Compounds and their use

This application claims the benefit of priority under 35 USC 119(e) to U.S. Provisional Application No. 63/122,690, filed on Dec. 8, 2020. The entire contents of the foregoing are hereby incorporated by reference.

Described in this specification are compounds (including salts thereof) that are modulators of RXFP1, uses of such compounds, compositions containing such compounds, intermediates useful in processes for preparing such compounds, and processes for preparing such compounds using such intermediates.

Relaxin is a pleiotropic hormone known to mediate systemic haemodynamic and renal adaptive changes during pregnancy. Relaxin has also been shown to have anti-fibrotic properties and to have beneficial effects in heart failure e.g. with acute decompensated heart failure (ADHF). Heart failure is associated with significant morbidity and mortality. It is characterized by complex tissue remodelling involving increased cardiomyocyte death and interstitial fibrosis. Relaxin activates a number of signalling cascades which have been shown to be beneficial in the setting of ischemia-reperfusion and heart failure. These signalling pathways include activation of the phosphoinositide 3-kinase pathway and activation of the nitric oxide signalling pathway (Bathgate R A et al. (2013) Physiol. Rev. 93(1): 405-480; Mentz R J et al. (2013) Am. Heart J 165(2): 193-199; Tietjens J et al. (2016) Heart 102: 95-99; Wilson S S et al. (2015) Pharmacology 35: 315-327).

Clinical trials have been conducted using unmodified recombinant human Relaxin-2, serelaxin. Continuous intravenous administration of serelaxin to hospitalized patients improved the markers of cardiac, renal and hepatic damage and congestion (Felker G M et al. (2014) J. Am. Coll. Cardiol. 64(15): 1591-1598; Metra M et al. (2013) J. Am. Coll. Cardiol. 61(2): 196-206; Teerlink J R et al. (2013) Lancet 381(9860): 29-39). However, due to the rapid clearance of serelaxin from the patients' circulation, the therapeutic effects were limited and the positive effects rapidly disappeared once intravenous injection stopped. Additionally, approximately one third of the patients experienced a significant blood pressure drop (>40 mm Hg) after receiving serelaxin intravenously, with the consequence that the dose had to be reduced by half or even more.

The cognate receptor for human relaxin is RXFP1 and is a well-validated pharmacologically important GPCR family 1c member whose activation by the hormone relaxin is associated with hemodynamic, anti-fibrotic and anti-inflammatory properties (Halls M L et al., (2015), Pharmacol Rev. 67(2): 389-440).

Small-molecule modulators of RXFP1 have been sought as relaxin mimetics. For example, Marugan, J. J., et al., WO2013/165606A1; Xiao J et al. (2013) Nat. Commun. 4:1953; and McBride A et al. (2017) Scientific Reports 7:10806 discuss small-molecule modulators of RXFP1.

Despite the foregoing, a need continues to exist for further compounds that are modulators of RXFP1 which may make the compounds especially promising for development as therapeutic agents. The compound(s) of the invention may also exhibit improved modulation of RXFP1 in comparison with other known RXFP1 modulators. The compound(s) of the invention is may also exhibit favourable pharmacokinetic profiles (for example, lower intrinsic clearance) and/or advantageous physical properties (for example, higher aqueous solubility) in comparison with other known RXFP1 modulators. Therefore, such compound(s) may be especially useful in the treatment of disease states in which modulation of RXFP1 is beneficial.

Briefly, this specification describes, in part, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Ring B is a 4- to 10-membered cycloalkyl; a 4- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; or a 4- to 10-membered cycloalkenyl;

R 7 is selected from —H, —F, —CH 3 and —OCH 3 ;

each R 8 is independently selected from C 1-4 alkyl substituted with 0-3 —F substituents; C 1-4 alkoxy; —OH; —F; and —COO(C 1-4 alkyl);

p is 0, 1 or 2;

Ring C is a 6- to 10-membered aryl; a 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4- to 10-membered cycloalkenyl; or a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen;

each R 9 is independently selected from C 1-4 alkyl, C 1-4 alkoxy, -halo and —OH;

q is 0, 1 or 2;

R 1 is selected from —COOH, —CONH 2 , —CONHMe, —CONMe 2 , —C(CH 2 OH) 2 NH 2 , —C(NH)NH 2 , —SO 2 NH 2 , —NHSO 2 Me,

X is selected from a bond, —CH 2 —, —O—, —S—, —CH 2 O— and —OCH 2 —;

Y is selected from C 2-6 alkylene substituted with 0-2 R 14 substituents; C 3-8 cycloalkylene substituted with 0-2 R 14 substituents; C 5-8 cycloalkenylene substituted with 0-2 R 14 substituents; 5- to 8-membered heterocycloalkylene having 1-3 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R 14 substituents; phenylene substituted with 0-2 R 14 substituents; 5- or 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-2 R 14 substituents; and

R 14 is selected from C 1-3 alkyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; C 1-3 alkoxy substituted with 0-3 —F substituents; cyclopropyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; —F; —OH; ═O; —CN; —NH 2 ; —NHMe; and —NMe 2 ;

Z is selected from a bond; C 1-3 alkylene substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 2-4 heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 3-4 cycloalkylene; and —CH═CH—;

R 5 is selected from —H, -Me and —F;

R 6 is —(CR 10 R 11 ) n R 12 ;

n is 0, 1 or 2;

R 10 and R 11 are each independently selected from —H, -Me and —F, or R 10 and R 11 together with the carbon to which they are attached form cyclopropyl;

R 12 is selected from C 3-8 alkyl substituted with 0-5 substituents selected from —OH, —F, —CN, and C 1-4 alkoxy; C 3-10 cycloalkyl substituted with 0-4 R 13 substituents; 5- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-4 R 13 substituents; phenyl substituted with 0-3 substituents selected from -halo, C 1-4 alkyl substituted with 0-3 —F substituents, C 3-5 cycloalkyl, —CN, —SF 5 , —OMe, —OCH 2 F, —OCHF 2 , —OCF 3 and —SO 2 CF 3 ; 6-membered heteroaryl having 1-2 nitrogen heteroatoms and substituted with 1-3 substituents selected from -halo, —SF 5 , —CF 3 , —OCF 3 and —SO 2 CF 3 ;

each R 13 is independently selected from —OH; —F; —CN; C 1-4 alkoxy substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt; and C 1-4 alkyl substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt;

U, V and W are each independently selected from C and N; provided that when U is N, R 2 is absent; when V is N, R 3 is absent; and when W is N, R 4 is absent;

and wherein

(i) R 2 , R 3 and R 4 are each independently selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me; or

(ii) U and V are each C;

R 2 and R 3 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 -Me substituents; and R 4 is selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me; or

(iii) V and W are each C;

R 3 and R 4 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 -Me substituents; and R 2 is selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me.

This specification also describes, in part, a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition selected from the group consisting of heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury.

This specification also describes, in part, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury.

This specification also describes, in part, a method for treating a disease or condition selected from the group consisting of heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

This specification also describes, in part, an Intermediate compound (as described herein), or a salt thereof.

This specification also describes, in part, a process for preparing a compound of Formula (I), or pharmaceutically acceptable salt thereof, using an Intermediate compound (as described herein), or a salt thereof.

Further aspects of Applicant's invention will be apparent to one skilled in the art from reading this specification.

Many embodiments are detailed throughout the specification and will be apparent to a reader skilled in the art. The specification is not to be interpreted as being limited to any particular embodiment(s) described herein.

In an embodiment there is provided a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

A is

Ring B is a 4- to 10-membered cycloalkyl; a 4- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; or a 4- to 10-membered cycloalkenyl;

R 7 is selected from —H, —F, —CH 3 and —OCH 3 ;

each R 8 is independently selected from C 1-4 alkyl substituted with 0-3 —F substituents; C 1-4 alkoxy; —OH; —F; and —COO(C 1-4 alkyl);

p is 0, 1 or 2;

Ring C is a 6- to 10-membered aryl; a 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4- to 10-membered cycloalkenyl; or a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen;

each R 9 is independently selected from C 1-4 alkyl, C 1-4 alkoxy, -halo and —OH;

q is 0, 1 or 2;

R 1 is selected from —COOH, —CONH 2 , —CONHMe, —CONMe 2 , —C(CH 2 OH) 2 NH 2 , —C(NH)NH 2 , —SO 2 NH 2 , —NHSO 2 Me,

X is selected from a bond, —CH 2 —, —O—, —S—, —CH 2 O— and —OCH 2 —;

Y is selected from C 2-6 alkylene substituted with 0-2 R 14 substituents; C 3-8 cycloalkylene substituted with 0-2 R 14 substituents; C 5-8 cycloalkenylene substituted with 0-2 R 14 substituents; 5- to 8-membered heterocycloalkylene having 1-3 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R 14 substituents; phenylene substituted with 0-2 R 14 substituents; 5- or 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-2 R 14 substituents; and

R 14 is selected from C 1-3 alkyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; C 1-3 alkoxy substituted with 0-3 —F substituents; cyclopropyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; —F; —OH; ═O; —CN; —NH 2 ; —NHMe; and —NMe 2 ;

Z is selected from a bond; C 1-3 alkylene substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 2-4 heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 3-4 cycloalkylene; and —CH═CH—;

R 5 is selected from —H, -Me and —F;

R 6 is —(CR 10 R 11 ) n R 12 ;

n is 0, 1 or 2;

R 10 and R 11 are each independently selected from —H, -Me and —F, or R 10 and R 11 together with the carbon to which they are attached form cyclopropyl;

R 12 is selected from C 3-8 alkyl substituted with 0-5 substituents selected from —OH, —F, —CN, and C 1-4 alkoxy; C 3-10 cycloalkyl substituted with 0-4 R 13 substituents; 5- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-4 R 13 substituents; phenyl substituted with 0-3 substituents selected from -halo, C 1-4 alkyl substituted with 0-3 —F substituents, C 3-5 cycloalkyl, —CN, —SF 5 , —OMe, —OCH 2 F, —OCHF 2 , —OCF 3 and —SO 2 CF 3 ; 6-membered heteroaryl having 1-2 nitrogen heteroatoms and substituted with 1-3 substituents selected from -halo, —SF 5 , —CF 3 , —OCF 3 and —SO 2 CF 3 ;

each R 13 is independently selected from —OH; —F; —CN; C 1-4 alkoxy substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt; and C 1-4 alkyl substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt;

U, V and W are each independently selected from C and N; provided that when U is N, R 2 is absent; when V is N, R 3 is absent; and when W is N, R 4 is absent;

and wherein

(i) R 2 , R 3 and R 4 are each independently selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me; or

(ii) U and V are each C;

R 2 and R 3 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 -Me substituents; and R 4 is selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me; or

(iii) V and W are each C;

R 3 and R 4 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 -Me substituents; and R 2 is selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me.

The following embodiments of moieties A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , n, p, q, r, U, V, W, X, Y, and Z may be applied, alone or in combination, to the descriptions of the compounds of Formula (I) provided herein.

Ring B is a 4- to 10-membered cycloalkyl; a 4- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; or a 4- to 10-membered cycloalkenyl.

Ring B is a monocyclic 5- to 7-membered cycloalkyl optionally bridged with C 1-3 alkylene; a monocyclic 5- to 7-membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen and oxygen and optionally bridged with C 1-3 alkylene; a monocyclic 5- to 7-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen and optionally bridged with C 1-3 alkylene; or a monocyclic 5- to 7-membered cycloalkenyl optionally bridged with C 1-3 alkylene.

Ring B is a 4- to 10-membered cycloalkyl, or a 4- to 10-membered cycloalkenyl.

Ring B is a 5- to 8-membered cycloalkyl, or a 5- to 8-membered cycloalkenyl.

Ring B is a monocyclic 5- to 7-membered cycloalkyl optionally bridged with C 1-3 alkylene; or a monocyclic 5- to 7-membered cycloalkenyl optionally bridged with C 1-3 alkylene.

Ring B is cyclohexyl optionally bridged with C 1-2 alkylene, or cyclohexenyl optionally bridged with C 1-2 alkylene.

Ring B is cyclohexyl 1,4-bridged with C 1-2 alkylene, or cyclohexenyl 1,4-bridged with C 1-2 alkylene.

Ring B is bicyclo[2.2.1]heptanyl or bicyclo[2.2.1]hept-2-enyl.

Ring B is bicyclo[2.2.1]heptanyl.

R 7 is selected from —H, —F, —CH 3 and —OCH 3 .

R 7 is selected from —H and —F.

R 7 is —H.

each R 8 is independently selected from C 1-4 alkyl substituted with 0-3 —F substituents; C 1-4 alkoxy; —OH; —F; and —COO(C 1-4 alkyl).

each R 8 is independently selected from C 1-2 alkyl substituted with 0-3 —F substituents; C 1-2 alkoxy; —OH; and —F.

each R 8 is independently selected from C 1-2 alkyl substituted with 0-3 —F substituents; and —F.

each R 8 is independently selected from -Me and —F.

p is 0, 1 or 2.

p is 0 or 1.

p is 0.

Ring C is a 6- to 10-membered aryl; a 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4- to 10-membered cycloalkenyl; or a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen.

Ring C is phenyl; a monocyclic 5- or 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a monocyclic 4- to 7-membered cycloalkenyl optionally bridged with C 1-3 alkylene; or a monocyclic 4- to 7-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen and optionally bridged with C 1-3 alkylene.

Ring C is a monocyclic 5- to 7-membered cycloalkenyl optionally bridged with C 1-2 alkylene; or a monocyclic 5- to 7-membered heterocycloalkenyl having 1 oxygen heteroatom and optionally bridged with C 1-2 alkylene.

Ring C is a mono- or poly-cyclic 6- to 10-membered aryl.

Ring C is phenyl.

Ring C is not phenyl.

each R 9 is independently selected from C 1-4 alkyl, C 1-4 alkoxy, -halo and —OH.

each R 9 is independently selected from C 1-2 alkyl, C 1-2 alkoxy, -halo and —OH.

q is 0, 1 or 2.

q is 0 or 1.

q is 0.

R 1 is selected from —COOH, —CONH 2 , —CONHMe, —CONMe 2 , —C(CH 2 OH) 2 NH 2 , —C(NH)NH 2 , —SO 2 NH 2 , —NHSO 2 Me,

R 1 is —COOH or a bioisotere of a carboxylic acid such as tetrazolyl. Such bioisoteres of carboxylic acids will be apparent to a person of skill in the art.

R 1 is selected from —COOH, —CONH 2 ,

R 1 is —COOH.

X is selected from a bond, —CH 2 —, —O—, —S—, —CH 2 O— and —OCH 2 —.

X is selected from a bond, —CH 2 —, —O—, —CH 2 O— and —OCH 2 —.

X is selected from a bond, —CH 2 —, and —O—.

X is selected from —CH 2 — and —O—.

X is —O—.

Y is selected from C 2-6 alkylene substituted with 0-2 R 14 substituents; C 3-8 cycloalkylene substituted with 0-2 R 14 substituents; C 5-8 cycloalkenylene substituted with 0-2 R 14 substituents; 5- to 8-membered heterocycloalkylene having 1-3 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R 14 substituents; phenylene substituted with 0-2 R 14 substituents; 5- or 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-2 R 14 substituents; and

Y is selected from C 2-6 alkylene substituted with 0-1 R 14 substituents; C 3-8 cycloalkylene substituted with 0-1 R 14 substituents; C 5-8 cycloalkenylene substituted with 0-1 R 14 substituents; 5- to 8-membered heterocycloalkylene having 1-3 heteroatoms independently selected from oxygen and sulfur and substituted with 0-1 R 14 substituents; phenylene substituted with 0-1 R 14 substituents; 5- or 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-1 R 14 substituents; and

Y is selected from C 2-4 alkylene substituted with 0-2 R 14 substituents; C 3-8 cycloalkylene substituted with 0-2 R 14 substituents; and 5- to 8-membered heterocycloalkylene having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R 14 substituents.

Y is selected from C 2-4 alkylene substituted with 0-1 R 14 substituents; C 3-8 cycloalkylene substituted with 0-1 R 14 substituents; and 5- to 8-membered heterocycloalkylene having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-1 R 14 substituents.

Y is selected from C 4-6 cycloalkylene substituted with 0-1 R 14 substituents; and 5- or 6-membered heterocycloalkylene having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-1 R 14 substituents.

Y is C 3-8 cycloalkylene substituted with 0-2 R 14 substituents.

Y is C 4-6 cycloalkylene substituted with 0-2 R 14 substituents.

Y is C 3-8 cycloalkylene substituted with 0-1 R 14 substituents.

Y is C 4-6 cycloalkylene substituted with 0-1 R 14 substituents.

Y is cyclohexylene substituted with 0-2 R 14 substituents.

Y is cyclohexylene substituted with 0-1 R 14 substituents.

Y is cyclohexylene substituted with 1 R 14 substituent.

Optionally, in any of the embodiments of Y described herein, the X and Z substituents are bonded to Y such that, where there are sufficient ring or chain atoms in Y, the X and Z substituents are not in a geminal or vicinal configuration.

r is 1, 2 or 3.

r is 1 or 2.

r is 2.

R 14 is selected from C 1-3 alkyl substituted with 0-1 substituents selected from —OH, —OMe, —F and —CN; C 1-3 alkoxy substituted with 0-1 —F substituents; cyclopropyl substituted with 0-1 substituents selected from —OH, —OMe, —F and —CN; —F; —OH; ═O; —CN; —NH 2 ; —NHMe; and —NMe 2 .

R 14 is selected from C 1-2 alkyl substituted with 0-1 substituents selected from —OH, —OMe, —F and —CN; C 1-2 alkoxy substituted with 0-1 —F substituents; cyclopropyl substituted with 0-1 substituents selected from —OH, —OMe, —F and —CN; —F; —OH; ═O; —CN; —NH 2 ; —NHMe; and —NMe 2 .

R 14 is selected from —H, -Me, -Et, —F, —OH, ═O, —OMe, —OEt, —CF 3 , —CH 2 OH, —CH 2 OMe, —CN, —CH 2 CN, —NH 2 , —NHMe and —NMe 2 .

R 14 is —H.

R 14 is not —H.

R 14 is -Me.

Z is selected from a bond; C 1-3 alkylene substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 2-4 heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 3-4 cycloalkylene; and —CH═CH—.

Z is selected from a bond; C 1-2 alkylene substituted with 0-1 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 2-3 heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-1 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 3-4 cycloalkylene; and —CH═CH—.

Z is selected from a bond, —CH 2 —, —CH 2 CH 2 —, —OCH 2 —, —CH 2 O—, —C(CH 3 ) 2 O—, —CH 2 CH 2 O—, —CH 2 CH 2 CH 2 O—, —CH 2 NH—, —CH(NH 2 )—, —CH(NMe 2 )-, —CH 2 CH(NMe 2 )-, —CH(NMe 2 )CH 2 —, —CH 2 CH(NH 2 )—, —CH(NH 2 )CH 2 —, —CH═CH—,

Z is selected from a bond, —CH 2 —, —CH 2 CH 2 —, and —CH 2 O—.

Z is a bond.

R 5 is selected from —H, -Me and —F.

R 5 is —H.

R 6 is —(CR 10 R 11 ) n R 12 .

R 6 is —(CR 10 R 11 )R 12 .

R 6 is —(CH 2 )R 12 .

R 6 is —R 12 .

R 6 is selected from

R 6 is selected from

R 6 is

n is 0, 1 or 2.

n is 0 or 1.

n is 0.

n is 1.

R 10 and R 11 are each independently selected from —H, -Me and —F, or R 10 and R 11 together with the carbon to which they are attached form cyclopropyl.

R 10 and R 11 are each independently selected from —H, -Me and —F.

R 10 and R 11 are each —H.

R 12 is selected from C 3-8 alkyl substituted with 0-5 substituents selected from —OH, —F, —CN, and C 1-4 alkoxy; C 3-10 cycloalkyl substituted with 0-4 R 13 substituents; 5- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-4 R 13 substituents; phenyl substituted with 0-3 substituents selected from -halo, C 1-4 alkyl substituted with 0-3 —F substituents, C 3-5 cycloalkyl, —CN, —SF 5 , —OMe, —OCH 2 F, —OCHF 2 , —OCF 3 and —SO 2 CF 3 ; 6-membered heteroaryl having 1-2 nitrogen heteroatoms and substituted with 1-3 substituents selected from -halo, —SF 5 , —CF 3 , —OCF 3 and —SO 2 CF 3 ;

R 12 is selected from C 3-8 alkyl substituted with 0-3 substituents selected from —OH, —F, —CN, and C 1-4 alkoxy; C 3-10 cycloalkyl substituted with 0-3 R 13 substituents; and 5- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-3 R 13 substituents.

R 12 is selected from C 4-6 alkyl substituted with 0-3 substituents selected from —F, —CN, and C 1-2 alkoxy; C 4-6 cycloalkyl substituted with 0-3 R 13 substituents; and 5- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-3 R 13 substituents.

R 12 is selected from C 4-6 alkyl substituted with 0-2 substituents selected from —F, —CN, and C 1-2 alkoxy; C 4-6 cycloalkyl substituted with 0-1 R 13 substituents; and 5- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-1 R 13 substituents.

R 12 is selected from C 4-6 alkyl substituted with 0-3 —F substituents; and C 4-6 cycloalkyl substituted with 0-3 substituents selected from —F and -Me.

R 12 is selected from C 3-6 alkyl substituted with 0-3 —F substituents; and C 3-6 cycloalkyl substituted with 0-3 substituents selected from —F and -Me.

R 12 is selected from C 3-6 alkyl substituted with 0-3 —F substituents; and C 3-6 cycloalkyl substituted with —F or -Me.

R 12 is selected from tert-butyl substituted with 0-3 —F substituents; cyclobutyl substituted with 0-2 substituents selected from —F and -Me; and bicyclo[1.1.1]pentanyl substituted with 0-2 substituents selected from —F and -Me.

R 12 is selected from tert-butyl substituted with 0-3 —F substituents; cyclobutyl substituted with 0-2 substituents selected from —F and -Me; and bicyclo[1.1.1]pentanyl substituted with 0-2 substituents selected from —F and -Me.

R 12 is selected from tert-butyl substituted with 0-3 —F substituents; cyclobutyl substituted with 0-1 substituents selected from —F and -Me; and bicyclo[1.1.1]pentanyl substituted with 0-2 substituents selected from —F and -Me.

R 12 is selected from

R 12 is selected from

R 12 is

R 12 is selected from phenyl substituted with 0-3 substituents selected from -halo, C 1-4 alkyl substituted with 0-3 —F substituents, C 3-8 cycloalkyl, —CN, —SF 5 , —OMe, —OCH 2 F, —OCHF 2 , —OCF 3 and —SO 2 CF 3 ; 6-membered heteroaryl having 1-2 nitrogen heteroatoms and substituted with 1-3 substituents selected from -halo, —SF 5 , —CF 3 , —OCF 3 and —SO 2 CF 3 ;

R 12 is selected from phenyl substituted with 1-2 substituents selected from -halo, C 1-4 alkyl substituted with 0-3 —F substituents, C 3-8 cycloalkyl, —CN, —SF 5 , —OMe, —OCH 2 F, —OCHF 2 , —OCF 3 and —SO 2 CF 3 .

R 12 is selected from

each substituted with 0-1 substituents selected from -halo, -Me, —CF 3 and —CN.

R 12 is selected from

each R 13 is independently selected from —OH; —F; —CN; C 1-4 alkoxy substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt; and C 1-4 alkyl substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt.

each R 13 is independently selected from —F; —CN; C 1-2 alkoxy substituted with 0-1 substituents selected from —F, —OMe and —OEt; and C 1-2 alkyl substituted with 0-1 substituents selected from —F, —OMe and —OEt.

each R 13 is independently selected from —F; —CN; C 1-4 alkoxy; and C 1-4 alkyl.

each R 13 is independently selected from —F; C 1-2 alkoxy; and C 1-2 alkyl.

each R 13 is independently selected from —F; —OMe; and -Me.

each R 13 is —F.

each R 13 is -Me.

U, V and W are each independently selected from C and N; provided that when U is N, R 2 is absent; when V is N, R 3 is absent; and when W is N, R 4 is absent.

U, V and W are each C.

R 2 , R 3 and R 4 are each independently selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me.

R 2 is selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe.

R 2 is selected from —H, -halo, —CN, C 1-2 alkyl substituted with 0-3 —F substituents, C 1-2 alkyl substituted with 0-1 —OMe substituents, and C 3-4 cycloalkyl substituted with 0-1 substituents selected from —F and —OMe.

R 2 is selected from —H, -halo, —CN, C 1-2 alkyl substituted with 0-3 —F substituents, C 1-2 alkyl substituted with 0-1 —OMe substituents, and cyclopropyl.

R 2 is not —H.

R 2 is —CN or —F.

R 2 is —CN.

R 2 is —F.

R 3 is selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe.

R 3 is selected from —H, -halo, —CN, C 1-2 alkyl substituted with 0-3 —F substituents, C 1-2 alkyl substituted with 0-1 —OMe substituents, and C 3-4 cycloalkyl substituted with 0-1 substituents selected from —F and —OMe.

R 3 is selected from —H, -halo, —CN, C 1-2 alkyl substituted with 0-3 —F substituents, C 1-2 alkyl substituted with 0-1 —OMe substituents, and cyclopropyl.

R 3 is —H.

R 4 is selected from —H, —F, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me.

R 4 is selected from —H, —F, and C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe.

R 4 is selected from —F and C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe.

R 4 is selected from —F and C 1-3 alkoxy substituted with 0-2 substituents selected from —F and —OMe.

R 4 is selected from —F and C 1-3 alkoxy substituted with 0-2 substituents selected from —F and —OMe.

R 4 is C 1-3 alkoxy substituted with 0-2 substituents selected from —F and —OMe.

R 4 is —OMe or —OEt.

R 4 is not —H.

R 4 is selected from —F and —OMe.

R 4 is —OMe.

R 2 and R 3 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 -Me substituents; and U and V are each C.

