PYRROL DERIVATIVES AS INHIBITORS OF APOLIPOPROTEIN L-1

FIELD OF THE INVENTION

This invention relates to compounds which inhibit apolipoprotein L-1 (APOL1), pharmaceutical compositions comprising the compounds, and the use of the compounds for the treatment of diseases mediated by APOL1, including kidney diseases and sepsis.

BACKGROUND OF THE INVENTION

Apolipoprotein L-1 (APOL1) is predominantly synthesized in the liver and circulates in the blood in complex with HDL particles. The circulating APOL1 is known to function as an innate immune system by conferring protection from Trypanosoma brucei brucei (T. b. brucei), a parasite that causes African sleeping sickness. Studies have suggested the association of two common variants (G1 and G2) of APOL1 among African ancestry patients with increased risk for developing kidney diseases (Genovese, G. et al. , Science 2010, 329(5993), 841-845). One variant includes the substitution of two amino acids (S342G and I384M; termed Gl), and the other includes the deletion of two consecutive amino acids (N388 and Y389; termed G2) compared to the non-risk allele (termed GO) (Genovese G. et al., Science 2010, 329(5993), 841-845). In addition, there are several reports linking the APOL1 risk alleles to an increased incidence of sepsis (Bird, Nature Reviews Immunology, 2021, 21, 759; Wu et al., Immunity, 2021, 54, 2632).

Chronic kidney disease (CKD) is a noncommunicable disease with significant morbidity and mortality. In particular, the cumulative risk for CKD varies by race (e.g., approximately 7.5% for individuals of African ancestry and 2.1% for individuals of European ancestry) (Kiberd, B.A. et al., J. Am. Soc. Nephrol. 2002, 13(6), 1635-1644). The risk exists in several forms of CKD, including end-stage kidney disease (ESKD), nondiabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), human immunodeficiency virus (HlV)-associated nephropathy (a distinct form of FSGS, also termed collapsing glomerulopathy), diabetic nephropathy, hypertensive nephrosclerosis, lupus nephritis, arterionephrosclerosis, microalbuminuria, and sickle cell nephropathy.

FSGS is a clinical syndrome involving podocyte injury and glomerular scarring, and includes genetic forms, reactive forms associated with other illnesses (including HIV-1 disease), and a primary form that accounts for the majority of cases including ESKD (Fogo, Nat. Rev. Nephrol. 2015, 11, 76-87). One defining feature of FSGS includes proteinuria, typically accompanied by hypoalbuminemia, hypercholesterolemia, and peripheral edema. FSGS has been shown to be the leading glomerular cause of ESKD (Rosenberg A. Z. et al., Clin. J. Am. Soc. Nephrol. 2017, 12(3), 502-517). G1 and G2 risk variants of APOL1 are prevalent in individuals of African ancestry and are linked not only to adult-onset FSGS but also to progression of other related kidney diseases including CKD, NDKD, and ESKD, regardless of diabetes status (Parsa, A. et al., N. Engl. J. Med. 2013, 369, 2183-2196; Dummer P. D. et al., Semin. Nephrol. 2015, 35(3), 222-36). An APOL1 inhibitor, VX-147, has been studied in clinical trials for treating APOL1 -Mediated Kidney Disease. (See WO 2020/131807; clinicaltrials.gov, NCT04340362 and NCT05312879).

Anti-hypertensive and anti-inflammatory treatments have been used to slow progression and reduce symptoms in some patients for some types of CKD, but there are no specific therapies for kidney diseases associated with APOL1. Thus, there remains a need for treatments for APOL1 associated kidney diseases including, but not limited to, CKD, FSGS, NDKD, ESKD, diabetic nephropathy, hypertensive nephrosclerosis, lupus nephritis, arterionephrosclerosis, microalbuminuria, and sickle cell nephropathy, as well as sepsis.

SUMMARY OF THE INVENTION

The invention relates to APOL1 inhibitors and uses thereof in the treatment of kidney diseases associated with APOL1 and sepsis.

In one aspect, the invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is selected from the group consisting of -(Cl-C6)alkyl, halo(Cl-C6)alkyl-, -(C3- C6)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- C10)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- C6)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- C10)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, -(Cl-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci- C ₆ )alkyl; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci- C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and - SO(Ci-Ce)alkyl, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-C ₆ )alkyl-Y, -(C ₂ -C6)alkenyl-Y, -(C ₃ -C6)cycloalkyl-Y, -(C ₆ - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C^azabicycloalkyl-Y;

Y is -CONH ₂ , -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ;

R ⁶ is -(Ci-Ce)alkyl, -(Ci-Ce)alkyl substituted by -CONH ₂ , hydroxy(Ci-C6)alkyl-, halo(Ci-C6)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, -pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C ₃ - Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or thiazolyl substituted by cyano;

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; and each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and hydroxy(Ci-C6)alkyl-.

In one aspect, the invention relates to a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof as defined herein, and a pharmaceutically acceptable excipient.

In one aspect, the invention relates to a method of treatment of a kidney disease or sepsis comprising administering to a human in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein.

In one aspect, the invention relates to a compound, or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of a kidney disease or sepsis. In one aspect, the invention relates to use of a compound, or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a kidney disease or sepsis.

DETAILED DESCRIPTION OF THE INVENTION

Various publications, articles and patents are cited or described in the background and throughout the specification. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the disclosure. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to the disclosure.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

The definitions for the various groups and substituent groups of any of the Formulas disclosed herein, or a pharmaceutically acceptable salt thereof provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species.

The term "alkyl" refers to a saturated hydrocarbon radical, straight or branched, having the specified number of carbon atoms. For example, the term "(Ci-C6)alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, //-propyl, isopropyl, //-butyl, isobutyl, .v-butyl, t-butyl, pentyl, and hexyl. In some embodiments, “Me” refers to a methyl group.

When the term "alkyl" is used in combination with other substituent groups, such as “halo(Ci-C6)alkyl” and “hydroxy(Ci-C6)alkyl”, the term “alkyl” is intended to encompass a divalent straight or branched chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.

The term “halo(Ci-C6)alkyl” refers to a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, which is a straight or branched chain carbon radical. Examples of "halo(Ci-C6)alkyl" groups include, but are not limited to, -CH2F (fluoromethyl), -CHF2 (difluoromethyl), -CF3 (trifluoromethyl), -CCh (trichloromethyl), 1,1 -difluoroethyl, 2- fluoro-2-methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

The term “hydroxy(Ci-C6)alkyl” refers to a radical having one or more hydroxy groups at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, which is a straight or branched chain carbon radical. Exemplary groups include, but are not limited to, hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH), and hydroxyisopropyl.

The term “amino(Ci-C6)alkyl” refers to a radical having one or more amino groups at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, which is a straight or branched chain carbon radical. Exemplary groups include, but are not limited to, aminomethyl (-CH2NH2), aminoethyl (-CH2CH2NH2), and aminoisopropyl.

The term "alkenyl" refers to a straight or branched hydrocarbon radical containing the specified number of carbon atoms and at least 1 double bond. For example, “(C2- Ce)alkenyl” has 2 to 6 carbon atoms. Exemplary groups include, but are not limited to, ethenyl and propenyl.

The term “alkoxy” refers to an -O-alkyl group, i.e., an alkyl group which is attached through an oxygen linking atom, wherein “alkyl” is defined above. For example, the term “(Ci-C6)alkoxy” refers to a straight or branched chain carbon radical having 1 to 6 carbon atoms attached through an oxygen linking atom. Exemplary “(Ci-Ce)alkoxy” groups include, but are not limited to, methoxy, ethoxy, //-propoxy, isopropoxy, //-butoxy, .v-butoxy, isobutoxy, and t-butoxy.

The term “halo(Ci-C6)alkoxy” refers to a straight or branched chain hydrocarbon radical, having at least 1 and up to 6 carbon atoms with one or more halogen atoms, which may be the same or different, attached to one or more carbon atoms, which radical is attached through an oxygen linking atom. Exemplary groups include, but are not limited to, -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), and OCH(CF3)2 (hexafluoroisopropoxy) .

The term “cycloalkyl” refers to a non-aromatic, saturated, monocyclic, hydrocarbon ring containing the specified number of carbon atoms. The term “(C3-C6)cycloalkyl” refers to a non-aromatic saturated, monocyclic, hydrocarbon ring having 3 to 6 carbon atoms. Exemplary “(C3-C6)cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of “(C3-C6)cycloalkyl(Ci-C4)alkyl-” groups useful in the present invention include, but are not limited to, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclobutylethyl, cyclopentylethyl, and cyclohexylethyl. The term “bicycloalkyl” refers to a saturated bicyclic hydrocarbon ring system containing the specified number of carbon atoms. Bicycloalkyl groups may be bridged, fused, or spiro. For example, “bicycloalkyl” may contain 5 to 10 carbon atoms, i.e., (C5- Cio)bicycloalkyl, or “bicycloalkyl” may contain 6 to 10 carbon atoms, i.e., (Ce- Cio)bicycloalkyl. Exemplary groups include, but are not limited to bicyclofl. l.l]pentanyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[4.3.1]decyl, bicyclo[2.2.0]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, octahydropentalenyl, bicyclo[4.2.0]octyl, decahydronaphthalenyl, spiro[3.3]heptyl, spiro[2.4]heptyl, spiro[3.4]octyl, spiro[2.5]octyl, spiro[4.4]nonyl, spiro[3.5]nonyl, and spiro[4.5]decyl.

The term “heterocycloalkyl” refers to a saturated or unsaturated 3 to 10 membered monocyclic or bicyclic ring, which must contain at least one heteroatom, which is selected from nitrogen, oxygen, and sulfur. Heterocycloalkyl groups may contain one or more C(O), S(O) or SO2 groups. However, heterocycloalkyl groups are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. The term “5- or 6- membered heterocycloalkyl” refers to a saturated or unsaturated 5- or 6- membered monocyclic ring, which must contain 1 or 2 non-carbon atoms, which are selected from nitrogen, oxygen, and sulfur. Exemplary groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, tetrahydro-2H-pyranyl, dihydropyranyl, morpholinyl, morpholinyl-3-one, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1 ,4-oxathiolanyl, 1,4- oxathianyl, 1,4-dithianyl, piperidyl-2-one, pyrimidinyl-2,4(lH,3H)-dione, thiomorpholinyl, and thiomorpholinyl 1,1 -dioxide.

The term "5- or 6-membered heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Exemplary groups include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl. The term “heterobicycloalkyl” refers to a saturated or unsaturated bicyclic ring containing at least one heteroatom, which is selected from nitrogen, oxygen, and sulfur. Heterobicycloalkyl groups may be bridged, fused or spiro bicyclic groups. However, heterobicycloalkyl groups are not aromatic. The term “5 to 10-membered heterobicycloalkyl” refers to a saturated or unsaturated 5 to 10- membered bicyclic ring containing 1 or 2 non-carbon atoms, which are selected from nitrogen, oxygen and sulfur. Exemplary 5 to 10-membered heterobicycloalkyl groups include, but are not limited to, azabicycloalkyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.2.1]heptanyl, and 7- oxabicyclo[4.1.0]heptanyl.

The term “azabicycloalkyl” refers to a saturated bicyclic ring containing one nitrogen ring atom in addition to the specified number of carbon ring atoms. Azabicycloalkyl groups can be bridged or fused. For example, “azabicycloalkyl” may contain 5 to 9 carbon atoms, i.e., (Cs-Cgjazabicycloalkyl. Exemplary groups include, but are not limited to azabicyclo[3.1.0]hexyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, and azabicyclo[2.2.2]octyl.

For the avoidance of doubt, all bicyclic ring systems may be attached at any suitable position on either ring.

The terms "halogen" and "halo" represent chloro (-C1), fluoro (-F), bromo (-Br), or iodo (-1) substituents.

The term “oxo” represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C = O).

The term "hydroxy" or “hydroxyl” is intended to mean the radical -OH.

The term “cyano” refers to the group -CN.

The term “amino” refers to the group -NH2.

The term “member atoms” refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group attached to a chain or ring are not member atoms in the chain or ring.

The term “independently selected” means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. Thus, each substituent is separately selected from the entire group of recited possible substituents. As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.

The term “optionally substituted” indicates that a group may be unsubstituted or substituted with one or more of the defined substituents. The term “substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

Compounds

In one aspect, the invention relates to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C6)alkyl, and -SO(Ci- C ₆ )alkyl; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and - SO(Ci-Ce)alkyl, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-Ce)alkyl-Y, -(C ₂ -C6)alkenyl-Y, -(C ₃ -C6)cycloalkyl-Y, -(C ₆ - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C^azabicycloalkyl-Y;

Y is -CONH ₂ , -CONHR ⁶ , - NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ; R ⁶ is -(Ci-Ce)alkyl, -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-C6)alkyl-, halo(Ci-C6)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3- Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or thiazolyl substituted by cyano;

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-; and each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and hydroxy(Ci-Ce)alkyl-.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, - (C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, - (C3-Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, - (Cs-Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, -halo(Ci-Ce)alkoxy, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , - SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(Cs-Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, 5- or 6- membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5-Cio)bicycloalkyl, 5- to 10- membered heterobicycloalkyl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci- Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , - SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(Cs-Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, 5- or 6- membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5-Cio)bicycloalkyl, 5- to 10- membered heterobicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci- Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci-C6)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , - SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-Ce)cycloalkyl, - (Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, - halo(Ci-C ₆ )alkoxy, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci- Ce)alkyl, and -SO(Ci-C6)alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(C3-C6)cycloalkyl, -(Cs- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci- Ce)alkyl. In another embodiment, X ¹ is selected from the group consisting of -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3-C6)cycloalkyl, -(C5-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano. In another embodiment, X ¹ is selected from the group consisting of -(C3-Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3-Ce)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of -F, -Cl, -Br, methyl, -CHF2, -CF3, and cyano.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci- C ₆ )alkyl-, halo(Ci-C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , - SO2(Ci-Ce)alkyl, and -SO(Ci-Ce)alkyl. In another embodiment, X ¹ is phenyl or 5- or 6- membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano. In another embodiment, X ¹ is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of -F, -Cl, -Br, methyl, -CHF2, -CF3, and cyano.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is a 5- or 6-membered heteroaryl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, and halo(Ci-C6)alkyl-. In another embodiment, X ¹ is a 5- or 6-membered heteroaryl having one ring heteroatom selected from nitrogen, sulfur and oxygen, and optionally one additional ring nitrogen atom, wherein the 5- or 6 -membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, and halo(Ci-C6)alkyl-. In another embodiment, X ¹ is a 5- or 6- membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, and imidazolyl, wherein the 5- or 6-membered heteroaryl is optionally substituted with halo, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, X ¹ is a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, and imidazolyl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl, -F, or -CF3.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is -(Ci-Ce)alkyl or halo(Ci-C6)alkyl-. In another embodiment, X ¹ is -(Ci- Ce)alkyl. In another embodiment, X ¹ is methyl, -CF3, or -C(CH3)3. In another embodiment, X ¹ is methyl or -C(CH3)3-

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is a -(C5-Cio)bicycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo and halo(Ci- Ce)alkyl-. In another embodiment, X ¹ is -(Cs-Cejbicycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo and halo(Ci-C6)alkyl-. In another embodiment, X ¹ is bicyclofl.1.1. Jpentanyl optionally substituted with halo or halo(Ci-C6)alkyl-. In another embodiment, X ¹ is bicyclofl.1.1. Jpentanyl optionally substituted with -F or -CF3.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is 5- or 6-membered heterocycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy-, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , - CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl. In another embodiment, X ¹ is 5- or 6-membered heterocycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, and halo(Ci-C6)alkyl-. In another embodiment, X ¹ is a 5- or 6-membered heterocycloalkyl selected from the group consisting of piperidinyl and tetrahydro-2H-pyranyl, wherein the 5- or 6-membered heterocycloalkyl is optionally substituted with -(Ci-Ce)alkyl. In another embodiment, X ¹ is a 5- or 6-membered heterocycloalkyl selected from the group consisting of piperidinyl and tetrahydro-2H-pyranyl, wherein the 5- or 6-membered heterocycloalkyl is optionally substituted with methyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is a -(C Cr cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halofCi-CeJalkyl-, and cyano. In another embodiment, X ¹ is a -(C i-Crjcycloalkyl optionally substituted with halolCi-Ce Jalkyl-. In another embodiment, X ¹ is cyclopropyl optionally substituted with - CF ₃ .

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halofCi-CeJalkyl-, halo(Ci- C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and - SO(Ci-Ce)alkyl, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, - (C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl; and each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci- Ce)alkyl, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is selected from the group consisting of -(C3-C6)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; and each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci- Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; and each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ¹ is a -(C3-C6)cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; and each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ² is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C6)cycloalkyl-Y. In another embodiment, X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y. In another embodiment, X ² is -(C3-C6)cycloalkyl-Y. In another embodiment, X ² is -(Ci-Ce)alkyl-Y. In another embodiment, X ² is -(CH2)2-Y or -(CH2)3- Y.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ . In another embodiment, Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ . In another embodiment, Y is - CONHR ⁶ or -NHR ⁶ . In another embodiment, Y is -CONHR ⁶ or -NHCOR ⁶ . In another embodiment, Y is -CONHR ⁶ .

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, R ⁶ is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or thiazolyl substituted by cyano.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, R ⁶ is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, R ⁶ is -(Ci-Ce)alkyl substituted by -CONH ₂ , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy. In another embodiment, R ⁶ is hydroxy(Ci- Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy. In another

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, X ² is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C ₆ )cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , - OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ; and R ⁶ is hydroxy(Ci-Ce) alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is - (Ci-Ce)alkyl-Y or -(C3-C ₆ )cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ; and R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is -(Ci-C6)alkyl-Y or -(C3- C6)cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ; and R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y; Y is -CONHR ⁶ or -NHR ⁶ ; and R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R ⁷ is hydrogen, halo, or -(Ci-Ce)alkyl. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, methyl, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, or methyl. In another embodiment, R ⁷ is hydrogen.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, or - CF ₃ .

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-C6)cycloalkyl, -(C5- Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , - SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-Ce)alkyl-Y, -(C3-C ₆ )cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C ₆ )alkyl-Y, or -(Ci-C6)alkyl-(C ₃ -C6)cycloalkyl-Y;

Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ;

R ⁶ is -(Ci-C6)alkyl substituted by -CONH ₂ , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;

R ⁷ is hydrogen, halo, cyano, methyl, or halo(Ci-C6)alkyl-; and each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

X ¹ is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-C6)cycloalkyl, -(C5- Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C ₆ )alkyl-, halo(Ci-C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , - SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C6)alkyl, and -SO(Ci-C ₆ )alkyl; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-C ₆ )alkyl-Y, -(C ₃ -C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C ₆ )alkyl-Y, or -(Ci-C6)alkyl-(C ₃ -C6)cycloalkyl-Y;

Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ;

R ⁶ is -(Ci-C6)alkyl substituted by -CONH ₂ , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;

R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-; and each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

X ¹ is selected from the group consisting of -(C3-Ce)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y;

Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy; and

R ⁷ is hydrogen, halo, cyano, methyl, or halo(Ci-C6)alkyl-.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

X ¹ is selected from the group consisting of -(C3-Ce)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y;

Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy; and

R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

X ¹ is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y;

Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ;

R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, methyl, or halo(Ci-C6)alkyl-.

In an embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

X ¹ is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y;

Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-.

The invention also relates to a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: X ² is -(Ci-Ce)alkyl-Y, -(C ₂ -C6)alkenyl-Y, -(C ₃ -C6)cycloalkyl-Y, -(C ₆ - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C^azabicycloalkyl-Y;

Y is -CONH2, -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ; each of R ^la , R ^lb , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci- C ₆ )alkyl-, halo(Ci-C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , - SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least two of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen;

R ⁶ is -(Ci-Ce)alkyl, -(Ci-Ce)alkyl substituted by -CONH ₂ , hydroxy(Ci-Ce)alkyl-, halo(Ci-Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3- Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or thiazolyl substituted by cyano;

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-; and each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl, and hydroxy(Ci-Ce)alkyl-.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , - SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and -SO(Ci-C ₆ )alkyl, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least two of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF ₂ , -CF3, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least two of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, X ² is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C6)cycloalkyl-Y. In another embodiment, X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y. In another embodiment, X ² is -(C3-C6)cycloalkyl-Y. In another embodiment, X ² is -(Ci-Ce)alkyl-Y. In another embodiment, X ² is -(CH2)2-Y or -(CH2)3- Y. In another embodiment, X ² is -(CH2)2-Y.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ . In another embodiment, Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ . In another embodiment, Y is - CONHR ⁶ or -NHCOR ⁶ . In another embodiment, Y is -CONHR ⁶ or -NHR ⁶ . In another embodiment, Y is -CONHR ⁶ .

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, R ⁶ is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or thiazolyl substituted by cyano.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, R ⁶ is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-. In another embodiment, R ⁶ is -(Ci- Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, X ² is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C ₃ -C6)cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , - OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ; and R ⁶ is hydroxy(Ci-Ce) alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is - (Ci-Ce)alkyl-Y or -(C3-C ₆ )cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ; and R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is -(Ci-C6)alkyl-Y or -(C3- Ce)cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ; and R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y; Y is -CONHR ⁶ or -NHR ⁶ ; and R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, methyl, or -CF3.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, or - CF ₃ .

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof, each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof: each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , )cycloalkyl-Y; NHR ⁶ ;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-.

In an embodiment of a compound of formula (II), or a pharmaceutically acceptable salt thereof: each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen;

X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ;

R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-.

The invention also relates to a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: each of R ^la , R ^lb , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci- C ₆ )alkyl-, halo(Ci-C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , - SO2(Ci-Ce)alkyl, and -SO(Ci-Ce)alkyl, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least two of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen;

R ⁶ is -(Ci-C6)alkyl substituted by -CONH2, hydroxy(Ci-Ce) alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-; and each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and hydroxy(Ci-Ce)alkyl-.

In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , - SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C6)alkyl, and -SO(Ci-C ₆ )alkyl, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least two of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least two of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen.

In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof, R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy. In another embodiment, R ⁶ is ,

In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, methyl, or -CF3. In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, or - CF ₃ .

In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof, each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.

In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof: each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-.

In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof: each of R ^la , R ^2a , R ^3a , R ^4a , R ^5a , R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen and at least three of R ^lb , R ^2b , R ^3b , R ^4b , and R ^5b are hydrogen;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-.

The invention also relates to a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: each of R ^3a and R ^3b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-.

In an embodiment of a compound of formula (IV), or a pharmaceutically acceptable salt thereof, each of R ^3a and R ^3b is independently selected from the group consisting of hydrogen, -F, -Cl, and -CF3.

In an embodiment of a compound of formula (IV), or a pharmaceutically acceptable salt thereof, R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy. In another embodiment, In another embodiment,

In an embodiment of a compound of formula (IV), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, methyl, or -CF3.

In an embodiment of a compound of formula (IV), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, or - CF ₃ .

The invention also relates to a compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein:

X ^la is halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, or cyano.

X ² is -(Ci-Ce)alkyl-Y, -(C ₂ -C6)alkenyl-Y, -(C ₃ -C6)cycloalkyl-Y, -(C ₆ - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C9)azabicycloalkyl-Y;

Y is -CONH2, -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and - SO(Ci-Ce)alkyl, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

R ⁶ is -(Ci-C6)alkyl, -(Ci-Ce)alkyl substituted by -CONH ₂ , hydroxy(Ci-C6)alkyl-, halo(Ci-C6)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3- Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or thiazolyl substituted by cyano;

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl, and hydroxy(Ci-Ce)alkyl-; and n is 1, 2, 3, or 4. In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, X ^la is halo(Ci-Ce)alkyl-. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, X ^la is -CF3.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and - SO(Ci-Ce)alkyl, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF ₂ , -CF3, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of F, -Br, -Cl, methyl, -CHF ₂ , -CF3, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, X ² is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C6)cycloalkyl-Y. In another embodiment, X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y. In another embodiment, X ² is -(C3-C6)cycloalkyl-Y. In another embodiment, X ² is -(Ci-Ce)alkyl-Y. In another embodiment, X ² is -(CH ₂ ) ₂ -Y or -(CH ₂ )3- Y. In another embodiment, X ² is -(CH ₂ ) ₂ -Y.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , -OC(O)NHR ⁶ , or -NHC(O)OR ⁶ . In another embodiment, Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ . In another embodiment, Y is - CONHR ⁶ or -NHCOR ⁶ . In another embodiment, Y is -CONHR ⁶ or -NHR ⁶ . In another embodiment, Y is -CONHR ⁶ .

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R ⁶ is -(Ci-Ce)alkyl substituted by -CONH ₂ , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C Cr cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or thiazolyl substituted by cyano.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R ⁶ is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or -(C3-C6)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-. In another embodiment, R ⁶ is -(Ci- Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is ,

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, X ² is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C ₃ -C6)cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , -NHR ⁶ , - OC(O)NHR ⁶ , or -NHC(O)OR ⁶ ; and R ⁶ is hydroxy(Ci-Ce) alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is - (Ci-C ₆ )alkyl-Y or -(C3-C ₆ )cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ; and R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is -(Ci-C6)alkyl-Y or -(C3- Ce)cycloalkyl-Y; Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ; and R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, X ² is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y; Y is -CONHR ⁶ or -NHR ⁶ ; and R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, methyl, or -CF3. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, -F, or methyl. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, or - CF ₃ .

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, n is 1, 2, or 3. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, n is 1 or 2. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, n is 1. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, n is 2. In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof:

X ^la is halo(Ci-C ₆ )alkyl-; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

X ² is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y;

Y is -CONHR ⁶ , -NHCOR ⁶ , or -NHR ⁶ ;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy;

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; and n is 1, 2, or 3.

In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof:

X ^la is -CF ₃ ; each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least drogen; )cycloalkyl-Y; NHR ⁶ ;

R ⁶ is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and

R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-; and n is 1.

The invention also relates to a compound of formula (VI): or a pharmaceutically acceptable salt thereof, wherein: each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and - SO(Ci-Ce)alkyl, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

R ⁶ is -(Ci-C6)alkyl substituted by -CONH ₂ , hydroxy(Ci-Ce) alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;

R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; and each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and hydroxy(Ci-C6)alkyl-.

In an embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C ₆ )alkoxy-, cyano, hydroxy, -COOR ⁸ , -CONR ⁹ R ¹⁰ , -SO ₂ NR ^U R ¹² , -SO ₂ (Ci-C ₆ )alkyl, and - SO(Ci-Ce)alkyl, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF ₂ , -CF3, and cyano, provided at least two of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of -F, -Br, -Cl, methyl, -CHF ₂ , -CF3, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen. In another embodiment, each of R ^la , R ^2a , R ^4a , and R ^5a is hydrogen and R ^3a is hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci- Ce)alkyl-, or cyano. In another embodiment, each of R ^la , R ^2a , R ^4a , and R ^5a is hydrogen and R ^3a is halo or halo(Ci-C6)alkyl-. In another embodiment, each of R ^la , R ^2a , R ^4a , and R ^5a is hydrogen and R ^3a is -F, -Cl, or -CF3. In an embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy. In another embodiment, R ⁶ is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy. In another embodiment, R ⁶ is ,

In an embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, methyl, or -CF3. In another embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, -F, or methyl. In another embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen.

