.0 Hz, 1H), 7.27 (dd, J = 2.0 , 6.8 Hz, 2H), 7.05 (d, J = 10.8 Hz, 1H), 6.82 (dd, J = 2.0, 6.8 Hz, 2H), 3.88 (s, 3H), 2.25 (s, 3H).

Step B: Methyl 4-(bromomethyl)-5-(4-chlorophenoxy)-2-fluorobenzoate

To a solution of methyl 5-(4-chlorophenoxy)-2-fluoro-4-methylbenzoate (10.7 g,

36.3 mmol) in chlorobenzene (30 mL) was added NBS (6.50 g, 36.3 mmol) and benzoyl peroxide (175 mg, 0.726 mmol). The resulting mixture was heated at reflux for 4 h and then concentrated. The residue was diluted with EtOAc (100 mL), washed with saturated aqueous sodium chloride solution (100 mL x 2), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc, 200: 1 to 50: 1) to give methyl 4-(bromomethyl)-5-(4-chlorophenoxy)-2-fluorobenzoate as a white solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 7.38 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 10.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 4.49 (s, 2H), 3.88 (s, 3H). Step C: (SVMethyl 5-(4-chlorophenoxy)-2-fluoro-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate

To a solution of (S)-4-methylpyrrolidin-2-one (2.2 g, 22 mmol) in DMF (30 mL) at 0 °C was added NaH (0.96 g, 24 mmol, 60% in mineral oil). The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-5-(4-chlorophenoxy)-2- fluorobenzoate (9.0 g, 24 mmol) in of DMF (50 mL) was added dropwise. The resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with saturated aqueous NH ₄ C1 (200 mL) and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (250 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column cliromatography (Si0 ₂ , petroleum ethenEtOAc, 10: 1 to 2: 1) to give (S)-methyl 5-(4-chlorophenoxy)-2-fluoro-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)benzoate as a yellow solid. Ή NMR (400 MHz, CDC1 ₃ ): δ 7.44 (d, J = 6.0 Hz, 1H), 7.30-7.26 (m, 2H), 7.26 (d, J = 10.4 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.54-4.42 (m, 2H), 3.88 (s, 3H) 3.45-3.40 (m, 1H), 2.91-2.87 (m, 1H), 2.59-2.54 (m, 1H), 2.48-2.73 (m, 1H), 2.08-2.02 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H).

Step D: (SVMethyl 2-fluoro-4-((4-methyl-2-oxopyrrolidin-l-vnmethylV5-(4-(4,4,5 ,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)benzoate

To a solution of (S)-methyl 5-(4-chlorophenoxy)-2-fluoro-4-((4-methyl-2- oxopynOlidin-l -yl)methyl)benzoate (4.6 g, 12 mmol) in dioxane (100 mL) was added B ₂ (pin)2 (7.6 g, 30 mmol), Pd(dba) ₂ (690 mg, 1.2 mmol), X-Phos (1.1 g, 2.4 mmol), and K ₂ C0 ₃ (3.7 g, 26 mmol). The resulting mixture was heated at 110 °C under N ₂ atmosphere for 10 h and then concentrated. The residue was diluted with EtOAc (150 mL), washed with saturated aqueous sodium chloride solution (100 mL x 2), dried over Na ₂ SC>4, and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc, 10: 1 to 1 : 1) to give (S)- methyl 2-fluoro-4-((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-5-(4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenoxy)benzoate as a colorless oil. MS: m/z = 484.1(M + 1). Ή NMR (400 MHz, CDCI3): δ 7.79 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 6.0 Hz, 1H), 7.10 (d, J = 10.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 4.52-4.41 (m, 2H), 3.87 (s, 3H), 3.46-3.37 (m, 1H), 2.93-2.84 (m, 1H), 2.62-2.51 (m, 1H), 2.47-2.35 (m, 1H), 2.06-2.00 (m, 1H), 1.34 (s, 12H), 1.09 (d, J = 6.8 Hz, 3H).

Step E: (SVMethyl 5-(4-(6-acetylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-methyl- 2- oxopyrrolidin-l -yl)methyl)benzoate

A mixture of (S)-methyl 2-fluoro-4-((4-methyl-2-oxopyrrolidin-l -yl)methyl)-5-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)benzoat e (3.5 g, 7.2 mmol), l-(6- chloropyridazin-3-yl)ethanone (1.4 g, 8.7 mmol), Pd(dppf)Cl ₂ (1.2 g, 1.4 mmol), and K3PO4 (3.9 g, 14.5 mmol) in toluene (100 mL) and water (20 mL) was heated at 70 °C for 36 h. The reaction mixture was concentrated, the residue diluted with EtOAc (120 mL), and washed with water (80 mL x 2). The organic phase was dried over Na ₂ SC>4, concentrated, and the residue purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc, 3:1 to EtOAc) to give (S)-methyl 5-(4- (6-acetylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-methyl-2-oxo pyrrolidin-l -yl)methyl)benzoate as a yellow solid. Ή NMR (400 MHz, CDCI3): δ 8.22-8.15 (m, 3H), 7.98 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 6.0 Hz, 1H), 7.16-7.06 (m, 3H), 4.54 (d, J = 15.6 Hz, 1H), 4.46 (d, J = 15.6 Hz, 1H), 3.90 (s, 3H), 3.45 (dd, J = 7.6, 9.2Hz, 1H), 2.93 (s, 3H), 2.92-2.89 (m, 1H), 2.63-2.52 (m, 1H), 2.47-2.43 (m, 1H), 2.09-1.98 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H).

Step F: (SVMethyl 2-fluoro-5-(4-(6-(2-hvdroxypropan-2-yl)pyridazin-3-yl)phenox y)-4-((4- methyl-2-oxopyrrolidin- 1 -vDmethvDbenzoate

To a solution of (S)-methyl 5-(4-(6-acetylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (789 mg, 1.70 mmol) in THF (20 mL) was added a solution of CH ₃ MgBr in diethyl ether (3.0 M, 0.66 mL, 2.0 mmol) at 0 °C. The reaction mixture was stirred at 23 °C for 16 h, then quenched with water (50 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc, 2: 1 to EtOAc) to give (S)-methyl 2-fluoro-5-(4-(6-(2-hydroxypropan-2-yl)pyridazin-3-yl)phenox y)-4-((4-methyl-2- oxopyrrolidin-l-yl)methyl)benzoate as a yellow solid. MS: m/z = 494.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.09 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 10.8 Hz, 1H), 7.06 (dd, J = 2.0, 6.8 Hz, 2H), 4.56 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 3.90 (s, 3H), 3.45 (dd, J = 7.6, 9.6 Hz, 1H), 2.91 (dd, J = 6.0, 9.2 Hz, 1H), 2.57 (dd, J = 8.8, 16.4 Hz, 1H), 2.45-2.43 (m, 1H), 2.03-2.01 (m, 1H), 1.69 (s, 6H), 1.1 1 (d, J = 6.4 Hz, 3H). Step G: (SVMethyl 2-fluoro-5-(4-(6-(2-fluoropropan-2-yl)pyridazin-3-yl)phenoxy -4-((4-methyl- 2-oxopyrrolidin- 1 -vDmethvDbenzoate

To a solution of (S)-methyl 2-fluoro-5-(4-(6-(2-hydroxypropan-2-yl)pyridazin-3- yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoat e (230 mg, 0.47 mmol) in anhydrous CH ₂ C1 ₂ (10 mL) at 0 °C was added DAST (0.62 mL, 4.7 mmol) dropwise. The reaction mixture was stirred at 23 °C for 3 h. The reaction mixture was quenched with water (20 mL) at 0 °C and extracted with CH ₂ C1 ₂ (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL x 3), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by prep-TLC (petroleum ethenEtOAc, 1 : 1) to give (S)- methyl 2-fluoro-5-(4-(6-(2-fluoropropan-2-yl)pyridazin-3-yl)phenoxy )-4-((4-methyl-2- oxopyrrolidin-l -yl)methyl)benzoate as a yellow solid. MS: m/z = 496.2 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.13-8.06 (m, 2H), 7.87 (d, J = 8.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 10.4 Hz, 1H), 7.08-7.01 (m, 2H), 4.55 (d, J = 15.6 Hz, 1H), 4.47 (d, J = 15.6 Hz, 1H), 3.90 (s, 3H), 3.50-3.43 (m, 1H), 2.91 (dd, J = 6.0, 9.2 Hz, 1H), 2.57 (dd, J = 2.0, 16.8 Hz, 1H), 2.48-2.39 (m, 1H), 2.04 (dd, J = 7.2, 16.8 Hz, 1H), 1.90 (s, 3H), 1.85 (s, 3H), 1.1 1 (d, J = 6.8 Hz, 3H).

Step H: (S -2-Fluoro-5-(4-(6-(2-fluoropropan-2-yl)pyridazin-3-yl)phenox y)-4-((4-methyl-2- oxopyrrolidin- 1 -vDmefhvDbenzoic acid

A mixture of (S)-methyl 2-fluoro-5-(4-(6-(2-fluoropropan-2-yl)pyridazin-3- yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoat e (170 mg, 0.34 mmol) and LiOH (16 mg in 2 mL of water, 0.69 mmol) in THF (6 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the residue was acidified with aqueous IN HC1 to pH 4. The resulting mixture was diluted with EtOAc (10 mL), washed with saturated aqueous sodium chloride solution (5 mL x 3), dried over Na ₂ S0 ₄ , and concentrated to give (S)-2-fluoro-5-(4-(6- (2-fluoropropan-2-yl)pyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin-l-yl)methyl)benzoic acid as a yellow solid. MS: m/z = 482.1 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.09 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.15 (d, J = 10.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.57 (d, J = 15.6 Hz, 1H), 4.49 (d, J = 15.6 Hz, 1H), 3.47 (dd, J = 7.6, 9.6 Hz, 1H), 2.96-2.92 (m, 1H), 2.60 (dd, J = 8.8, 16.8 Hz, 1H), 2.48-2.39 (m, 1H), 2.08-2.04 (m, 1H), 1.90 (s, 3H), 1.84 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H).

INTERMEDIATE C43

2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-o xooxazolidin-3-yl)methyl)benzoic acid

StepA: Methyl 2-fluoro-5-methoxy-4-((2-oxooxazolidin-3-yl)methyl)benzoate

To a solution of oxazolidin-2-one (250 mg, 3.45 mmol) in DMSO (10 mL) was added NaH (60% dispersion, 149 mg, 3.73 mmol). The mixture was stirred at 23 °C for 10 min before addition of a solution of methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate (955 mg, 3.45 mmol) in of DMSO (10 mL). The mixture was stirred at 23 °C for 10 min and then diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with water (3x) and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of

hexanes:EtOAc, 100:0 to 15:85, to give the title compound. MS: mlz = 284.1 (M + 1). Step B: Methyl 2-fluoro-5-hvdiOxy-4-((2-oxooxazolidin-3-yl)methyl ^" )benzoate

A solution of BBr ₃ in CH2CI2 (1 M, 15 mL, 15 mmol) was added to methyl 2- fluoro-5-methoxy-4-((2-oxooxazolidin-3-yl)methyl)benzoate (615 mg, 2.17 mmol) in CH2CI2 (10 mL) at 0 °C. The reaction mixture was stirred at 23 °C for 18 h and then diluted with methanol. The resulting mixture was concentrated and the residue then dissolved in methanol (20 mL). The mixture was acidified with concentrated H ₂ S0 ₄ until pH ~ 3 and then heated at reflux for 6 h. The reaction mixture was cooled to 23 °C and then diluted with saturated aqueous sodium bicarbonate solution, then with water and extracted with CH2CI2 (3x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc, 100:0 to 15:85, to give the title compound. MS: mlz = 270.1 (M + 1).

Step C: Methyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy -4-((2-oxooxazolidin-3- vDmethvDbenzoate

To a solution of methyl 2-fluoro-5-hydroxy-4-((2-oxooxazolidin-3- yl)methyl)benzoate (96 mg, 0.36 mmol) in deoxygenated NMP (2 mL) was added 3-(4- iodophenyl)-6-isopropylpyridazine (231 mg, 0.713 mmol), CuCl (35 mg, 0.36 mmol), 2,2,6,6- tetramethyl-3,5-heptanedione (66 mg, 0.36 mmol), and Cs ₂ C0 ₃ (581 mg, 1.78 mmol). The reaction mixture was heated at 90 °C for 90 min and then cooled to 23 °C. The reaction mixture was then diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous ammonium chloride (3x) and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified via reverse- phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the title compound. MS: mlz = 466.2 (M + l).

Step D: 2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxoo xazolidin-3- vDmethvDbenzoic acid A mixture of aqueous NaOH (2.8 M, 0.064 mL, 0.064 mmol) and methyl 2- fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxooxa zolidin-3-yl)methyl)benzoate (56 mg, 0.12 mmol) in 1 : 1 THF:MeOH (2 mL) was stirred at 23 °C for 48 h. A solution of 2N HCl in ether was then added to the mixture until pH ~ 3 and the reaction mixture concentrated to give the title compound. MS: mlz = 452.1 (M + 1).

INTERMEDIATE C44

4- ((3-(te^Butyl)-2-oxoimidazolidin-l -yl)methyl)-2-fluoro-5-(4-(5-isopropyl-1 ,4 hiadiazol-2- yl)phenoxy)benzoic acid

Step A: Methyl 4-((3-(ter^-butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-5 -(4-(5-isopropyl- L3,4-thiadiazol-2-yl)phenoxy)benzoate

A mixture of methyl 4-((3-(teri-butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-

5- hydroxybenzoate (200 mg, 0.617 mmol), 2-(4-iodophenyl)-5-isopropyl-l,3,4-thiadiazole (300 mg, 0.925 mmol), cesium carbonate (600 mg, 1.85 mmol), copper(I) chloride (67 mg, 0.68 mmol), and 2,2,6,6-tetramethylheptane-3,5-dione (65 μί, 0.31 mmol) in deoxygenated NMP (1.5 mL) was heated at 80 °C under nitrogen for 16 h. The reaction mixture was cooled to 23 °C and partitioned between ethyl acetate (100 mL) and saturated aqueous ammonium chloride solution (100 mL). The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel

chromatography (hexanes initially, grading to 70% EtOAc in hexanes) to give the title compound. MS: mlz = 527.2 (M + 1).

Step B : 4-((3 -( er -Butyl)-2-oxoimidazolidin- 1 -yl)methyl)-2-fluoro-5-( 4-( 5-isopropyl- 1 ,3 ,4- thiadiazol-2-yl)phenoxy)benzoic acid

A mixture of methyl 4-((3-(½r/-butyl)-2-oxoimidazolidin-l -yl)methyl)-2-fluoro- 5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)benzoate (167 mg, 0.317 mmol) and lithium hydroxide monohydrate (53 mg, 1.3 mmol) in methanol (5 mL) was heated at 60 °C for 16 h. The mixture was cooled to 23 °C, neutralized with a solution of HC1 in ethyl ether (2 M, 0.60 mL, 1.3 mmol), and concentrated to give the title compound. MS: m/z = 513.2 (M +

INTERMEDIATE C45

3-(4-(6-Isopropylpyridazin-3-yl)phenoxy)-4-( ^' 2-oxo-L2-dihvdropyridine-3-carbonyl)benzoic acid

Step A: Methyl 4-f(2-methoxypyridin-3-yl)methyl ^' )-3-(4-( ^' 4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenoxy)benzoate

To a solution of bis(pinacolato)diboron (3.1 g, 12 mmol) and benzoyl peroxide

(123 mg, 0.510 mmol) in MeCN (100 mL) was added methyl 3-(4-aminophenoxy)-4-((2- methoxypyridin-3-yl)methyl)benzoate (3.7 g, 10 mmol). The reaction mixture was stirred at 23 °C for 10 min and then i-BuONO (1.6 g, 15 mmol) was added dropwise. After addition, the reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was then concentrated. The residue was dissolved in EtOAc (150 mL), washed with NH ₄ OH (5% aqueous solution, 80 mL x 3) and saturated aqueous sodium chloride solution (80 mL), dried over Na ₂ S0 ₄ , and

concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum

ether:EtOAc, 50: 1 to 20: 1) to give methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)benzoate as a white solid. MS: mlz = 476.2 (M + 1). 'H NMR (400 MHz, CD ₃ OD): 5 7.97 (dd, J = 2.0, 4.8 HZ, lH), 7.78 (dd, J = 1.6, 8.0 Hz,

1H), 7.73 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.43 (dd, J = 1.6, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.87-6.83 (m, 3H), 3.99 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 1.36 (s, 12H).

Step B: Methyl 3-r4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-methoxypyridi n-3- vDmethvDbenzoate

A mixture of methyl 4-((2-methoxypyridin-3-yl)methyl)-3-(4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate (1.0 g, 2.1 mmol), 3-chloro-6- isopropylpyridazine (0.50 g, 3.2 mmol), Pd(dppf)Cl ₂ (171 mg, 0.210 mmol), and Κ ₃ Ρ0 ₄ ·3Η ₂ 0 (1.7 g in 5 mL water, 6.3 mmol) in toluene (50 mL) was heated at 70 °C under N for 16 h. The reaction mixture was then cooled to 23 °C, diluted with water (80 mL), and extracted with EtOAc (80 mL x 2). The combined organic layers were dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum

ether:EtOAc, 10: 1 to 3:1) to give methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2- methoxypyridin-3-yl)methyl)benzoate as a white solid. MS: mlz = 470.2 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.10-8.06 (m, 3H), 7.97 (dd, J = 1.6, 5.2 Hz, 1H), 7.81 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 1.6, 7.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.05-7.03 (m, 2H), 8.86 (dd, J = 5.2, 7.2 Hz, 1H), 4.04 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.34-3.33 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H). Step C: Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-(2-methoxy-l,2-di hydropyridine-3- carbonyDbenzoate

To a solution of methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2- methoxypyridin-3-yl)methyl)benzoate (0.67 g, 1.4 mmol) in acetone (50 mL) was added KMn0 ₄ (1.1 g, 7.1 mmol) and the reaction mixture stirred at reflux for 2 d. The reaction mixture was cooled to 23 °C and filtered through a pad of Celite ^® and the filter cake was then washed with acetone (100 mL). The filtrate was concentrated and the residue dissolved in acetone (50 mL). KMn0 ₄ (1.1 g, 7.1 mmol) was added and the reaction mixture was heated at reflux for 3 d. The reaction mixture was concentrated and the residue purified by column chromatography (Si0 ₂ , petroleum ethenEtOAc, 10:1 to 3:1) to obtain the methyl 3-(4-(6-isopropylpyridazin-3- yl)phenoxy)-4-(2-methoxy-l,2-dihydropyridine-3-carbonyl)benz oate as a colorless oil. MS: mlz = 485.1 (M + 1). Ή NMR (400 MHz, CDCI3): δ 8.24 (dd, J = 1.6, 6.4 Hz, 1H), 7.99-7.92 (m, 3H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.91 (dd, J = 6.4, 8.0 Hz, 1H), 6.81-6.78 (m, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 3.38-3.31 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H).

Step 4: 3-(4-(6-Isopropylpyridazin-3-yl)phenoxy)-4-(2-oxo-l ,2-dihydropyridine-3- carbonyl)benzoic acid

Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-(2-methoxy-l,2- dihydropyridine-3-carbonyl)benzoate (140 mg, 0.29 mmol) was dissolved in aqueous 40% HBr (5 mL) and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was cooled to 23 °C and concentrated. The residue was diluted with water (25 mL) extracted with EtOAc (25 mL x 5). The combined organic layers were dried over Na ₂ S0 ₄ , filtered, and concentrated to obtain 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-(2-oxo-l,2-dihydr opyridine-3- carbonyl)benzoic acid as a white solid. MS: mlz = 455.2 (M). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.94 (dd, J = 1.5, 6.3 Hz, 1H), 7.82-7.75 (m, 3H), 7.65 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.43 (dd, J = 1.5, 8.1 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 6.38 (t, J = 6.0 Hz, 1H), 3.31-3.22 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H).

INTERMEDIATE C46

2-Fluoro-5-(3-fluoro-4-( 5-isopropyl- 1 ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxopyrazin- 1 (2H)- yl)methyl)benzoic acid Step A: Methyl 2-fluoro-5-methoxy-4-r(2-oxopyrazin- 1 (2H)-yl)methyl)benzoate

Sodium hydride (95% dispersion in mineral oil, 501 mg, 19.8 mmol) was added to a solution of pyrazin-2(lH)-one (1.90 g, 19.8 mmol) in DMF (60 mL) at 0 °C. The resulting suspension was stirred at 0 °C for 30 min before a solution of methyl 4-(bromomethyl)-2-fluoro- 5-methoxybenzoate (5.00 g, 18.0 mmol) in DMF (30 mL) was added. The resulting mixture was gradually warmed to 23 °C and stirred for 6 h. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:EtOAc, 95:5 to 15:85, followed by a gradient of dichloromethane:MeOH, 99: 1 to 90: 10, to give the title compound. MS: mlz = 293.1 (M + 1).

Step B: Methyl 2-fluoro-5-hydroxy-4-((2-oxopyrazin-l(2H)-yl)methyl)benzoate

Methyl 2-fluoro-5-methoxy-4-((2-oxopyrazin-l(2H)-yl)methyl)benzoate (200 mg, 0.684 mmol) in a solution of HBr in acetic acid (33%, 3.40 mL) was heated at 100 °C for 20 h. The mixture was cooled to 23 °C, slowly quenched with methanol, and concentrated. The residue was diluted with methanol, a catalytic amount of concentrated H ₂ S0 ₄ was added, and the resulting mixture was heated at 100 °C for 20 h. The reaction mixture was cooled to 23 °C, concentrated, diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: mlz = 279.1 (M + 1). Step C: Methyl 2-fluoro-5-f3-fluoro-4-(5-isopropyl-L3,4-thiadiazol-2-yl)phe noxy)-4-((2- oxopyrazin- 1 (2H)-yl)methyl)benzoate

A mixture of copper(I) chloride (78.0 mg, 0.791 mmol), methyl 2-fluoro-5- hydro xy-4-((2-oxopyrazin-(2H)-yl)methyl)benzoate (200 mg, 0.719 mmol), 2-(2-fluoro-4- iodophenyl)-5-isopropyl-l,3,4-thiadiazole (300 mg, 0.863 mmol), 2,2,6,6-tetramethyl-3,5- heptanedione (66.0 μί, 0.359 mmol), and cesium carbonate (1.17 g, 3.59 mmol) in deoxygenated NMP (2.4 mL) was heated at 100 °C in a sealed vessel for 2 h. The mixture was cooled to 23 °C, diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:EtOAc, 90:10 to 0:100, to give the title compound. MS: mlz = 499.1 (M + 1). Step D: 2-Fluoro-5-(3-fluoro-4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-( (2-oxopyrazin- l(2H)-yl)methyl)benzoic acid

A solution of methyl 2-fluoro-5-(3-fluoro-4-(5-isopropyl-l,3,4-thiadiazol-2- yl)phenoxy)-4-((2-oxopyrazin-l(2H)-yl)methyl)benzoate (270 mg, 0.542 mmol) and aqueous sodium hydroxide (3 M, 0.27 mL, 0.82 mmol) in methanol (5.40 mL) was heated at 50 °C for 2 h. The reaction mixture was cooled to 23 °C, neutralized with aqueous HC1 (3 M, 0.27 mL,

0.81 mmol), and concentrated to yield the title compound. MS: mlz = 485.1 (M + 1).

INTERMEDIATE C47

2-Fluoro-5-(3-fluoro-4-(5-isopropyl-l,3,4-thiadiazol-2-yl )phenoxy-4-((6-oxopyrimidin-l(6H)- yl)methyl)benzoic acid

Step A: Methyl 2-fluoro-5-methoxy-4-((6-oxopyrimidin-l(6H)-yl)methylbenzoat e

To a solution of pyrimidin-4(3H)-one (1.00 g, 10.1 mmol) in DMSO (25 mL) was added NaH (60% dispersion, 541 mg, 13.5 mmol). The reaction mixture was stirred at 23 °C for 10 min before addition of a solution of methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate (3.75 g, 13.7 mmol) in DMSO (25 mL). The reaction mixture was stirred at 23 °C for 10 min and then quenched with water. The reaction mixture was then diluted with ethyl acetate and the layers separated. The organic phase was washed with water (3x) and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The reside was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc, 100:0 to 10:90, to give the title compound. MS: m/z = 293.1 (M + 1).

Step B: Methyl 2-fluoro-5-hydroxy-4-((6-oxopyrimidin-l(6H -vnmethylbenzoate

Methyl 2-fluoro-5-methoxy-4-((6-oxopyrimidin-l(6H)-yl)methylbenzoat e (1.1 g, 3.8 mmol) was added to a solution of 36% HBr in AcOH (9 mL). The reaction mixture was heated at 90 °C for 18 h and then cooled to 23 °C. The reaction mixture was then quenched with MeOH and concentrated. The residue was dissolved in MeOH (20 mL), concentrated H ₂ SO ₄ was added to the mixture until pH ~ 3, and the mixture was heated at reflux for 18 h. After cooling to 23 °C, the mixture was concentrated. The residue was purified via reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: m/z = 279.1 (M+l).

Step C: Methyl 2-fluoro-5-(3-fluoro-4-(5-isopropyl-L3,4-thiadiazol-2-yl)phe noxy)-4-((6- oxopyrimidin- 1 (6H)-yl)methyl)benzoate

To a solution of methyl 2-fluoro-5-hydroxy-4-((6-oxopyrimidin-l(6H)- yl)methylbenzoate (75 mg, 0.27 mmol) in deoxygenated NMP (3 mL) was added 2-(4-bromo-2- fluorophenyl)-5-isopropyl-l ,3,4-thiadiazole (122 mg, 0.404 mmol), CuCl (29 mg, 0.30 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (50 mg, 0.27 mmol), and CS2CO3 (439 mg, 1.35 mmol). The reaction mixture was heated at 120 °C for 1 h and then cooled to 23 °C. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layers were washed with saturated aqueous ammonium chloride (3x) and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The residue was purified via reverse-phase HPLC, eluting with 10% acetonitrile in water (0.05% NH4OH used as a modifier) initially, grading to 95% acetonitrile in water, to give the title compound. MS: m/z = 499.1 (M+l). Step D: 2-Fluoro-5-(3-fluoro-4-(5-isopropyl-1 ,4-thiadiazol-2-yl)phenoxy-4-((6-oxopyrimidin- l(6H)-yl)methyl)benzoic acid

A mixture of NaOH (2.8 M, 0.064 mL, 0.18 mmol) and methyl 2-fluoro-5-(3- fluoro-4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((6-oxopyrimidin-l(6H)- yl)methyl)benzoate (60 mg, 0.12 mmol) in 1 : 1 2-MeTHF/MeOH (2 mL) was stirred at 23 °C for 18 h. A solution of 2 N HC1 in ether was then added until pH ~ 3 and the reaction mixture concentrated to give the title compound which was used without purification. MS: mlz = 485.1 (M + l).

INTERMEDIATE C48

3-(3-Fluoro-4-(5-(2-hvdroxypropan-2-yl)-l,3,4-thiadiazol-2-y l)phenoxy)-4-((2-oxopyridin- l(2H)-yl methyl)benzoic acid Step A: Methyl 3-methoxy-4-((2-oxopyridin-l (2H)-yl)methyl)benzoate

A solution of pyridin-2(lH)-one (8.81 g, 93.0 mmol) in DMF (100 mL) was added to a slurry of NaH (3.86 g, 60% dispersion in mineral oil, 23.2 mmol) in DMF (100 mL) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C before a solution of methyl 4- (bromomethyl)-3-methoxybenzoate (20 g, 77 mmol) in DMF (100 mL) was added. The resulting mixture was warmed to 23 °C and stirred for 1 h. The mixture was cooled to 0 °C, diluted with saturated aqueous ammonium chloride solution, and extracted with EtOAc (3x). The combined organic layers were washed with saturated aqueous sodium chloride solution (3x), dried over MgS0 ₄ , filtered, and concentrated. The residue was dissolved in CH ₂ C1 ₂ (260 mL), cooled to 0 °C, and then a solution of boron tribromide in CH2CI2 (232 mL, 232 mmol, 1M) was slowly added. The reaction mixture was stirred at 0 °C for 1 h and then warmed to 23 °C over the course of 1 h. The mixture was cooled to 0 °C, diluted with excess MeOH, and then

concentrated. The residue was taken up in MeOH and concentrated (2x). The residue was diluted with saturated aqueous sodium bicarbonate and extracted with CH ₂ C1 ₂ . The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated to give the title compound. LC-MS m/z = 260.2 [M+l]. Step B: Methyl 3-f3-fluoro-4-(5-(2-hvdroxypropan-2-yl -l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2- oxopyridin- 1 (2H)-yl)methyl)benzoate

2,2,6,6-Tetramethylheptane-3,5-dione (19.6 mg, 0.106 mmol) was added to a solution of methyl 3-hydroxy-4-((2-oxopyridin- 1 (2H)-yl)methyl)benzoate (50 mg, 0.19 mmol), 2-(5-(4-bromo-2-fluorophenyl)-l ,3,4-thiadiazol-2-yl)propan-2-ol (105 mg, 0.289 mmol, copper(I) chloride (21.0 mg, 0.212 mmol), and cesium carbonate (314 mg, 0.964 mmol) in NMP (643 μΐ). The resulting mixture was heated at 120 °C under Ar in a sealed vial for 1 h. The reaction mixture was cooled to 23 °C and filtered through a syringe filter washing with DMF (2 mL). Purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound as the TFA salt. The residue was diluted with saturated aqueous Na ₂ C0 ₃ , extracted with EtOAc, dried over MgS0 ₄ , filtered, and concentrated to give the title compound. LC-MS m/z found = 496.1 [M+1]. Step C: 3-(3-Fluoro-4-(5-(2-hydroxypropan-2-yl)-L3,4-thiadiazol-2-yl )phenoxy)-4-((2- oxopyridin- 1 (2H)-yl)methyl)benzoic acid

A mixture of NaOH (1.0 M, 0.41 mL, 0.41 mmol) and methyl 3-(3-fluoro-4-(5-(2- hydroxypropan-2-yl)-l,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxo pyridin-l(2H)-yl)methyl)benzoate

(68 mg, 0.14 mmol) in MeOH (1.3 mL) was stirred at 23 °C for 18 h. A solution of 6 N aqueous HCl (0.41 mL, 0.41 mmol) and the reaction mixture concentrated to give the title compound with

3 eq of sodium chloride. MS: mlz = 482.0 (M + 1).