R 3 and R 4 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 -Me substituents; and V and W are each C. Optionally, R 3 and R 4 are selected such that the ring containing R 3 , R 4 , V and W is

and wherein said ring is optionally substituted with 0-2 -Me substituents. Optionally, R 3 and R 4 are selected such that the ring containing R 3 , R 4 , V and W is or

In one embodiment, R 2 is —CN; R 3 is —H; R 4 is —OMe; and R 5 is —H.

In one embodiment, R 2 is —F; R 3 is —H; R 4 is —OMe; and R 5 is —H.

In one embodiment A is

Ring B is a 4- to 10-membered cycloalkyl; a 4- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; or a 4- to 10-membered cycloalkenyl;

R 7 is selected from —H, —F, —CH 3 and —OCH 3 ;

each R 8 is independently selected from C 1-4 alkyl substituted with 0-3 —F substituents; C 1-4 alkoxy; —OH; —F; and —COO(C 1-4 alkyl);

p is 0, 1 or 2;

Ring C is a 6- to 10-membered aryl; a 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4- to 10-membered cycloalkenyl; or a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen;

each R 9 is independently selected from C 1-4 alkyl, C 1-4 alkoxy, -halo and —OH;

q is 0, 1 or 2;

R 1 is selected from —COOH, —CONH 2 , —CONHMe, —CONMe 2 , —C(CH 2 OH) 2 NH 2 , —C(NH)NH 2 , —SO 2 NH 2 , —NHSO 2 Me,

X is selected from a bond, —CH 2 —, —O—, —S—, —CH 2 O— and —OCH 2 —;

Y is selected from C 2-6 alkylene substituted with 0-2 R 14 substituents; C 3-8 cycloalkylene substituted with 0-2 R 14 substituents; C 5-8 cycloalkenylene substituted with 0-2 R 14 substituents; 5- to 8-membered heterocycloalkylene having 1-3 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R 14 substituents; phenylene substituted with 0-2 R 14 substituents; 5- or 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-2 R 14 substituents; and

R 14 is selected from C 1-3 alkyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; C 1-3 alkoxy substituted with 0-3 —F substituents; cyclopropyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; —F; —OH; ═O; —CN; —NH 2 ; —NHMe; and —NMe 2 ;

Z is selected from a bond; C 1-3 alkylene substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 2-4 heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 3-4 cycloalkylene; and —CH═CH—;

R 5 is selected from —H, -Me and —F;

R 6 is —(CR 10 R 11 ) n R 12 ;

n is 0, 1 or 2;

R 10 and R 11 are each independently selected from —H, -Me and —F, or R 10 and R 11 together with the carbon to which they are attached form cyclopropyl;

R 12 is selected from C 3-8 alkyl substituted with 0-5 substituents selected from —OH, —F, —CN, and C 1-4 alkoxy; C 3-10 cycloalkyl substituted with 0-4 R 13 substituents; 5- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-4 R 13 substituents; phenyl substituted with 0-3 substituents selected from -halo, C 1-4 alkyl substituted with 0-3 —F substituents, C 3-5 cycloalkyl, —CN, —SF 5 , —OMe, —OCH 2 F, —OCHF 2 , —OCF 3 and —SO 2 CF 3 ; 6-membered heteroaryl having 1-2 nitrogen heteroatoms and substituted with 1-3 substituents selected from -halo, —SF 5 , —CF 3 , —OCF 3 and —SO 2 CF 3 ;

each R 13 is independently selected from —OH; —F; —CN; C 1-4 alkoxy substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt; and C 1-4 alkyl substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt;

U, V and W are each independently selected from C and N; provided that when U is N, R 2 is absent; when V is N, R 3 is absent; and when W is N, R 4 is absent;

R 2 and R 3 are each independently selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me; and

R 4 is selected from —F and C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe; optionally R 4 is C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe; optionally R 4 is —OMe.

In one embodiment A is

Ring B is a 4- to 10-membered cycloalkyl; a 4- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen; or a 4- to 10-membered cycloalkenyl;

R 7 is —H;

each R 8 is independently selected from C 1-4 alkyl substituted with 0-3 —F substituents; C 1 . 4 alkoxy; —OH; —F; and —COO(C 1-4 alkyl);

p is 0, 1 or 2, optionally p is 0;

Ring C is a 6- to 10-membered aryl; a 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4- to 10-membered cycloalkenyl; or a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen;

each R 9 is independently selected from C 1-4 alkyl, C 1-4 alkoxy, -halo and —OH;

q is 0, 1 or 2, optionally q is 0;

R 1 is —COOH;

X is selected from a bond, —CH 2 —, —O—, —S—, —CH 2 O— and —OCH 2 —; optionally X is —O—;

Y is

r is 1 or 2;

R 14 is selected from C 1-3 alkyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; C 1-3 alkoxy substituted with 0-3 —F substituents; cyclopropyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; —F; —OH; ═O; —CN; —NH 2 ; —NHMe; and —NMe 2 ;

Z is selected from a bond; C 1-3 alkylene substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 2-4 heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-2 substituents selected from -Me, —NH 2 , —NHMe and —NMe 2 ; C 3-4 cycloalkylene; and —CH═CH—; optionally Z is a bond;

R 5 is selected from —H, -Me and —F, optionally R 5 is —H;

R 6 is —(CR 10 R 11 ) n R 12 ;

n is 0, 1 or 2;

R 10 and R 11 are each independently selected from —H, -Me and —F, or R 10 and R 11 together with the carbon to which they are attached form cyclopropyl;

R 12 is selected from C 4-6 alkyl substituted with 0-3 substituents selected from —F, —CN, and C 1-2 alkoxy; C 4-6 cycloalkyl substituted with 0-3 R 13 substituents; and 5- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-3 R 13 substituents; or

R 12 is selected from

each substituted with 0-1 substituents selected from -halo, -Me, —CF 3 and —CN;

each R 13 is independently selected from —OH; —F; —CN; C 1-4 alkoxy substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt; and C 1-4 alkyl substituted with 0-3 substituents selected from —F, —OH, —OMe and —OEt;

U, V and W are each independently selected from C and N; provided that when U is N, R 2 is absent; when V is N, R 3 is absent; and when W is N, R 4 is absent;

R 2 and R 3 are each independently selected from —H, -halo, —CN, C 1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and -Me; and

R 4 is selected from —F and C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe; optionally R 4 is C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe; optionally R 4 is —OMe.

In one embodiment, A is

Ring B is a 5- to 8-membered cycloalkyl, or a 5- to 8-membered cycloalkenyl;

R 7 is selected from —H and —F;

each R 8 is independently selected from C 1-2 alkyl substituted with 0-3 —F substituents; and —F;

p is 0 or 1; optionally p is 0;

R 1 is selected from —COOH, —CONH 2 ,

X is —O—;

Y is

r is 1 or 2;

R 14 is selected from C 1-2 alkyl substituted with 0-1 substituents selected from —OH, —OMe, —F and —CN; C 1-2 alkoxy substituted with 0-1 —F substituents; cyclopropyl substituted with 0-1 substituents selected from —OH, —OMe, —F and —CN; —F; —OH; ═O; —CN; —NH 2 ; —NHMe; and —NMe 2 ;

Z is a bond;

R 5 is —H;

R 6 is —(CR 10 R 11 ) n R 12 ;

n is 0 or 1; optionally n is 1;

R 10 and R 11 are each independently selected from —H, -Me and —F, or R 10 and R 11 together with the carbon to which they are attached form cyclopropyl;

R 12 is selected from C 4-6 alkyl substituted with 0-3 substituents selected from —F, —CN, and C 1-2 alkoxy; C 4-6 cycloalkyl substituted with 0-3 R 13 substituents; and 5- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-3 R 13 substituents; or

R 12 is selected from

each substituted with 0-1 substituents selected from -halo, -Me, —CF 3 and —CN;

each R 13 is independently selected from —F; —CN; C 1-2 alkoxy substituted with 0-1 substituents selected from —F, —OMe and —OEt; and C 1-2 alkyl substituted with 0-1 substituents selected from —F, —OMe and —OEt;

U, V and W are each C;

R 2 is selected from —H, -halo, —CN, C 1-2 alkyl substituted with 0-3 —F substituents, C 1-2 alkyl substituted with 0-1 —OMe substituents, and cyclopropyl; optionally R 2 is —F or —CN;

R 3 is selected from —H, -halo, —CN, C 1-2 alkyl substituted with 0-3 —F substituents, C 1-2 alkyl substituted with 0-1 —OMe substituents, and cyclopropyl; optionally R 3 is —H;

R 4 is selected from —F and C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe; optionally R 4 is C 1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe; optionally R 4 is —OMe.

In an embodiment, there is provided a compound of Formula (IIa) or Formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein R 2 and R 6 are as defined for Formula (I).

In an embodiment, there is provided a compound of Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —F or —CN; and R 6 is selected from

In an embodiment, there is provided a compound of Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —F; and R 6 is

In an embodiment, there is provided a compound of Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —CN; and R 6 is

In an embodiment, there is provided a compound of Formula (IIa) or Formula (IIb), or a CH 3 pharmaceutically acceptable salt thereof, wherein R 2 is —CN; and R 6 is

In an embodiment, there is provided a compound of Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —CN; and R 6 is

In an embodiment, there is provided a compound of Formula (IIIa) or Formula (IIIb):

or a pharmaceutically acceptable salt thereof, wherein R 2 and R 6 are as defined for Formula (I).

In an embodiment, there is provided a compound of Formula (IIIa) or Formula (IIIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —F or —CN; and R 6 is selected from

In an embodiment, there is provided a compound of Formula (IIIa) or Formula (IIIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —F; and R 6 is

In an embodiment, there is provided a compound of Formula (IIIa) or Formula (IIIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —CN; and R 6 is

In an embodiment, there is provided a compound of Formula (IIIa) or Formula (IIIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —CN; and R 6 is

In an embodiment, there is provided a compound of Formula (IIIa) or Formula (IIIb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —CN; and R 6 is

In an embodiment, there is provided a compound of Formula (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 2 is —F or —CN; and R 6 is selected from

In an embodiment, there is provided a compound of Formula (IVa) or Formula (IVb):

or a pharmaceutically acceptable salt thereof, wherein R 2 and R 6 are as defined for Formula (I).

In an embodiment, there is provided a compound of Formula (IVa) or Formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R 2 is —F or —CN; and R 6 is selected from

In an embodiment, the compound of Formula (I) is

pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula (I) is

In an embodiment, the compound of Formula (I) is

In an embodiment, the compound of Formula (I) is

In an embodiment, the compound of Formula (I) is

In an embodiment, a compound is provided that is any one of the compounds from COMPOUND LIST A, or a pharmaceutically acceptable salt thereof.

In an embodiment, a compound is provided that is any one of the compounds from COMPOUND LIST A.

In an embodiment, the compound of Formula (I) is selected from the compounds of COMPOUND LIST A, or pharmaceutically acceptable salts thereof.

In an embodiment, the compound of Formula (I) is selected from the compounds of COMPOUND LIST A.

Compound List a:

4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((cyclobutylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-(fluoromethoxy)-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methyl-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 6-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylic acid; 4-(2-fluoro-5-((3-(isopropylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-(cyclohexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-(difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((3-(fluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((perfluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((3-fluoro-5-(pentafluoro-_ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-cyano-4-methylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-(trifluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((4-bromo-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((2-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-chlorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((2-chloro-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-bromo-4-cyanophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((4-cyano-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((5-chloropyridazin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((6-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((4-(trifluoromethyl)pyrimidin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3,3-difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-(isobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((2,2-dimethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((1-(1-methylcyclopropyl)ethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((2,4-dimethylpentan-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclohexyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((2-cyano-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 3-(5-((4-carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide; 4-(5-((3-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((3-methylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2-((2,2-dimethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2-((2-ethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2-((3,3-dimethylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2-((2,4-dimethylpentan-3-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((1-(1-methylcyclopropyl)ethyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclohexyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-(isobutylcarbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclopropyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2-((2-cyano-2-methylpropyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((cyclopropylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((1-cyanocyclopropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((3-methylcyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-hydroxycyclopentyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2-hydroxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((1-fluoro-2-methylpropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-isopropylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-(methoxymethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methoxycyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((adamantan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((cycloheptylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-propylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((2,2,3,3-tetramethylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2-(isopropylamino)-2-oxoethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-ethylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((3,3-dimethylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2-fluoro-3-hydroxypropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((1-methylcyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(butylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-fluorocyclopentyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-cyanocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-fluorocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2,2-difluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2-fluoro-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(tert-butylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((1-methylcyclopropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((4,4-difluoro-1-hydroxycyclohexyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((2,2,3,3,3-pentafluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-hydroxycycloheptyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-(ethoxymethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methylcycloheptyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-isobutylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((4-cyanocyclohexyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((2-phenylpropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((1-(hydroxymethyl)cyclopentyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methoxycyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-([1,1′-bi(cyclopropan)]-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3-hydroxyadamantan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(((4-(difluoromethyl)pyrimidin-2-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(propylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(hexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((2-phenylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((1-cyclohexylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(cyclohexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3-isopropoxypropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3,4-difluorobenzyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((3-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(tert-pentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((4,4-dimethylcyclohexyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((2-methoxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3,3-dimethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2-fluoro-2-phenylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3-cyclopropylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((2-(2,2,2-trifluoroethyl)cyclohexyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3-fluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((2,5-dimethylbenzyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((3-methylbenzyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-(cyclopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((1-phenylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(neopentylcarbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((3-ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 3-(5-((4-carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid; 3-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((4-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)thiophen-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-methyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-((cycloheptylmethyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-(((1-phenylcyclopropyl)methyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-(((3-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-chlorophenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-((3-fluoro-3-methylbutan-2-yl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-(tert-pentylcarbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-((2-fluoro-2-methylpropyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((5-chloro-2-((2-cyclopropylpropan-2-yl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((2-((3-fluorobenzyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((2-((2-ethylbutyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((5-methyl-2-(pentan-3-ylcarbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((5-methyl-2-((4-methylcyclohexyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((5-methyl-2-((3-methylbutan-2-yl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((5-methyl-2-((3-methylcyclobutyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((2-(((1-fluorocyclobutyl)methyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-methylphenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((5-methyl-2-(((1-methylcyclopropyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((4,4,4-trifluorobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-(cyclobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((4-(difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-(pentafluoro-_ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((4-(pentafluoro-_ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((2,6-difluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((3-iodophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3,4,5-trifluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-(tert-butyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-cyclopropylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-cyano-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-methoxy-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3-(difluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((3-isopropylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(5-((3-((3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-(difluoromethoxy)-2-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((3-((3-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((3-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 4-(5-((2,4-dimethyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((4,5-dimethyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)naphthalen-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-methyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 3-(4-methoxy-3-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)propanoic acid; 3-(5-((1H-pyrazol-4-yl)methyl)-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 2-(4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazol-1-yl)acetic acid; 1-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-5-carboxylic acid; 1-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-3-carboxylic acid; 2-(4-methoxy-3-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)benzyl)benzoic acid; 2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-3,4′-dimethoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2,2′-difluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)nicotinic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxylic acid; 2′-fluoro-4,4′-dimethoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′,4-difluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′,3-difluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2,2′-difluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; 2-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-2-yl)acetic acid; 2′,3-difluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 3-(5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-2-yl)propanoic acid; 3-(5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)propanoic acid; 3-(dimethylamino)-2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 4-((2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)butanoic acid; 2′-fluoro-4′-methoxy-3,5-dimethyl-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2-(6-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-2,3-dihydrobenzofuran-3-yl)acetic acid; (5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-2-yl)glycine; 2-((5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)oxy)acetic acid; 3-(6-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-3-yl)propanoic acid; 2-((2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)-2-methylpropanoic acid; 2-((2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid; 3-(2-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)thiazol-5-yl)propanoic acid; 3-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 3-(6-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridazin-3-yl)propanoic acid; 2′-fluoro-4′-methoxy-3-methyl-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-3-hydroxy-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 3-(5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)propanoic acid; 3-(2′-fluoro-3,4′-dimethoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; (E)-3-(5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)acrylic acid; 2-(5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylic acid; 2-(5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylic acid; 3-(6-fluoro-4-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(4′-(2-amino-1,3-dihydroxypropan-2-yl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(4′-(3-amino-4-hydroxy-3-(hydroxymethyl)butyl)-3′,6-difluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-2-oxopyridin-1(2H)-yl)propanoic acid; 2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 3-(4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propanoic acid; 2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid; 6-fluoro-4-methoxy-N3-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)-[1,1′-biphenyl]-3,4′-dicarboxamide; 2-(4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)acetic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-2-carboxylic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 2-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)oxazole-4-carboxylic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)pyrazine-2-carboxylic acid; 2-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)isonicotinic acid; 6-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)nicotinic acid; 6-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)pyrimidine-2-carboxylic acid; 2-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; 3-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; 3-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-3-carboxylic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-2-carboxylic acid; 2-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiazole-4-carboxylic acid; 2-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiazole-5-carboxylic acid; 1-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid; 2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 2-amino-3-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; 2-(dimethylamino)-2-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; 2-(dimethylamino)-2-(2′-fluoro-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; 2′-fluoro-5′-((3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-((3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-5′-((3-((3-fluoro-5-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′,4′-difluoro-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-((3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 5′-((3-((3-cyano-4-fluorophenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 5′-((3-((3-cyano-5-fluorophenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((3-((1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-((3-((1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4-hydroxy-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2-(2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; 3-(2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; 2-(2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; 3-(2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 3-(5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-1,3,4-thiadiazol-2-yl)propanoic acid; 3-(2-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-5-yl)propanoic acid; 3-(6-fluoro-4-methoxy-4′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(6-fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2-((2′-cyano-4′-methoxy-5′-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid; 2-((2′-fluoro-4′-methoxy-5′-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((7-(tert-butoxycarbonyl)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((4-((4-fluoro-3-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-(neopentylcarbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-((4-fluoro-3-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((4-((4-fluoro-3-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-((4-fluoro-3-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cycloheptyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-fluoro-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclohexyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-(trifluoromethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-(trifluoromethyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-(difluoromethyl)-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(3-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-methoxy-2-methyl-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-ethyl-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-cyano-2-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 1-methyl-4-((1-methyl-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid; 1-methyl-4-((1-methyl-6-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-1H-indazol-4-yl)oxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-(methoxymethyl)-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-methoxy-3-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxy-2-methylphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-ethyl-5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-ethoxy-2-fluoro-5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-ethoxy-2-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 1-ethyl-4-(2-fluoro-4-methoxy-5-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(3-fluoro-5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-(2-methoxyethoxy)-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-chloro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2,4-difluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((2,3-dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-chloro-2-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyclopropyl-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-methoxy-2-(methoxymethyl)-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(3-chloro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(3-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(4-methoxy-3-methyl-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 1-methyl-4-((7-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3-dihydrobenzofuran-5-yl)oxy)cyclohexane-1-carboxylic acid; 1-methyl-4-((8-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)quinolin-6-yl)oxy)cyclohexane-1-carboxylic acid; 4-(2-chloro-4-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-chloro-4-methoxy-5-((3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-chloro-5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-chloro-4-methoxy-5-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 1-fluoro-4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 1-fluoro-4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 3-(4-fluoro-2-methoxy-5-((4-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(4-fluoro-2-methoxy-5-((4-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(4-fluoro-2-methoxy-5-((4-methyl-4-(1H-tetrazol-5-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(5-((4-carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid; 1-(cyanomethyl)-4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 3-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid; 4-(4-methoxy-3-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 3-(4-methoxy-3-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 2-(4-methoxy-3-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 4-(2,4-difluoro-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 5-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-2,2-dimethylpentanoic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-(pentafluoro-_ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 3-(5-((4-carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(3-(pentafluoro-_ 6 -sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 6-fluoro-4-methoxy-N3-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-[1,1′-biphenyl]-3,4′-dicarboxamide; 6-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)hexanoic acid; 7-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)heptanoic acid; 9-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)nonanoic acid; 4-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 4-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclohexane-1-carboxylic acid; 4-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)bicyclo[2.2.2]octane-1-carboxylic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid; 3-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutane-1-carboxylic acid; 3-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 2-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 3-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 4-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 5-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)pentanoic acid; 2-(4-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)-2-methylpropanoic acid; 2-(3-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)acetic acid; 2-(3-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)-2-methylpropanoic acid; 6-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)hexanoic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)butanoic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 1-amino-4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 3-(4-fluoro-2-methoxy-5-((4-(methylsulfonamido)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 4-(2-fluoro-4-methoxy-5-((6-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)hexahydro-4,7-methanobenzo[d][1,3]dioxol-5-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 3-(4-fluoro-2-methoxy-5-((4-sulfamoylcyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 4-(2-bromo-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(4-methoxy-2-methyl-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(4-methoxy-3-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 3-((2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid; 2-(3-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid; 2-(4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(trifluoromethyl)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)benzoic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 4-(2-fluoro-4-isopropoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxycarbonyl)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-isopropoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(5-((1-acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((4,4-difluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(5-((5,6-dihydroxy-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((4-hydroxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((4-methoxy-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; 3-(5-((4-carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide; 3-(5-((4-carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 4-(2-cyano-4-methoxy-5-((3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((2,2-dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 3-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methoxycyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methoxycyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 4-(2-cyano-4-fluoro-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 2′-fluoro-5′-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-methoxycyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-(methoxymethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(((1-cyanocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((3,3,3-trifluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((1,1,1-trifluoropropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(cyclobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(cyclopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(tert-butylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((1-((trifluoromethyl)sulfonyl)pyrrolidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-(((1-fluorocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((2-methoxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((2-hydroxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-5-((3-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-(trifluoromethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-(((1-(trifluoromethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((3-cyano-3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(((1-ethylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-fluoro-4-methoxy-5-((3-((2,2,3,3,3-pentafluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-((3,3-difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(5-((3-(((3,3-difluorocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; 4-(2-cyano-5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; and 4-(2-cyano-5-((3-((3,3-difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid.

In a further embodiment there is provided a compound selected from:

(1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((cyclobutylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-(fluoromethoxy)-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methyl-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (2R,4r,6R)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylic acid; (2S,4s,6S)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(isopropylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(cyclohexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-(difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-(fluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((perfluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-fluoro-5-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-cyano-4-methylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-(trifluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((4-bromo-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-chlorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-chloro-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-bromo-4-cyanophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((4-cyano-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((5-chloropyridazin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((6-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-(trifluoromethyl)pyrimidin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,3-difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(isobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-dimethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-1-(1-methylcyclopropyl)ethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-1-(1-methylcyclopropyl)ethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,4-dimethylpentan-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclohexyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-cyano-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2S)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((3S,4R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide; (1s,4s)-4-(5-((3-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((S)-3-methylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2S)-2-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1R,2S)-2-((2,2-dimethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1R,2S)-2-((2-ethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((R)-3-methylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1R,2S)-2-(((S)-3,3-dimethylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1R,2S)-2-((2,4-dimethylpentan-3-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((R)-1-(1-methylcyclopropyl)ethyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((S)-1-(1-methylcyclopropyl)ethyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((1-methylcyclohexyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1R,2S)-2-(((R)-3,3-dimethylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2S)-2-(isobutylcarbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((1-methylcyclopropyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1R,2S)-2-((2-cyano-2-methylpropyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((cyclopropylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((1-cyanocyclopropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1s,3R)-3-methylcyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-hydroxycyclopentyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((2-hydroxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((1-fluoro-2-methylpropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-isopropylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-(methoxymethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methoxycyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((3S,5S)-adamantan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((cycloheptylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-propylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((2,2,3,3-tetramethylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((2-(isopropylamino)-2-oxoethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-ethylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((3,3-dimethylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((S)-2-fluoro-3-hydroxypropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((1-methylcyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(butylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-fluorocyclopentyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-cyanocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-fluorocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((2,2-difluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((2-fluoro-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(tert-butylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((1-methylcyclopropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((4,4-difluoro-1-hydroxycyclohexyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((2,2,3,3,3-pentafluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-hydroxycycloheptyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-(ethoxymethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcycloheptyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-isobutylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((4-cyanocyclohexyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-phenylpropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1-(hydroxymethyl)cyclopentyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methoxycyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-([1,1′-bi(cyclopropan)]-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((1r,3S)-3-hydroxyadamantan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((4-(difluoromethyl)pyrimidin-2-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(propylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(hexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-2-phenylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((S)-3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((R)-1-cyclohexylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(cyclohexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-isopropoxypropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3,4-difluorobenzyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((((1s,3R)-3-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-2-phenylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(tert-pentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((4,4-dimethylcyclohexyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-methoxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3,3-dimethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((S)-2-fluoro-2-phenylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-cyclopropylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1S,2S)-2-(2,2,2-trifluoroethyl)cyclohexyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-fluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((2,5-dimethylbenzyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-methylbenzyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(cyclopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-1-phenylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-1-phenylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(neopentylcarbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3-ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-3-ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; (1S,3s)-3-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid; (1S,3s)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((4-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)thiophen-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-methyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-((cycloheptylmethyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-(((1-phenylcyclopropyl)methyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-((((1s,3s)-3-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((2-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-chlorophenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-((5-chloro-2-(((R)-3-fluoro-3-methylbutan-2-yl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-(tert-pentylcarbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-((2-fluoro-2-methylpropyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((5-chloro-2-((2-cyclopropylpropan-2-yl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-cyano-5-((2-((3-fluorobenzyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-cyano-5-((2-((2-ethylbutyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-cyano-4-methoxy-5-((5-methyl-2-(pentan-3-ylcarbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-cyano-4-methoxy-5-((5-methyl-2-(((1r,4r)-4-methylcyclohexyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-((5-methyl-2-(((R)-3-methylbutan-2-yl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-cyano-4-methoxy-5-((5-methyl-2-(((1s,3s)-3-methylcyclobutyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-cyano-5-((2-(((1-fluorocyclobutyl)methyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((2-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-methylphenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-cyano-4-methoxy-5-((5-methyl-2-(((1-methylcyclopropyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4,4,4-trifluorobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(cyclobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((4-(difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,6-difluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-iodophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,4,5-trifluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-(tert-butyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-cyclopropylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-cyano-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-methoxy-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-(difluoromethoxy)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-isopropylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3R,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1R,2S,3R,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-(difluoromethoxy)-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((4-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; (1s,4s)-4-(5-((2,4-dimethyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(5-((4,5-dimethyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)naphthalen-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((4-methyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 3-(4-methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)propanoic acid; 3-(4-methoxy-3-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)propanoic acid; (1R,2S,3R,4S)-3-(5-((1H-pyrazol-4-yl)methyl)-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 2-(4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazol-1-yl)acetic acid; 1-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-5-carboxylic acid; 1-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-3-carboxylic acid; 2-(4-methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)benzyl)benzoic acid; 2-(4-methoxy-3-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)benzyl)benzoic acid; 2′-fluoro-3,4′-dimethoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-3,4′-dimethoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2,2′-difluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2,2′-difluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)nicotinic acid; 5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)nicotinic acid; 4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxylic acid; 4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxylic acid; 2′-fluoro-4,4′-dimethoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4,4′-dimethoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′,4-difluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′,4-difluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′,3-difluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′,3-difluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2,2′-difluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2,2′-difluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-2-yl)acetic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-2-yl)acetic acid; 2′,3-difluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-2-yl)propanoic acid; 3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)propanoic acid; 3-(dimethylamino)-2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 4-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)butanoic acid; 2′-fluoro-4′-methoxy-3,5-dimethyl-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2-((S)-6-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-2,3-dihydrobenzofuran-3-yl)acetic acid; 2-((R)-6-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-2,3-dihydrobenzofuran-3-yl)acetic acid; (5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-2-yl)glycine; 2-((5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)oxy)acetic acid; 3-(6-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-3-yl)propanoic acid; 2-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)-2-methylpropanoic acid; 2-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid; 3-(2-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)thiazol-5-yl)propanoic acid; 3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 3-(6-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridazin-3-yl)propanoic acid; 2′-fluoro-4′-methoxy-3-methyl-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-3-hydroxy-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)propanoic acid; 3-(2′-fluoro-3,4′-dimethoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; (E)-3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)acrylic acid; (1R,2R)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylic acid; (1S,2S)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylic acid; (1R,2R)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylic acid; (1S,2S)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylic acid; (1R,2S,3R,4S)-3-(6-fluoro-4-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,2S,3R,4S)-3-(4′-(2-amino-1,3-dihydroxypropan-2-yl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,2S,3R,4S)-3-(4′-(3-amino-4-hydroxy-3-(hydroxymethyl)butyl)-3′,6-difluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 3-(4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-2-oxopyridin-1(2H)-yl)propanoic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 3-(4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propanoic acid; (R)-2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylic acid; (S)-2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid; 6-fluoro-4-methoxy-N3-((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)-[1,1′-biphenyl]-3,4′-dicarboxamide; 2-(4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)acetic acid; 4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-2-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-2-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 2-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)oxazole-4-carboxylic acid; 2-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)oxazole-4-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)pyrazine-2-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)pyrazine-2-carboxylic acid; 2-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)isonicotinic acid; 2-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)isonicotinic acid; 6-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)nicotinic acid; 6-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)nicotinic acid; 6-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 6-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid; 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)pyrimidine-2-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)pyrimidine-2-carboxylic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; 3-(2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; 3-(2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; 3-(2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 3-(2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-3-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-3-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-2-carboxylic acid; 5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-2-carboxylic acid; 2-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiazole-4-carboxylic acid; 2-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiazole-4-carboxylic acid; 2-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiazole-5-carboxylic acid; 2-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiazole-5-carboxylic acid; 1-(2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid; 1-(2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid; (S)-2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1R,2S,3R,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; (S)-2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; (R)-2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1R,2S,3R,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; (R)-2-amino-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; (R)-2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; (R)-2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; (S)-2-(dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; (R)-2-(dimethylamino)-2-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; (S)-2-(dimethylamino)-2-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; (R)-2-(dimethylamino)-2-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; (S)-2-(dimethylamino)-2-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1S,2S,3R,4R)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-5′-(((1S,2S,3R,4R)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((3-fluoro-5-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1S,2S,3R,4R)-3-((3-fluoro-5-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′,4′-difluoro-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′,4′-difluoro-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1S,2S,3R,4R)-3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 5′-(((1R,2R,3S,4S)-3-((3-cyano-4-fluorophenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 5′-(((1S,2S,3R,4R)-3-((3-cyano-4-fluorophenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 5′-(((1R,2R,3S,4S)-3-((3-cyano-5-fluorophenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 5′-(((1S,2S,3R,4R)-3-((3-cyano-5-fluorophenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-(((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-(((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2S,3R,4S)-3-(((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-(((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-(((R)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-(((R)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-yl)acetic acid; 3-(2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-yl)propanoic acid; 2-(2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-4-yl)acetic acid; 3-(2′-fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid; 3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-1,3,4-thiadiazol-2-yl)propanoic acid; 3-(2-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-5-yl)propanoic acid; 3-(5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)propanoic acid; 3-(5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)propanoic acid; (1R,2S,3R,4S)-3-(6-fluoro-4-methoxy-4′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,2R,3S,4S)-3-(6-fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1S,2S,3R,4R)-3-(6-fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2-((2′-cyano-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid; 2-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid; (1R,4s)-4-(5-(((1R,2R,3S,4S)-7-(tert-butoxycarbonyl)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(5-(((1S,2S,3R,4R)-7-(tert-butoxycarbonyl)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2S)-2-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2R)-2-fluoro-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((2S,3R)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((2S,3R)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2S)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2S)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclohexyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-(trifluoromethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-(trifluoromethyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-(difluoromethyl)-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(3-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-methoxy-2-methyl-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-ethyl-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-cyano-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-1-methyl-4-((1-methyl-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid; (1S,4s)-1-methyl-4-((1-methyl-6-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-1H-indazol-4-yl)oxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-(methoxymethyl)-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-methoxy-3-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxy-2-methylphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-ethyl-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-ethoxy-2-fluoro-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-ethoxy-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-1-ethyl-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(3-fluoro-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-(2-methoxyethoxy)-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-chloro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2,4-difluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1S,2R,5S)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1R,2S,5R)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,5S)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,5R)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-chloro-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyclopropyl-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-methoxy-2-(methoxymethyl)-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(3-chloro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(3-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(4-methoxy-3-methyl-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-1-methyl-4-((7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3-dihydrobenzofuran-5-yl)oxy)cyclohexane-1-carboxylic acid; (1S,4s)-1-methyl-4-((8-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)quinolin-6-yl)oxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-chloro-4-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-chloro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-chloro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-chloro-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-chloro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-fluoro-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1S,2S,3R,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4r)-1-fluoro-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4r)-1-fluoro-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(1H-tetrazol-5-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,4r)-1-(cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-1-(cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,3s,5S,6S)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid; (1R,3r,5S,6R)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid; (1R,3r,5S,6S)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid; (1R,3s,5S,6R)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid; 4-(4-methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 4-(4-methoxy-3-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 3-(4-methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 3-(4-methoxy-3-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 2-(4-methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 2-(4-methoxy-3-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; (1S,4s)-4-(2,4-difluoro-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 5-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-2,2-dimethylpentanoic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; 6-fluoro-4-methoxy-N3-((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-[1,1′-biphenyl]-3,4′-dicarboxamide; 6-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)hexanoic acid; 7-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)heptanoic acid; 9-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)nonanoic acid; 4-((2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; (1R,4r)-4-((2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-((2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclohexane-1-carboxylic acid; 4-((2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)bicyclo[2.2.2]octane-1-carboxylic acid; (2R,5R)-5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid; (2S,5S)-5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid; (1R,3r)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutane-1-carboxylic acid; (1S,3s)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,3R)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,3S)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,3S)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,3R)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; 2-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 2-((2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 3-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 3-((2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 4-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 4-((2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid; 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)pentanoic acid; 5-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)pentanoic acid; 2-(4-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)-2-methylpropanoic acid; 2-(4-((2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)-2-methylpropanoic acid; 2-(3-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)acetic acid; 2-(3-((2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)acetic acid; 2-(3-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)-2-methylpropanoic acid; 2-(3-((2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)phenyl)-2-methylpropanoic acid; 6-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)hexanoic acid; 6-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)hexanoic acid; 4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)butanoic acid; 4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)butanoic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4r)-1-amino-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-1-amino-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-(methylsulfonamido)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1r,4R)-4-(methylsulfonamido)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((3aS,4S,5R,6S,7R,7aR)-6-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)hexahydro-4,7-methanobenzo[d][1,3]dioxol-5-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-(((1r,4R)-4-sulfamoylcyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-sulfamoylcyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1S,4s)-4-(2-bromo-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(4-methoxy-2-methyl-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(4-methoxy-3-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,3r)-3-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid; (1S,3s)-3-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid; 2-((1R,3r)-3-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid; 2-((1S,3s)-3-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid; 2-((1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid; 2-((1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(trifluoromethyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid; 4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)benzoic acid; 4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; 4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)benzoic acid; (1R,4r)-4-(2-fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxycarbonyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2S)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(5-(((1S,2R)-4,4-difluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(5-(((1R,2S)-4,4-difluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R,5R,6S)-5,6-dihydroxy-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1S,2R,4S)-4-hydroxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1R,2S,4R)-4-hydroxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((4-methoxy-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide; (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide; (1R,4s)-4-(2-fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-2,2-dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-2,2-dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,3s)-3-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methoxycyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methoxycyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3aR,4S,5S,6aS)-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3aS,4R,5R,6aR)-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(5-(((3R,4S)-1-acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(5-(((3S,4R)-1-acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cycloheptyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cycloheptyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,4S)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,4R)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,4R)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,4S)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,5S)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,5R)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1S,2S,5S)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1R,2R,5R)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1S,2S,3R,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1S,2S,3R,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-(3,3,3-trifluoropropyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-(3,3,3-trifluoropropyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((2S,3R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((2R,3S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((2S,3R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((2R,3S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,4R)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,4S)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,4R)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,4S)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,4R)-4-methoxy-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,4S)-4-methoxy-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4-hydroxy-4′-methoxy-5′-(((1R,2S,3R,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; 2′-fluoro-4-hydroxy-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S,4S)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3R,4R)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S,4R)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3R,4S)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(5-(((1S,2R,3S,5S)-2,3-dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(5-(((1R,2S,3R,5R)-2,3-dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((3S,4R)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((3R,4S)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S,4R)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3R,4S)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R)-2-(neopentylcarbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(neopentylcarbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1S,2R)-2-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((1R,2S)-2-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-methoxy-5-(((1R,2S)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((3S,4S)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-5-(((3R,4R)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S,4R)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3R,4S)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S,4R)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3R,4S)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S,4R)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3R,4S)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid; (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-fluoro-5-(((2S,3R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1R,4s)-4-(2-cyano-4-fluoro-5-(((2R,3S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; 2′-fluoro-5′-(((1R,2S,3R,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; 2′-fluoro-5′-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methoxycyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-(methoxymethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((1-cyanocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,3,3-trifluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-1,1,1-trifluoropropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(cyclobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(cyclopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-1,1,1-trifluoropropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(tert-butylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R)-1-((trifluoromethyl)sulfonyl)pyrrolidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-1-((trifluoromethyl)sulfonyl)pyrrolidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-fluorocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-methoxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((2-hydroxy-2-methylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-(trifluoromethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-(trifluoromethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3-cyano-3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-3-cyano-3-methylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((1-ethylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((2,2,3,3,3-pentafluoropropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,3-difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((3,3-difluorocyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1R,2R,3S,4S)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3,3-difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid; and (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid;

and pharmaceutically acceptable salts thereof.

In one embodiment there is provided 4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided 4-(2-cyano-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided 4-(2-cyano-4-methoxy-5-((3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided 4-(2-cyano-5-((3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-cyano-5-(((1R,2R,3S,4S)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid.

In one embodiment there is provided (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid.

In one embodiment there is provided (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid.

In one embodiment there is provided (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid.

In further embodiments there is provided any one of the Example compounds (as named hereinafter in the Experimental section), or a pharmaceutically acceptable salt thereof.

In further embodiments there is provided any one of the Example compounds (as named hereinafter in the Experimental section).

The compounds of Formula (I) may be prepared from the Intermediate compounds (as named or shown hereinafter in the Experimental section) using the methods described in the Experimental section. The skilled person will understand that alternative methods may also be used to prepare the compounds of Formula (I) from such Intermediate compounds.

Accordingly, in further embodiments there is provided any one of the Intermediate compounds (as named or shown hereinafter in the Experimental section).

Accordingly, in further embodiments there is provided any one of the Intermediate compounds (as named or shown hereinafter in the Experimental section), or a salt thereof.

Therefore, examples of just some of the above-mentioned embodiments are given below: In one embodiment there is provided Intermediate 75, or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(Tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided Intermediate 68, or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-cyano-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-cyano-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided Intermediate 5, or a salt thereof.

Therefore, in this case, there is provided Methyl 5-(1,3,6,2-dioxazaborocan-2-yl)-4-fluoro-2-methoxybenzoate, or a salt thereof.

In one embodiment there is provided Intermediate 11, or a salt thereof.

Therefore, in this case, there is provided Naphthalen-1-ylmethyl (1r,4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate, or a salt thereof.

In one embodiment there is provided Intermediate 12, or a salt thereof.

Therefore, in this case, there is provided Methyl 4-fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate, or a salt thereof.

In one embodiment there is provided Intermediate 35, or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-(4-Cyano-5-hydroxy-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide, or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-(4-Cyano-5-hydroxy-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide, or a salt thereof.

In one embodiment there is provided (1R,2S,3R,4S)-3-(4-fluoro-5-hydroxy-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide, or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-(4-fluoro-5-hydroxy-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide, or a salt thereof.

In one embodiment there is provided Intermediate 13, or a salt thereof.

Therefore, in this case, there is provided 4-Fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid, or a salt thereof.

In one embodiment there is provided Intermediate 15, or a salt thereof.

Therefore, in this case, there is provided Methyl (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate, or a salt thereof.

In one embodiment there is provided Methyl (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate, or a salt thereof.

In one embodiment there is provided Intermediate 16, or a salt thereof.

Therefore, in this case, there is provided (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided Intermediate 584, or a salt thereof.

Therefore, in this case, there is provided (1S,2S,3R,4R)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided (1R,2S,3R,4S)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided Intermediate 20, or a salt thereof.

Therefore, in this case, there is provided tert-Butyl ((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate, or a salt thereof.

In one embodiment there is provided tert-Butyl ((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate, or a salt thereof.

In one embodiment there is provided Intermediate 21, or the free base or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided Intermediate 22, or the free base or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided Intermediate 224, or the free base or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided Intermediate 223, or the free base or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-amino-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-amino-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride, or the free base or a salt thereof.

In one embodiment there is provided Intermediate 73, or a salt thereof.

Therefore, in this case, there is provided 5-(((1s,4s)-4-(Tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid, or a salt thereof.

In one embodiment there is provided Intermediate 69, or a salt thereof.

Therefore, in this case, there is provided Methyl 4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate, or a salt thereof.

In one embodiment there is provided Intermediate 70, or a salt thereof.

Therefore, in this case, there is provided 4-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid, or a salt thereof.

In one embodiment there is provided Intermediate 71, or a salt thereof.

Therefore, in this case, there is provided Methyl (1S,2S,3R,4R)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate, or a salt thereof.

In one embodiment there is provided Methyl (1R,2S,3R,4S)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate, or a salt thereof.

In one embodiment there is provided Intermediate 72, or a salt thereof.

Therefore, in this case, there is provided (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a salt thereof.

In one embodiment there is provided (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a salt thereof.

In one embodiment there is provided Intermediate 403, or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided Intermediate 127, or a salt thereof.

Therefore, in this case, there is provided Methyl (1R,2S,3R,4S)-3-(5-bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylate, or a salt thereof.

In one embodiment there is provided Methyl (1S,2S,3R,4R)-3-(5-bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylate, or a salt thereof.

In one embodiment there is provided Intermediate 128, or a salt thereof.

Therefore, in this case, there is provided (1R,2S,3R,4S)-3-(5-Bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided (1S,2S,3R,4R)-3-(5-Bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, or a salt thereof.

In one embodiment there is provided Intermediate 136, or a salt thereof.

Therefore, in this case, there is provided Benzyl 5-(((1s,4s)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoate, or a salt thereof.

In one embodiment there is provided Intermediate 521, or a salt thereof.

Therefore, in this case, there is provided (1s,4s)-4-(2-fluoro-4-methoxy-5-(methoxycarbonyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or a salt thereof.

In one embodiment there is provided a process for preparing a compound of Formula (I), or pharmaceutically acceptable salt thereof, using an Intermediate compound (as described herein, or named or shown hereinafter in the Experimental section), or a salt thereof.

In one embodiment there is provided a process for preparing (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or pharmaceutically acceptable salt thereof, using an Intermediate compound (as described herein, or named or shown hereinafter in the Experimental section), or a salt thereof.

In one embodiment there is provided a process for preparing (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or pharmaceutically acceptable salt thereof, using an Intermediate compound (as described herein, or named or shown hereinafter in the Experimental section), or a salt thereof.

In one embodiment there is provided a process for preparing (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid, or pharmaceutically acceptable salt thereof, using an Intermediate compound (as described herein, or named or shown hereinafter in the Experimental section), or a salt thereof.

In one embodiment there is provided a process for preparing (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid, or pharmaceutically acceptable salt thereof, using an Intermediate compound (as described herein, or named or shown hereinafter in the Experimental section), or a salt thereof.

Terms not specifically defined herein should be understood to have the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. In the groups defined below, the number of carbon atoms is often specified preceding the group, for example, C 1-4 alkyl means an alkyl group or radical having 1 to 4 carbon atoms.

“Alkyl” means a saturated aliphatic branched or straight-chain hydrocarbon group having the specified number of carbon atoms. For example, C 1-4 alkyl means a group having from 1-4 carbon atoms in a linear or branched arrangement, such as —CH 2 CH 2 CH 2 CH 3 or —CH 2 CH(CH 3 ) 2 . An “Alkylene” is a divalent alkyl group.

“Alkoxy” means an alkyl group attached through an oxygen linking atom. For example, C 1-3 alkoxy includes methoxy, ethoxy and propoxy.

“Aryl” means an aromatic monocyclic or polycyclic hydrocarbon ring system having the specified number of carbon atoms. For example, C 6-10 aryl includes groups such as phenyl and naphthalenyl. An “Arylene” is a divalent aryl group.

“Cycloalkyl” means a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, cycloalkyl includes groups such as cyclohexyl, adamantyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl and decahydronaphthalenyl. As a further example, monocyclic C 3-6 cycloalkyl means a group having from 3-6 carbon atoms arranged in a monocyclic ring, such as cyclopropyl and cyclohexyl. A “Cycloalkylene” is a divalent cycloalkyl group.

“Cycloalkoxy” means a cycloalkyl group attached through an oxygen linking atom. For example, C 3-4 cycloalkoxy includes cyclopropoxy and cyclobutoxy.

“Cycloalkenyl” means a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic unsaturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, cycloalkenyl includes groups such as cyclohexenyl, spiro[4.4]non-2-enyl, bicyclo[2.2.1]hept-2-enyl and 1,2,3,4,4a,5,8,8a-octahydronaphthalenyl. As a further example, monocyclic C 5-6 cycloalkenyl means a group having from 3-6 carbon atoms arranged in a monocyclic ring, such as cyclopentenyl and cyclohexenyl. A “Cycloalkenylene” is a divalent cycloalkenyl group.

“Heteroaryl” means an aromatic monocyclic or polycyclic ring system containing carbon atoms and the specified number of heteroatoms (such as O, N or S) in the ring structure, and having the specified total number of atoms in the ring structure. For example, 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur includes groups such as indolyl, pyridyl, thiazolyl and oxazolyl. A “Heteroarylene” is a divalent heteroaryl group.

“Heterocycloalkyl” means a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic saturated group containing carbon atoms and the specified number of heteroatoms (such as O, N or S) in the ring structure, and having the specified total number of atoms in the ring structure. For example, 4- to 8-membered heterocycloalkyl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur includes groups such as pyrrolidinyl, oxetanyl, 2-oxa-6-azaspiro[3.3]heptanyl, hexahydro-2H-thieno[2,3-c]pyrrolyl and 7-oxabicyclo[2.2.1]heptanyl. A “Heterocycloalkylene” is a divalent heterocycloalkyl group.

“Heterocycloalkenyl” means a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic unsaturated group containing carbon atoms and the specified number of heteroatoms (such as O, N or S) in the ring structure, and having the specified total number of carbon atoms and heteroatoms in the ring structure. For example, 4- to 8-membered heterocycloalkenyl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur includes groups such as 2,5-dihydro-1H-pyrrolyl, 7-oxabicyclo[2.2.1]hept-2-enyl and 4,5,6,6a-tetrahydro-2H-thieno[2,3-c]pyrrol-3-yl. A “Heterocycloalkenylene” is a divalent heterocycloalkenyl group.

“Heteroalkyl” means an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. The specified number of members in the heteroalkyl group refers to the total number of carbon atoms and heteroatoms in the chain. For example, —CH 2 OCH 2 CH 3 and —CH 2 N(CH 3 )CH 2 CH 3 . As a further example, a 4-membered heteroalkyl group containing one heteroatom selected from oxygen and sulfur includes groups such as —CH 2 OCH 2 CH 3 , —SCH(CH 3 ) 2 , and —CH(CH 3 )CH 2 OH. A “Heteroalkylene” is a divalent heteroalkyl group.

“Halogen” means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

The chemical names of compounds described in this specification were generated using ChemDraw® Professional version 19.0.0.22 from PerkinElmer®. The skilled person will understand that different chemical naming software may generate different chemical names for a particular compound. In case a compound described herein is depicted in form of a chemical name and as a formula, the formula shall prevail in case of any discrepancy.

In substituents such as —OH and —CN, “—” denotes the point of attachment of the substituent to the remainder of the molecule.

In fragments such as

designates the point of attachment of the fragment to the remainder of the molecule.

The term “pharmaceutically acceptable” is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use , P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zürich:Wiley-VCH/VHCA, 2002.

A suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid-addition salt or a base-addition salt. An acid addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. An acid addition salt may for example be formed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.

Therefore, in one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid salt.

Compounds described in this specification may form base addition salts. A base-addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person. For example, it may be possible to make an alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., an ethoxide or methoxide) or a suitably basic organic amine (e.g., a choline or meglumine) in an aqueous medium. Therefore, in one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a sodium, potassium, lithium, calcium, choline or meglumine salt.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I).

In one embodiment there is provided a pharmaceutically acceptable salt of a compound of Formula (I).

Compounds and salts described in this specification may exist in solvated forms and unsolvated forms. For example, a solvated form may be a hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or an alternative quantity thereof. All such solvated and unsolvated forms of compounds of Formula (I) are encompassed herein.

Atoms of the compounds and salts described in this specification may exist as their isotopes. All compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is an 11 C or 13 C carbon isotope, or where one or more hydrogen atoms is a 2H or 3 H isotope) are encompassed herein.

Compounds of the application may exist in one or more geometrical, optical, enantiomeric, and diastereomeric forms, including, but not limited to, cis- and trans-forms, E- and Z-forms, and R-, S- and meso-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaptation of known methods.

The compounds of Formula (I) may include one or more chiral centres. To the extent a structure or chemical name in this specification does not indicate chirality, the structure or name is intended to encompass any single stereoisomer corresponding to that structure or name, as well as any mixture of stereoisomers (e.g. a racemate). Where a structure in this specification includes bonds drawn as solid and hashed wedges (i.e. and ), it is intended that the solid and hashed wedges indicate the absolute configuration of a chiral centre unless the “or” or “&” chiral flags are present at the chiral centre. Groups of related chiral flags are indicated with the same integer, for example “or1”, “&1”, “or2”, “&2” etc. The skilled person will understand the meaning of chiral flags at a chiral centres. For example, the structure

indicates that the compound is a single stereoisomer with the defined absolute configuration. As a further example, the structure

indicates that the compound is a single stereoisomer with the defined relative configuration at the flagged chiral centres, but unknown absolute configuration at the flagged chiral centres. As a further example, the structure

indicates that the compound is a mixture of stereoisomers having the defined relative configuration at the flagged chiral centres.

It is well-known in the art how such optically-active forms can be separated. For example, a single stereoisomer can be obtained by isolating it from a mixtures of isomers (e.g. a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained through direct synthesis from, for example, a chiral starting material.

According to one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is a single enantiomer being in enantiomer excess (% ee) of ≥95%, ≥98%, or ≥99%. Conveniently a single enantiomer is present in an enantiomer excess of ≥99%.

According to one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is a single enantiomer being in enantiomer excess (% ee) in the range 95 to 100%.

According to one embodiment, there is provided a pharmaceutical composition, which comprises a compound of Formula (I) which is a single enantiomer being in enantiomer excess (% ee) of ≥95%, ≥98%, or ≥99% or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. Conveniently, the single enantiomer is present in an enantiomer excess of ≥99%.

According to one embodiment, there is provided a pharmaceutical composition, which comprises a compound of Formula (I) which is a single enantiomer being in enantiomer excess (% ee) in the range 95 to 100%, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

Compounds of the application may exist in one or more tautomeric forms, including, but not limited to, keto-, and enol-forms. A reference to a particular compound includes all tautomeric forms, including mixtures thereof. Accordingly, a structure depicted herein as one tautomer is intended to also include other tautomers.

The compounds of Formula (I) may be administered in the form of a prodrug, which is a compound which that is broken down in the human or animal body to release the compound of Formula (I). Such, pharmaceutically acceptable, prodrugs of compounds for Formula (I) also form an embodiment. Various forms of prodrugs are known in the art. For example, see

a) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984).