In an embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, R ⁷ is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-. In another embodiment, R ⁷ is hydrogen, halo, cyano, or -CF3. In another embodiment, R ⁷ is hydrogen, -F, -I, -CN, or - CF ₃ .

In an embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.

In an embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof: each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen; R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and R ⁷ is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-.

In an embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof: each of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R ^la , R ^2a , R ^3a , R ^4a , and R ^5a are hydrogen;

R ⁶ is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and R ⁷ is hydrogen, -F, or methyl.

In another embodiment, the invention relates to a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

5 In another embodiment, the invention relates to a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a compound selected from the group consisting of: pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a compound selected from the or a pharmaceutically acceptable salt thereof.

It is to be understood that the references herein to a compound of formula (I), (II), (III), (IV), (V), or (VI) or a salt thereof includes a compound of formula (I), (II), (III), (IV), (V), or (VI) as a free base or acid, or as a salt thereof, for example as a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of formula (I), (II), (III), (IV), (V), or (VI). In another embodiment, the invention is directed to a salt of a compound of formula (I), (II), (III), (IV), (V), or (VI). In a further embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of formula (I), (II), (III), (IV), (V), or (VI). In another embodiment, the invention is directed to a compound of formula (I), (II), (III), (IV), (V), or (VI), or a salt thereof. In another embodiment, the invention is directed to a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof.

Because of its potential use in medicine, it will be appreciated that a salt of a compound of formula (I), (II), (III), (IV), (V), or (VI) is preferably pharmaceutically acceptable.

The term "pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and 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, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Furthermore, pharmaceutically acceptable salts of the compound of formulas (I)-(VI) may be prepared during further processing of the free acid or base form, for example in situ during manufacture into a pharmaceutical formulation.

Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley- VCH/VHCA, 2011.

Non-pharmaceutically acceptable salts may be used, for example as intermediates in the preparation of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts can include acid or base addition salts. Such base addition salts can be formed by reaction of a compound of formula (I), (II), (III), (IV), (V), or (VI) (which, for example, contains a carboxylic acid or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration. Such acid addition salts can be formed by reaction of a compound of formula (I), (II), (III), (IV), (V), or (VI) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallization and filtration.

Salts may be prepared in situ during the final isolation and purification of a compound of formula (I), (II), (III), (IV), (V), or (VI). If a basic compound of formula (I),

(II), (III), (IV), (V), or (VI) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base. Similarly, if a compound of formula (I), (II),

(III), (IV), (V), or (VI) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid.

It will be understood that if a compound of formula (I), (II), (III), (IV), (V), or (VI) contains two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.

Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of formula (I), (II), (III), (IV), (V), or (VI) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1 ,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene- 1,5 -disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p- aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-l,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N’- dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-r-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t- butylamine, and zinc.

It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” For example, a complex with water is known as a “hydrate.” Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, ethanol, zTo-propyl alcohol, and /V-mcthyl pyrrolidinone may be used to form solvates. Methods for the identification of solvates include, but are not limited to, NMR and microanalysis. Compounds of formula (I), (II), (III), (IV), (V), or (VI), or salts thereof, may exist in solvated and unsolvated form.

The compounds of the invention may be in crystalline or amorphous form. The most thermodynamically stable crystalline form of a compound of the invention is of particular interest.

Crystalline forms of compounds of the invention may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid-state nuclear magnetic resonance (ssNMR).

The compounds of formula (I), (II), (III), (IV), (V), or (VI), and pharmaceutically acceptable salts thereof may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in a compound of formula (I), (II), (III), (IV), (V), or (VI) or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds of formula (I), (II), (III), (IV), (V), or (VI) and pharmaceutically acceptable salts thereof containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

The invention also includes all suitable isotopic variations of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ O, ¹⁸ F and ³⁶ C1, respectively. Certain isotopic variations of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a salt or solvate thereof, for example, those in which a radioactive isotope such as ³ H or ¹⁴ C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³ H, and carbon- 14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically salt thereof, can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.

Pharmaceutical Compositions

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, and a pharmaceutically acceptable excipient (also referred to as carriers and/or diluents in the pharmaceutical arts). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of formula (I), (II), (III), (IV), (V), or (VI), or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as described herein, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).

When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a “quick-dissolve” medicine. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.

In some embodiments, a pharmaceutical composition is a tablet or capsule for oral delivery.

Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI) depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

A therapeutically effective amount of a compound as defined herein will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication. However, an effective amount of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof of the invention for the treatment of kidney diseases will generally be in the range of 0.001 to 100 mg/kg body weight of recipient per day, suitably in the range of 0.01 to 10 mg/kg body weight per day. For a 70 kg adult mammal, the actual amount per day would suitably be from 7 to 700 mg and this amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. Inhaled daily dosages range from 10 pg - 10 mg/day, with preferred 10 pg - 2 mg/day, and more preferred 50 pg - 500 pg/day. An effective amount of a salt or solvate, etc., may be determined as a proportion of the effective amount of the compound of formula (I), (II), (III), (IV), (V), or (VI) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.

In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of formula (I), (II), (III), (IV), (V), or (VI) or salt thereof (e.g., pharmaceutically acceptable salt thereof) with at least one excipient.

Methods/Uses

The invention also provides a method of treatment in a subject, especially a human. Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, kidney diseases associated with AP0L1, for example, chronic kidney disease (CKD), end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), Human Immunodeficiency Virus (HlV)-associated nephropathy (a distinct form of FSGS, also termed collapsing glomerulopathy), diabetic nephropathy, hypertensive nephrosclerosis, lupus nephritis, arterionephrosclerosis, microalbuminuria, diabetic nephropathy, IgA nephropathy, transplant nephropathy, autoimmune nephropathy, drug-induced nephropathy, and hypertension-related nephropathy. The term “kidney disease(s) associated with AP0F1” refers to a disease or condition that impairs kidney function and can be attributed to AP0F1. In some embodiments, a kidney disease associated with AP0F1 can be found in patients having two AP0F1 risk alleles (i.e., homozygous or heterozygous for the G1 or G2 alleles). In some embodiments, the kidney disease associated with AP0F1 includes, but is not limited to, CKD, ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, and microalbuminuria.

The term “treatment” refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted patient or subject.

The term “therapeutically effective amount” refers to the quantity of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, which will elicit the desired biological response in the human body. It may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.

The term “subject” refers to a human body.

In another aspect, the invention provides a method of treatment of a kidney disease or sepsis comprising administering to a human in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, or a pharmaceutical composition disclosed herein. In one embodiment, the invention provides a method of treatment of a kidney disease. In another embodiment, the invention provides a method of treatment of sepsis.

In another aspect, the invention provides a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, or a pharmaceutical composition disclosed herein for use in the treatment of a kidney disease or sepsis. In one embodiment, provided is a compound or pharmaceutical composition according to any one of the embodiments disclosed herein for use in the treatment of a kidney disease. In one embodiment, provided is a compound or pharmaceutical composition according to any one of the embodiments disclosed herein for use in the treatment of sepsis.

In another aspect, the invention provides use of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a kidney disease or sepsis. In one embodiment, provided is use of a compound or pharmaceutical composition according to any one of the embodiments disclosed herein in the manufacture of a medicament for the treatment of a kidney disease. In one embodiment, provided is use of a compound or pharmaceutical composition according to any one of the embodiments disclosed herein in the manufacture of a medicament for the treatment of sepsis.

In one embodiment, the kidney disease includes, but is not limited to, chronic kidney disease (CKD), end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), human immunodeficiency virus- associated nephropathy (HIV AN), diabetic kidney disease (also called diabetic nephropathy), hypertensive nephrosclerosis, arterionephrosclerosis, lupus nephritis, proteinuria, microalbuminuria and sickle cell nephropathy. In another embodiment, the kidney disease includes, but is not limited to, chronic kidney disease (CKD), end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), and human immunodeficiency virus-associated nephropathy (HIV AN). In another embodiment, the kidney disease includes, but is not limited to, chronic kidney disease, diabetic kidney disease (diabetic nephropathy), hypertensive nephrosclerosis, arterionephrosclerosis, lupus nephritis, proteinuria, and microalbuminuria. In another embodiment, the kidney disease includes diabetic kidney disease (diabetic nephropathy). In another embodiment, the kidney disease includes FSGS. In another embodiment, the kidney disease includes FSGS, wherein the FSGS is primary FSGS, virus-associated FSGS, or drug-associated FSGS.

Combination Therapy

The compounds of the invention disclosed herein can be combined with or coadministered with other therapeutic agents, particularly agents that may enhance the activity or time of disposition of the compounds. Combination therapies according to the invention comprise the administration of at least one compound of the invention and the use of at least one other treatment method, including administration of one or more other therapeutic agents.

By the term "co-administration" and derivatives thereof as used herein refers to either simultaneous administration or any manner of separate sequential administration of an AP0L1 inhibiting compound of the invention, as described herein, and a further active ingredient or ingredients. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment. Typically, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, the compounds may be administered in the same or separate dosage form, e.g., one compound may be administered orally and another compound may be administered intravenously.

Other therapeutic agents which may be used in combination with a compound of the invention include, but are not limited to, antigen immunotherapy, anti-histamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), mineralocorticoid receptor antagonists e.g., spironolactone, epleronone, canrenone), sodium-glucose transport protein 2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast) iNOS inhibitors, tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, elastase inhibitors, beta-2 integrin antagonists, adenosine a2a agonists, chemokine antagonists such as CCR3 antagonists or CCR4 antagonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DPI antagonists, DP2 antagonists, pI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g., sodium 3-(3-(tert- butylthio)-l-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpy ridin-2-yl)methoxy)-lH- indol-2-yl)-2,2-dimethylpropanoate), methotrexate, and similar agents; monoclonal antibody therapy such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; receptor therapies e.g., etanercept and similar agents; antigen non-specific immunotherapies (e.g., interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and similar agents)), inhibitors of TGFP synthesis, for example pirfenidone, tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinases, for example intedanib (BIBF-1120) and imatinib mesylate (GLEEVEC), endothelin receptor antagonists, for example ambrisentan or macitentan, antioxidants, such as N-acetylcysteine (NAC or fluimucil), broad-spectrum antibiotics, such as tetracyclines, for example minocycline hydrochloride, phosphodiesterase 5 (PDE5) inhibitors for example sildenafil, or a _v Pe integrin antagonists, e.g., monoclonal antibodies such as those described in WO 2003/100033 A2.

EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

All temperatures are given in degrees Celsius, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon (Ar) or nitrogen (N2) atmosphere where necessary.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. The CombiFlash® system used for purification in this application was purchased from Isco, Inc. CombiFlash® purification was carried out using prepacked silica gel columns, a detector with UV wavelength at 254 nm and a variety of solvents or solvent combinations.

Preparative HPLC was performed using a Gilson Preparative System with variable wavelength UV detection or an Agilent Mass Directed AutoPrep (MDAP) system with both mass and variable wavelength UV detection or Waters Preparative System with UV / PDA detection or a Shimadzu PREP LC 20AP. A variety of reverse phase columns, e.g., Luna 5m Cl 8(2) 100A, SunFire Cl 8, XBridge Cl 8, Atlantics T3 were used in the purification with the choice of column support dependent upon the conditions used in the purification. The compounds are eluted using a gradient of CH3CN and water. Neutral conditions used an CH3CN and water gradient with no additional modifier, acidic conditions used an acid modifier, 0.1% TFA (added to both the CH3CN and water) or 0.1 % formic acid and basic conditions used a basic modifier, 0.1% NH4OH (added to the water) or 10 mM ammonium bicarbonate.

Analytical HPLC was run using an Agilent system, Shimadzu/Sciex LCMS with variable wavelength UV detection using reverse phase chromatography with a CH3CN and water gradient with a 0.02 or 0.1% TFA modifier (added to each solvent). LC-MS was determined using either a PE Sciex Single Quadrupole 150EX LC-MS, or Waters ZQ Single Quadrupole LC-MS or Agilent 1200 series SL (detectors: Agilent 6140 single quadrupole and Agilent 1200 MWD SL) instruments. The compound is analyzed using a reverse phase column, e.g., Thermo Hypersil Gold C18, eluted using a gradient of CH3CN and water with a low percentage of an acid modifier such as 0.02% TFA or 0.1 % formic acid or a base modifier such as 5mM ammonium bicarbonate (adjusted to pH 10 with aqueous ammonia). When specified “acid method” refers to 0.1 % formic acid in water and CH3CN gradient (1.8 min. 0.9 mL/min flow) with a Waters Acquity UPLC HSS C18; 1.8)4,; 2.1x50mm at 50 °C; “basic method” refers to 95:5 H2O+0.1% NH4OH:CH3CN (pH = 9.4) and water gradient (1.8 min. 0.9 mL/min flow) with a Waters Acquity UPLC BEH C18; 1.7p; 2.1x50mm at 50 °C and “overnight basic method” refers to 95:5 H2O+0.1% NFLOH:CH3CN (pH = 9.4) and water gradient (16 min. 0.8 mL/min flow) with a Waters Acquity UPLC BEH C18; 1.7p; 2.1x50mm at 50 °C.

Preparative Chiral SFC was performed using a Thar/W aters Preparative SFC System with single wavelength UV detection system or PDA detector. A variety of chiral SFC columns, e.g. Chiralpak IA, IC, AY, AD. OD, OJ, C2 were used in the purification. The compounds are eluted using supercritical fluid CO2 and co-solvents, such as MeOH, EtOH, IP A, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1 % of TFA, NH4OH, DEA) would be used as needed.

Analytical Chiral SFC was run using a Thar/W aters SFC system with variable wavelength UV detection or PDA detector. A variety of chiral SFC columns, e.g. Chiralpak IA, IB, IC, ID, AY, AD, AS, CCL4 were used in the purification. The compounds are eluted using supercritical fluid CO2 and co-solvents, such as MeOH, EtOH, IPA, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1 % of TFA, NH4OH, DEA) would be used as needed.

Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado. Isolute® is a functionalized silica gel based sorbent, and is a registered trademark of Biotage AB Corp., Sweden. Nuclear magnetic resonance spectra were recorded at 400 MHz using a Bruker AVANCE 400 or Brucker DPX400 or Varian MR400 400 MHz spectrometer. CDCh is deuteriochloroform, DMSO-De is hexadeuteriodimethylsulfoxide, and MeOD is tetradeuteriomethanol, CD2CI2 is deuteriodichloromethane. Chemical shifts are reported in parts per million (5) downfield from the internal standard tetramethylsilane (TMS) or calibrated to the residual proton signal in the NMR solvent (e.g., CHCh in

CDCh). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz.

Heating of reaction mixtures with microwave irradiations was carried out on a Biotage Initiator® or CEM microwave reactor, typically employing the high absorbance setting.

Cartridges or columns containing polymer based functional groups (acid, base, metal chelators, etc) can be used as part of compound workup. The "amine" columns or cartridges are used to neutralize or basify acidic reaction mixtures or products. These include NH2 Aminopropyl SPE-ed SPE Cartridges available from Applied Separations and diethylamino SPE cartridges available from United Chemical Technologies, Inc.

General methods used in examples:

Acidic Method (Analytical)

HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

Eluent A: 0.1% Formic Acid in Water

Eluent B: CH3CN

Flow Rate: 0.9 ml/min

Column: Waters Acquity UPLC HSS C18; 1.8)4,; 2.1x50mm

Column T : 50°C

Capillary voltage: 3000V on ES pos (2700V on ES Neg)

Fr agmentor/Gain : 190 on ES pos (160 on ES neg)

Gain: 1

Drying gas flow: 12.0 L/min

Gas Temperature: 345 °C

Nebulizer Pressure: 60 psig

Scan Range: 125-1000 amu

Ionization Mode: ElectroSpray Positive-Negative switching

Basic Method (Analytical)

HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

Eluent A: 95:5 H2O+0.1% NH4OH:CH3CN (pH = 9.4)

Eluent B: CH ₃ CN

Flow Rate: 0.9 ml/min

Column: Waters Acquity UPLC BEH C18; 1.7p; 2.1x50mm

Column T: 50°C

Capillary voltage: 3000V on ES pos (2700V on ES Neg)

Fr agmentor/Gain: 190 on ES pos (160 on ES neg) Gain: 1

Drying gas flow: 12.0 L/min

Gas Temperature: 345 °C

Nebulizer Pressure: 60 psig

Scan Range: 125-1000 amu

Ionization Mode: ElectroSpray Positive-Negative switching

Overnight Basic Method (Analytical)

HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

Eluent A: 95:5 H2O+0.1% NH4OH:CH3CN (pH = 9.4)

Eluent B: CH ₃ CN

Flow Rate: 0.8 ml/min

Column: Waters Acquity UPLC BEH C18; 1.7p; 2.1x50mm

Column T : 50°C Ionization Mode: ElectroSpray Positive-Negative switching

Intermediate 1

(3S,4/?)-3-Amino-4-hydroxypyrrolidin-2-one, hydrochloride

Step 1: Methyl (2S)-2-(((benzyloxy)carbonyl)amino)-4-(methylsulfinyl)butano ate

To a stirred solution of methyl ((benzyIoxy)carbonyI)-L-methioninate (200 g, 673 mmol) in methanol (2.4 mL) at 0 °C was added a solution of sodium periodate (151 g, 706 mmol) in water (IL) dropwise over 10 min. The resulting mixture was stirred at 0 °C for 1 h, warmed to RT and stirred for an additional 2 h. The resultant white precipitate was removed by filtration under vacuum and the residue was washed with methanol. The filtrate was concentrated under reduced pressure. The resultant colorless oil was partitioned between DCM and water. The aqueous phase was extracted with 2 x DCM. Methanol was added to the combined organic extracts to obtain an homogeneous solution which was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. The oil was purified via normal phase silica gel (0-2% methanol in DCM). The desired fractions were combined, concentrated, and dried to afford the title compound as an off-white solid (66 g, 31% yield). LCMS m/z = 314.0 [M+H] ⁺ .

Step 2: Methyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate A solution of methyl (2 _l S')-2-(((benzyloxy)carbonyl)amino)-4-(methylsulfinyl)b utanoate (66 g, 211 mmol) in diphenyl ether (1300 mL) was heated to 145 °C (bath temp. = 170 °C) for 30 min and then 180 °C (bath temp. = 190 °C) for 4 h. The reaction was subsequently cooled to RT and allowed to stand for 8 h. The reaction contents were poured onto 3 kg silica gel (60-120 mesh) and eluted with petroleum ether (20 L) to remove the diphenyl ether. Elution with 50% ethyl acetate in petroleum ether (2 L) and concentration under reduced pressure afforded an orange oil (40 g) as crude product. The crude product was absorbed onto 150 g silica gel (60-120 mesh) and purified using silica gel chromatography, eluting with 0-15 % ethyl acetate in petroleum ether (90 mins). The product-containing fractions were concentrated under reduced pressure to afford the title compound as a pale, yellow oil (23 g, 43% yield). LCMS m/z = 250.0 [M+H] ⁺ .

Step 3: Methyl (2S)-2-(((benzyloxy)carbonyl)amino)-2-(oxiran-2-yl)acetate

To a solution of methyl ( _l S')-2-(((benzyloxy)carbonyl)amino)but-3-enoate (50 g, 201 mmol) in dichloromethane (DCM) (1000 mL) under an atmosphere of nitrogen at 0 °C was added mCPBA (90 g, 401 mmol) portion-wise over 15 min. The reaction mixture was warmed from 0 °C to 50 °C over 12 h. The reaction mixture was quenched with 10 % aqueous Na2SC>3 solution (1000 mL) and extracted with ethyl acetate (2 x 1000 mL). The combined organic layers were washed with 10 % aqueous sodium bicarbonate solution (100 mL), and brine (1000 mL). The combined organic layers were dried over anhydrous sodium sulfate (200 g) and concentrated under reduced pressure to afford the crude product as a yellow liquid. The crude product was adsorbed onto silica gel (100 g, 60-120 mesh) and purified by silica gel chromatography (330 g column), eluting with 0-30 % ethyl acetate in petroleum ether. The product-containing fractions were collected and concentrated under reduced pressure to provide the title compound as a yellow oil (42 g, 66% yield). LCMS m/~ = 266.0 [M+H] ⁺ . Step 4: Methyl (2S)-4-azido-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoa te

To a solution of methyl (2 _l S')-2-(((benzyloxy)carbonyl)amino)-2-(oxiran-2-yl)acet ate (25 g, 94 mmol) in /V V-di methyl formamide (DMF) (250 mL) under an atmosphere of nitrogen at 0 °C was added ammonia hydrochloride (5.55 g, 104 mmol) and sodium azide (7.35 g, 113 mmol) in one portion over 1 min. The resulting reaction mixture was warmed to 50 °C and stirred for 1 h. Following this duration, the reaction mixture was immediately carried forward to the next step without further purification.

Step 5: Benzyl ((3S,4^)-4-hydroxy-2-oxopyrrolidin-3-yl)carbamate

To the previously-described (see Step 4) solution of methyl (2S')-4-azido-2- (((benzyloxy)carbonyl)amino)-3-hydroxybutanoate (25 g, 81 mmol) in DMF at RT was added triphenylphosphine (23 g, 89 mmol). After 30 min, water (100 mL) was added and the resulting mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was subsequently cooled to RT and concentrated under reduced pressure to afford the crude product. The crude product was absorbed onto silica gel (60-120 mesh, 300 g) and purified by column chromatography (750 g column), eluting with 0-6% methanol in DCM. The product-containing fractions were collected and concentrated under reduced pressure to provide the title compound as an off-white solid (1.5 g, 7% yield). LCMS m/z = 251.2 [M+H] ⁺ .

Step 6: (3.S,4/?)-3-Ainiiio-4-liydroxypyrrolidin-2-one

To a solution of benzyl ((3>S',4R)-4-hydroxy-2-oxopyrrolidin-3-yl)carbamate (18.5 g, 73.9 mmol) in methanol (1200 mL) under an atmosphere of nitrogen at RT was added 20% palladium on carbon (7.87 g, 7.39 mmol) in one portion. An atmosphere of hydrogen was administered by a balloon. The reaction mixture was stirred RT for 12 h, after which it was filtered through a bed of Celite and washed with methanol (500 mL). The filtrate was concentrated under reduced pressure to afford the crude title compound as an off-white solid (8.6 g, 100% yield). LCMS m/z = 117.1 [M+H] ⁺ .

Step 7: (3S,47?)-3-Amino-4-hydroxypyrrolidin-2-one, hydrochloride

To a solution of (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one (8.6 g, 74.1 mmol) in Methanol (200 mL) stirred under nitrogen at 0 °C was added 4 M HCI in dioxane (40 ml, 160 mmol) in dropwise during 5 min. The reaction mixture was stirred at rt for 15 min. The reaction mixture was concentrated under reduced pressure to get crude compound as a off white solid. The solid was triturated with MTBE (2 x 100 mL). The MTBE was subsequently decanted and the residue was concentrated under high vacuum to afford (3>S',4R)-3-amino-4-hydroxypyrrolidin-2-one, hydrochloride (9.6 g, 84% yield) as an off- white solid. LCMS m/z = 117.2 [M+H-HC1] ⁺ .

[a]o = -59 degrees (c = 2.46 mg/mL, MeOH, 22.11 °C)

' H NMR (400 MHz, DMSO-d ₆ ) 5 8.65 (br s, 3H), 8.26 (s, 1H), 5.99 (br s, 1H), 4.36 (q, J = 7.8 Hz, 1H), 3.74 (br d, J= 8.8 Hz, 1H), 3.46 (ddd, J = 9.4, 7.7, 2.0 Hz, 1H), 3.00 (dd, J = 9.3, 7.8 Hz, 1H)

' H NMR (400 MHz, METHANOL-ch) 5 4.59 - 4.26 (m, 1H), 3.88 (d, J = 8.8 Hz, 1H), 3.64 (dd, J= 9.8, 7.8 Hz, 1H), 3.19 (dd, J= 9.8, 7.8 Hz, 1H). Intermediate 2

2,2-dimeth yl-4-oxo-5-(pyridin- 1 -ium- 1 - ylmeth yl)-4H- 1 ,3-dioxin-6-olate

To a solution of 2, 2-dimethyl-l,3-dioxane-4, 6-dione (57.69 g, 1 Eq, 400.3 mmol) in Pyridine (400 mL) was added formaldehyde, 37% aqueous solution (32.7 g, 30.0 mL, 37% Wt, 1.01 Eq, 403 mmol) in one portion. The mixture stirred under nitrogen at room temperature for 2 hours then the mixture was concentrated in vacuo to a light yellow solid. The solids were triturated vigorously with 400 mL 1 : 1 DCM/Heptane using an overhead stirrer. The solids were filtered off and rinsed once with 100 mL 1:1 DCM/Heptane. The solids were air-dried overnight to give the title compound as a light yellow powder (86.1 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) 5 8.91 (br d, J = 5.5 Hz, 2H), 8.51 - 8.34 (m, 1H), 8.10 - 7.86 (m, 2H), 5.33 (br s, 2H), 1.50 (s, 6H).

Example 1 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hvdr oxy-2-oxopyrrolidin-3- vDpropanamide Step 1: l,4-bis(4-fluorophenyl)butane-l, 4-dione

To a solution of 2-bromo-l-(4-fluorophenyl)ethan-l-one (2 g, 9.03 mmol) in N,N- Dimethylformamide (DMF) (14 mL) was added sodium hydroxymethanesulfinate (Rongalite) (1.111 g, 9.03 mmol). The reaction mixture was stirred at room temperature overnight. Water (36 mL) was added, and the light yellow solid was collected via filtration and washed with more water. The solid was dissolved in CHCL and washed with IN NaOH twice, brine, dried over Na2SC>4, filtered, and concentrated under vacuum on rotavap to give a white solid residue, which was purified by silica gel chromatography (0% to 15% EtOAc:Heptane) to give the title compound as a white solid (525 mg, 42% yield). LCMS (ES) m/z = 275 [M+H] ⁺ . ' H NMR (400 MHz, CHLOROFORM-<7) 5 ppm 8.11 - 8.03 (m, 4H), 7.19 - 7.11 (m, 4H), 3.43 (s, 4H).