INTERMEDIATE C49

(S)-5-(3,5-Difluoro-4-(6-isopropylpyridazin-3-yl)phenoxy) -2-fluoro-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoic acid

To a solution of 3-(2,6-difluoro-4-iodophenyl)-6-isopropylpyridazine (0.500 g, 1.78 mmol) and methyl 2-fluoro-5-hydroxy-4-methylbenzoate (0.768 g, 2.13 mmol) in NMP (10 mL) was added 2,2,6,6-tetramethylheptane-3,5-dione (0.212 mL, 0.977 mmol), CuCl (0.194 g, 1.96 mmol) and CS2CO3 (1.74 g, 5.33 mmol). The reaction mixture was stirred at 90 °C under N ₂ for 16 h, then cooled to 23 °C, and diluted with water (20 mL). The resulting mixture was acidified to pH 3 with concentrated aqueous HCl solution, the layers separated, and the aqueous phase extracted with EtOAc (15 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over Na ₂ S04, and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum ether:EtOAc, 1 : 1) to give the title compound as a brown oil. MS: mlz = 500.1 (M + 1). Ή NMR (300 MHz, CDC1 ₃ ): δ 7.87 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 6.0 Hz, 1H), 7.17 (d, J = 10.2 Hz, 1H), 6.62 (d, J = 9.0 Hz, 2H), 4.56 (d, J = 15.3 Hz, 1H), 4.47 (d, J = 15.6 Hz, 1H), 3.63-3.49 (m, 2H), 3.01-2.96 (m, 1H), 2.71-2.66 (m, 1H), 2.60-2.48 (m, 1H), 2.21-2.13 (m, 1H), 1.47 (d, J = 6.9 Hz, 6H), 1.15 (d, J = 6.9 Hz, 3H).

INTERMEDIATE C50

5- (2-Cyclobutyl-l-oxo-6-isoquinolyl ^' )oxy1-2-fluoro-4-[[(4S)-4-methyl-2-oxo-pyrrolidin-l- yl]methyl]-N-( 1 -tetrahvdropyran-4-yl-4-piperidyl)benzamide

Step A: 6-Bromo-2-cvclobutyl-isoquinolin-l-one

To a solution of 6-bromoisoquinolin-l(2H)-one (0.108 g, 0.482 mmol) in DMF (2 mL) was added K ₂ C0 ₃ (0.200 g, 1.45 mmol) and bromocyclobutane (0.227 mL, 2.41 mmol). The reaction mixture was stirred at 23 °C for 16 h. Bromocyclobutane (0.227 mL, 2.41 mmol) was added and the reaction mixture heated at 105 °C for 2 days. 1 M aqueous ΝΗ ₄ Ο (5 mL) was added and the mixture extracted with ether (10 mL x 2). The combined organic layers were concentrated and the residue purified by reverse phase HPLC on a C- 18 column, eluting with a gradient of H ₂ 0:CH ₃ CN:HCOOH, 95:5:0.1 to 15:85:0.1 , to give the title compound as pale yellow solid. MS: m/z = 278.0 and 280.1 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ) δ 8.29 (d, J = 8.6 Hz, 1H), 7,69 (d, J = 1.9 Hz, 1 H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 5.26 (m, 1H), 2.54 (m, 2H), 2.29 (m, 2H), 1.93 (m, 2H). Step B: 5- (2-Cvclobutyl-l-oxo-6-isoquinolyl)oxy1-2-fluoro-4- (4S)-4-methyl-2-oxo- pyrrolidin-1 -yl]methyl]benzoic acid

To a mixture of (S)-ethyl 2-fluoro-5-hydroxy-4-[(4-methyl-2-oxopyn lidin-l- yl)methyl]benzoate (30.0 mg, 0.102 mmol), 6-bromo-2-cyclobutyl-isoquinolin-l-one (28.3 mg, 0.102 mmol), Cs ₂ C0 ₃ (165 mg, 0.508 mmol) in NMP (0.2 mL) under N ₂ was added 2,2,6,6- tetramethylheptane-3,5-dione (12 μΐ, 0.056 mmol) and copper(I) chloride (1 1.1 mg, 0.112 mmol). The reaction mixture was heated at 1 10 °C for 16 h. The reaction mixture was diluted with EtOAc, filtered, the solid washed with EtOAc/methanol, and the combined filtrates concentrated. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes then 5% methanol in EtOAc to afford the title compound as pale brown solid. MS: mlz = 465.2 (M + 1).

INTERMEDIATE C51

4-((3-(fe^Butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro- 5-(4-(6-isopropylpyridazin-3- yl)phenoxy)benzoic acid

Step A: Methyl 4-((3-(ter^-butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-5 -methoxybenzoate

Sodium hydride (60% dispersion in mineral oil, 325 mg, 8.12 mmol) was added to a solution of 1 -fc -butyl-2-imidazolidinone (1.16 g, 8.12 mmol) in DMF (10 mL) and the resulting mixture stirred at 23 °C for 30 min. Methyl 4-(bromomethyl)-2-fluoro-5- methoxybenzoate (1.50 g, 5.41 mmol) was added and the reaction mixture stirred for 20 min. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexanes initially, grading to 30% EtOAc in hexanes) to give the title compound. MS: mlz = 339.2 (M + 1).

Step B: Methyl 4-((3-(fer -butyl)-2-oxoimidazolidin-l -yl)methyl)-2-fluoro-5-hydroxybenzoate Boron tribromide (1M in dichloromethane, 2.0 mL, 2 mmol) was added to a solution of methyl 4-((3-(ier/-butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-5 - methoxybenzoate (350 mg, 1.03 mmol) in dichloromethane (5 mL) at 23 °C and the resulting mixture was stirred for 2 h. The reaction mixture was quenched slowly with methanol (25 mL), stirred for 30 min, and then concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: mlz = 325.2 (M + 1). Step C: Methyl 4-(f3-(te^butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-5-( 4-(6- isopropylpyridazin-3-yl)phenoxy)benzoate

A mixture of methyl 4-((3-(teri-butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro- 5-hydroxybenzoate (219 mg, 0.675 mmol), 3-(4-iodophenyl)-6-isopropylpyridazine (328 mg, 1.01 mmol), cesium carbonate (660 mg, 2.02 mmol), copper(I) chloride (73 mg, 0.74 mmol), and 2,2,6,6-tetramethylheptane-3,5-dione (70 μί, 0.34 mmol) in deoxygenated NMP (2 mL) was heated at 80 °C under nitrogen for 20 h. The reaction mixture was cooled to 23 °C, partitioned between ethyl acetate (100 mL) and saturated aqueous ammonium chloride (2 ^χ 50 mL). The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexanes initially, grading to 70% EtOAc in hexanes) to give the title compound. MS: mlz = 521.3 (M + 1).

Step D: 4-((3-(te^Butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-5-( 4-(6-is0propylpyridazin- 3-yl)phenoxy)benzoic acid

A mixture of methyl 4-((3-(ier<-butyl)-2-oxoimidazolidin-l -yl)metbyl)-2-fluoro-

5-(4-(6-isopropylpyridazin-3-yl)phenoxy)benzoate (53 mg, 0.10 mmol) and lithium hydroxide (25 mg, 1.0 mmol) in methanol (1 mL) was heated at 65 °C for 16 h. The reaction mixture was cooled to 23 °C, neutralized with a solution of HC1 in ethyl ether (2 M, 0.5 mL, 1.0 mmol), and concentrated to give the title compound. MS: mlz = 507.2 (M + 1).

INTERMEDIATE C52

2-Fluoro-4-((5-fluoro-2-oxopyiidin-l(2H)-yl)methyl)-5-(4-(6- isopropylpyridazin-3- yl)phenoxy)benzoic acid

Step A: Methyl 2-fluoro-4-((5-fluoro-2-oxopyridin-U2H)-yl)methyl)-5-rnethox ybenzoate

To a solution of 5-fluoropyridin-2-ol (1.50 g, 13.3 mmol) in DMF (50 mL) was added NaH (60% dispersion, 690 mg, 17.2 mmol). The reaction was stirred at 23 °C for 10 min before addition of a solution of methyl 4-(bromomethyl)-2-fluoro-5-methoxybenzoate (4.41 g, 15.9 mmol) in DMF (50 mL). The reaction mixture was stirred at 23 °C for 1 h and then quenched with water. The reaction mixture was then diluted with ethyl acetate and the organic phase washed with water (3x) and saturated aqueous sodium chloride. The combined organic layers were then dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc, 95:5 to 10:90, to give the title compound. MS: mlz = 310.0 (M + 1). Step B: Methyl 2-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)-5-hvdrox ybenzoate

To a solution of methyl 2-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)-5- methoxybenzoate (2.30 g, 7.44 mmol) in CH ₂ C1 ₂ (70 mL) was added a solution of BBr ₃ in CH ₂ C1 ₂ (1.0 M, 22.3 mL, 22.3 mmol). The reaction mixture was stirred for 48 h at 23 °C and then cooled to 0 °C. The reaction mixture was quenched with MeOH and concentrated. The residue was dissolved in MeOH (20 mL). Concentrated H ₂ S0 ₄ was added until pH ~ 3 and the reaction mixture heated at reflux for 18 h. The reaction mixture was cooled to 23 °C and then concentrated. The residue was recrystallized from MeOH to give the title compound. MS: mlz - 296.0 (M + 1). Step C: Methyl 2-fluoro-4-((5-fluoro-2-oxopyridin-l (2H)-yl)methyl)-5-(4-(6-isopropylpyridazin- 3 -yl)phenoxy)benzoate

To a mixture of methyl 2-fluoro-4-((5-fluoro-2-oxopyridin-l (2H)-yl)methyl)-5- hydroxybenzoate (3.00 g, 10.2 mmol) and 3-(4-iodophenyl)-6-isopropylpyridazine (4.94 g, 15.2 mmol) in deoxygenated NMP (50 mL) was added Cs ₂ C0 ₃ (16.6 g, 50.8 mmol), CuCl (1.12 g, 1 1.2 mmol), and 2,2,6,6-tetramethyl-3,4-heptanedione (1.87 g, 10.2 mmol). The resultant mixture was heated at 120 °C for 2 h in a sealed vessel. The reaction mixture was then diluted with ethyl acetate and the organic phase washed with saturated aqueous ammonium chloride (3x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc, 100:0 to 10:90, to give the title compound. MS: mlz = 492.0 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.10 (d, J = 8.3 Hz, 2 H); 7.77 (d, J = 8.7 Hz, 1 H); 7.52 (d, J = 5.9 Hz, 1 H); 7.42 (d, J = 8.8 Hz, 1 H); 7.26-7.27 (m, 3 H); 7.08 (d, J = 8.3 Hz, 2 H); 6.56 (dd, J = 10.0, 5.3 Hz, 1 H); 5.14 (s, 2 H); 3.88 (s, 3 H); 3.35-3.37 (m, 1 H); 1.43 (d, J = 6.9 Hz, 6 H).

Step C: 2-Fluoro-4-((5-fluoro-2-oxopyridin-l (2H)-yl)methyl)-5-(4-(6-isopropylpyridazin-3- yl)phenoxy)benzoic acid

A mixture of methyl 2-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)-5-(4-

(6-isopropylpyridazin-3-yl)phenoxy)benzoate (3.60 g, 7.32 mmol) and aqueous NaOH (2.8M, 3.92 mL, 11.0 mmol) in 1 : 1 THF.MeOH (60 mL) was stirred at 23 °C for 18 h. A solution of 2 N HC1 in ether was then added to the mixture until pH ~ 3 and the reaction mixture concentrated to afford the title compound. MS: mlz = 478.0 (M + 1).

6-(4-(5-Cvclopropyl-l,3,4-thiadiazol-2-yl phenoxy)-5-((2-oxopyrrolidin-l-yl)methyl)picolinic acid

Step A: Methyl 6-chloro-5-((2-oxopyrrolidin-l-yl)methyl)picolinate

A solution of pyrrolidin-2-one (0.354 g, 4.16 mmol)) in DMF (8 mL) was added to a slurry of NaH (0.181 g, 60% dispersion in mineral oil, 4.54 mmol) in DMF (8 mL) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C and a solution of methyl 5-(bromomethyl)-6- chloropicolinate (1.00 g, 3.78 mmol) in DMF (8 mL) was added. The resulting mixture was slowly allowed to warm to 23 °C and stirred for 1 h. The mixture was cooled to 0 °C, diluted with saturated aqueous ammonium chloride and extracted with extracted EtOAc (3x). The combined organic layers were washed with saturated aqueous sodium chloride solution (3x), dried over MgS0 ₄ , filtered, and concentrated. Purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1 % trifluoroacetic acid) gave the title compound as the TFA salt. The residue was diluted with saturated aqueous Na ₂ C0 ₃ , extracted with EtOAc, dried over MgS0 ₄ , filtered, and concentrated to give the title compound. LC-MS m/z found = 269.3 [M+l].

Step B: 6-(4-(5-Cvclopropyl-L3,4-thiadiazol-2-yl)phenoxy)-5-(( ^" 2-oxopyrrolidin-l- vDmethvDpicolinic acid

Cesium carbonate (240 mg, 0.74 mmol) was added to a solution of methyl 6- chloro-5-((2-oxopyrrolidin-l-yl)methyl)picolinate (50 mg, 0.19 mmol) and 4-(5-cyclopropyl- l ,3,4-thiadiazol-2-yl)phenol (160 mg, 0.74 mmol) in DMA (2 mL). The resulting mixture was heated at 140 °C for 18 h. The mixture was cooled to 23 °C and filtered through a syringe filter washing with DMF (1 mL). Purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound as the TFA salt. The residue was diluted with saturated aqueous Na ₂ C0 ₃ , extracted with EtOAc, dried over MgSC>4, filtered, and concentrated to give the title compound. LC-MS m/z— ll .2 [M+l].

4-((5-(difluoromethyl)-2-oxopyridin-l(2H)-yl)methyl)-2-fluoi O-5-(4-(6-is

opropylpyridazin-3 -yl)phenoxy)benzoic acid

Step A: Methyl 5-acetoxy-2-fluoro-4-methylbenzoate

Acetic anhydride (32.6 mL, 345 mmol) was added via an additional funnel to a stirred, room temperature mixture of methyl 2-fluoro-5-hydroxy-4-methylbenzoate (53 g, 288 mmol) and DMAP (3.52 g, 28.8 mmol) in dichloromethane (576 mL). N,N- diisopropylethylamine (151 mL, 863 mmol) was added and the mixture was stirred at room temperature for 14 h. The mixture was diluted with dichloromethane (500 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1 x 450 mL), dried (MgS04), filtered and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether ( 2 x 300 mL) to obtain a grey solid (48 g), the wash was concentrated and the residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane = 40% to give a light brown solid. The residue was purified by column chromatography, eluting with a gradient of

EtOAc/isohexane = 40% to give the title compound. MS: mlz = 227.0 (M + 1).

Step B: Methyl 5-acetoxy-4-(bromomethyl)-2-fluorobenzoate

AIBN (4.28 g, 26.1 mmol) was added to a stirred, room temperature mixture of methyl 5-acetoxy-2-fluoro-4-methylbenzoate (59 g, 261 mmol) and NBS (55.7 g, 313 mmol) in chloroform (652 mL). The mixture was degassed and allowed to stir under an atmosphere of nitrogen at 80 °C for 14 h. NBS (20 g) and AIBN (1.5 g) were added and the reaction mixture was allowed to stir at 80 °C for 6 h. The reaction mixture was cooled to room temperature, the insoluble material filtered off, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15% EtOAc in isohexane, to give semipure methyl 5-acetoxy-4-(dibromomethyl)-2-fluorobenzoate.

Diethyl phosphite (30.9 ml, 240 mmol) was added to a stirred, room temperature mixture of semipure methyl 5-acetoxy-4-(dibromomethyl)-2-fluorobenzoate (92 g, 240 mmol) in isopropyl acetate (599 ml). N,N-diisopropylethylamine (23.01 ml, 132 mmol) was added dropwise via an additional funnel and the mixture was stirred at room temperature for 14 h. The mixture was diluted with ethyl acetate (500 mL), washed with water (400 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure. The resultant solid was triturated with diethyl ether and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15% EtOAc in isohexane to give the title compound. MS: mlz = 306.7 (M + 1).

Step C: Methyl 5-acetoxy-4-((5-bromo-2-oxopyridin-l(2H)-yl)methyl)-2-fluoro benzoate

5-Bromo-2-hydroxypiperidine (2.74 g, 15.73 mmol) was added to a stirred, room temperature mixture of methyl 5-acetoxy-4-(bromomethyl)-2-fluorobenzoate (4 g, 13.1 1 mmol) and K2CO3 (3.62 g, 26.2 mmol) in N,N-dimethylformamide (32.8 ml). The reaction mixture was allowed to stir at room temperature for 3 h. The mixture was diluted with ethyl acetate (200 mL), washed with water (60 mL), and brine (60 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (50-100%) to give the title compound. MS: mlz = 399.6 (M + 1). Step D: Methyl 5-acetoxy-2-fluoro-4-( ^' (2-oxo-5-vinylpyi-idin-l(2H)-yl)methyl)benzoate

Methyl 5-acetoxy-4-((5-bromo-2-oxopyridin-l(2H)-yl)methyl)-2-fluoro benzoate (1.6 g, 4.02 mmol), 1 , l'-bis(di-ier/-butylphosphino ferrocene palladium dichloride (0.524 g, 0.804 mmol) and Na ₂ C0 ₃ (1.278 g, 12.05 mmol) were dissolved in dioxane (16.07 mL) and water (4.02 mL). Vinylboronic acid dibutyl ester (1.152 mL, 5.22 mmol) was added and the resultant mixture degassed. The reaction mixture was warmed to 80 °C in a microwave reactor and allowed to stir under an atmosphere of nitrogen for 1 h. The mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (40%- 100%) to give the title compound. MS: mlz = 345.8 (M + l).

Step E: Methyl 2-fluoro-5-hvdroxy-4-((2-oxo-5-vinylpyridin-l(2H)-yl)methyl) benzoate

K ₂ C0 ₃ (680 mg, 4.92 mmol) was added to a stirred, room temperature mixture of methyl 5-acetoxy-2-fluoro-4-((2-oxo-5-vinylpyridin-l(2H)-yl)methyl) benzoate (850 mg, 2.461 mmol) in methanol (10 mL). The reaction mixture was allowed to stir at room temperature for 30 min. The mixture was diluted with ethyl acetate (80 mL), washed with water (1 x 10 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure to give the title compound. MS: m/z = 303.9 (M + 1).

Step F: Methyl 2-fluoro-5-hvdroxy-4-((2-oxo-5-vinylpyi-idin-l(2H)-yl)methyl )benzoate

3-(4-bromophenyl)-6-isopropyIpyridazine (548 mg, 1.978 mmol), methyl 2- fluoro-5-hydroxy-4-((2-oxo-5-vinylpyridin-l(2H)-yl)methyl)be nzoate (400 mg, 1.319 mmol), bis(tetrabutylammonium)copper(I) iodide (148 mg, 0.264 mmol), copper(I) chloride (131 mg,

1.319 mmol) and Cs ₂ C0 ₃ (1289 mg, 3.96 mmol) were dissolved in degassed NMP (6.594 mL).

2,2,6,6-Tetramethyl-3,5-heptanedione (122 mg, 0.659 mmol) was added and the reaction mixture was warmed to 70 °C. The reaction mixture was allowed to stir for 14 h. The reaction mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous ammonium chloride (saturated, 1 x 10 mL) and water (3 x 10 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (50%- 100%), to give the title compound. MS: mlz = 500.8 (M + 1).

Step G: Methyl 2-fluoro-4-((5-formyl-2-oxopyiidin-K2H)-yl)methyl)-5-i4-(6- isopropylpyridazin-3-yl)phenoxy)benzoate

Sodium periodate (1.079 g, 5.04 mmol) was added to a stirred, room temperature mixture of methyl 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxo- 5-vinylpyridin- l(2H)-yl)methyl)benzoate (0.84 g, 1.682 mmol) and osmium tetroxide (2.5% in tert-butanol) (1.478 ml, 0.118 mmol) in tetrahydrofuran (8.43 ml)/water (4.21 ml). The reaction mixture was allowed to stir for 14 h. Aqueous sodium thiosulfate (saturated, 10 mL) and aqueous sodium hydrogen carbonate (saturated, 10 mL) were added and the mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were washed with brine (10 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure to give the title compound. MS: mlz = 502.1 (M + 1).

Step H: Methyl 4-((5-(difluoromethyl)-2-oxopyridin-l(2H)-yl)methyl)-2-fluor o-5-(4-(6- isopropylpyridazin-3-yl)phenoxy)benzoate

Bis(2-methoxyethyl)aminosulfur trifluroide (50% solution in THF) (6.102 mL, 14.76 mmol) was added to a stirred, room temperature mixture of methyl 2-fluoro-4-((5-formyl- 2-oxopyridin-l(2H)-yl)methyl)-5-(4-(6-isopropylpyridazin-3-y l)phenoxy)benzoate (740 mg, 1.476 mmol) in THF (7.38 mL). The reaction mixture was warmed to 70 °C allowed to stir for 14 h. The mixture was concentrated and the the residue was purified by column chromatography on silica gel, eluting with 50% EtOAc in isohexane, to give the title compound. MS: mlz = 524.1 (M + l).

Step I: 4-(( 5-(difluoromethyl)-2-oxopyridin-l (2H)-yl)methyl)-2-fluoro-5-(4-(6-is

opropylpyridazin-3 -yl)phenoxy)benzoic acid

Lithium hydroxide monohydrate (80 mg, 1.910 mmol) was added to a stirred, room temperature mixture of methyl 4-((5-(difluoromethyl)-2-oxopyridin-l (2H)-yl)methyl)-2- fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)benzoate (500 mg, 0.955 mmol) in

tetrahydrofuran (4.776 mL)/MeOH (2.388 mL)/water (2.388 mL). The reaction mixture was allowed to stir at room temperature for 2 h. The mixture was concentrated, the residue was diluted with ethyl acetate (20 mL), the aqeuous layer was acidified with hydrochloric acid (2M) to pH ~4, and extracted with ethyl acetate (2 x 10 mL). The combined organic phase was dried (MgSC>4), filtered, and concentrated to give the title compound. MS: mlz = 510.0 (M + 1).

(S)-3-(4-Chlorophenoxy)-N-( 1 -cvclopentylpiperidin-4-yl)-4- (4-methyl-2-oxopyrrolidin- 1 - vDmethyllbenzamide Step A:(S)-Methyl 3-(4-chlorophenoxy)-4- (4-methyl-2-oxopyrrolidin-l-yl)methyl)1benzoate

l-Chloro-4-iodobenzene (2.3 g, 9.5 mmol) was added to a solution of (S)-mefhyl

3-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]benzoa te, (2.0 g, 7.6 mmol), 2,2,6,6- tetramethyl-3,5-heptanedione (0.87 mL, 4.2 mmol), copper (I) chloride (0.83 g, 8.4 mmol), and cesium carbonate (7.42 g, 22.8 mmol) in ΝΜΡ (13 mL). The resulting mixture was deoxygenated and stirred under N ₂ at 80 °C for 3 h. The reaction mixture was cooled to 23 °C, diluted with saturated NH ₄ C1 solution (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with H ₂ 0 (2 x 10 mL), saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with gradient of hexane and EtOAc: 100:0 to 0: 100. The desired fractions were combined and repurified by reverse-phase HPLC, eluting with 10% acetonitnle in water (0.1% formic acid used as a modifier) initially, grading to 90% acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS: mlz = 374.2 (M + 1).

Step B: (S)-3-(4-ChloiOphenoxy)-4- (4-methyl-2-oxopyrrolidin-l -yl)methyl]benzoic acid

A mixture of aqueous sodium hydroxide (1 M, 2.41 mL, 2.41 mmol) and (S)- methyl 3-(4-chlorophenoxy)-4-[(4-methyl-2-oxopyrrolidin-l -yl)methyl]benzoate, (300 mg, 0.80 mmol) in MeOH (3.2 mL) and THF (13 mL) stirred at 50 °C for 1.5 h. The reaction mixture was cooled to 23 °C and concentrated hydrochloric acid (37%, aqueous, 0.198 mL, 2.41 mmol) was added. The reaction mixture was concentrated, the residue dissolved in H ₂ 0 (10 mL) and C¾CN (10 mL), and then lyophilized to give the title compound. MS: mlz = 360.1 (M + 1).

Step C: (S)-3-(4-Chlorophenoxy)-N-( 1 -cvclopentylpiperidin-4-yl)-4- (4-methyl-2-oxopyrrolidin- 1 -yl)methyl]benzamide

PyBOP (313.5 mg, 0.603 mmol) was added to a solution of (S)-3-(4- chlorophenoxy)-4-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]benz oic acid (237 mg, 0.402 mmol), 1 -cyclopentylpiperidin-4-amine dihydrochloride (174 mg, 0.732 mmol), and triethylamine (0.42 mL, 3.0 mmol) in DMF (8 mL) at 23 °C and the resulting mixture stirred at 23 °C for 4 h. The reaction mixture was partitioned between H ₂ 0 (10 mL) and EtOAc (30 mL). The organic layer was washed with H ₂ 0 (3 x 5 mL), saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with gradient of CH ₂ Cl2:(CH ₃ 0H:CH ₂ Cl2, 10:90), 90: 10 to 0: 100, to give the title compound. MS: m/z = 510.3 (M + 1).

(S)-3-Hvdroxy-4- (4-methyl-2-oxopyrrolidin-l -yl)methyll-N-ri-(tetrahvdro-2H-pyran-4- yl)piperidin-4-yl]benzamide

Step A: (SWe -Butyl 4-{3-hvdroxy-4- (4-methyl-2-oxopyrrolidin-l- vDmethyllbenzamido } piperidine- 1 -carboxylate

To a solution of (S)-3-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]benzo ic acid (540 mg, 2.17 mmol) in DMF (6 mL) at 23 °C was added ieri-butyl 4-aminopiperidine-l- carboxylate (434 mg, 2.17 mmol), EDC (831 mg, 4.33 mmol), HOBt (332 mg, 2.17 mmol), and DIPEA (1.90 mL, 10.8 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was partitioned between EtOAc (40 mL) and water (3 x 15 mL). The organic layer was dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of CH ₂ Cl ₂ :methanol:NH ₄ OH, 100:0:0 to 95:5:0.5, to give the title compound. MS: m/z = 432.2 (M+l).

Step B: (S -3-Hvdroxy-4-r(4-methyl-2-oxopyrrolidin-l-yl)methyl]-N-(pipe ridin-4-yl)benzamide hydrochloride

(S)-/er/-Butyl 4-{3-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l- yl)methyl]benzamido}piperidine-l-carboxylate (300 mg, 0.695 mmol) was dissolved in 4 M HC1 in 1 ,4-dioxane (5 mL) and water (0.5 mL) and the reaction mixture was stirred at 23 °C for 2 h. The reaction mixture was concentrated to give the title compound. MS: m/z = 332.21 (M+l).

Step C: (S)-3-Hvdroxy-4-r(4-methyl-2-oxopyrrolidin-l -yl)methyl ^" |-N-[ 1 -(tetrahvdro-2H-pyran-4- yl)piperidin-4-yl1benzamide

To a solution of (S)-3-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-N-

(piperidin-4-yl)benzamide hydrochloride (254 mg, 0.690 mmol) in THF (5 mL) at 23 °C was added acetic acid (0.5 mL) and dihydro-2H-pyran-4(3H)-one (0.128 mL, 1.38 mmol) and the reaction mixture was stirred for 15 mins. The reaction mixture was cooled to 0 °C, sodium triacetoxyborohydride (293 mg, 1.38 mmol) added, the reaction was warmed to 23 °C, and stirred for 2 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 mL) and CH ₂ C1 ₂ (20 mL). The organic layer was washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of CH ₂ Cl ₂ :MeOH:NH ₄ OH, 100:0:0 to 90: 10: 1, to give the title compound. MS: m/z = 416.3 (M+l).

3-(4-((Cyclopropylmethyl)carbamoyl)benzyl)-4-((2-oxopyrrolid in-l -yl)methyl)benzoic acid

Step A: Methyl 4-((2-oxopyrrolidin-l-yl)methyl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yPbenzoate PdCl ₂ (dppf) (29 mg, 0.040 mmol) was added to a mixture of methyl 3-bromo-4- ((2-oxopynOlidin-l-yl)methyl)benzoate (250 mg, 0.80 mmol, prepared from methyl 3-bromo-4- (bromomethyl)benzoate using methods described above), bis(pinacolato)diboron (250 mg, 1.0 mmol), and potassium acetate (160 mg, 1.6 mmol) in dioxane (5 mL). The resulting mixture was heated at 80 °C for 18 h. The mixture was cooled to 23 °C and concentrated. Purification of the residue by silica gel chromatography (100→ 90% CH ₂ C1 ₂ / MeOH) gave the title compound. LC-MS m/z found = 360.4 [M+l].

Step B: 4-(5-(Methoxycarbonyl)-2-((2-oxopyrrolidin-l-yl)methyl)benzy l)benzoic acid

Sodium carbonate (210 μΐ , aqueous, 2 M, 0.42 mmol) was added to a solution of methyl 4-((2-oxopyrrolidin-l-yl)methyl)-3-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2-yl)benzoate (50 mg, 0.14 mmol), 4-bromomethylbenzoic acid mono teri-butyl ester (49 mg, 0.18 mmol), and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (5.7 mg, 7.0 μιηοΐ) in DMF (700 μί). The resulting mixture was stirred at 85 °C for 30 min. The mixture was cooled to 23 °C and filtered through a syringe filter washing with DMF (1 mL). Purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) followed by addition of excess TFA and

concentration gave the title compound. LC-MS m/z found = 368.2 [M+l].

Step C: Methyl 3-(4-((cvclopropylmethyl)carbamoyl)benzyl)-4-((2-oxopyrrolid in-l- vDmethvDbenzoate

N-Methylmorpholine (18 μΤ, 0.16 mmol) was added to a solution of 4-(5- (methoxycarbonyl)-2-((2-oxopyrrolidin-l-yl)methyl)benzyl)ben zoic acid (15 mg, 0.041 mmol), cyclopropylmethylamine (7.1 0.082 mmol), EDC (14 mg, 0.071 mmol), and HOAt (2.8 mg, 0.020 mmol) in DMF (450 iL). The resulting solution was stirred at 40 °C for 1 h. The mixture was cooled to 23 °C and TCFH (11 mg, 0.041 mmol) was added. The reaction mixture was stirred for 1 h and then diluted with water (100 μί). Purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1 % trifluoroacetic acid) gave the title compound. LC-MS m/z found = 421.4 [M+l]. Step D: 3-(4-((CvclopiOpylmethyl)carbamoyl)benzyl)-4-((2-oxopyrrolid in-l-yl)methyl)benzoic acid

A mixture of NaOH (140 μί, aqueous, 1 M, 0.14 mmol) and methyl 3-(4- ((cyclopropylmethyl)carbamoyl)benzyl)-4-((2-oxopyrrolidin-l- yl)methyl)benzoate (10 mg, 0.024 mmol) in MeOH (250 ih) was stirred at 23 °C for 1 h. Aqueous HC1 (6 M, 24 ί, 0.14 mmol) was added and the mixture was concentrated to give the title compound and six equivalents of NaCl. LC-MS m/z found = 407.3 [M+l].