In one embodiment there is provided a prodrug of a compound of Formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a prodrug of a compound of Formula (I) as herein defined, wherein said prodrug is a compound of Formula (I) as herein defined except that R 1 is —COO(C 1-4 alkyl), or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided an N-oxide of a compound of Formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.

As a result of their modulation of RXFP1, the compounds of Formula (I), and pharmaceutically acceptable salts thereof are expected to be useful in therapy.

The term “therapy” is intended to have its normal meaning of dealing with a disease or condition in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease or condition and secondary prophylaxis whereby the disease or condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or condition, or the development of new symptoms associated with the disease or condition.

The term “treatment” is used synonymously with “therapy”. Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

Accordingly, the compounds or pharmaceutical compositions described herein may be used in therapy, for example for treating a disease or disorder. Also provided is a method of treating a disease or disorder comprising administering to a subject or patient in need thereof a therapeutically effective amount of the compounds described herein.

It will be understood that the compounds described herein may be used in the treatment of cardiovascular diseases, for example for the treatment of heart failure.

As used herein, the term “heart failure” includes acute heart failure, chronic heart failure (CHF) and acute decompensated heart failure (ADHF). The term “heart failure” may also include more specific diagnoses such as heart failure with preserved ejection fraction (HFpEF), heart failure with mid-range ejection fraction or heart failure with reduced ejection fraction (HFrEF).

The compounds described herein may also be used in the treatment of kidney disease (including chronic kidney disease), acute kidney injury, lung disease and fibrotic disorders, for example fibrotic disorders of the kidney, heart, lung and liver, and in wound healing (Sherwood O D (2004) Endocrine Reviews 25(2): 205-234). The compounds described herein may also be used in the reversal of insulin resistance in diabetic patients (Bonner J S et al. (2013) Diabetes 62(9):3251-3260). The compounds described herein may also be used in the treatment of various forms of pulmonary hypertension. The compounds described herein may also be used in the treatment of disorders that are a result of or a cause of arterial stiffness, reduced arterial elasticity, reduced arterial compliance and distensibility including hypertension, kidney disease, peripheral arterial disease, carotid and cerebrovascular disease (i.e. stroke and dementia), diabetes, microvascular disease resulting in end organ damage, coronary artery disease, and heart failure. The compounds described herein may also be used in the treatment of pre-eclampsia.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition selected from the group consisting of heart failure, heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, and/or heart failure with reduced ejection fraction.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic kidney disease and/or acute kidney injury.

In one embodiment there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of heart failure, heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury.

The term “therapeutically effective amount” refers to an amount of a compound of Formula (I) as described in any of the embodiments herein which is effective to provide “therapy” in a subject, or to “treat” a disease or condition in a subject. The therapeutically effective amount may cause any of the changes observable or measurable in a subject as described in the definition of “therapy”, “treatment” and “prophylaxis” above. As recognized by those skilled in the art, effective amounts may vary depending on route of administration, excipient usage, and co-usage with other agents. For example, where a combination therapy is used, the amount of the compound of Formula (I) or pharmaceutically acceptable salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, jointly effective to treat a targeted disorder or condition in the subject. In this context, the combined amounts are in a “therapeutically effective amount” if they are, when combined, sufficient to decrease the symptoms of a disease or condition responsive to modulation and/or agonism of RXFP1 as described above. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of Formula (I) or pharmaceutically acceptable salt thereof and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).

“Subjects” include, for example, mammals, for example, humans.

In one embodiment there is provided a method for treating a disease or condition selected from the group consisting of heart failure, heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury.

The compounds of Formula (I), and pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients.

Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients , Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, 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 composition and what other excipients are present in the composition.

The pharmaceutical compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures well known in the art. Compositions intended for oral use may contain additional components, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

The compound of Formula (I) will normally be administered to a subject at a unit dose within the range 2.5-5000 mg/m 2 body area of the subject, or approximately 0.05-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 0.1-400 mg of active ingredient. The daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co-administered, and the severity of the disease or condition being treated.

The pharmaceutical compositions described herein comprise compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.

As such, in one embodiment there is provided a pharmaceutical composition for use in therapy, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g. oral dosage forms such as tablets) comprising the active compound.

The different physical properties of the crystalline forms with respect to each other and with respect to the non-crystalline state may influence markedly the chemical and pharmaceutical processing of a compound, particularly when the compound is prepared or used on an industrial scale.

Further, in the manufacture of oral drug compositions, it is important that a reliable and reproducible plasma concentration profile of drug is provided following administration to a patient. Inter-patient variability in the absorption profile of a drug within the stomach, intestine or bloodstream can have an effect on drug safety and efficacy.

Chemical stability, solid state stability and “shelf life” of the active ingredients are also very important factors. The drug substance, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).

Moreover, it is also important to be able to provide drug in a form which is as chemically pure as possible.

Amorphous materials may present problems in this regard. For example, such materials are typically difficult to handle and to formulate, provide for unreliable solubility, and are often found to be unstable and chemically impure.

The skilled person will appreciate that, if a drug can be readily obtained in a stable crystalline form, the above problems may be solved.

Thus, in the manufacture of commercially viable, and pharmaceutically acceptable, drug compositions, it is important, wherever possible, to provide drug in a crystalline, and stable, form.

It is to be noted, however, that this goal is not always achievable. Indeed, typically, it is not possible to predict, from molecular structure alone, what the crystallisation behaviour of a compound, either as such or in the form of a salt, will be. This can only be determined empirically.

In one embodiment, certain compounds and salts thereof may be prepared in crystalline forms. These crystalline forms may be characterised as being a particular polymorphic form. When it is stated that an embodiment relates to a crystalline form, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.

The specific solid forms described herein provide X-ray powder diffraction patterns substantially the same as the X-ray powder diffraction patterns shown in the Figures and have the various 2-theta values as described herein. It will be understood that the 2-theta values of a X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute.

It is known that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions. Therefore it should be understood that the solid forms described herein are not limited to the crystals that provide X-ray powder diffraction patterns that are identical to the X-ray powder diffraction pattern shown in the Figures, and any crystals providing X-ray powder diffraction patterns substantially the same as those shown in the Figures fall within the scope of the embodiments described herein. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of X-ray powder diffraction patterns.

Persons skilled in the art of X-ray powder diffraction will realise that the relative intensity of peaks can be affected by, for example, grains above 30 μm in size and non-unitary aspect ratios, which may affect analysis of samples. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence the diffraction pattern data presented are not to be taken as absolute values. (Jenkins, R & Snyder, R. L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons 1996 ; Bunn, C. W . (1948), Chemical Crystallography, Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction Procedures). The peak intensities are described herein as vs (very strong), s (strong), m (medium) and w (weak) and correspond to % relative intensity (based on the most intense peak) of 25-100%, 10-25%, 3-10% and 1-3%, respectively. The relative intensities are derived from diffractograms measured with fixed slits.

Generally, a measurement error of a diffraction angle in an X-ray powder diffractogram is about 5% or less, in particular plus or minus 0.5° 2-theta, and such degree of a measurement error should be taken into account when considering the X-ray powder diffraction patterns in the Figures herein when reading the data described herein. Furthermore, it should be understood that intensities may fluctuate depending on experimental conditions and sample preparation (preferred orientation).

The X-ray powder diffraction analysis was performed according to standard methods, which can be found in e.g. Kitaigorodsky, A. I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.

X-ray powder diffraction data was measured with Corundum as an internal reference. The X-ray powder diffraction (referred to herein as XRPD) pattern was determined by mounting a sample on a zero background holder single silicon crystal and spreading out the sample into a thin layer.

The powder X-ray diffraction was recorded with a theta-two theta scan axis and in one dimensional scan with Rigaku Miniflex 600 (wavelength of X-rays 1.5418 Å nickel-filtered Cu K α radiation, 40 kV, 15 mA) equipped with D/Tex detector. Automatic variable divergence and anti scattering slits were used, and the samples were rotated at 80 revolution per minute during measurement. Samples were scanned from 2.4-50° 2-theta using a 0.01° and 1°/min step width and scan speed respectively.

In this specification (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Example 1) is also referred to as “Compound X”. Several useful crystalline polymorphic forms have subsequently been produced using the conditions described in Example 1. In all of the embodiments relating to solid forms recited herein, the peaks of the X-ray diffraction patterns are measured using Cu K α radiation.

Therefore in one embodiment there is provided polymorphic Form A of Compound X. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 7.5, 10.7, 12.8, 14.5 and 15.8°.

Polymorphic Form A of Compound X is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 1 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 7.5 (s), 10.3 (m), 10.7 (s), 12.8 (s), 14.5 (vs), 15.3 (s), 15.8 (s), 17.5 (m), 19.6 (s) and 21.3 (s).

In one embodiment there is provided the polymorphic Form A of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.5, 10.7, 12.8, 14.5 and 15.8°.

In one embodiment there is provided the polymorphic Form A of Compound X, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=7.5, 10.3, 10.7, 12.8, 14.5, 15.3, 15.8, 17.5, 19.6, and 21.3°.

In one embodiment there is provided polymorphic Form A of Compound X which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 1 .

In one embodiment there is provided polymorphic Form A of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=7.5, 10.7, 12.8, 14.5 and 15.8° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form A of Compound X, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=7.5, 10.3, 10.7, 12.8, 14.5, 15.3, 15.8, 17.5, 19.6, and 21.3° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided polymorphic Form B of Compound X. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 6.9, 8.2, 9.2, 11.5, and 15.9°.

Polymorphic Form B of Compound X is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 2 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 6.9 (vs), 8.2 (vs), 9.2 (vs), 9.6 (s), 11.5 (s), 12.3 (vs), 13.0 (m), 15.9 (vs), 16.3 (s) and 23.1 (vs).

In one embodiment there is provided the polymorphic Form B of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=6.9, 8.2, 9.2, 11.5, and 15.9°.

In one embodiment there is provided the polymorphic Form B of Compound X, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=6.9, 8.2, 9.2, 9.6, 11.5, 12.3, 13.0, 15.9, 16.3, and 23.1°.

In one embodiment there is provided polymorphic Form B of Compound X which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 2 .

In one embodiment there is provided polymorphic Form B of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=6.9, 8.2, 9.2, 11.5, and 15.9° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form B of Compound X, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=6.9, 8.2, 9.2, 9.6, 11.5, 12.3, 13.0, 15.9, 16.3, and 23.1° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided polymorphic Form D of Compound X. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 7.0, 7.7, 14.0, 16.1 and 16.9°.

Polymorphic Form D of Compound X is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 3 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 7.0 (m), 7.7 (vs), 14.0 (vs), 15.0 (m), 16.1 (vs), 16.9 (vs), 18.3 (s), 19.4 (vs), 20.2 (s) and 20.9 (vs).

In one embodiment there is provided the polymorphic Form D of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.0, 7.7, 14.0, 16.1 and 16.9°.

In one embodiment there is provided the polymorphic Form D of Compound X, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=7.0, 7.7, 14.0, 15.0, 16.1, 16.9, 18.3, 19.4, 20.2, and 20.9°.

In one embodiment there is provided polymorphic Form D of Compound X which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 3 .

In one embodiment there is provided polymorphic Form D of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=7.0, 7.7, 14.0, 16.1 and 16.9° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form D of Compound X, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=7.0, 7.7, 14.0, 15.0, 16.1, 16.9, 18.3, 19.4, 20.2, and 20.9° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided polymorphic Form E of Compound X. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 6.1, 7.5, 8.2, 14.5 and 15.6°.

Polymorphic Form E of Compound X is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 4 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 6.1 (vs), 7.5 (m), 8.2 (m), 9.4 (m), 10.3 (m), 10.7 (m), 14.5 (s), 15.6 (vs), 16.4 (s) and 20.1 (s).

In one embodiment there is provided the polymorphic Form E of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=6.1, 7.5, 8.2, 14.5 and 15.6°.

In one embodiment there is provided the polymorphic Form E of Compound X, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=6.1, 7.5, 8.2, 9.4, 10.3, 10.7, 14.5, 15.6, 16.4, and 20.1°.

In one embodiment there is provided polymorphic Form E of Compound X which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 4 .

In one embodiment there is provided polymorphic Form E of Compound X, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=6.1, 7.5, 8.2, 14.5 and 15.6° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form E of Compound X, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=6.1, 7.5, 8.2, 9.4, 10.3, 10.7, 14.5, 15.6, 16.4, and 20.1° wherein said values may be plus or minus 0.2° 2-theta.

In this specification (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Example 592) is also referred to as “Compound Y” Several useful crystalline polymorphic forms have subsequently been produced using the conditions described in Example 592. In all of the embodiments relating to solid forms recited herein, the peaks of the X-ray diffraction patterns are measured using Cu K α radiation.

Therefore in one embodiment there is provided polymorphic Form A of Compound Y. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 6.7, 10.5, 13.5, 15.2 and 18.6°.

Polymorphic Form A of Compound Y is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 5 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 6.7 (m), 10.5 (vs), 11.8 (m), 13.5 (s), 14.1 (m), 15.2 (s), 16.0 (m), 16.8 (s), 18.6 (vs) and 19.8 (vs).

In one embodiment there is provided the polymorphic Form A of Compound Y, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=6.7, 10.5, 13.5, 15.2 and 18.6°.

In one embodiment there is provided the polymorphic Form A of Compound Y, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=6.7, 10.5, 11.8, 13.5, 14.1, 15.2, 16.0, 16.8, 18.6, and 19.8°.

In one embodiment there is provided polymorphic Form A of Compound Y which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 5 .

In one embodiment there is provided polymorphic Form A of Compound Y, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=6.7, 10.5, 13.5, 15.2 and 18.6° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form A of Compound Y, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=6.7, 10.5, 11.8, 13.5, 14.1, 15.2, 16.0, 16.8, 18.6, and 19.8° wherein said values may be plus or minus 0.2° 2-theta.

Therefore in one embodiment there is provided polymorphic Form B of Compound Y. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 6.0, 7.6, 8.6, 19.0 and 20.2°.

Polymorphic Form B of Compound Y is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 6 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 6.0 (m), 7.6 (m), 8.6 (s), 9.5 (vs), 9.7 (vs), 17.2 (s), 19.0 (s), 20.2 (s), 23.2 (m) and 23.9 (s).

In one embodiment there is provided the polymorphic Form B of Compound Y, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=6.0, 7.6, 8.6, 19.0 and 20.2°.

In one embodiment there is provided the polymorphic Form B of Compound Y, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=6.0, 7.6, 8.6, 9.5, 9.7, 17.2, 19.0, 20.2, 23.2, and 23.9°.

In one embodiment there is provided polymorphic Form B of Compound Y which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 6 .

In one embodiment there is provided polymorphic Form B of Compound Y, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=6.0, 7.6, 8.6, 19.0 and 20.2° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form B of Compound Y, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=6.0, 7.6, 8.6, 9.5, 9.7, 17.2, 19.0, 20.2, 23.2, and 23.9° wherein said values may be plus or minus 0.2° 2-theta.

In this specification (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Example 621) is also referred to as “Compound Z”. Several useful crystalline polymorphic forms have subsequently been produced using the conditions described in Example 621. In all of the embodiments relating to solid forms recited herein, the peaks of the X-ray diffraction patterns are measured using Cu K α radiation.

Therefore in one embodiment there is provided polymorphic Form A of Compound Z. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 6.0, 7.5, 8.5, 17.5 and 19.4°.

Polymorphic Form A of Compound Z is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 7 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 6.0 (w), 7.5 (m), 8.5 (m), 11.0 (w), 15.6 (w), 17.1 (m), 17.5 (m), 19.4 (s), 22.7 (m) and 23.2 (w).

In one embodiment there is provided the polymorphic Form A of Compound Z, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=6.0, 7.5, 8.5, 17.5 and 19.4°.

In one embodiment there is provided the polymorphic Form A of Compound Z, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=6.0, 7.5, 8.5, 11.0, 15.6, 17.1, 17.5, 19.4, 22.7, and 23.2°.

In one embodiment there is provided polymorphic Form A of Compound Z which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 7 .

In one embodiment there is provided polymorphic Form A of Compound Z, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=6.0, 7.5, 8.5, 17.5 and 19.4° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form A of Compound Z, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=6.0, 7.5, 8.5, 11.0, 15.6, 17.1, 17.5, 19.4, 22.7, and 23.2° wherein said values may be plus or minus 0.2° 2-theta.

Therefore in one embodiment there is provided polymorphic Form B of Compound Z. This polymorphic form may be characterised in that it provides at least one of the following 20 values measured using Cu K α radiation: 4.7, 6.1, 7.7, 9.3 and 13.0°.

Polymorphic Form B of Compound Z is characterised in providing an X-ray powder diffraction pattern, substantially as shown in FIG. 8 .

The ten most prominent X-Ray powder diffraction peaks for this polymorphic form [Angle 2-theta (20), Intensity] are: 4.7 (vs), 6.1 (vs), 6.5 (m), 7.7 (vs), 9.3 (s), 13.0 (vs), 14.0 (s), 15.4 (s), 17.5 (vs) and 20.4 (vs).

In one embodiment there is provided the polymorphic Form B of Compound Z, which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=4.7, 6.1, 7.7, 9.3 and 13.0°.

In one embodiment there is provided the polymorphic Form B of Compound Z, which has an X-ray powder diffraction pattern with specific peaks at about 2-theta=4.7, 6.1, 6.5, 7.7, 9.3, 13.0, 14.0, 15.4, 17.5, and 20.4°.

In one embodiment there is provided polymorphic Form B of Compound Z which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 8 .

In one embodiment there is provided polymorphic Form B of Compound Z, which has an X-ray powder diffraction pattern with at least five specific peaks at 2-theta=4.7, 6.1, 7.7, 9.3 and 13.0° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a polymorphic Form B of Compound Z, which has an X-ray powder diffraction pattern with specific peaks at 2-theta=4.7, 6.1, 6.5, 7.7, 9.3, 13.0, 14.0, 15.4, 17.5, and 20.4° wherein said values may be plus or minus 0.2° 2-theta.

In one embodiment there is provided a pharmaceutical composition comprising a crystalline form as described herein and a pharmaceutically acceptable excipient.

The figures relate to solid forms of the compounds: Compound X, Compound Y or Compound Z.

FIG. 1 : X-Ray Powder Diffraction Pattern—Form A of Compound X

FIG. 2 : X-Ray Powder Diffraction Pattern—Form B of Compound X

FIG. 3 : X-Ray Powder Diffraction Pattern—Form D of Compound X

FIG. 4 : X-Ray Powder Diffraction Pattern—Form E of Compound X

FIG. 5 : X-Ray Powder Diffraction Pattern—Form A of Compound Y

FIG. 6 : X-Ray Powder Diffraction Pattern—Form B of Compound Y

FIG. 7 : X-Ray Powder Diffraction Pattern—Form A of Compound Z

FIG. 8 : X-Ray Powder Diffraction Pattern—Form B of Compound Z

The compounds described in this specification are further illustrated in the following Examples. These Examples are given by way of illustration only and are non-limiting.

In the examples, high resolution mass spectra were recorded on a Micromass LCT mass spectrometer equipped with an electrospray interface (LC-HRMS).

1 H NMR measurements were performed on Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at 1 H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25° C. Chemical shifts are given in ppm with the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet.

Flash chromatography was performed using either normal phase silica FLASH+® (40M, 25M or 12M), Biotage® SNAP Cartridges KP-Sil (340, 100, 50 or 10), or Agela® Flash Column Silica-CS Cartridges (330, 180, 120, 80) unless otherwise stated.

Reversed phase flash chromatography was performed using Agela® C-18 spherical 20-35 μm 100A cartridges unless otherwise stated.

Purifications were performed by preparative HPLC, preparative SFC or reversed phase flash chromatography on a standard equipment, using MS or UV triggered fraction collection, and using one of the following methods; Method PrepAcidic-A The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/FA (0.1%) buffer system; Method PrepAcidic-B The compound was purified by preparative HPLC on a Xselect CSH F-Phenyl OBD column (5 μm 250×19 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.05%) buffer system; Method PrepAcidic-C The compound was purified by preparative HPLC on a XBridge Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.05%) buffer system; Method PrepAcidic-D The compound was purified by preparative HPLC on a XBridge Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.1%) buffer system; Method PrepAcidic-E The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H 2 O/FA (0.1%) buffer system; Method PrepAcidic-F The compound was purified by preparative HPLC on a Kromasil C18 column (10 μm 250×20 mm ID) using a gradient of MeCN in a H 2 O/MeCN/FA (95/5/0.2) buffer system; Method PrepAcidic-G The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.05%) buffer system; Method PrepAcidic-H The compound was purified by preparative HPLC on a Kromasil C18 column (10 μm 250×20 mm ID) using a gradient of MeCN in a H 2 O/MeCN/Acetic acid (95/5/0.2) buffer system; Method PrepAcidic-I The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/FA (0.1%) buffer system; Method PrepAcidic-J The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.5%) buffer system; Method PrepAcidic-K The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.05%) buffer system; Method PrepAcidic-L The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/FA (0.05%) buffer system; Method PrepAcidic-M The compound was purified by preparative HPLC on a XSelect CSH OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.10%) buffer system; Method PrepAcidic-N The compound was purified by preparative HPLC on a Xselect CSH F-Phenyl OBD column (5 μm 250×19 mm ID) using a gradient of MeCN in a H 2 O/TFA (0.1%) buffer system; Method PrepAcidic-O The compound was purified by preparative HPLC on a Phenomenex Luna C18 column (10 μm 50×100 mm ID) using a gradient of MeCN (40-70% over 25 min) in a H 2 O (0.05% HCl) buffer system; Method PrepAcidic-P The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 80-95% MeCN in a TFA (0.05%) buffer system as mobile phase; Method PrepBasic-A The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×19 mm ID) using a gradient of MeCN in a H 2 O/MeCN/NH 3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-B The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 50×19 mm ID) using a gradient of MeCN in a H 2 O/MeCN/NH 3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-C The compound was purified by preparative HPLC on a WatersSunfire C18 ODB column (5 μm 150×30 mm ID) using a gradient of MeCN in a H 2 O/MeCN/NH 3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-D The compound was purified by preparative HPLC on a Xbridge C18 column (10 μm 250×19 mm ID) using a gradient of MeCN in a H 2 O/MeCN/NH 3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-E The compound was purified by preparative HPLC on a Xbridge C18 ODB column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/MeCN/NH 3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-F The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 mm ID) using a gradient of MeCN in a H 2 O/MeCN/NH 3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-G The compound was purified by preparative HPLC on a Xbridge C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-H The compound was purified by preparative HPLC on a Xbridge C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H 2 O/NH 3 (0.1)/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-I The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 20-90% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-J The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 50-70% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-K The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 70-90% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-L The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 30-45% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-M The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 20-70% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-N The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 15-60% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-O The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 30-60% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-P The compound was purified by preparative HPLC on a Ultimate XB-C18 (11 μm 250×50 mm ID) using a gradient of 45-65% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-Q The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 40-65% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-R The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 50-70% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-S The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 25-60% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-T The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 65-75% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-U The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 40-90% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-V The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 35-65% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase; Method PrepBasic-W The compound was purified by preparative HPLC on a XBridge C18 column (5 μm 150×30 mm ID) using a gradient of 10-50% MeCN in a H 2 O/NH 3 (0.05%) buffer system as mobile phase; Method PrepBasic-X The compound was purified by preparative HPLC on a XBridge C18 column (5 μm 150×30 mm ID) using a gradient of 15-60% MeCN in a H 2 O/NH 3 (0.05%) buffer system as mobile phase; Method PrepBasic-Y The compound was purified by preparative HPLC on a XBridge C18 column (5 μm 150×30 mm ID) using a gradient of 10-70% MeCN in a H 2 O/NH 3 (0.05%) buffer system as mobile phase; Method SFC-A The compound was purified by preparative SFC on a Phenomenex Luna HILIC column (5 μm 250×30 ID mm) using MeOH/20 mM NH 3 in CO 2 as mobile phase; Method SFC-B The compound was purified by preparative SFC on a Waters BEH 2-EP column (5 μm 250×30 ID mm) using MeOH/20 mM NH 3 in CO 2 as mobile phase; Method SFC-C The compound was purified by preparative SFC on a Waters BEH 2-EP column (5 μm 250×30 ID mm) using MeOH/H 2 O (97/3)+50 mM NH 3 in CO 2 as mobile phase; Method SFC-D The compound was purified by preparative SFC on a Waters BEH column (5 μm 250×30 ID mm) using MeOH/20 mM NH 3 in CO 2 as mobile phase; Method SFC-E The compound was purified by preparative SFC on a Waters Acquity UPC2 BEH column (3.5 μm 250×30 mm ID) using MeOH/H 2 O (97/3)+50 mM NH 3 in CO 2 as mobile phase; Method SFC-F The compound was purified by preparative SFC on a Waters BEH column (5 μm 250×30 ID mm) using MeOH/H 2 O (97/3)+50 mM NH 3 in CO 2 as mobile phase; Method SFC-G The compound was purified by chiral preparative SFC on a Chiralpak IC column (5 μm 250×20 ID mm) using IPA in CO 2 (g) as mobile phase; Method SFC-H The compound was purified by chiral preparative SFC on a Daicel Chiralpak AD column (10 μm 250×50 ID mm) using 55% 0.1% NH 4 OH (aq) and 45% IPA as the mobile phase; Method FlashAcid-A The compound was purified by preparative flash chromatography on a WelFlash C18, 120 g column using a gradient of 45-90% MeCN in a FA (0.05%) buffer system as mobile phase; Method FlashBasic-A The compound was purified by preparative flash chromatography on a WelFlash C18, 120 g column using a gradient of 30-80% MeCN in a H 2 O/NH 4 HCO 3 (10 mM) buffer system as mobile phase;

In general, all solvents used were commercially available and of analytical grade. Anhydrous solvents were routinely used for reactions.

Phase Separators used in the examples are ISOLUTE® Phase Separator columns.

The Intermediates and Examples named below were named using ChemDraw Professional version 19.0.0.22 from PerkinElmer.