Step 2: 2,5-bis(4-fluorophenyl)-lH-pyrrole

A mixture of 1 ,4-bis(4-fluorophenyl)butane- 1,4-dione (522 mg, 1.884 mmol) and ammonium acetate (889 mg, 11.31 mmol) in Acetic Acid (12 mL) was heated at 115 °C overnight. Cooled to room temperature, the reaction mixture was poured into ice-water. The off-white precipitate was collected and washed with water and air dried to give the title compound as an off-white solid (456 mg, 93 % yield). LCMS (ES) m/z = 254 [M-H]". ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.23 (br s, 1H), 7.84 - 7.70 (m, 4H), 7.27 - 7.16 (m, 4H), 6.55 (d, J = 2.4 Hz, 2H). Step 3: 2,5-bis(4-fluorophenyl)-3-iodo-lH-pyrrole

To a solution of 2,5-bis(4-fluorophenyl)-lH-pyrrole (452 mg, 1.735 mmol) in N,N- Dimethylformamide (DMF) (12 mL) cooled in an ice/ Acetone bath (-10 °C) was added a solution of N-iodosuccinimide (447 mg, 1.909 mmol) in N,N-Dimethylformamide (DMF) (6 mL) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. The mixture was diluted with EtOAc (75 mL), washed with water, 5% LiCl, brine, and dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a brown viscous oil residue, which was purified by silica gel chromatography (0 to 5% EtOAc :Heptane) to give the title compound as a white solid (466 mg, 70% yield). LCMS (ES) m/z = 382 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.66 (br s, 1H), 7.84 - 7.64 (m, 4H), 7.40 - 7.28 (m, 2H), 7.27 - 7.17 (m, 2H), 6.76 (d, J = 2.4 Hz, 1H).

Step 4: benzyl (E)-3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)acrylate

To a solution of 2,5-bis(4-fluorophenyl)-3-iodo-lH-pyrrole (466 mg, 1.210 mmol) in N,N- Dimethylformamide (DMF) (8 mL) was added benzyl acrylate (0.567 mL, 3.63 mmol), EtsN (0.506 mL, 3.63 mmol) and bis(triphenylphosphine)palladium(II) chloride (87 mg, 0.121 mmol). The reaction mixture was degassed with N2, then heated to 90 °C and stirred at 90 °C overnight. The mixture was cooled to room temperature, filtered through a pad of Celite and concentrated under vacuum on rotavap to give a brown oil, which was purified by silica gel chromatography (0 to 75% DCM: Heptane) to give the title compound as a ,

To a suspension of benzyl (E)-3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)acrylate (369 mg, 0.879 mmol) in Methanol (8 mL) and Ethyl acetate (8 mL) was added Pd/C (Degussa type E101 NE/W, 10% wt loading dry basis) (187 mg, 0.088 mmol). The mixture was degassed under vacuum and stirred under hydrogen balloon for 8 h. LCMS showed (TIC) a major peak with corresponding mass for the desired product. The reaction mixture was degassed under vacuum again and stirred under hydrogen balloon for another 30 minutes. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give a colorless viscous oil. The residue was taken up in EtOAc, dried over Na2SC>4, filtered and concentrated to afford the title compound as an off-white solid (281 mg, 96 % yield).

LCMS (ES) m/z = 328 [M+H] ⁺ . ' H NMR (400 MHz, DMSO-tfc) 5 ppm 12.17 - 11.95 (br s, 1H), 11.06 (br s, 1H), 7.77 - 7.63 (m, 2H), 7.58 - 7.45 (m, 2H), 7.34 - 7.23 (m, 2H), 7.23 - 7.10 (m, 2H), 6.48 (d, J = 2.4 Hz, 1H), 2.84 - 2.71 (m, 2H), 2.56 - 2.51 (m, 2H).

Step 6: 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hydr oxy-2- oxopyrrolidin-3-yl)propanamide

To a solution of 3-(2, 5-bis(4- fluorophenyl)- lH-pyrrol-3-yl)propanoic acid (80 mg, 0.240 mmol) and triethylamine (0.134 mL, 0.958 mmol) in N,N-Dimethylformamide (DMF) (2.5 mL) was added 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate (DMTMMT) (105 mg, 0.311 mmol), and the mixture was stirred at room temperature for 30 minutes, then (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (57.7 mg, 0.359 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL). The combined organic extract was washed with 5% LiCl, brine, dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a light brown viscous oil, which was purified by silica gel chromatography (0 to 50% 3:1 EtOAc/EtOH:Heptane) to give the title compound as an off-white solid (90.2 mg, 84 % yield). LCMS (ES) m/z = 426 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.04 (br d, J = 2.4 Hz, 1H), 8.19 (d, J= 7.8 Hz, 1H), 7.81 - 7.71 (m, 3H), 7.59 - 7.51 (m, 2H), 7.35 - 7.25 (m, 2H), 7.22 - 7.12 (m, 2H), 6.54 (d, J= 2.9 Hz, 1H), 5.47 (d, J= 5.4 Hz, 1H),

4.20 - 4.08 (m, 2H), 3.39 (ddd, J= 9.0, 7.1, 1.5 Hz, 1H), 2.92 (dd, J= 9.3, 6.8 Hz, 1H), 2.79 (dd, J= 9.0, 6.6 Hz, 2H), 2.47 - 2.40 (m, 2H).

The compounds described in Table 1 were prepared analogously to Example 1: Table 1

Example 4 3-(2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S ,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide

And

Step 1: l,4-bis(4-(trifluoromethyl)phenyl)butane-l, 4-dione

To a solution of 2-bromo-l-(4-(trifluoromethyl)phenyl)ethan-l-one (2 g, 7.26 mmol) in N,N-Dimethylformamide (DMF) (8 mL) was added sodium hydroxymethanesulfinate dihydrate (1.296 g, 7.99 mmol). The reaction mixture was stirred at room temperature overnight. Water (20 mL) was added, and the white solid was collected via filtration and washed with more water.

To a solution of 2-bromo-l-(4-(trifluoromethyl)phenyl)ethan-l-one (3 g, 10.90 mmol) in N,N-Dimethylformamide (DMF) (12 mL) was added sodium hydroxymethanesulfinate dihydrate (1.945 g, 11.99 mmol). The reaction mixture was stirred at room temperature for 3 h. Water (30 mL) was added, and the white solid was collected via filtration and washed with more water. The solid was dissolved in DCM, and the solution was combined with the white solid obtained above in DCM, dried over Na2SC>4, filtered, and concentrated under vacuum on rotavap to give a white solid residue, which was purified by silica gel chromatography (0% to 65% DCM:Heptane) to give the title compound as a white solid (1.465 g, 43% overall yield). LCMS (ES) m/z = 375 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- db) 5 ppm 8.27 - 8.15 (m, 4H), 7.93 (d, J = 7.8 Hz, 4H), 3.50 (s, 4H).

Step 2: 2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrole

A mixture of l,4-bis(4-(trifluoromethyl)phenyl)butane- 1,4-dione (1.464 g, 3.72 mmol) and ammonium acetate (1.754 g, 22.30 mmol) in Acetic Acid (25 mL) was heated at 115 °C overnight.

Cooled to room temperature, the reaction mixture was poured into ice-water. The white precipitate was collected and washed with water and air dried to give the title compound as a white solid (1.345 g, 97% yield). LCMS (ES) m/z = 354 [M-H]’. ¹ H NMR (400 MHz, DMSO-A) 5 ppm 11.68 (br s, 1H), 8.02 (d, J = 8.3 Hz, 4H), 7.75 (d, J = 8.3 Hz, 4H), 6.86 (d, 7= 2.4 Hz, 2H).

Step 3: 5-((2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)methyl )-2,2-dimethyl- l,3-dioxane-4, 6-dione

To a solution of 2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrole (180 mg, 0.481 mmol) in Acetonitrile (2.5 mL) cooled in an ice bath at 0 °C was added a solution of 2,2-dimethyl-4- oxo-5-(pyridin-l-ium-l-ylmethyl)-4H-l,3-dioxin-6-olate (119 mg, 0.505 mmol) in Acetonitrile (2.5 mL) dropwise. After the completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. More 2,2-dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4H-l,3-dioxi n-6-olate (56.6 mg, 0.241 mmol) was added, and the reaction mixture was stirred at room temperature overnight. More 2,2-dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4H-l,3-dioxi n-6-olate (56.6 mg, 0.241 mmol) was added, and the reaction mixture was stirred at room temperature for two more days. The reaction mixture was concentrated under vacuum on rotavap to give a yellow viscous oil, which was purified by silica gel chromatography (0 to 40% EtOAc:Heptane) to give the title compound as a light yellow solid (107 mg, 43% yield). LCMS (ES) m/z = 512 [M+H] ⁺ , 510 [M-H]’. ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.52 (br d, J = 1.5 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.85 - 7.77 (m, 4H), 7.72 (d, J = 8.3

Hz, 2H), 6.65 (d, J= 2.9 Hz, 1H), 4.73 (t, J= 5.1 Hz, 1H), 3.31 (d, J= 4.9 Hz, 2H), 1.83 (s, 3H), 1.67 (s, 3H).

Step 4: 3-(2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S ,4R)-4-hydroxy-2- oxopyrroIidin-3-yI)propanamide and 3-(2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrol- 3-yl)propanoic acid

To a solution of 5-((2,5-bis(4-(trifhroromethyl)phenyl)-lH-pyrrol-3-yl)methyl )-2,2- dimethyl-l,3-dioxane-4, 6-dione (106 mg, 0.205 mmol) and (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one hydrochloride (36.3 mg, 0.226 mmol) in N-Methyl-2-pyrrolidone (NMP) (1.2 mL) in a microwave vial was added DIPEA (0.143 mL, 0.821 mmol). The vial was capped and the reaction mixture was stirred at room temperature for 30 minutes, then heated at 120 °C overnight. Cooled to room temperature, water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL). The combined organic extract was washed with 5% LiCl, brine twice, dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a brown viscous oil, which was purified by silica gel chromatography (0 to 50% 3:1 EtOAc/EtOH: Heptane) to give 3-(2,5-bis(4- (trifluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hydrox y-2-oxopyrrolidin-3- yl)propanamide as a light beige solid (60.2 mg, 53 % yield). LCMS (ES) m/z. = 526 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.44 (br d, J = 2.4 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.86 - 7.74 (m, 5H), 7.70 (d, J = 8.3 Hz, 2H), 6.82 (d, J= 2.4 Hz, 1H), 5.46 (d, J= 5.4 Hz, 1H), 4.21 - 4.07 (m, 2H), 3.43 - 3.34 (m, 1H), 2.96 - 2.82 (m, 3H), 2.48 - 2.45 (m, 2H). 3-(2,5-bis(4-(trifhroromethyl)phenyl)-lH-pyrrol- 3-yl)propanoic acid was also isolated as a light brown solid (14.3 mg, 16 % yield). LCMS (ES) m/z = 428 [M+H] ⁺ . ' H NMR (400 MHz, DMSO- ₆ ) 5 ppm 12.15 (br s, 1H), 11.48 (br d, J = 2.4 Hz, 1H), 7.95 (d, J= 8.3 Hz, 2H), 7.86 - 7.76 (m, 4H), 7.72 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 2.9 Hz, 1H), 2.94 - 2.81 (m, 2H), 2.59 (t, J = 7.6 Hz, 2H). The compounds described in Table 2 were prepared analogously to Example 4:

Table 2 3-(2,5-bis(4- 1H NMR (DMSO-d6, 400 J = , 6 8 0 4 = 3 6 8, = Example 9 N-((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)-3-(4-iodo-2,5-dip henyl-1H-pyrrol-3- yl)propanamide

Step 1: 3-iodo-2,5-diphenyl-lH-pyrrole To a solution of 2,5-diphenyl-lH-pyrrole (923 mg, 4.17 mmol) in N,N-

Dimethylformamide (DMF) (30 mL) cooled in an Acetone/Dry ice bath (-60 °C to -50 °C) was added a solution of N-iodosuccinimide (1.074 g, 4.58 mmol) in N,N-

Dimethylformamide (DMF) (15 mL) dropwise. The reaction mixture was allowed to warm up to 0 °C (2 h in total), then stirred for another 30 minutes to 10 °C, followed by another 15 minutes at room temperature. The mixture was diluted with EtOAc (100 mL), washed with water twice, 5% LiCl, brine, and dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a light yellow viscous oil residue, which was purified by silica gel chromatography (0% to 5% EtOAc: Heptane) to give the title compound as a colorless viscous oil (1.20 g, 81 % yield). LCMS (ES) m/z = 346 [M+H] ⁺ . ' H NMR (400 MHz, CHLOROFORM-<7) 5 ppm 8.50 (br s, 1H), 7.75 - 7.63 (m, 2H), 7.54 - 7.32 (m, 7H), 7.26

- 7.21 (m, 1H), 6.72 (d, J = 2.9 Hz, 1H).

Step 2: ethyl (E)-3-(2,5-diphenyl-lH-pyrrol-3-yl)acrylate

To a solution of 3-iodo-2,5-diphenyl-lH-pyrrole (1.20 g, 3.37 mmol) in N,N- Dimethylformamide (DMF) (20 mL) was added ethyl acrylate (1.501 mL, 13.49 mmol), EtsN (1.410 mL, 10.12 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.242 g, 0.337 mmol). The reaction mixture was degassed with N2, then heated to 90 °C and stirred at 90 °C overnight. The mixture was cooled to room temperature, filtered through a pad of Celite, and the filtrate was concentrated under vacuum on rotavap to give a brown oil with some solid, which was purified by silica gel chromatography (0% to 75% DCM:Heptane) to give the title compound as a light yellow foam (700 mg, 65 % yield). LCMS (ES) m/z = 318 [M-H]’. ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.75 (br s, 1H), 7.80 (dd, J= 8.3, 1.0

Hz, 2H), 7.64 - 7.50 (m, 5H), 7.49 - 7.37 (m, 3H), 7.29 - 7.22 (m, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.31 (d, J= 15.7 Hz, 1H), 4.14 (q, J= 7.3 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).

Step 3: ethyl 3-(2,5-diphenyl-lH-pyrrol-3-yl)propanoate

To a solution of ethyl (E)-3-(2,5-diphenyl-lH-pyrrol-3-yl)acrylate (700 mg, 2.183 mmol) in Ethanol (10 mL) and Ethyl acetate (10 mL) was added Pd/C (Degussa type E101 NE/W, 10% wt loading dry basis) (465 mg, 0.218 mmol). The mixture was degassed under vacuum and stirred under hydrogen balloon for 9 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under vacuum on rotavap to give an almost colorless viscous oil, which was purified by silica gel chromatography (0 to 15% EtOAc:Heptane) to give the title compound as a colorless viscous oil (638 mg, 91 % yield). LCMS (ES) m/z = 320 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-tfc) 5 ppm 11.06 (br s, 1H), 7.71 (dd, J= 8.3, 1.0 Hz, 2H), 7.57 - 7.50 (m, 2H), 7.49 - 7.41 (m, 2H), 7.39 - 7.32 (m, 2H), 7.32 - 7.25 (m, 1H), 7.20 - 7.13 (m, 1H), 6.52 (d, J= 2.4 Hz, 1H), 4.05 (q, J= 7.3 Hz, 2H), 2.89 - 2.81 (m, 2H), 2.65 - 2.58 (m, 2H), 1.16 (t, J= 7.1 Hz, 3H).

Step 4: ethyl 3-(4-iodo-2,5-diphenyl-lH-pyrrol-3-yl)propanoate

To a solution of ethyl 3-(2,5-diphenyl-lH-pyrrol-3-yl)propanoate (638 mg, 1.977 mmol) in N,N-Dimethylformamide (DMF) (10 mL) cooled in an ice bath was added a solution of N- iodosuccinimide (533 mg, 2.274 mmol) in N,N-Dimethylformamide (DMF) (5 mL). The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. The mixture was diluted with EtOAc (75 mL), washed with water, 5% LiCl, brine, and dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a dark brown residue, which was purified by silica gel chromatography (0 to 80% DCM:Heptane) to give the title compound as an off-white solid (734 mg, 83 % yield). LCMS (ES) m/z = 444 [M- H]’. ' H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.57 (s, 1H), 7.73 - 7.67 (m, 2H), 7.54 - 7.49 (m, 2H), 7.46 (t, J = 7.8 Hz, 4H), 7.37 - 7.30 (m, 2H), 4.04 (q, J = 7.3 Hz, 2H), 2.87 - 2.78 (m, 2H), 2.58 - 2.52 (m, 2H), 1.22 - 1.13 (m, 3H).

Step 5: 3-(4-iodo-2,5-diphenyl-lH-pyrrol-3-yl)propanoic acid

To a solution of ethyl 3-(4-iodo-2,5-diphenyl-lH-pyrrol-3-yl)propanoate (200 mg, 0.445 mmol) in Methanol (4 mL) and Tetrahydrofuran (THF) (2 mL) was added IN NaOH (1.5 mL, 1.500 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was acidified with IN HC1, and extracted with EtOAc (35 mL x2). The combined organic layer was washed with brine, and dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give the title compound as an off-white solid (192 mg, 100 % yield). LCMS (ES) m/z = 416 [M-H]’. NMR (400 MHz, DMSO-tfc) 5 ppm 12.14 (br s, 1H), 11.56 (s, 1H), 7.75 - 7.64 (m, 2H), 7.56 - 7.38 (m, 6H), 7.37 - 7.25 (m, 2H), 2.84 - 2.70 (m, 2H), 2.49 - 2.41 (m, 2H).

Step 6: N-((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)-3-(4-iodo-2,5-dip henyl-lH- pyrrol-3-yl)propanamide To a solution of 3-(4-iodo-2,5-diphenyl-lH-pyrrol-3-yl)propanoic acid (192 mg, 0.446 mmol) and triethylamine (0.249 mL, 1.785 mmol) in N,N-Dimethylformamide (DMF) (4.5 mL) was added 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate (DMTMMT) (196 mg, 0.580 mmol), and the mixture was stirred at room temperature for 30 minutes, then (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (108 mg, 0.670 mmol) was added. The reaction mixture was stirred at room temperature overnight. More 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4- ium tetrafluoroborate (DMTMMT) (22.65 mg, 0.067 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, then more (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one hydrochloride (14.34 mg, 0.089 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. Water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL). The combined organic extract was washed with 5% LiCl, brine twice, dried over Na2SC>4, filtered and concentrated under vacuum on added, and the mixture was filtered through a pad of Celite. The filtrate was transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (20 mL). The combined organic extract was washed with 5% LiCl, brine twice, dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a brown viscous oil, which was purified by silica gel chromatography (0% to 10% MeOH:DCM) to give the title compound as a brown solid (21.2 mg, 30 % yield). LCMS (ES) m/z = 415 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 12.05 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.6, 1.2 Hz, 2H), 7.75 (s, 1H), 7.65 - 7.47 (m, 6H), 7.46 - 7.34 (m, 2H), 5.49 (d, J = 5.4 Hz, 1H), 4.21 - 4.06 (m, 2H), 3.37 (ddd, J = 9.3, 7.3, 1.5 Hz, 1H), 2.95 - 2.84 (m, 3H), 2.49 - 2.42 (m, 2H).

Example 11

3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)-N-((3 S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide

Step 1: 2,5-diphenyl-3-(trifluoromethyl)-lH-pyrrole

A reaction mixture of 3-iodo-2,5-diphenyl-lH-pyrrole (965 mg, 2.66 mmol), diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (2.192 g, 5.31 mmol) and copper (506 mg, 7.97 mmol) in N,N-Dimethylformamide (DMF) (20 mL) in a microwave vial was capped and heated at 60 °C overnight. Cooled to room temperature, the mixture was diluted with EtOAc, filtered through a pad of Celite. The filtrate was transferred to a separatory funnel, washed with water, 5% LiCl, brine, dried over Na2SC>4, filtered, and concentrated under vacuum on rotavap to give a brown oil residue, which was purified by silica gel chromatography (0% to 10% EtOAc: Heptane) to give the title compound as a yellow oil (644 mg, 76 % yield). LCMS (ES) m/z = 288 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-tfc) 5 ppm 11.99 (br s, 1H), 7.86 - 7.77 (m, 2H), 7.62 - 7.55 (m, 2H), 7.54 - 7.47 (m, 2H), 7.47 - 7.36 (m, 3H), 7.31 - 7.22 (m, 1H), 6.92 (d, J= 2.9 Hz, 1H).

Step 2: 3-iodo-2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrole

To a solution of 2,5-diphenyl-3-(trifluoromethyl)-lH-pyrrole (644 mg, 2.018 mmol) in N,N-Dimethylformamide (DMF) (14 mL) cooled in an ice bath was added a solution of N- iodosuccinimide (520 mg, 2.219 mmol) in N,N-Dimethylformamide (DMF) (7 mL) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 2 h, then heated to 50 °C and stirred at 50 °C overnight. The mixture was diluted with EtOAc (75 mL), washed with water, 5% LiCl, brine, and dried over Na2SO4, filtered and concentrated under vacuum on rotavap to give a brown viscous oil residue, which was purified by silica gel chromatography (0% to 30% DCM:Heptane) to give the title compound as a white solid (754 mg, 87 % yield). LCMS (ES) m/z = 412 [M-H]". ¹ H NMR (400 MHz, DMSO-tfc) 5 ppm 12.29 (s, 1H), 7.71 - 7.61 (m, 2H), 7.55 - 7.36 (m, 8H). Step 3: benzyl (E)-3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)acryl ate

To a solution of 3-iodo-2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrole (752 mg, 1.747 mmol) in N,N-Dimethylformamide (DMF) (12 mL) was added benzyl acrylate (0.818 mL, 5.24 mmol), EtsN (0.731 mL, 5.24 mmol) and bis(triphenylphosphine)palladium(II) chloride (125 mg, 0.175 mmol). The reaction mixture was degassed with N2, then heated to 90 °C and stirred at 90 °C overnight.

The mixture was cooled to room temperature, filtered through a pad of Celite and concentrated under vacuum on rotavap to give a dark brown oil, which was purified by silica gel chromatography (0 to 75% DCM:Heptane) to give the title compound as a light brown foam (706 mg, 88 % yield).

LCMS (ES) m/z = 448 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-tfc) 5 ppm 12.42 (s, 1H), 7.68 (d, J= 16.1 Hz, 1H), 7.58 - 7.43 (m, 10H), 7.42 - 7.29 (m, 5H), 6.09 (dd, J = 16.1, 1.0 Hz, 1H), 5.17 (s, 2H).

Step 4: 3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)propanoic acid

(ETHYLACETATE To a solution of benzyl (E)-3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)acryl ate (702 mg, 1.537 mmol) in Methanol (15 mL) and Ethyl acetate (15 mL) was added Pd/C (Degussa type E101 NE/W, 10% wt loading dry basis) (327 mg, 0.154 mmol). The mixture was degassed under vacuum and stirred under hydrogen balloon for 8 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to give a colorless viscous oil. The residue was taken up in EtOAc, dried over Na2SC>4, filtered and concentrated to give the title compound as an off-white solid (669 mg, 92 % yield). LCMS (ES) m/z = 358 [M-H]’. ' H NMR (400 MHz, DMSO-tfc) 5 ppm 12.22 (br s, 1H), 11.77 (s, 1H), 7.58 - 7.32 (m, 10H), 4.04 (q, J = 6.8 Hz, 2H), 2.91 - 2.81 (m, 2H), 2.49 - 2.41 (m, 2H), 2.00 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H).

Step 6: 3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)-N-((3S,4 R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide To a solution of 3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)propanoic acid (ETHYLACETATE (SOLVATE), 1:1) (125 mg, 0.265 mmol) and triethylamine (0.148 mL, 1.062 mmol) in N,N-Dimethylformamide (DMF) (2.5 mL) was added 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate (DMTMMT) (117 mg, 0.345 mmol), and the mixture was stirred at room temperature for 30 minutes, then (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (63.9 mg, 0.398 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL). The combined organic extract was washed with 5% LiCl, brine twice, dried over Na2SO4, filtered and concentrated under vacuum on rotavap to give a light brown viscous oil, which was purified by silica gel chromatography (0 to 60% 3:1 EtOAc/EtOH:Heptane) to give the title compound as a white solid (98.6 mg, 80 % yield). LCMS (ES) m/z = 456 [M-H]’. ¹ H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.75 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.60 - 7.29 (m, 10H), 5.48 (d, J = 5.9 Hz, 1H), 4.20 - 4.07 (m, 2H), 3.38 (ddd, J = 9.4, 7.5, 1.7 Hz, 1H), 2.95 - 2.81 (m, 3H), 2.46 - 2.38 (m, 2H).

Example 12a

3-(5-(4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-lH-py rrol-3-yl)-N-((3S,4R)-4- hvdroxy-2-oxopyrrolidin-3-yl)propanamide And Example 12b

3-(2-(4-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)-lH-py rrol-3-yl)-N-((3S,4R)-4- hydroxy-2-oxopyrrolidin-3-yl)propanamide Step 1 : l-(4-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)butane-l, 4-dione

Anhydrous zinc chloride (1.510 g, 10.75 mmol) was stirred in Toluene (7 mL), and to this mixture was added diethylamine (1.123 mL, 10.75 mmol) dropwise followed by addition of tert-butanol (1.028 mL, 10.75 mmol). The mixture was stirred at room temperature for 2 h. l-(4-fluorophenyl)ethan-l-one (1 g, 7.17 mmol) and 2-bromo-l-(4- (trifluoromethyl)phenyl)ethan-l-one (2.368 g, 8.60 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for five days. Water and EtOAc were added, the mixture was filtered through a pad of Celite, and the filtrate was transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic extract was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum on rotavap to give a yellow solid, which was purified by silica gel chromatography (0% to 15%

EtOAc :Heptane) to give the title compound as a light yellow solid (1.81 g, 76 % yield). Hz,

A mixture of l-(4-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)butane- 1,4-dione (1.808 g, 5.41 mmol) and ammonium acetate (2.55 g, 32.4 mmol) in Acetic Acid (40 mL) was heated at 115 °C overnight. Cooled to room temperature, the reaction mixture was poured into ice-water. The white precipitate was collected and washed with water and air dried to give the title compound as a beige solid (1.61 g, 94 % yield). LCMS (ES) m/z = 304 [M- H]’. ^J H NMR (400 MHz, DMSO-7 ₆ ) 5 ppm 11.46 (br s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.88

- 7.79 (m, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.32 - 7.21 (m, 2H), 6.83 - 6.75 (m, 1H), 6.63 (dd, 7= 3.4, 2.4 Hz, 1H).