N-(3-Amino-4,4-difluorobutyl)-3-((6-(m

vDmethvDbenzamide

Step A: fe -Butyl (1 J-difluoro-4-(3-((6-(methylsulfonyl)pyridin-3-yl)oxy)-4-((2- oxopyrrolidin- l-yl)methvDbenzamido)butan-2-vDcarbamate

N-Methylmorpholine (8.8 μΐ, 0.080 mmol) was added to a solution of 3-((6-

(methylsulfonyl)pyridin-3-yl)oxy)-4-((2-oxopynOlidin-l -yl)methyl)benzoic acid with three equivalents of sodium chloride (15 mg, 0.027 mmol), tert-butyl (4-amino-l,l-difluorobutan-2- yl)carbamate maleic acid salt (9.0 mg, 0.027 mmol), EDC (7.6 mg, 0.040 mmol), and HOAt (1.08 mg, 7.95 μιηοΐ) in ΝΜΡ (265 μΐ). The resulting mixture was heated at 50 °C for 1 h. The mixture was cooled to 23 °C and filtered through a syringe filter washing with DMF (500 uL). Purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.01% ammonium hydroxide) gave the racemic title compound. LC-MS m/z found— 497.2 [M-Boc+1].

Step B: N-(3-Amino-4,4-difluorobutyl)-3-((6-(methylsulfonyl)pyridin- 3-yl)oxy)-4-((2- oxopyrrolidin- 1 -vDmethvDbenzamide

Hydrogen chloride (4 M in dioxane, 37.3 μΐ, 0.149 mmol) was added to a solution of tert-butyl (l , l-difluoro-4-(3-((6-(methylsulfonyl)pyridin-3-yl)oxy)-4-((2- oxopyrrolidin-l- yl)methyl)benzamido)butan-2-yl)carbamate (8.9 mg, 0.015 mmol). The resulting mixture was stirred at 23 °C for 10 min. The mixture was concentrated to give the title compound (mixture of isomers) as the HC1 salt. LC-MS m/z = 497.2 [M+l]. Ή NMR (499 MHz, DMSO): δ 8.83 (t, J = 5.7 Hz, 1 H); 8.53 (d, J = 3.0 Hz, 1 H); 8.04 (d, J = 8.7 Hz, 1 H); 7.84 (d, J = 7.9 Hz, 1 H); 7.64 (s, 1 H); 7.51-7.49 (m, 2 H); 6.36 (t, J = 53.9 Hz, 1 H); 4.42 (s, 2 H); 3.71 -3.66 (m, 1 H); 3.47-3.44 (m, 1 H); 3.36-3.34 (m, 1 H); 3.27 (s, 3 H); 3.21 (t, J = 7.1 Hz, 2 H); 2.1 1 (t, J = 8.0 Hz, 2 H); 1.95-1.91 (m, 2 H); 1.85-1.81 (m, 4 H). EXAMPLE 2

N-((2,4-Dimethyloxazol-5-yl)methyl)-3-(4-(ethylcarbamoyl)phe noxy)-4-((2-oxopiperidin-l- vDmethyDbenzamide

N-Methylmorpholine (10.6 mg, 0.105 mmol) was added to a solution of 3-(4- (ethylcarbamoyl)phenoxy)-4-((2-oxopiperidin-l-yl)methyl)benz oic acid with three equivalents of sodium chloride (15 mg, 0.026 mmol), 5-(aminomethyl)-2,4-dimethyloxazol-3-ium chloride (6.4 mg, 0.039 mmol), EDC (8.8 mg, 0.046 mmol), and HOAt (1.8 mg, 0.013 mmol) in DMF (262 μΐ). The resulting mixture was heated at 50 °C for 30 min. The reaction mixture was diluted with water (200 μΐΐ,). Purification by reverse phase HPLC (C-18, 95→ 5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound as the TFA salt. HRMS m/z found = 505.2446 [M+l]. Ή NMR (499 MHz, DMSO): δ 8.94 (t, J = 5.4 Hz, 1 H); 8.40 (t, J = 5.5 Hz, 1 H); 7.86 (d, J = 8.4 Hz, 2 H); 7.72 (d, J = 8.1 Hz, 1 H); 7.48 (s, 1 H); 7.36 (d, J = 8.0 Hz, 1 H); 6.98 (d, J = 8.4 Hz, 2 H); 4.51 (s, 2 H); 4.37 (d, J = 5.4 Hz, 2 H); 3.27 (p, J = 6.6 Hz, 2 H); 3.20- 3.18 (m, 2 H); 2.29 (s, 3 H); 2.21 (t, J = 5.8 Hz, 2 H); 2.04 (s, 3 H); 1.68-1.63 (m, 4 H); 1.11 (t, J = 7.2 Hz, 3 H).

3 -(4-(Cvclopropylcarbamoyl)phenoxy)-N-(2-( 1 -(4-fluorobenzyl)- 1 H-imidazol-5-yl)ethyl)-4-( (2- oxopyrrolidin- 1 -yl)methyl)benzamide

To a mixture of 3-(4-(cyclopropylcarbamoyl)phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoic acid with three equivalents of sodium chloride (20 mg, 0.035 mmol), mono(2- (1 -(4-fluorobenzyl)- lH-imidazol-5-yl)ethanaminium) dichloride (20 mg, 0.070 mmol), HOAt (4.8 mg, 0.035 mmol), and EDC (13 mg, 0.070 mmol) in DMF (0.35 mL) was added 4- methylmorpholine (0.019 mL, 0.18 mmol) and the resulting mixture was stin-ed at 23 °C for 16 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 40% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound.

HRMS: m/z = 596.2668 (M + 1). Ή NMR (500 MHz, CD ₃ OD): δ 7.83 (d, J = 8.6 Hz, 2 H); 7.68 (s, 1 H); 7.63 (dd, J = 7.9, 1.7 Hz, 1 H); 7.47 (d, J = 8.0 Hz, 1 H); 7.42 (d, J = 1.7 Hz, 1 H); 7.16 (t, J = 6.6 Hz, 2 H); 7.06 (t, J = 8.6 Hz, 2 H); 6.99 (d, J = 8.6 Hz, 2 H); 6.83 (s, 1 H); 4.53 (s, 2 H); 3.50 (t, J - 7.1 Hz, 2 H); 3.35 (t, J = 7.0 Hz, 2 H); 2.83-2.84 (m, 1 H); 2.78 (t, J = 7.1 Hz, 2 H); 2.28 (t, J = 8.1 Hz, 2 H); 1.93-1.95 (m, 2 H); 0.80-0.82 (m, 2 H); 0.63-0.65 (m, 2 H).

N-(l-Benzyl-5-oxopyrrolidin-3-yl)-3-(4-((2-fluorophenyl)c arbamoyl)phenoxy)-4-((2- oxoimidazolidin- 1 -vDmefhvDbenzamide

A mixture of 4-(5-((l-benzyl-5-oxopyrrolidin-3-yl)carbamoyl)-2-((2- oxoimidazolidin-l-yl)methyl)phenoxy)benzoic acid (50 mg, 0.095 mmol), 2-fluoroaniline (13 mg, 0.1 1 mmol), HATU (43 mg, 0.1 1 mmol), and Et ₃ N (29 mg, 0.28 mmol) in DMF (4 mL) was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound (mixture of isomers) as a yellow solid. MS: m/z = 622.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.95 (dd, J = 2.0, 6.8 Hz, 2H), 7.70- 7.64 (m, 2H), 7.49-7.45 (m, 2H), 7.28-7.14 (m, 8H), 7.02 (dd, J = 2.0, 6.8 Hz, 2H), 4.61-4.56 (m, 1H), 4.50-4.43 (m, 2H), 4.37 (s, 2H), 3.68-3.63 (m, 1H), 3.34-3.20 (m, 5H), 2.87-2.80 (m, 1H), 2.54-2.49 (m, 1H).

EXAMPLE 5

3-(4-(f2^-Dimethylphenyl)^

oxoimidazolidin- 1 -yl)methyl)benzamide

To a solution of 4-(5-((2-(5-methyl-lH-imidazol-4-yl)ethyl)carbamoyl)-2-((2- oxoimidazolidin- 1 -yl)methyl)phenoxy)benzoic acid (30 mg, 0.65 mmol) in DMF (5 mL) was added 2,4-dimethylaniline (9.4 mg, 0.78 mmol), Et ₃ N (20 mg, 0.20 mmol), and HATU (45 mg, 0.12 mmol). The resulting mixture was stirred at 23 °C for 16 h and then concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a white solid. MS: m/z = 567.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 5 7.96 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 1.6, 8.0 Hz, 1H), 7.49-7.42 (m, 3H), 7.15 (d, J = 7.6 Hz, 1H), 7.08-7.00 (m, 4H), 4.39 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 3.38-3.33 (m, 4H), 2.77 (t, J = 7.2 Hz, 2H), 2.29 (s, 3H), 2.22 (s, 3H), 2.08 (s, 3H).

N-[(3S)-l -Cyclopropyl-5-oxopyiTOlidin-3-yl]-4- ([(^

[4-(tetrahvdro-2H-pyran-4-ylcarbamoyl)phenoxy1benzamide

To a solution of 4-{[(^S)-2-oxo-4-phenylpyrrolidin-l-yl]methyl}-3-[4-(tetrahy dro- 2H-pyran-4-ylcarbamoyl)phenoxy]benzoic acid (26 mg, 0.051 mmol) in DMF (1 mL) was added (4S)-4-amino-l -cyclopropylpyrrolidin-2-one hydrochloride (9.8 mg, 0.056 mmol), HATU (25 mg, 0.066 mmol), and ΝΜΜ (0.017 mL, 0.15 mmol) and the resulting mixture was stirred at 23 °C for 18 h. The reaction mixture was quenched with water, filtered, and purified via reverse- phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. HRMS: mlz = 637.3013 (M+l). Ή NMR (400 MHz, CDC1 ₃ ) δ 7.71 (m, 2 H), 7.57 (d, 1 H, J = 8.0 Hz), 7.41 -7.45 (m, 2 H), 7.32 (t, 2 H, J = 7.4 Hz ), 7.15 (d, 2 H, J = 7.5 Hz ), 6.91 (m, 3 H), 6.07 (dd, 1 H, J = 7.7 Hz), 4.61 (m, 1 H), 4.58 (m, 2 H), 4.2 (m, 1 H), 4.01 (d, J = 1 1.8 Hz, 2 H), 3.69-3.71 (m, 2 H), 3.54 (t, 1H, J = 1 1.9 Hz), 3.34 (d, 1 H, / = 8.3 Hz), 3.21 (d, 1 H, J = 10.7 Hz), 2.81 (dd, 2 H, J = 17.0, 8.9 Hz), 2.54-2.63 (m, 2 H), 2.38 (m, 1 H), 1.99-2.04 (m, 2 H), 0.74 (m, 2 H), 0.65 (m, 2 H).

N-[(3S)-l-Cvclopropyl-5-oxopyrrolidin-3-yl]-4-{[(^R or ^S)-[2-oxo-4-phenylpyrrolidin-l - yl1methyl)-3-r4-(pyridin-4-ylcarbamoyl)phenoxy benzamide

4- { [(4R,S)-[2-Oxo-4-phenylpyrrolidin- 1 -yl]methyl} -3-[4-(pyridin-4- ylcarbamoyl)phenoxy]benzoic acid (75.3 mg, 0.1 10 mmol, with 3 eq. of sodium chloride), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (45.1 mg, 0.235 mmol), 1- hydroxy-7-azabenzotriazole (8.2 mg, 0.060 mmol), N-methylmorpholine (0.048 mL, 0.44 mmol), and (^R,S)-4-amino-l -cyclopropyl-2-pyrrolidinone hydrochloride (24.3 mg, 0.138 mmol) were dissolved in NN-dimethylfonnamide (1.1 mL) at 25 °C. The reaction mixture was heated at 50 °C and stirred for 10 min. The reaction was diluted with water (ca 0.3 mL) and trifluoroacetic acid (ca 0.3 mL). The reaction mixture was purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water (10-85%) acetonitrile) with 0.1% trifluoroacetic acid. The product fractions were treated with solid sodium bicarbonate and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (1 x 10 mL), dried (sodium sulfate), and concentrated to give four diastereomers of the title compound as a white solid. The diastereomers were separated on a Chiralpak AS-H column, eluting with supercritical carbon dioxide/ethanol (65/35) with 0.1% diethylamine. Two peaks were recovered, each containing two compounds. Peak 1 from the first separation was further separated on a Chiralcel OJ-H column, eluting with supercritical carbon dioxide/methanol (70/30) with 0.1% diethylamine. Each of these diastereomers were then further purified by preparative HPLC (Reverse phase (C-18), loading in DMF), eluting with acetonitrile/water (10-85% acetonitrile) with 0.1% trifluoroacetic acid. The product fractions of each treated with solid sodium bicarbonate and extracted with ethyl acetate (2 x 15 mL). The combined organic layers of each were washed with saturated aqueous sodium chloride solution (1 x 10 mL), dried (sodium sulfate), and concentrated. First eluting diastereomer (A, peak 1 from AS-H and OJ-H separations) recovered as a white solid. Second eluting diastereomer (B, (title compound) peak 1 from AS-H separation, peak 2 from OJ-H separation) recovered as a white solid. Peak 2 from the AS-H separation was further separated on a Chiralcel OJ-H column, eluting with supercritical carbon dioxide/methanol (75/25) with 0.1% diethylamine. First eluting diastereomer (C, peak 2 from AS-H separation, peak 1 from OJ-H separation) recovered as a white solid. Second eluting diastereomer (D, peak 2 from AS-H separation, peak 2 from OJ-H separation) recovered as a white solid. Diastereomer B (title compound): HRMS found mlz = 630.2705 (M+l). Ή NMR (400 MHz, CDC1 ₃ ): δ 9.36 (s, 1 H); 8.47 (d, J = 5.4 Hz, 2 H); 8.20 (d, J = 6.9 Hz, 1 H); 7.77 (d, J = 8.0 Hz, 4 H); 7.71 (dd, J = 8.0, 1.7 Hz, 1 H); 7.58

(d, J = 1.7 Hz, 1 H); 7.31-7.33 (m, 3 H); 7.22-7.28 (m, 1 H); 7.16-7.18 (m, 2 H); 6.72 (d, J = 8.5 Hz, 2 H); 4.58 (s, 1 H); 4.44 (q, J = 15.5 Hz, 2 H); 3.65-3.67 (m, 2 H); 3.56 (t, J = 8.3 Hz, 1 H); 3.36 (dd, J = 9.5, 7.2 Hz, 1 H); 3.13 (dd, J = 10.6, 3.3 Hz, 1 H); 2.83 (dd, J = 17.0, 8.9 Hz, 1 H); 2.58-2.60 (m, 3 H); 2.24 (dd, J = 17.3, 4.0 Hz, 1 H); 2.08 (s, 1 H); 0.69-0.71 (m, 2 H); 0.59-0.61 (m, 2 H).

N-(l-Cvclopropyl-5-oxopyriOlidin-3-yl)-4-((2-oxopwrolidm^

2H-pyran-4-yl)-l ,3,4-thiadiazol-2-yl)phenoxy)benzamide

N-Methylmorpholine (13.4 μΐ, 0.122 mmol) was added to a solution of 4-((2- oxopyrrolidin-l-yl)methyl)-3-(4-(5-(tetrahydro-2H-pvran-4-yl )-l ,3,4-thiadiazol-2- yl)phenoxy)benzoic acid with three equivalents of sodium chloride (20 mg, 0.031 mmol), 4- amino-l-cyclopropyl-pyrrolidin-2-one hydrochloride (6.7 mg, 0.038 mmol), EDC (10.3 mg, 0.053 mmol), and HOAt (2.1 mg, 0.015 mmol) in DMF (305 μΐ). The resulting solution was stirred at 50 °C for 30 min and then water (200 μί,) was added. Purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound as the TFA salt. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound (mixture of isomers). HRMS m/z found = 602.2427 [M+l]. ^l H NMR (500 MHz, DMSO): δ 8.75 (d, J = 6.7 Hz, 1 H); 7.96 (d, J - 8.5 Hz, 2 H); 7.77 (dd, J = 8.0, 1.7 Hz, 1 H); 7.57 (d, J = 1.7 Hz, 1 H); 7.44 (d, J = 8.0 Hz, 1 H); 7.06-7.05 (m, 2 H); 5.76 (d, J = 7.0 Hz, 1 H); 4.40 (s, 2 H); 3.94 (d, J = 11.3 Hz, 2 H); 3.59 (dd, J = 10.0, 7.4 Hz, 1 H); 3.50-3.48 (m, 2 H); 3.22 (t, J = 7.0 Hz, 1 H); 3.12 (dd, J = 10.0, 4.1 Hz, 1 H); 2.98-2.97 (m, 1 H); 2.64-2.62 (m, 2 H); 2.32 (dd, J = 17.0, 4.9 Hz, 1 H); 2.16-2.14 (m, 3 H); 2.03 (dd, J = 13.1 , 3.6 Hz, 2 H); 1.83-1.79 (m, 3 H); 1.48-1.47 (m, 1 H); 0.97 (t, J = 7.2 Hz, 1 H); 0.63 (d, J = 6.7 Hz, 4 H).

EXAMPLE 9

N-(l-Methyl-5-oxopyrrolidin-3-yl)-3-(4-(5-methylpyrazin-2-yl )phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzamide

A mixture of 3-(4-(5-methylpyrazin-2-yl)phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoic acid (21 mg, 0.051 mmol), 4-amino-l -methylpyiTolidin-2-one (5.8 mg, 0.051 mmol), HATU (23 mg, 0.061 mmol), and Et ₃ N (2 mL) in DMF (2 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 95% acetonitrile in water) gave the title compound (mixture of isomers) as the TFA salt. MS: m/z = 500.2 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.96 (s, 1H), 8.59 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 9.6 Hz, 1H), 7.54 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.1 1 (d, J = 8.8 Hz, 2H), 4.68-4.61 (m, 1H), 4.58 (s, 2H), 3.83 (dd, J = 7.6, 10.4 Hz, 1H), 3.40-3.37 (m, 3H), 2.85-2.78 (m, 4H), 2.60 (s, 3H), 2.46 (dd, J = 4.4, 17.2 Hz, 1H), 2.31 (t, J = 8.0 Hz, 2H), 2.00-1.93 (m, 2H).

( _l $ -3-(4-n-Cvclobutyl-l,2,4-oxadiazol-5-yl)phenoxy)-N-(l-cyclop ropyl-5-oxopwolidin-3-yl)-4- ((2-oxopyrrolidin- 1 -yl)methyl)benzamide

N-Methylmorpholine (11.6 μΐ, 0.105 mmol) was added to a solution of 3-(4-(3- cyclobutyl-l,2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxopyrrolidin -l-yl)methyl)benzoic acid with three equivalents of sodium chloride (16 mg, 0.026 mmol), (S)-4-amino-l-cyclopropyl- pyrrolidin-2-one (4.6 mg, 0.033 mmol), EDC (8.8 mg, 0.046 mmol), and HOAt (1.8 mg, 0.013 mmol) in DMF (260 μΐ). The resulting solution was stirred at 50 °C for 30 min and then water (200 \L) was added. Purification by reverse phase HPLC (C- 18, 95— 5% water/ acetonitrile with 0.1 % trifluoroacetic acid) gave the title compound as the TFA salt. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. HRMS m/z found = 556.2535 [M+l]. Ή NMR (500 MHz, DMSO): 8 8.76 (d, J = 6.7 Hz, 1 H); 8.1 1 (d, J = 8.5 Hz, 2 H); 7.80 (dd, J = 8.0, 1.7 Hz, 1 H); 7.62 (s, 1 H); 7.46 (d, J = 8.0 Hz, 1 H); 7.10 (d, J = 8.5 Hz, 2 H); 4.38 (s, 2 H); 3.72- 3.70 (m, 1 H); 3.59 (dd, J = 10.0, 7.4 Hz, 1 H); 3.20 (t, J = 7.0 Hz, 2 H); 3.13 (dd, J = 10.0, 4.1 Hz, 1 H); 2.65-2.63 (m, 2 H); 2.34-2.32 (m, 5 H); 2.10-2.08 (m, 3 H); 1.97 (br s, 1 H); 1.83 (p, J = 7.5 Hz, 2 H); 0.63 (d, J = 6.7 Hz, 4 H).

EXAMPLE 1 1

3-(4-Chloro-3-fluorophenoxy)-N-(3-chlorobenzyl)-4-((2-oxopyr rolidin-l-yl)methyl) benzamide

(Benzotriazol- 1 -yloxy)ira(dimethylamino)phosphonium hexafluorophosphate (86 mg, 0.20 mmol) was added to a solution of 3-(4-chloro-3-fluorophenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzoic acid (70 mg, 0.13 mmol), (3-chlorophenyl)methanamine, (18 mg, 0.13 mmol), and triethylamine (0.04 mL, 0.3 mmol) in DMF (1 mL) and the resulting mixture was stirred at 23 °C for 18 h. The reaction mixture was purified by reverse phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were eluted through a varian 0.4 g CX column, eluting with methanol then with 2 M NH ₃ /MeOH. The basic eluent was concentrated to give the title compound. MS: mlz = 488.0 (M + 1) . Ή NMR (500 MHz, CD ₃ OD) δ 7.73 (m, 1H), 7.42-7.50 (m, 3H), 7.24-7.33 (m, 4H), 6.92 (m, 1H), 6.77 (m, 1H), 4.86 (d, J = 1.4 Hz, 2H), 4.52 (d, J = 8.8 Hz, 2H), 3.39 (m, 2H), 2.31 (t, J = 8.1 Hz, 2H), 1.96 (m, 2H).

N-r(3S)-l-Cvclopropyl-5-oxopyrrolidin-3-yll-2-fluoro-4-(r(^S or ^R)-4-(4-methoxyphenyl)-2- oxopyrrolidin-l -yl]methyl}-5-r4-(3-methyl-L2,4-oxadiazol-5-yl)phenoxylbenza mide

To a solution of 2-fluoro-4- {[(4S or 4i?)-4-(4-methoxyphenyl)-2-oxopyrrolidin-l- yl]methyl}-5-[4-(3-methyl-l ,2,4-oxadiazol-5-yl)phenoxy]benzoic acid

(12 mg, 0.023 mmol) in DMF (1 mL) was added ( S)-4-amino-l-cyclopropylpyrrolidin-2-one hydrochloride (4.5 mg, 0.026 mmol), HATU (8.8 mg, 0.023 mmol), and TEA (10 uL, 0.07 mmol). The resulting mixture was stirred at 23 °C for 30 min. The reaction mixture was diluted with water, filtered, and purified via reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. HRMS: mlz = 640.2555 (M+l). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.08 (dd, J = 8.7, 2.3 Hz, 2 H); 7.72 (d, J = 6.4 Hz, 1 H); 7.20 (d, J = 1 1.7 Hz, 1 H); 7.08 (d, J = 8.3 Hz, 2 H); 7.01 (d, J = 8.5 Hz, 2 H); 6.88-6.90 (m, 1 H); 6.86 (d, J = 8.3 Hz, 2 H); 4.68 (s, 1 H); 4.53-4.55 (m, 2 H); 3.80 (s, 3 H); 3.76-3.78 (m, 1 H); 3.66 (t, J = 8.9 Hz, 1 H); 3.48-3.50 (m, 1 H); 3.27-3.28 (m, 2 H); 2.88 (dd, J = 17.3, 8.4 Hz, 1 H); 2.79 (dd, J = 17.0, 8.9 Hz, 1 H); 2.67-2.69 (m, 1 H); 2.54 (dd, J = 17.0, 8.6 Hz, 1 H); 2.47 (s, 3 H); 2.40 (dd, J = 17.3, 4.8 Hz, 1 H); 0.78-0.80 (m, 4 H).

N-((S -l -Cyclopropyl-5-oxopyrrolidin-3-yl)-3-(4-(5-methyl-1 ,4-thiadiazol-2-yl)phenoxy)-4-((2- oxo-4-(trifluoromethyl)pyrrolidin- 1 -yl)methyl)benzamide

N-Methylmorpholine (100 μΐ, 0.92 mmol) was added to a solution of 3-(4-(5- methyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxo-4-(trifluoromethyl)p yrrolidin-l- yl)methyl)benzoic acid with three equivalents of sodium chloride (150 mg, 0.23 mmol), (S)-4- amino- 1 -cyclopropylpyrrolidin-2-one (49 mg, 0.28 mmol), EDC (77 mg, 0.40 mmol), and HOAt (16 mg, 0.12 mmol) in DMF (2 mL) and the reaction mixture was stirred at 50 °C for 30 min. Water (200 μΕ) was added and purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound as the TFA salt. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound along with its diastereomer. The diastereomers were separated by chiral chromatography (ChiralPak AD-H column; 70% supercritical carbon dioxide and 30% methanol) to give diastereomer 1 (first eluted peak), LC- MS m/z found = 600.1 [M+l]; Ή NMR (500 MHz, DMSO): δ 8.75 (d, J = 6.7 Hz, 1 H); 7.95 (d, J = 8.4 Hz, 2 H); 7.76 (dd, J = 8.0, 1.7 Hz, 1 H); 7.55 (s, 1 H); 7.44 (d, J = 8.0 Hz, 1 H); 7.08 (d, J = 8.4 Hz, 2 H); 4.47-4.45 (m, 3 H); 3.58-3.56 (m, 2 H); 3.12 (dd, J = 10.0, 4.1 Hz, 1 H); 2.77 (s, 3 H); 2.62-2.59 (m, 5 H); 2.34-2.31 (m, 2 H); 0.64 (d, J = 6.8 Hz, 4 H) and diastereomer 2 (second eluted peak, title compound), LC-MS m/z found = 600.1 [M+l]; Ή NMR (500 MHz, DMSO): δ 8.76 (d, J = 6.7 Hz, 1 H); 7.95 (d, J = 8.4 Hz, 2 H); 7.76 (d, J = 8.0 Hz, 1 H); 7.55 (s, 1 H); 7.44 (d, J = 8.0 Hz, 1 H); 7.08 (d, J = 8.4 Hz, 2 H); 4.47-4.45 (m, 3 H); 3.58-3.56 (m, 2 H); 3.12 (dd, J = 10.0, 4.1 Hz, 1 H); 2.77 (s, 3 H); 2.62-2.59 (m, 5 H); 2.35-2.31 (m, 2 H); 0.63 (d, J = 6.8 Hz, 4 H).

(S)-N-(l-Cvclopropyl-5-oxopyrrolidin-3-yl)-3-((6-(3-methyl-l ,2,4-oxadiazol-5-yl)pyridin-3- yl)oxy)-4-((2-oxopyrrolidin- 1 -yl)methyl)benzamide

A mixture of 3-((6-(3-methyl-l,2,4-oxadiazol-5-yl)pyridin-3-yl)oxy)-4-((2 - oxopyrrolidin-l -yl)methyl)benzoic acid (85 mg, 0.25 mmol), (S)-4-amino-l- cyclopropylpyrrolidin-2-one (43 mg, 0.31 mmol), HATU (120 mg, 0.32 mmol) and Et ₃ N (180 uL, 1.3 mmol) in DMF (3 mL) was stirred at 23 °C under N ₂ for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05%> ammonia, V/V):acetonitrile to give the title compound. MS: m/z = 517.2 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 5 8.45 (d, J = 2.8 Hz, 1 H), 8.23 (d, J = 8.4 Hz, 1 H), 7.80 (dd, J = 1.6, 8.0 Hz, 1 H), 7.61 (d, J = 1.6 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.50 (dd, J = 3.2, 8.8 Hz, 1 H), 4.62-4.57 (m, 1 H), 4.55 (s, 2 H), 3.80-3.76 (m, 1 H), 3.37- 3.33 (m, 3 H), 2.85-2.78 (m, 1 H), 2.64-2.60 (m, 1 H), 2.48-2.43 (m, 4 H), 2.25 (t, J = 8.0 Hz, 2 H), 1.98-1.91 (m, 2 H), 0.76-0.72 (m, 4 H).

EXAMPLE 15

(S)-N-(l-Cyclopentylpiperidin-4-yl)-3-(4-(3 -methyl- L2,4-oxadiazol-5-yl)phenoxy)-4-((2-oxo-4- phenylpyrrolidin- 1 -yl)methyl)benzamide

(Benzotriazol- 1 -yloxy)irzs(dimethylamino)phosphonium hexafluorophosphate (32 mg, 0.074 mmol) was added to a solution of (S)-2-fluoro-5-(4-(3-methyl-l,2,4-oxadiazol-5- yl)phenoxy)-4-((2-oxo-4-phenylpyrrolidin-l-yl)methyl)benzoic acid (32 mg, 0.049 mmol), 1- cyclopentylpiperidin-4-amine (20 mg, 0.12 mmol), and triethylamine (0.03 mL, 0.2 mmol) in DMF (0.2 mL) and the resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water to give the title compound as the TFA salt. MS: mlz = 620.2 (M + 1). Ή NMR (500 MHz, DMSO): δ 9.06 (br s, 1 H); 8.51 (d, J = 7.3 Hz, 1 H); 8.10 (d, J = 8.3 Hz, 2 H); 7.80 (d, J = 7.9 Hz, 1 H); 7.62 (s, 1 H); 7.53 (d, J = 7.9 Hz, 1 H); 7.27-7.31 (m, 2 H); 7.19-7.23 (m, 2 H); 7.11 (d, J = 8.4 Hz, 2 H); 4.43-4.47 (m, 2 H); 3.59 (t, J = 9.0 Hz, 1 H); 3.45-3.51 (m, 3 H); 2.99-3.07 (m, 2 H); 2.50 (s, 3 H); 2.40 (s, 3 H); 2.02 (t, J = 14.2 Hz, 5 H); 1.62-1.71 (m, 6 H); 1.55 (br s, 3 H).