The following abbreviations were used

Aq Aq

AIBN 2,2′-Azobis(2-methylpropionitrile)

APCI Atmospheric pressure chemical ionization

Boc 2 O Di-tert-butyl dicarbonate

B 2 Pin 2 4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane

BuOAc n-Butyl acetate

BuOH Butanol

Calcd Calculated

Dba (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one

DBAD Di-tert butyl azodicarboxylate

DCM Dichloromethane

DEA Diethylamine

DIA Diisopropylamine

DIAD Diisopropyl (E)-diazene-1,2-dicarboxylate

DIPEA N-Ethyl-N-isopropyl-propan-2-amine

DMA N,N-dimethylacetamide

DMAP N,N-dimethylpyridin-4-amine

DMF N,N-dimethylformamide

DMSO Dimethylsulfoxide

DPPA Diphenylphosphoryl azide

Dppf 1,1′-bis(diphenylphosphino)ferrocene

DTBBPY 4,4′-Di-tert-butyl-2,2′-dipyridyl

Dtbpf 1,1′-Bis(di-tert-buthylphosphino)ferrocene

EDC 3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine; hydrochloride

ESI Electrospray ionization

Et Ethyl

Et 2 O Diethyl ether

EtOAc Ethylacetate

EtOH Ethanol

FA Formic acid

h/hr Hour(s)

HATU (Dimethylamino)-N,N-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridinyl)methaniminium hexafluorophosphate

HBTU 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V)

HOAt 3H-1,2,3-Triazolo[4,5-b]pyridin-3-ol

HOBt 1-Hydroxybenzotriazole; hydrate

HPLC High performance liquid chromatography

HRMS High resolution mass spectrometry

IPA Isopropyl alcohol

IPAC Isopropyl acetate

[Ir(COD)OMe] 2 Bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I)

L Litre

Me Methyl

MeCN Acetonitrile

mL Millilitre

MeOH Methanol

2-Me-THF 2-Methyltetrahydrofuran

Min Minutes

MS Mass spectrometry

MTBE Methyl tert-butyl ether

NBS 1-Bromopyrrolidine-2,5-dione

NMR Nuclear magnetic resonance

OAc Acetate

OTf Trifluoromethanesulfonate

PE Petroleum ether

Pd—C Palladium on charcoal

Rt Room temperature

Sat Saturated

SM Starting material

SFC Supercritical fluid chromatography

T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide

TBAF Tetra-n-butylammonium fluoride

TCFH N-(Chloro(dimethylamino)methylene)-N-methylmethanaminium

hexafluorophosphate(V)

TEA Triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TCFH N-(Chloro(dimethylamino)methylene)-N-methylmethanaminium

hexafluorophosphate(V)

Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

Intermediate 1: Ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate

A solution of DIA (576 mL, 413 g, 4.08 mol) in THF (3.50 L) was cooled to −50 to −40° C. and a solution of n-BuLi (2.5 M in hexane, 1.09 kg, 3.92 mol) was added over 3 h, maintaining the temperature between −50 to −40° C. The solution was stirred for 3 h at −50 to −40° C., followed by the addition of a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (700 g, 3.27 mol, 2.34 M in THF) over 2 h, maintaining the temperature between −50 to −40° C. The reaction mixture was stirred for 4 h at −50 to −40° C. before the addition of methyl iodide (603 g, 4.25 mol, 3.04 M in THF) over 3 h, maintaining the temperature between −50 to −30° C. The reaction mixture was further stirred for 2 h at −50 to −30° C. followed by the addition of aq NH 4 Cl (3.50 L, 20% w/w in H 2 O) over 1 h, maintaining the temperature <0° C. The solution was warmed to between 15 to 25° C., held for 0.5 h then the layers were separated and the organic layer washed with aq NH 4 Cl (2×3.50 L, 20% w/w in H 2 O). Exchange of the organic reaction solvent from THF to EtOH under reduced pressure, maintaining the temperature <45° C., gave the title compound as a 27% w/w solution in EtOH (2.51 kg, 2.91 mol, 89%). 1 H NMR for purified compound (400 MHz CDCl 3 ) δ 1.18 (3H, s), 1.27-1.22 (3H, m), 1.47-1.35 (2H, m), 1.70-1.56 (4H, m), 2.13 (2H, d), 3.92 (4H, s), 4.14 (2H, q), MS (ESI): m/z [M+H] + 229.2.

Intermediate 2: 8-Methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid

To a solution of Intermediate 1 (1.13 kg, 1.31 mol, 27% w/w in EtOH) was added EtOH (900 mL) followed by aq NaOH (2.63 L, 5.26 mol, 2 M in H 2 O) maintaining the temperature between 15 to 30° C. The solution was heated to between 50 to 60° C., then held for 6 h before cooling to 15 to 30° C. and concentration of the solution to between 1.8 to 2.4 L under reduced pressure. Hexane (1.50 L) was added and the layers separated. The aq layer was collected and the pH adjusted to between 3 to 4 by the addition of aq HCl (1.30 L, 5.2 mol, 4 M in H 2 O) maintaining the temperature <20° C. This aq solution was extracted with DCM (2×1.50 L) and the combined organic phases were concentrated under reduced pressure, maintaining the temperature <30° C. to give the title compound as a 17% w/w solution in DCM (1.43 kg, 1.24 mol, 94%). 1 H NMR for purified compound (500 MHz CDCl 3 ) δ 1.25 (3H, s), 1.53 (2H, dt), 1.62-1.72 (4H, m), 2.05-2.19 (2H, m), 3.93 (4H, s). MS (ESI): m/z [M+Na] + 223.1.

Intermediate 3: 1-Methyl-4-oxocyclohexane-1-carboxylic acid

Method A

To a solution of Intermediate 2 (367 g, 250 mmol, 14% w/w in DCM) was added TFA (95.3 mL, 142 g, 1.25 mol). The reaction temperature was maintained between 25 to 35° C. for 20 h before cooling to between 0 to 10° C. H 2 O (250 mL) was added to the reaction solution and the pH of the aq phase adjusted to between 9 and 10 by the addition of aq NaOH (440 mL, 1.76 mol, 4 M in H 2 O). The layers were separated and the aq layer was retained and cooled to between 0 to 10° C. The pH was adjusted to between 2 and 3 by the addition of aq HCl (73.5 mL, 294 mmol, 4 M in H 2 O) then extracted with DCM (3×250 mL) and the combined DCM solutions concentrated to between 150 to 200 mL under reduced pressure. Exchange of the organic reaction solvent from DCM to MeCN under reduced pressure, maintaining the temperature <40° C., gave the title compound as a 30% w/w solution in MeCN (119 g, 227 mmol, 91%). 1 H NMR for purified compound (400 MHz CDCl3) δ 1.39 (3H, s), 1.73 (2H, td), 2.43 (6H, m). MS (ESI): m/z [M+H] + 157.1.

Method B

To a solution of Intermediate 2 (6.17 kg, 3.83 mol, 12.4% in DCM) was added TFA (1.42 L, 2.18 kg, 19.13 mol). The reaction temperature was maintained between 25 to 35° C. for 20 h before cooling to between 0 to 10° C. A solution of aq NaOH (918 g, 22.96 mol dissolved in 7.66 L H 2 O) was added to the reaction solution and the pH of the aqueous phase was adjusted to between 9 and 11. The layers were separated and the aq layer was retained and cooled to between 0 to 10° C. Addition of DCM (3.83 L) followed by aq HCl (1.52 L, 6.08 mol, 4 M in H 2 O) adjusts the pH to between 3 and 4. The organic layer was retained and the aqueous extracted with DCM (2×3.83 L) and the combined organic phase was washed with brine (2.3 L, 15% w/w NaCl). The organic phase was concentrated under reduced pressure to 2.3 to 3.1 L. Exchange of the organic reaction solvent from DCM to MeCN under reduced pressure, maintaining the temperature <45° C., gave the title compound as a 18% solution in MeCN (2.85 kg, 3.32 mol, 87%). 1 H NMR for purified compound (400 MHz CDCl3) δ 1.39 (3H, s), 1.73 (2H, td), 2.43 (6H, m). MS (ESI): m/z [M+H] + 157.1.

Intermediate 4: Naphthalen-1-ylmethyl 1-methyl-4-oxocyclohexane-1-carboxylate

Method A

To a solution of Intermediate 3 (119 g, 192 mmol, 25% w/w in MeCN) was added 1-chloromethylnaphthalene (32.2 g, 183 mmol) followed by DIPEA (70.0 mL, 49.7 g, 384 mmol) and NaI (2.88 g, 19.2 mmol). The solution was heated to between 50 to 60° C. for 8 h before cooling to between 0 to 10° C. H 2 O (240 mL) was added and the pH of the reaction mixture adjusted to between 3 and 4 by the addition of aq HCl (55.0 mL, 220 mmol, 4 M in H 2 O). The reaction mixture was extracted with MTBE (2×150 mL) and the combined organic phases washed with aq NaHCO 3 (150 mL, 144 mmol, 8% w/w in H 2 O). The organic reaction solvent was exchanged from MTBE to IPA under reduced pressure, maintaining the temperature <40° C. The temperature of the reaction solution was lowered to between −10 to 3° C. and the solution stirred for 2 h, upon which a solid precipitate formed. The solids were filtered and dried under N 2 for 15 h to give the title compound as a white solid (42.8 g, 144 mmol, 74%); 1 H NMR (500 MHz, CDCl 3 ) 1.30 (3H, s), 1.65 (2H, td), 2.16-2.47 (6H, m), 5.66 (2H, s), 7.46 (1H, dd), 7.51-7.63 (3H, m), 7.78-7.93 (2H, m), 7.93-8.05 (1H, m). MS (ESI): m/z [M+Na] + 319.1.

Method B

To a solution of Intermediate 3 (2.66 kg, 3.09 mol, 18.2% in MeCN) was added 1-chloromethylnapthalene (535 g, 2.94 mol) followed by potassium carbonate (513 g, 3.71 mol) and a further portion of fresh MeCN (714 mL). The suspension was heated to between 50 to 60° C. for 17 h before cooling to 25 to 30° C. The solid was removed by filtration through a Celite pad, which was washed through with MeCN (2×967 mL). Concentrate the filtrates to 1.45 to 1.93 L under reduced pressure. The MeCN was exchanged to isopropanol under reduced pressure, maintaining the temperature <50° C. The temperature of the mixture was lowered to between 20 to 25° C., upon which a solid precipitate formed. The mixture was cooled further to −10 to 0° C., and the solids were then filtered, washed with isopropanol and dried under N 2 to give the title compound as a white solid (752.6 g, 2.49 mol, 80.5%); 1 H NMR (500 MHz, CDCl 3 ) 1.30 (3H, s), 1.65 (2H, td), 2.16-2.47 (6H, m), 5.66 (2H, s), 7.46 (1H, dd), 7.51-7.63 (3H, m), 7.78-7.93 (2H, m), 7.93-8.05 (1H, m). MS (ESI): m/z [M+Na] + 319.1.

Intermediate 5: Methyl 5-(1,3,6,2-dioxazaborocan-2-yl)-4-fluoro-2-methoxybenzoate

Method A

B 2 Pin 2 (362 g, 1.43 mol) was added to 2-Me-THF (1.75 L) that had been degassed with N 2 to <1% oxygen. The solution was held between 20 to 30° C. and methyl 4-fluoro-2-methoxybenzoate was added (250 g, 1.36 mol). DTBBPY (1.09 g, 4.10 mmol) was added and the reaction vessel evacuated and re-filled with N 2 until the oxygen level was <0.5%. [Ir(COD)OMe] 2 (1.35 g, 2.04 mmol) was added and the reaction vessel evacuated and re-filled with N 2 until the oxygen level was <0.5%. The reaction mixture was heated to between 80 to 85° C. and held at that temperature for a further 2 h. The reaction mixture was cooled to between 0 to 5° C. followed by the slow addition of diethanolamine (428 g, 4.07 mol, 10.9 M in IPA) over a period of 2.5 h, with the concurrent generation of H 2 gas. The reaction mixture was stirred for 2.5 h between 0 to 5° C., followed by filtration and washing of the solids with 2-Me-THF (3×750 mL). The solid was dried under N 2 for 10 h to give the title compound as a white solid (356 g, 1.20 mol, 88%); 1 H NMR (500 MHz, DMSO-d6) δ 2.81-2.89 (2H, m), 3.14 (2H, dq), 3.71 (2H, ddd), 3.74 (3H, s), 3.78 (3H, s), 3.84 (2H, td), 6.77 (1H, d), 7.10 (1H, s), 7.83 (1H, d). MS (ESI): m/z [M+H] + 297.1.

Method B

B 2 Pin 2 (29.0 g, 114 mmol) and methyl 4-fluoro-2-methoxybenzoate (20.6 g, 109 mmol) were added to 2-Me-THF (140 mL) that had been degassed with N 2 to <1% oxygen. The solution was held between 20 to 30° C. then DTBBPY (88 mg, 0.33 mmol) and [Ir(COD)OMe] 2 (108 mg, 0.16 mmol) were added and the reaction vessel evacuated and re-filled with N 2 until the oxygen level was <0.5%. The reaction mixture was heated to between 80 to 85° C. and held at that temperature for a further 3 h. The reaction mixture was cooled to between 0 to 10° C. followed by the slow addition of isopropanol (12.4 mL, 218 mmol), with the concurrent generation of H 2 gas. Addition of seed (100 mg of Intermediate 5) followed by addition of diethanolamine (22.84 g, 218 mmol) dissolved in IPA (20 mL) gave a mobile slurry. The slurry was warmed to 20 to 30° C. and the solid collect by filtration. It was then washed with 2-Me-THF (160 ml) and the solid was dried under N 2 for 10 h to give the title compound as a white solid (29.1 g, 96 mol, 88%); 1 H NMR (500 MHz, DMSO-d6) δ 2.81-2.89 (2H, m), 3.14 (2H, dq), 3.71 (2H, ddd), 3.74 (3H, s), 3.78 (3H, s), 3.84 (2H, td), 6.77 (1H, d), 7.10 (1H, s), 7.83 (1H, d). MS (ESI): m/z [M+H] + 297.1.

Intermediate 6: Methyl 4-fluoro-5-hydroxy-2-methoxybenzoate

Method A

To a suspension of Intermediate 5 (350 g, 1.18 mol) in H 2 O (1.05 L) was added THF (1.75 L) and the reaction mixture stirred until a clear solution is obtained. (NH 4 ) 2 CO 3 (136 g, 1.41 mol) was added and the heterogenous mixture cooled to between 0 to 10° C. NaBO 3 .4H 2 O (217 g, 1.41 mol) was added in 10 equal portions over a period of 2 h maintaining the reaction temperature between 0 to 30° C. The reaction temperature was adjusted to between 20 to 30° C. and held for 1 h. An aq solution of NaHSO 3 (1.96 L, 942 mmol, 0.48 M in H 2 O) was added over 3 h and the reaction mixture stirred for an additional 0.5 h. The reaction mixture was filtered, the solids washed with ethylacetate (700 mL) and the filtrate and wash combined to give a biphasic solution. The solution was separated and the retained organic phase solvent exchanged from THF/ethylacetate to MeOH under reduced pressure, maintaining the temperature <40° C. H 2 O (3.50 L) was added drop-wise over a period of 4 h and the reaction mixture cooled to between 0 to 5° C. and held for 2 h. The reaction mixture was filtered, the collected solids washed with H 2 O (3×350 mL) and dried under hot air at <40° C. to give the title compound as a white solid (195 g, 974 mmol, 83% yield); 1 H NMR (500 MHz, CDCl 3 ) δ 3.82 (3H, s), 3.86 (3H, s), 6.72 (1H, d), 7.54 (1H, d). MS (ESI): m/z [M+H] + 201.0.

Method B

Intermediate 5 (32.41 g, 67.3 mmol) was dissolved in 2-Me-THF (100 mL) with acetic acid (12.13 g, 202 mmol) and cooled to between 0 to 10° C. Hydrogen peroxide solution (30% w/w, 9.16 g, 80.8 mmol) was added over 2 hours and then the reaction temperature was adjusted to between 20 to 30° C. and held for 18 hours. An aq solution of Na 2 S 2 O 3 .5H 2 O (20% w/w, 50 mL) quenches the mixture and gives a phase separation. The aqueous is discarded, and the organic washed twice with aq solution of Na 2 S 2 O 3 .5H 2 O (5% w/w, 100 mL). The organic phase was concentrated to 60 mL under reduced pressure followed by another 2 vacuum distillations with 2-Me-THF (100 mL) to give a dissolved solution at 35 to 45° C. Nucleation was controlled by addition of seed (100 mg of Intermediate 6) followed by slow addition of 300 mL n-heptane over 5 hours. The resulting slurry was adjusted to between 20 to 30° C. and stirred overnight prior to filtration. The collected solid was washed with n-heptane (2×60 mL) and dried to give the title compound as a white solid (12.5 g, 62.5 mmol, 93% yield); 1 H NMR (500 MHz, CDCl 3 ) δ 3.82 (3H, s), 3.86 (3H, s), 6.72 (1H, d), 7.54 (1H, d). MS (ESI): m/z [M+H] + 201.0.

Intermediate 7: (1R,2R,3S,4S)-3-(Methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

To a solution of (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione (387 g, 2.36 mol) in toluene (4.64 L) was added quinidine (843 g, 2.60 mol) followed by toluene (774 mL). The reaction mixture was cooled to between −10 to −5° C. and MeOH (227 g, 286 mL, 7.08 mol) was added drop-wise over 1.5 h before holding at between −10 to −5° C. for 14 h. The reaction mixture was warmed to between −5 to 5° C., held for 2 h, then filtered. The solids were washed with toluene (3×387 mL), the filtrate and washes combined and cooled to between 0 to 10° C. In a separate vessel an aq solution of HCl (590 mL, 7.08 mol, 12 M in H 2 O) and NaCl (1.24 kg, 21.2 mol) were added to H 2 O (6.39 L) and the resulting solution added dropwise to the main reaction vessel, maintaining the reaction solution <10° C. The reaction mixture was warmed to between 10 to 20° C., held for 0.5 h then filtered. The solids were washed with toluene (1.94 L), the filtrate and wash combined, and the biphasic solution separated. The organic phase was washed with aq NaCl (3.87 L, 20% w/w in H 2 O) and stored at <5° C. to give the title compound as a 5.9% w/w solution in toluene (6.19 kg, 1.83 mol, 78%); 1 H NMR for purified compound (400 MHz DMSO-d 6 ) δ 1.25-1.32 (1H, m), 1.95 (1H, d), 2.48-2.50 (2H, m), 2.93 (2H, s), 3.51 (3H, s), 6.15-6.22 (2H, m), 12.21 (1H, s). MS (ESI): m/z [M+Na] + 219.1.

Intermediate 8: Methyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

To a solution of Intermediate 7 in toluene (6.19 kg, 5.9% w/w, 1.85 mol) at between −5 to 5° C. was added TEA (307 mL, 223 g, 2.22 mol) followed by DPPA (538 g, 1.94 mol), maintaining the reaction solution <5° C. The reaction mixture was stirred for 4 h at between −5 to 5° C. then TEA was added (767 mL, 557 g, 5.55 mol) followed by citric acid (352 g, 1.85 mol). The reaction mixture was stirred for 6 h at between −5 to 5° C. then H 2 O (3.6 L) was added maintaining the reaction solution <10° C. The biphasic reaction solution was stirred for 0.5 h, the phases separated and the organic phase washed with H 2 O (3.6 L) and aq NaCl (3.6 L, 15% w/w in H 2 O) then stored between 2 to 8° C. to give methyl (1S,2S,3R,4R)-3-(azidocarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (Intermediate 9) as a solution in toluene that was used directly in the next step. Intermediate 9 as a solution in toluene at between 2 to 8° C. was added over 2 h to a reactor containing toluene (1.80 L) at between 70 to 80° C., maintaining the reaction temperature <80° C. The resulting solution was stirred for 1 h before cooling to between 20 to 30° C. Exchange of the organic reaction solvent from toluene to 1,4-dioxane under reduced pressure, maintaining the temperature <50° C., gave Methyl (1S,2S,3R,4R)-3-isocyanatobicyclo[2.2.1]hept-5-ene-2-carboxylate (Intermediate 10) as a solution in 1,4-dioxane that was used directly in the next step. To a solution of Intermediate 10 in 1,4-dioxane at between 10 to 20° C. was added HCl (420 mL, 1.68 mol, 4 M in 1,4-dioxane) followed by H 2 O (360 mL, 1.68 mol, 4.67 M in 1,4-dioxane). The reaction mixture was warmed to between 25 to 35° C. and held for 16 h. MTBE (1.65 L) was added drop-wise and the reaction mixture filtered, the solids washed with MTBE/1,4-dioxane (1:1, 660 mL) and MTBE (660 mL), then dried at between 30 to 40° C. under vacuum to give the title compound as a white solid (258 g, 1.27 mol, >99% ee, 75%); 1 H NMR (400 MHz, DMSO-d6) δ 1.45 (1H, d), 2.04 (1H, d), 2.52-2.67 (1H, m), 2.94-3.10 (2H, m), 3.19 (1H, d), 3.65 (3H, s), 6.21 (1H, m), 6.30 (1H, m), 8.34 (3H, s). MS (ESI): m/z [M+H] + 168.1.

Intermediate 11: Naphthalen-1-ylmethyl (1r,4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate

Route A

To a solution of Na 2 HPO 4 .12H 2 O (8.25 g, 23.0 mmol), NaH 2 PO 4 (0.55 g, 4.48 mmol) and MgCl 2 (0.11 g, 1.10 mmol) in H 2 O (550 mL) at 20 to 30° C. was added Intermediate 4 (50.0 g, 169 mmol) as a solution in IPA (450 mL). The pH of the reaction solution was adjusted to between 7.3 to 7.8 using 6 M HCl and NAD+ (0.66 g, 1.00 mmol) was added followed by ADH-230 (7.50 g, 0.15 wt %). ADH-230 is an alcohol dehydrogenase available from Johnson Matthey PLC, UK (catalogue no. ADH-230). The reaction mixture was then held at 33 to 37° C. for 18 h before concentration to between 300 and 400 mL under reduced pressure, maintaining the temperature <45° C. NaCl (150 g), Celite® (20.0 g, 0.4 wt %) and MTBE (500 mL) was added and the reaction held for 0.5 h. The mixture was filtered and the filter cake washed with MTBE (250 mL). The combined filtrate was separated and the aq phase extracted with MTBE (500 mL). The organic phases were combined and washed with H 2 O (250 mL) before solvent exchange to THF under reduced pressure, maintaining the temperature <45° C., gave the title compound (138 g, 33% w/w %, >99:1 trans:cis, <0.1% IPA, 92% yield) as a solution in THF that was used directly in the next step. 1 H NMR for purified compound (500 MHz, CDCl 3 ) δ 1.21 (3H, s), 1.48-1.58 (2H, m), 1.62-1.77 (4H, m), 1.82-1.93 (2H, m), 3.74-3.77 (1H, m), 5.57 (2H, s), 7.41-7.48 (1H, m), 7.48-7.57 (3H, m), 7.85 (1H, d), 7.87-7.91 (1H, m), 7.98 (1H, d). MS (ESI): m/z [M+Na] + 321.1.

Route B

A solution of lithium tri-sec-butylborohydride (1.06 g, 5.6 mmol) in THF (5 mL) was added dropwise to a stirred solution of Intermediate 4 (1.00 g, 3.37 mmol) in THF (10 mL) cooled to −78° C., over a period of 1 min under nitrogen. The resulting solution was stirred at −78° C. for 2 h. The reaction mixture was quenched with 0.1 M HCl (10 mL) at −78° C. and then extracted with EtOAc (3×50 mL). The organic layers were pooled and dried over Na 2 SO 4 filtered and evaporated. The residue was purified by preparative TLC (EtOAc/PE, 1:3), to afford the title compound (0.488 g, 48.5%) as a pale yellow gum. The isolated material had a 3:100 cis/trans ratio. 1 H NMR (400 MHz, CDCl 3 ) δ1.21-1.25 (s, 3H), 1.37-1.49 (m, 1H), 1.49-1.61 (m, 2H), 1.61-1.74 (m, 4H), 1.83-1.95 (m, 2H), 3.74-3.83 (dq, 1H), 5.57-5.61 (s, 2H), 7.43-7.54 (dd, 1H), 7.50-7.61 (m, 3H), 7.84-7.94 (m, 2H), 7.97-8.04 (m, 1H). MS (ESI): m/z [M+Na] + 321.

Intermediate 12: Methyl 4-fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

To a solution of Intermediate 11 in THF (736 g, 34% w/w, 839 mmol) was added THF (156 mL), PPh 3 (248 g, 944 mmol) and Intermediate 6 (140 g, 699 mmol). The solution was heated to 30° C. prior to the drop-wise addition of DIAD (184 g, 909 mmol) over 1 h maintaining the reaction temperature <40° C. The solution was held at between 30 and 40° C. for 1 h before cooling to between 20 and 30° C. followed by the addition of an aq solution of NaCl (700 mL, 20% w/w in H 2 O). The layers were separated and the crude solution of the title compound in THF was used directly in the next step. 1 H NMR for purified compound (500 MHz, CDCl 3 ) δ 1.17 (3H, s), 1.20-1.30 (2H, m), 1.58 (2H, qd), 1.88-1.98 (2H, m), 2.29 (2H, d), 3.84 (3H, s), 3.88 (3H, s), 4.05 (1H, tq), 5.61 (2H, s), 6.72 (1H, d), 7.43-7.58 (5H, m), 7.82-7.94 (2H, m), 8.00 (1H, d). MS (ESI): m/z [M+Na] + 503.2.