Step 3: 5-((2-(4-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)-lH-pyrr ol-3-yl)methyl)- 2,2

-dimethyl-l,3-dioxane-4, 6-dione and 5-((5-(4-fluorophenyl)-2-(4-

(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)methyl)-2,2-dimet hyl-l,3-dioxane-4, 6-dione

To a solution of 2-(4-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole (400 mg, 1.258 mmol) in Acetonitile (8 mL) cooled in an ice bath at 0 °C was added 2,2-dimethyl- 4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4H-l,3-dioxin-6-olate (355 mg, 1.509 mmol) in portions. After the completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. More 2,2-dimethyl-4-oxo-5- (pyridin-l-ium-l-ylmethyl)-4H-l,3-dioxin-6-olate (74.0 mg, 0.314 mmol) was added, and the reaction mixture was stirred at room temperature for two more days. The reaction mixture was concentrated under vacuum on rotavap to give a brown viscous oil, which was purified by silica gel chromatography (0 to 40% EtOAc: Heptane) to give a mixture of the title compounds as a yellow solid (285 mg, 47 % yield). LCMS (ES) m/z = 462 [M+H] ⁺ . For major isomer, ¹ H NMR (400 MHz, DMSO-7e) 5 ppm 11.38 (br s, 1H), 7.88 - 7.78 (m, 2H), 7.74 - 7.60 (m, 4H), 7.36 - 7.27 (m, 2H), 7.26 - 7.20 (m, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.70 (t, J= 4.9 Hz, 1H), 3.25 (d, J= 4.9 Hz, 2H), 1.83 (s, 3H), 1.67 (s, 3H). Step 4: 3-(5-(4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-lH-pyrro l-3-yl)-N- ((3S,4R)-4-hydroxy-2-oxopyrroIidin-3-yI)propanamide and 3-(2-(4-fluorophenyl)-5- (4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hyd roxy-2-oxopyrrolidin-3-

To a solution of a mixture of 5-((2-(4-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)-lH- pyrrol-3-yl)methyl)-2,2-dimethyl-l,3-dioxane-4, 6-dione and 5-((5-(4-fluorophenyl)-2-(4- (trifluoromethyl)phenyl)-lH-pyrrol-3-yl)methyl)-2,2-dimethyl -l,3-dioxane-4, 6-dione (284 mg, 0.292 mmol) and (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (103 mg, 0.643 mmol) in N-Methyl-2-pyrrolidone (NMP) (3.3 mL) in a microwave vial was added DIPEA (0.409 mL, 2.339 mmol). The vial was capped and the reaction mixture was stirred at room temperature for 30 minutes, then heated at 120 °C overnight. Cooled to room temperature, water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL). The combined organic extract was washed with 5% LiCl, brine twice, dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a brown viscous oil, which was purified by silica gel chromatography (0 to 50% 3:1 EtOAc/EtOH: Heptane) to give a mixture of the title compounds as a yellow solid (188 mg).

The above mixture was further purified using Chiral SFC method (ColumnIG (5p, 4.6 mm x 150 mm), Co-Solvent (40% Ethanol), Temperature (30°C), Flow rate (3 mL/min)) to give 3-(5-(4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-lH-pyrro l-3-yl)-N-((3S,4R)-4- hydroxy-2-oxopyrrolidin-3-yl)propanamide as an off-white solid (13 mg, 9 % yield). LCMS (ES) m/z = 476 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.21 (br d, J = 2.4 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.87 - 7.63 (m, 7H), 7.26 - 7.17 (m, 2H), 6.61 (d, J = 2.4 Hz, 1H), 5.46 (d, J = 5.4 Hz, 1H), 4.21 - 4.07 (m, 2H), 3.43 - 3.36 (m, 1H), 2.97 - 2.82 (m, 3H), 2.48 - 2.43 (m, 2H). 3-(2-(4-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)- lH-pyrrol-3-yl)-N-((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)pr opanamide was also isolated as an off-white solid (113.6 mg, 78 % yield). LCMS (ES) m/z = 476 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) 5 ppm 11.29 (br d, J = 2.0 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.94 (d, J= 8.3 Hz, 2H), 7.75 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.62 - 7.53 (m, 2H), 7.37 - 7.26 (m, 2H), 6.77 (d, J = 2.4 Hz, 1H), 5.46 (d, J = 5.4 Hz, 1H), 4.20 - 4.08 (m, 2H), 3.39 (ddd, J= 9.2, 7.2, 1.7 Hz, 1H), 2.92 (dd, J= 9.3, 6.8 Hz, 1H), 2.80 (t, J= 7.6 Hz, 2H), 2.48 - 2.43 (m, 2H).

Example 13

3-(2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-(( 3S,4R)-4-hvdroxy-2- oxopyrrolidin 3-yl)propanamide

Step 1: 2,5-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrr ole A mixture of IH-pyrrole (0.25 g, 3.73 mmol), fhpim (0.946 g, 3.73 mmol), [Ir (cod) OMe]2 (0.037 g, 0.056 mmol), and 4, 4'-di-tert-butyl-2, 2'-dipyridyl (0.035 g, 0.130 mmol) in tetrahydrofuran (THF) (5.0 mL) was stirred for 18 hours at 80°C. After cooling to the room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic extract was washed with brine (30 mL) and dried over anhydrous MgSCL. It was filtered and the filtrate was concentrated to give the title compound 2, 5-bis(4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrrole (0.88 g, 2.207 mmol, 59.2 % yield) as off white solid used as the intermediate without further purification. ^J H NMR (400 MHz, CDCL) 5 ppm 9.31 (br s, 1 H) 6.86 (d, J= 1.96 Hz, 2 H) 1.34 (s, 24 H).

Step 2: 2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrole

A mixture of 2, 5-bis(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrrole (750 mg, 1.881 mmol), l-bromo-4-(difluoromethyl)benzene (779 mg, 3.76 mmol), tetrakis(triphenylphosphine)palladium(0) (217 mg, 0.188 mmol), and potassium carbonate (780 mg, 5.64 mmol) in 1,4-dioxane (8.0 mL) and water (2 mL) was stirred for 2 hours at 100°C. After cooling to the room temperature, the mixture was diluted with brine (20 mL) and extracted with ethyl acetate (20 mL). The organic extract was washed with brine (20 mL) and dried over anhydrous MgSCL. It was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel eluting with a gradient of 0 to 30% ethyl acetate in heptane to give the title compound (500 mg, 54.1% yield) as light brown solid. LC-MS m/z 320.1 (M+H) ⁺ , 1.30 min (ret. time). ' H NMR (400 MHz, DMSO ) 5 ppm 11.50 (br s, 1 H) 7.93 (d, J=8.31 Hz, 4 H) 7.59 (d, J=8.8O Hz, 4 H) 6.88 - 7.18 (m, 2 H) 6.77 (d, J=2.45 Hz, 2 H). Step 3: 5-((2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrol-3-yl)methyl) -2,2-dimethyl- l,3-dioxane-4, 6-dione

To a solution of 2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrole (0.5 g, 1.566 mmol) in acetonitrile (10 ml) was added 2,2-dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4H-l,3- dioxin-6-olate (0.442 g, 1.879 mmol) portionwise at room temperature. After addition, the mixture was stirred for 2 hours at room temperature. To the mixture was added additional 2,2-dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4H-l,3-dioxi n-6-olate (0.221 g, 0.94 mmol) and stirred overnight at room temperature. To the mixture was added additional 2,2- dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4H-l,3-dioxin-6- olate (0.221 g, 0.94 mmol) and it was stirred overnight. Additional 2,2-dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)- 4H-l,3-dioxin-6-olate (0.221 g, 0.94 mmol) was added and stirred for 3 days at room temperature. The mixture was concentrated and the crude product was purified on the flash column chromatography on silica gel eluting with a gradient of 0 to 40% ethyl acetate in heptane to give the title compound 5-((2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrol-3- yl)methyl)-2,2-dimethyl-l,3-dioxane-4, 6-dione (220 mg, 0.463 mmol, 29.6 % yield) as yellow solid. LC-MS m/z 476.2 (M+H) ⁺ , 0.78 min (ret. time). ^J H NMR (400 MHz, DMSO- d ₆ ) 5 ppm 11.32 - 11.42 (m, 1 H) 7.80 (d, J=8.31 Hz, 2 H) 7.70 - 7.77 (m, 2 H) 7.62 - 7.69 (m, 2 H) 7.56 (d, J=8.31 Hz, 2 H) 6.86 - 7.24 (m, 2 H) 6.56 (d, J=2.45 Hz, 1 H) 4.72 (t, J=5.14 Hz, 1 H) 3.32 (d, J=4.89 Hz, 2 H) 1.84 (s, 3 H) 1.68 (s, 3 H). Step 4: 3-(2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S, 4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide A mixture of 5-((2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrol-3-yl)methyl) -2,2-dimethyl- l,3-dioxane-4, 6-dione (215 mg, 0.452 mmol), (3S,4R)-3-amino-4-hydroxypyrrolidin-2- one, hydrochloride (83 mg, 0.543 mmol) and DIPEA (0.316 mL, 1.809 mmol) in N- methyl-2-pyrrolidone (NMP) (2.5 mL) was stirred for 18 hours at 120°C. After cooling to the room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was concentrated and the crude product was purified by reverse phase HPLC (30-85% acetonitrile: water (10 mM ammonium bicarbonate in H2O adjusted to pH 10 with ammonia), XSELECT CSH C18 column (150mm x 30mm), 40 mL/min, 19 minute gradient) to give the title compound (70 mg, 31.6% yield) as white solid. LC-MS m/z 490.1 (M+H) ⁺ , 0.94 min (ret. time). ' H NMR (400 MHz, DMSO-7e) 8 ppm 11.29 (br d, 7=1.96 Hz, 1 H) 8.21 (d, 7=7.82 Hz, 1 H) 7.90 (d, 7=8.31 Hz, 2 H) 7.76 (s, 1 H) 7.62 - 7.72

(m, 4 H) 7.55 (d, 7=8.31 Hz, 2 H) 6.86 - 7.23 (m, 2 H) 6.74 (d, 7=2.93 Hz, 1 H) 5.47 (d, 7=5.38 Hz, 1 H) 4.06 - 4.21 (m, 2 H) 3.35 - 3.46 (m, 1 H) 2.93 (dd, 7=9.78, 6.85 Hz, 1 H) 2.86 (t, 7=7.83 Hz, 2 H) 2.44 - 2.50 (m, 2 H). Example 14

3-(5-(4-fluorophenyl)-2-(p-tolyl)-lH-pyrrol-3-yl)-N-((3S, 4R)-4-hvdroxy-2- oxopyrroIidin-3-yI)propanamide Step 1: tert-Butyl 2-(4-fluorophenyl)-4-iodo-lH-pyrrole-l-carboxylate

A mixture of 4-fluorobenzoyl chloride (4.73 mL, 40 mmol), tert-butyl prop-2-yn-l- ylcarbamate (6.21 g, 40.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.562 g, 0.800 mmol), copper(I) iodide (0.305 g, 1.600 mmol), and TEA (6.13 mL, 44.0 mmol) in tetrahydrofuran (THF) (100 mL) was stirred for 1 hour at room temperature. To the mixture was then added sodium iodide (30.0 g, 200 mmol), p-toluenesulfonic acid monohydrate (15.22 g, 80 mmol), and tert-butanol (20 mL). The reaction mixture was stirred for 1 hour at room temperature. The mixture was diluted with brine (100 mL) and extracted with ethyl acetate (50 mL). The organic extract was washed with water (2 x 100 mL) and dried over anhydrous MgSCL. It was filtered and the filtrate was concentrated. The crude product was purified on the flash column chromatography on silica gel eluting with a gradient of 0 to 10% ethyl acetate in heptane to give the title compound tert-butyl 2- (4-fluorophenyl)-4-iodo-lH-pyrrole-l-carboxylate (12.5 g, 32.3 mmol, 81 % yield) as white solid. LC-MS m/z 388.0 (M+H) ⁺ , 1.51 min (ret. time). ^T H NMR (400 MHz, DMSO- d ₆ 5 ppm 7.49 (d, J=1.96 Hz, 1 H) 7.34 - 7.43 (m, 2 H) 7.21 (t, J=9.05 Hz, 2 H) 6.38 (d, J=1.96 Hz, 1 H) 1.33 (s, 9 H).

Step 2: tert -Butyl 2-(4-fluorophenyl)-4-(3-methoxy-3-oxopropyl)-lH-pyrrole-l- carboxylate

To a round bottle flask containing tert-butyl 2-(4-fluorophenyl)-4-iodo-lH-pyrrole-l- carboxylate (8.6 g, 22.21 mmol) and RuPhos Pd G3 (0.557 g, 0.666 mmol) (backfilled with N2) was added (3-methoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (133 ml, 66.6 mmol). The mixture was stirred for 5 min at room temperature and the pyrrole was dissolved. The reaction mixture was heated to 60°C and stirred for 2 hours. After cooling to the room temperature, the mixture was poured into ice water and diluted with saturated NH4CI (aq) (100 mL) and ethyl acetate (200 mL). The organic layer was separated and washed with brine (2 x 200 mL). The organics were dried over anhydrous MgSCL and filtered. The filtrate was concentrated and the crude product was purified by the flash column chromatography with a gradient of 0 to 10% ethyl acetate in heptane to give the title compound tert-butyl 2-(4-fluorophenyl)-4-(3-methoxy-3-oxopropyl)-lH-pyrrole-l- carboxylate (6.32 g, 18.19 mmol, 82 % yield) as dark colored oil. LC-MS m/z 348.2 (M+H) ⁺ , 1.34 min (ret. time). ¹ H NMR (400 MHz, DMSO-tfc) 5 ppm 7.35 (dd, J=9.05, 5.62 Hz, 2 H) 7.16 - 7.25 (m, 2 H) 7.08 - 7.16 (m, 1 H) 6.16 (d, J=1.96 Hz, 1 H) 3.61 (s, 3 H) 2.66 (br d, J=5.87 Hz, 2 H) 2.57 - 2.63 (m, 2 H) 1.32 (s, 9 H). Step 3: 3-(l-(ferf-Butoxycarbonyl)-5-(4-fluorophenyl)-lH-pyrrol-3-yl )propanoic acid

To a solution of tert-butyl 2-(4-fluorophenyl)-4-(3-methoxy-3-oxopropyl)-lH-pyrrole-l- carboxylate (6.3 g, 18.14 mmol) in methanol (25 mL) and tetrahydrofuran (THF) (25 mL) was added LiOH (1.303 g, 54.4 mmol) in water (16 mL) slowly at room temperature. After addition, the mixture was stirred for 10 min at room temperature, and then cooled in an ice bath. The mixture was acidified to pH = 5 ~ 6 with 6.0 N HC1 (aq) at 0 °C and then organic solvents were removed. The resulting precipitate was filtered, washed with water and dried to give the title compound as light brown solid used as the intermediate without further purification. LC-MS m/z 334.1 (M+H) ⁺ , 0.75 min (ret. time). ' H NMR (400 MHz, DMSO- d&) 5 ppm 12.11 (br s, 1 H) 7.31 - 7.38 (m, 2 H) 7.15 - 7.23 (m, 2 H) 7.12 - 7.15 (m, 1 H) 6.17 (d, J=1.96 Hz, 1 H) 2.60 - 2.68 (m, 2 H) 2.42 - 2.50 (m, 2 H) 1.32 (s, 9 H). Step 4: tert -Butyl 2-(4-fluorophenyl)-4-(3-(((3S,4R)-4-hydroxy-2-oxopyrrolidin- 3- yl)amino)-3-oxopropyl)-lH-pyrrole-l-carboxylate A mixture of 3-(l-(tert-butoxycarbonyl)-5-(4-fluorophenyl)-lH-pyrrol-3-yl )propanoic acid (5.55 g, 13.32 mmol), (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one, hydrochloride (3.05 g, 19.98 mmol), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate (DMTMMT) (6.55 g, 19.98 mmol) and TEA (8.35 ml, 59.9 mmol) in N,N-dimethylformamide (DMF) (44.4 ml) was stirred for 2 hours at room temperature. It was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic extract was washed with brine (2 x 150 mL) and dried over anhydrous MgSCL. It was filtered and the filtrate was concentrated. The crude product was purified by the flash column chromatography eluting with a gradient of 10% to 65% ethyl acetate/ethanol (3:1) yl)amino)-3-oxopropyl)-lH-pyrrole-l-carboxylate (5.4 g, 12.52 mmol) in tetrahydrofuran (THF) (100 mL) was added NBS (2.228 g, 12.52 mmol) at 0°C. The mixture was stirred for 30 min at 0°C. It was treated with 100 mL of saturated Na2S2Ch (aq) and stirred for 5 min, it was then added brine (100 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with brine (200 mL) and dried over anhydrous MgSCL- It was filtered and the filtrate was concentrated. The crude product was purified by the flash column chromatography on silica gel eluting with a gradient of 20 to 70% ethyl acetate/ethanol (3:1) in heptane to give the title compound tert-butyl 2-bromo-5-(4-fluorophenyl)-3-(3- (((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)amino)-3-oxopropyl) - 1 H-pyrrole- 1 -carboxylate (6.07 g, 11.89 mmol, 95 % yield) as white solid. LC-MS m/z 510.0 (M+H) ⁺ , 0.99 min (ret. time). ^J H NMR (400 MHz, DMSO-tfc) 5 ppm 8.19 (d, J=7.82 Hz, 1 H) 7.75 (s, 1 H) 7.31 - 7.37 (m, 2 H) 7.20 - 7.28 (m, 2 H) 6.36 (s, 1 H) 5.46 (d, J=5.38 Hz, 1 H) 4.06 - 4.19 (m, 2 H) 3.35 - 3.41 (m, 1 H) 2.91 (dd, J=9.29, 6.85 Hz, 1 H) 2.59 - 2.67 (m, 2 H) 2.34 - 2.43 (m, 2 H) 1.31 (s, 9 H).

Step 6: tert- Butyl 5-(4-fluorophenyl)-3-(3-(((3S,4R)-4-hydroxy-2-oxopyrrolidin- 3- yl)amino)-3-oxopropyl)-2-(p-tolyl)-lH-pyrrole-l-carboxylate

A mixture of tert-butyl 2-bromo-5-(4-fluorophenyl)-3-(3-(((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)amino)-3-oxopropyl)-lH-pyrrole-l-carboxyl ate (120 mg, 0.235 mmol), p-tolylboronic acid (38.4 mg, 0.282 mmol), tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol), and potassium carbonate (65.0 mg, 0.470 mmol) in 1,4-dioxane (1.5 mL) and water (0.5 mL) was stirred for 1 hour at 100°C. After cooling to the room temperature, the mixture was diluted with brine (2 mL) and extracted with ethyl acetate (2 mL). The organic extract was dried over anhydrous MgSCL. It was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel eluting with a gradient of 10 to 55% ethyl acetate/ethanol (3:1) in heptane to give the title compound tert-butyl 5-(4-fluorophenyl)-3-(3-(((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)amino)-3-oxopropyl)-2-(p-tolyl)-lH-pyrrol e-l-carboxylate (72 mg, 0.138 mmol, 58.7 % yield) as off white solid. LC-MS m/z 522.2 (M+H) ⁺ , 1.13 min (ret. time). ^J H NMR (400 MHz, DMSO-tfc) 5 ppm 8.12 (d, 7=8.31 Hz, 1 H) 7.74 (s, 1 H) 7.35 - 7.42 (m, 2 H) 7.13 - 7.28 (m, 6 H) 6.31 (s, 1 H) 5.43 (d, 7=5.38 Hz, 1 H) 4.06 - 4.18 (m, 2 H) 3.34 - 3.39 (m, 1 H) 2.90 (dd, 7=9.78, 6.85 Hz, 1 H) 2.43 - 2.49 (m, 2 H) 2.37 (s, 3 H)

A solution of tert-butyl 5-(4-fluorophenyl)-3-(3-(((3S,4R)-4-hydroxy-2-oxopyrrolidin- 3- yl)amino)-3-oxopropyl)-2-(p-tolyl)-lH-pyrrole-l-carboxylate (70 mg, 0.134 mmol) in isopropanol (1.5 mL) was irritated via microwave reactor on normal absorption at 140°C for 2 hours. After cooling to the room temperature, the mixture was concentrated and the crude product was dissolved in DMSO (1.5 mL) and purified on the MDAP (formic acid, extended method C) to give the title compound 3-(5-(4-fluorophenyl)-2-(p-tolyl)-lH- pyrrol-3-yl)-N-((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)propa namide (23 mg, 0.055 mmol, 40.7 % yield) as white solid. LC-MS m/z 422.2 (M+H) ⁺ , 0.90 min (ret. time). ¹ H NMR (400 MHz, DMSO-7 ₆ ) 5 ppm 10.96 (br d, J=2.45 Hz, 1 H) 8.17 (d, J=7.83 Hz, 1 H) 7.71 - 7.79 (m, 3 H) 7.42 (d, J=8.31 Hz, 2 H) 7.26 (d, J=7.82 Hz, 2 H) 7.17 (t, J=9.05 Hz, 2 H) 6.52 (d, J=2.93 Hz, 1 H) 5.46 (d, J=5.38 Hz, 1 H) 4.08 - 4.19 (m, 2 H) 3.36 - 3.41 (m, 1 H) 2.92 (dd, J=9.29, 6.85 Hz, 1 H) 2.80 (dd, J=8.8O, 6.85 Hz, 2 H) 2.40 - 2.45 (m, 2 H) 2.35 (s, 3 H). Table 3 Example LCMS m/z [M+H] ⁺ Structure Name # ¹ H-NMR (400 MHz) ) 5 0 - , 3 2 - 0 , , , ) 2 5 , Example 17 (3S,4R)-3-((3-(2,5-bis(4-fluorophenyl)-1H-pyrrol-3-yl)propyl )amino)-4- hydroxypyrrolidin-2-one

Step 1: ethyl 3-(2,5-bis(4-fluorophenyl)-17Z-pyrrol-3-yl)propanoate A solution of (3-(2,5-bis(4-fluorophenyl)-177-pyrrol-3-yl)propanoic acid) (3 g, 9.17 mmol) and H2SO4 (0.049 mL, 0.917 mmol) in ethanol (61 mL) was heated at 70 °C for 3 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc (125 mL), and the mixture was washed with saturated NaHCCL (50 mL), then saturated NaCl (10 mL). The organic layer was dried (Na2SC>4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (80 g silica), eluting with 0-15% EtOAc:heptane, to give the title compound as a pale pink solid (2.875 g, 84% yield). LCMS (ES) m/z = 356 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-tfc) 5 ppm 11.08 (br d, J = 1.9 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.58 - 7.52 (m, 2H), 7.32 - 7.26 (m, 2H), 7.23 - 7.16 (m, 2H), 6.48 (d, J= 2.9 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 2.84 - 2.78 (m, 2H), 2.63 - 2.57 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H).

Step 2: 3-(2,5-bis(4-fluorophenyl)-17/-pyrrol-3-yl)propanal

To a solution of ethyl 3-(2,5-bis(4-fluorophenyl)-lZ7-pyrrol-3-yl)propanoate (0.5 g, 1.407 mmol) in toluene (17.6 mL) at -78 °C under nitrogen was added diisobutylaluminum hydride (1 M in toluene, 1.913 mL, 1.913 mmol) dropwise. After 2 h at -78 °C, the reaction was quenched with 1 M HC1 (20 mL), slowly at first, then portionwise. The mixture was extracted with EtOAc twice (50 mL, then 25 mL). The combined organic extracts were washed with saturated NaCl (20 mL), dried (Na2SC>4), filtered, and concentrated in vacuo. The crude product was absorbed onto isolute and purified by column chromatography (40 g silica), eluting with 10-25% EtOAc:heptane, to give the title compound as a white solid followed by addition of NaCNBtE (0.042 g, 0.662 mmol). After 40 min, the reaction was concentrated and taken up in DCM (10 mL) and 1 N NaOH (5 mL). A precipitate formed between the two layers. Most of the aqueous layer was removed by pipet. Water (5 mL) was added, and most of the aqueous layer was removed by pipet. Saturated NaCl (5 mL) was added, and the biphasic mixture (containing the precipitate between the two layers) was vacuum filtered. The filter cake was washed with 1:1 DCM:water (4 X 1 mL) to give the title compound as a pale yellow solid (111 mg, 79%). LCMS (ES) m/z = 412 [M+H] ⁺ . ^J H NMR (400 MHz, methanol-cL) 5 ppm 7.67 - 7.61 (m, 2H), 7.55 - 7.49 (m, 2H), 7.19 - 7.12 (m, 2H), 7.11 - 7.04 (m, 2H), 6.45 (s, 1H), 4.26 - 4.19 (m, 1H), 3.54 (dd, J= 7.3, 9.8 Hz, 1H), 3.24 (d, J= 6.9 Hz, 1H), 3.05 (dd, J= 6.4, 9.8 Hz, 1H), 2.90 - 2.80 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.93 - 1.84 (m, 2H).

The compound described in Table 4 was prepared analogously to Example 17:

Table 4

Example 19 (H,3S)-3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((3R,4S) -4-hydroxy-2- oxopyrrolidin-3-yl)cvclobutane-l-carboxamide

Step 1: 2,5-bis(4-fluorophenyl)-1H-pyrrole A solution of 4-(4-fluoro 2.258 mmol), (4- fluorophenyl)boronic acid (632 mg, 4.52 mmol), and zinc chloride (615 mg, 4.52 mmol) in THF (15 mL) was bubbled by nitrogen for 5 min before the addition of Ni(dppe)Cl ₂ (120 mg, 0.226 mmol). The reaction mixture was stirred at 100 °C overnight. The mixture was diluted with EtOAc and washed with NaHCO ₃ and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (40 g silica), eluting with 0-100% EtOAc:heptane, to give the title compound (500 mg, 87%). LCMS (ES) m/z = 254 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.29 - 11.18 (m, 1H), 7.78 (dd, J = 5.4, 9.3 Hz, 4H), 7.22 (t, J = 9.0 Hz, 4H), 6.55 (d, J = 2.4 Hz, 2H).

Step 2: 3-(2,5-bis(4-fluorophenyl )-l/7-pyrrol-3-yl)cyclobutane-l-carboxylic acid

To a solution of 2,5-bis(4-fluorophenyl)-l //-pyrrole (500 mg, 1.959 mmol), 3- oxocyclobutane- 1 -carboxylic acid (246 mg, 2.155 mmol), and triethylsilane (1.564 mL, 9.79 mmol) in DCM (10 mL) was slowly added TFA (0.9 mL, 9.79 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with EtOAc and washed with NaHC'CL and brine. The organic layer was dried (MgSCL), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (40 g silica), eluting with 0-100% EtOAc:heptane, to give the title compound (470 mg, 68%). LCMS (ES) m/z = 354 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-d _d ) 5 ppm 12.06 (s, 1H), 11.11 - 10.99 (m, 1H), 7.87 - 7.69 (m, 2H), 7.55 - 7.38 (m, 2H), 7.31 - 7.24 (m, 2H), 7.19 (br d, J= 4.4 Hz, 2H), 6.76 - 6.59 (m, 1H), 3.64 - 3.52 (m, 1H), 3.43 - 3.33 (m, 1H), 3.16 - 3.06 (m, 1H), 3.02 - 2.91 (m, 1H), 2.37 - 2.28 (m, 1H), 2.26 - 2.17 (m, 1H).