N-((S)-l -Cyclopropyl-5-oxopyrrolidin-3-yl)-3-(4-(6-methylpyridazin-3 -yl)phenoxy)-4-(((S)-2- oxo-4-phenylpyrrolidin-l-yl)methyl)benzamide To a mixture of (S)-3-(4-(6-methylpyridazin-3-yl)phenoxy)-4-((2-oxo-4- phenylpyrrolidin-l -yl)methyl)benzoic acid (60 mg, 0.13 mmol), HATU (71 mg, 0.17 mmol), and triethylamine (0.055 mL, 0.38 mmol) in DMF (3 mL) was added (S)-4-amino-l- cyclopropylpyrrolidin-2-one (21 mg, 0.15 mmol). The resulting mixture was stirred at 23 °C for 16 h and then concentrated. The residue was purified by reverse phase HPLC (Column:

Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V): acetonitrile to give the title compound as white solid. MS: m/z = 602.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.67 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.73 (dd, J = 1.6, 8.0Hz, 1H), 7.56-7.54 (m, 2H), 7.28-7.21 (m, 2H), 7.19-7.13 (m, 5H), 4.62-4.55 (m, 2H), 3.78- 3.70 (m, 2H), 3.52-3.42 (m, 1H), 3.35-3.30 (m, 2H), 2.86 (s, 3H), 2.79-2.62 (m, 3H), 2.48-2.42 (m, 2H), 0.75-0.70 (m, 4H).

3-(4-Chloro-3-fluorophenoxy)-N-((S)-l-cvclopropyl-5-oxopy rrolidin-3-yl -4-((2-oxo-4- phenylimidazolidin- 1 -yl methyl)benzamide

A mixture of 3-(4-chloro-3-fluorophenoxy)-4-((2-oxo-4-phenylimidazolidin- l - yl)methyl)benzoic acid (40 mg, 0.09 mmol), (S)-4-amino-l -cyclopropylpyrrolidin-2-one (20 mg, 0.14 mmol), Et ₃ N (52 uL, 0.37 mmol), and HATU (42 mg, 0.1 1 mmol) in DMF (3 mL) was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water: acetonitrile to give the title compound as a yellow oil. MS: m/z = 564.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 5 7.70 (dd, J = 1.6, 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.43 (t, J = 8.8 Hz, 1H), 7.36-7.29 (m, 5H), 6.90 (dd, J = 2.8, 10.4 Hz, 1H), 6.76 (dd, J = 2.8, 10.4 Hz, 1H), 4.76-4.74 (m, 1H), 4.62-4.58 (m, 1H), 4.46 (s, 2H), 3.82-3.75 (m, 2H), 3.33-3.30 (m, 1H), 3.13 (dd, J = 7.2, 8.8 Hz, 1H), 2.86-2.80 (m, 1H), 2.68-2.62 (m, 1H), 2.49 (dd, J = 4.8, 14.4 Hz, 1H), 0.77-0.72 (m, 4H).

(S)-N-(l-Cvclobutylpiperidin-4-yl)-3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin- 1 -vDmethvDbenzamide

A mixture of (S)-3-(4-(5-isopropyl-l,3,4-thiadiazol-2-yl)phenoxy)-4-((4-m ethyl-

2-oxopyrrolidin-l-yl)methyl)benzoic acid (60 mg, 0.13 mmol), l-cyclobutylpiperidin-4-amine (25 mg, 0.16 mmol), HATU (61 mg, 0.16 mmol), and Et ₃ N (0.055 mL, 0.4 mmol) in DMF (3 mL) was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a white solid. MS: m/z = 588.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 8 7.98 (d, J = 8.8 Hz, 2H), 7.74 (dd, J = 1.6, 8.0 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 4.60-4.50 (m, 2H), 4.01-3.95 (m, 1H), 3.53-3.47 (m, 2H), 3.11-3.08 (m, 3H), 2.97-2.93 (m, 1H), 2.50-2.39 (m, 2H), 2.26-2.13 (m, 4H), 2.03-1.93 (m, 5H), 1.80-1.71 (m, 4H), 1.49 (d, J = 6.8 Hz, 6H), 1.06 (d, J = 6.8 Hz, 3H).

3-(4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-N-( -methyl- l ,4'-bipiperidin1-4-yl)-4-((2- oxopyrrolidin- 1 -yl)methyl)benzamide

Step A: N-([ L4'-Bipiperidinl-4-yl)-3-(4-(5-isopropyl-L3,4-thiadiazol-2-y l)phenoxy)-4-((2- oxopyrrolidin-l-yl)methyl)benzamide 2,2,2-trifluoroacetate (Benzotriazol- 1 -yloxy) ra(dimethylamino)phosphonium hexafluorophosphate (91 mg, 0.21 mmol) was added to a solution of 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4- ((2-oxopyn lidin-l-yl)methyl)benzoic acid, (60 mg, 0.14 mmol), [l ,4'-bipiperidin]-4-amine (28 mg, 0.15 mmol), and triethylamine (0.03 mL, 0.2 mmol) in DMF (0.5 rriL) and the resulting mixture was stirred at 23 °C for 1 day. The reaction mixture was diluted with water (0.2 mL) and purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 70% acetonitrile in water. Trifluoroacetic acid (0.25 mL) was added to the desired fractions and the solution was stirred for 2 days. The fractions were combined and concentrated to give the title compound. MS: m/z = 603.4 (M+l).

Step B : 3 -(4-( 5-Isopropyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-N-( 1 '-methyl-Γ 1 ,4'-bipiperidinl -4-yl)-4- ((2-oxopyrrolidin-l-yl)methyl)benzamide

Formaldehyde (0.019 mL, 0.26 mmol) was added to a solution ofN-([l,4'- bipiperidin]-4-yl)-3-(4-(5-isopropyl-l,3,4 hiadiazol-2-yl)phenoxy)-4-((2-oxopyrrolidin-l- yl)methyl)benzamide 2,2,2-trifluoroacetate (37 mg, 0.052 mmol) in DCE (0.5 mL) at 23 °C and the reaction mixture was stirred for 15 minutes. Sodium triacetoxyborohydride resin (33 mg, 0.16 mmol) was added and the resulting mixture was stirred for 18 h. The reaction mixture was diluted with EtOAc, filtered, and concentrated. The residue was purified by reverse phase HPLC, eluting with acetonitrile/water + 0.1% TFA (5/95 to 60/40). The fractions were concentrated, dissolved in CH ₂ C1 ₂ (3 mL), and MP carbonate resin was added. After stirring for 15 min, the mixture was filtered and concentrated to give the title compound. MS: mlz = 617.3250 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.86 (d, J = 8.3 Hz, 2 H); 7.59 (d, J = 8.4 Hz,

1 H); 7.46 (s, 1 H); 7.37 (d, J = 8.1 Hz, 1 H); 7.18 (br s, 1 H); 6.97 (d, J = 8.4 Hz, 2 H); 4.51 (s,

2 H); 4.17 (br s, 1 H); 3.66 (d, J = 13.2 Hz, 3 H); 3.45-3.52 (m, 3 H); 3.31 (t, J = 7.3 Hz, 2 H); 2.97 (br s, 4 H); 2.80 (s, 3 H); 2.46 (br s, 2 H); 2.37 (t, J = 8.2 Hz, 2 H); 2.18-2.27 (m, 2 H); 2.07

(br s, 4 H); 1.95-1.99 (m, 4 H); 1.47 (d, J = 6.9 Hz, 6 H).

N-( 1 -Cvclopentylpiperidin-4-vD^

1 -yl)methyl)benzamide

To a solution of 3 -(4-(3 -methyl- l ,2,4-triazin-6-yl)phenoxy)-4-((2-oxopyrrolidin- 1 -yl)methyl)benzoic acid (40 mg, 0.10 mmol) in DMF (5 mL) was added 1 -cyclopentylpiperidin- 4-amine (17 mg, 0.15 mmol), Et ₃ N (30 mg, 0.30 mmol), and HATU (45 mg, 0.12 mmol). The resulting mixture was stirred at 23 °C for 16 h and then concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a white solid. MS: m/z = 555.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 5 9.17 (s, 1H), 8.18-8.16 (m, 2H), 7.23 (dd, J = 1.6, 8.0 Hz,

1H), 7.54 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.15-7.13 (m, 2H), 4.56 (s, 2H), 4.1 1- 4.03 (m, 1H), 3.56-3.48 (m, 2H), 3.37 (t, J = 6.8 Hz, 2H), 3.01-2.99 (m, 1H), 2.99-2.80 (m, 4H), 2.29 (t, J = 8.0 Hz, 2H), 2.19-2.03 (m, 4H), 2.00-1.75 (m, 6H), 1.74-1.59 (m, 4H), 1.34-1.28 (m, 1H).

(R)-N-(l-Cvclopentylpiperidin-4-yl)-3-(4-(5-isopropyl-l,3,4- thiadiazol-2-yl)phenoxy)-4-((4- methyl-2-oxoimidazolidin- 1 -yl)methyl)benzamide

To a mixture of (R)-3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4- methyl-2-oxoimidazolidin-l -yl)methyl)benzoic acid (60 mg, 0.13 mmol), HATU (60 mg, 0.16 mmol), and triethylamine (40 mg, 0.4 mmol) in DMF (3 mL) was added 1 -cyclopentylpiperidin- 4-amine (27 mg, 0.16 mmol). The resulting mixture was stirred at 23 °C for 16 h and then concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05%> ammonia, V/V):acetonitrile to give the title compound as colorless oil. MS: m/z = 603.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 7.98 (dd, J = 2.0, 6.8 Hz, 2H), 7.74 (dd, J =1.6, 7.6 Hz, 1H), 7.53-7.51 (m, 2H), 7.1 1 (dd, J = 2.0, 6.8 Hz, 2H), 4.48 (d, J = 15.6 Hz, 1H), 4.37 (d, J = 15.6 Hz, 1H), 3.89-3.88 (m, 1H), 3.75-3.70 (m, 1H), 3.55-3.48 (m, 2H), 3.11 -3.08 (m, 2H), 2.94 (dd, J = 6.8, 9.2 Hz, 1H), 2.59-2.56 (m, 1H), 2.19-2.13 (m, 2H), 1.95-1.92 (m, 4H), 1.74-1.59 (m, 6H), 1.49 (d, J = 6.8 Hz, 6H), 1.45-1.40 (m, 2H), 1.18 (d, J = 6.0 Hz, 3H).

N-(l-Cvclopentylpiperidin-4-yl)-4-((5-methyl-2-oxopyridin-l- (2H ^' )-yl)metliyl)-3-(4-(6- methylpyridazin-3-yl)phenoxy)benzamide

To a solution of 4-((5-methyl-2-oxopyridin-l-(2H)-yl)methyl)-3-(4-(6- methylpyridazin-3-yl)phenoxy)benzoic acid (90 mg, 0.21 mmol) in DMF (5 mL) was added Et ₃ N (64 mg, 0.63 mmol), HATU (96 mg, 0.25 mmol), and l-cyclopentylpiperidin-4-amine (42 mg, 0.25 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give N-(l-cyclopentylpiperidin-4-yl)-4- ((5-methyl-2-oxopyridin-l -(2H)-yl)methyl)-3-(4-(6-methylpyridazin-3-yl)phenoxy)benzam ide as a white solid. MS: m/z = 578.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.07-8.03 (m, 3H),

7.64 (dd, J = 2.0, 8.0 Hz, 2H), 7.47-7.46 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 2.4, 9.2 Hz, 1H), 7.08 (dd, J = 2.0, 6.8 Hz, 2H), 6.45 (d, J = 9.2 Hz, 1H), 5.25 (s, 2H), 3.87-3.80 (m, 1H), 3.08 (d, J = 12.0 Hz, 2H), 2.71 (s, 3H), 2.61 -2.55 (m, 1H), 2.19-2.13 (m, 2H), 2.03 (s, 3H), 1.99-1.89 (m, 4H), 1.74-1.56 (m, 6H), 1.45-1.38 (m, 2H).

N-(l-Cvclopentylpiperidin-4-yl)-3-(4-((l-cvclopentylpiperidi n-4-yl)carbamoyl)phenoxy)-4-((2- oxopyrrolidin- 1 -yl)methyl)benzamide

To a solution of 3-(4-carboxyphenoxy)-4-[(2-oxopyrrolidin-l-yl)methyl]benzoic acid (100 mg, 0.234 mmol) in DMF (1.5 mL) at ambient temperature was added 1- cyclopentylpiperidin-4-amine (94 mg, 0.56 mmol), EDC (179 mg, 0.934 mmol), HOBt (71.5 mg, 0.467 mmol), and DIPEA (0.410 mL, 2.34 mmol). The reaction mixture was stirred for 16 h. The mixture was purified by reverse phase HPLC, eluting with 0% acetonitrile in water (0.1% formic acid as a modifier) initially, grading to 50% acetonitrile in water, and the desired fractions were lyophilized to give the title compound as the formate salt. MS: m/z = 656.6 (M+l). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.85 (d, 2H, J = 8.8 Hz), 7.71 (dd, 1H, J = 7.9, 1.6 Hz), 7.49 (d, 1H, J = 1.6 Hz), 7.47 (d, 1H, J = 8.0 Hz), 6.99 (d, 2H, J = 8.8 Hz), 4.51 (s, 2H), 4.07-4.10 (m, 2H), 3.54 (t, 4H, J = 14.6 Hz), 3.32-3.38 (m, 4H), 2.92-302 (m, 4H), 2.26 (t, 2H, J = 8.2 Hz), 2.11-2.18 (m, 9H), 1.82-1.95 (m, 1 1H), 1.66-1.68 (m, 6H).

N-((S)-l-Cvclopropyl-5-oxopyrrolidin-3-yl)-3-(4-(6-(difluoro methyl)pyridazin-3-yl)phenoxy)-4- (((S)-4-methyl-2-oxopyrrolidin- 1 -yl)methyl)benzamide

A mixture of (S)-3-(4-(6-(difluoromethyl)pyridazin-3-yl)phenoxy)-4-((4-me thyl- 2-oxopyrrolidin-l-yl)m ethyl )benzoic acid (100 mg, 0.22 mmol), (S)-4-amino-l- cyclopropylpyrrolidin-2-one (36 mg, 0.26 mmol), HATU (100 mg, 0.26 mmol), and Et ₃ N (67 mg, 0.66 mmol) in DMF (5 mL) was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V): acetonitrile to give the title compound as white solid. MS (ESI) m/z = 576.3 [M + 1]. Ή NMR (400 MHz, CD ₃ OD) δ 8.32 (d, J = 9.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H) 7.73 (dd, J = 1.2, 8.0 Hz, 2H), 7.55 (d, J = 1.2 Hz, lH), 7.48(d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.07 (t, J = 54.4 Hz, 1H), 4.60-4.50 (m, 3H), 3.77 (dd, J = 7.2, 10.4 Hz, 1H), 3.50 (dd, J = 8.0, 10.0 Hz, 1H), 3.35-3.33 (m, 1 H), 2.95 (dd, J = 6.0, 9.6 Hz, 1 H), 2.81 (dd, J = 8.8, 17.2 Hz, 1 H), 2.64-2.62 (m, 1 H), 2.51 - 2.39 (m, 3H), 1.96 (dd, J = 6.4, 16.0 Hz, 1H), 1.06 (d, J = 6.4 Hz, 3H), 0.75-0.70 (m, 4H).

4-(( ^' (S -4-Methyl-2-oxopyiTolidin-l -yl)methyl)-3-(4-(6-n ethylpyridazin-3-yl phenoxy)-N- (octahydroindolizin-7-yl)benzamide

A mixture of (S)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)-3-(4-(6- methylpyridazin-3-yl)phenoxy)benzoic acid (15 mg, 0.037 mmol), octahydroindolizin-7- amine (5.0 mg, 0.037 mmol), HATU (17 mg, 0.044 mmol), and Et ₃ N (21 uL, 0.15 mmol) in DMF (2 mL) was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound (mixture of isomers) as yellow oil. MS: mlz = 540.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD, as observed): δ 8.55 (d, J = 8.8Hz, 1H), 8.16-8.1 1 (m, 3H), 7.80-7.72 (m, 1H), 7.60-7.49 (m, 2H), 7.16-7.12 (m, 2H), 4.58 (d, J = 9.2 Hz, 1 H), 4.51 (d, J = 15.2 Hz, 1H), 3.72-3.59 (m, 2H), 3.53-3.46 (m, 1.4H), 3.13-3.00 (m, 1.6H), 2.95-2.90 (m, 1H), 2.83 (s, 3H), 2.49-2.35 (m, 3H), 2.33-2.00 (m, 5.6H), 1.97-1 .91 (m, 1.4H), 1.89-1 .83 (m, 1H), 1.78-1.66 (m,

1.5H), 1.49-1.47 (m, 0.5H), 1.04 (d, J = 6.8 Hz, 3H).

2-Fluoro-4-(((S)-4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-N-( 1 -(2-methylcvclohexyl)piperidin-4- yl)-5-(4-(6-methylpyridazin-3-yl)phenoxy)benzamide A mixture of (S)-2-fluoro-4-((4-methyl-2-oxopyrrolidin-l -yl)methyl)-5-(4-(6- methylpyridazin-3-yl)phenoxy)benzoic acid (50 mg, 0.12 mmol), l-(2- methylcyclohexyl)piperidin-4-amine (25 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and Et^N (48 uL, 0.35 mmol) in DMF (2 mL) was stirred at 23 °C for 16 h. The reaction mixture was, concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound (mixture of isomers) as a yellow solid. MS: m/z = 614.5 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.1 1 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 10.4 Hz, 1H),7.12 (d, J = 8.8 Hz, 2H), 4.55 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 3.98-3.93 (m, 1H), 3.52-3.47 (m, 1H), 3.32-3.29 (m, 1H), 3.00-2.95 (m, 1H), 2.72 (s, 3H), 2.52-2.40 (m, 6H), 1.99-1.71 (m, 8H), 2.00-1.87 (m, 6H), 1.54-1.40 (m, 6H), 1.07 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H).

(S)-2-Fluoi -5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)-N-(l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)ben zamide

To solution of (S)-2-fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4- ((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid, (400 mg, 0.85 mmol), 1 -(tetrahydro-2H- pyran-4yl)piperdin-4-amine dihydrochloride, (282 mg, 1.10 mmol), and triethylamine (0.32 mL, 2.3 mmol) in DMF (0.5 mL) were added HOAt (35 mg, 0.26 mmol) and EDC (330 mg, 1.7 mmol). The resulting mixture was stirred at 23 °C for 1.5 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 55% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: m/z = 636.3 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 7.89-7.90 (m, 2 H); 7.72 (d, J = 6.5 Hz, 1 H); 7.13 (d, J = 1 1.7 Hz, 1 H); 6.97-6.98 (m, 2 H); 6.62 (dd, J = 13.5, 7.7 Hz, 1 H); 4.46-4.47 (m, 2 H); 4.00-4.02 (m, 3 H); 3.49 (p, J = 6.9 Hz, 1 H); 3.39-3.41 (m, 3 H); 2.88-2.92 (m, 3 H); 2.55 (dd, J = 16.7, 8.6 Hz, 1 H); 2.39-2.49 (m, 2 H); 2.34 (t, J = 1 1.1 Hz, 2 H); 2.07 (s, 1 H); 2.04 (d, J = 6.3 Hz, 2 H); 2.01 (d, J = 7.1 Hz, 1 H); 1.75 (d, J = 12.6 Hz, 2 H); 1.56-1.60 (m, 3 H); 1.49 (d, J = 7.1 Hz, 6 H); 1.09 (d, J = 6.8 Hz, 3 H).

2-Fluoro-N-(l-(2-fluorocvclohexynpiperidin-4-yl)-5-(4-(5-iso propyl-l ,3,4-thiadiazol-2- yl)phenoxy)-4-(((S)-4-methyl-2-oxopyrrolidin-l-yl)methyl)ben zamide

(Benzotriazol- 1 -yloxy)/ra(dimethylamino)phosphonium hexafluorophosphate (57 mg, 0.13 mmol) was added to a solution of (S)-2-fluoro-5-(4-(5-isopropyl-l,3,4-thiadiazol-2- yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (40 mg, 0.085 mmol), l-(2- fluorocyclohexyl)piperidin-4-amine (14 mg, 0.070 mmol), and triethylamine (0.047 mL, 0.34 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 23 °C for 3 d. The reaction mixture was diluted with water (0.2 mL) and purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 60% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: m/z = 652.3 (M + 1). Ή NMR (400 MHz, CDCI ₃ ): δ 7.89-7.90 (m, 2 H); 7.72 (d, J = 6.5 Hz, 1 H); 7.13 (d, J = 1 1.7 Hz, 1 H); 6.97-6.98 (m, 2 H); 6.62 (dd, J = 13.5, 7.8 Hz, 1 H); 5.05 (dd, J = 50.9, 3.7 Hz, 1 H); 4.47-4.48 (m, 2 H); 3.98 (br s, 1 H); 3.49-3.50 (m, 1 H); 3.42 (dd, J = 9.5, 7.7 Hz, 1 H); 2.97 (t, J = 9.4 Hz, 2 H); 2.90 (d, J = 6.1 Hz, 1 H); 2.88 (d, J = 6.1 Hz, 1 H); 2.52-2.55 (m, 3 H); 2.39-2.42 (m, 2 H); 2.00-2.03 (m, 3 H); 1.84 (t, J = 1 1.3 Hz, 1 H); 1.71 -1.75 (m, 2 H); 1.57 (m, 3 H); 1.48 (d, J = 6.7 Hz, 6 H); 1.28-1.34 (m, 2 H); 1.09 (d, J = 6.8 Hz, 3 H).

EXAMPLE 29

2-FluoiO-5-(4-(5-isopropyl-1 ^-thiadiazol-2-yl phenoxy -4-((2-oxopyridin-U2H)-yl methyl)-N- f 1 -(tetrahvdro-2H-pyran-3-yl)piperidin-4-yl)benzamide

(Benzotriazol- 1 -yloxy)ira(dimethylamino)phosphonium hexafluorophosphate (74 mg, 0.17 mmol) was added to a solution of 2-fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2- yl)phenoxy)-4-((2-oxopyridin-l(2H)-yl)methyl)benzoic acid (52 mg, 0.1 1 mmol),

l-(tetrahydro-2H-pyran-3-yl)piperidin-4-amine dihydrochloride (29 mg, 0.1 1 mmol), and triethylamine (0.062 mL, 0.45 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 23 °C for 3 days. The reaction mixture was diluted with water (0.2 mL) and purified by reverse phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 60% acetonitrile in water. The desired fractions were eluted through a varian 0.4 g CX column, eluting with methanol then with 2M NHyMeOH. The basic eluent was

concentrated to give the title compound. MS: mlz = 632.2 (M + 1). 1H NMR (400 MHz, CDC1 ₃ ): δ 7.89-7.90 (m, 2 H); 7.66 (d, J = 6.4 Hz, 1 H); 7.33-7.35 (m, 1 H); 7.29-7.31 (m, 1 H); 7.00 (d, J = 8.4 Hz, 2 H); 6.55-6.60 (m, 1 H); 6.57 (d, J = 9.1 Hz, 1 H); 6.11 (t, J = 6.7 Hz, 1 H); 5.14 (s, 2 H); 4.01 (br d, J = 11.4 Hz, 1 H); 3.94 (br s, 1 H); 3.85 (d, J = 1 1.2 Hz, 1 H); 3.50 (p, J = 6.9 Hz, 1 H); 3.26-3.28 (m, 2 H); 2.88 (m, 2 H); 2.40-2.45 (m, 1 H); 2.37-2.41 (m, 2 H); 1.98- 2.02 (m, 3 H); 1.65-1.75 (m, 5 H); 1.49 (d, J = 6.9 Hz, 6 H).

N-( 1 -Cvclopentylpiperidin-4-yl)-4-((2,4-dioxo-3 ,4-dihvdropyrimidin- 1 (2H)-yl)methyl)-3 -( 4-(6- methylpyridazin-3-yl)phenoxy)benzamide To a solution of 4-((2,4-dioxo-3,4-dihydiOpyi-imidin-l (2H)-yl)methyl)-3-(4-(6- methylpyridazin-3-yl)phenoxy)benzoic acid (55 mg, 0.13 mmol) in DMF (3 mL) was added HATU (73 mg, 0.20 mmol), Et ₃ N (89 uL, 0.64 mmol), and l-cyclopentylpiperidin-4-amine (43 mg, 0.26 mmol). The reaction mixture was stirred at 23 °C for 16 h, diluted with water (0.2 mL), and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a colorless oil. MS: m/z = 581.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.08 (dd, J = 2.0, 6.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.70-7.63 (m, 3H), 7.55 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.12 (dd, J = 2.0, 6.8 Hz, 2H), 5.57 (d, J = 8.0 Hz, 1H), 5.05 (s, 2H), 3.95-3.87 (m, 1H), 3.21-3.13 (m, 2H), 2.78 (t, J = 8.0 Hz, lH), 2.72 (s, 3H), 2.36 (t, J = 11.2 Hz, 2H), 1.99-1.94 (m, 4H), 1.74-1.49 (m, 9H).

N-( 1 -Cyclopentylpiperidin-4-yl)-4-(((S)-4-methyl-2-oxopyrrolidin -l -yl)methyl)-3-(4-( 6-(2,2,2- trifluoro- 1 -hvdroxyethyl)pyridazin-3-yl)phenoxy)benzamide

A mixture of 4-(((£ 4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-3-(4-(6-(2,2,2- trifluoro-l -hydroxyethyl)pyridazin-3-yl)phenoxy)benzoic acid (40 mg, 0.080 mmol), 1 - cyclopentylpiperidin-4-amine (16 mg, 0.096 mmol), HATU (36 mg, 0.096 mmol), and Et ₃ N (24 mg, 0.24 mmol) in DMF (5 mL) was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound (mixture of isomers) as a white solid. MS: m/z = 652.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.24 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 9.2 Hz, 1H), 7.70 (dd, J = 1.6, 9.6 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 5.41 (q, J = 6.8 Hz, 1H), 4.60-4.50 (m, 3H), 3.90-3.84 (m, 1H), 3.48 (dd, J = 7.6, 9.6 Hz, 1H), 3.12-3.09 (m, 2H), 2.94 (dd, J = 6.0, 10.0 Hz, 1H), 2.62-2.58 (m, 1H), 2.49-2.34 (m, 2H), 2.22-2.18 (m, 1H), 1.97-1.92 (m, 5H), 1.70-1.57 (m, 6H), 1.46-1.40 (m, 2H), 1.08 (d, J = 6.8 Hz, 3H).

N-(l -Cvclopentylpiperidin-4-yl)-3-(4-(6-isopropylpyridazin-3-yl ^' )phenoxy)-4-((2-oxo-l ,2- dihydropyridin-3-yl)methyl)benzamide

To a solution of 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxo-l,2- dihydropyridin-3-yl)methyl)benzoic acid (80 mg, 0.18 mmol) in DMF (5 mL) was added Et ₃ N (91 mg, 0.90 mmol), HATU (100 mg, 0.27 mmol), and 1 -cyclopentylpiperidin-4-amine dihydrochloride (63 mg, 0.27 mmol). The reaction mixture was stirred at 23 °C for 16 h, diluted with water (0.2 mL), and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a white solid. MS: m/z = 592.3 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): 5 7.97 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.41-7.37 (m, 3H), 7.19 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 6.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 6.4 Hz, 1H), 6.11 (dd, J = 6.8, 6.8 Hz, 1H ), 4.01-3.86 (m, 3H), 3.39-3.28 (m, 1H), 3.11-2.86 (m, 3H), 2.64-2.56 (m, 1H), 2.25-2.16 (m, 2H), 2.06-1.98 (m, 2H), 1.90-1.61 (m, 2H), 1.71-1.60 (m, 4H), 1.60-1.35 (m, 9H).

N-(l-Cvclopentylpiperidin-4-yl)-3-(4-(6-isopropylpyridazin-3 -yl)phenoxy)-4-((l-methyl-2-oxo- 1 ₁ 2-dihydropyridin-3 - vDmethvDbenzamide

To a solution of 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((l-methyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)benzoic acid (82 mg, 0.18 mmol) in DMF (5 mL) was added Et ₃ N (91 mg, 0.90 mmol), HATU (103 mg, 0.270 mmol), and 1 -cyclopentylpiperidin-4-amine dihydrochloride (63 mg, 0.27 mmol). The reaction mixture was stirred at 23 °C for 16 h, diluted with water (0.2 raL), and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a white solid. MS: mlz = 606.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.07-8.02 (m, 3H), 7.71 (d, J = 8.8 Hz, IH), 7.66 (dd, J = 1.6, 8.0 Hz, IH), 7.51-7.45 (m, 3H), 7.24 (dd, J = 1.6, 6.8 Hz, IH), 7.05-7.01 (m, 2H), 6.23 (dd, J = 6.8, 6.8 Hz, IH ), 3.93-3.85 (m, 3H), 3.52 (s, 3H), 3.35-3.30 (m, IH), 3.10-3.07 (m, 2H), 2.63-2.56 (m, IH), 2.19-2.13 (m, 2H), 1.97-1.88 (m, 4H), 1.73-1.66 (m, 6H), 1.48-1.38 (m, 8H).

N-r(S)-5-Benzyl-4-oxo-5-azaspiror2.4]heptan-7-vn-2-fluoro-5- r4-(5-isopropyl-l,3,4-thiadiazol- 2-yl)phenoxyl-4-{[(S)-4-methyl-2-oxopyrrolidin-l-yllmethyl|b enzamide

(S)-2-Fluoro-5-[4-(5-isopropyl-l,3,4-thiadiazol-2-yl)phenoxy ]-4-[(4-methyl-2- oxopyrrolidin-l-yl)methyl]benzoic acid, (73.9 mg, 0.157 mmol), (S)-7-amino-5-benzyl-5- azaspiro[2.4]heptan-4-one (34.0 mg, 0.157 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (65.8 mg, 0.343 mmol), l-hydroxy-7-azabenzotriazole (12.6 mg, 0.093 mmol), and 4-methylmorpholine (0.081 mL, 0.738 mmol) were dissolved in DMF (1 mL). The resulting mixture was stirred at 50 °C for 60 min. The reaction was diluted with water (ca 0.3 mL) and then purified by reverse phase HPLC, eluting with 10% acetonitrile in water

(0.1% formic acid used as a modifier) initially, grading to 60% acetonitrile in water. The desired fractions were lyophilized to give the product. The product was then purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc, 90: 10 to 0: 100, then with a gradient of (CH ₂ Cl ₂ :CH ₃ OH, 90: 10)/CH ₂ C1 _2, 80:20 to 40:60, to give the title compound. MS: m/z = 668.4 (M + 1). Ή NMR (500 MHz, CD ₃ OD) δ 7.91 (m, 2H), 7.24 (m, 7H), 7.03 (m, 2H), 4.53 (s, IH), 4.51 (m, IH), 4.46 (m, 3H), 4.42 (m, IH), 3.72 (dd, IH, J = 10.7, 7.8 Hz), 3.45 (m, 2H), 2.90 (dd, IH, J = 9.7, 6.2 Hz), 2.43 (dd, IH, J = 16.3, 8.6 Hz), 2.36 (m, IH), 1.91 (dd, IH, J = 16.3, 6.7 Hz), 1.44 (dd, 6H, J = 6.9, 2.6 Hz), 1.10 (m, 2H), 1.06 (m, IH), 1.02 (m, 5H).