Intermediate 13: 4-Fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

To the crude solution of Intermediate 12 used directly from the previous step at between 0 and 5° C., was added a aq solution of LiOH.2H 2 O (88.0 g, 2.10 mol, in 525 mL of H 2 O) over 1 h maintaining the reaction temperature <10° C. The solution was warmed to between 15 and 30° C. and vigorously stirred for 16 h. IPAC (1.68 L) was added and the solution cooled to between 0 and 10° C. followed by the drop-wise addition of H 3 PO 4 (1.26 L, 2.52 M, 2 M in H 2 O), maintaining the reaction temperature <10° C., to give a solution pH of between 4.0 and 5.0. The organic layer was separated and washed with of an aq solution of NaCl (700 mL, 20% w/w in H 2 O). The THF was removed under reduced pressure, maintaining the temperature <50° C. and IPAC (4.20 L) was added to give the title compound in IPAC that was used directly in the next step. 1 H NMR for purified compound (500 MHz, CDCl 3 ) δ 1.18 (3H, s), 1.22-1.36 (2H, m), 1.58 (2H, qd), 1.95 (2H, dt), 2.29 (2H, d), 4.02 (3H, s), 4.19 (1H, td), 5.60 (2H, s), 6.82 (1H, d), 7.46 (1H, dd), 7.49-7.62 (3H, m), 7.78 (1H, d), 7.82-7.94 (2H, m), 7.99 (1H, d).

Intermediate 14: 4-Fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate cyclohexanaminium salt

To a crude solution of Intermediate 13 in IPAC used directly from the previous step at between 50 and 55° C., was added a solution of cyclohexylamine (280 mL, 699 mmol, 2.5 M in IPAC) drop-wise over 3 h. The heterogenous slurry was stirred at between 50 and 55° C. for 0.5 h then at between 40 and 45° C. for a further 1 h. The reaction mixture was filtered and the solids washed with IPAC (3×0.98 L) pre warmed to between 40 and 45° C. and dried under a flow of N 2 at 45° C. for 16 h. To the dried collected solids was added MeOH (3.64 L) and the mixture heated to between 55 and 56° C. H 2 O (1.58 L) was added drop-wise over 1 h then the mixture stirred for 1 h before cooling to between 0 and 5° C. over 3 h. The heterogenous slurry was held for a further 1 h then filtered, washed with 5:3 MeOH:H 2 O at 0° C. (2×750 mL) and the solids dried under N 2 at 45° C. for 16 h to give the title compound as a white solid (332 g, 85% from methyl 4-fluoro-5-hydroxy-2-methoxybenzoate); 1 H NMR (500 MHz, CDCl 3 ) δ 0.96 (1H, ddt), 1.03-1.36 (6H, m), overlapping 1.14 (3H, S), 1.46-1.7 (5H, m), 1.91 (4H, dt), 2.26 (2H, d), 2.81 (1H, t), 3.76 (3H, s), 4.03 (1H, tt), 5.59 (2H, s), 6.65 (1H, d), 7.37-7.49 (2H, m), 7.49-7.6 (3H, m), 7.81-7.93 (2H, m), 7.98 (1H, d). MS (ESI): m/z [M+Na] + 489.2.

Intermediate 15: Methyl (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

To a solution of Intermediate 14 (149 g, 264 mmol) in DCM (750 mL) at between 15 and 30° C. was added H 2 O (450 mL) followed by the slow addition of HCL (300 mL, 1 M in H 2 O). The biphasic solution was stirred for 0.5 h then separated and the organic phased washed with HCl (750 mL, 0.2 M in H 2 O) then with H 2 O (3×750 mL). The organic solution was concentrated under reduced pressure, maintaining the temperature below 30° C., to dry to <0.1% H 2 O. The solution was diluted with DCM (450 mL) to bring the total volume to 750 mL before the addition of Intermediate 8 (59.3 g, 291 mmol) to give a heterogenous slurry. To this mixture was added DIPEA (137 g, 1.06 mol) followed by T3P (252 g, 397 mmol, 50% w/w in EtAOc) and the solution stirred for 1 h. The solution was cooled to between 0 and 10° C. followed by the addition of H 2 O (750 mL) and subsequently stirred for a further 0.5 h. The biphasic solution was separated and the organic phase washed with H 2 O (2×750 mL) before solvent exchange to THF under reduced pressure gave the title compound in THF that was used directly in the next step. 1 H NMR for purified compound (500 MHz, CDCl 3 ) δ1.16 (3H, s), 1.25 (2H, td), 1.49-1.69 (3H, m), 1.92-2.01 (2H, m), 2.04-2.1 (1H, m), 2.28 (2H, d), 2.71 (1H, dd), 2.83 (1H, s), 2.92-3.05 (1H, m), 3.61 (3H, s), 3.93 (3H, s), 4.17 (1H, td), 4.46 (1H, td), 5.60 (2H, s), 6.25 (2H, ddd), 6.72 (1H, d), 7.46 (1H, dd), 7.48-7.6 (3H, m), 7.81-7.95 (3H, m), 7.99 (1H, d), 8.60 (1H, d). MS (ESI): m/z [M+H] + 616.3.

Intermediate 16: (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

A crude solution of Intermediate 15 in THF (750 mL) from the previous step was cooled to between 0 and 5° C. An aq solution of LiOH.2H 2 O (27.7 g, 661 mmol, in 150 mL of H 2 O) was added and the solution held for 36 h. The pH of the solution was adjusted to 2 with the portion wise slow addition of HCl (0.5 M, 1.45 L, 2.90 mol) and held for 1 h between 0 and 5° C. The heterogenous slurry was filtered and the solids washed with 1:3 MeOH:H 2 O at 0° C. (600 mL) and the solids dried under N 2 at 45° C. for 16 h to give crude title compound as a white solid (158 g, 99%). The crude (150 g) was slurried in IPAC (1.13 L) at between 60 and 65° C. for 0.5 h. The heterogenous mixture was cooled to between 0 and 5° C. over 3 h then further stirred for 1 h before filtration. The collected solids were with IPAC at between 0 and 5° C. (2×300 mL) then dried under N 2 at 45° C. for 12 h to give the title compound as a white solid (127 g, 82% from Intermediate 14); 1 H NMR (500 MHz, CDCl 3 ) δ1.16 (3H, s), 1.2-1.35 (2H, m), 1.50-1.69 (3H, m), 1.89-2.08 (3H, m), 2.27 (2H, ddd), 2.72 (1H, dd), 2.80 (1H, s), 3.06 (1H, s), 3.75 (3H, s), 4.15 (1H, tt), 4.43-4.54 (1H, m), 5.59 (2H, s), 6.24 (2H, ddd), 6.53 (1H, d), 7.45 (1H, dd), 7.47-7.58 (3H, m), 7.8-7.9 (3H, m), 7.94-8.05 (1H, m), 8.59 (1H, d). MS (ESI): m/z [M+H] + 602.3.

Intermediate 17: Naphthalen-1-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

To a solution of DIPEA (6.45 g, 49.9 mmol) in DCM (300 mL) at between 0 and 5° C. was added Intermediate 16 (30.6 g, 49.9 mmol) followed by (1-methylcyclobutyl)methanamine hydrochloride (8.63 g, 62.4 mmol). DIPEA (25.8 g, 200 mmol) was added drop-wise maintaining the temperature between 0 and 5° C., followed by the addition of T3P (50.8 g, 79.8 mmol, 50% w/w in EtAOc) over 0.5 h. The solution was warmed to between 15 and 25° C. and stirred for 1 h followed by the drop-wise addition of H 2 O (150 mL) maintaining the temperature below 30° C. The biphasic solution was separated and the organic phase washed with H 2 O (2×150 mL) then the solvent exchanged to EtOH under reduced pressure to give the title compound as a crude solution in EtOH (128 g, 26% w/w, 96% yield) that was used directly in the next step. 1 H NMR for purified compound (500 MHz, CDCl 3 ) δ 0.98 (3H, s), 1.16 (3H, s), 1.21-1.29 (2H, m), 1.51-1.66 (5H, m), 1.66-1.76 (3H, m), 1.76-1.82 (1H, m), 1.88-2.02 (2H, m), 2.26 (3H, dd), 2.40 (1H, dd), 2.80 (1H, s), 3.00 (1H, s), 3.05 (1H, dd), 3.21 (1H, dd), 3.93 (3H, s), 4.06-4.2 (1H, m), 4.39 (1H, td), 5.60 (2H, s), 5.64 (1H, t), 6.19-6.38 (2H, m), 6.70 (1H, d), 7.46 (1H, dd), 7.49-7.62 (3H, m), 7.75-7.93 (3H, m), 8.00 (1H, d), 8.66 (1H, d). MS (ESI): m/z [M+H] + 683.3.

Intermediate 19: (1S,2S,3R,4R)-3-((tert-Butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

A solution of (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid (0.90 g, 5.88 mmol) in H 2 O (15 mL) was added dropwise to a stirred solution of Boc 2 O (2.05 mL, 8.8 mmol) and Et 3 N (2.46 mL, 17.6 mmol) in 1,4-dioxane (20 mL) at 5° C., and under nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 14 h, and then diluted with EtOAc (250 mL). The organic layer was washed sequentially with sat NaHCO 3 (100 mL), H 2 O (100 mL), and sat brine (2×100 mL), dried over Na 2 SO 4 , filtered and evaporated. The crude product was precipitated from EtOAc and PE to give the title compound (1.49 g, 100%) as a pale yellow solid; MS (ESI) m/z [M+Na] + 276

Intermediate 20: tert-Butyl ((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate

DIPEA (5.49 mL, 31.4 mmol) was added dropwise to a solution of Intermediate 19 (1.99 g, 7.86 mmol), (1-methylcyclobutyl)methanamine hydrochloride (1.07 g, 7.86 mmol), EDC (3.77 g, 19.64 mmol) and HOBt (3.01 g, 19.64 mmol) in DMF (60 mL) at 20° C. and under nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 14 h and then diluted with EtOAc (125 mL). The organic layer was washed sequentially with sat NH 4 Cl (125 mL), H 2 O (125 mL), and sat brine (125 mL), dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by flash chromatography using a gradient of 0-12% EtOAc in PE as mobile phase, to give the title compound (2.5 g, 95%) as a pale yellow solid.

Intermediate 21: (1S,2S,3R,4R)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

HCl (25 mL, 100 mmol, 4 M in 1,4-dioxane) was added dropwise to Intermediate 20 (2.5 g, 7.47 mmol) at 0° C., under nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure, and the crude product was purified by precipitation from EtOAc and diisopropyl ether to give the title compound (1.70 g, 84%) as a white solid.

Intermediate 22: (1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

Pd—C (0.086 g, 0.81 mmol) was added to a solution of Intermediate 21 (1.1 g, 4.06 mmol) in MeOH (30 mL) and the reaction mixture was stirred under an atmosphere of hydrogen (1.5 atm) at 20° C. for 14 h. The reaction mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure to give the title compound (1.10 g, 99%); MS (ESI) m/z [M+H] + 237.

Intermediate 23: Methyl 5-bromo-4-fluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

(2-(Chloromethoxy)ethyl)trimethylsilane (1.87 g, 11.2 mmol) was added dropwise to a solution of K 2 CO 3 (3.11 g, 22.5 mmol) and methyl 5-bromo-4-fluoro-2-hydroxy-benzoate (2.8 g, 11.2 mmol) in DMF (25 mL) at 20° C. under a nitrogen atmosphere. The reaction mixture was heated at 80° C. for 14 h, and then cooled to rt and diluted with EtOAc (250 mL). The organic layer was washed with sat brine (3×150 mL), dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-3% EtOAc in PE as mobile phase, to give the title compound (3.0 g, 70%); MS (ESI) m/z [M+Na] + 401.4.

Intermediate 24: Methyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

Intermediate 23 (3.0 g, 7.91 mmol) was added to a suspension of B 2 Pin 2 (3.01 g, 11.86 mmol), KOAc (2.33 g, 23.73 mmol) and PdCl 2 (dppf) (0.58 g, 0.79 mmol) in 1,4-dioxane (50 mL) and the reaction mixture was stirred at 60′° C. for 14 h. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in EtOAc (20 mL). The organic layer was washed with H 2 O (3×20 mL), dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-10% of EtOAc in PE as mobile phase, to give the title compound (2.5 g, 74%); MS (ESI) m/z [M+Na] + 449.

Intermediate 25: Methyl 4-fluoro-5-hydroxy-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

A solution of sodium perborate (2.71 g, 17.59 mmol) in H 2 O (20 mL) was added slowly to a stirred solution of Intermediate 24 (2.5 g, 5.86 mmol) in THF (40 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 3 h, and then diluted with DCM (50 mL). The organic laver was washed with sat brine (3×50 mL), dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:PE, 1:3) to give the title compound (1.5 g, 81%); MS (ESI) m/z [M+Na] + 339.

Intermediate 26: Methyl 4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

A solution of DBAD (1.74 g, 7.54 mmol) in toluene (10 mL) was added dropwise to a stirred solution of Intermediate 11 (1.5 g, 5.03 mmol), Intermediate 25 (1.75 g, 5.53 mmol) and Ph 3 P (1.98 g, 7.54 mmol) in DCM (40 mL) at 20° C. and the reaction mixture was stirred at rt for 14 h. The reaction mixture was diluted with EtOAc (200 mL) and the organic layer was washed sequentially with sat NH 4 Cl (100 mL), sat NaHCO 3 (100 mL) and sat brine (100 mL), dried over Na 2 SO 4 , filtered, and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:5) to give the title compound (2.50 g, 83%); MS (ESI) m/z [M+Na] + 619.

Intermediate 27: Methyl 4-fluoro-2-hydroxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

HCl in 1.4-dioxane (1.27 mL, 4.2 M) was added dropwise to a stirred solution of Intermediate 26 (2.5 g, 4.19 mmol) in THF (40 mL) at 0° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 0° C. for 3 h. The solvent was removed under reduced pressure and the crude product was purified by precipitation from EtOAc and DCM to give the title compound (1.50 g, 77%); MS (ESI) m/z [M+Na] + 589.

Intermediate 28: Methyl 4-fluoro-2-(fluoromethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

A solution of N-((fluoromethyl)(oxo)(phenyl)-λ 6 -sulfaneylidene)-4-methylbenzenesulfonamide (351 mg, 1.07 mmol) in DMSO (15 mL) was added dropwise to a stirred solution of Intermediate 27 (500 mg, 1.07 mmol) and NaH (50 mg, 1.25 mmol) in DMSO (10 mL) at 20° C. and under a nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 3 h, and then sat NH 4 Cl (10 mL) was added. The H 2 O phase was extracted with EtOAc (3×25 mL) and the combined organic layer was dried over Na 2 SO 4 , filtered, and evaporated. The process described above was repeated two more times using in total 1.46 mmol of Intermediate 27. The crude products were combined and purified by preparative TLC (EtOAc:PE, 1:3) to give the title compound (0.52 g, 41%); MS (ESI) m/z [M+Na] + 521.

Intermediate 29: 4-Fluoro-2-(fluoromethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

A solution of LiOH (14.4 mg, 0.60 mmol) in H 2 O (2.0 mL) was added dropwise to a stirred solution of Intermediate 28 (200 mg, 0.40 mmol) in THF (4 mL) and the reaction mixture was stirred at rt for 3 h. The process was repeated two more times using in total 0.64 mmol of Intermediate 28. The reaction mixtures were combined and pH adjusted to 3 with aq HCl (3 M). The reaction mixture was diluted with EtOAc (250 mL) and the organic layer was washed sequentially with sat brine (200 mL), H 2 O (200 mL) and sat brine (150 mL), dried over Na 2 SO 4 , filtered, and evaporated. The crude product was purified by preparative TLC (MeOH:DCM, 1:5) to give the title compound (310 mg, 60%); MS (ESI) m/z [M+Na] + 507.

Intermediate 30: Naphthalen-1-ylmethyl (1S,4s)-4-(2-fluoro-4-(fluoromethoxy)-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

DIPEA (0.56 mL, 3.20 mmol) was added dropwise to a solution of Intermediate 29 (310 mg, 0.64 mmol), Intermediate 22 (302 mg, 1.28 mmol), EDC (368 mg, 1.92 mmol) and HOBt (294 mg, 1.92 mmol) in DMF (10 mL) at 0° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (50 mL), and the organic layer was washed sequentially with sat NH 4 Cl (50 mL), sat NaHCO 3 (50 mL), and sat brine (50 mL), dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (227 mg, 50%); MS (ESI) m/z [M+H] + 703.

Intermediate 31: Methyl 4-fluoro-2-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

Intermediate 11 (1.10 g, 3.69 mmol), methyl 4-fluoro-5-hydroxy-2-methylbenzoate (1.02 g, 5.53 mmol), DIAD (1.43 mL, 7.37 mmol) and triphenylphosphine (1.45 g, 5.53 mmol) were dissolved in THF (20 mL) and the reaction mixture was heated at 60° C. for 5 h The reaction mixture was concentrated under reduced pressure and DCM (20 mL) was added to the crude product. The organic layer was washed with H 2 O (3×20 mL), dried over Na 2 SO 4 , filtered, and evaporated. The crude product was purified by reversed phase flash chromatography on a C18 column, using a gradient of 0-70% of MeCN in H 2 O as mobile phase, to give the title compound (1.50 g, 88%); MS (ESI) m/z [M+H] + 465.

Intermediate 32: 4-Fluoro-2-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

Intermediate 31 (1.40 g, 3.01 mmol) and LiOH (217 mg, 9.04 mmol) was dissolved in a mixture of THF (12 mL) and H 2 O (3 mL), and the reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in DCM (10 mL). The organic layer was washed with H 2 O (3×5 mL), dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc, 3:1), to give the title compound (800 mg, 59%); MS (ESI) m/z [M+H] + 299.

Intermediate 33: Naphthalen-1-ylmethyl (1S,4s)-4-(2-fluoro-4-methyl-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

Intermediate 32 (300 mg, 0.67 mmol), Intermediate 21 (156 mg, 0.67 mmol), HATU (380 mg, 1.00 mmol) and DIPEA (0.349 mL, 2.00 mmol) were dissolved in DMF (20 mL), and the reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in DCM (10 mL). The organic layer was washed with H 2 O (3×5 mL), dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc, 3:1), to give the title compound (300 mg, 68%); MS (ESI) m/z [M+H] + 667.

Intermediate 34: Benzyl (2RS,4r,6R)-6-hydroxyspiro[3.3]heptane-2-carboxylate

NaBH 4 (46.5 mg, 1.23 mmol) was added slowly to a solution of benzyl 6-oxospiro[3.3]heptane-2-carboxylate (300 mg, 1.23 mmol) in MeOH (2 mL) cooled to 0° C. and under nitrogen. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL). The organic layer was washed with H 2 O (3×15 mL), dried over Na 2 SO 4 , filtered and evaporated. The residue was purified by preparative TLC (PE:EtOAc, 2:1), to give the title compound (230 mg, 76%) as a colourless oil; MS (ESI) m/z [M+H] + 247.

Intermediate 35: (1R,2S,3R,4S)-3-(4-Cyano-5-hydroxy-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

4-Cyano-5-hydroxy-2-methoxybenzoic acid (500 mg, 2.59 mmol) was added to a solution of Intermediate 22 (847 mg, 3.11 mmol), EDC (744 mg, 3.88 mmol), HOBt (525 mg, 3.88 mmol) and DIPEA (1.0 g, 7.77 mmol) in DMF (20 mL) and the reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (150 mL). The organic layer was washed sequentially with sat NaHCO 3 (150 mL), H 2 O (150 mL), and sat brine (150 mL), dried over Na 2 SO 4 , filtered, and evaporated. The crude product was purified by preparative TLC (MeOH:DCM, 1:10), to give the title compound (360 mg, 34%); MS (ESI) m/z [M+H] + 412.3.

Intermediate 36: Benzyl (2RS,4r,6R)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylate

Intermediate 35 (350 mg, 0.85 mmol) was added to a solution of Intermediate 34 (314 mg, 1.28 mmol), Ph 3 P (335 mg, 1.28 mmol) and DBAD (294 mg, 1.28 mmol) in a mixture of toulene/DCM (16 mL, 1:1) at 20° C. The reaction mixture was stirred at 30° C. for 12 h and then cooled to rt and diluted with DCM (200 mL). The organic layer was washed sequentially with sat NH 4 Cl (200 mL), H 2 O (200 mL) and sat brine (200 mL), dried over Na 2 SO 4 , filtered, and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 3:1), to give the title compound (190 mg, 35%); MS (ESI) m/z [M+H] + 640.4.

Intermediate 37: Benzyl (2R*,4r,6R)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylate Isomer 1

Intermediate 38: Benzyl (2R*,4r,6R)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylate Isomer 2

The isomers of Intermediate 36 (200 mg, 0.31 mmol) were separated by preparative chiral HPLC on a Chiralpak IG column (5 μm, 250×20 mm ID) using 10% of EtOH in a hexane:DCM (5:1, 10 mM NH 3 in MeOH) buffer system as mobile phase, to give the first eluting compound Isomer 1 Intermediate 37 (60 mg, 30%); MS (ESI) m/z [M+H] + 640.4, and the second eluting compound Isomer 2 Intermediate 38 (70 mg, 30%); MS (ESI) m/z [M+H] + 640.4.

Intermediate 39: rac-Methyl (1R,2R,3S,4S)-3-isocyanato-7-oxabicyclo[2.2.1]heptane-2-carboxylate

Step A. Intermediate 40: rac-(1R,2R,3S,4S)-3-(Methoxycarbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

Pd—C (0.107 g, 1.01 mmol, 10%) was added to a solution of rac-(1R,4S)-3-(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylic acid (2 g, 10.09 mmol) in MeOH (150 mL), and the reaction mixture was stirred under an atmosphere of hydrogen (1.5 atm) at rt for 5h. The reaction mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure to give the title compound (2 g, 99%). The crude product was used directly without further purification in the next step.

Ethyl chloroformate (1.30 g, 12 mmol) was added dropwise to a solution of Intermediate 40 (2 g, 9.99 mmol) and TEA (1.52 g, 15.0 mmol) in acetone (20 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. A solution of NaN 3 (0.97 g, 15.0 mmol) in H 2 O (10 mL) was added dropwise over a period of 15 min to the stirred reaction mixture at 0° C., and under a nitrogen atmosphere, and the reaction mixture was stirred at 0° C. overnight. The reaction mixture was diluted with toluene (150 mL), and washed sequentially with sat brine (250 mL), sat NaHCO 3 (250 mL), and H 2 O (200 mL). The organic layer was dried over Na 2 SO 4 , and filtered. The filtrate was diluted with toluene (30 mL) and the reaction mixture was stirred at 110° C. overnight. The solvent was removed under reduced pressure to give the title compound (1.7 g, 88%) as a brown oil.

Intermediate 41: rac-Methyl (1R,2R,3S,4S)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate hydrochloride

A solution of HCl (2.6 mL, 86.2 mmol, 12 M, aq) in H 2 O (10 mL) was added to a solution of Intermediate 39 (1.7 g, 8.62 mmol) in THF (20 mL). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure to give the title compound (1.75 g, 98%) as a crude product which was used without further purification.

Intermediate 42: rac-Methyl (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylate

Boc 2 O (3.91 mL, 16.8 mmol) and TEA (5.87 mL, 42.14 mmol) were added to a solution of Intermediate 41 (1.75 g, 8.43 mmol) in THF (20 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (50 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give the title compound (2.1 g, 92%) as a crude product which was used without further purification.

Intermediate 43: rac-(1R,2R,3S,4S)-3-((tert-Butoxycarbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

LiOH (0.556 g, 23.22 mmol) was added to a solution of Intermediate 42 (2.1 g, 7.74 mmol) in MeOH (8 mL) and H 2 O (4 mL) and the reaction mixture was stirred at rt for 5h. The reaction mixture was acidified with citric acid (0.5 M, aq), diluted with EtOAc (20 mL), and washed with sat brine (3×2 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give the title compound Intermediate 43 (1.23 g, 62%) as yellow solid, which was used without further purification; MS (ESI) m/z [M+Na] + 280.

Intermediate 44: tert-Butyl ((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate Isomer 1

Intermediate 45: tert-Butyl ((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate Isomer 2

4-Fluoro-3-(trifluoromethyl)aniline (1.028 g, 5.74 mmol), HATU (5.45 g, 14.34 mmol), DIPEA (2.472 g, 19.12 mmol) and Intermediate 43 (1.23 g, 4.78 mmol) were suspended in DMF (15 mL) and the reaction mixture was stirred at 80° C. for 5h. The reaction mixture was diluted with EtOAc (75 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by flash chromatography using a gradient of 0-40% PE in EtOAc as mobile phase, and then by preparative HPLC, Method PrepBasic-G, using decreasingly polar mixtures of the mobile phase. The enantiomers were separated by preparative chiral HPLC on a Chiralpak IA column (5 μm, 150×4.6 mm ID), using 20% IPA (0.1% DEA) in CO 2 (g) as mobile phase, to give the first eluting Isomer 1 Intermediate 44 (170 mg, 8.5%) as a white solid; MS (ESI) m/z [M+H] + 419, and the second eluting Isomer 2 Intermediate 45 (170 mg, 8.5%) as a white solid, MS (ESI) m/z [M+H] + 419. The stereochemistry of the two enantiomers were determined using VCD experiments. Experimental VCD spectra of both enantiomers were compared to the DFT calculated spectra. The assignment of the configuration was based of fits of 5 different regions of the spectrum.

Intermediate 46: (1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide 2,2,2-trifluoroacetate

TFA (3 mL) was added to a solution of Intermediate 44 (50 mg, 0.12 mmol) in DCM (3 mL) and the reaction mixture was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure to give the title compound (35 mg, 92%) as a white solid; MS (ESI) m/z [M+H] + 318.

Intermediate 47: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide 2,2,2-trifluoroacetate

The title compound was prepared from Intermediate 45 in an analogues way as described for Intermediate 46 to give the title compound (35 mg, 92%) as a white solid; MS (ESI) m/z [M+H] + 319.

Intermediate 48: Benzyl ((1R,2S)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclobutyl)carbamate

DIPEA (0.315 mL, 1.81 mmol) was added dropwise to a solution of (1S,2R)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid (150 mg, 0.60 mmol), 4-fluoro-3-(trifluoromethyl)aniline (129 mg, 0.72 mmol), and HATU (458 mg, 1.20 mmol) in DMF (10 mL) at 20° C. under a nitrogen atmosphere, and the reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat brine (150 mL), and H 2 O (125 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (196 mg, 79%) as a pale yellow solid; MS (ESI) m/z [M+H] + 411.