Step 3: 3-(2,5-bis(4-fluorophenyl)-l/7-pyrrol-3-yl)-iV-((3/f,4S)-4-h ydroxy-2- oxopyrrolidin-3-yl)cyclobutane-l-carboxamide To a solution of 3-(2,5-bis(4-fluorophenyl)-177-pyrrol-3-yl)cyclobutane-l -carboxylic acid (200 mg, 0.566 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (119 mg, 0.679 mmol) in DMF (5 mL) was added /V-mcthylmorpholinc (0.187 mL, 1.698 mmol) and (32?,4S)-3- amino-4-hydroxypyrrolidin-2-one, hydrochloride (104 mg, 0.679 mmol). The reaction mixture was stirred at rt for 1 h. The crude product mixture was purified by MDAP system, using XS ELECT CSH Cl 8 column (150 mm X 30 mm i.d. 5 pm packing diameter at ambient temperature), eluting with 30-85% McCN/lLO/O.1 % formic acid, to provide the title compound (160 mg, 63%). LCMS (ES) m/z = 452 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-d _d ) 5 ppm 11.13 - 10.99 (m, 1H), 8.04 - 7.94 (m, 1H), 7.86 - 7.66 (m, 3H), 7.52 - 7.40 (m, 2H), 7.28 (s, 2H), 7.20 (s, 2H), 6.78 - 6.58 (m, 1H), 5.75 (s, 1H), 5.45 (dd, J= 1.7, 5.6 Hz, 1H), 4.22 - 4.14 (m, 1H), 4.13 - 4.05 (m, 1H), 3.67 - 3.56 (m, 1H), 3.43 - 3.36 (m, 1H), 3.16 - 3.07 (m, 1H), 2.96 - 2.88 (m, 1H), 2.44 - 2.35 (m, 1H), 2.25 (br s, 2H).

Step 4: ( ls,3.S)-3-(2,5-bis(4-fluoroplieiiyl)-l//-pyrrol-3-yl)-A-((3/ ?,4.S)-4-hydro\y-2- oxopyrrolidin-3-yl)cyclobutane-l-carboxamide

3-(2,5-bis(4-fluorophenyl)-177-pyrrol-3-yl)-A-((37?,4 _l S')-4-hydroxy-2-oxopyrrolidin-3- yl)cyclobutane- 1 -carboxamide (150 mg) was subjected to chiral HPLC purification, using a Chiralpak IC column (5p, 20 mm X 250 mm) and isocratic 85:15 heptane :ethanol with 50 mM ammonium acetate. The temperature was ambient and the flow rate was 20 mL/min. Sample concentration was 10 mg/mL and the injection volume was 1 mL. The first eluting isomer was concentrated in vacuo and lyophilized to give the title compound (47.7 mg, 32%). Analytical chiral HPLC: >99% chiral purity. LCMS (ES) m/z = 452 [M+H] ⁺ . ' H NMR (400 MHz, DMSO-d<s) 5 ppm 11.10 - 11.00 (m, 1H), 8.06 - 7.92 (m, 1H), 7.80 - 7.74 (m, 2H), 7.73 - 7.68 (m, 1H), 7.51 - 7.45 (m, 2H), 7.32 - 7.23 (m, 2H), 7.18 (s, 2H), 6.62 - 6.58 (m, 1H), 5.46 - 5.42 (m, 1H), 4.21 - 4.13 (m, 1H), 4.07 (s, 1H), 3.41 - 3.33 (m, 2H), 2.99 - 2.87 (m, 2H), 2.45 - 2.36 (m, 2H), 2.28 - 2.19 (m, 2H).

The compounds described in Table 5 were prepared analogously to Example 19:

Table 5

Example 27 -(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((3R,4S)-4-hydro xy-2-oxopyrrolidin-3- yl)propanamide

Step 1: 2,5-dioxopyrrolidin-l-yl 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)propanoate

Under N2 atmosphere, 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)propanoic acid (5 g, 15.28 mmol) was suspended in Dichloromethane (DCM) (150mL). TEA (8.52 mL, 61.1 mmol) followed by bis(2,5-dioxopyrrolidin-l-yl) carbonate (8.61 g, 33.6 mmol) was added. The cloudy suspension stirred 2h at 25°C. The suspension became less cloudy was complete after 2h.

Beige solid that had precipitated (NHS byproduct) was filtered and the filtrate concentrated in vacuo. The resulting clear brown gum was redissolved in EtOAc and washed with saturated aqueous bicarbonate solution twice, dried over Na2SO4, concentrated in vacuo, chased with DCM twice and put on high vacuum 24h.

To provide the title compound as a beige solid (7.4 g, 17.44 mmol, 114 % yield). LCMS (ES) m/z = 425.2 [M+H] ^{+ J} H NMR (400 MHz, DMSCW6) 5 ppm 2.82 (s, 4 H) 2.87 - 2.93 (m, 2 H) 2.96 - 3.02 (m, 2 H) 6.61 (d, 7=2.45 Hz, 1 H) 7.15 - 7.24 (m, 2 H) 7.25 -7.33 (m,

2 H) 7.50 - 7.58 (m, 2 H) 7.70 - 7.76 (m, 2 H) 11.14 (br d, 7=1.96 Hz, 1 H). General array procedure for Examples 27-38

A stock solution of 2,5-dioxopyrrolidin-l-yl 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3- yl)propanoate (0.100 g, 0.2 mmol, per 1 mL) in DCM was prepared and dispensed via multipipette into 4 mL vials each containing 0.2 mmol of a building block amine. TEA (0.112 mL, 0.800 mmol) was dispensing via multipipette in each vial. The reactions stirred at 25 °C for 24 h. All samples were dried on N2 drying unit for 1 h.

Products containing BOC protected amines were treated with 1 mL 4 M HC1 in dioxane, vented and stirred 90 min. These were dried on N2 drying unit for 3h.

All dried samples were dissolved in 1 mL DMSO, filtered through 0.5 um filter block and purified via Waters MDAP or Teledyne ISCO ACCQPrep HP150 HPLC utilizing various gradients with acidic or basic modifiers.

Step 2: 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((3R,4S)-4-hydr oxy-2- oxopyrrolidin-3-yl)propanamide

The crude material was purified on MDAP HPLC (Phenomenex Gemini C 18, 50 x 30 mm, 5um column, 25-65% gradient acetonitrile/water with 0.1% formic Acid, 40 mL/min flow rate, 22 min run time).

Title compound resulted as a white solid (38.0 mg, 0.089 mmol, 44.7 % yield). LCMS (ES) m/z = 426 [M+H] ^{+ 1} H NMR (400 MHz, DMSCW6) 5 ppm 2.43 (dd, 7=9.05, 6.60 Hz, 2 H) 2.78 (t, 7=7.83 Hz, 2 H) 2.91 (dd, 7=9.54, 6.60 Hz, 1 H) 3.32 (s, 1 H) 3.38 (ddd, 7=9.17, 7.46, 1.47 Hz, 1 H) 4.07 - 4.18 (m, 2 H) 5.45 (d, 7=5.38 Hz, 1 H) 6.53 (d, 7=2.45 Hz, 1 H) 7.14 - 7.21 (m, 2 H) 7.24 - 7.32 (m, 2 H) 7.51 - 7.58 (m, 2 H) 7.73 - 7.77 (m, 2 H) 8.17 (d, 7=7.82 Hz, 1 H) 11.03 (br d, 7=1.96 Hz, 1 H).

The compounds described in Table 6 were prepared analogously to Example 27:

Table 6

Example 39 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-(2-oxocyclopent yl)propanamide

The crude material prepared analogously to Examples 28-38, differing only in the purification method. Here, Example 39 was purified on a Teledyne ISCO ACCQPrep HP150 HPLC (CSH XSelect column, 30 x 75 mm, 5 um) 40-70% gradient acetonitrile/water with 0.1% formic Acid, 45 mL/min flow rate, 10 min run time). Title compound resulted as a white solid (31.7 mg, 0.078 mmol, 33.4 % yield). LCMS (ES) m/z = 409 [M+H] ⁺ ' H NMR (400 MHz, METHANOL-74) 5 ppm 1.72 - 1.90 (m, 2 H) 2.00 - 2.09 (m, 1 H) 2.17 - 2.38 (m, 3 H) 2.48 - 2.60 (m, 2 H) 2.87 - 2.93 (m, 2 H) 4.09 (dd, 7=10.76, 8.31 Hz, 1 H) 6.43 - 6.46 (m, 1 H) 7.02 - 7.09 (m, 2 H) 7.11 - 7.17 (m, 2 H) 7.47 - 7.53 (m, 2 H) 7.59 - 7.66 (m, 2 H) 10.52 (br s,l H). The compounds described in Table 7 were prepared and purified analogously to Example 39:

Example 49

3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((2S,3S)-l,3 -dihydroxybutan-2- yl)propanamide

The crude material was prepared analogously to Examples 27-39, differing only in the purification method. Here, Example 49 was purified on a Teledyne ISCO ACCQPrep HP150 HPLC, XBridge (30 x 75 mm, 5 um column), 30-60% gradient, acetonitrile/ lOmM

Ammonium Bicarb and 0.075% Ammonium Hydroxide (adjusted to pH=10), 45 mL/min flow rate, 10 min run time.

Title compound resulted as a white solid (11.7 mg, 0.028 mmol, 10.7 % yield). LCMS (ES) m/z = 415 [M+H] ⁺ 'H NMR (400 MHz, METHANOL-74) 5 ppm 1.04 (d, 7=6.36 Hz, 3 H) 2.53 - 2.60 (m, 2 H) 2.89 - 2.96 (m, 2 H) 3.48 - 3.54 (m, 1 H) 3.57 - 3.62 (m,1 H) 3.80 (td, J=6.24, 3.18 Hz, 1 H) 3.96 (qd, J=6.36, 2.93 Hz, 1 H) 6.44 (s, 1 H) 7.02 - 7.09 (m, 2 H) 7.11 - 7.17 (m, 2 H) 7.48 - 7.55 (m, 2 H) 7.58- 7.65 (m, 2 H). Example 50 3-(2,5-Bis(4-fluorophenyl)-4-methyl-1H-pyrrol-3-yl)-N-((3S,4 R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide Step 1: 1-(4-Fluorophenyl)propan-1-one O-(4-nitrobenzoyl) NO ₂ To a 1 L Optimax reactor at 25 °C was charged 1-(4-fluorophenyl)propan-1-one (50 g, 328.6 mmol, 1 equiv), hydroxylamine HCl (27.4 g, 394.3 mmol, 1.2 equiv), ammonium acetate (30.393 g, 394.3 mmol, 1.2 equiv), and MeOH (375 mL, 7.5 V). The reaction was heated to 60 °C and stirred overnight. Upon completion, the reaction mixture was cooled to 20 °C, and the solvent was swapped to DCM (250 mL, 5 V). Then water (250 mL, 5 vol) was added. The mixture was stirred for 10 min. Stirring was stopped, and the layers were allowed to separate. The DCM layer was collected, and the remaining aqueous layer was extracted with additional DCM (250 mL, 5 V). The combined DCM layers were dried over anhydrous MgSCL. concentrated, reconstituted in 500 mL DCM, then and charged back into the cleaned OptiMax reactor. The temperature was adjusted to 10 °C. Then triethylamine (49.874 g, 68.697 mL, 492.9 mmol, 1.5 equiv) was added. p-Nitrobenzoyl chloride was added portion-wise as a solid over approximately 10 minutes to keep the reaction temperature below 25 °C. After equilibration, the reaction temperature was set to 25 °C, and the reaction mixture was stirred overnight.

Upon completion, a NaHCCh solution (250 mL, 5 V, 10wt% aqueous) was charged to the reactor, and the mixture was stirred for 30 minutes at 25 °C. The aqueous layer was removed, and the organic layer was dried over anhydrous MgSCL, filtered, and concentrated to dryness. The resulting off-white solid was redissolved in hot EtOH (500 mL, 10 V) at 80 °C. Upon clarifying, the solution was held at 80 °C for 30 minutes and then cooled to 20 °C over 3 hours. The mixture was aged overnight.

The resulting white solids were collected via filtration and washed with EtOH (2 X 100 mL, 2 V). The solids were dried in a vacuum oven overnight. The title compound was oxopentanoate (50 g, 208.9 mmol, 1 equiv) and acetonitrile (400 mL, 8 V). Then sodium iodide (47.184 g, 314.8 mmol, 1.5 equiv) was charged to the reactor, and the mixture was stirred for approximately 15 minutes until all of the sodium iodide dissolved.

Triethylamine (31.854 g, 43.876 mL, 314.8 mmol, 1.5 equiv) was added next followed by chlorotrimethylsilane (34.198 g, 39.951 mL, 314.8 mmol, 1.5 equiv). The reaction was stirred at 25 °C overnight.

Upon completion, hexane (500 mL, 10 V) was added, and the resulting mixture was stirred for 15 minutes. The acetonitrile layer was separated and extracted two more times with hexane (500 mL, 10 V). The combined hexane layers were dried with anhydrous MgSCL, filtered and concentrated to give the title compound as a yellow oil which was used crude )

In a 250 mL Optimax reactor under N2 at 25 °C was charged (Z)-[l-(4- fluorophenyl)propylidene] amino 4-nitrobenzoate (10 g, 31.617 mmol, 1 equiv) and acetonitrile (50 mL, 5 V), and the reaction mixture was stirred at 150 RPM. Ethyl (4E)-5- (4-fluorophenyl)-5-[(trimethylsilyl)oxy]pent-4-enoate (24.538 g, 79.042 mmol, 2.5 equiv) was charged neat. The reaction mixture was aged for 5 min, and then ferrous chloride (2.004 g, 15.808 mmol, 0.5 equiv) was charged. The reaction was heated to 50 °C and stirred overnight.

Upon completion, The reaction mixture was cooled to room temperature, and the solvent was swapped to EtOAc (100 mL, 10 V). Then a K2CO3 solution (100 mL, 10 V, 20 wt% aqueous) was charged, and the mixture was stirred at 300 RPM for 15 min. Stirring was stopped, and the layers were allowed to separate for 15 min. The top organic layer was a clear orange solution, and the bottom aqueous layer was dark red slurry. The organic layer solvent was swapped from EtOAc to THF (37.5mL, 5 V) and used directly in the hydrolysis.

In a 250 mL OptiMax reactor under N2 at 25 °C was charged the ethyl 3-[2,5-bis(4- fluorophenyl)-4-methyl-l//-pyrrol-3-yl]propanoate solution. A lithium hydroxide solution (73 mL, 2.5 M aqueous) was charged to the reactor. A slight endotherm was observed, and two layers formed. The mixture was heated to 55 °C. After 2 hours, the reaction was complete, and one clear, homogenous layer was observed. The reaction was cooled to 25 °C. Then TBME (19 mL, 2.5 V) and a LiCl solution (37 mL, 5 V, 3 M aqueous) were charged to the reactor. The mixture was stirred for 15 min at 250 RPM and then held for 10 minutes for layer separation. The aqueous layer was removed. Additional TBME (56 mL, 7.5V) was added, and the organic layer was washed sequentially with NH4CI (75 mL, 10 V, 20wt% aqueous), NH4CI (2 X 75 mL, 10 V, 5wt% aqueous), and NaHSCL (75 mL, 10 V, 1 M aqueous). The organic layer was azeotroped dry twice with TBME. The resulting oil was diluted with TBME (75 mL, 10V).

Dicyclohexylamine (4.417 g, 24.363 mmol, 1.2 equiv) was charged dropwise over 3 minutes. The solution turned from red to light yellow after a few drops. Solids formed

Step 4: 3-(2,5-Bis(4-fluorophenvI)-4-methvI-lH-pyrroI-3-vI)-N-((3S,4 R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide

To a 50 mL EasyMax reactor purged with N2 at 25 °C was charged dicyclohexylammonium 3-[2,5-bis(4-fluorophenyl)-4-methyl-l//-pyrrol-3-yl]propanoa te (5 g, 9.566 mmol, 1 equiv), (35, 4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (1.752 g, 11.479 mmol, 1.2 equiv), N-Ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (3.075 g, 12.436 mmol, 1.3 equiv) and 2-MeTHF (25 mL, 0.383 M, 5 V). The reaction mixture was stirred at 200RPM, and then /V-Ethyldiisopropylamiiic (1.607 g, 2.172 mL, 0.74 g/mL, 12.436 mmol, 1.3 equiv) was charged. The reaction was heated to 60 °C and stirred at 250RPM for 16 hours.

Upon completion, the reaction was cooled to 50 °C, and DI water (25 mL, 5 V) was charged. The mixture was stirred at 350RPM for 15 min. The layers were separated, and the organic layer was washed with additional DI water (25 mL, 5 V) Note: Ensured DCHA was fully purged. The organic layer was azeotropically dried and brought to 5 V (25 mL) of MeTHF. The mixture was reheated to 50 °C and stirred at 300 RPM. Heptane (25 mL, 5 V) was charged over 1 hour. By end of addition a thick slurry was obtained and stirring was increased to 600 RPM. The slurry was cooled to 20 °C and aged for 1 hour. The solids were filtered and washed with heptane (25 mL, 5 V). The solids were dried in a vacuum oven. The title compound was isolated as a white solid (3.55 g, 8.078 mmol, 84% yield). ' H NMR (400 MHz, DMSO-d(5) 5 ppm 10.81 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.75 (br s, 1H), 7.59 - 7.49 (m, 4H), 7.30 - 7.20 (m, 4H), 5.48 (d, J= 4.0 Hz, 1H), 4.20 - 4.05 (m, 2H), 3.43 - 3.35 (m, 1H), 2.92 (dd, J = 8.0 Hz, 8.0 Hz, 1H), 2.80 - 2.70 (m, 2H) 2.39 - 2.31 (m, 2H) 2.14 (s, 3H). Example 51 3-(2-(4-Fluorophenyl)-5-(2,4'6-trifluorophenyl)-lZZ-pyrrol-3 -yl)-A ^f -((3S,4/?)-4-

Step 1: l-(4-Fluorophenyl)-4-(2,4,6-trifluorophenyl)butane-l,4-dione

3-Chloro-l-(4-fluorophenyl)propan-l-one (5 g, 26.794 mmol, 1 equiv) and DMF (25 mL, 5 vol.) were charged to a 100 mL EasyMax reactor. The mixture is stirred at 25 °C under nitrogen. Triethylamine (3.254 g, 4.482 mL, 0.726 g/mL, 32.153 mmol, 1.2 equiv) was charged to the reactor. The mixture was stirred for 2 h. 3-Benzyl-5-(2-hydroxyethyl)-4- methyl-l,3-thiazol-3-ium chloride (1.084 g, 4.019 mmol, 0.15 equiv) was charged to the reactor. The reaction mixture was cooled to 7 °C. A solution of 2,4,6- trifluorobenzaldehyde (5.147 g, 32.153 mmol, 1.2 equiv) in DMF (15 mL, 3 vol.) was charged over approximately 1.5 h. The mixture was stirred for 65 h. The reaction mixture was warmed to 20 °C. Water (20 ml, 4 vol.) was charged to the reaction mixture over 40 minutes and stirred for 2 h. Water (15 ml, 3 vol.) was charged to the reaction mixture over 20 minutes and stirred for 1 h. The slurry was filtered, and the wet cake was washed with DMF/Water (2:1, 2 x 3 vol.) and water (2 x 3 vol.). The wet cake was air-dried overnight and dried under high vacuum at 40 °C for 6 days to give the title compound as a light yellow solid (7.86 g, 94.6%). LCMS (ES) m/z = 311 [M+H] ⁺ . ^T H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.08 - 8.00 (m, 2H), 7.19 - 7.10 (m, 2H), 6.79 - 6.69 (m, 2H), 3.46 - 3.39 (m, 2H), 3.34 - 3.26 (m, 2H).

Step 2: 2-(4-Fhioroplieiiyl)-5-(2,4,6-trifhioroi)henyl )-!//- pyrrole l-(4-Fluorophenyl)-4-(2, 4, 6-trifluorophenyl)butane- 1,4-dione (5 g, 16.1 mmol, 1 equiv), ammonium acetate (2.46 g, 32.2 mmol, 2 eq.) and IPA (25 mL, 5 vol.) were charged to a 100 mL EasyMax reactor. The reaction mixture was heated to 95 °C for 18 h. Additional ammonium acetate (1.23 g, 16.1 mmol, 1 eq.) was charged to the reactor and heated to 95 °C for 4 h. The reaction mixture was cooled to 35 °C. Water (35 mL, 7 vol.) was charged to the reaction mixture over 2 h and stirred for 1 h. The slurry was filtered, and the wet cake was washed with IPAAVater (5:7, 2 x 4 vol., 2 x 20 mL) and water (2 x 4 vol., 2 x 20 mL). The wet cake was dried under high vacuum at 35 °C for 16 h to give the title compound as a solid (4.43 g, 94.5%) LCMS (ES) m/z = 292 [M+H] ⁺ . ^J H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.24 (br s, 1H), 7.69 - 7.61 (m, 2H), 7.30 - 7.21 (m, 2H), 7.03

Meldrum's acid (1.237 g, 8.584 mmol, 1.25 equiv.) and IPA (10 mL, 5 vol.) were charged to a 40 mL scintillation vial followed by pyridine (0.679 g, 0.693 mL, 0.98 g/mL, 8.584 mmol, 1.25 equiv) and 37% aqueous formaldehyde (0.258 g, 0.697 mL, 37 w/v %, 8.584 mmol, 1.25 equiv). The reaction mixture was stirred under nitrogen at 20 °C. 2-(4-Fluorophenyl)-5-(2,4,6-trifluorophenyl)-177-pyrrole (2 g, 6.867 mmol, 1 equiv) and IPA (18 mL, 9 vol.) were charged to a separate 40 mL scintillation vial. The reaction mixture was stirred (600 rpm) at 20 °C. A thick slurry formed. Approximately 2/3 of the z'n-sz'tM-prepared Meldrum's acid adduct (yellow solution) was charged over 10 minutes. The mixture turned into a free-flowing slurry and stirred for 30 minutes. The remaining in- sz'tM-prepared Meldrum's acid adduct solution was charged over 30 minutes and stirred for 66 h. The slurry was filtered, and the wet cake was washed with IPA (1 x 3 vol., 1 x 3 mL and 1 x 2 vol., 1 x 2 mL). The wet cake was dried under high vacuum at 40 °C for 23 h to give the title compound as an off-white solid (2.25 g, 73.4%). LCMS (ES) m/z = 448

A mixture of 5-((2-(4-fluorophenyl)-5-(2,4,6-trifluorophenyl)-177-pyrrol- 3-yl)methyl)-2,2- dimethyl-l,3-dioxane-4, 6-dione (40.8 g, 1 equiv, 91.2 mmol), pyridine (350 mL) and water (35 mL) was heated at 90 °C under a nitrogen atmosphere for 8 hours. After cooling, the reaction mixture was diluted with diethyl ether and concentrated under reduced pressure. Diethyl ether was added to the residue and the mixture was concentrated again under reduced pressure. The resulting oil solidified upon standing. The solids were broken up and stirred vigorously with 500 mL IN HC1 to give a suspension. The solids were isolated by filtration, rinsed multiple times with water and dried to give 3-(2-(4-fluorophenyl)-5- (2,4,6-trifluorophenyl)-177-pyrrol-3-yl)propanoic acid as a tan powder (33.3 g , 100% yield). LCMS (ES) m/z = 364 [M+H] ⁺ , 362 [M-H]’. ¹ H NMR (400 MHz, CHLOROFORM- d) 5 ppm 8.81 (br d, J = 4.9 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.18 - 7.12 (m, 2H), 6.82 - 6.72 (m, 3H), 3.02 - 2.96 (m, 2H), 2.72 - 2.67 (m, 2H). Step 5: 3-(2-(4-Fluorophenyl)-5-(2,4,6-trifluorophenyl)-1H-pyrrol-3- yl)-N-((3S,4R)-4- hydroxy-2-oxopyrrolidin-3-yl)propanamide A mixture of 3-(2-(4-fluo 1H-pyrrol-3-yl)propanoic acid (33.3 g, 1 equiv, 91.6 mmol), (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one, Hydrochloride (15.5 g, 1.1 equiv, 101.3 mmol) and DIPEA (29.7 g, 40.0 mL, 2.5 equiv, 230 mmol) in DCM (600 mL) under nitrogen was treated with DMTMMT (33.1 g, 1.1 equiv, 101.0 mmol). After 17 hours the reaction mixture was quenched with 600 mL water. After stirring vigorously for several minutes, the resulting pasty solids were isolated by filtration, rinsed with excess water and approximately 300 mL DCM. The solids were dried to give 3-(2-(4-fluorophenyl)-5-(2,4,6-trifluorophenyl)-1H-pyrrol-3- yl)-N-((3S,4R)-4- hydroxy-2-oxopyrrolidin-3-yl)propanamide as a cream-colored powder (37.2 g, 88% yield). LCMS (ES) m/z = 462 [M+H] ⁺ , 460 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (br d, J = 1.5 Hz, 1H), 8.15 (d, J = 7.3 Hz, 1H), 7.72 (s, 1H), 7.56 – 7.50 (m, 2H), 7.33 – 7.24 (m, 4H), 6.36 (s, 1H), 5.44 (d, J = 5.4 Hz, 1H), 4.16 – 4.04 (m, 2H), 3.40 – 3.34 (m, 1H), 2.90 (dd, J = 9.3, 6.8 Hz, 1H), 2.84 – 2.77 (m, 2H), 2.47 – 2.40 (m, 2H). Example 52 3-(2-(4-Fluorophenyl)-5-(1-(trifluoromethyl)cyclopropyl)-1H- pyrrol-3-yl)-N-((3S,4R)- 4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

Step 1: 3-[Methoxy(methyl)amino]-l-[l-(trifluoromethyl)cyclopropyl]p ropan-l-one

To a 250 mL OptiMax reactor under N2 at 25 °C was added N-methoxy-N-methyl-1- (trifluoromethyl)cyclopropane-l -carboxamide (10 g, 50.721 mmol, 1.0 equiv) and THF (100 mL, 10 V). The solution was cooled to -20 °C. Then a vinylmagnesium bromide solution in THF (76.1 mL, 76.1 mmol, 1 M, 1.5 equiv) was added. Note that the exotherm did not exceed -5 °C. The reaction was warmed to 25 °C over 1 hour and stirred for 30 minutes at this temperature. Upon completion, the reaction mixture was cooled to 10 °C and slowly quenched with water (50 mL, 5 V). Brine (50 mL, 5 V) was added. The mixture was stirred for 10 minutes and then allowed to separate. The aqueous layer was removed and back extracted with THF (50 mL, 5 V). The combined organic extracts were dried over MgSCL, filtered, and concentrated. The product was purified by column chromatography (120 g column, 0-100% EtOAc in hexane). The title compound was lodomethane (7.8 mL, 125 mmol) was charged to a vial containing 3- [methoxy(methyl)amino]-l-[l-(trifluoromethyl)cyclopropyl]pro pan-l-one (6.1 g, 27.1 mmol). The vial was wrapped in aluminium foil to shield from light. The resulting solution was stirred at ambient temperature for 4 days. Tetrahydrofuran (22 mL) was added to the solidified mass and the mixture stirred for 0.25 h giving a slurry. The solid was filtered off and washed with tetrahydrofuran (3 x 6 mL), then dried to give an off- white solid (6.13 g, 62% yield). Purity = 99.1wt% by quantitative NMR. ^J H NMR (400 MHz, DMSO-tfc) 5 ppm 1.41 - 1.61 (m, 2 H) 1.67 - 1.79 (m, 2 H) 2.99 (t, J = 7.34 Hz, 2 H) 3.46 (s, 6 H) 3.78 (s, 3 H) 3.95 (t, J= 7.21 Hz, 2 H).