2-oxopyrrolidin- 1 -yl)methyl)benzamide

A mixture of (S)-5-(4-(6-ethylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-meth yl-2- oxopyrrolidin-l-yl)methyl)benzoic acid (150 mg, 0.35 mmol), HATU (160 mg, 0.42 mmol), and triethylamine (240 uL, 1.8 mmol) in DMF (3 mL) was stirred at 23 °C for 10 min. 1- cyclopentylpiperidin-4-amine (107 mg, 0.42 mmol) was added. The reaction mixture was stirred at 23 °C for 12 h. The reaction mixture was concentrated and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia,

V/V):acetonitrile to give (S)-N-(l-cyclohexylpiperidin-4-yl)-5-(4-(6-ethylpyridazin-3- yl)phenoxy)-2-fluoro-4-((4-methyl-2-oxopyrrolidin-l-yl)methy l)benzamide as a white solid. MS: m/z = 614.4 (M + 1). 1H NMR (400 MHz, CD ₃ OD): δ 8.10-8.06 (m, 3H), 7.69 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.24 (d, J = 10.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.56-4.46 (m, 2H), 3.85-3.83 (m, 1H), 3.51-3.49 (m, 1H), 3.04-3.02 (m, 2H), 2.97-2.94 (m, 3H), 2.45-2.41 (m, 5H), 1.98-1.93 (m, 5H), 1.89-1.80 (m, 2H), 1.72-1.60 (m, 3H), 1.39 (t, J = 7.6 Hz, 3H), 1.39- 1.21 (m, 4H), 1.19-1.07 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H).

(S)-2-Fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)-N-( 1 -( 1 -methylcyclopentyl)piperidin-4-yl)benzamide (Benzotriazol- 1 -yloxy)im(dimethylamino)phosphonium hexafluorophosphate (42 mg, 0.096 mmol) was added to a solution of (S)-2-fluoro-5-(4-(5-isopropyl-l ,3,4-fhiadiazol-2- yl)phenoxy)-4-((4-methyl-2-oxopyri lidin- 1 -yl)methyl)benzoic acid (30 mg, 0.064 mmol), 1-(1- methylcyclopentyl)piperidin-4-amine hydrochloride (14 mg, 0.064 mmol), and triethylamine (0.027 ml, 0.19 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 23 °C for 3 d. The reaction mixture was diluted with water (0.2 mL) and purified by reverse phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 65% acetonitrile in water. The desired fractions were eluted through a varian 0.4 g CX column, with methanol then with 2M NH ₃ /MeOH. The basic eluent was concentrated to give the title compound. MS: mlz = 634.3 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 7.90 (d, J = 8.5 Hz, 2 H); 7.72 (d, J = 6.5 Hz, 1 H); 7.13 (d, J = 1 1.7 Hz, 1 H); 6.98 (d, J = 8.5 Hz, 2 H); 6.63 (dd, J = 13.4, 7.9 Hz, 1 H); 4.47 (dd, J = 28.1, 15.5 Hz, 2 H); 3.98 (br s, 1 H); 3.45-3.53 (m, 1 H); 3.42 (t, J = 8.6 Hz, 1 H); 2.85-2.89 (m, 3 H); 2.55 (dd, J = 16.7, 8.6 Hz, 1 H); 2.39-2.43 (m, 3 H); 2.00- 2.03 (m, 3 H); 1.70-1.74 (m, 2 H); 1.60 (m, 8 H); 1.48 (d, J = 6.9 Hz, 6 H); 1.09 (d, J = 6.8 Hz, 3 H); 0.97 (s, 3 H).

2-Fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxo-2,3-dihvdro-lH- benzo d1imidazol-l-yl)methyl)-N-(l-(tetrahvdro-2H-pyran-4-yl)piper idin-4-yl)benzamide

(Benzotriazol- 1 -yloxy)ira(dimethylamino)phosphonium hexafluorophosphate (92.0 mg, 0.208 mmol) was added to a solution of 2-fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2- yl)phenoxy)-4-((2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)m ethyl)benzoic acid (80.0 mg, 0.159 mmol), l-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride (48.9 mg, 0.190 mmol), and triethylamine (77 μί, 0.56 mmol) in DMF (1.5 mL). The resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were concentrated, and the residues were combined and diluted with 9: 1 MeOH:CH2Cl ₂ (2.0 mL) and stirred with MP- carbonate for 1 h. The mixture was filtered and concentrated to give the title compound. MS: mlz = 671.3 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 7.90 (d, J = 8.3 Hz, 2 H); 7.71 (d, J= 6.4 Hz, 1 H); 7.06 (m, 2H); 7.00(d, J = 8.6 Hz, 2 H); 6.87 (d, J = 7.6 Hz, 2 H); 6.58 (dd, J = 13.3, 7.6 Hz, 1 H); 5.1 1 (s, 2 H); 4.02 (dd, J= 1 1.4, 4.5 Hz, 2 H); 3.97 (m, 3 H); 3.49 (m, 1 H); 3.36 (t, J = 1 1.6 Hz, 3 H); 2.89 (d, J= 1 1.1 Hz, 3 H); 2.47 (t, J= 10.7 Hz, 1 H); 2.32 (t, J= 1 1.0 Hz, 2 H); 2.03 (d, J= 1 1.8 Hz, 3 H); 1.73 (d, J= 12.2 Hz, 2 H); 1.49 (d, J= 6.9 Hz, 7 H).

EXAMPLE 38

3-(4-(5-Isopropyl-l,3,4-thiadiazol-2-yl)phenoxy)-4-(l-(2-oxo pyrrolidin-l-yl)ethyl)-N-(l- (tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzamide

A mixture of 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-(l -(2- oxopyiTolidin-l -yl)ethyl)benzoic acid (30 mg, 0.052 mmol), 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-amine dihydrochloride (16 mg, 0.062 mmol), triethylamine (25 μί, 0.18 mmol), and BOP (34 mg, 0.078 mmol) in DMF (0.2 mL) was stirred at 23 °C for 1 h. The reaction mixture was purified by reverse phase HPLC (CI 8 column), eluting with 5% acetonitrile in water (0.1% ΝΗ ₄ ΟΗ used as a modifier) initially, grading to 95% acetonitrile in water to give the title compound. MS: mlz = 618.4 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 7.87 (d, 2H, J = 8.4 Hz), 7.57 (d, 1H, J = 8.1 Hz), 7.51 (d, 1H, J = 8.2 Hz), 7.42 (s, 1H), 6.97 (d, 2H, J = 8.5 Hz), 6.07 (d, 1H, J = 7.9 Hz), 5.58 (q, 1H, J = 7.1 Hz); 3.98-4.02 (m, 3H); 3.49 (sep, 1H, J = 6.9 Hz), 3.35- 3.37 (m, 2H), 2.97-3.01 (m, 3H), 2.48-2.57 (m, 1H), 2.30-2.40 (m, 2H), 2.21 -2.24 (m, 2H), 2.01- 2.05 (m, 3H), 1.83-1.88 (m, 1H), 1.67-1.79 (m, 3H), 1.58-1.64 (m, 4H), 1.53 (d, 3H, 7 = 7.4 Hz); 1.48 (d, 6H, J = 6.9 Hz).

EXAMPLE 39

N-n-CvclopentvIpiperidin-4-yl)-2-

1 ,2-dihvdropyridin-3 -yl)methyl)benzamide

(Benzotriazol- 1 -yloxy)ira(dimethylamino)phosphonium hexafluorophosphate (62.6 mg, 0.141 mmol) was added to a solution of 2-fiuoro-5-(4-(6-isopropylpyridazin-3- yl)phenoxy)-4-((2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoic acid (50.0 mg, 0.109 mmol), 1- cyclopentylpiperidin-4-amine dihydrochloride (28.9 mg, 0.120 mmol), and triethylamine (53.1 0.381 mmol) in DMF (1.08 mL). The resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were concentrated, the residues were combined and diluted with 9: 1 MeOH:CH ₂ Cl ₂ (2.0 mL) and stirred with MP-carbonate for 1 h. The mixture was filtered and concentrated to give the title compound. MS: m/z = 610.4 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.00-8.01 (m, 2 H); 7.70-7.71 (m, 2 H); 7.38-7.39 (m, 1 H); 7.19-7.22 (m, 2 H); 6.99-7.00 (m, 2 H); 6.62 (dd, J = 13.6, 7.8 Hz, 1 H); 6.12-6.14 (m, 1 H); 3.96-4.02 (m, 1 H); 3.90 (s, 2 H); 3.33-3.34 (m, 1 H); 2.92 (dt, J = 11.7, 4.8 Hz, 2 H); 2.49-2.51 (m, 1 H); 2.16 (t, J = 10.8 Hz, 2 H); 1.99-2.04 (m, 2 H); 1.84-1.89 (m, 2 H); 1.66-1.70 (m, 2 H); 1.54-1.57 (m, 4 H); 1.40-1.41 (m, 8 H).

N-(l-Cvclopenrylpiperidin-4-yl)-2-fluoro-5-(4-(5-isopropyl-L 3,4-thiadiazol-2-yl)phenoxy)-4-((6- methyl-3-oxo-2,3-dihvdropyridazin-4-yl)methyl)benzamide (Benzotriazol- 1 -yloxy)irz ^' i(dimethylamino)phosphonium hexafluorophosphate (55.2 mg, 0.125 mmol) was added to a solution of 2-fluoro-5-(4-(5-isopropyl-l,3,4-thiadiazol-2- yl)phdihydropyridazin-4 acid (50.0 mg, 0.104 mmol), 1 -cyclopentylpiperidin-4-amine dihydrochloride (27.6 mg, 0.114 mmol), and triethylamine (50.8 μί, 0.364 mmol) in DMF (1.04 mL). The resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were concentrated under nitrogen. The residues were combined and diluted with 9: 1

MeOH:CH ₂ Cl ₂ (2.00 mL) and stirred with MP-carbonate for 1 h. The mixture was filtered and concentrated to give the title compound. MS: mlz = 631.3 (M + 1). Ή NMR (500 MHz,

CDClj): δ 7.86-7.87 (m, 2 H); 7.70-7.71 (m, 1 H); 6.92-6.93 (m, 2 H); 6.76 (s, 1 H); 6.61-6.64 (m, 1 H); 3.97-4.03 (m, 1 H); 3.90 (s, 2 H); 3.48-3.49 (m, 2 H); 2.94 (dd, J = 11.3, 5.7 Hz, 2 H); 2.50 (p, J = 8.1 Hz, 1 H); 2.14-2.15 (m, 5 H); 2.03 (d, J = 12.5 Hz, 2 H); 1.84-1.88 (m, 2 H); 1.66-1.69 (m, 2 H); 1.48 (dd, J = 6.9, 2.5 Hz, 8 H); 1.37-1.42 (m, 3 H).

2-Fluoro-N-(l-(2-hydroxy-2-methylcvclopentyl)piperidin-4-yl) -5-(4-(6-isopropylpyridazin-3- yl)phenoxy)-4-(((S)-4-methyl-2-oxopyrrolidin-l -yl methyl)benzamide

A mixture of 2-(4-aminopiperidin-l-yl)-l-methylcyclopentanol (52 mg, 0.26 mmol), (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l- yl)methyl)benzoic acid (100 mg, 0.22 mmol), HATU (98 mg, 0.26 mmol), and Et ₃ N (150 uL, 1.1 mmol) in DMF (3 mL) was stirred at 23 °C for 16 h. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V): acetonitrile to give the title compound as a white solid. MS: m/z = 644.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 5 8.1 1-8.04 (m, 3H), 7.70 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 6.0 Hz, 1H), 7.23 (d, J = 10.4 Hz, 1H), 7.14-7.07 (m, 2H), 4.56-4.45 (dd, J = 15.2, 25.6 Hz, 2H), 3.87-3.77 (m, 1H), 3.53-3.39 (m, 2H), 2.96 (dd, J = 6.0, 10.0 Hz, 2H), 2.51- 2.32 (m, 3H), 2.19-1.84 (m, 6H), 1.83-1.73 (m, 1H), 1.71 -1.43 (m, 7H), 1.40 (d, J = 7.2 Hz, 6H), 1.21 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H).

N-(l-Cvclopentylpiperidin-4-yl)-2-fluoro-5-(4-(6-isopropylpy ridazin-3-yl)phenoxy)-4-((2- oxopiperidin-l-yl)methyl)benzamide

To a solution of 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2- oxopiperidin-l-yl)methyl)benzoic acid (20 mg, 0.043 mmol) in DMSO (1 mL) was added 1- cyclopentylpiperidin-4-amine hydrochloride (13 mg, 0.065 mmol), BOP (19 mg, 0.043 mmol), and TEA (0.018 mL, 0.13 mmol). The reaction mixture was stirred at 23 °C for 1 h and then passed through a syringe filter. The residue was purified via reverse phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. HRMS: mlz = 614.3496 (M+l). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.06 (d, J = 8.4 Hz, 2 H); 7.72 (m, 2 H); 7.40 (d, J = 8.0 Hz, 1 H); 7.15 (d, J = 8.7 Hz, 1H); 7.03 (d, J = 8.4 Hz, 2 H); 6.64 (br s, 1 H); 4.62 (s, 2 H); 4.00 (m, 1 H); 3.21-3.35 (m, 3 H); 2.91 (m, 1 H); 2.51 (m, 1 H); 2.41 (m, 2 H); 2.10-2.41 (m, 3 H); 1.98-2.06 (m, 2 H); 1.65-1.91 (m, 10 H); 1.42 (d, J = 6.9 Hz, 6 H); 1.25 (m, 2 H); 0.85 (m, 2 H).

N-n-Cyclopentylpiperidin-4-yl)-^

isopropylpyridazin-3-yl)phenoxy)benzamide

To a solution of 4-(difluoro(2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3-(4-(6- isopropylpyridazin-3-yl)phenoxy)benzoic acid (18 mg, 0.038 mmol) in DMF (2 mL) was added Et ₃ N (21 uL, 0.15 mmol), HATU (17 mg, 0.046 mmol), and 1 -cyclopentylpiperidin-4-amine dihydrochloride (1 1 mg, 0.046 mmol). The reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to obtain N-(l-cyclopentylpiperidin-4-yl)-4-(difluoro(2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3-(4- (6-isopropylpyridazin-3-yl)phenoxy)benzamide as a yellow solid. MS: mlz = 628.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 5 8.07-8.01 (m, 2H), 8.00-7.91 (m, 3H), 7.83-7.78 (m, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 10.0 Hz, 2H), 6.30-6.26 (m, 1H), 3.97-3.89 (m, 1H), 3.20 (d, J = 12.0 Hz, 2H), 2.79-2.77 (m, 1H), 2.38-2.35 (m, 2H), 2.00- 1.98 (m, 4H), 1.76-1.68 (m, 4H), 1.61 (d, J = 4.8 Hz, 2H), 1.51-1.48 (m, 2H), 1.42-1.40 (m, 7H).

N-((3S.^R)-3-Fluoro-l -(tetrahydro-2H-pyi-an-4-yl)piperidm-4-yl)-3-(4-(6-isopropyl

pyridazin-3-yl)phenoxy)-4-(((S)-4-methyl-2-oxopyrrolidin- l-yl)methyl)benzamide

To a solution of (S)-3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin-l-yl)methyl)benzoic acid, (140 mg, 0.31 mmol), and (3S,4R)-3-fluoro-l- (tetrahydro-2H-pyran-4-yl)piperidin-4-amine (76 mg, 0.38 mmol) in DMF (1.0 mL) was added HOAt (12 mg, 0.094 mmol) and EDC (120 mg, 0.63 mmol). The resulting mixture was stirred at 23 °C for 18 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse- phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 55% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: mlz = 630.3 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.07 (d, J = 9.0 Hz, 2 H); 7.76 (d, J = 8.8 Hz, 1 H); 7.52 (dd, J = 7.9, 1.7 Hz, 1 H); 7.38-7.45 (m, 2 H); 7.41 (d, J = 8.8 Hz, 1 H); 7.05 (d, J = 8.8 Hz, 2 H); 6.32 (d, J = 8.7 Hz, 1 H); 4.78 (br d, J = 49.6 Hz, 1 H); 4.59 (d, J = 15.4 Hz, 1 H); 4.54 (d, J = 15.5 Hz, 1 H); 4.16-4.19 (m, 1 H); 4.03 (dd, J = 11.5, 4.1 Hz, 2 H); 3.43 (dd, J = 9.6, 7.7 Hz, 1 H); 3.34-3.36 (m, 3 H); 3.02 (br d, J = 11.3 Hz, 1 H); 2.89 (dd, J = 9.6, 6.0 Hz, 1 H); 2.50-2.60 (m, 2 H); 2.30-2.45 (m, 2 H); 2.01 (dd, J = 16.6, 7.0 Hz, 1 H); 1.88-1.91 (m, 2 H); 1.72 (m, 3 H); 1.59-1.64 (m, 3 H); 1.42 (d, J = 7.0 Hz, 6 H); 1.07 (d, / = 6.8 Hz, 3 H).

(S -5-(4-(6-Cvclopent lpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-methyl-2-oxopyrrolid m^ yl methyl)-N-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl benzamide

To a solution of (S)-5-(4-(6-cyclopentylpyridazin-3-yl)phenoxy)-2-fluoro-4-(( 4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (100 mg, 0.204 mmol) in DMF (5 mL) was added Et ₃ N (62 mg, 0.61 mmol), HATU (93 mg, 0.25 mmol), and 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-amine (45 mg, 0.25 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated and purified by reverse phase HPLC (Column:

Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a white solid. MS: m/z = 656.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.12-8.03 (m, 3H), 7.69 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 6.0 Hz, 1H), 7.24 (d, J = 10.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.54 (d, J = 15.6 Hz, 1 H), 4.48 (d, J = 15.6 Hz, 1H), 3.99 (dd, J = 4.0, 10.8 Hz, 2H), 3.91-3.82 (m, 1H), 3.54-3.47 (m, 1H), 3.46-3.35 (m, 3H), 3.04 (d, J = 1 1.6 Hz, 2H), 2.96 (dd, J = 6.0, 10.0 Hz, 1H), 2.59-2.30 (m, 5H), 2.25-2.15 (m, 2H), 2.05-1.76 (m, 11H), 1.69-1.49 (m, 4H), 1.06 (d, J - 6.8 Hz, 3H).

EXAMPLE 46

(S)-2-Fluoi -5-(4-(6-f2-fluoropropan-2-yl)pyridazin-3-yl)phenoxy)-4-((4- methyl-2- oxopyrrolidin- 1 -yl)methyl)-N-( 1 -( ^" tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide

A mixture of (S)-2-fluoro-5-(4-(6-(2-fluoropropan-2-yl)pyridazin-3-yl)phe noxy)- 4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (85 mg, 0.18 mmol), 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-amine (43 mg, 0.21 mmol), HATU (81 mg, 0.21 mmol), and Et ₃ N (74 μί, 0.53 mmol) in DMF (3 mL) was stirred at 23 °C for 16 h. The reaction mixture was

concentrated and the residue purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a yellow solid. MS: m/z = 648.5 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.20 (d, J = 9.2 Hz, 1H), 8.16-8.13 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.24 (d, J = 10.8 Hz, 1H), 7.15 (d, J = 9.2 Hz, 2H), 4.57-4.45 (m, 2H), 3.99-3.98 (m, 2H), 3.89-3.85 (m, 1H), 3.54- 3.45 (m, 1H), 3.39 (t, J = 1 1.6 Hz, 2H), 3.06-2.92 (m, 3H), 2.55-2.25 (m, 5H), 2.05-1.90 (m, 3H), 1.88-1.76 (m, 8H), 1.68-1.47 (m, 4H), 1.07 (d, J = 6.8 Hz, 3H).

2-Fluoro-5-(4-(6-isopiOpylpyridazin-3-yl)phenoxy)-4-((2-oxoo xazolidin-3-yl)methyl)-N-(l - (tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzamide

To a solution of 2-fluoro-5-(4-(6-isopropylpyridazin-3-yl) phenoxy)-4-((2- oxooxazolidin-3-yl)methyl)benzoic acid (54 mg, 0.12 mmol) in DMSO (2 mL) was added 1 - (tetrahydro-2H-pyran-4-yl)piperidin-4-amine hydrochloride (40 mg, 0.18 mmol), BOP (53 mg, 0.12 mmol), and TEA (0.050 mL, 0.36 mmol). The reaction mixture was stirred at 23 °C for 1 h and then passed through a syringe filter. The residue was purified via reverse phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound.

HRMS: m/z = 618.3093 (M+l). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.07 (d, J = 8.6 Hz, 2 H); 7.74- 7.76 (m, 2 H); 7.41 (d, J = 8.8 Hz, 1 H); 7.26 (d, J = 8.7 Hz, 1 H); 7.05 (d, J = 8.6 Hz, 2 H); 6.62 (m, 1 H); 4.51 (s, 2 H); 4.29 (t, J = 8.0 Hz, 2 H); 4.03 (br s, 3 H); 3.53 (t, J = 8.0 Hz, 2 H); 3.36-3.38 (m, 3 H); 2.91 (br s, 1 H); 2.25-2.53 (br m, 3 H); 2.07 (br s, 2 H); 1.75 (br s, 2 H); 1.59 (br s, 5 H); 1.42 (d, J = 7.0 Hz, 6 H).

2-Fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy ^' )-4-((2-oxoimidazolidin-l-yl)methyl)- N-( 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzamide

Step A: 4-((3-(te^-Butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-5- (4-(5-isopropyl-l ,4- thiadiazol-2-yl)phenoxy ^' )-N-(l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzam ide

A mixture of 4-((3-(teri-butyl)-2-oxoimidazolidin-l -yl)methyl)-2-fluoro-5-(4-(5- isopropyl-l,3,4-thiadiazol-2-yl)phenoxy)benzoic acid (163 mg, 0.318 mmol), 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-amine dihydrochloride (98 mg, 0.38 mmol), BOP (21 1 mg, 0.477 mmol), and triethylamine (260 \L, 1.91 mmol) in DMF (1.6 mL) was stirred at 23 °C for 1 h. The reaction mixture was filtered and the filtrate purified by reverse phase HPLC (CI 8 column), eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: m/z = 679.3 (M + 1). Step B: 2-Fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl phenoxy)-4-((2-oxoimidazolidin-l - yl)methyl)-N-(l-(tetrahvdro-2H-pyi-an-4-yl)piperidin-4-vDben zamide

A solution of 4-((3-(tert-butyl)-2-oxoimidazolidin-l-yl)methyl)-2-fluoro-5 -(4-(5- isopropyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-N-( 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)benzamide (137 mg, 0.202 mmol) in methanesulfonic acid (1.5 mL) was heated at 80 °C for 30 min. The reaction mixture was cooled to 0 °C, basified to pH ~8 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (120 mL). The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound as a white solid. MS: mlz = 623.3 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 7.89 (d, 2H, J = 8.5 Hz), 7.72 (d, 1H, J = 6.5 Hz), 6.98 (d, 2H, J = 8.5 Hz), 6.62-6.65 (m, 1H), 4.41 (s, 2H), 4.32 (s, 1H), 4.00-4.05 (m, 3H), 3.49-3.50 (m, 1H), 3.37-3.40 (m, 6H), 2.88-2.93 (m, 2H), 2.45-2.51 (m, 1H), 2.29-2.38 (m, 2H), 2.04-2.08 (m, 3H), 1.73-1.77 (m, 2 H), 1.59-1.63 (m, 3H), 1.48 (d, 6H, J = 6.9 Hz).

EXAMPLE 49

4-(Hvdroxy(2-oxo-l ,2-dihvdropyridin-3-yl)methyl)-3-(4-(6-isopropylpyridazin-3- yl)phenoxy)-N- ( 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide

Step A: 3-(4-(6-Isopropylpyridazin-3-yl)phenoxy)-4-(2-oxo-L2-dihvdro pyridine-3-carbonyl)-N- ( 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzamide

To a solution of 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-(2-oxo-l ,2- dihydropyridine-l-carbonyl)benzoic acid (120 mg, 0.26 mmol) in DMF (5 mL) was added Et ₃ N (131 mg, 1.30 mmol), HATU (148 mg, 0.390 mmol), and l-(tetrahydro-2H-pyran-4-yl)piperidin- 4-amine dihydrochloride (100 mg, 0.39 mmol) and the reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to obtain 3-(4-(6- isopropylpyridazin-3-yl)phenoxy)-4-(2-oxo-l ,2-dihydropyridine-3-carbonyl)-N-( 1 -(tetrahydro- 2H-pyran-4-yl)piperidin-4-yl)benzamide as a yellow solid. MS: mlz = 622.5 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.60 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.81 -7.74 (m, 2H), 7.62 (d, J = 5.2 Hz, 1H), 7.53 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.42 (t, J = 6.8 Hz, 1H), 4.20-4.05 (m, 3H), 3.74-3.67 (m, 2H), 3.55-3.43 (m, 4H), 3.19 (t, J = 7.2 Hz, 2H), 2.30-2.22 (m, 2H), 2.10-2.02 (m, 2H), 2.02-1.90 (m, 2H), 1.87- 1.75 (m, 2H), 1.48 (d, J = 7.2 Hz, 6H).

Step B: 4-(Hydroxyf2-oxo-l ,2-dihvdropyridin-3-yl)methvn-3-i4-(6-isopropylpyridazin-3- yl)phenoxy)-N-( 1 -( tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide

To a solution of 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-(2-oxo-l,2- dihydropyridine-3-carbonyl)-N-(l-(tetrahydro-2H-pyran-4-yl)p iperidin-4-yl)benzamide (25 mg, 0.040 mmol) in MeOH (5 mL) at 0 °C was added NaBH ₄ (15 mg, 0.40 mmol). The reaction mixture was stirred for 30 min, and then diluted with water (25 mL) and extracted with EtOAc (25 mL x 5). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated to obtain 4- (hydroxy(2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3-(4-(6-isopropylpyridazin-3- yl)phenoxy)-N-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide as a white solid. MS: mlz = 624.1 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.06 (d, J = 8.8 Hz, 1H), 8.03-8.00 (m, 2H), 7.72-7.70 (m, 3H), 7.56 (dd, J = 1.6, 8.4 Hz, 1H), 7.45 (s, 1H), 7.28 (dd, J = 1.6, 8.4 Hz, 1H), 7.07-7.00 (m, 2H), 6.33 (t, J = 6.8 Hz, 1H), 6.26 (s, 1H), 4.02-3.98 (m, 2H), 3.90-3.84 (m, 1H), 3.41 (t, J = 12 Hz, 2H), 3.29-3.22 (m, 1H), 3.13-3.09 (m, 2H), 2.65-2.56 (m, 1H), 2.39 (t, J = 12 Hz, 2H), 1.98 (m, 2H), 1.85 (m, 2H), 1.72-1.53 (m, 4H), 1.42 (d, J = 7.2 Hz, 6H).

2-Fluoro-5-(3-fluoro-4-(5-isopropyl-L3,4-thiadiazol-2-yl)phe noxy)-4-((2-oxopyrazin-l (2H)- yl)methyl)-N-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)ben zamide

(Benzotriazol- 1 -yloxy)//'w(dimethylamino)phosphonium hexafluorophosphate (41 mg, 0.094 mmol) was added to a solution of 2-fluoro-5-(3-fluoro-4-(5-isopropyl-l ,3,4-thiadiazol- 2-yl)phenoxy)-4-((2-oxopyrazin-l (2H)-yl)methyl)benzoic acid (35 mg, 0.072 mmol), 1- (tetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride (22 mg, 0.087 mmol), and triethylamine (35 μΐ,, 0.25 mmol) in DMF (0.7 mL). The resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were concentrated under nitrogen. The residues were combined and diluted with 9: 1 MeOH:CH ₂ Cl ₂ (2 mL) and stirred with MP-carbonate for 1 h. The solution was filtered and concentrated to give the title compound. MS: m/z = 651.3 (M +

1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.36 (t, J = 8.4 Hz, 1 H); 8.16 (d, J = 1.2 Hz, 1 H); 7.73 (dd, J = 6.4, 1.0 Hz, 1 H); 7.36 (d, J = 11.4 Hz, 1 H); 7.16 (dd, J = 4.4, 1.3 Hz, 1 H); 6.88 (dd, J = 8.8, 2.4 Hz, 1 H); 6.75 (dd, J = 1 1.5, 2.4 Hz, 1 H); 6.61 (dd, J = 13.1, 7.8 Hz, 1 H); 5.08 (s, 2 H); 3.98-4.01 (m, 3 H); 3.53-3.54 (m, 1 H); 3.37 (td, J = 11.8, 1.9 Hz, 2 H); 2.88-2.92 (m, 2 H); 2.45-2.49 (m, 1 H); 2.33 (t, J = 1 1.1 Hz, 2 H); 2.02-2.06 (m, 2 H); 1.71-1.74 (m, 2 H); 1.56-1.56 (m, 4 H); 1.50 (d, J = 6.9 Hz, 6 H).

2-Fluoro-5-(3-fluoro-4-(5-isopropyl-L3,4-thiadiazol-2-yl)phe noxy)-4-((6-oxopyrimidin-l(6H)- yl)methyl)-N-(l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)ben zamide

To a solution of 2-fluoro-5-(3-fluoro-4-(5-isopropyl-l ,3,4-thiadiazol-2- yl)phenoxy)-4-((6-oxopyrimidin-l(6H)-yl)methyl)benzoic acid (60 mg, 0.12 mmol) in DMSO (1 mL) was added l-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine hydrochloride (41 mg, 0.19 mmol), BOP (55 mg, 0.12 mmol), and TEA (0.05 mL, 0.4 mmol). The reaction was stirred at 23 °C for 30 min and then passed through a syringe filter. The mixture was purified via reverse- phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound.