Intermediate 49: (1S,2R)-2-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclobutane-1-carboxamide hydrobromide

Intermediate 48 (100 mg, 0.24 mmol) was added to a solution of HBr in glacial acetic acid (10 mL, 33%) at 0° C., and the reaction mixture was stirred at 0° C. for 2 h. The solvent was removed under reduced pressure to give the title compound (67 mg) which was used without further purification; MS (ESI) m/z [M+H] + 277.

Intermediate 50: Methyl (R)-4-((1-phenylethyl)amino)-2,5-dihydrofuran-3-carboxylate

(R)-1-Phenylethan-1-amine (920 mg, 7.63 mmol) was added dropwise to a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (1 g, 6.94 mmol), and Yb(OTf) 3 (0.129 g, 0.21 mmol) in toluene (50 mL) at 20° C. under a nitrogen atmosphere and the suspension was stirred at 110° C. for 42 h. The reaction mixture was filtered through Celite®, and the solvent was removed under reduced pressure to give the title compound (750 mg, 44%) as a pale yellow oil which solidified on standing.

Intermediate 51: Methyl (3R,4S)-4-(((R)-1-phenylethyl)amino)tetrahydrofuran-3-carboxylate

NaBH 4 (320 mg, 8.49 mmol) was added portion wise to acetic acid (25 mL) and the resulting suspension was stirred at 20° C. for 1 h, and then cooled to 0° C. A solution of Intermediate 50 (700 mg, 2.83 mmol) in MeCN (25 mL) was added to the mixture under a nitrogen atmosphere, and the resulting suspension was stirred at 0° C. for 2 h. The reaction mixture was quenched with H 2 O (125 mL), and concentrated under reduced pressure. The aq phase was extracted with EtOAc (3×150 mL), and the combined organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by flash chromatography, using a gradient of 0-30% EtOAc in PE as mobile phase, to give the title compound (410 mg, 58%) as a pale yellow oil which solidified on standing; MS (ESI) m/z [M+H] + 250.

Intermediate 52: Methyl (3R,4S)-4-aminotetrahydrofuran-3-carboxylate

Pd—C (35 mg, 0.33 mmol) was added to a solution of Intermediate 51 (407 mg, 1.63 mmol) in MeOH (20 mL) and the reaction mixture was stirred under an atmosphere of hydrogen (1.5 atm) at 20° C. for 14 h. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure to give the title compound (237 mg, 100%) as a pale yellow solid.

Intermediate 53: Methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-carboxylate

TEA (0.341 mL, 2.45 mmol) was added dropwise to a solution of Intermediate 52 (237 mg, 1.63 mmol) and Boc 2 O (0.46 mL, 1.96 mmol) in THF (20 mL) at 20° C. under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with sat brine (2×150 mL), H 2 O (150 mL), and sat NaHCO 3 (150 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give the title compound (448 mg) as a yellow gum.

Intermediate 54: (3RS,4S)-4-((tert-Butoxycarbonyl)amino)tetrahydrofuran-3-carboxylic acid

LiOH (219 mg, 9.13 mmol) was added portion wise to a solution of Intermediate 53 (448 mg, 1.83 mmol) in MeOH (10 mL) and H 2 O (10 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was acidified to pH-3 with citric acid (aq, 0.5 M). The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with sat brine (2×150 mL), H 2 O (125 mL), and sat NH 4 Cl (125 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give a crude containing the title compound (350 mg, 83%) as a yellow gum. The crude product was used without further purification.

Intermediate 55: tert-Butyl ((3S,4R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamate

DIPEA (0.79 mL, 4.54 mmol) was added dropwise to a solution of 4-fluoro-3-(trifluoromethyl)aniline (407 mg, 2.27 mmol), Intermediate 54 (350 mg, 1.51 mmol) and HATU (2.88 g, 7.57 mmol) in DMF (40 mL) and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat brine (100 mL), sat NaHCO 3 (100 mL), and H 2 O (100 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:1), to give the title compound (240 mg, 40%) as a white solid; MS (ESI) m/z [M+H] + 393.

Intermediate 56: (3R,4S)-4-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)tetrahydrofuran-3-carboxamide

The Boc-protecting group of Intermediate 55 (240 mg, 0.61 mmol) was partly deprotected upon standing and the mixture was purified by preparative chiral-HPLC, Method SFC-G, using an isocratic run of 15% of IPA as mobile phase, to give the title compound (40 mg, 22%) as a yellow solid; MS (ESI) m/z [M+Na] + 293.

Intermediate 57: 2-Chloro-N-((1-methylcyclobutyl)methyl)-6-nitrobenzamide

DIPEA (0.65 mL, 3.72 mmol) was added dropwise to a solution of 2-chloro-6-nitrobenzoic acid (250 mg, 1.24 mmol), (1-methylcyclobutyl)methanamine hydrochloride (168 mg, 1.24 mmol), EDC (476 mg, 2.48 mmol), and HOBt (380 mg, 2.48 mmol) in DMF (5 mL) at 20° C. under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat NaHCO 3 (100 mL), sat NH 4 Cl (150 mL), and sat brine (100 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:3), to give the title compound (350 mg, 100%) as a white waxy solid; MS (ESI) m/z [M+H] + 283.

Intermediate 58: 2-Amino-6-chloro-N-((1-methylcyclobutyl)methyl)benzamide

NH 4 Cl (662 mg, 12.38 mmol) was added portion wise to a suspension of Intermediate 57 (350 mg, 1.24 mmol) and Fe(s) (346 mg, 6.19 mmol) in H 2 O (2 mL) and EtOH (18 mL, 99.5%) at 20° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 80° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat NaHCO 3 (75 mL), sat brine (75 mL), and H 2 O (75 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by precipitation from EtOAc and PE to give the title compound (290 mg, 93%) as a white waxy solid; MS (ESI) m/z [M+H] + 253.

Intermediate 59: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((3-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

Intermediate 58 (250 mg, 0.99 mmol) was added to a solution of Intermediate 13 (692 mg, 1.48 mmol), T3P (5.9 mL, 9.89 mmol, 50% in EtOAc), and DIPEA (384 mg, 2.97 mmol) in BuOAc (10 mL) at 20° C., and the reaction was stirred at 120° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (150 mL). The organic layer was washed sequentially with sat NH 4 Cl (250 mL), H 2 O (150 mL), and sat brine (250 mL), dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:3), to give the title compound (280 mg, 40%) as a yellow solid; MS (ESI) m/z [M+Na] + 723.3.

Intermediate 60: Benzyl (1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate

TEA (18.2 mL, 130.8 mmol) was added to a solution of (1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (5.0 g, 21.8 mmol), phenylmethanol (3.54 g, 32.7 mmol), EDC (12.54 g, 65.42 mmol) and HOBt (10.02 g, 65.42 mmol) in DMF (50 mL) and the reaction mixture was stirred at 20° C. for 15 h. The reaction mixture was concentrated and diluted with EtOAc (125 mL), and washed sequentially with sat NaHCO 3 (125 mL), H 2 O (3×125 mL), and sat brine (2×125 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by flash chromatography using a gradient of 10-15% in EtOAc in PE to give the title compound (5.0 g, 72%) as a white solid.

Intermediate 61: Benzyl (1S,2R)-2-aminocyclopentane-1-carboxylate hydrochloride

HCl (10 mL, 40.0 mmol, 4 M in 1,4-dioxane) was added to a solution of Intermediate 60 (2 g, 6.26 mmol) in 1,4-dioxane (10 mL) at 20° C. The resulting suspension was stirred at 20° C. for 30 min. The solvent was removed under reduced pressure to give the title compound (2 g) as a yellow oil; MS (ESI) m/z [M+H] + 220.

Intermediate 62: tert-Butyl (1S,4s)-4-(5-(((1R,2S)-2-((benzyloxy)carbonyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

DIPEA (2.28 mL, 13.1 mmol) was added dropwise to a solution of Intermediate 73 (1.0 g, 2.61 mmol), Intermediate 61 (0.67 g, 2.61 mmol) and HATU (2.98 g, 7.84 mmol) in DMF (20 mL) at 20° C. under a nitrogen atmosphere and the reaction mixture was stirred at 30° C. for 4 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with H 2 O (3×50 mL), sat NaHCO 3 (50 mL), and sat brine (50 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:3), to give the title compound (0.90 g, 59%) as a pale yellow oil which solidified on standing; MS (ESI) m/z [M+H] + 584.

Intermediate 63: (1S,2R)-2-(5-(((1s,4S)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)cyclopentane-1-carboxylic acid

Pd—C (164 mg, 0.15 mmol) was added to a solution of Intermediate 62 (900 mg, 1.54 mmol) in MeOH (20 mL) and the reaction mixture was stirred at 20° C. under an atmosphere of hydrogen (1.3 atm) for 3 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give the title compound (700 mg, 92%) as a white solid; MS (ESI) m/z [M+H] + 494.

Intermediate 64: Benzyl 5-(((1s,4s)-4-(tert-butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

DIAD (1.46 mL, 7.53 mmol) was added dropwise to a solution of Intermediate 117 (1.39 g, 5.02 mmol), tert-butyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (1.2 g, 6.0 mmol) and PPh 3 (1.97 g, 7.53 mmol) in THF (10 mL) at 60° C., and the reaction mixture was stirred at 60° C. for 3 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, using a gradient of 0-10% EtOAc in petroleum ether as mobile phase, to give the title compound (1.55 g, 67%) as a white solid; MS (ESI) m/z [M+Na] + 481.

Intermediate 65: 5-(((1s,4s)-4-(tert-Butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

Pd—C (0.67 g, 0.63 mmol, 10%) was added to a solution of Intermediate 64 (1.45 g, 3.16 mmol) in MeOH (50 mL) at 20° C. The reaction mixture was stirred at 20° C. for 4 h under an atmosphere of hydrogen The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give the title compound (1.10 g, 94%) as a white solid; MS (ESI) m/z [M+Na] + 368.

Intermediate 66: Methyl (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(tert-butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylate

DIPEA (2.61 mL, 14.93 mmol) was added dropwise to a solution of Intermediate 65 (1.1 g, 2.99 mmol), Intermediate 120 (2.8 g, 13.61 mmol) and HATU (3.41 g, 8.96 mmol) in DMF (20 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed with sat brine (3×25 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1), to give the title compound (0.56 g, 36%) as a brown yellow oil which solidified on standing; MS (ESI) m/z [M+H] + 520.

Intermediate 67: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(tert-Butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

LiOH (106 mg, 4.43 mmol) was added to a solution of Intermediate 66 (460 mg, 0.89 mmol) in MeOH (4 mL) and water (2 mL), and the reaction mixture was stirred at 20° C. for 5 h. The solvent was removed under reduced pressure. The reaction mixture was acidified with citric acid (0.5 M, aq) and the solids were filtered off to give the title compound (385 mg, 86%) as a white solid; MS (ESI) m/z [M+H] + 506.

Intermediate 68: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-cyano-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Step A. Intermediate 69: Methyl 4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

A solution of methyl 4-cyano-5-hydroxy-2-methoxybenzoate (1.4 g, 6.7 mmol), Intermediate 11 and PPh 3 (2.6 g, 10.1 mmol) in THF (30 mL) was stirred at 60° C. for 10 min. After slow addition of DIAD (1.97 mL, 10.1 mmol), the reaction mixture was stirred at 60° C. for 14 h. The solvent was then removed under reduced pressure and the residue redissolved in EtOAc (150 mL), washed sequentially with NaHCO 3 (sat, 200 mL), NH 4 Cl (sat, 250 mL) and brine (sat, 250 mL). The organic layer was separated and dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-18% EtOAc in PE as mobile phase to give the title compound (3.25 g, 99%) as a white solid. MS (ESI): m/z [M+Na] + 510.3.

Step B. Intermediate 70: 4-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

LiOH (1.6 g, 66.7 mmol) was added portionwise to a stirred solution of Intermediate 69 (3.25 g, 6.7 mmol) in H 2 O:THF 1:3 (80 mL) at 10° C. and the resulting suspension was stirred at 20° C. After 3 h, the pH of the reaction mixture was adjusted to pH 3 by the addition of HCl (2 M). The reaction mixture was diluted with EtOAc (350 mL), and washed sequentially with brine (sat, 350 mL), H 2 O (350 mL), and brine (350 mL). The organic layer was separated, dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The crude product was purified by crystallisation from IPA/EtOAc to afford the title compound (3.16 g, 100%) as a white solid. MS (ESI): m/z [M+Na] + 496.3.

Step C. Intermediate 71: Methyl (1S,2S,3R,4R)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

DIPEA (3.5 mL, 20 mmol) was added to a solution of Intermediate 70 (3.16 g, 6.67 mmol), Intermediate 8 (1.291 g, 6.34 mmol), EDC (1.9 g, 10 mmol) and HOBt (1.533 g, 10.01 mmol) in DMF (60 mL) at 10° C. and the resulting suspension was stirred at rt for 13 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed sequentially with NH 4 Cl (sat, 200 mL), H 2 O (300 mL), and brine (sat, 250 mL). The organic layer was dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in PE as mobile phase to afford the title compound (2.6 g, 62%) as a white solid. MS (ESI): m/z [M+H] + 623.4.

Step D. Intermediate 72: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

Intermediate 71 (5.7 g, 9.15 mmol) and Pd/C (0.584 g, 0.55 mmol) in MeOH (100 mL) was stirred at 20° C. under an atmosphere of hydrogen (1.5 atm) for 14 h. The mixture was filtered through a Celite® pad and the solvent was removed under reduced pressure. The crude product was purified by crystallisation from EtOAc/EtOH to afford the title compound (5.1 g) as a pale yellow solid. MS (ESI): m/z [M+H] + 485.4.

Step E. (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-cyano-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

A solution of LiOH (50 mL, 52.6 mmol, 1.05 M in H 2 O) was added to a stirred solution of Intermediate 72 (5.1 g, 10.5 mmol) in THF (100 mL) at 10° C. The reaction mixture was allowed to warm to rt and stirred for 14 h, then acidified to pH 2 using HCl (1 M, aq). The reaction mixture was diluted with EtOAc (350 mL), and washed sequentially with brine (300 mL, sat), H 2 O (300 mL) and brine (300 mL, sat). The organic phase was separated and dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The crude product was purified by precipitation from EtOAc/Et 2 O followed by reversed phase flash chromatography on a C18 column using a gradient of 0-50% MeCN in HCl (0.4%, aq) as mobile phase to afford the title compound (4.00 g, 82%) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 1.13 (s, 3H), 1.20 (s, 1H), 1.23 (s, 2H), 1.33 (t, 2H), 1.46 (q, 4H), 1.84 (d, 1H), 1.92 (d, 2H), 2.03-2.14 (m, 4H), 2.38 (d, 1H), 2.67 (d, 1H), 3.89 (s, 3H), 4.23 (t, 1H), 4.43 (dt, 1H), 7.54 (s, 1H), 7.59 (s, 1H), 8.67 (d, 1H), 12.30 (s, 2H). MS (ESI): m/z [M+H] + 471.3.

Intermediate 73: 5-(((1s,4s)-4-(Tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

Pd(OH) 2 /C (20 wt %, 78 mg, 0.11 mmol) was added to a solution of Intermediate 136 (527 mg, 1.12 mmol) in MeOH (11 mL). The reaction suspension was stirred at rt for 3 h under an atmosphere of hydrogen (2 atm). The reaction mixture was filtered through a pad of Celite® and the solvent removed under reduced pressure to afford the title compound (427 mg, 100%) as a colorless thick oil; MS (ESI): m/z [M−H] − 381.2.

Intermediate 74: tert-Butyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(neopentylcarbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

DIPEA (68 μL, 0.39 mmol) was added to a solution of Intermediate 73 (40 mg, 0.1 mmol) in DCM (0.4 mL). HATU (119 mg, 0.31 mmol) was added followed by 2-amino-N-(2,2-dimethylpropyl)benzamide (25.9 mg, 0.13 mmol) and the reaction mixture was stirred at rt overnight. Na 2 CO 3 (sat) was added and the biphasic mixture stirred for 10 min before the two layers were separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using a gradient of 5-95% EtOAc in heptane as mobile phase to afford the title compound (50.4 mg, 84%) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 0.91 (s, 9H), 1.08 (s, 3H), 1.20-1.34 (m, 3H), 1.42 (s, 11H), 1.92 (d, 2H), 2.05 (d, 2H), 3.12 (d, 2H), 3.98 (s, 3H), 4.20 (t, 1H), 7.15-7.28 (m, 2H), 7.49 (t, 1H), 7.63 (d, 1H), 7.74 (d, 1H), 8.46-8.67 (m, 2H), 11.70 (s, 1H). MS (ESI): m/z [M−H] − 569.3

Intermediate 75: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Palladium on carbon (7 mg, 0.07 mmol) was added to a solution of Intermediate 76 (400 mg, 0.66 mmol) in MeOH (30 mL). The reaction suspension was stirred at rt for 3 h under an atmosphere of hydrogen (1.3 atm). The suspension was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (208 mg, 60.8%) as a white solid. MS (ESI): m/z [M+H] + 520.4.

Intermediate 76: Benzyl (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

Step A. Intermediate 77: Benzyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

HCl (4 M in MeOH, 20 mL, 80 mmol) was added dropwise to a solution of Intermediate 108 (2.0 g, 5.82 mmol) in MeOH (10 mL) at 0° C. The resulting mixture was stirred at 20° C. for 16 h. The solvent was removed under reduced pressure to afford the title compound (1.6 g) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (d, 1H), 2.06 (d, 1H), 2.65-2.71 (m, 1H), 2.98 (s, 1H), 3.06 (s, 1H), 3.24 (s, 1H), 5.09 (d, 1H), 5.22 (d, 1H), 6.24 (dd, 1H), 6.32 (dd, 1H), 7.29-7.47 (m, 5H), 8.22 (s, 3H).

Step B. Benzyl (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

DIPEA (5.1 mL, 29.4 mmol) was added dropwise to a solution of Intermediate 73 (2.25 g, 5.88 mmol), Intermediate 77 (1.88 g, 6.47 mmol) and HATU (6.71 g, 17.65 mmol) in DMF (20 mL) under nitrogen. The reaction mixture was stirred at rt for 14 h after which it was diluted with EtOAc and washed sequentially with NaHCO 3 (sat) and brine (sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated under reduce pressure. The crude product was purified by flash silica chromatography using a gradient of 10-15% EtOAc in PE as mobile phase to afford 2.6 g the title compound as a pale yellow oil which solidified on standing. MS (ESI): m/z [M+H] + 608.4.

Intermediate 78: Tert-butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-3-ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. Isomer 1

Intermediate 79: Tert-butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-3-ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. Isomer 2

To a solution of Intermediate 75 (138 mg, 0.27 mmol) in DCM (2.7 mL) was added DIPEA (139 μL, 0.8 mmol) followed by HATU (303 mg, 0.8 mmol). 3-Ethylpentan-2-amine (66 μL, 0.4 mmol) was added to the solution and the reaction stirred at rt overnight. Na 2 CO 3 (sat) was added and the biphasic mixture stirred for 10 min. The organic layer was separated. The aq phase was washed with DCM twice. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using a gradient of 10-90% EtOAc in heptane as mobile phase to give the first eluting compound Intermediate 78, isomer 1 (67 mg, 41%); 1 H NMR (400 MHz, CDCl 3 ) δ 0.75 (d, 3H), 0.89 (td, 6H), 1.16-1.34 (m, 10H), 1.47 (s, 9H), 1.57 (d, 7H), 2.01 (dd, 3H), 2.21 (d, 3H), 2.42 (d, 1H), 2.54 (s, 1H), 3.93 (s, 4H), 4.06-4.23 (m, 1H), 4.41 (t, 1H), 5.40 (d, 1H), 6.71 (d, 1H), 7.88 (d, 1H), 8.53 (d, 1H); MS [ESI] m/z [M+H] + 617.5; and the second eluting compound Intermediate 79, isomer 2 (55 mg, 33%); 1 H NMR (400 MHz, CDCl 3 ) δ 0.61 (t, 3H), 0.68 (t, 3H), 0.86-0.92 (m, 2H), 1.04 (d, 4H), 1.25 (dd, 8H), 1.47 (s, 9H), 1.51-1.64 (m, 6H), 1.98 (d, 2H), 2.11 (d, 1H), 2.21 (d, 3H), 2.35 (d, 1H), 2.48 (s, 1H), 3.93 (s, 3H), 3.97-4.07 (m, 1H), 4.08-4.18 (m, 1H), 4.43 (t, 1H), 5.35 (d, 1H), 6.69 (d, 1H), 7.90 (d, 1H), 8.78 (d, 1H); MS [ESI] m/z [M+H] + 617.5.

Intermediate 80: (1S,3s)-3-(2-Cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

Step A. Intermediate 81: Methyl 4-cyano-2-methoxy-5-((1s,3s)-3-(methoxycarbonyl)-3-methylcyclobutoxy)benzoate

Methyl (1r,3r)-3-hydroxy-1-methylcyclobutane-1-carboxylate (60 mg, 0.42 mmol) was added dropwise to a solution of DIAD (123 μL, 0.62 mmol), PPh 3 (164 mg, 0.62 mmol) and methyl 4-cyano-5-hydroxy-2-methoxybenzoate (86 mg, 0.42 mmol) in THF (13.7 mL) at 50° C. under nitrogen. The resulting solution was stirred at the same temperature for 15 h. The reaction was allowed to cool to rt and it was diluted with EtOAc (150 mL). The organic phase was washed sequentially with H 2 O (2×50 mL) and brine (sat, 2×50 mL). The organic layer was separated, dried over a phase separator, filtered and the solvent removed under reduced pressure. The crude material was purified by Method PrepAcidic-F using a gradient of 15-55% followed by flash chromatography using a gradient from of 10-50% of EtOAc in heptane as mobile phase to afford the title compound (0.126 g, 91%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.48 (s, 3H), 2.47 (ddd, 2H), 2.73 (ddd, 2H), 3.74 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 4.77 (p, 1H), 7.15 (d, 2H). MS [ESI] m/z [M+H] + 334.3.

Cesium hydroxide hydrate (21.9 mg, 0.15 mmol) was added in one portion to a solution of Intermediate 81 (126 mg, 0.38 mmol) in MeOH/H 2 O 1:1 (4 mL) at 20° C. The resulting suspension was stirred at 50° C. for 15 h. The reaction was allowed to cool to rt and it was acidified with HCl (aq, 3.8 M). The product was extracted with EtOAc (3×5 mL) and concentrated under reduced pressure to afford the title compound. The product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 1.54 (s, 3H), 2.5-2.63 (m, 3H), 2.76 (ddq, 3H), 4.07 (s, 3H), 4.85 (p, 1H), 7.28 (s, 1H), 7.54 (s, 1H). MS (ESI): m/z [M−H] − 304.3.

Step C. (1S,3s)-3-(2-Cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

Intermediate 82 (42 mg, 0.14 mmol) was dissolved in DCM (2.7 mL). DIPEA (28 μL, 0.16 mmol) was added to the solution, followed by HATU (157 mg, 0.41 mmol) and Intermediate 21 (69.6 mg, 0.14 mmol) and the reaction stirred at ambient temperature for 2 h. The reaction was quenched with Na 2 CO 3 (sat) and the biphasic mixture stirred for 1 h. The organic layer was separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by Method PrepAcidic-F using a gradient of 15-55% to afford the title compound (17.5 mg, 24%) as a white solid; 1 H NMR (400 MHz, CD 3 OD) δ 1.08 (s, 3H), 1.45 (s, 3H), 1.51 (dt, 1H), 1.59-1.67 (m, 2H), 1.74-1.92 (m, 4H), 2.20 (dt, 1H), 2.42 (dd, 1H), 2.45-2.59 (m, 4H), 2.69 (d, 1H), 2.84 (s, 1H), 3.07 (dd, 1H), 3.21 (dd, 1H), 3.86 (s, 3H), 3.98 (td, 1H), 6.18-6.33 (m, 2H), 7.29 (s, 1H), 7.39 (s, 1H), 7.76 (d, 1H), 7.99 (t, 1H); MS (ESI): m/z [M+H] + 522.6.

Intermediate 83: (1S,3s)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

Step A. Intermediate 84: Methyl 4-fluoro-2-methoxy-5-((1s,3s)-3-(methoxycarbonyl)-3-methylcyclobutoxy)benzoate

Methyl (1r,3r)-3-hydroxy-1-methylcyclobutane-1-carboxylate (60 mg, 0.42 mmol) was added dropwise to a solution of DIAD (123 μL, 0.62 mmol), PPh 3 (164 mg, 0.62 mmol) and Intermediate 6 (83 mg, 0.42 mmol) in THF (13.7 mL) at 50° C. under nitrogen. The resulting solution was stirred at the same temperature for 6 h. The reaction was stirred at 30° C. over the weekend. The reaction was diluted with EtOAc (150 mL). The organic phase was washed sequentially with H 2 O (2×50 mL) and brine (sat, 2×50 mL). The organic layer was separated, dried over a phase separator, filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography using a gradient from of 5-50% of EtOAc in heptane as mobile phase to afford the title compound (102 mg, 75%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 1.36 (s, 3H), 2.32 (ddd, 2H), 2.58 (ddd, 2H), 3.62 (s, 3H), 3.77 (d, 6H), 4.60 (p, 1H), 6.66 (d, 1H), 7.26 (d, 1H). MS [ESI] m/z [M+H] + 327.3.

Hydrolysis of Intermediate 84 (524 mg, 3.12 mmol) was carried out analogous to the procedure described for Intermediate 81 to afford the title compound. The product was used in the next step directly without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 1.51 (s, 3H), 2.51 (ddd, 2H), 2.72 (ddd, 2H), 4.04 (s, 3H), 4.79 (p, 1H), 6.86 (d, 1H), 7.62 (d, 1H). MS (ESI): m/z [M+H] + 299.3.