Step 3: l-(4-Fluorophenyl)-4-(l-(trifluoromethyl)cyclopropyl)butane- l, 4-dione

Methoxydimethyl{3-oxo-3-[l-(trifluoromethyl)cyclopropyl]p ropyl}azanium iodide (1.0 g, 2.72 mmol) and 3-benzyl-5-(2-hydroxyethyl)-4-methyl-l,3-thiazol-3-ium chloride (0.234 g, 0.872 mmol, 0.3 equiv) were charged to a 20 mL vial with stirrer and placed under an inert atmosphere in a glove box.

/V./V-dinicthylformamidc (5 mL) was charged to the vial , giving a pale yellow solution. 4- Fluorobenzaldehyde (0.350 mL, 3.27 mmol, 1.2 equiv) was injected, followed by triethylamine (1.91 mL, 13.6 mmol, 5 equiv), causing the mixture to become cloudy after about half of the base had been added. The mixture was stirred at ambient temperature for

24 h.

The vial was removed from the glove box. The mixture was diluted with ethyl acetate (25 mL) and washed with IM aqueous hydrochloric acid (14 mL, pH was 1-2 afterwards), water (10 mL) and brine, dried (MgSCL) and evaporated under reduced pressure to give a pale orange oil. The oil was chromatographed (loaded with toluene, silica, 5-100% ethyl acetate/hexane) to give l-(4-fluorophenyl)-4-[l-(trifluoromethyl)cyclopropyl]butane- l,4- dione as a colorless oil (635 mg, 81%) and a second peak (95 mg, benzoin by-product, 2.64 min in HPLC). HPLC in 10% aqueous acetonitrile and NMR in CDCL- Product purity

97% by area. LCMS (ES) m/z = 289 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-<7) 5 ppm 1.33 - 1.41 (m, 2 H) 1.44 - 1.52 (m, 2 H) 3.14 - 3.23 (m, 2 H) 3.23 - 3.33 (m, 2 H) 7.10 - 7.19 (m, 2 H) 7.94 - 8.09 (m, 2 H). Step 4: 2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-17/-py rrole l-(4-Fluorophenyl)-4-[l-(trifluoromethyl)cyclopropyl]butane- l, 4-dione (0.835 g, 2.90 mmol) was charged to a 20 mL vial. 2-Propanol (4.2 mL, 5 vol) was added, followed by ammonium acetate (0.497 g, 6.45 mmol). The mixture was stirred in a heating block at 90 °C for 3.5 h. Additional ammonium acetate (0.220 g, 2.85 mmol) was added and heating was continued for 2 h, when there was <1% starting material by HPLC. The mixture was concentrated under reduced pressure to ~2 vol and water (10 mL) added over 0.5 h. The mixture was stirred 3 h, then filtered. The solid was washed with water (2 x 2 mL) and airdried to give 2-(4-fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-lZ7-py rrole as a tan solid (0.696 g, 88%). LCMS (ES) m/z = 270 [M+H] ⁺ . ^J H NMR (400 MHz, CHLOROFORM-7) 5 ppm 1.08 - 1.17 (m, 2 H) 1.32 - 1.38 (m, 2 H) 6.21 (dd, 7=3.42, 2.69 Hz, 1 H) 6.31 - 6.38 (m, 1 H) 7.01 - 7.13 (m, 2 H) 7.37 - 7.50 (m, 2 H) 8.37 (br s, 1 H).

Step 5: 3-(2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-177 -pyrrol-3- yl)propanoic acid

To a mixture of 2-(4-fluorophenyl)-5-(l -(trifluoromethyl)cyclopropyl)-l 77-pyrrole (8.8 g, 1 equiv, 32.8 mmol) in 10% water in EtOH (90 mL) was added Hydrogen chloride (5-6N in iPrOH, 1.2 g, 6.5 mL, 0.99 equiv, 33 mmol) followed by 2,2-dimethyl-4-oxo-5-(pyridin-l- ium-l-ylmethyl)-4Z7-l,3-dioxin-6-olate (8.5 g, 1.1 equiv, 36.1 mmol). The reaction was capped and stirred at ambient temperature for 15 hours at which time it was combined with other similar crude reaction mixtures from other runs. The combined mixtures were partitioned between 1000 mL 1:1 Et2O/hexanes and 500 mL water. The layers were separated and the organics were washed once with 500 mL water then once with 100 mL 15% Na2SC>4. The organics were dried with MgSCL. filtered and concentrated under reduced pressure to a foam. The foam was scraped and suspended in hexanes. The slurry was concentrated under reduced pressure then further dried under vacuum to give crude 5- ((2-(4-fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-177- pyrrol-3-yl)methyl)-2,2- dimethyl-l,3-dioxane-4, 6-dione as a tan-yellow powder (19.81 g, 101% combined yield). LCMS (ES) m/z = 426 [M+H] ⁺ , 424 [M-H]’.

A solution of crude 5-((2-(4-fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-l/ /-pyrrol- 3-yl)methyl)-2,2-dimethyl-l,3-dioxane-4, 6-dione (19.6 g, 1 equiv, 46.0 mmol) in pyridine (200 mL) and water (20 mL) was kept under nitrogen and heated at 90 °C for 5.5 hours. After cooling, the reaction mixture was diluted with diethyl ether and concentrated under reduced pressure. The residue was treated with diethyl ether and concentrated under reduced pressure again. The mixture was chromatographed over silica gel (ISCO, 330 g Gold, 200 mL/min, 10-21.2% (10% NH4OH in MeOH) / DCM over 33.7 minutes). The product-containing fractions were collected and concentrated under reduced pressure. MeOH was added to the residue and the mixture was concentrated to a foam. MeOH was again added and the mixture was again concentrated to a foam. The residue was dissolved in tBME and filtered over cotton into a tared round bottom flask. The mixture was concentrated to a foam then further dried under vacuum to give 3- (2-(4-fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-lZ7-p yrrol-3-yl)propanoic acid as a tan solid (12.4 g, 79% yield). LCMS (ES) m/z = 342 [M+H] ⁺ , 340 [M-H]’. ' H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.10 (br s, 1H), 7.40 - 7.31 (m, 2H), 7.17 - 7.07 (m, 2H), 6.12 - 6.07 (m, 1H), 2.93 - 2.85 (m, 2H), 2.65 - 2.58 (m, 2H), 1.35 - 1.28 (m, 2H), 1.14 - 1.06 (m, 2H).

Step 6: Dicyclohexylammonium 3-(2-(4-fluorophenyl)-5-(l-(trifluoromethyl)- cyclopropyl)-l//-pyrrol-3-yl)propanoate

To a solution of the 3-(2-(4-fluorophenyl)-5-(l -(trifluoromethyl)cyclopropyl)-l H-pyrrol-3- yl)propanoic acid (12.4 g, 1 equiv, 36.5 mmol) in tert-butyl methyl ether (65 mL) was added dicyclohexylamine (6.7 g, 7.3 mL, 1.0 equiv, 36.7 mmol). The resulting slurry was stirred at ambient temperature for 15 hours then the solids were isolated via filtration and rinsed with a minimal amount of tert-butyl methyl ether. The solids were dried under vacuum to give the dicyclohexylammonium 3-(2-(4-fluorophenyl)-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)propanoate as a cream-colored powder (15.89 g, 83% yield). LCMS (ES) m/z = 342 [M+H] ⁺ , 340 [M-H]’. ^J H NMR (400 MHz, DMSO-d ₆ ) 5 ppm 10.98 (br s, 1H), 7.50 - 7.43 (m, 2H), 7.28 - 7.21 (m, 2H), 6.10 (d, J= 2.5 Hz, 1H), 2.74 - 2.68 (m, 2H), 2.61 - 2.53 (m, 2H), 2.45 - 2.38 (m, 2H), 1.83 - 1.75 (m, 4H), 1.66 (dt, J= 12.8, 3.1 Hz, 4H), 1.55 (dt, J= 12.0, 3.5 Hz, 2H), 1.28 - 1.12 (m, 8H), 1.11 - 0.92 (m, 6H).

Step 7: 3-(2-(4-FIuorophenyI)-5-(l-(trifluoromethyI)cydopropyI)-17/- pyrroI-3-yI)-iV-

((3S,41f)-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

A mixture of dicyclohexylammonium 3-(2-(4-fluorophenyl)-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)propanoate (15.9 g, 1 equiv, 30.4 mmol), (3>S',47?)-3-amino-4-hydroxypyrrolidin-2-one, Hydrochloride (7.0 g, 1.5 equiv, 45.6 mmol) and the DIPEA (5.9 g, 8.0 mL, 1.5 equiv, 46 mmol) in DMAc (80 mL) was treated with 4- (4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate (DMTMMT) (12.7 g, 1.5 equiv, 45.7 mmol). The flask was capped and stirred at ambient temperature. After 20 hours the reaction was quenched with 500 mL water. The mixture was treated with approximately 50 g Na2SC>4 then extracted three times with 100 mL EtOAc. The combined organics were washed twice with 50 mL IN HC1, once with 50 mL saturated NaHCCh and once with 50 mL 15% Na2SC>4. The organics were dried with MgSCL, filtered and concentrated under reduced pressure. The material was chromatographed over silica gel (ISCO, 750 g Gold, 300 ml/min, 0-47.9% (3:1 EtOAc / EtOH) / Hexanes over 95.7 minutes). The fractions containing product were collected and concentrated on the rotovap. The residue was further purified via reverse-phase Cl 8 chromatography in multiple similar runs (ISCO Cl 8 Reverse Phase, 415 g Gold, 150 ml/min, 5-60% acetonitrile / water both with 0.1% NH4OH over 45 minutes). The fractions containing product were concentrated on the rotovap to a slurry, frozen and lyophilized. The residue was transferred to a RBF using DCM, acetonitrile and heptane. The mixture was rotovapped then dried under vacuum to give 3-(2-(4-fluorophenyl)-5-(l- (trifluoromethyl)cyclopropyl)-l/7-pyrrol-3-yl)-iV-((3 _l S',4R)-4-hydroxy-2-oxopyrrolidin-3- yl)propanamide as a white solid (10.2 g, 76% yield). LCMS (ES) m/z = 440 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 ppm 10.98 (br d, J = 1.5 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.49 - 7.43 (m, 2H), 7.28 - 7.21 (m, 2H), 6.12 (d, J= 3.0 Hz, 1H), 5.43 (d, J = 5.0 Hz, 1H), 4.15 - 4.04 (m, 2H), 3.40 - 3.34 (m, 1H), 2.90 (dd, J= 9.3, 6.8 Hz, 1H), 2.71 (dd, J= 9.3, 6.8 Hz, 2H), 2.38 (dd, J= 9.3, 6.8 Hz, 2H), 1.27 - 1.21 (m, 2H), 1.21 - 1.14 (m, 2H).

Example 53

3-(2-(4-Chlorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)- pyrrol-3-yl)-A ^f -((3S,4 ?)-

4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

Step 1: l-(4-Chlorophenyl)-4-(l-(trifluoromethyl)cyclopropyl)butane- l, 4-dione Anhydrous zinc(II) chloride (867 mg, 6.17 mmol) was stirred in toluene (4 mL), and to this mixture was added diethylamine (638 pL, 6.17 mmol) dropwise followed by addition of 2- methylpropan-2-ol (590 pL, 6.17 mmol). The mixture was stirred at room temperature for 2 h. l-(4-Chlorophenyl)ethan-l-one (786 mg, 4.93 mmol) and 2-bromo-l-(l- (trifluoromethyl) cyclopropyl)ethan-l-one (1.00 g, 4.11 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 10 days. Water and EtOAc were added, and the mixture was filtered through a pad of Celite, and the filtrate was transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum on rotovap to give a yellow oil, which was purified by silica gel chromatography (0% to 10% EtOAc: Heptane) give the title compound as a light yellow oil, which slowly solidified to a light yellow solid after standing at room temperature (198 mg, 15 % yield). LCMS (ES) m/z = 305 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-tfc) 5 ppm 8.02 - 7.95 (m, 2H), 7.64 1.49 - 1.41

A mixture of l-(4-chlorophenyl)-4-(l-(trifluoromethyl)cyclopropyl)butane- 1,4-dione (196 mg, 0.611 mmol) and ammonium acetate (288 mg, 3.67 mmol) in acetic acid (6 mL) was heated at 115 °C overnight. Cooled to room temperature, the reaction mixture was poured into ice-water. The mixture was extracted with EtOAc twice (50 mL, 30 mL), and the combined organic extract was washed with saturated aqueous NaHCOs three times, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a brown viscous oil (183 mg, 100 % yield). LCMS (ES) m/z = 286 [M+H] ⁺ . ' H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.36 (br s, 1H), 7.73 - 7.64 (m, 2H), 7.44 - 7.33 (m, 2H), 6.47 (dd, J = 3.7, 2.7 Hz, 1H), 6.18 (dd, J = 3.4, 2.4 Hz, 1H), 1.33 - 1.27 (m, 2H), 1.21 - 1.12 (m, 2H). Step 3: 5-((2-(4-Chlorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-l/ /-pyrrol-3- yl)methyl)-2,2-dimethyl-l,3-dioxane-4, -dione/ 5-((5-(4-chlorophenyl)-2-(l- (trifluoromethyl)cyclopropyl)-l//-pyrrol-3-yl)methyl)-2,2-di methyl-l,3-dioxane-4,6- dione

To a solution of 2-(4-chlorophenyl)-5-( 1 -(trifluoromethyl)cyclopropyl)- 1 //-pyrrole (183 mg, 609 pmol) in acetonitrile (5 mL) cooled in an acetone/ice bath at -10 °C was added 2,2-dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4//-l,3-diox in-6-olate (181 mg, 730 pmol) in portions. After the completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was again cooled in an acetone/ice bath at -10 °C, more 2,2-dimethyl-4-oxo-5- (pyridin-l-ium-l-ylmethyl)-4//-l,3-dioxin-6-olate (45.2 mg, 183 pmol) was added, and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum on rotovap to give a brown viscous oil, which was purified by silica gel chromatography (0 to 30% EtOAc:Heptane) to give the title compound as an off-white solid (177 mg, 64 % yield), which appeared to be a mixture of two regioisomers with a ratio greater than 100:1 or a single regio isomer by HNMR. LCMS (ES) m/z = 442 [M+H] ⁺ , 440 [M-H]". For the major regio isomer, ^J H NMR (400 MHz, DMSO-t e) 8 ppm 11.09 (br s, 1H), 7.60 - 7.37 (m, 4H), 6.05 (d, J = 2.4 Hz, 1H), 4.61 (t, J = 4.6 Hz, 1H), 3.21 (d, J = 4.4 Hz, 2H), 1.79 (s, 3H), 1.61 (s, 3H), 1.32 - 1.21 (m, 2H), 1.18 - 1.06 (m, 2H).

Step 4: 3-(2-(4-Chlorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-l// -pyrrol-3-yl)-/V-

((3S,4^)-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

To a mixture of 5-((2-(4-chlorophenyl)-5-(l -(trifluoromethyl)cyclopropyl)-l H-pyrrol-3- yl)methyl)-2,2-dimethyl-l,3-dioxane-4, 6-dione / 5-((5-(4-chlorophenyl)-2-(l- (trifluoromethyl) cyclopropyl)- l#-pyrrol-3-yl)methyl)-2,2-dimethyl- 1 ,3-dioxane-4, 6-dione (176 mg, 195 pmol) and (3S,47?)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (75.2 mg, 468 pmol) in NMP (1.5 mL) in a microwave vial was added /V-cthyl-/V- isopropylpropan-2-amine (202 mg, 1.56 mmol). The vial was capped and the reaction mixture was stirred at room temperature for 45 minutes, then heated at 120 °C overnight. Cooled to room temperature, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4- ium tetrafluoroborate (DMTMMT) (39.6 mg, 117 pmol) was added, and the mixture was stirred at room temperature for 30 minutes, (3>S',47?)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (25.1 mg, 156 pmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL). The combined organic extract was washed with 5% LiCl, brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum on rotovap to give a brown oil, which was purified by silica gel chromatography (0 to 50% 3:1 EtOAc/EtOH:Heptane) to afford an off-white solid, which seemed to contain quite a bit of EtOAc and Heptane. The solid was redissolved with DCM, hexane was added, and the sample was concentrated on rotovap and further dried under high vacuum to give the title compound as an off-white solid (120 mg, 64 % yield). LCMS (ES) m/z = 456 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-tfc) 5 ppm 11.05 (br d, J = 2.0 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.46 (s, 4H), 6.14 (d, J= 2.4 Hz, 1H), 5.43 (d, J = 5.4 Hz, 1H), 4.16 - 4.04 (m, 2H), 3.40 - 3.34 (m, 1H), 2.90 (dd, J = 9.5, 7.1 Hz, 1H), 2.74 (dd, J= 9.0, 6.6 Hz, 2H), 2.38 (dd, J= 9.0, 6.6 Hz, 2H), 1.26 - 1.22 (m, 2H), 1.21 - 1.14 (m, 2H). Example 54

3-(2-(4-Fluorophenyl)-4-methyl-5-(l-(trifluoromethyl)cvcl opropyl)-lH-pyrrol-3-yl)-/V- -4-hvdroxy-2-oxopyrrolidin-3-yl)propanamide

Step 1: (E)-l-(l-(trifluoromethyl)cyclopropyl)propan-l-one O-(4-nitrobenzoyl) oxime

To a stirred solution of /V-mcthoxy-/V-mcthyl- 1 -(trifluoromethyl)cyclopropane- 1 - carboxamide (1.5 g, 7.6 mmol, 1 equiv) in anhydrous THF (11.25 mL, 7.5 vol) at -5 °C was added dropwise ethyllithium solution (0.5 M in benzene/cyclohexane, 22.8 mL, 11.14 mmol, 1.5 equiv) over 5 minutes. The mixture was warmed to 25 °C over 30 min then aged an additional 30 min at that temperature. Upon completion, the mixture was cooled to 5 °C and 2 M HC1 solution (3.75 mL, 2.5 vol) was added slowly followed by brine (7.5 mL, 5 vol) and methylene chloride (15 mL, 10 vol). The mixture was stirred for 30 min, phase cut and the DCM layer was dried over anhydrous MgSCL and the solvents were removed by simple distillation (temperature ramp from 40 °C to 85 °C) to afford the ethyl ketone as a slightly yellowish oil.

The crude ethyl ketone was dissolved in methanol (11.25 mL, 7.5 vol) to which hydroxylamine hydrochloride (0.634 g, 9.13 mmol, 1.2 equiv) and ammonium acetate (0.704, 9.13 mmol, 1.2 equiv) were added and the resulting suspension was heated to 60 °C and stirred overnight. Following completion of reaction, the methanol was removed via simple distillation and the resulting residue was dissolved in dichloromethane (15 mL, 10 vol) and washed with water (7.5 mL, 5 vol). The DCM layer was dried over anhydrous MgSCL which was washed with an additional 15 mL (10 vol) of DCM and the combined DCM extract azeotroped to 10 volumes (15 mL) via simple distillation.

To this DCM solution of free oxime E/Z isomer mixture at 10 °C was added triethylamine (1.59 mL, 11.4 mmol, 1.5 equiv) followed by p-nitrobenzoyl chloride (2.18 g, 11.4 mmol, 1.5 equiv) portion-wise as a solid over approximately 10 minutes to keep the reaction temperature below 25 °C. After equilibration, the reaction temperature was set to 25 °C, and the reaction mixture was aged overnight.

Upon completion, a NaHCCh solution (7.5 mL, 5 V, 10wt% aqueous) was charged to the reactor, and the mixture was stirred for 30 minutes at 25 °C. The aqueous layer was removed, and the organic layer was dried over anhydrous MgSCL, filtered, and concentrated to dryness. The residue was purified via flash chromatography on silica gel (eluted with 100% hexanes to 30% ethyl acetate/hexanes) followed by trituration with n- heptane (15 mL, 10 vol) to afford (E)-l-(l-(trifluoromethyl)cyclopropyl)propan-l-one O- (4-nitrobenzoyl) oxime as a white crystalline solid (650 mg, 26% yield). ^J H NMR (400 m iodide (47.184 g, 314.8 mmol, 1.5 equiv) was charged to the reactor, and the mixture was stirred for approximately 15 minutes until all of the sodium iodide dissolved.

Triethylamine (31.854 g, 43.876 mL, 314.8 mmol, 1.5 equiv) was added next followed by chlorotrimethylsilane (34.198 g, 39.951 mL, 314.8 mmol, 1.5 equiv). The reaction was stirred at 25 °C overnight.

Upon completion, hexane (500 mL, 10 V) was added, and the resulting mixture was stirred for 15 minutes. The acetonitrile layer was separated and extracted two more times with hexane (500 mL, 10 V). The combined hexane layers were dried with anhydrous MgSCL, filtered and concentrated to give the title compound as a yellow oil which was used crude in the next step (50 g, 161.0 mmol, 77% yield). ¹ H NMR (400 MHz, CHLOROFORM-<7) 5 ppm 7.31 - 7.22 (m, 2H), 6.87 - 6.77 (m, 2H), 5.01 (t, J= 6.0 Hz, 1H), 4.05 - 3.95 (m, 2H), 2.44 - 2.31 (m, 2H), 2.30 - 2.16 (m, 2H), 1.11 (t, J = 8.0 Hz, 3H), - 0.02 (s, 9H).

Step 3: Dicyclohexylammonium 3-(2-(4-fluorophenyl)-4-methyl-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)propanoate

To a stirred solution of (E)-l -(1 -(trifluoromethyl)cyclopropyl)propan- 1-one O-(4- nitrobenzoyl) oxime (330 mg, 1 mmol, 1 equiv) in anhydrous acetonitrile (2 mL, 6 vol) was charged ethyl (E)-5-(4-fluorophenyl)-5-((trimethylsilyl)oxy)pent-4-enoate (775 mg, 2.5 mmol, 2.5 equiv) followed by ferrous chloride (63 mg, 0.5 mmol, 0.5 equiv) in a single portion. The mixture was heated to 55 °C and aged overnight at that temperature.

Upon completion, the reaction mixture was cooled to room temperature, and the CAN solvent was swapped to EtOAc (6.6 mL, 20 vol). Then a K2CO3 solution (3.3 mL, 10 V, 20 wt% aqueous) was charged, and the mixture was stirred at ambient temperature for 15 min then phase cut. The organic layer was dried over anhydrous MgSCL, filtered and concentrated to afford a gum that was purified via flash chromatography (hexanes to 20% ethyl acetate/hexanes) to give the ethyl 3-(2-(4-fluorophenyl)-4-methyl-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)propanoate intermediate (65 mg) as a yellowish oil which was used in the next step directly.

The ethyl ester was dissolved in THF (0.55 mL, 10 vol) and LiOH solution (0.55 mL, 2.5 M aqueous) was charged to the stirred mixture which was heated to 55 °C and aged for 2 hours. After assessing completion by HPLC, the mixture was cooled to 25 °C and TBME (5 mL) was charged followed by IM HC1 (0.25 mL) and the resulting biphase was stirred for 1 h then phase cut. The organic layer was dried over anhydrous MgSCL. which was then washed with additional TBME and the combined filtered organic extracts were reduced in volume to 0.55 mL (10 vol) in vacuo.

To the resulting TBME solution of the crude carboxylic acid was added dicyclohexylamine (31.3 uL, 0.157 mmol, 1.1 equiv intermediate basis') and the resulting mixture was stirred for 15 min at ambient temperature then //-heptane (0.55 mL, 10 vol) was charged d/w (solids formed after -30% of heptane added). The resulting slurry was aged for 1 h then filtered. The solids were washed with 50:50 TBME/heptane (0.5 mL) and dried in vacuo to afford dicyclohexylammonium 3-(2-(4-fluorophenyl)-4-methyl-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)propanoate as an off white solid (55 mg, 10% yield over 2 steps). LCMS (ES) m/z = 356 [M+H] ⁺ .

Step 4: 3-(2-(4-Fluorophenyl)-4-methyl-5-(l-(trifluoromethyl)cyclopr opyl)-17Z-pyrrol-

3-yl)-iV-((3S,4^)-4-hydroxy-2-oxopyrrolidin-3-yl)propanam ide

To a stirred solution of dicyclohexylammonium 3-(2-(4-fluorophenyl)-4-methyl-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)propanoate (55 mg, 0.102 mmol, 1 equiv) and (3>S',47?)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (0.023 g, 0.154 mmol, 1.5 equiv) in anhydrous DMF (0.3 mL, 6 vol) at 25 °C was charged DIPEA (27 uL, 0.154 mmol, 1.5 equiv) followed by DMTMM (43 mg, 0.154 mmol, 1.5 equiv). The mixture was aged for 1 h at 25 °C then heated to 55 °C and water (1.5 mL) was charged. The resulting biphasic mixture was extracted with EtOAc (5 mL) and phase cut. The top organic layer was dried over anhydrous MgSCL, filtered, and concentrated in vacuo then purified via flash chromatography on silica gel (100% DCM to 5% MeOH/DCM) to afford a gum that was triturated with pentane to provide 3-(2-(4-fluorophenyl)-4-methyl-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)-A-((3>S',4 7?)-4-hydroxy-2-oxopyrrolidin-3- yl)propanamide as an off white solid (33 mg, 72% yield). LCMS (ES) m/z = 454 [M+H] ⁺ . ^J H NMR (400 MHz. CDCI3) 5 8.11 (br. s, 1H) 7.37 (m, 2H) 7.11 (m, 2H) 6.44 (s, 1H) 6.33 (s, 1H) 5.59 (s, 1H) 4.19 (m, 1H) 4.02 (dd, J = 8.3, 2.0, 1H) 3.61 (ddd, J = 9.7, 8.0, 2.0 Hz, 1H) 3.23 (dd, J = 9.7, 8.8 Hz, 1H) 2.91 (dd, J = 9.7, 7.1 Hz, 2H) 2.42 (dd, J= 8.6, 6.2 Hz, 2H) 2.11 (s, 3H) 1.36 (dd, J= 6.9, 5.0 Hz, 2H) 1.08 (m, 2H).