HRMS: m/z = 651.2560 (M+l). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.36 (m, 1 H); 8.22 (s, 1 H); 7.84 (d, J = 6.6 Hz, 1 H); 7.72 (d, J = 6.3 Hz, 1 H); 7.39 (d, J = 1 1.4 Hz, 1 H); 6.86 (d, J = 8.8 Hz, 1 H); 6.79 (d, J = 1 1.4 Hz, 1 H); 6.61 (br s, 1 H); 6.45 (d, J = 6.6 Hz, 1 H); 5.10 (s, 2 H); 4.03 (br s, 3 H); 3.55 (m, 1 H); 3.38 (m, 2 H); 2.9 (br s, 2 H); 2.47 (br s, 1 H); 2.35 (br s, 2 H); 2.05 (br s, 2 H); 1.75 (br s, 2 H); 1.55-1.65 (m, 4 H); 1.51 (d, J = 6.9 Hz, 6 H).

3-(3-Fluoro-4-(5-(2-hvdroxypropan-2-yl)-l ,4-thiadiazol-2-yl)phenoxy)-4-((2-oxopyridin- 1 (2H -yl)methyl)-N-( 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzamide

N-Methylmorpholine (30.1 μΐ, 0.274 mmol) was added to a solution of 3-(3- fluoro-4-(5-(2-hydroxypropan-2-yl)- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-4-((2-oxopyridin- 1 (2H)- yl)methyl)benzoic acid with three equivalents of sodium chloride (45 mg, 0.069 mmol), 1- (tetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride (22 mg, 0.086 mmol), EDC (23 mg, 0.12 mmol), and HOAt (4.7 mg, 0.034 mmol) in DMF (685 μΐ . The resulting solution was stirred at 50 °C for 30 min. The mixture was diluted with water (200 μί) and then purified by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid). The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. LC-MS m/z found = 648.4 [M+l]. Ή NMR (400 MHz, DMSO): δ 8.20 (t, J = 8.6 Hz, 1 H); 7.72-7.70 (m, 2 H); 7.57 (d, J - 1.6 Hz, 1 H); 7.39-7.38 (m, 1 H); 7.27-7.24 (m, 1 H); 7.06 (dd, J = 12.1 , 2.5 Hz, 1 H); 6.97 (dd, J =

8.8, 2.4 Hz, 1 H); 6.36 (dd, J = 9.2, 1.2 Hz, 1 H); 6.33 (s, 1 H); 6.20 (td, J = 6.7, 1.4 Hz, 1 H);

3.88-3.83 (m, 2 H); 5.13 (s, 2 H); 3.72-3.67 (m, 2 H); 3.14-3.08 (m, 2 H); 2.86-2.85 (m, 2 H);

2.67-2.66 (m, 1 H); 2.33-2.32 (m, 1 H); 2.14 (m, 2 H); 1.81 -1.74 (m, 2 H); 1.61 (s, 6 H); 1.46-

1.43 (m, 2 H); 1.20-1.14 (m, 2 H).

EXAMPLE 53

2-Fluoro-N-(f 3R.4S)-3 -fluoro- 1 -( tetrahvdro-2H-pyran-4-yl ^' )piperidin-4-yl ^' )-5-f 4-( 6- isopropylpwida2in-3-yl)phenoxy)-4-((( ^" S)-4-methyl-2-oxopyrrolidin-l-yl)methyl)benzamide

To a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4~ methyl-2-oxopynOlidin-l-yl)methyl)benzoic acid (150 mg, 0.32 mmol) and (3R, 4S)-3 -fluoro- 1- (tetrahydro-2H-pyran-4-yl)piperidin-4-amine (72 mg, 0.36 mmol) in DMF (0.5 mL) was added HOAt (13 mg, 0.097 mmol) and EDC (124 mg, 0.647 mmol). The resulting mixture was stirred at 23 °C for 18 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse- phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 55% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: m/z = 648.4 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.07 (d, J = 8.8 Hz, 2 H); 7.75 (d, J = 8.8 Hz, 1 H); 7.71 (d, J = 6.4 Hz, 1 H); 7.40 (d, J = 8.8 Hz, 1 H); 7.15 (d, J = 1 1.6 Hz, 1 H); 7.04 (d, J = 8.8 Hz, 2 H); 6.99-7.03 (m, 1 H); 4.79 (d, J = 49.5 Hz, 1 H); 4.52 (d, J = 5.4 Hz, 1 H); 4.48 (d, J = 15.3 Hz, 1 H); 4.17-4.21 (m, 1 H); 4.03 (dd, J = 1 1.4, 4.1 Hz, 2 H); 3.44 (dd, J = 9.5, 7.7 Hz, 1 H); 3.35-3.40 (m, 3 H); 3.25-3.31 (m, 1 H); 2.98-3.00 (m, 1 H); 2.91 (dd, J = 9.5, 6.1 Hz, 1 H); 2.51-2.62 (m, 2 H); 2.33-2.49 (m, 2 H); 2.03 (dd, J = 16.7, 7.0 Hz, 1 H); 1.90-1.93 (m, 2 H); 1.72-1.76 (m, 2 H); 1.57-1.63 (m, 3 H); 1.42 (d, J = 7.0 Hz, 6 H); 1.10 (d, J = 6.8 Hz, 3 H).

fS)-5-n,5-Difluoro-4-(6-isopropylpyridazin-3-yl)phenoxy)-2-f luoiO-4-( ^' (4-methyl-2- oxopyrrolidin- 1 -yl)methyl)-N-( 1 -(tetrahydiO-2H-pyran-4-yl)piperidin-4-yl)benzamide

To a solution of (S)-5-(3,5-difluoiO-4-(6-isopropylpyt"idazin-3-yl)phenoxy)-2 - fluoi -4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (100 mg, 0.20 mmol) in dry CH ₂ C1 ₂ (5 mL) was added HOBt (32 mg, 0.24 mmol), EDC (46 mg, 0.24 mmol), and Et ₃ N (81 mg, 0.80 mmol). The reaction mixture was stirred at 23 °C for 0.5 h and then 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-amine hydrochloride (62 mg, 0.24 mmol) was added. The resulting mixture was stirred 23 °C for 16 h and concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give (S)-5-(3,5-difluoro-4-(6-isopropylpyridazin-3-yl)phenoxy)-2- fluoro-4- ((4-methyl-2-oxopyrrolidin- 1 -yi)methyl)-N-( 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)benzamide. MS: mlz = 666.5 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): 5 7.79 (d, J = 6.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 1 1.6 Hz, 1H), 6.66 (dd, J = 7.6, 13.2 Hz, 1H), 6.58 (d, J = 8.8 Hz, 2H), 4.45 (d, J = 8.0 Hz, 1H), 4.38 (d, J = 8.0 Hz, 1H), 4.04-4.01 (m, 3H), 3.43-3.35 (m, 4H), 2.92-2.85 (m, 3H), 2.54-2.36 (m, 5H), 2.08-2.03 (m, 3H), 1.76-1.55 (m, 6H), 1.42 (d, J = 6.8 Hz, 6H), 1.10 (d, J = 6.8 Hz, 3H).

2-Fluoro-N-(C3S. R)-3-fluoro- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4-( ( 5-fluoro-2- oxopyridin-l (2H)-yl)methyl)-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)benz amide

To a solution of 2-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)-5-(4-(6- isopropylpyridazin-3-yl)phenoxy)benzoic acid (100 mg, 0.21 mmol) in DMF (3 mL) was added Et ₃ N (90 uL, 0.63 mmol) and HATU (96 mg, 0.25 mmol). The reaction mixture was stirred at 23 °C for 30 min and then (3S,^R)-3-fluoro-l-(tetrahydro-2H-pyran-4-yl)piperidin-4-ami ne (51 mg, 0.25 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with water (0.2 mL) and then purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound. MS: mlz = 662.4 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.05 (dd, J = 3.3, 8.8 Hz, 3H), 7.79 - 7.73 (m, 1H), 7.71 - 7.65 (m, 1H), 7.51 - 7.42 (m, 1H), 7.31 - 7.27 (m, 1H), 7.20 (d, J = 10.8 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.55 - 6.43 (m, 1H), 5.20 (s, 2H), 4.84-4.72 (m, 1H), 4.12 - 4.00 (m, 1H), 3.96 (dd, J = 3.8, 1 1.3 Hz, 2H), 3.41 - 3.32 (m, 3H), 3.29 - 3.21 (m, 1H), 2.98 (d, J = 9.8 Hz, 1H), 2.57 - 2.29 (m, 3H), 1.93-1.72 (m, 1H), 1.83 - 1.69 (m, 3H), 1.61 - 1.44 (m, 2H), 1.39 (d, J = 7.0 Hz, 6H).

N-r(RV3 -Difluoro-l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl1-2-fluo ro-5-r4-(6- isopropylpyridazin-3-yl)phenoxy1-4-r((S)-4-methyl-2-oxopyrro lidin-l-yl ^' )methyllbenzamide

Tetrahydro-4H-pyran-4-one (29.2 mg, 0.292 mmol) was added to a solution of N-

((R)-3,3-difluoropiperidin-4-yl)-2-fluoro-5-[4-(6-isoprop ylpyridazin-3-yl)phenoxy]-4-[((S)-4- methyl-2-oxopyrrolidin-l-yl)methyl]benzamide (139 mg, 0.146 mmol) in CH ₂ C1 ₂ (1.5 mL) and the resulting mixture stirred at 23 °C for 15 min. Sodium triacetoxyborohydride (155 mg, 0.729 mmol) was added and the reaction mixture was stirred at 23 °C for 16 h. The reaction mixture diluted with saturated aqueous NaHC0 ₃ (5 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by reverse-phase HPLC, eluting with 0% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 60%

acetonitnle in water. The desired fractions were lyophilized to give the title compound as the TFA salt. MS: mlz = 666.6 (M + 1). Ή NMR (500 MHz, CD ₃ OD) δ 8.45 (d, 1H, J = 9.0 Hz), 8.13 (m, 2H), 8.09 (d, 1H, J = 9.1 Hz), 7.34 (d, 1H, 7 = 6.0 Hz), 7.28 (d, 1H, J = 10.3 Hz), 7.15 (m, 2H), 4.81 (m, 1H), 4.50 (dd, 2H, J = 32.0, 15.4 Hz), 4.08 (dd, 2H, J = 1 1.5, 3.8 Hz), 4.02 (m, 1H), 3.68 (m, 2H), 3.57 (m, 1H), 3,51 (dd, 1H, J = 9.7, 7.7 Hz), 3.41 (m, 3H), 3.34 (dd, 1H, J = 12.8, 3.0 Hz), 2.96 (dd, 1H, J = 9.7, 6.0 Hz), 2.47 (dd, 1H, J = 16.3, 8.6 Hz), 2.41 (m, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 2.03 (m, 2H), 1.95 (dd, 1H, J = 16.3, 6.6 Hz), 1.80 (m, 2H), 1.44 (d, 6H, J = 7 Hz), 1.05 (d, 3H, J = 6.7 Hz).

2-Fluoro-N-( ( 3S, R)-3-fluoro- 1 -( tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)-5-(4-( 6- isopropylpyridazin-3-yl)phenoxy)-4-(((S

To a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (60.0 mg, 0.129 mmol) and (j?S,4R)-3-fluoro- l-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (28.8 mg, 0.142 mmol) in DMF (1.0 mL) was added BOP (86.0 mg, 0.194 mmol) and Et ₃ N (54 μΐ,, 0.36 mmol). The resulting mixture was stirred at 23 °C for 18 h. The reaction mixture was purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1 % TFA used as a modifier) initially, grading to 55% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. MS: m/z = 648.3 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.07 (d, J= 8.6 Hz, 2 H); 7.75 (d, J= 8.8 Hz, 1 H); 7.71 (d, J = 6.4 Hz, 1 H); 7.40 (d, J= 8.8 Hz, 1 H); 7.15 (d, J= 1 1.6 Hz, 1 H); 7.04 (d, J= 8.6 Hz, 2 H); 6.98-7.04 (m, 1H); 4.78 (d, J= 49.6 Hz, 1 H); 4.54 (d, J= 15.6 Hz, 1 H); 4.48 (d, J= 15.6 Hz, 1 H); 4.15-4.23 (m, 1H); 4.03 (dd, J= 1 1.2, 4.0 Hz, 2 H); 3.44 (dd, J= 9.5, 7.8 Hz, 1 H); 3.35-3.37 (m, 3 H); 3.28 (br t, J= 1 1.9 Hz, 1 H); 2.98-3.00 (m, 1H); 2.91 (dd, J= 9.5, 6.1 Hz, 1 H); 2.50- 2.60 (m, 2 H); 2.34-2.48 (m, 2 H); 2.03 (dd, J= 16.6, 7.1 Hz, 1 H); 1.91-1.93 (m, 2 H); 1.72-1.74 (m, 2 H); 1.59-1.61 (m, 3 H); 1.42 (d, J = 7.0 Hz, 6 H); 1.09 (d, J - 6.8 Hz, 3 H).

EXAMPLE 58

2-Fluoro-5-(4-(6-isopropylp idazin-3-yl)pheno

yl)piperidin-4-yl)-4-f(fS -4-methyl-2-oxopyn-olidin-l-yl)methyl)benzamide

A mixture of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl- 2-oxopyrrolidin-l-yl)methyl)benzoic acid (50 mg, 0.11 mmol), 2-methyl-l-(tetrahydro-2H- pyran-4-yl)piperidin-4-amine (23 mg, 0.12 mmol), HATU (45 mg, 0.12 mmol), and Et ₃ N (0.04 mL, 0.3 mmol) in DMF (2 mL) was stirred at 25 °C for 5 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound as a white solid. MS: m/z = 644.5 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.13-8.05 (m, 3H), 7.70 (d, J = 8.8 Hz, IH), 7.29 (d, J = 6.0 Hz, IH), 7.23 (d, J = 10.4 Hz, IH), 7.11 (d, J = 8.8 Hz, 2H), 4.57- 4.44 (m, 2H), 3.99-3.95 (m, 2H), 3.89-3.78 (m, IH), 3.54-3.33 (m, 4H), 3.25-3.22 (m., IH), 3.09- 3.05 (m, IH), 3.00-2.92 (m, IH), 2.52-2.33 (m, 3H), 2.07-1.82 (m, 4H), 1.71-1.47 (m, 4H), 1.47- 1.32 (m, 8H), 1.18 (d, J = 6.0 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H).

2-Fluoro-5-(4-(6-isopropylpyi-idazin-3-yl)phenoxy)-4-(((S)-4 -methyl-2-oxopyrrolidin-l- yl)methyl)-N-(l-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethy l)piperidin-4-yl)benzamide

A mixture of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-

2-oxopyrrolidin-l-yl)methyl)benzoic acid (120 mg, 0.26 mmol), 1 -(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)piperidin-4-amine (60 mg, 0.24 mmol), HATU (1 10 mg, 0.29 mmol) and Et ₃ N (0.1 mL, 0.7 mmol) in DMF (3 mL) was stirred at 25 °C for 5 h. The reaction mixture was diluted with water (0.2 mL) and purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the racemic title compound and a diastereomer of the title compound (as a racemate), peak Al (isomers A and B) and peak A2 (isomers C and D). Further separation of peak Al using SFC conditions gave the title compound (peak B2, isomer B) and its enantiomer (peak Bl , isomer A) as white solids. Isomer B: MS: m/z = 698.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.12-8.08 (m, 3H), 7.72 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H), 7.26 (d, J = 10.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 4.60 (d, J = 16.0 Hz, 1H), 4.52 (d, J = 10.4 Hz, 1H) 4.01 - 3.92 (m, 3H), 3.52 - 3.32 (m, 5H), 3.17 - 2.95 (m, 3H), 2.52 - 2.46 (m, 3H), 2.23 - 2.16 (m, 1H), 2.05 - 1.98 (m, 2H), 1.89 - 1.74 (m, 2H), 1.63 - 1.47 (m, 4H), 1.42 (d, J = 7.2 Hz, 6H), 1.08 (d, J = 6.4 Hz, 3H).

( -2-Ρ1υοΓθ-5- 4-(5-ί5ο Γορν1-1 ,3,4-Φί3άί3ζο1-2-ν1^6ηοχν)-4-((4^6Λν1-2-ο ορνιτο1ϊάίη-1- yl)methyl)-N-(l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)ben zamide

(S)-2-Fluoro-5-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)-N-( 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide (10 mg, 0.016 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 0.76 mg, 0.019 mmol) in THF (5 mL) at 23 °C. After 5 minutes, methyl iodide (Ι . ΙμΙ,, 0.13 mmol) was added. After 1 h, the mixture was diluted with H ₂ 0 and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of Ο¾Ο ₂ :Μβ0Η, 100:0 to 85: 15, to give the title compound. MS: m/z = 650.3 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 7.89 (dd, J = 8.8, 2.8 Hz, 2 H); 7.07-7.09 (m, 1 H); 6.92-7.00 (m, 3 H); 4.46-4.50 (m, 2 H); 4.00-4.03 (m, 2 H); 3.38-3.42 (m, 4 H); 3.02-3.07 (m, 1 H); 2.89-2.91 (m, 1 H); 2.52-2.55 (m, 1 H); 2.35-2.59 (m, 2 H); 2.32 (br s, 1 H); 2.01 -2.05 (m, 2 H); 1.70-1.83 (m, 2 H); 1.62-1.77 (br m, 3 H); 1.54-1.62 (m, 8 H); 1.47 (d, J = 6.89, 6 H); 1.1 1 (t, J = 6.3 Hz, 3 H).

EXAMPLE 61

Tetrahydro-2H-pyran-4-yl 3- (3-r4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy ^" |-4-[(2- oxopyrrolidin- 1 -yl)methyl ^" |benzamido 1 azetidine- 1 -carboxylate

To a solution of tetrahydro-2H-pyran-4-ol (0.012 n L, 0.13 mmol) in acetonitrile (1 mL) at 23 °C was added Et ₃ N (0.095 mL, 0.68 mmol) and bis(2,5-dioxopyrrolidin-l- yl)carbonate (50 mg, 0.12 mmol) and the reaction mixture was stirred for 16 h. N-(Azetidin-3- yl)-3-[4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy]-4-[(2-oxopyrrolidin-l-yl)methy l]benzamide hydrochloride (60 mg, 0.1 1 mmol) in acetonitrile (1 mL) and Et ₃ N (0.095 mL, 0.68 mmol) were added to the reaction mixture and the reaction mixture was stirred at 23 °C for 4 h. The reaction mixture was purified by reverse phase HPLC, eluting with 15% acetonitrile in water (0.1% formic acid as a modifier) initially, grading to 65% acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS: m/z = 620.4 (M+l). Ή NMR (500 MHz, CD ₃ OD) δ 7.95 (d, 2H, J = 6.8 Hz), 7.74 (dd, 1H, J = 7.9, 1.6 Hz), 7.55 (s, 1H), 7.49 (d, 1H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.6 Hz), 4.71-4.79 (m, 2H), 4.54 (s, 2H), 4.30 (m, 2H), 3.98 (m, 2H), 3.84-3.88 (m, 2H), 3.46-3.54 (m, 3H), 3.34-3.37 (m, 2H), 2.28 (t, 2H, J = 8.1 Hz), 1.89-1.97 (m, 4H), 1.58-1.64 (m, 2H), 1.46 (d, 6H, J = 7.0 Hz).

N-(l -((7R, R)-2-Hvdroxycyclopentyl)piperidin-4-yl)-3-(4-(6-isopropylpyr idazin-3-yl)phenoxy)- 4-( ( (S)-4-methyl-2-oxopyrrolidin- 1 -vDmethyDbenzamide and N-( 1 -( ( 7S.2S)-2- hvdroxycvclopentyl)piperidin-4-yl)-3-(4-(6-isopropylpyridazi n-3-yl)phenoxy)-4-(((S)-4-methyl- 2-oxopyrrolidin- 1 -yl)methyl)benzamide A mixture of (S)-3-[4-(6-isopropylpyridazin-3-yl)phenoxy]-4-[(4-methyl-2- oxopyiTolidin-l -yl)methyl]-N-(piperidin-4-yI)benzamide trifluoroacetate (127 mg, 0.147 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.255 mL, 1.47 mmol) in EtOH (1.5 mL) was sonicated for 15 min. 6-Oxabicyclo[3.1.0]hexane (0.19 mL, 2.2 mmol) was added and the reaction mixture was heated at 80 °C for 24 h. The reaction mixture was cooled and purified by reverse phase HPLC, eluting with 10% acetonitrile in water (0.1% formic acid used as a modifier) initially, grading to 40% acetonitrile in water. The desired fractions were lyophilized to give the title compounds. MS: mlz = 612.5 (M + 1). lH NMR (500 MHz, CD ₃ OD) δ 8.08 (t, 3H, J = 8.5 Hz), 7.70 (m, 2H), 7.51 (d, 1H, J = 1.4 Hz), 7.47 (d, 1H, J = 8.0 Hz), 7.11 (d, 2H, J = 8.8 Hz), 4.55 (dd, 2H, J = 24.0, 15.2 Hz), 4.29 (dd, 1H, J = 13.5, 6.6 Hz), 4.12 (m, 1H), 3.81 (m, 1H), 3.58 (d, 1H, J = 12.1 Hz), 3.49 (dd, 1H, J = 9.8, 7.8 Hz), 3.31 (m, 1H), 3.26 (m, 1H), 3.14 (m, 2H), 2.94 (dd, 1H, J = 9.8, 6.0 Hz), 2.65 (s, 1H), 2.46 (m, 1H), 2.39 (m, 1H), 2.20 (m, 3H), 2.03 (m, 1H), 1.92 (m, 3H), 1.71 (m, 4H), 1.39 (d, 6H, J = 7.0 Hz), 1.04 (d, 3H, J = 6.8 Hz).

N-(l-Cyclohexylazetidin-3-yl)-3-[4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy]-4-[(2- oxopyrrolidin- 1 -yl)methyl ^" |benzamide Step A: fe -Butyl 3-{3-r4-(5-isopropyl-L3,4-thiadiazol-2-yl)phenoxy]-4- (2-oxopyrrolidin-l- vDmethyl]benzamido } azetidine- 1 -carboxylate

To a solution of 3-[4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy]-4-[(2- oxopyrrolidin-l-yl)methyl]benzoic acid (330 mg, 0.75 mmol) in DMF (3 mL) at 23 °C was added tert-butyl 3 -aminoazetidine-1 -carboxylate (195 mg, 1.13 mmol), EDC (289 mg, 1.51 mmol), HOBt (1 16 mg, 0.754 mmol), and DIPEA (0.66 mL, 3.78 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of

CH ₂ Cl ₂ :methanol, 100:0 to 95:5, to give the title compound. MS: m/z = 592.4 (M+l). Step B: N-(Azetidin-3-yl)-3-[4-(5-isopropyl-1 ,4 M

1 -yl)niethyl ^" |benzamide hydrochloride

fcrt-Butyl 3-{3-[4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy]-4-[(2- oxopynOlidin-l-yl)methyl]benzamido}azetidine-l-carboxylate (440 mg, 0.74 mmol) was treated with 4 M HC1 in 1 ,4-dioxane (6 mL) and water (0.6 mL) and the reaction mixture stirred at 23 °C for 2 h. The reaction mixture was concentrated to give the title compound. MS: m/z = 492.2 (M+l). Ste C: N-(l -Cvclohexylazetidin-3-yl)-3-[4-(5-isopropyl-l,3,4-thiadiazol -2-yl phenoxyl-4-r(2- oxopyrrolidin-l-yl)methyl ^~ |benzamide

To a solution of N-(azetidin-3-yl)-3-[4-(5-isopropyl-l,3,4-thiadiazol-2- yl)phenoxy]-4-[(2-oxopyrrolidin-l-yl)methyl]benzamide hydrochloride (60 mg, 0.11 mmol) in THF (1 mL) at 23 °C was added acetic acid (0.1 mL) and cyclohexanone (1 1 mg, 0.1 1 mmol) and the reaction mixture was stirred for 15 minutes. The reaction mixture was cooled to 0 °C and sodium triacetoxyborohydride (48 mg, 0.23 mmol) was added. The reaction mixture was warmed to 23 °C and stirred for 2 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 mL) and CH ₂ C1 ₂ (20 mL). The organic layer was washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of CH ₂ Cl ₂ :methanol:NH ₄ OH, 100:0:0 to 90: 10: 1, to give the title compound. MS: m/z = 574.4 (M+l). Ή NMR (500 MHz, DMSO) δ 8.76 (d, 1H, J = 6.1 Hz), 7.94 (d, 2H, J = 8.7 Hz), 7.76 (d, 1H, J = 8.6 Hz), 7.57 (d, 1H, J = 1.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 7.05 (d, 2H, J = 8.6 Hz), 4.39 (s, 2H), 3.42-3.51 (m, 3H), 3.21 (t, 2H, J = 7.0 Hz), 2.90-2.95 (m, 2H), 2.14 (t, 2H, J = 8.0 Hz), 1.96-2.00 (m, 1H), 1.83 (q, 2H, J = 7.6 Hz), 1.62 (m, 4H), 1.49-1.51 (m, 1H), 1.39 (d, 6H, J = 6.8 Hz), 1.10-1.18 (m, 3H), 0.89-0.94 (m, 2H).

(S -2-FluoiO-5- 4-(6-isopropylpyridazin-3-yl)phenoxy1-4-[(4-methyl-2-oxopyi' rolidin- 1 -yl)methyl ^" |-N- { 1 -[(tetrahydro-2H-pyran-4-yl)methyllpiperidin-4-yll ben

zamide

Tetrahydropyran-4-carbaldehyde (18 mg, 0.17 mmol) was added to a solution of (S)-2-fluoro-5-[4-(6-isopropylpyi"idazin-3-yl)phenoxy]-4-[(4 -methyl-2-oxopyrrolidin-l- yl)methyl]-N-(piperidin-4-yl)benzamide trifluoroacetate (84 mg, 0.083 mmol) in CH ₂ CI ₂ (0.8 mL) and the resulting mixture was stirred at 23 °C for 15 min. To this solution was added sodium triacetoxyborohydride (175 mg, 0.827 mmol) and the reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was partitioned between NaHC0 ₃ (5 mL) and CH ₂ CI ₂ (5 mL). The aqueous layer was then extracted with CH ₂ CI ₂ (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by reverse phase HPLC, eluting with 0% acetonitrile in water (0.1% formic acid used as a modifier) initially, grading to 70% acetonitrile in water. The desired fractions were lyophilized to give the title compound as the formate salt. MS: ml2. = 644.5 (M + 1). Ή NMR (500 MHz, CD ₃ OD) δ 8.07 (m, 3H), 7.70 (d, 1H, J = 8.9 Hz), 7.30 (d, 1H, J = 5.9 Hz), 7.23 (m, 1H), 7.12 (m, 2H), 4.50 (dd, 2H, J = 28.5, 16.5 Hz), 3.91 (m, 3H), 3.50 (dd, 1H, J = 9.6, 8.0 Hz), 3.41 (m, 2H), 3.33 (q, 1H, J = 7.0 Hz), 3.02 (d, 2H, J = 11.1 Hz), 2.95 (dd, 1H, J = 9.8, 6.1 Hz), 2.47 (dd, 1H, J = 16.4, 8.6 Hz), 2.40 (m, 3H), 2.31 (m, 2H), 1.96 (m, 3H), 1.86 (m, 1H), 1.69 (m, 4H), 1.39 (d, 6H, J = 6.9 Hz), 1.26 (m, 2H), 1.05 (d, 3H, J = 6.8 Hz).

(S^-2-Fluoro-5- 4-(6-isopropylpyridazin-3-yl)phenoxyl-4- (4-methyl-2-oxopyrrolidin-l- yl)methyl1-N-[ l-((3-methyloxetan-3-yl)methyl)piperidin-4-yllbenzamide

3-Methyl-oxetane-3-carbaldehyde (5.87 mg, 0.059 mmol) was added to a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l- yl)methyl)-N-(piperidin-4-yl)benzamide trifluoroacetate (40 mg, 0.039 mmol) in CH ₂ CI ₂ (0.5 mL) and the resulting mixture was stirred at 23 °C for 15 min. Sodium triacetoxyborohydride (41.4 mg, 0.195 mmol) was added and the reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was partitioned between saturated aqueous NaHC0 ₃ (5 mL) and CH2CI2 (5 mL). The aqueous layer was then extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by prep TLC plate (1000 micron), eluting with

CH ₂ Cl2:CH ₃ OH:NH 0H (100: 10: 1) to give the title compound. MS: mlz = 630.4 (M + 1). Ή NMR (500 MHz, CD ₃ OD) δ 8.06 (dd, 3H, J = 12.0, 8.8 Hz), 7.68 (d, 1H, J = 8.9 Hz), 7.29 (d, 1H, J = 5.8 Hz), 7.21 (d, 1H, J = 10.4 Hz), 7.09 (d, 2H, J = 8.7 Hz), 4.47 (m, 3H), 4.25 (m, 2H), 3.81 (m, 1H), 3.48 (m, lH), 2.93 (m, 1H), 2.64 (d, 2H, J = 1 1.6 Hz), 2.54 (s, 2H), 2.45 (dd, 1H, J = 16.3, 8.6 Hz), 2.37 (m, 1H), 2.14 (t, 2H, J = 11.5 Hz), 1.93 (dd, 1H, J = 16.4, 6.7 Hz), 1.87 (d, 2H, J = 12.4 Hz), 1.61 (m, 2H), 1.37 (m, 9H), 1.26 (m, 2H), 1.03 (d, 3H, J = 6.7 Hz).

EXAMPLE 66

N-(2-(l ,l-Dioxidotetrahvdro-2H-thiopyran-4-yl)-2-azaspiror3.3]hepta n-6-yl)-3-(4-(5-isopropyl- l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2-oxopyrrolidin-l-yl)methy l)benzamide

To a solution of 3-(4-(5-isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((2- oxopyrrolidin-l-yl)methyl)-N-(2-azaspiro[3.3]heptan-6-yl)ben zamide (50 mg, 0.094 mmol) in THF (1 mL) at 23 °C was added acetic acid (0.05 mL) and dihydro-2H-thiopyran-4(3H)-one-l ,l - dioxide (14 mg, 0.094 mmol) and the reaction mixture was stirred for 15 minutes. The reaction mixture was cooled to 0 °C and sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added. The reaction mixture was stirred for 2 h at 23 °C. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 mL) and CH2CI2 (20 mL). The organic layer was washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of CH ₂ C1 ₂ : methanol :NH ₄ OH, 100:0:0 to 90: 10: 1, to give the title compound. MS: m/z = 664.3 (M+l). Ή NMR (500 MHz, CD ₃ OD) δ 7.95 (d, 2H, J = 8.8 Hz), 7.69 (dd, 1H, J = 8.0, 1.7 Hz), 7.50 (d, 1H, J = 1.8 Hz), 7.47 (d, 1H, J = 8.0 Hz), 7.07 (d, 2H, J = 7.8 Hz), 4.53 (s, 2H), 4.32 (q, 1H, J = 8.1 Hz), 3.49 (q, 1H, J = 6.9 Hz), 3.33-3.36 (m, 2H), 3.32 (s, 2H), 3.19 (s, 2H), 3.09-3.12 (m, 2H), 2.96-2.98 (m, 2H), 2.50-2.55 (m, 1H), 2.33-2.39 (m, 2H), 2.27 (t, 2H, J = 8.1 Hz), 2.17-2.22 (m, 2H), 2.02-2.06 (m, 2H), 1.93 (q, 2H, J = 7.7 -1.85 (m, 2H), 1.47 (d, 6H, J = 7.0 Hz).

(S)-N-( 1 -( 1, 1 -dioxidotetrahvdro-2H-thiopyran-4-yl)piperidin-4-yl -2-fluoro-5-(4-(6- isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2-oxopy^

Dihydro-2H-thiopyran-4-(3H)-one- 1 ,1 -dioxide (19.7 mg, 0.134 mmol) was added to a solution of (S)-2-fluoro-5-[4-(6-isopropylpyridazin-3-yl)phenoxy]-4-[(4- methyl-2- oxopyrrolidin-l-yl)methyl]-N-(piperidin-4-yl)benzamide trifluoroacetate (45 mg, 0.044 mmol) in CH ₂ CI ₂ (0.5 mL) and the resulting mixture was stirred at 23 °C for 15 min. To this solution was added sodium triacetoxyborohydride (47 mg, 0.22 mmol) and the reaction mixture was stirred at 23 °C for 2 h, and then heated at 50 °C for 16 h. The reaction mixture was partitioned between saturated aqueous NaHCC>3 (5 mL) and CH ₂ CI ₂ (5 mL). The aqueous layer was extracted with CH ₂ CI ₂ (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSC , filtered, and concentrated. The residue was purified by prep TLC plate (1000 micron), eluting with CH ₂ CI ₂ /CH ₃ OH/NH ₄ OH (100/10/1) to give the product. The product was then repurified by reverse phase HPLC, eluting with 0% acetonitrile in water (0.1 % formic acid used as a modifier) initially, grading to 40% acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS: mlz = 678.5 (M + 1). Ή NMR (500 MHz, CD ₃ OD) δ 8.09 (m, 3H), 7.69 (d, 1H, J = 9.0 Hz), 7.30 (m, 1H), 7.20 (m, 1H), 7.10 (m, 2H), 4.49 (dd, 2H, J = 28.3, 15.4 Hz), 3.84 (m, 1H), 3.49 (dd, 1H, J = 9.7, 7.8 Hz), 3.32 (m, 1H), 3.10 (m, 4H), 2.94 (m, 3H), 2.73 (m, 1H), 2.43 (m, 4H), 2.16 (m, 4H), 1.94 (m, 3H), 1.61 (m, 2H), 1.39 (d, 6H, J = 6.9 Hz), 1.04 (d, 3H, J = 6.6 Hz). EXAMPLE 68

(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2-oxopyrc^

To a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)-N-(2-azaspiro[3.3]heptan -6-yl)benzamide hydrochloride (50 mg, 0.084 mmol) in DCE (5 mL) was added Et ₃ N (0.014 mL, 0.084 mmol) and dihydro-2H- thiopyran-4-(3H)-one- 1 ,1 -dioxide (12 mg, 0.084 mmol). The reaction mixture was stirred at 23 °C for 2 h and then NaBH(OAc) ₃ (36 mg, 0.17 mmol) was added. The reaction mixture was stirred at 23 °C for 20 h and then concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia,

V/V):acetonitrile to give the title compound as yellow oil. MS: mlz = 690.5 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.06 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.14 (d, J = 1 1.6 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.86 (m, 1H), 4.55-4.41 (m, 3H), 3.46-3.25 (m, 4H), 3.24 (s, 2H), 3.14 (s, 2H), 2.95-2.85 (m, 1H), 2.80-2.71 (m, 2H), 2.65-2.51 (m, 3H), 2.49-2.31 (m, 2H), 2.19-1.91 (m, 7H), 1.41 (d, J = 6.8 Hz, 6H), 1.09 (d, J = 6.8 Hz, 3H).

(S)-2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-N-(l -(3-methoxycvclobutyl)piperidin-4- yl)-4-((4-methyl-2-oxopyrrolidin- 1 -vDmethvDbenzamide Step A: ( S)-ter -Butyl 4-( ^" 2-fluoi -5-(4-(6-isopi pylpyi-idazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzamido)piperidine- 1 -carboxylate

To a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyiTolidin-l-yl)methyl)benzoic acid (400 mg, 0.86 mmol) in DMF (8 mL) was added HATU (360 mg, 0.95 mmol), Et ₃ N (0.36 mL, 2.6 mmol), and teri-butyl 4- aminopiperidine-1 -carboxylate (190 mg, 0.95 mmol). The reaction mixture was stirred at 23 °C for 16 h and then diluted with EtOAc (30 mL). The resulting mixture was washed with H ₂ 0 (20 mL x 3) and saturated aqueous sodium chloride solution (20 mL), dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by column chromatography (Si0 ₂ , petroleum

ether:EtOAc, 5: 1 to 1 : 1) to give (S)-ter/-butyl 4-(2-fluoro-5-(4-(6-isopropylpyridazin-3- yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)benzamido)piperidine- 1 -carboxylate as yellow solid. MS: mlz = 646.2 (M + 1). Ή NMR (400 MHz, CD ₃ OD): 8 8.12-8.08 (m, 3H), 7.73 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 6.4 Hz, 1H), 7.25 (d, J = 10.4 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 4.55 (d, J = 15.6 Hz, 1H), 4.49 (d, J = 15.6 Hz, 1H), 4.08-4.02 (m, 3H), 3.54-3.52 (m, 1H), 3.01-2.96 (m, 4H), 2.50-2.46 (m, 2H), 1.96-1.92 (m, 4H), 1.49-1.47 (m, 10H), 1.42 (d, J = 6.8 Hz, 6H), 1.07 (d, J = 6.8 Hz, 3H).

Step B: (S)-2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l- yl)methyl)-N-(piperidin-4-yl)benzamide hydrochloride

(S)-feri-Butyl-4-(2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)p henoxy)-4-((4-methyl- 2-oxopyrrolidin-l-yl)methyl)benzamido)piperidine-l -carboxylate (400 mg, 0.62 mmol) was dissolved in a solution of HCl in MeOH (4 Ν, 5 mL) and the reaction mixture stirred at 23 °C for 4 h. The reaction mixture was concentrated to give (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3- yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)-N-(pip eridin-4-yl)benzamide hydrochloride as a yellow solid. Ή NMR (400 MHz, CD ₃ OD): 5 8.95 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 9.2 Hz, 1H), 8.22 (d, J = 9.2 Hz, 2H), 7.40 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 10.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H),4.55 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 4.18-4.15 (m,lH), 3.56-3.51 (m, 4H), 3.16-2.98 (m, 3H), 2.49-2.45 (m, 2H), 2.22-2.19 (m, 2H), 2.01 -1.91 (m, 3H), 1.52 (d, J = 6.8 Hz, 6H), 1.07 (d, J = 6.8 Hz, 3H).

Step C: (S)-2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-N-(l-( 3- methoxycyclobutyl)piperidin-4-yl)-4-((4-methyl-2-oxopyrrolid in-l -yl)methyl)benzamide To a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)metfiyl)-N-(piperidin-4-yl)benza mide hydrochloride (100 mg, 0.183 mmol) in DCE (4 mL) was added 3-methoxycyclobutanone (18.4 mg, 0.183 mmol) and AcOH (0.021 mL, 0.37 mmol). The reaction mixture was stirred at 23 °C for 0.5 h and then

NaBH(OAc) ₃ (76 mg, 0.36 mmol) was added. The resulting mixture was stirred at 23 °C for 16 h and then concentrated. The residue was purified by reverse phase HPLC (Column:

Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give the title compound and a diastereomer of the title compound as a light yellow oil. The diastereomers were further separated by SFC (Column: Chiralpak AD: Supercritical C0 ₂ /EtOH, 60/40, containing 0.1% NH ₄ OH) to give the title compound as peak 1 (isomer A) and a diastereomer of the title compound as peak 2 (isomer B). Isomer A: MS: mlz = 630.5 (M + 1). Ή NMR (400 MHz, CDC1 ₃ ): δ 8.05 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 12.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.66- 6.62 (m, 1H), 4.52 (d, J = 15.6 Hz, 1H), 4.46 (d, J = 15.2 Hz, 1H), 3.98-3.96 (m, 1H), 3.60-3.52 (m, 1H), 3.50-3.25 (m, 2H), 3.22 (s, 3H), 2.90-2.80 (m, 1H), 2.76-2.75 (m, 2H), 2.58-2.50 (m, 1H), 2.49-2.25 (m, 4H), 2.05-1.95 (m, 6H), 1.80-1.75 (m, 2H), 1.60-1.50 (m, 2H), 1.41 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 3H).

EXAMPLE 70

3- 4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy]-4-r(2-oxopyiTolidin-l-yl)methy ll-N-(3- pyrrolidin-l -ylcvclobutvDbenzamide

Step A: ter/-Butyl N-(3-pyrrolidin-l -ylcvclobutyl)carbamate

To a solution of feri-butyl N-(cw-3-aminocyclobutyl)carbamate (47.8 mg, 0.257 mmol) in THF (5 mL) was added 1 ,4-dibromobutane (32.2 μΐ, 0.269 mmol) and N-ethyl-N- isopropylpropan-2-amine (224 μΐ, 1.28 mmol). The reaction mixture was stirred at 23 °C for 2 h, and then heated at 70 °C for 16 h. The mixture was cooled, concentrated and the residue was purified by silica gel chromatography, eluting with a gradient of (with 10% ammonia), 100:0 to 95:5, to give the title compound as white solid. MS: mlz = 241.1 (M + 1).

Step B: 3-| ^" 4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy]-4-[(2-oxopyrrolidin-l-yl)methy l]-N-(3- pyrrolidin- 1 -ylcyclobutvDbenzamide

To a solution of tert-buty\ N-(3-pyiTolidin-l-ylcyclobutyl)carbamate (31.4 mg, 0.131 mmol) in CH ₂ CI ₂ (0.5 mL) was added TFA (0.25 mL). The reaction mixture was stirred at 23 °C for 2 h and then concentrated. The residue was taken up in DMF (1 mL) and 3-[4-(5- isopropyl-l,3,4-thiadiazol-2-yl)phenoxy]-4-[(2-oxopyrrolidin -l-yl)methyl]benzoic acid (57.2 mg, 0.131 mmol), lH-benzo[d][l,2,3]triazol-l-ol (17.7 mg, 0.131 mmol), N-ethyl-N- isopropylpropan-2-amine (0.1 14 mL, 0.653 mmol), and EDC (38.0 mg, 0.199 mmol) were added. The reaction mixture was stirred at 23 °C for 16 h. Water (0.5 mL) was added and the mixture was purified by reverse phase HPLC on a C- 18 column, eluting with a gradient of H ₂ 0:CH ₃ CN:HCOOH, 95:5:0.1 to 20:80:0.1, to give the title compound as the formate salt. MS: m/z = 560.4 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ) δ 8.54 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.80 (dd, J = 8.8, 1.5 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.70 (m, 1H), 4.55 (s, 2H), 3.51 (m, 1H), 3.29 (t, J = 7.1 Hz, 2H), 3.18 (m, 1H), 3.07 (b), 2.86-2.75 (m, 4H), 2.63 (s, 1H), 2.37 (t, J = 8.1 Hz, 2H), 2.09 (m, 4H), 1.97 (m, 2H), 1.50 (d, J = 7.0 Hz, 6H).

(S)-N-(2-Cvclobutyl-2-azaspiro[3.31heptan-6-yl)-2-fluoro-5-( 4-(6-isopropylpyridazin-3- yl)phenoxy)-4-((4-methyl-2-oxopynOlidin-l-yl)methyl)benzamid e

Step A: (S fe -Butyl 6-(2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-m ethyl-2- oxopyrrolidin-l-yl)methyl)benzamido)-2-azaspiror3.3 heptane-2-carboxylate

To a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (500 mg, 1.1 mmol) in DMF (3 mL) was added HATU (490 mg, 1.3 mmol) and Et ₃ N (0.75 mL, 5.4 mmol). After stirring for 30 min, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.2 mmol) was added and the reaction mixture stirred at 23 °C for 16 h. After concentration, the residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V):acetonitrile to give (S)-teri-butyl 6-(2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4- ((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzamido)-2-azaspiro [3.3]heptane-2-carboxylate as a yellow solid. MS: mlz = 658.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.14-8.07 (m, 3H), 7.73 (d, J = 8.8 Hz, IH), 7.32 (d, J = 6.0 Hz, IH), 7.26 (d, J = 10.4 Hz, IH), 7.16-7.10 (m, 2H), 4.56 (d, J = 15.6 Hz, IH), 4.52 (d, J = 15.6 Hz, IH), 4.36-4.33 (m, 1H), 4.00 (s, 2H), 3.87 (s, 2H), 3.53 (dd, J = 7.6, J ₂ = 9.6 Hz, IH), 3.38-3.34 (m, IH), 2.98 (dd, J = 6.0, J ₂ = 9.6 Hz, IH), 2.65-2.57 (m, 2H), 2.52-2.37 (m, 2H), 2.30-2.22 (m, 2H), 2.01-1.94 (m, IH), 1.44-1.41 (m, 9H), 1.34 (d, J = 7.2 Hz, 6H), 1.08 (d, J = 6.8 Hz, 3H).

Step B: (S)-2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l- yl)methyl)-N-(2-azaspiro[3.3]heptan-6-yl)benzamide hydrochloride

(S)-tert-Butyl 6-(2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-m ethyl- 2-oxopyrrolidin-l-yl)methyl)benzamido)-2-azaspiro[3.3]heptan e-2-carboxylate (600 mg, 0.92 mmol) was dissolved in solution of HCl in MeOH (4 Ν, 15 mL) and the reaction mixture stirred at 23 °C for 2 h. The reaction mixture was concentrated to give (S)-2-fluoro-5-(4-(6- isopropylpyridazin-3 -yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-N-(2- azaspiro[3.3]heptan-6-yl)benzamide hydrochloride as a yellow solid. MS: mlz = 558.2 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.94 (d, J = 9.2 Hz, IH), 8.58 (d, J = 9.2 Hz, IH), 8.21 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 6.0 Hz, IH), 7.33-7.28 (m, IH), 7.21 (d, J = 8.8 Hz, 2H), 4.56 (d, J = 15.2 Hz, IH), 4.48 (d, J = 15.2 Hz, IH), 4.36-4.34 (m, IH), 4.18 (s, 2H), 4.08 (s, 2H), 3.57-3.47 (m, 2H), 2.96-2.91 (m, IH), 2.80-2.70 (m, 2H), 2.51-2.35 (m, 4H), 1.97-1.91 (m, IH), 1.53 (d, J = 7.2 Hz, 6H), 1.07 (d, J = 6.8 Hz, 3H).

Step C: (S)-N-(2-Cvclobutyl-2-azaspiro[ ^' 3.31heptan-6-yl)-2-fluoro-5-(4-(6-isopropylpyridazin-3 - yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)benzamide

To a solution of (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)-N-(2-azaspiro[3.3]heptan -6-yl)benzamide hydrochloride (30 mg, 0.05 mmol) in anhydrous THF (5 mL) was added TEA (21 uL, 0.15 mmol),

cyclobutanone (18 mg, 0.25 mmol), and HOAc (3 mg, 0.05 mmol). The reaction mixture was stirred at 23 °C for 2 h and then NaBH(OAc) ₃ (32 mg, 0.15 mmol) was added. The resulting mixture was stirred at 23 °C for 16 h, diluted with water (1 mL), and concentrated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini) eluting with 95:5 to 5:95 water (0.05% ammonia, V/V): acetonitrile to give (S)-N-(2-cyclobutyl-2-azaspiro[3.3]heptan-6- yl)-2-fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l - yl)methyl)benzamide. MS: m/z = 612.3 (M + 1). Ή NMR (400 MHz, CD ₃ OD): δ 8.1 1-8.06 (m, 3H), 7.70 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 7.23 (d, J = 10.4 Hz, 1H), 7.1 1 (d, J = 8.8 Hz, 2H), 4.52 (d, J = 15.2 Hz, 1H), 4.50 (d, J = 15.2 Hz, 1H), 4.31-4.29 (m, 1H), 3.50-3.49 (m, 1H), 3.34-3.31 (m, 3H), 3.18 (s, 2H), 3.13-3.11 (m, 1H), 2.96-2.91 (m, 1H), 2.58-2.49 (m, 2H), 2.49-2.34 (m, 2H), 2.21 -2.14 (m, 2H), 2.01-1.91 (m, 3H), 1.86-1.65 (m, 4H), 1.40 (d, J = 7.2 Hz, 6H), 1.05 (d, J = 6.8 Hz, 3H).

(S)-N-(l-Cvclopentylpiperidin-4-yl)-3-(4-(2-isopropylthiazol -5-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzamide

A mixture of (S)-3-(4-chlorophenoxy)-N-(l-cyclopentylpiperidin-4-yl)-4-[( 4- methyl-2-oxopyrrolidin-l-yl)methyl]benzamide (60 mg, 0.12 mmol), bis(pinacolato)diboron (36 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (12 mg, 0.012 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (1 1 mg, 0.024 mmol), and potassium acetate (35 mg, 0.36 mmol) in dioxane (1.2 mL) was purged with argon and heated at 1 10 °C for 2 h. The reaction mixture was cooled to 23 °C and 5-bromo-2-isopropylthiazole (26 mg, 0.130 mmol) and l,r-bis(diphenylphosphmo)ferrocene-palladium(II)dichloride

dichloromethane complex (19 mg, 0.024 mmol) were added. The reaction vessel was deoxygenated, aqueous potassium carbonate (1 M, 0.474 mL, 0.474 mmol) was added the reaction mixture was heated at 90 °C for 2.5 h. The reaction mixture was cooled to 23 °C. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by purified reverse phase HPLC, eluting with 0% acetonitrile in water (0.1%) fonnic acid used as a modifier) initially, grading to 40%> acetonitrile in water. The desired fractions were lyophilized to give the title compound as the formate salt. MS: m/z = 601.5 (M + 1). 1H NMR (500 MHz, CD ₃ OD) δ 7.84 (m, 1H), 7.66 (m, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 7.00 (m, 2H), 4.53 (m, 2H), 3.98 (m, 1H), 3.47 (dd, 1H, J = 9.6, 7.8 Hz), 3.34 (m, 3H), 3.05 (s, 1H), 2.93 (dd, 1H, J = 9.7, 6.0 Hz), 2.65 (s, 2H), 2.47 (dd, 1H, J = 15.9, 8.6 Hz), 2.40 (m, 1H), 2.36 (m, 4H), 1.95 (dd, 1H, J = 16.7, 6.8 Hz ), 1.76 (m, 4H), 1.60 (m, 4H), 1.43 (m, 1H), 1.41 (d, 6H, J = 7.0 Hz), 1.04 (d, 3H, J = 6.7 Hz).

(SV4-r(4-Methyl-2-oxopyrrolidin-l-yl)mem^

4-yl)piperidin-4-yl]benzamide

To a solution of (S)-3-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-N-[l -

(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]benzamide (40 mg, 0.096 mmol) in NMP (0.5 mL) at 23 °C was added 6-iodoquinoline (37 mg, 0.14 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.011 mL, 0.053 mmol), cesium carbonate (31 mg, 0.096 mmol), and copper(I) chloride (10.5 mg, 0.106 mmol) and the reaction mixture was deoxygenated with N ₂ . The reaction mixture was stirred at 80 °C for 3 h and then cooled. The reaction mixture was partitioned between 1M aqueous NH ₄ C1 solution (5 mL) and EtOAc (3 x 8 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 10 mL), dried by MgSCH, filtered, and concentrated. The reaction mixture was purified by reverse phase HPLC, eluting with 0% acetonitrile in water (0.1% formic acid as a modifier) initially, grading to 50% acetonitrile in water. The desired fractions were lyophilized to give the title compound as the formate salt. MS: m/z = 543.3 (M+l). Ή NMR (500 MHz, CD ₃ OD) δ 8.77 (d, 1H, J = 3.1 Hz), 8.23 (d, 1H, J = 7.9 Hz), 8.07 (d, 1H, J = 9.3 Hz), 7.73 (d, 1H, J = 9.1 Hz), 7.57 (dd, 1H, J = 9.2, 2.7 Hz), 7.54 (d, 1H, J = 1.2 Hz), 7.52 (m, 2H), 7.26 (s, 1H), 4.56 (s, 2H), 4.03 (m, 2H), 3.38-3.50 (m, 5H), 3.14-3.19 (m, 2H), 2.92-2.95 (m, 3H), 2.37-2.42 (m, 2H), 2.12 (d, 2H, J = 12.3 Hz), 1.92- 2.00 (m, 2H), 1.81-1.90 (m, 3H), 1.66-1.73 (m, 2H), 1.00 (d, 3H, J = 6.6 Hz).

EXAMPLE 74

(S)-3-(4-(6-Aminopwidin-3-yl)phenoxy)-N-(l -cvclopen^

oxopyrrolidin- 1 -yl)methyl)benzamide

To a solution of (S)-3-(4-Chlorophenoxy)-N-(l -cyclopentylpiperidin-4-yl)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzamide (20 mg, 0.039 mmol) in dioxane (1 mL) was added bis(pinacolato)diboron (12 mg, 0.047 mmol), tris(dibenzylideneacetone)dipalladium- chloroform adduct (4.1 mg, 3.9 μιηοΐ), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (3.7 mg, 7.8 μηιοΐ), and potassium acetate (19 mg, 0.20 mmol). The reaction mixture was deoxygenated with nitrogen and then heated at 1 10 °C for 3 h. The reaction mixture was cooled to 23 °C and 2-amino-4-bromopyridine (0.059 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (6.4 mg, 7.8 μηιοΐ), and aqueous potassium carbonate (IN, 0.157 mL, 0.157 mmol) were added. The reaction mixture was stirred at 90 °C for 3 h and then cooled to 23 °C. The reaction mixture was diluted with water (2 mL) and EtOAc (2 mL). The organic layer was separated and stirred with SiliaBond DMT (ca 60 mg) for 16 h. The solution was filtered and concentrated. The residue was dissolved in DMSO (1 mL), filtered, and purified by reverse-phase HPLC to give the title compound as the formate salt. MS: m/z = 568.3 (M + 1 ).

(S)-2-Fluoro-5-(4-(2-isopropylpyi ^' imidin-5-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l - yl)methyl)-N-(l -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzamide To a solution of 2-isopropyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyrimidine (60 mg, 0.24 mmol) in dioxane (2.5 mL) was added (S)-2-fluoro-5-(4- iodophenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-N-( 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)benzamide (50 mg, 0.079 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (12 mg, 0.016 mmol), and 1M aqueous K2CO3 (0.39 mL, 0.39 mmol). The reaction mixture was deoxygenated with nitrogen and then heated at 80 °C for 1 h. The reaction mixture was cooled to 23 °C, diluted with EtOAc and washed with water. The organic layer was dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by reverse phase HPLC, eluting with 10% acetonitrile in water (0.1% formic acid used as a modifier) initially, grading to 90% acetonitrile in water. The desired fractions were lyophilized to give the title compound as the formate salt. MS: m/z = 630.4 (M + 1). Ή NMR (500 MHz, CD ₃ OD) δ 8.96 (s, 2H), 7.73 (d, 2Η, J = 8.5 Hz), 7.29 (d, IH, J = 6 Hz), 7.24 (d, IH, J = 10.5 Hz), 7.12 (d, 2H, J = 8.5 Hz), 4.52 (q, 2H), 4.06 (m, 3H), 3.52 (dd, IH, J = 7.5, 9.5 Hz), 3.43 (m, 4H), 3.24 (m, IH), 3.17 (br s, IH), 2.95 (m, 3H), 2.47 (m, 2H), 2.17 (m, 2H), 2.98 (m, 3H), 1.85 (m, 2H), 1.73 (m, 2H), 1.38 (s, 3H), 1.37 (s, 3H), 1.08 (d, 3H, J = 7 H).

N-(l-Cvclopent^lpiperidin-4-yl -3-(4-(5-(isopropylamino)-L3,4-thiadiazol-2-yl)phenoxy)-4-(( 2- oxopyrrolidin- 1 -vDmethvDbenzamide

Step A: fe -Butyl (5-(4-(5-((l-cyclopentylpiperidin-4-yl)carbamoyl)-2-((2-oxop yrrolidin-l- yl)methyl)phenoxy)phenyl)- 1 ,3 ,4-thiadiazol-2-yl)carbamate

To a solution of 3-(4-chlorophenoxy)-N-(l-cyclopentylpiperidin-4-yl)-4-((2- oxopyrrolidin- 1 -yl)methyl)benzamide (80 mg, 0.16 mmol) in dioxane (5 mL) was added tris(dibenzylideneacetone)dipalladium-chloroform adduct (16 mg, 0.016 mmol), 2- (dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (15 mg, 0.032 mmol), and potassium acetate (79 mg, 0.81 mmol). The reaction mixture was deoxygenated with nitrogen, warmed to 1 10 °C, and stirred for 3 h. The reaction mixture was cooled to 23 °C and ter/-butyl (5-bromo- l ,3,4-thiadiazol-2-yl)carbamate (45 mg, 0.16 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (26 mg, 0.032 mmol), and 1 M aqueous K2CO3 (0.65 mL, 0.65 mmol) were added. The reaction mixture was deoxygenated with nitrogen and heated at 90 °C for 2 h. The reaction mixture was cooled to 23 °C and diluted with EtOAc. The organic phase was washed with water, dried over MgS0 ₄ , filtered, and

concentrated. The residue was purified by reverse phase HPLC, eluting with 10% acetonitrile in water (0.1 % formic acid used as a modifier) initially, grading to 90% acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS: m/z = 661.4 (M + 1). Step B: N-(l-Cvclopentylpiperidin-4-yl)-3-(4-(5-(isopropylamino -l ,3,4-thiadiazol-2- yl)phenoxy)-4-((2-oxopyrrolidin- 1 -yl)methyl)benzamide

A solution of HC1 (4M 0.11 mL, 0.45 mmol) in dioxane was added to /eri-Butyl (5-(4-(5-(( 1 -cyclopentylpiperidin-4-yl)carbamoyl)-2-((2-oxopyrrolidin- 1 - yl)methyl)phenoxy)phenyl)-l,3,4-thiadiazol-2-yl)carbamate (30 mg, 0.045 mmol) in EtOAc (2 mL) at 0 °C and the reaction mixture stirred at 23 °C for 2 h. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHC0 ₃ , water, and saturated aqueous sodium chloride, dried over MgS0 , filtered, and concentrated. Decaborane (6.5 mg, 0.054 mmol) was added to the crude product in a mixture of MeOH/acetone (2: 1, 3 mL) at 23 °C and the reaction mixture stirred at 23 °C for 16 h. Another 3 portions of decaborane (6.5 mg, 0.054 mmol) was added at regular intervals while heating the reaction mixture at 50 °C for 1 d. The reaction mixture was cooled to 23 °C and concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHC0 ₃ , water, and saturated aqueous sodium chloride, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by reverse phase HPLC, eluting with 10% acetonitrile in water (0.1% formic acid used as a modifier) initially, grading to 90% acetonitrile in water. The desired fractions were lyophilized to give the title compound as the formate salt. MS: m/z = 603.4 (M + 1). Ή NMR (500 MHz, CD ₃ OD) δ 7.76 (m, 2H), 7.68 (dd, 1H, J = 7.5, 1.5 Hz), 7.48 (d, 1H, 1.5 Hz), 7.46 (d, 1H, J = 8 Hz), 7.02 (m, 2H), 4.57 (br s, 2H), 4.54 (s, 2H), 3.92 (q, 2H), 3.35 (t, 2H, J = 7 Hz), 3.21 (m, 2H), 2.83 (br s, 1H), 2.42 (br s, 2H), 2.28 (t, 2H, J = 15 Hz), 1.97 (m, 6H), 1.73 (m, 3H), 1.61 (m, 2H), 1.48 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H).

EXAMPLE 77

(S)-5-((2-(CvclopropylmethylH-oxo-l ,2-dm^

oxopyrrolidin- 1 -yl)methyl)-N-( 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)benzamide

Step A: (S)-2-Fluoro-5-hvdroxy-4-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl1-N-[ 1 -(tetrahvdro-2H- pyran-4-yl)piperidin-4-yllbenzamide

To a solution of (S)-2-fluoro-5-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l- yl)methyl]-N-(piperidin-4-yl)benzamide hydrochloride (2.00 g, 5.18 mmol) in THF (25 mL) at 23 °C were added acetic acid (4 mL) and dihydro-2H-pyran-4(3H)-one (0.957 mL, 10.4 mmol) and the resulting mixture stirred for 15 minutes. The reaction mixture was cooled to 0 °C and sodium triacetoxyborohydride (2.20 g, 10.4 mmol) was added. The reaction mixture was allowed to warm to 23 °C and stirred for 2 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (200 mL) and CH ₂ C1 ₂ (200 mL). The organic layer was washed with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over MgS0 ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of CH ₂ Cl ₂ :methanol:NH ₄ OH 100:0:0 to 90: 10: 1. The desired fractions were concentrated and the residue repurified by reverse phase HPLC, eluting with 0% acetonitrile in water (0.1% formic acid as a modifier) initially, grading to 50% acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS: m/z = 434.3 (M+l).

Step B: 6-Bromo-2-(cyclopropylmethyl)isoquinolin-l(2H)-one

Cesium carbonate (654 mg, 2.01 mmol) was added to a solution of 6- bromoisoquinolin-l-(2H)-one (150 mg, 0.67 mmol) in DMF (2 mL) at 0 °C and the reaction mixture was stirred for 30 min. (Bromomethyl)cyclopropane (0.325 mL, 3.35 mmol) was added and the mixture was stirred at 23 °C for 16 h. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried over MgSC , filtered, and concentrated. The residue was purified by silica gel cliromatography, eluting with a gradient of hexanes:EtOAc, 100:0 to 75:25, to give the title compound. MS: m/z = 280.1 (M+l).