Example 55

3-(2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclobutyl)-l ZZ-pyrrol-3-yl)-A ^f -((3S,4/?)-4- hydroxy-2-oxopyrrolidin-3-yl)propanamide

Step 1 : iV-Methoxy-iV-methyl-l-(trifluoromethyl)cyclobutane-l-carbox amide

Two identical reactions were set up as follows: Oxalyl chloride (606 pL, 6.92 mmol) was added dropwise to a stirred cold solution of l-(trifluoromethyl)cyclobutane-l -carboxylic acid (1.00 g, 5.77 mmol) and 2 drops of DMF in DCM (25 mL) at 0 °C. The mixture was allowed to warm up to room temperature and stirred at room temperature for 4 h. A solution of N, O-dimethylhydroxylamine hydrochloride (861 mg, 8.65 mmol) and diisopropylethylamine (3.02 mL, 17.3 mmol) in DCM (5 mL) was added slowly, and the reaction mixture was stirred at room temperature for 1.5 h. All the reaction mixtures were combined and diluted with ether (100 mL), washed with 1 M KH2PO4 (2 x 30 mL), saturated aqueous NaHC'CL (30 mL), brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum on rotovap to give the title compound as an almost colorless oil (2.663 g, 100 % yield, 92% Wt, which contained some /V/,/V2-dimcthoxy-/V/,/V2- dimethyloxalamide). LCMS (ES) m/z = 212 [M+H] ⁺ . ^J H NMR (400 MHz, CDCL-d) 5 ppm 3.67 (s, 3H), 3.23 (s, 3H), 2.75 - 2.61 (m, 2H), 2.54 - 2.40 (m, 2H), 2.18 - 2.00 (m, 1H), 1.88 - 1.73 (m, 1H).

Step 2: l-(l-(Trifluoromethyl)cyclobutyl)ethan-l-one

To a solution of /V-mcthoxy-/V-mcthy 1-1 -(trifluoromethyl)cyclobutane-l -carboxamide (2.66 g, 92% Wt, 11.6 mmol) in THF (20 mL) cooled in an ice bath was added methylmagnesium bromide (3M in diethyl ether) (7.73 mL, 23.2 mmol) dropwise. The reaction mixture (a cloudy solution) was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4CI (30 mL), and the mixture was extracted with Et20 twice (70 mL, 35 mL), and the combined organic extract was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum on rotovap (water bath temperature: 35 °C, vacuum: 100

To a solution of l-(l-(trifluoromethyl)cyclobutyl)ethan-l-one (920 mg, 75% Wt, 4.15 mmol) in dichloromethane (4 mL) cooled in a water bath was added bromine (664 mg, 4.15 mmol) dropwise. The reaction mixture was subsequently stirred for 1.5 h. The reaction mixture was concentrated under vacuum on rotovap (water bath temperature: 25 °C, vacuum: 75 Torr) to afford crude 2-bromo-l-(l-(trifluoromethyl)cyclobutyl)ethan-l- one as a yellowish brown oil. A mixture of l-fluoro-4-vinylbenzene (175 mg, 1.39 mmol), 2-bromo-l-(l- (trifluoromethyl) cyclobutyl)ethan-l-one, cobalt(II) acetylacetonate (36.8 mg, 139 pmol), tert-butyl hydroperoxide (0.77 mL, 70% Wt, 5.56 mmol) in triethylamine (6 mL, 43.0 mmol) under N2 was stirred at 95 °C overnight. Cooled to room temperature, EtOAc (75 mL) was added, and the mixture was filtered through a pad of Celite. The filtrate was transferred to a separatory funnel, water was added, and the organic layer was separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic extract was washed with saturated aqueous NaiSiCL. water, brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum on rotovap to give a dark brown viscous oil, which was purified by silica gel chromatography (0% to 10% EtOAc: Heptane) give the title compound as a brown oil (99 mg, 22 % yield). LCMS (ES) m/z. = 303 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-tfc) 5 ppm 8.12 - 8.04 (m, 2H), 7.41 - 7.32 (m, 2H), 3.37 - 3.32 (m, 2H), 3.01 - 2.93 (m, 2H), 2.73 - 2.63 (m, 2H), 2.44 - 2.34 (m, 2H), 2.09 - 1.99 (m, 1H), 1.96 - 1.85 (m, 1H).

Step 4: 2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclobutyl)-17/-pyr role

A mixture of l-(4-fluorophenyl)-4-(l-(trifluoromethyl)cyclobutyl)butane- 1,4-dione (179.1 mg, 562.9 pmol) and ammonium acetate (265.6 mg, 3.377 mmol) in EtOH (7 mL) was heated at 75 °C overnight. The solvent was removed on rotovap. Water was added, and the mixture was extracted with DCM twice (40 mL, 20 mL). The combined organic extract was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum on rotovap to give a yellow oil, which was purified by silica gel chromatography (0% to 30% DCM:Heptane) to give the title compound as a colorless oil (141 mg, 87 % yield). LCMS (ES) m/z = 284 [M+H] ⁺ , 282 [M-H]’. ¹ H NMR (400 MHz, DMSO- ₆ ) 5 ppm 11.05 (br s, 1H), 7.75 - 7.66 (m, 2H), 7.23 - 7.15 (m, 2H), 6.45 - 6.40 (m, 1H), 6.14 (dd, J = 3.4, 2.4 Hz, 1H), 2.63 - 2.52 (m, 3H), 2.48 - 2.43 (m, 1H), 2.02 - 1.91 (m, 2H). Step 5: 5-((2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclobutyl)-l// -pyrrol-3- yl)methyl)-2,2-dimethyl-l,3-dioxane-4, -dione/ 5-((5-(4-fluorophenyl)-2-(l- (trifluoromethyl)cyclobutyl)-l//-pyrrol-3-yl)methyl)-2,2-dim ethyl-l,3-dioxane-4,6- dione

To a solution of 2-(4-fluorophenyl)-5-( 1 -(trifluoromethyl)cyclobutyl)- 1 //-pyrrole (139 mg, 481 pmol) in acetonitrile (4 mL) cooled in an acetone/ice bath at -15 °C was added 2,2- dimethyl-4-oxo-5-(pyridin-l-ium-l-ylmethyl)-4//-l,3-dioxin-6 -olate (143 mg, 577 pmol) in portions. After the completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was again cooled in an acetone/ice bath at -15 °C, more 2,2-dimethyl-4-oxo-5-(pyridin-l-ium- l-ylmethyl)-4//-l,3-dioxin-6-olate (23.8 mg, 95% Wt, 0.2 Eq, 96.2 pmol) was added, and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for two days. The reaction mixture was concentrated under vacuum on rotovap to give a yellow viscous oil, which was purified by silica gel chromatography (0 to 30% EtOAc:Heptane) to give the title compound as an off-white foam (148 mg, 67 % yield), which appeared to be a mixture of two regioisomers with a ratio greater than 100:1 or a single regio isomer by HNMR. LCMS (ES) m/z = 440 [M+H] ⁺ , 438 [M-H]". For the major regio isomer, ^J H NMR (400 MHz, DMSO-t e) 8 ppm 10.90 (br s, 1H), 7.57 - 7.47 (m, 2H), 7.31 - 7.20 (m, 2H), 5.97 (d, J = 2.9 Hz, 1H), 4.59 (t, J= 4.6 Hz, 1H), 3.22 (d, J = 4.9 Hz, 2H), 2.58 - 2.51 (m, 2H), 2.47 - 2.35 (m, 2H), 1.98 - 1.89 (m, 2H), 1.78 (s, 3H), 1.60 (s, 3H).

Step 6: 3-(2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclobutyl)-l//- pyrrol-3-yl)-/V- ((3S,4^)-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

To a mixture of 5-((2-(4-fluorophenyl)-5-(l -(trifluoromethyl)cyclobutyl)-l //-pyrrol-3- yl)methyl)-2,2-dimethyl-l,3-dioxane-4, 6-dione / 5-((5-(4-fluorophenyl)-2-(l- (trifluoromethyl)cyclobutyl)-l#-pyrrol-3-yl)methyl)-2,2-dime thyl-l,3-dioxane-4, 6-dione (147 mg, 159 pmol) and (3S,47?)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (61.3 mg, 381 pmol) in NMP (1.5 mL) in a microwave vial was added /V-cthyl-/V- isopropylpropan-2-amine (221 pL, 1.27 mmol). The vial was capped and the reaction mixture was stirred at room temperature for 45 minutes, then heated at 115 °C overnight. Cooled to room temperature, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4- ium tetrafluoroborate (DMTMMT) (32.2 mg, 95.3 pmol) was added, and the mixture was stirred at room temperature for 30 minutes, after which (3>S',47?)-3-amino-4- hydroxypyrrolidin-2-one hydrochloride (20.4 mg, 127 pmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL). The combined organic extract was washed with 5% aqueous LiCl, brine twice, dried over Na2SC>4, filtered and concentrated under vacuum on rotovap to give a brown oil, which was purified by silica gel chromatography (0 to 50% 3:1 EtOAc/EtOH:Heptane) to give the title compound as an off-white solid (92.5 mg, 61 % yield). LCMS (ES) m/z = 454 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- ₆ ) 5 ppm 10.86 (br d, J= 2.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.56 - 7.48 (m, 2H), 7.35 - 7.26 (m, 2H), 6.15 (d, J= 2.5 Hz, 1H), 5.49 (d, J= 5.5 Hz, 1H), 4.22 - 4.12 (m, 2H), 3.42 (ddd, J= 9.1, 7.1, 1.8 Hz, 1H), 3.37 - 3.33 (m, 1H), 2.96 (dd, J= 9.5, 7.0 Hz, 1H), 2.79 (dd, J = 9.3, 6.8 Hz, 2H), 2.64 - 2.57 (m, 2H), 2.53 - 2.49 (m, 1H), 2.48 - 2.41 (m, 2H), 2.04 - 1.97 (m, 2H). Example 56

3-(4-Fluoro-2-(4-fluorophenyl)-5-(l-(trifluoromethyl)cvdo propyl)-lZZ-pyrrol-3-yl)-iV-

((3S,4/?)-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

Step 1: Ethyl 3-fluoro-5-(4-fluorophenyl)-177-pyrrole-2-carboxylate

A mixture of Ehpii (67.9 g, 267 mmol, 1.20 eq), ethyl 3-fluoro-177-pyrrole-2-carboxylate (35.0 g, 223 mmol, 1.00 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (2.4 g, 8.9 mmol, 0.04 equiv), and [Ir(OMe)(COD)]2 (3.22 g, 4.45 mmol, 0.02 equiv) in THF (440 mL) was wanned to 70 °C stirred for 1 b. After 1 h, the reaction mixture was cooled to 20 °C, and the reaction mixture was used in the next step without work-up. The mixture was quenched with water (100 mL) at 0 °C, and l-fluoro-4-iodobenzene (54.3 g, 245 mmol, 1.10 equiv), Pd(Ph3P)4 (12.9 g, 11.13 mmol, 0.05 equiv), K2CO3 (92.0 g, 668 mmol, 3.00 equiv) were added at 0 °C, and then the reaction mixture was warmed up to 100 °C and stirred for 4 h, then cooled to 20 °C, combined with two crude reaction mixtures for work up (15.98g, 63.6 mmol, 63g, 223 mmol), and the combined reaction mixtures were diluted with brine (600 mL) and extracted with ethyl acetate (500 mL x 3). The organic extract was washed with water (300 mL x 2) and dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to obtain crude product. The crude product (320 g) was dissolved in DCM (1.00 L), and 400 g of silica gel (100-200 mesh silica gel) was added. The resulting mixture was concentrated at 40 °C in vacuo to give a dry flowing solid. The crude solid was loaded in 1.20 kg silica gel (100-200 mesh silica gel, self-prepared column chromatography) and eluted with (n-heptane / ethyl acetate = 100 / 1 to 1 / 1), TLC (petroleum ether / ethyl acetate = 4 / 1, Rf product = 0.6). The fraction was combined and evaporated in vacuo at 40 °C to give product as tan solid (150 g). The residue was triturated with (n-heptane / ethyl acetate = 1 / 8) (500 mL) at 20 °C and stirred for 60 min. The resulting solid was collected by filtration, the filter cake was washed with (n-heptane / ethyl acetate = 1 / 8) (500 mL). The filter cake was collected and dried to give the title compound as a light yellow solid (90.0 g, 351 mmol, 69.0% combined yield). LCMS (ES) m/z = 252 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d6) δ ppm 11.9 (s, 1H), 7.87-7.90 (m, 2H), 7.21-7.26 (m, 2H), 6.67 (d, J = 2.8 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). ate (80.0 g, 312 mmol, 1.00 equiv) in DMF (640 mL) was added NIS (91.0 g, 406 mmol, 1.30 equiv) portion-wise at 0 °C. After addition, the reaction mixture was stirred for 120 min at 20 °C. After 2 h, the reaction was cooled and combined with a similar batch (10g, 31.8 mmol) for work-up, the combined crude reaction mixture was diluted with saturated Na2S2O3 (aq) (600 mL) and water (600 mL), and extracted with ethyl acetate (1.20 L x 3). The organic extract was washed with water (2 x 400 mL) and concentrated to crude product (140 g) that was triturated with petroleum ether / ethyl acetate = 8 / 1 (4 V, 560 mL) at 20 °C for 1 h and filtered. The filtrate was concentrated in vacuo at 40 °C to give the title compound as an off-white solid, (109 g, 283 mmol, 81 % combined yield). LCMS (ES) m/z = 378.0 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d6) δ ppm 12.5 (s, 1H), 7.67-7.70 (m, 2H), 7.30-7.35 (m, 2H), 4.28 (q, J = 7.2 Hz, 2H), 1.29 (m, J = 6.8 Hz, 3H). Step 3: Ethyl (E)-4-(3-(benzyloxy)-3-oxoprop-1-en-1-yl)-3-fluoro-5-(4-fluo rophenyl)- 1H-pyrrole-2-carboxylate

Two reactions were carried out in parallel.

A mixture of ethyl 3-fluoro-5-(4-fluorophenyl)-4-iodo-l//-pyrrole-2-carboxylate (49.5 g, 129 mmol, 1.00 equiv), benzyl acrylate (62.6 g, 386 mmol, 3.00 equiv), Pd(PPh3)2C12 (7.22 g, 10.3 mmol, 0.08 equiv), and TEA (53.8 mL, 386 mmol, 3.00 equiv) in DMF (625 mL) at 25 °C was stirred for 3 h at 100 °C. After 3 h, the reaction was cooled to 20 °C, and combined with two batches for work-up (10.70 g, 26 mmol and 53.03 g, 129 mmol). The combined mixture was diluted with water (2.00 L) and extracted with ethyl acetate (1.00 L x 3). The organic phase washed with brine (500 mL x 2) and dried over anhydrous Na2SC>4. The filtrate was concentrated in vacuo to obtain a brown solid that was triturated with petroleum ether / ethyl acetate = 10 / 1 (2.00 L) at 20 °C and stirred for 60 min. The resulting solid was collected by filtration, the filter cake was washed with petroleum ether / ethyl acetate = 9 / 1 (1.00 L). The filter cake was collected and dried to give the title compound as an off-white solid (92.0 g, 219 mmol, 81.0% combined yield). LCMS (ES) m/z = 412.2 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-tfc) 8 ppm 12.5 (s, 1H), 7.53 (m, 2H), 7.34-7.41 ( _m , 8H), 6.33 (d , J = 8.0 Hz, 1H), 5.17 (s, 1H), 4.30 (q, J = 6.8 Hz, 2H), 1.30 (t, 7= 7.2 Hz, 3H).

Step 4: 3-(5-(Ethoxycarbonyl)-4-fluoro-2-(4-fluorophenyl)-17Z-pyrrol -3-yl)propanoic acid

Two duplicate reactions were carried out, each involving a mixture of ethyl (E)-4-(3- (benzyloxy)-3 -oxoprop- 1 -en- 1 -yl)-3-fluoro-5-(4-fluorophenyl)- 1 H-py iTolc-2-carboxy I ate (43.5 g, 104 mmol, 1.00 equiv) and Pd-C (22.1 g, 20.7 mmol, 0.20 equiv) in ethyl acetate (200 mL), methanol (200 mL) and THF (435 mL). The reactions were each stirred for 18 h at 35 °C under hydrogen atmosphere (30 PSI). After 18 h, the two reactions were combined along with another batch (1.53 g, 4.76 mmol) for work-up. The combined mixture was filtered through Celite and the filtrate was concentrated in vacuo at 40 °C to give the title

Two duplicate reactions were carried out, each involving a mixture of 3-(5- (ethoxycarbonyl)-4-fluoro-2-(4-fluorophenyl)-lH-pyrrol-3-yl) propanoic acid (29.0 g, 85 mmol, 1.00 equiv) and NaOH (17.0 g, 426 mmol, 5.00 equiv) in ethylene glycol (464 mL). The reactions were each stirred for 2 h at 140 °C. After 2 h, each reaction was cooled to 20 °C, and they were combined along with another batch (21.34 g, 85 mmol) for work-up. The combined reaction mixture was diluted with water (1 L) and acidified to pH = 6 with 1.0 N HC1 (aq). The resulting mixture was extracted with ethyl acetate (800 mL x 3) and the organic extract was washed with water (2 x 500 mL). The organic extract was dried over Na2SC>4, filtered and concentrated in vacuo at 45 °C to give the crude product (58.0 g) which was dissolved in DCM (400 mL), and 70.0 g of silica gel (100-200 mesh silica gel) was added. The resulting mixture was concentrated at 40 °C in vacuo to give a flowing solid. The crude solid was loaded onto 220 g silica gel (100-200 mesh silica gel, selfprepared column chromatography) and eluted with (n-heptane / ethyl acetate = 8 / 1 to 1/1), TLC (petroleum ether / ethyl acetate = 1 / 1, Rf product = 0.5). The pure fractions were combined and evaporated in vacuo at 40 °C to give the title compound as a pink solid (40.0 g, 157 mmol, 85.0 % combined yield). LCMS (ES) m/z = 252.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-tfc) / ppm 12.1 (s, 1H), 10.6 (s, 1H), 7.41-7.45 (m, 2H), 7.20-7.24 (m, 2H), 6.55 (d, J = 1.6 Hz, 1H), 2.73-2.77 (m, 2H), 2.35-2.39 (m , 2H). Step 6: 3-(4-Fluoro-2-(4-fluorophenyl)-1H -pyrrol-3-yl)-A ^r -((3S,4^)-4-hydroxy-2- oxopyrro!idin-3-yI)propanamide

To a solution of 3-(4-fluoro-2-(4-fluorophenyl)-l//-pyrrol-3-yl)propanoic acid (31.0 g, 205 mmol, 1.0 equiv) and (3S,4R )-3-amino-44iydroxypyrrolidin-2-one (56.7 g, 205 mmol, 1.50 equiv) in DMF (280 mL) was added DIPEA (35.8 mL, 205 mmol, 1.50 equiv) at 25 °C and the reaction mixture was stirred for 8 h at 25 °C under nitrogen. After 8 h reaction the reaction was cooled and combined with another batch (5.41 g, 15.5 mmol) for work-up. The combined reaction mixture was diluted with water (650 mL) and extracted with ethyl acetate (6 x 500 mL). The organic extract was washed with brine (2 x 500 mL) and dried over anhydrous Na2SO4. It was filtered and the filtrate was concentrated to give a tan semisolid. This crude product (80.0 g) was dissolved in DCM (500 mL), and 90.0 g of silica gel (100-200 mesh silica gel) was added. The resulting mixture was concentrated at 40 °C in vacuo to give a flowing solid. The crude solid was loaded in 240 g silica gel (100-200 mesh silica gel, self-prepared column chromatography) and eluted with (n-heptane / ethyl acetate = 10 / 1 to 3 / 1), TLC (petroleum ether / ethyl acetate = 0 / 1, Rf product = 0.2). The pure fractions were combined and evaporated in vacuo at 40 °C to give a light yellow solid which was dissolved in 150 mL of acetonitrile and 450 mL of water and lyophilized for 48 h (-70 °C, 128 pressure / oil pump) to give the title compound as an light yellow solid (24.3 g, 68.2 mmol, 43.7 % yield). LCMS (ES) m/z = 350.1 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-</ ₆ ) 8 ppm 10.7 (s, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.74 (s, 1H), 7.46-7.49 (m, 2H), 7.24-7.29 (m, 2H), 6.69 (t, J = 4.0 Hz, 1H), 5.46 (d, J = 8.0 Hz, 1H), 4.05-4.16 (m, 2H), 3.35-3.39 (m , 1H), 2.88-2.92 (m, 1 H), 2.72-2.76 (m, 2 H), 2.36-2.40 (m, 2H).

Step 7: 3-(5-Bromo-4-fluoro-2-(4-fluorophenyl)-177-pyrrol-3-yl)-N-(( 3S,4^)-4- hydroxy-2-oxopyrroIidin-3-yI)propanamide

To a solution of 3-(4-fluoro-2-(4-fluorophenyl)-lZ7-pyrrol-3-yl)-A-((3>S', 47?)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide (1.0 g, 1 equiv, 2.9 mmol) in DMF (12.000 mL) was added NBS (510.0 mg, 1.0 equiv, 2.9 mmol) portion-wise at 0 °C. After addition, the reaction mixture was stirred for 20 min at 0 °C. It was subsequently diluted with 30 mL saturated Na2S20a (aq) and 20 mL brine. The resulting mixture was extracted with ethyl acetate (40 mL). The organic extract was washed with brine (3 x 40 mL) and dried over anhydrous MgSCL. It was filtered and the filtrate was concentrated to afford the title compound as off-white solid (1.14 g, 2.66 mmol, 93% yield) which was carried forward without further purification. LCMS (ES) m/z = 428 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- d ₆ ) 3 ppm 11.49 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.58 - 7.39 (m, 2H), 7.36 - 7.20 (m, 2H), 5.46 (br s, 1H), 4.18 - 4.04 (m, 2H), 3.41 - 3.36 (m, 1H), 2.95 - 2.86 (m, 1H), 2.80 - 2.68 (m, 2H), 2.42 - 2.30 (m, 2H).

Step 8: 3-(4-Fluoro-2-(4-fluorophenyl)-5-(3,3,3-trifluoroprop-l-en-2 -yl)-LH-pyrrol-3- yl)-iV-((3S,4^)-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

A mixture of 3-(5-bromo-4-fluoro-2-(4-fluorophenyl)-lZ7-pyrrol-3-yl)-A-(( 3>S',47?)-4- hydroxy-2-oxopyrrolidin-3-yl)propanamide (1.1 g, 1 equiv, 2.6 mmol), 4,4,6-trimethyl-2- (3,3,3-trifluoroprop-l-en-2-yl)-l,3,2-dioxaborinane (900.0 mg, 1.5 equiv, 4.1 mmol), cataCXium® A Pd G3 (230.0 mg, 0.1 eq, 315.8 pmol), and cesium fluoride (840.0 mg, 2.1 eq, 5.5 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was stirred for 20 hours at 80 °C. After cooling to room temperature, the mixture was diluted with brine (30 mL) and extracted with ethyl acetate (30 mL). The organic extract was dried over anhydrous MgSCL- It was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel eluting with a gradient of 5% to 55% ethyl was added a degassed solution of 3-(4-fluoro-2-(4-fluorophenyl)-5-(3,3,3-trifluoroprop-l- en-2-yl)-177-pyrrol-3-yl)-A-((3>S',47?)-4-hydroxy-2-oxopy rrolidin-3-yl)propanamide (540.0 mg, 55% wt, 1 equiv, 669.9 pmol) in DMSO (10 mL). The reaction vial was placed into a Photoreactor m2 setup at 450 nm and irradiated for 1 hour. Following this duration, the mixture was diluted with water (30 mL) and ethyl acetate (30 mL). The resulting suspension was filtered through Celite. The filtrate was diluted wit brine (10 mL) and the organic layer was separated and washed with water (2 x 40 mL). It was subsequently dried over anhydrous MgSCL and filtered. The filtrate was concentrated and the crude product was purified by flash column chromatography on silica gel eluting with a gradient of 5 to 55% ethyl acetate/ethanol (3:1) in heptane. Further purification was conducted by mass- guided, reverse-phase HPLC (30-85% CH ₃ CN:(10 mM NH4-HCO3 with 0.075% NH ₄ OH (pH 10 mixture)), 22 min gradient) to afford the title compound as white solid (110 mg, 0.236 mmol, 35% yield). LCMS (ES) m/z = 458 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- dd) d ppm 11.06 (br s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.57 - 7.44 (m, 2H), 7.35 - 7.20 (m, 2H), 5.46 (d, J = 5.4 Hz, 1H), 4.16 - 4.04 (m, 2H), 3.37 (ddd, J = 9.3, 7.3, 1.5 Hz, 1H), 2.90 (dd, J = 9.3, 6.8 Hz, 1H), 2.75 - 2.66 (m, 2H), 2.41 - 2.30 (m, 2H), 1.38 -

Step 1 : A-Methoxy-iV-methyl-l-(trifluoromethyl)cyclopropane-l-carbox amide

To a solution of l-(trifluoromethyl)cyclopropane-l -carboxylic acid (20.1 g, 1.0 equiv, 130 mmol) in DCM (200 mL) cooled in an ice/water bath was added CDI (27.5 g, 1.30 equiv, 170 mmol) portion-wise over 5 minutes. The reaction mixture was warmed to room temperature (over ~ 30 minutes) and stirred for 1 hour at room temperature. TEA (19.8 g, 27.3 mL, 1.5 equiv, 196 mmol) and A, O-dimethyl-hydroxylamine hydrochloride (19.1 g, 1.5 equiv, 196 mmol) were subsequently added and the reaction was stirred for 18 hours. The reaction was quenched by pouring into 100 mL of ice cold 3N HC1 (aq), and the layers were separated. Organics were washed with satd. NaHCOs and water, dried over sodium sulfate, then concentrated under vacuum on rotovap at 100 Torr and 25°C. The crude product was dissolved in 300 mL diethyl ether and washed with IN HC1 (50 mL x 2), then water. Organics were concentrated under vacuum on rotovap at 100 Torr and 25°C for 30 minutes, then dried on high vacuum pump for 5 minutes to give the title compound (24.4 g, 86 % yield) as a pale yellow liquid. Purity was estimated at 90 % by ^J H NMR. LCMS (ES) m/z = 198 [M+H] ⁺ . ^J H NMR (400 MHz, CHLOROFORM-d) 5 ppm

To a solution of tert-butyl prop-2-yn-l-ylcarbamate (14.9 g, 1.5 equiv, 95.9 mmol) in THF (200 mF) under nitrogen and cooled in an acetone/dry ice bath was added n-butyll ithium (1.6 M in hexanes) (12.3 g, 120 mF, 1.6 molar, 3.0 equiv, 192 mmol). The mixture became thick and stirring ceased. More THF (25 mF) was added and stirring resumed. The mixture was stirred cooled for 60 minutes, then a solution of /V-mcthoxy-/V-mcthyl- l - (trifluoromethyl)cyclopropane-l -carboxamide (14.0 g, 90% Wt, 1.0 equiv, 63.9 mmol) in THF (65 mF) was added. The dry ice/acetone bath was removed and the reaction was stirred in an ice/water bath for 30 minutes. To the reaction mixture (still cooled in ice/water bath) was added IN HC1 in portions (100 mF total), then dropwise added 6N HC1 (~ 30 mF) until the mixture was pH ~ 4. Diethyl ether and water were added and the layers were separated. The organics were washed with water and brine, then concentrated under vacuum on rotovap to an orange oil which was stirred in heptane (100 mF). The resulting solid was stirred for 60 minutes, filtered and dried to give the title compound (11.25 g, 58 % yield) as a pale orange solid. FCMS (ES) m/z not determined because product did not ionize. ¹ H NMR (400 MHz, CHEOROFORM-d) 5 ppm 4.85 - 4.70 (m, 1H), 4.10 (br d, J = 5.9 Hz, 2H), 1.69 - 1.62 (m, 2H), 1.54 - 1.45 (m, 11H). The filtrate was concentrated and purified by silica gel chromatography (0 - 20 % EtOAc:heptane) to give an orange oil which was stirred in heptane (20 mL). The resulting solid was stirred for 10 minutes, filtered and dried to give the title compound (1.62 g, 9 % yield) as a light orange solid.

Step 3: tert-Butyl 4-bromo-2-( 1 -(trifl uoromethy Dey clop ropy y role- 1- carboxylate

To a solution of tert-butyl (4-oxo-4-(l-(trifluoromethyl)cyclopropyl)but-2-yn-l- yl)carbamate (12.9 g, 95% Wt, 1.0 equiv, 42.0 mmol) in DCM (200 mL) cooled in an ice/water bath was added quickly dropwise hydrobromic acid (33% in acetic acid) (12.4 g, 9.1 mL, 33% Wt, 1.2 equiv, 50.4 mmol). The reaction mixture was stirred cooled for 25 minutes. While still cooled, the reaction was quenched with satd. NaHCCL, then diluted with water. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine and concentrated under vacuum on rotovap. The crude product was purified by a short silica gel plug, eluting with 20%

To a solution of tert-butyl 4-bromo-2-(l -(trifluoromethyl)cyclopropyl)-l //-pyrrole- 1- carboxylate (10.3 g, 99% Wt, 1.0 equiv, 28.7 mmol) in THF (50 mL) under nitrogen was added (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 ’-biphenyl) [2-(2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate (RuPhos-Pd-G3) (1.2 g, 0.05 equiv, 1.4 mmol) and (3-ethoxy-3-oxopropyl)zinc(II) bromide (0.5 M in THF) (14.2 g, 114.9 mL, 0.5 molar, 2.0 equiv, 57.5 mmol). The reaction was stirred and refluxed for 22 hours, then cooled to room temperature. It was diluted with satd. NH4CI and diethyl ether and filtered through a Celite plug to remove solids. The layers of the filtrate were separated, and the organics were dried over sodium sulfate, filtered and concentrated under vacuum on rotovap. The crude product was purified by a short silica gel plug, eluting with 0-40% DCM:heptane. The less pure fractions were combined, concentrated and purified by silica gel chromatography (0-5% EtOAc:heptane). The purest fractions from both purifications were combined, concentrated under vacuum on rotovap and dried to give the title compound (8.58 g, 77 % yield) as a yellow oil. LCMS (ES) m/z = 376 [M+H] ⁺ . ^J H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.13 - 7.09 (m, 1H), 6.20 (d, J = 2.0 Hz, 1H), 4.16 (q, J= 7.3 Hz, 2H), 2.76 - 2.70 (m, 2H), 2.59 - 2.53 (m, 2H), 1.61 (s, 9H), 1.45 - 1.39 (m, 2H), 1.30 - 1.24 (m, 3H), 1.18 - 1.11 (m, 2H).

Step 5: tert-Butyl 2-bromo-3-(3-ethoxy-3-oxopropyl)-5-(l-

( t rifhionmiet hy l)cych)p ropy 1)-1//- yrrole- Lea rboxy late tert-Butyl 4-(3-ethoxy-3-oxopropyl)-2-(l -(trifluoromethyl)cyclopropyl)-l //-pyrrole- 1 - carboxylate (11.3 g, 97% Wt, 1.0 equiv, 29.1 mmol) was dissolved in DMF (110 mL) under nitrogen and the solution was cooled in an ice/water bath. NBS (5.4 g, 97% Wt, 1.0 equiv, 29.4 mmol) was added portion- wise over 2 minutes and the reaction was stirred cooled for 20 minutes. The reaction was diluted with water (150 mL) and diethyl ether (150 mL), and the layers were separated. The organics were washed with water and brine, then concentrated under vacuum on rotovap and dried to give the title compound (12.35 g, 91 % yield) as a light orange oil. LCMS (ES) m/z = 454/456 [M+H] ⁺ (bromine pattern). ¹ H NMR (400 MHz, CHLOROFORM-d) 5 ppm 6.21 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 2.76 - 2.69 (m, 2H), 2.57 - 2.50 (m, 2H), 1.64 (s, 9H), 1.43 - 1.37 (m, 2H), 1.30 - 1.24 (m, 3H), 1.20 - 1.15 (m, 2H).

Step 6: tert-Butyl 3-(3-ethoxy-3-oxopropyl)-5-(l-(trifluoromethyl)cyclopropyl)- 2-(4- (trifluoromethyl)phenyl)-lH-pyrrole-l-carboxylate tert-Butyl 2-bromo-3-(3-ethoxy-3-oxopropyl)-5-( 1 -(trifluoromethyl)cyclopropyl)-l H- pyrrole-1 -carboxylate (12.2 g, 97% Wt, 1.0 equiv, 26.1 mmol) was dissolved in 1,4- dioxane (150 mL) and water (40 mL), then added (4-(trifluoromethyl)phenyl)boronic acid (5.9 g, 1.2 equiv, 31.3 mmol), tetrakis(triphenylphosphine)palladium(0) (1.51 g, 0.05 equiv, 1.3 mmol) and potassium carbonate (9.0 g, 2.50 equiv, 65.1 mmol). Nitrogen was bubbled through the reaction mixture for 5 minutes, then it was stirred under nitrogen for 2 hours and 15 minutes at 100 °C. After cooling to room temperature, the mixture was diluted with brine (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (100 mL), dried over sodium sulfate and concentrated under vacuum on rotovap. The crude product was purified by a short silica gel plug, eluting with 0-5% EtOAc:heptane to give the title compound (13.5 g, 94 % yield) as a yellow oil. LCMS (ES) m/z = 520 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.67 (d, 7= 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.27 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.67 - 2.59 (m, 2H), 2.49 - 2.43 (m, 2H), 1.49 - 1.43 (m, 2H), 1.28 - 1.20 (m, 14H).

Step 7: 3-(5-(l-(Trifluoromethyl)cyclopropyl)-2-(4-(trifluoromethyl) phenyl)-177- pyrrol-3-yl)propanoic acid

To a solution of tert-butyl 3-(3-ethoxy-3-oxopropyl)-5-(l-(trifluoromethyl)cyclopropyl)- 2- (4-(trifluoromethyl)phenyl)-l//-pyrrole-l -carboxylate (12.2 g, 95% Wt, 1.0 equiv, 22.3 mmol) in THF (50 mL) and methanol (100 mL) was added sodium hydroxide (5.4 g, 26.8 mL, 5.0 molar, 6.00 equiv, 134 mmol). The reaction mixture was refluxed for 48 hours. After cooling to room temperature, the reaction was combined with a smaller scale reaction (theoretical yield = 0.93 g), the organic solvents were removed under vacuum on rotovap and the residue was diluted with water (50 mL). The resulting mixture was acidified with 6.0 N HC1 (aq), diluted with diethyl ether (200 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum on rotovap. The crude solid was triturated in 10% EtOAc:heptane (100 mL) and filtered. The filtrate was concentrated under vacuum on rotovap to a solid and triturated 5% EtOAc:heptane (40mL) and filtered. The isolated batches were combined and dried to give the title compound (8.65 g, 88 % yield) as a light yellow solid. LCMS r

To a solution of 3-(5-( 1 -(trifluoromethyl)cyclopropyl)-2-(4-(trifluoromethyl)phenyl) - 1 H- pyrrol-3-yl)propanoic acid (550 mg, 1.0 equiv, 1.4 mmol) in DCM (9.0 mL) was added (3S,47?)-3-amino-44iydroxypyrrolidin-2-one, Hydrochloride (236 mg, 1.10 equiv, 1.55 mmol) and DIEA (454 mg, 612 pL, 2.50 equiv, 3.51 mmol). The mixture was stirred until most solids dissolved, then DMTMMT (507 mg, 1.10 equiv, 1.55 mmol) was added and reaction mixture was stirred for 3 hours at room temperature. The reaction was diluted with water and layers were separated. The aqueous layer was extracted with DCM, the organics were combined, washed with brine and concentrated. The crude product was purified by silica gel chromatography (0-45% [3:1 ethyl acetate: EtOH] :heptane) to give the title compound (550 mg, 78% yield) as a white solid. LCMS (ES) m/z = 490 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 ppm 11.21 (br d, J = 2.0 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.78 - 7.73 (m, 3H), 7.67 (d, J = 8.0 Hz, 2H), 6.20 (d, J= 2.5 Hz, 1H), 5.44 (d, J= 5.0 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.41 - 3.35 (m, 1H), 2.91 (dd, J= 9.3, 6.8 Hz, 1H), 2.80 (dd, J = 9.0, 6.5 Hz, 2H), 2.42 (dd, J = 9.0, 6.5 Hz, 2H), 1.30 - 1.25 (m, 2H), 1.24 - 1.20 (m, 2H).

Example 58

3-(5-(2,2-Difluoro-l-(trifluoromethyl)cvclopropyl)-2-(4-f luorophenyl)-lH-pyrrol-3- yl)-A ^f -( -4-hvdroxy-2-oxopyrrolidin-3-yl)propanamide

Step 1: 2-(2,2-Difluoro-l-(trifluoromethyl)cyclopropyl)-5-(4-fluorop henyl)-17Z-pyrrole

Two identical reactions were set up as follows: To tert-Butyl 2-(4-fluorophenyl)-5 -(3,3,3 - trifluoroprop- l -cn-2-yl )- 1 H-pyiTolc- 1 -carboxylate (3.2 g, 8.9 mmol) was added sodium fluoride (74.45 mg, 1.77 mmol). A stir bar were added. To this mixture was added trimethylsilyl 2,2-difluoro-2-((trifluoromethyl)sulfonyl)acetate (5.3 g, 17.7 mmol) slowly via a syringe. The reaction was heated to 50 °C for 1 h, then 100 °C for 2 h, and the mixtures from both reactions were combined and dissolved in ethyl acetate and washed with aq NaHCO s solution and brine. The organic phase was separated and dried over sodium sulfate. Concentration under reduced pressure afforded crude tert-butyl 2-(2,2- difluoro- 1 -(trifluoromethyl)cyclopropyl)-5-(4-fluorophenyl)- 177-pyrrole- 1 -carboxylate as a solid which was used without further purification.

To a 500 ml round bottom flask was charged a suspension of the crude tert-butyl 2-(2,2- difluoro- 1 -(trifluoromethyl)cyclopropyl)-5-(4-fluorophenyl)- 177-pyrrole- 1 -carboxylate (7.0 g, 17.269 mmol) in methanol (200.0 mL). Hydrogen chloride (4.0M in dioxane, 12.6 g, 86.3 mL, 345.4 mmol) was subsequently added. The reactor was kept under a positive stream of nitrogen, stirred and a reflux condenser was installed, loosely covered with a cap. The reaction mixture was heated to an internal temperature of 50 °C. After 5 h heating, the reaction mixture was cooled and the solvents were removed under reduced pressure. The crude material was partitioned between 800 mL ethyl acetate and 100 mL water. The layers were separated and the organics was washed once with 200 mL water, once with 100 mL saturated NaHCCh and once with 100 mL brine. The organics were dried with MgSCL, filtered and concentrated under reduced pressure to give a solid. The solids were further purified by silica gel chromatography (eluting 0-20% of ethyl acetate in hexane) to afford the title compound as a tan solid (3.2 g, 58%). LCMS (ES) m/z. = 306 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO-d<s) 5 ppm 11.56 (br s, 1H), 7.57-7.83 (m, 2H), H).

Two identical reactions were set up as follows: To a 100 mL round bottom flask containing the crude 2-(2,2-difluoro-l-(trifluoromethyl)cyclopropyl)-5-(4-fluorop henyl)- 177-pyrrole (1.14 g, 3.73 mmol) was added a stir bar and 10% water in EtOH (25.0 mL). Hydrogen chloride (5-6 N in iPrOH, 136.2 mg, 747.0 pL, 3.735 mmol) was added followed by 2,2-dimethyl-4-oxo-5-(pyridin- 1 -ium- 1 -yl mcthyl )-4H- 1 ,3-dioxin-6-olate (966.5 mg, 4.1 mmol). The reaction was capped and stirred at ambient temperature for 14 h. The reaction mixture were partitioned between 100 mL 1:1 Et2O/hexanes and 35 mL water. The organics were further washed once with 35 mL brine, dried over anhydrous MgSCL, filtered and concentrated under reduced pressure to afford crude material which further purified by silica gel chromatography (eluting with 0-20% of ethyl acetate in heptane) to obtain the title compound. (900 mg, 49.6%). LCMS (ES) m/z = 462 [M+H] ⁺ . ' H NMR (400 MHz, DMSO-d ₆ ) 5 ppm 11.40 (br s, 1H), 7.48-7.69 (m, 2H), 7.19-7.43 (m, 2H), 6.10-6.32 (m, 1H), 4.68 (t, J=4.8 Hz, 1H), 3.28 (d, J=4.5 Hz, 2H), 2.61-2.79 (m, 1H), 2.39-2.52 (m, 1H), 1.85 (s, 3H), 1.67 (s, 3H).

Step 3: 3-(5-(2,2-Difluoro-l-(trifluoromethyl)cyclopropyl)-2-(4-fluo rophenyl)-177- pyrrol-3-yl)-A ^r -((3S,41f)-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide

Two identical reactions were set up as follow: A solution of 5-((5-(2,2-difluoro-l- (trifluoromethyl)cyclopropyl)-2-(4-fluorophenyl)-177-pyrrol- 3-yl)methyl)-2,2-dimethyl- l,3-dioxane-4, 6-dione (0.72 g, 1.56 mmol) in pyridine (15.0 mL) was charged into a 50 ml round bottom flask equipped with a stir bar, reflux condenser, nitrogen inlet and temperature probe. Water (1.5 mL) was subsequently added and the reaction vessel was placed onto a heating mantle and the internal temperature was warmed to 90 °C. After 5 h heating, the reaction mixture was diluted with ethyl acetate. The mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate. The solution was dried over Na2SOa and the organic solution was filtered. The filtrate was concentrated under reduced pressure to give a foam and further dried under vacuum to give crude 3-(5- (2,2-difluoro-l-(trifluoromethyl)cyclopropyl)-2-(4-fluorophe nyl)-l -pyrrol-3-yl)propanoic acid (LCMS (ES) m/z = 31% [M+H] ⁺ ).

To a 100 mL round bottom flask containing crude 3-(5-(2,2-difluoro-l- (trifluoromethyl)cyclopropyl)-2-(4-fluorophenyl)-l//-pyrrol- 3-yl)propanoate (1.2 g, 3.0 mmol) was added a stir bar and DMF (15 mL) to give a slurry. DMTMM (1.3 g, 4.5 mmol) was added followed by DIPEA (979.0 mg, 1.3 mL, 7.6 mmol). The reaction mixture remained a thick slurry. (3>S',4R)-3-Amino-4-hydroxypyrrolidin-2-one, Hydrochloride (693.4 mg, 4.5 mmol) was added and the flask was capped. The reaction was stirred at RT for 3 h. The reaction was quenched with 100 mL water to give a clear solution. The mixture was extracted three times with 500 mL EtOAc. The organics were further washed twice with 50 mL brine. The organics were dried over anhydrous MgSCL. filtered and concentrated under reduced pressure to give a cream-colored foam and further dried under vacuum to give 2 g crude product. DCM was added to the material and the mixture was absorbed onto silica gel. Silica gel chromatography (0-40% (3:1 EtOAc / EtOH) / Hexane) afforded the title compound (1.1 g, 73%) LCMS (ES) m/z = 476 [M+H] ⁺ . ' H NMR (600 MHz, DMSO-d _d ) 5 ppm 11.29 (br s, 1H), 8.13 (dd, J = 7.9, 2.9 Hz, 1H), 7.74 (s, 1H), 7.48 (ddd, J = 8.8, 5.5, 2.1 Hz, 2H), 7.27 (t, J = 8.4 Hz, 2H), 6.25 (t, J = 3.0 Hz,lH), 5.44(d, J= 5.3 Hz, 1H), 4.05 - 4.13 (m, 2H), 3.35 - 3.39 (m, 1H), 2.90 - 2.92 (m, 1H), 2.73 - 2.77 (m, 2H), 2.55 - 2.62 (m, 1H), 2.50 - 2.50 (m, 1H), 2.34 - 2.44 (m, 2H).

The compounds listed in Table 8 were prepared using analogous procedures to those described in the examples above.

Table 8. List of Compounds

The compounds listed in Table 9 may be prepared using analogous procedures to those described in the examples above.

Table 9. List of Compounds

APOL1 Thallium Flux Assay

APOL1 gene is a pleiotropic gene with an association with increased likelihood of renal disease. It is expressed in the human kidney and has a soluble circulating form associated with innate immunity, which is part of human immunity to trypanosome infection. The wild-type version (GO) is the most widespread, but two isoforms, G1 and G2 are commonly found in African populations as well as populations with African ancestry. The gain of function associated with G1 and G2 leads to increased likelihood of podocyte death, as well as increased mortality of other kidney cell types, but do provide the advantage of increased resistance to subspecies of trypanosomes which have developed a resistance to the wild-type AP0L1 GO associated immunity. AP0L1 proteins form potassium-permeable cation pores in the plasma membrane. AP0L1 risk variants (G1 and G2) induce greater potassium flux than GO in cells. Thallium has identical charge and very similar atomic radius when compared to potassium and is known to pass through the ligand-gated potassium channels. To identify and develop compounds that inhibit AP0L1 associated potassium flux, a FLIPR thallium assay was performed to measure the flux of thallium (T1+) through ligand-gated potassium channels.

List of Biological Reagents

• Cell line - U2OS, DMEM/F12 adapted. Homo sapiens derived.

• AP0L1 GO (wild-type) BacMam virus - pHTBV.huApoLl.FL, Gene ID 8542. Gene symbol AP0L1. Species Homo sapiens. External Identifier Name Entrez Gene Id Alias APO-L, APOL, APOL-I, FSGS4, titer = 6.38e ⁸ PFU/ml.

• APOL1 G2 (disease-specific variant) BacMam virus - pHTBVlmcs3-ApoLl.NYK388- 389K, Gene ID 8542. Gene symbol APO-L, Gene ID alias APO-L, APOL, APOL-I, FSGS4, titer = 1.37e ⁹ PFU/ml.

List of Chemical Reagents

Note, any chemical in this protocol can be replaced with an analogous product from another supplier if needed.

• BTC-AM - a cell-permeant coumarin benzothiazole-based calcium / thallium indicator, Invitrogen catalog # B6791.

• Probenicid - Sigma catalog # P8761-100G.

• Pluronic acid F-127 - Invitrogen catalog# P6866. • Potassium gluconate - Sigma, P1847-500G.

• Calcium D-gluconate - Sigma, C8231-500G.

• Magnesium D-gluconate - Sigma, M7554-500G.

• Sodium gluconate - Sigma, S2054-500G. • Amaranth - Sigma, A1016-50G.

• T artrazine - Sigma, T0388 - 100G.

• Ouabain octahydrate - Sigma, O3125-250MG.

• Thallium (I) sulfate - Aldrich, 204625.

• HEPES - Sigma, H3375-25G. • D-(+) glucose - Sigma, G5767.

• NaOH - J.T. Baker, 1 N, catalog # 5635-02.

Solutions

Table 10. Cell growth medium

Medium was sterile filtered with 0.22 pM sterilizing filter flasks and stored at 4°C. Table 11. Chloride free buffer (all chemicals purchased from Sigma) Final pH was about 7.35 adjusted with 1 N NaOH and final osmolarity was about 315 mOsm/kg adjusted with distilled water. Buffer was sterile filtered with 0.22 pM sterilizing filter flasks and stored at 4°C.

Table 12. General buffer (for dye load, compound buffer and thallium challenge).

List of Equipment

Note, any equipment here can be replaced with a similar piece of equipment as needed.

• Incubator - 37°C, 5% CO2 - Hera Cell Vios 250i.

• Compound plates - Greiner catalog number 782270.

• Plate washer - BlueCatBio Blue washer, serial # 57429.

• biosafety cabinet - NuAire model Nu-440600, series 20, s/n 77744050202 (or equivalent).

• Sonicator - Branson model number 5510R-MTH, s/n RNB120399391E (or equivalent).

• Scale - Sartorius genius, catalog # ME2155, s/n 13604271 (or equivalent).

• Microscope - Olympus 1X50, model IX50-58F2, number 8C05054 (or equivalent).

• water bath - any suitable 37°C bath.

• FLIPR - 1536 head - Molecular devices, serial # FT0045, FT0046 and FT0529.

• FLIPR 1536-well tip gasket - Molecular devices, part # 9000-0746.

• Echo 655T - Labcyte, asset # 2T33167.

• Filter flasks - Thermo Scientific, 1 liter, 0.2 pM SFCA membrane.

• Osmometer - Fiske model 210, s/n 07040424C.

• Cell plates - Greiner Bio-one, 1536 well plate (high base), black with clear bottom, catalog #782092.

• Lids - Greiner Bio-one, catalog # 656191. • Liquid boat - Thermo Scientific Omni tray, catalog # 264728.

• Liquid dispenser - Thermo Scientific, Multi Drop Combi, type 836, s/n 836-207 and 836-81022.

• Dispense head for liquid dispenser - Thermo Scientific, catalog # 24073290, work order 3945793.

• Cell counter - Beckman Coulter ViCell XR, system ID 467740, s/n AH0602.

• pH meter - Thermo Orion 2 star, s/n B30457.

Protocol Description

Solution was made the day before the experiment

• Made distilled water-based stocks of amaranth (66 mM) and tartrazine (99 mM). o Amaranth and tartrazine stocks are good at room temperature for at least a month.

• Made a thallium sulfate buffer stock (25 mM thallium) based on chlorine free buffer. o Thallium stock is good indefinitely.

• Made 10 mM DMSO-based stocks of ouabain. o Freeze these as 500 pl stocks and keep until they are used up.

• chloride free buffer was placed at room temperature (long term storage at 4°C).

Cell transduction and plating.

• Thawed needed number of frozen vials briefly in a water bath until only a sliver of ice remained in the vial.

• Added cell stock to a 15 or 50 ml tube, then added medium drop by drop to at least a ratio of 5 ml medium to 1 ml cell stock.

• Inverted the tube twice to mix.

• Centrifuged the vial for five minutes at 300g.

• Aspirated the medium, then added 500 pl and triturated with a pl 000 pipettor.

• Added 15 ml of medium for each vial of cells used.

• Added 140 pl cell stock to 560 pl PBS and put on the ViCell to count (1:5 dilution).

• Added medium to adjust volume of cell suspension to achieve a density of 6.25e ⁵ cells / ml (to give 5K cells at 8 pl / well in 1536).

• Added a sufficient volume of APOL1 GO BacMam to create an MOI of 100. o Note - if running an Apo-Ll G2 experiment, all parameters will be exactly the same, with one exception. Use the Apo-Ll G2 BacMam instead of the Apo-Ll GO BacMam and use an MOI of 3 instead of 100.

• Gently agitated to mix the solution.

• Used a COMBI and a small tube cassette, dispensed 8 pl per well at high speed into 1536 well plate.

• Put a lid on each plate and incubated cell plates at 37°C, 5% CO2 in a cell stacker wrapped with wet paper towels.

• Discarded all extra reagents and wiped the hood with ethanol.

Preparation the day of the experiment.

• Warmed tubes of BTC-AM to room temperature in a dark container to protect from light. o When thawed, added 80 pl DMSO and vortexed to mix.

• Thawed a vial of ouabain.

• Allowed sealed, pre-stamped assay plates to come room temperature.

• Made a new 100 mM probenecid stock for the day’s compound buffer.

• Put a new gasket on the 1536 head.

• Put a new single well boat in the FLIPR for thallium buffer.

• Made a new general buffer from chloride free buffer (see details in table below). Used this to make all other buffers.

Running of the assay

• Turned on the FLIPR instrument.

• Removed cell plates from the 37°C incubator.

• Removed cell culture medium with BlueWasher on light spin.

• Added 4 pl of loading buffer using the Multidrop.

• Incubated in the dark for 60 minutes at room temperature.

• Solubilized compound plates by adding 8 pl per well of compound buffer.

• Put a cell plate and compound plate on the FLIPR and ran the compound addition protocol. o 2 l from each well of the compound plate was added to the 4 pl of loading buffer that was already resident in each well of the plate.

■ Compound stamps were done so that the vehicle load in each compound plate is 3% DMSO.

• As the cell plate contained 4 pl of dye load and the FLIPR added 2 pl of each well of the compound plate to the cell plate, the final DMSO concentration in assay was 1%.

• After the protocol was completed, the cell plate was stored in the dark at room temperature for 20 minutes.

• Ran the thallium addition protocol on the FLIPR. o The FLIPR added 2 pl of the 8 mM thallium solution from the ligand plate for a final thallium concentration of 2 mM. o In both FLIPR protocols, excitation was 470-495 nm and emission was 515-575 nm. o Aspirated source liquid - volume 2 pl, height = 6, speed - 2 pl/sec. o Dispensed liquid - volume pl, height = 10, speed 10 pl/sec. o Read interval = 1 second. o Reads pre-dispense = 10. o Reads post-dispense = 10. o Washed tips - two cycles, 3 pl per stroke, aspirate speed = 2 pl/sec, five strokes, pump speed = fast.

• Exported data with the following options:

• Export metric = AUC. Start read = 10, end read = maximum allowable.

• Corrections o spatial uniformity correction: ON o subtract bias based on sample 1 : ON

Analysis

• Positive control is in columns 35 and 36 of each compound plate.

• Negative control will be vehicle (1% DMSO) in columns 11 and 12 of each compound plate.

• Normalized data = 100*(value - low)/(high - low).

• Each plate will pass QC if the Z’ is above 0.4.

• Single shot data from the primary screen is posted as percent inhibition. • Data from full curve experiments are done as 11 point dose-response. o Results from these experiments are inhibition at each concentration as well as the pICso of entire eleven point dilution series, where pICso is the log concentration of compound at which 50% of APOL1 specific signal is achieved. Table 13 illustrates the pICso’ s of Compounds 1-223 and 226-231 determined using the procedures described above. The data demonstrates that the compounds of the invention as described herein are inhibitors of APOL1 activity.

Table 13. ApoLl Activity Data for Examples 1-223 and 226-231