Step C: (S -5-{[2-fCvclopiOpylmethyl)-l -oxo-l ,2-dihvdroisoquinolin-6-ylloxy|-2-fluoiO-4- (4- methyl-2-oxopyrrolidin- 1 -yl)methyl ^" |-N-f 1 -(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl ^" |benzamide trifluoroacetate

To a solution of (S)-2-fluoro-5-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l- yl)methyl]-N-[l -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]benzamide (50 mg, 0.12 mmol) in ΝΜΡ (0.5 mL) at 23 °C was added 6-bromo-2-(cyclopropylmethyl)isoquinolin-l(2H)-one (32 mg, 0.12 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.013 mL, 0.063 mmol), cesium carbonate (188 mg, 0.577 mmol), and copper(I) chloride (13 mg, 0.13 mmol). The reaction mixture was deoxygenated with N ₂ and then heated at 120 °C for 16 h. The reaction mixture was partitioned between 1 M aqueous NH ₄ C1 (5 mL) and EtOAc (3 x 8 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 10 mL), dried over MgS04, filtered, and concentrated. The reaction mixture was purified by reverse phase HPLC, eluting with 20% acetonitnle in water (0.1%) formic acid as a modifier) initially, grading to 40% acetonitnle in water. The desired fractions were lyophilized to give the title compound as the formate salt. MS: m/z = 631.5 (M+l). ^] H NMR (500 MHz, CD ₃ OD) δ 8.32 (d, 1H, J = 8.9 Hz), 7.41 (d, 1H, J = 7.4 Hz), 7.35 (d, 1H, J = 5.8 Hz), 7.27 (d, 1H, J = 10.3 Hz), 7.16 (dd, 1H, J = 9.0, 2.6 Hz), 6.99 (d, 1H, J = 2.3 Hz), 6.57 (d, 1H, J = 7.4 Hz), 4.47 (dd, 2H, J = 24.3, 15.5 Hz), 4.05-4.12 (m, 3H), 3.89 (d, 2H, J = 7.2 Hz), 3.46 (d, 2H, J = 12.2 Hz), 3.40-3.49 (m, 4H), 3.13-3.18 (m, 2H), 2.92 (dd, 1 H, J = 9.6, 6.0 Hz), 2.28-2.43 (m, 4H), 2.02-2.04 (m, 2H), 1.72- 1.91 (m, 5H), 1.28-1.31 (m, 1H), 1.01 (d, 3H, J = 6.7 Hz), 0.54-0.58 (m, 2H), 0.41-0.44 (m, 2H)

5-f(2-Cvclobutyl-l-oxo-6-isoquinolyl)oxy]-2-fluoro-4-ff(4S)- 4-methyl-2-oxo-pyrrolidin-l- yllmethyl]-N-( 1 -tetrahvdropyran-4-yl-4-piperidyl)benzamide Step A: 6-Bromo-2-cyclobutyl-isoquinolin-l-one

To a solution of 6-biOmoisoquinolin-l(2H)-one (0.108 g, 0.482 mmol) in DMF (2 mL) was added K ₂ C0 ₃ (0.200 g, 1.45 mmol) and bromocyclobutane (0.227 mL, 2.41 mmol) and the reaction mixture was stirred at 23 °C for 16 h. Bromocyclobutane (0.227 mL, 2.41 mmol) was added and the reaction mixture was heated at 105 °C for 2 days. Aqueous NH ₄ CI solution (1M, 5 mL) was added and the aqueous layer extracted with ether (10 mL x 2). The combined organic layers were concentrated and the residue purified by reverse phase HPLC on a C- 18 column, eluting with a gradient of H ₂ 0:CH ₃ CN:HCOOH, 95:5:0.1 to 15:85:0.1, to give the title compound as a pale yellow solid. MS: m/z = 278.0 and 280.1 (M + 1). Ή NMR (500 MHz,

CDCI3) δ 8.29 (d, J = 8.6 Hz, 1H), 7,69 (d, J = 1.9 Hz, 1 H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 5.26 (m, 1H), 2.54 (m, 2H), 2.29 (m, 2H), 1.93 (m, 2H). Step B: 5-[ ^" (2-Cvclobutyl-l-oxo-6-isoquinolyl)oxyl-2-fluoro-4- (4S)-4-methyl-2-oxo- pyrrolidin- 1 -yllmethyllbenzoic acid

A mixture of (S)-ethyl 2-fluoro-5-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l- yl)methyl]benzoate (30.0 mg, 0.102 mmol), 6-bromo-2-cyclobutyl-isoquinolin-l-one (28.3 mg, 0.102 mmol), and Cs ₂ C0 ₃ (165 mg, 0.508 mmol) in NMP (0.2 mL) was deoxygenated with N ₂ and then 2,2,6,6-tetramethylheptane-3,5-dione (12 μΐ, 0.056 mmol) and copper(I) chloride (1 1 mg, 0.1 1 mmol) were added. The reaction mixture was purged with N ₂ and heated at 110 °C for 16 h. The reaction mixture was diluted with EtOAc, filtered, and the solid washed with EtOAc and methanol. The mixture was concentrated and the residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes then 5% methanol in EtOAc to afford the title compound as pale brown solid. MS: mlz = 465.2 (M + 1).

Step C: 5-[(2-Cvclobutyl-l-oxo-6-isoquinolyl)oxyl-2-fluoro-4-[[(4S)- 4-methyl-2-oxo- pyrrolidin- 1 -yl1methyl ^" |-N-( 1 -tetrahydropyran-4-yl-4-piperidyl)benzamide

To a solution of 5-[(2-cyclobutyl-l -oxo-6-isoquinolyl)oxy]-2-fluoro-4-[[(4>S}-4- methyl-2-oxo-pyrrolidin-l-yl]methyl]benzoic acid (16 mg, 0.035 mmol) in DMF (0.25 mL) was added l-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (11 mg, 0.042 mmol), 1H- benzo[d][l ,2,3]triazol-l-ol (4.7 mg, 0.035 mmol), N-ethyl-N-isopropylpropan-2-amine (0.049 mL, 0.28 mmol), and EDC (15 mg, 0.079 mmol). The reaction mixture was stirred at 23 °C for 16 h and then filtered. The mixture was purified by reverse phase HPLC on a C-l 8 column, eluting with a gradient of H ₂ 0:CH ₃ CN:HCOOH, 95:5:0.1 to 25:75:0.1 , to give the title compound as pale yellow solid. MS: m/z = 631.4 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ) δ 8.42 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 6.5 Hz, 1H), 7.28 (d, J - 7.7 Hz, 1 H), 7.19 (d, J = 1 1.8 Hz, 1H), 7.09 (dd, J = 8.9, 2.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.69 (m, 1H), 6.41 (d, J = 7.6 Hz, 1H), 5.28 (m, 1H), 4.51 (d, J = 15.5 Hz, 1H), 4.46 (d, J = 15.7 Hz, 1H), 4.07 (dd, J = 11.0, 4.2 Hz, 2 H), 3.43 (m, 2H), 3.05 (m, 2H), 2.91 (dd, J = 9.6, 6.2 Hz, 1H), 2.68 (m, 1H), 2.59-2.52 (m, 3H), 2.48-2.41 (m, 3H), 2.29 (m, 2H), 2.12 (m, 4H), 2.04 (dd, J = 16.8, 7.1 Hz, 1H), 1.91 (m, 2H), 1.86 (m, 2H), 1.72-1.66 (m, 4H), 1.1 1 (d, J = 6.7 Hz, 3H).

5-{[2-(Cvclopropylmethyl ^' )-l-oxo-L2-dihvdroisoquinolin-6-ylloxyl-N-[(R ^' )-3,3-difluoro-l-

(tetrahvdro-2H-pyran-4-yl)piperidin-4-yl -2-fluoro-4- ((S)-4-methyl-2-oxopyrrolidin-l- yl)methyl ^" |benzamide

Step A: (S)-5-{ 2-(Cvclopropylmethyl)-l-oxo-l,2-dihvdroisoquinolin-6-yl1oxy} -2-fluoro-4-[(4- methyl-2-oxopyrrolidin- 1 -yl)methyl]benzoic acid

To a solution of (S)-ethyl 2-fluoro-5-hydroxy-4-[(4-methyl-2-oxopyrrolidin-l- yl)methyl]benzoate (100 mg, 0.339 mmol) in ΝΜΡ (1 mL) at 23 °C was added 6-bromo-2- (cyclopropylmethyl)isoquinolin-l-(2H)-one (94.0 mg, 0.339 mmol), 2,2,6,6-tetramethyl-3,5- heptanedione (0.039 mL, 0.19 mmol), cesium carbonate (552 mg, 1.69 mmol), and copper(I) chloride (36.9 mg, 0.372 mmol). The reaction mixture was deoxygenated with N ₂ and then heated at 120 °C for 16 h. The reaction mixture was cooled to 23 °C, methanol (10 mL) was added, and the mixture was filtered through a pad of Celite ^® . The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with a gradient of

CH ₂ Cl ₂ :methanol, 100:0 to 75:25. The desired fractions were concentrated and the residue further purified by reverse phase HPLC, eluting with 0% acetonitrile in water (0.1 % formic acid as a modifier) initially, grading to 60% acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS : m/z = 465.3 (M+l).

Step B: ( S)-ter f-Butyl 4- {5-r(2-(cvclopropylmethyl)-l -oxo-l ,2-dihydroisoquinolin-6-yl)oxy]-2- fluoro-4-[((S)-4-methyl-2-oxopyrrolidin-l -yl)methyl]benzamidol -3 ,3-difluoropiperidine-l - carboxylate

To a solution of (S)-5- {[(2-(cyclopropylmethyl)-l -oxo-l ,2-dihydroisoquinolin-6- yl]oxy} -2-fluoro-4-[(4-methyl-2-oxopyrrolidin-l -yl)methyl)]benzoic acid (50 mg, 0.1 1 mmol) in DMF (1 mL) at 23 °C was added (R)-tert-butyl 4-amino-3,3-difluoropiperidine-l-carboxylate dihydrochloride (50 mg, 0.16 mmol), EDC (41 mg, 0.22 mmol), HOBt (17 mg, 0.1 1 mmol), and DIPEA (0.094 mL, 0.54 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water and purified by reverse phase HPLC, eluting with 0% acetonitrile in water (0.1 % TFA as a modifier) initially, grading to 50% acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS: m/z = 683.4 (M+l).

Step C: 5- { [2-(Cvclopropylmethyl)- 1 -oxo- 1 ,2-dihvdroisoquinolin-6-yl ^~ |oxy) -N-((R)-3 ,3- difluoropiperidin-4-yl)-2-fluoro-4- ((S)-4-methyl-2-oxopyrrolidin-l -yl)methyl1benzamide hydrochloride

TFA (0.3 mL) was added to a solution of (R)-teri-butyl 4- {5-[(2- (cyclopropylmethyl)-l-oxo-l ,2-dihydroisoquinolin-6-yl]oxy} -2-fluoro-4- {[((S)-4-methyl-2- oxopyrrolidin-l -yl)methyl]benzamido} -3,3-difluoropiperidine-l -carboxylate (70.0 mg, 0.108 mmol) in CH2CI2 (1 mL) and the reaction mixture stirred at 23 °C for 2 h. To the reaction mixture was added aqueous 1M HC1 solution (0.5 mL) and the reaction mixture was

concentrated to give the title compound. MS: m z 583.3 (M+l).

Step D: 5- ( 2-(Cyclopropylmethyl)-l -oxo-L2-dihvdroisoquinolin-6-ylloxy}-N- (R)-3,3-difluoro- l-(tetrahvdro-2H-pyran-4-yl)piperidin-4-yll-2-fluoro-4-[((S -4-methyl-2-oxopyrrolidin-l - yl)methyl]benzamide

To a solution of 5- {[2-(cyclopropylmethyl)-l -oxo-l ,2-dihydroisoquinolin-6- yl]oxy}-N-((R)-3,3-difluoropiperidin-4-yl)-2-fluoro-4-[((S)- 4-methyl-2-oxopyrrolidin-l - yl)methyl]benzamide hydrochloride (60 mg, 0.097 mmol) in CH ₂ C1 ₂ (1 mL) at 23 °C was added acetic acid (0.1 mL) and tetrahydro-4H-pyran-4-one (0.018, 0.19 mmol) and the reaction mixture was stirred for 15 minutes. The reaction mixture was cooled to 0 °C and sodium

triacetoxyborohydride ( 103 mg, 0.485 mmol) added. The reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 raL) and CH2CI2 (20 mL). The organic layer was washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over MgSC , filtered, and concentrated. The residue was purified by reverse phase HPLC, eluting with 10% acetonitrile in water (0.1 % formic acid as a modifier) initially, grading to 90%> acetonitrile in water. The desired fractions were lyophilized to give the title compound. MS: m/z = 667.5 (M+l). Ή NMR (500 MHz, CD ₃ OD) 5 8.32 (d, 1H, J = 9.0 Hz), 7.40 (d, 1H, J = 7.4 Hz), 7.37 (d, 1H, J = 5.9 Hz), 7.28 (d, 1H, J = 10.5 Hz), 7.18 (dd, 1H, J = 9.0, 2.6 Hz), 6.98 (d, 1H, J = 2.5 Hz), 6.57 (d, 1H, J = 7.4 Hz), 4.47 (dd, 2H, J = 23.7, 15.4 Hz), 4.33-4.42 (m, 1H), 3.96-3.99 (m, 2H), 3.89 (d, 2H, J = 7.2 Hz), 3.46 (dd, 1H, J = 9.6, 7.6 Hz), 3.39 (t, 2H, J = 1 1.6 Hz), 3.22-3.24 (m, 1H), 3.01 (d, 1H, J = 11.8 Hz), 2.91 (dd, 1H, J = 9.8, 6.2 Hz), 2.54-2.65 (m, 2H), 2.30-2.44 (m, 3H), 1.95-1.98 (m, 1H), 1.85-1.90 (m, 1H), 1.74-1.81 (m, 3H), 1.49-1.61 (m, 2H), 1.26-1.32 (m, 1H), 1.01 (d, 3H, J = 6.6 Hz), 0.54-0.58 (m, 2H), 0.41-0.44 (m, 2H).

(S)-6-(4-(5-Cvclopropyl-l,3,4-thiadiazol-2-yl)phenoxy)-N-(l- cvclopropyl-5-oxopyrrolidin-3-yl)- 5-( (2-oxopyrrolidin- 1 -yl)methyl)picolinamide

N-Methylmorpholine (34 μί, 0.31 mmol) was added to a solution of 6-(4-(5- cyclopropyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin- 1 -yl)methyl)picolinic acid (56 mg, 0.076 mmol), (S)-4-amino-l-cyclopropylpyrrolidin-2-one (13 mg, 0.092 mmol), EDC (26 mg, 0.13 mmol), and HO At (0.038 mmol) in DMF (750 μί) and the resulting mixture stirred at 50 °C for 30 min. Water (100 μί) was added and the residue was purified by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1%> trifluoroacetic acid). The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the title compound. LC-MS m/z found = 559.2 [M+l ]. Ή NMR (500 MHz, DMSO): δ 8.10 (d, J = 7.5 Hz, 1 H); 7.97 (d, J = 8.4 Hz, 2 H); 7.92 (d, J = 7.6 Hz, 1 H); 7.82 (d, J = 7.6 Hz, 1 H); 7.34 (d, J = 8.4 Hz, 2 H); 4.52 (s, 2 H); 4.44-4.41 (m, 1 H); 3.55 (dd, J = 9.9, 7.3 Hz, 1 H); 3.04 (dd, J = 9.9, 4.4 Hz, 1 H); 2.57- 2.56 (m, 4 H); 2.26-2.24 (m, 3 H); 1.96-1.94 (m, 2 H); 1.27-1.25 (m, 3 H); 1.09-1.08 (m, 2 H); 0.54-0.51 (m, 4 H).

N-(l-Cvclopropyl-5-oxopyrrolidin-3-yl)-4-((2-oxopyre^

pyran-4-yl)carbamoyl)benzyl)berizamide

N-Methylmorpholine (15 μί, 0.14 mmol) was added to a solution of 4-((2- oxopyrrolidin- 1 -yl)methyl)-3-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)benzyl )benzoic acid with six equivalents of sodium chloride (21 mg, 0.034 mmol), 4-amino-l-cyclopropyl-pyrrolin-2-one (7.6 mg, 0.043 mmol), EDC (12 mg, 0.060 mmol), and HOAt (2.3 mg, 0.017 mmol) in DMF (350 xL). The resulting solution was stirred at 23 °C for 1 h. Water (100 \L) was added and the mixture was purified by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid). The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to give the racemic title compound. HRMS m/z found = 559.2888 [M+l]. Ή NMR (500 MHz, DMSO): δ 8.69 (d, J = 6.6 Hz, 1 H); 8.22 (d, J = 7.7 Hz, 1 H); 7.76 (d, J = 7.9 Hz, 2 H); 7.72-7.71 (m, 2 H); 7.26 (d, J = 7.9 Hz, 1 H); 7.18 (d, J = 8.0 Hz, 2 H); 4.49-4.46 (m, 1 H); 4.10 (s, 2 H); 4.37 (s, 2 H); 3.98-3.96 (m, 1 H); 3.88- 3.86 (m, 2 H); 3.60 (dd, J = 10.0, 7.3 Hz, 1 H); 3.34-3.33 (m, 2 H); 3.14 (dd, J = 9.9, 4.1 Hz, 1 H); 3.07 (t, J = 7.1 Hz, 2 H); 2.66-2.64 (m, 2 H); 2.35 (dd, J = 17.0, 4.9 Hz, 1 H); 2.19 (t, J = 8.1 Hz, 2 H); 1.81-1.79 (m, 2 H); 1.75-1.72 (m, 2 H); 1.56 (qd, J = 12.0, 4.3 Hz, 2 H); 0.64 (d, J = 6.4 Hz, 4 H).

EXAMPLE 82

4-((5-( difluoromethyl)-2-oxopyridin- 1 ( 2H)-yl)methyl)-2-fluoro-N-(3 -fluoro- 1 -(3-fluoro- tetrahvdro-2H-pyran-4-yl)piperidin-4-yl)-5-(4-( ^' 6-isopropylpyridazin-3-yl)phenoxy)benzamide

N,N-diisopropylethylamine (0.021 mL, 0.118 mmol) was added to a stirred, room temperature mixture of 3-fluoro-l-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-ami ne (isomer 2) (10.38 mg, 0.047 mmol), 4-((5-(difluoromethyl)-2-oxopyridin-l(2H)-yl)methyl)-2-fluor o-5-(4- (6-isopropyl pyridazin-3-yl)phenoxy)benzoic acid (20 mg, 0.039 mmol), HOBt (9.02 mg, 0.059 mmol) and EDC (1 1.29 mg, 0.059 mmol) in dichloromethane (2 mL) and the mixture was allowed to stir at room temperature for 14 h. The mixture was diluted with dichloromethane (2 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1 x 2 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC (Xbridge CI 8 column), eluting with 8% acetonitrile in water (0.1% DEA used as a modifier), grading 47% acetonitrile in water to give the title compound. MS: mlz = 712.5 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.09 (d, J = 9 Hz, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 6.5 Hz, 1H), 7.64 (s, 1H), 7.45-7.39 (m, 3H), 7.05 (d, J = 8.5 Hz, 2H), 7.03-6.99 (m, 1H), 6.63 (d, J = 9.5 Hz, 1H), 6.31 (t, J = 56 Hz, 1H), 5.20 (s, 2H), 4.89 (d, J = 49 Hz, 1H), 4.76 (d, J = 49.5 Hz, 1H), 4.42 - 4.1 l(m, 3H), 3.51-3.35 (m, 4H), 3.05 (d, J = 11.5 Hz, 1H), 2.80 (d, J = 13.5 Hz, 1H), 2.76-2.62 (m, 2 H), 2.24-2.16 (m, 1H), 2.02-1.93 (m, 2 H), 1.63 (d, J = 13 Hz, 1H), 1.46 (d, J = 7 Hz, 6H).

EXAMPLE 83

N-(r-cvclopropyl-3-fluoro-Fl,4'-bip^

yl)phenoxy)-4-(((S)-4-methyl-2-oxopyrrolidin-l-yl)methyl)ben zaniide

N,N-diisopropylethylamine (0.301 mL, 1.726 mmol) was added to a stirred, room temperature mixture of HATU (180 mg, 0.475 mmol), -cyclopropyl-3-fluoro-[l,4'-bipiperidin]- 4-amine trihydrochloride (151 mg, 0.431 mmol), and (S)-2-fluoro-5-(4-(6-isopropylpyridazin-3- yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (200 mg, 0.431 mmol) in dichloromethane (10 mL) and the mixture was allowed to stir for 1 h. The mixture was diluted with dichloromethane (10 mL), washed with water (1 x 5 mL), dried (MgS0 ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column

chromatography on silica gel, eluting with CH ₂ Cl ₂ /MeOH/NH ₃ (aq.) to give the title compound. MS: mlz =687.53 (M + 1). Ή NMR (500 MHz, CDC1 ₃ ): δ 8.07-8.05 (d, 2H); 7.76-7.74 (d,lH); 7.71-7.69 (d, 1H); 7.41-7.39 (d, 1H); 7.258-7.15 (d, 1H); 4.80-4.70 (d, 1H); 4.55-4.45 (q, J=16Hz, 2H); 4.110-4.195 (m, 1H); 3.457-3.423 (m, 1H); 3.353-3.325 (m, 1H); 3.208 (m, 1H); 3.116-3.093 (d, 2H); 2.920-2.889 (m, 2H); 2.571-2.472 (m, 4H); 2.448-2.392 (m, 2H); 2.217- 2.172 (m, 2H); 2.040-2.007 (m, 1H); 1.918-1.882 (m, 2H); 1.769-1.721 (m, 2H);1.582-1.510 (m, 3H); 1.421-1.407 (d, J=7.0Hz, 6H); 1.092-1.079 (d, J=7.0Hz, 3H); 0.451-0.413 (m, 4H). The examples appearing in the following table were prepared by analogy to the above examples, as described or prepared as a result of similar transformations with

modifications known to those skilled in the art. The requisite starting materials were described herein, commercially available, known in the literature, or readily synthesized by one skilled in the art. Straight forward protecting group strategies were applied in some routes.

N-cyclopentyl-3- {4-[5-(l- methylethyl)- 1 ,3,4- thiadiazol-2-

96 505.2 1 yl]phenoxy}-4-[(2- oxopyrrolidin- 1 - yl)methyl]benzami

de

N-(lH-indol-2- ylmethyl)-3-{4-[5-

(1-methylethyl)- l,3,4-thiadiazol-2-

97 566.2 1 yl]phenoxy}-4-[(2- oxopyrrolidin-1- yl)methyl]benzami

de

3-{4-[5-(l- metbylethyl)- 1,3,4- thiadiazol-2- yl]phenoxy}-N-

[(i-

98 548.2 2 methylpiperidin-3 - yl)methyl]-4-[(2- oxopyrrolidin-1- yl)methyl]benzami

de

3-{4-[5-(l- methylethyl)- 1 ,3,4- thiadiazol-2- yl]phenoxy}-4-[(2-

99 543.2 1 oxopyrrolidin-1- yl)metbyl]-N-(2- pyrazin-2- ylethyl)benzamide

yl]methyl}benzami

de

2-fluoro-5- {4-[5- (1-methylethyl)- l ,3,4-thiadiazol~2- yl]phenoxy} -N-[ 1 - (4- methyltetrahydro- 646.28

163 1

2H-pyran-4- 56 yl)piperidin-4-yl]- 4-[(2-oxopyridin-

1(2H)- yl)methyl]benzami

de

N-[l-(4,4- difluorocyclohexyl

)piperidin-4-yl]-2- fluoro-5-{4-[5-(l- methylethyl)- 1,3,4-

670.30

164 thiadiazol-2- 1

32 yl]phenoxy}-4- {[(4S)-4-methyl-2- oxopyrrolidin-1- yl]methyl}benzami

de

2-fluoro-5- {4-[5- (l -methylethyl)- l,3,4-thiadiazol-2- yl]phenoxy}-4- {[(4S)-4-methyl-2-

165 629.3 1 oxopyrrolidin-1 - yl]metbyl}-N-(l - pyridin-4- ylpiperidin-4- yl)benzamide

3-(4- chlorophenoxy)-4- [(2-oxopyrrolidin-

427.12

170 l-yl)methyl]-N- 1

93 (lH-tetrazol-5- ylmethyl)benzamid

e

N-[2-(5-methyl- lH-imidazol-4- yl)ethyl]-4-[(2-

487.19

171 oxopyrrolidin-1- 1

6 yl)methyl]-3-[4- (trifluoromethyl)p

henoxy]benzamide

3-[4- (cyclopropylcarba

moyl)phenoxy] -N- [2-(2-methyl-lH-

502.24

172 imidazol-4- 1

55 yl)ethyl]-4-[(2- oxopyrrolidin-1 - yl)methyl]benzami

de

3-[4- (cyclopropylcarba

moyl)phenoxy]-N-

0 r- ^N {2-[l - (fluoromethyl)- 1 H- 520.23

173 1 imidazol-4- 55 yl]ethyl}-4-[(2- oxopyrrolidin- 1 - yl)methyl]benzami

de

3-[4-( l ,3- benzothiazol-2- yl)phenoxy]-N-( 1 -

? rV cyclopropyl-5-

296 oxopyrrolidin-3- 567.2 2 yl)-4-[(2- oxopyrrolidin- 1 - yl)methyl]benzami

de

N-( 1 -cyclopropyl- 5-oxopyrrolidin-3- yl)-3-[4-(lH- imidazo[4,5-

297 c]pyridin-2- 551.2 2 yl)phenoxy]-4-[(2- oxopyrrolidin-1 - yl)methyl]benzami

de

N-( 1 -cyclopropyl- 5-oxopyrrolidin-3- yl)-3-(4-

0 _r N

[l ,3]oxazolo[4,5-

298 b]pyridin-2- 552.2 2 ylphenoxy)-4- [ (2- oxopyrrolidin- 1 - yl)methyl]benzami

de

2-fluoro-5- {4-[5- (1 -methylethyl)- l ,3,4-thiadiazol-2- yl]phenoxy}-4-

{[(4R)-4-methyl-2-

299 oxopyrrolidin-1 - 650.4 1 yl]methyl}-N-[ l - (4- methyltetrahydro- 2H-pyran-4- yl)piperidin-4-

2-fluoro-5-{4-[6-

(i-

/^ Ν 0 F methylethyl)pyrida

zin-3 -yljphenoxy} -

H 11 1 4- {[(4S)-4-methyl-

332 2-oxopyrrolidin-l- 652.5 1 yl]methyl}-N- {l-

[2-

(methylsulfonyl)et

hyl]piperidin-4- yl}benzamide

N-[l-(2,2- difluoroethyl)piper

idin-4-yl]-2- fluoro-5- {4-[6-(l- methylethyl)pyrida

333 610.4 1 zin-3-yl]phenoxy}-

4-{[(4S)-4-methyl-

2-oxopyrrolidin- 1 - yl]methyl}benzami

de

N-{ l-[2-

(dimethylamino)et

1 hyl]piperidin-4- yl}-2-fluoro-5-{4-

[6-(l-

334 methylethyl)pyrida 617.5 1 zin-3 -yljphenoxy } - 4-{[(4S)-4-methyl- 2-oxopyrrolidin- 1 - yl]methyl} benzami

de

2-fluoro-5-{4-[6-

(i- methyl ethyl)pyrida

335 658.6 1 zin-3-yl]phenoxy}- 4-{[(4S)-4-methyl- 2-oxopyrrolidin-l-

N-(l -cyclopropyl- 5-oxopyrrolidin-3- yl)-3-[4-(6-

0 P cyclopropylpyridin

-3-yl)-3-

367 569.25 2 fluorophenoxy] -4- [(2-oxopyrrolidin- 1- yl)methyl]benzami

de

N-( 1 -cyclopropyl- 5-oxopyrrolidin-3- yl)-3-{3-fluoro-4- o _N P [6-( 1 -hydroxy- 1- methylethyl)pyridi

368 587.26 2 n-3-yl]phenoxy}- 4-[(2- oxopyrrolidin-1- yl)methyl]benzami

de

N-( 1 -cyclopropyl- 5-oxopyrrolidin-3 - yl)-3-{4-[6- o P (difluoromethyl)py

ridin-3-yl]-3-

369 579.21 2 fluorophenoxy} -4- [(2-oxopyrrolidin- 1 - yl)methyl]benzarni

de

N-(l- cyclopentylpiperidi

n-4-yl)-4-{[(4S)-4- methyl-2-

370 632.28 1 oxopyrrolidin- 1 - yl]methyl}-3-{4- [6-

(methylsulfonyl)py ridazin-3- yl]phenoxy}benza

mide

N-(l- cyclopentylpiperidi

n-4-yl)-4- {[(4S)-4- methyl-2-

371 oxopyrrolidin-1- 603.33 1 yl]methyl}-3-(4- quinolin-3- ylphenoxy)benzam

ide

3-[4-(2- aminopyrimidin-5- yl)phenoxy]-N-( 1 - cyclopentylpipendi

372 n-4-yl)-4-{[(4S)-4- 569.32 1 methyl-2- oxopyrrolidin-1- yl]methyl}benzami

de

N-(l - cyclopentylpiperidi

n-4-yl)-4-{[(4S)-4- methyl-2- oxopyrrolidin-1 -

373 yl]methyl}-3-[4- 620.32 1

(4-oxo-3,4- dihydroquinazolin- 7- yl)phenoxy]benza

mide

3-[4-(5-tert-butyl- l ,3,4-thiadiazol-2- yl)phenoxy]-N-(l-

374 616.32 1 cyclopentylpiperidi

n-4-yl)-4-{[(4S)-4- methyl-2- oxopyrrolidin-1 - yl]methyl}benzami

de

N-(l- cyclopentylpiperidi

n-4-yl)-4-{[(^S)-4- methyl-2- oxopyrrolidin- 1 -

375 yl]methyl}-3-(4- 645.3 1

(6-

[(methylsulfonyl)

methyl]pyridin-3 - yl } phenoxy)benza

mide

2-fluoro-4-{[(4S)-

4-methyl-2- oxopyrrolidin-1 - yl]methyl}-5-[4- (6-morpholin-4-

376 ylpyridin-3- 672.35 1 yl)phenoxy]-N-[ 1 - (tetrahydro-2H- pyran-4- yl)piperidin-4- yljbenzamide

2-fluoro-4-{[(4S

4-methyl-2- oxopyrrolidin- 1 - yl]methyl}-5-{4- [2-(lH-pyrazol-l-

377 yl)pyrimidin-5- 654.31 1

N N yl]phenoxy}-N-[l -

(tetrahydro-2H- pyran-4- yl)piperidin-4- yljbenzamide