Step C. (1S,3s)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)-methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

Intermediate 85 (46.5 mg, 0.16 mmol) was dissolved in DCM (2.7 mL). DIPEA (28 μL, 0.16 mmol) was added to the solution, followed by HATU (178 mg, 0.47 mmol) and Intermediate 21 (69.6 mg, 0.14 mmol) and the reaction stirred at ambient temperature for 2 h. The reaction was quenched with Na 2 CO 3 (sat) and the biphasic mixture stirred for 1 h. The organic layer was separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by Method PrepAcidic-F using a gradient of 25-65% to afford the title compound (17.7 mg, 22%) as a white solid; MS (ESI): m/z [M+H] + 515.6.

Intermediate 86: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

3-((tert-Butoxycarbonyl)amino)isonicotinic acid (84 mg, 0.35 mmol) and TCFH (124 mg, 0.44 mmol) were added to a solution of 1-methyl-1H-imidazole (82 μL, 1.03 mmol) and (1-methylcyclobutyl)methanamine hydrochloride (40 mg, 0.29 mmol) in MeCN (5.6 mL). The vial was sealed and the reaction was run at 120° C. for 80 min in a microwave reactor. The reaction mixture was then diluted with EtOAc (6 mL) and H 2 O (4 mL). The layers were separated, the aq layer was extracted with EtOAc (4 mL) and the combined organic layer was washed with H 2 O (4 mL) and passed through a phase separator. After removal of the solvent under reduced pressure, the title compound was progressed to the next step without further purification. MS (ESI): m/z [M+H] + 320.2.

HCl in 1,4-dioxane (2.9 mL, 11.6 mmol) was added to a solution of Intermediate 87 (93 mg, 0.29 mmol) in 1,4-dioxane (2 mL). After 2 h, few drops of MeOH were added until a clear solution was achieved and the reaction was stirred for additional 5 h. The solvent was removed under reduced pressure and the title compound was progressed to the next step without further purification. MS (ESI): m/z [M+H] + 220.1.

Step C. Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)-methyl)carbamoyl)pyridin-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

Intermediate 13 (176 mg, 0.38 mmol) and TCFH (122 mg, 0.44 mmol) were added to a microwave vial followed by a solution of 1-methyl-1H-imidazole (81 μL, 1.02 mmol) in MeCN. After stirring for 1 min, a solution of Intermediate 88 (74.2 mg, 0.29 mmol) in MeCN was added and the vial was sealed. The reaction was stirred at 120° C. for 80 min in a microwave reactor. The reaction was then diluted with EtOAc and H 2 O. The layers were separated, the aq layer was extracted with isopropyl acetate and the combined organic layers were washed with H 2 O, dried over a phase separator, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a gradient from of 10-60% of EtOAc in heptane as mobile phase to give the title compound (115 mg, 59%) as a white solid; MS (ESI): m/z [M+H] + 668.4. 1 H NMR (500 MHz, CDCl 3 ) δ 1.18 (d, 6H), 1.21-1.38 (m, 3H), 1.60 (q, 2H), 1.72-1.80 (m, 2H), 1.81-2.00 (m, 6H), 2.29 (d, 2H), 3.47 (d, 2H), 4.06 (s, 3H), 4.1-4.26 (m, 1H), 5.61 (s, 2H), 6.78 (d, 1H), 7.37-7.67 (m, 5H), 7.86 (d, 1H), 7.89 (d, 2H), 8.00 (d, 1H), 8.38 (d, 1H), 10.02 (s, 1H), 11.69 (s, 1H).

Intermediate 89: Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1SR,2RS)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

Step A. Intermediate 90: rac-tert-Butyl ((1R,2S)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamate

Rac-(1R,2S)-2-((tert-Butoxycarbonyl)amino)cyclooctane-1-carboxylic acid (96 mg, 0.35 mmol) and TCFH (124 mg, 0.44 mmol) were added to a microwave vial followed by a solution of 1-methyl-1H-imidazole (82 μL, 1.03 mmol) in MeCN (2.8 mL). After stirring for 1 min, a solution of (1-methylcyclobutyl)methanamine hydrochloride (40 mg, 0.29 mmol) in MeCN (2.8 mL) was added and the vial was sealed. The reaction was stirred at 120° C. for 80 min in a microwave reactor. The reaction was then diluted with EtOAc (6 mL) and H 2 O (4 mL). The layers were separated, the aq layer was extracted with iPrOAc and the combined organic layers were washed with H 2 O, dried over a phase separator, filtered and concentrated under reduced pressure to afford the title compound. The product was used in the next step without further purification. MS (ESI): m/z [M+H] + 353.3.

Intermediate 90 was dissolved in 1,4-dioxane (2 mL) and HCl (4 M in dioxane) was added. After stirring at rt for 12 h, the title compound was obtained. The product was used in the next step without further purification. MS (ESI): m/z [M+H] + 253.1.

Step C. Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1SR,2RS)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

Intermediate 91 was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86, to obtain the title compound (75%) as a white solid; MS (ESI): m/z [M+H] + 701.6.

Intermediate 92: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

Step A. Intermediate 93: tert-Butyl (3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamate

4-((tert-Butoxycarbonyl)amino)-3-methylisothiazole-5-carboxylic acid was coupled with (1-methylcyclobutyl)methanamine hydrochloride in an analogous way to Intermediate 90 to afford the title compound. The product was used in the next step without further purification. MS (ESI): m/z [M+H] + 340.2.

Hydrolysis of Intermediate 93 was carried out in an analogous way to Intermediate 91 to afford the title compound. The product was used in the next step without further purification.

Step C. Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

Intermediate 94 was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86 to obtain the title compound (46%) as a white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 1.07 (s, 3H), 1.18 (s, 3H), 1.26 (t, 3H), 1.58-1.65 (m, 4H), 1.81 (d, 3H), 1.96 (d, 2H), 2.29 (d, 2H), 2.44 (s, 3H), 3.36 (d, 2H), 4.04 (s, 3H), 4.16 (d, 1H), 5.61 (s, 2H), 6.84 (d, 1H), 6.94 (s, 1H), 7.46 (t, 1H), 7.54 (dq, 3H), 7.83-7.91 (m, 3H), 8.00 (d, 1H), 9.84 (s, 1H). MS (ESI): m/z [M+H] + 688.3.

Intermediate 95: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((5-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

2-Amino-4-chloro-N-((1-methylcyclobutyl)methyl)benzamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86, to give the title compound (60%) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 1.11 (s, 3H), 1.13 (s, 3H), 1.36 (dt, 4H), 1.53-1.66 (m, 2H), 1.72-2.03 (m, 6H), 2.09 (d, 2H), 3.98 (s, 3H), 4.21 (s, 1H), 5.62 (s, 2H), 7.21 (d, 1H), 7.28 (dd, 1H), 7.48-7.63 (m, 4H), 7.66 (d, 1H), 7.72 (d, 1H), 7.92-8.05 (m, 3H), 8.70 (d, 1H), 8.74 (t, 1H), 11.93 (s, 1H). MS (ESI): m/z [M+H] + 701.6.

Intermediate 96: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-methyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

2-Amino-3-methyl-N-((1-methylcyclobutyl)methyl)benzamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86, to give the title compound (62%) as a white solid; MS (ESI): m/z [M+H] + 681.7.

Intermediate 97: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((4-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

2-Amino-5-chloro-N-((1-methylcyclobutyl)methyl)benzamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86 to give the title compound (80%) as a white solid; MS (ESI): m/z [M+H] + 701.6. 1 H NMR (400 MHz, DMSO-d6) δ 1.10 (s, 3H), 1.12 (s, 3H), 1.36 (dt, 4H), 1.54-1.65 (m, 2H), 1.73-1.99 (m, 6H), 2.09 (d, 2H), 3.98 (s, 3H), 4.20 (s, 1H), 5.61 (s, 2H), 7.21 (d, 1H), 7.48-7.63 (m, 5H), 7.65 (dd, 1H), 7.72 (d, 1H), 7.86-8.07 (m, 3H), 8.57 (d, 1H), 8.78 (s, 1H), 11.74 (s, 1H).

Intermediate 98: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)thiophen-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

3-Amino-N-((1-methylcyclobutyl)methyl)thiophene-2-carboxamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86 to give the title compound (96%) as a white solid; MS (ESI): m/z [M+H] + 673.6. 1 H NMR (400 MHz, DMSO-d6) δ 1.10 (s, 3H), 1.12 (s, 3H), 1.29-1.47 (m, 4H), 1.55-1.68 (m, 2H), 1.73-1.93 (m, 4H), 1.98 (td, 2H), 2.09 (d, 2H), 3.27 (d, 2H), 4.01 (s, 3H), 4.22 (s, 1H), 5.62 (s, 2H), 7.21 (d, 1H), 7.47-7.66 (m, 4H), 7.7-7.84 (m, 2H), 7.91-8.09 (m, 3H), 8.17-8.28 (m, 2H), 12.51 (s, 1H).

Intermediate 99: ((1s,3s)-3-Methylcyclobutyl)methanamine

The title compound was obtained from 3-methylcyclobut-1-ene-1-carboxylic acid in 39% yield as colorless oil (Liebigs Ann. Chem. 1990, 411-414). 1 H NMR (400 MHz, CD 3 OD): δ 1.06 (dd, 3H), 1.79-1.86 (m, 2H), 2.28-2.39 (m, 3H), 2.89-2.98 (m, 1H).

Intermediate 100 (35 g, 0.3 mol) was dissolved in anhydrous THF (500 mL) and N-methyl-morpholine (37.2 g, 0.36 mol) was added. The resulting solution was cooled to 0° C. and isobutyl chloroformate (50 g, 0.36 mol) was added dropwise over 30 min. NH 3 (g) was bubbled through the resulting solution during 30 min, then the resulting mixture was stirred at overnight. The reaction was diluted with HCl (1 M). The organic layer was separated and dried over MgSO 4 , filtered and the solvent removed under reduced pressure. The residue was recrystallized from PE and EtOAc to obtain the title compound (15 g, 35%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.16 (d, 3H), 1.76-1.84 (m, 2H), 2.24-2.37 (m, 3H), 2.87-2.96 (m, 1H).

Borane dimethylsulfide (30 g, 0.39 mol) was added to a solution of Intermediate 101 (15 g, 0.13 mol) in anhydrous THF (200 mL) at 0° C. After 30 min at rt, the reaction mixture was heated to 80° C. and stirred at the same temperature for 16 h. The reaction was quenched with MeOH at 0° C. and the solvent removed under reduced pressure. A mixture of HCl (4 M)/EtOAc was added and the resulting slurry stirred for 30 min. The solid was filtered and dried under reduced pressure to obtain the HCl salt of the title compound (9 g, 50%) as a white solid. MS (ESI): m/z [M+H] + 100.

Intermediate 102: 4-Chloro-2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)benzoic acid

Step A. Intermediate 103: Methyl 4-chloro-2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)benzoate

Intermediate 70 (1.00 g, 2.09 mmol) was dissolved in MeCN (5.0 mL) and methyl 2-amino-4-chlorobenzoate (0.78 g, 4.18 mmol), was added followed by TCFH (0.89 g, 3.14 mmol) and 1-methyl-1H-imidazole (0.52 g, 6.27 mmol). The mixture was heated to 100° C. and stirred overnight at the same temperature. The reaction was then quenched with H 2 O and extracted with EtOAc. The crude material was purified by silica gel column with PE/EA (1:1) to obtain the title compound (187 mg, 13%) as alight yellow solid. MS (ESI): m/z [M+Na] + 663.1.

Step B. 4-Chloro-2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)benzoic acid

LiOH (16.8 mg, 0.69 mmol) was added to a solution of Intermediate 103 (150 mg, 0.23 mol) in THF/H 2 O (10 mL) and the mixture was stirred overnight at rt. The mixture was extracted with EtOAc and the organic layer was purified by silica gel column chromatography with PE/EA (1:1) to give the title compound (128 mg, 78.4%) as a light yellow solid. MS (ESI): m/z [M+Na] + 649.1.

Intermediate 104: 2-(4-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-4-methylbenzoic acid

Step A. Intermediate 105: Methyl 2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-4-methylbenzoate

Intermediate 70 (1.00 g, 2.09 mmol) was dissolved in MeCN (5 mL) and methyl 2-amino-4-methylbenzoate (0.698 g, 4.18 mmol) was added followed by TCFH (0.889 g, 3.14 mmol) and 1-methyl-1H-imidazole (0.520 g, 6.27 mmol). The mixture was heated to 100° C. and stirred for 1 h under nitrogen atmosphere. The reaction was then quenched with H 2 O and extracted with EtOAc. The crude material was purified by silica gel column chromatography and elution with PE/EA (1:1) gave the title compound (220 mg, 14%) as a light yellow solid. MS (ESI): m/z [M+H] + 621.2.

Step B. 2-(4-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-4-methylbenzoic acid

LiOH (11 mg, 0.45 mmol) was added to a solution of Intermediate 105 (100 mg, 0.16 mol) in THF/H 2 O (2:1, 30 mL) and the mixture was stirred overnight at rt. The reaction was quenched with H 2 O and acidified with HCl. Extraction with EtOAc followed by purification by silica gel column chromatography and elution with PE/EA (1:1) gave the title compound (78 mg, 77%) as a yellow solid. MS (ESI): m/z [M+H] + 607.2

Intermediate 106: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(Ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Step A. Intermediate 107: Methyl (1S,2S,3R,4R)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

(Boc) 2 O (22.8 mL, 98.2 mmol) was added to Intermediate 8 (10.0 g, 49.1 mmol) and TEA (34.2 mL, 245.5 mmol) in THF (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into brine (150 mL, sat), extracted with EtOAc (3×50 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (13.0 g, 99%) as a yellow oil. The product was used in the next step directly without further purification.

Step B. Intermediate 19 (1S,2S,3R,4R)-3-((tert-Butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

LiOH (6.5 g, 271.4 mmol) was added to Intermediate 107 (13.0 g, 48.63 mmol) in THF (40 mL), MeOH (10 mL) and H 2 O (10 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into H 2 O (300 mL), and acidified with 2 M HCl. The reaction mixture was extracted with EtOAc (3×125 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (12.0 g, 97%) as a colorless gum.

Step C. Intermediate 108: Benzyl (1S,2S,3R,4R)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

TEA (23.11 mL, 165.8 mmol) was added dropwise to Intermediate 19 (12.0 g, 47.38 mmol), phenylmethanol (7.68 g, 71.06 mmol) and EDC (19.98 g, 104.2 mmol), HOBt (15.96 g, 104.2 mmol) in DMF (60 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The mixture was poured into NaHCO 3 (350 mL, sat), extracted with EtOAc (3×150 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford a pale yellow oil. The crude product was purified by flash chromatography using a gradient of 0-5% EtOAc in heptane as mobile phase to give the title compound (15.0 g, 92%) as a colorless gum. MS (ESI): m/z [M+H-Boc] + 244.2.

TFA (6.06 mL, 78.6 mmol) was added to Intermediate 108 (5.4 g, 15.7 mmol) in DCM (60 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was diluted with EtOAc (250 mL), and washed with NaHCO 3 (150 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to dryness to afford the title compound (3.80 g, 99%) as a pale yellow solid. The product was used in the next step directly without further purification. 1 H NMR (300 MHz, DMSO-d6): δ 1.44 (m, 1H), 2.00-2.08 (m, 1H), 2.56 (dd, 1H), 2.76 (d, 1H), 2.98 (d, 1H), 3.22 (dd, 1H), 5.06 (d, 1H), 5.19 (d, 1H), 6.05 (s, 2H), 6.16-6.29 (br s, 2H, NH 2 ), 7.32-7.45 (m, 5H). MS (ESI): m/z [M+H] + 244.5.

Step E. Intermediate 110: Benzyl (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

HATU (4.88 g, 12.8 mmol) was added portion wise to Intermediate 111 (3.64 g, 10.69 mmol), Intermediate 109 (2.6 g, 10.7 mmol) and DIPEA (4.14 g, 32.06 mmol) in DMF (50 mL) at Rt. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into NaHCO 3 (200 mL, sat), extracted with EtOAc (3×75 mL), the organic layer was washed with brine (2×100 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford a brown oil. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (5.50 g, 91%) as a pale yellow gum. 1 H NMR (300 MHz, CDCl 3 ): δ 1.27-1.30 (m, 3H), 1.69 (dtt, 5H), 2.01 (td, 4H), 2.11 (dt, 1H), 2.41 (tt, 1H), 2.75-2.86 (m, 2H), 3.05 (s, 1H), 3.84 (s, 3H), 4.17 (dd, 2H), 4.45 (tt, 1H), 4.49-4.57 (m, 1H), 5.08 (s, 2H), 6.24 (dd, 1H), 6.30 (dd, 1H), 6.69 (d, 1H), 7.18-7.28 (m, 5H), 7.90 (d, 1H), 8.62 (d, 1H). MS (ESI): m/z [M+H] + 566.4.

Step F. (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(Ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Pd—C (0.6 g, 5.6 mmol) was added to Intermediate 110 (5.5 g, 9.7 mmol) in MeOH (75 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to give the title compound (4.1 g, 88%) as a white solid. MS (ESI): m/z [M+H] + 478.4.

Intermediate 111: 5-(((1s,4s)-4-(Ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

NBS (43.8 g, 246 mmol) was added portion wise to 4-fluoro-2-hydroxybenzoic acid (32 g, 205 mmol) in DMF (250 mL) at 0° C. The resulting solution was stirred at 20° C. for 20 h. The reaction mixture was poured into brine (1 L, sat), extracted with EtOAc (3×500 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (48.0 g, 100%) as a brown solid. The product was used in the next step directly without further purification. 1 H NMR (300 MHz, CDCl 3 ): δ 6.79 (d, 1H), 8.15 (d, 1H). (ESI): m/z [M−H] + 233.

MeI (77 mL, 1225.5 mmol) was added dropwise to Intermediate 112 (48 g, 204.2 mmol) and potassium carbonate (70.6 g, 510.6 mmol) in acetone (400 mL) at 20° C. over a period of 20 Min. The resulting suspension was stirred at 60° C. for 15 h. The reaction mixture was filtered through Celite®. The reaction mixture was diluted with EtOAc (750 mL), the organic layers was washed with brine (2×400 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford a brown solid. The dried solid was triturated with EtOAc/PE (1/4) (50 mL) and filtered to afford the tile compound (37.0 g, 68.9%) as a pink solid. 1 H NMR (300 MHz, CDCl 3 ): δ 3.90 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H), 8.06 (d, 1H). (ESI): m/z [M+H] + 262.9.

A solution of NaOH (16.88 g, 421.95 mmol) in H 2 O (80 mL) was added slowly to a stirred solution of Intermediate 113 (37 g, 140.6 mmol) in MeOH (250 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into ice/H 2 O (2 L), extracted with DCM (3×500 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (34.0 g, 97%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ): δ 4.09 (s, 3H), 6.88 (d, 1H), 8.41 (d, 1H). (ESI): m/z [M+H] + 249.8.

(Bromomethyl)benzene (15.76 mL, 132.51 mmol) was added slowly to Intermediate 114 (30 g, 120.5 mmol) and potassium carbonate (19.98 g, 144.56 mmol) in DMF (200 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The reaction mixture was poured into brine (1 L, sat), extracted with EtOAc (3×350 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (38.0 g, 93%) as an orange oil which solidified on standing. 1 H NMR (300 MHz, CDCl 3 ): δ 3.91 (s, 3H), 5.36 (s, 2H), 6.79 (d, 1H), 7.37-7.50 (m, 5H), 8.08 (dd, 1H). (ESI): m/z [M+H] + 341.3.

Step E. Intermediate 116: Benzyl 4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

PdCl 2 (Dppf)-CH 2 Cl 2 Adduct (4.57 g, 5.60 mmol) was added to Intermediate 115 (38 g, 112.0 mmol), B 2 Pin 2 (34.1 g, 134.4 mmol) and potassium acetate (27.5 g, 280.1 mmol) in 1,4-dioxane (240 mL) at 20° C. The resulting solution was stirred at 100° C. for 15 h under nitrogen. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (40.0 g, 92%) as a yellow oil which solidified on standing. 1 H NMR (300 MHz, 23.0° C., CDCl3): δ 1.37 (s, 12H), 3.93 (s, 3H), 5.37 (s, 2H), 6.63-6.70 (m, 1H), 7.36-7.43 (m, 3H), 7.46-7.51 (m, 2H), 8.29 (d, 1H). (ESI): m/z [M+H] + 387.4.

H 2 O 2 (30.0 mL, 30 weight %, 293.7 mmol) was added slowly to Intermediate 116 (44 g, 113.9 mmol) in MeOH (200 mL) at 20° C. The resulting solution was stirred at 25° C. for 5 h. The reaction mixture was poured into ice H 2 O. The precipitate was collected by filtration, and dried under vacuum to afford the title compound (20.00 g, 63.5%) as a pale yellow solid. (ESI): m/z [M+H] + 277.1.

Step G. Intermediate 118: Benzyl 5-(((1s,4s)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

DIAD (12.67 mL, 65.16 mmol) was added dropwise to Intermediate 117 (15 g, 54.30 mmol), ethyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (9.35 g, 54.30 mmol) and triphenylphosphane (17.09 g, 65.16 mmol) in THF (35 mL) at 50° C. The resulting solution was stirred at 60° C. for 15 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-10% EtOAc in heptane as mobile phase to give the title compound (17.0 g, 72.7%) as a colorless oil which solidified on standing. 1 H NMR (300 MHz, CDCl 3 ): δ 1.30 (dd, 3H), 1.59-1.81 (m, 4H), 1.93-2.07 (m, 4H), 2.42 (tt, 1H), 3.88 (s, 3H), 4.15-4.23 (m, 2H), 4.36 (tt, 1H), 5.37 (s, 2H), 6.77 (d, 1H), 7.35-7.44 (m, 3H), 7.45-7.50 (m, 2H), 7.59 (d, 1H). (ESI): m/z [M+Na] + 453.3.

Pd—C (0.20 g, 1.88 mmol) was added to Intermediate 118 (0.5 g, 1.16 mmol) in MeOH (40 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (0.300 g, 76%) as a white solid which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 1.20 (d, 3H), 1.67 (dt, 4H), 1.73-1.87 (m, 4H), 2.40-2.49 (m, 1H), 3.78 (s, 3H), 4.08 (2H, d), 4.42 (1H, d), 7.11 (1H, d), 7.46 (1H, d), 12.67 (1H, s). MS (ESI): m/z [M+H] + 341.

Intermediate 119: (1R,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

Step A. Intermediate 120: Methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride

Pd—C (11.9 mg, 0.11 mmol) and Intermediate 8 (228 mg, 1.12 mmol) in MeOH (25 mL) was stirred under an atmosphere of hydrogen at 1.5 atm and 25° C. for 14 h. The mixture was filtered through a Celite® pad. The solvent was removed under reduced pressure to the title compound (230 mg, 100%) as a pale yellow solid. This was used in the next step without further purification.

Step B. Intermediate 121: Methyl (1R,2S,3R,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptane-2-carboxylate

Boc 2 O (1.81 mL, 7.78 mmol) was added Intermediate 120 (1 g, 4.86 mmol) and TEA (2.71 mL, 19.45 mmol) in THF (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into brine (150 mL, sat), extracted with EtOAc (3×50 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (1.20 g, 92%) as a yellow oil. The crude product was used in the next step directly without further purification. 1 H NMR (300 MHz, CDCl 3 ): δ 1.10-1.36 (m, 4H), 1.43 (s, 9H), 1.56-1.60 (m, 1H), 1.78-1.87 (m, 1H), 2.15 (d, 1H), 2.44 (dd, 1H), 2.64-2.79 (m, 1H), 3.65 (s, 3H), 3.97 (t, 1H), 5.01 (d, 1H).

Step C. Intermediate 122: (1R,2S,3R,4S)-3-((tert-Butoxycarbonyl)amino)bicyclo[2.2.1]heptane-2-carboxylic acid

LiOH (0.320 g, 13.37 mmol) was added to Intermediate 121 (1.2 g, 4.46 mmol) in THF (12 mL), MeOH (3 mL) and H 2 O (3 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h.

The reaction mixture was poured into H 2 O (150 mL), the reaction mixture was acidified with 2 M HCl. The reaction mixture was extracted with EtOAc (3×50 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (1.100 g, 97%) as a colorless gum. The crude product was used in the next step directly without further purification. 1 H NMR (300 MHz, CDCl 3 ): δ 1.18 (ddd, 2H), 1.47 (s, 9H), 1.50-1.69 (m, 3H), 1.98 (d, 1H), 2.17-2.22 (m, 1H), 2.51 (d, 1H), 2.61-2.72 (m, 1H), 3.93 (t, 1H), 6.99 (d, 1H).

Step D. Intermediate 123: tert-Butyl ((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

HATU (0.357 g, 0.94 mmol) was added portion wise to 4-fluoro-3-(trifluoromethyl)aniline (0.140 g, 0.78 mmol), Intermediate 122 (0.2 g, 0.78 mmol) and DIPEA (0.304 g, 2.35 mmol) in DMF (10 mL). The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into sat NaHCO 3 (200 mL), extracted with EtOAc (3×75 mL), the organic layer was washed with brine (2×100 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford a yellow oil. The residue was purified by preparative TLC (EtOAc/PE 1/5), to afford the title compound (0.260 g, 80%) as a yellow oil which solidified on standing. MS (ESI): m/z [M+H] + 417.

Step E. (1R,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

TFA (0.241 mL, 3.12 mmol) was added to Intermediate 123 (0.26 g, 0.62 mmol) in DCM (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was diluted with EtOAc (150 mL), and washed with sat NaHCO 3 (75 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to dryness to afford the title compound (0.180 g, 91%) as a yellow gum which was used in the next step without further purification. MS (ESI): m/z [M+H] + 317.

Intermediate 124: (1R,2S,3R,4S)-3-Amino-N-phenylbicyclo[2.2.1]heptane-2-carboxamide

Step A. Intermediate 125: tert-butyl ((1S,2R,3S,4R)-3-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

Aniline (82 mg, 0.88 mmol), HATU (402 mg, 1.06 mmol), DIPEA (0.246 mL, 1.41 mmol) and DMAP (8.61 mg, 0.07 mmol) were added to a solution of Intermediate 122 (180 mg, 0.71 mmol) in DMF (5 mL). The reaction mixture was stirred at Rt for 1.5 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×10 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product. The residue was purified by preparative TLC (PE/EtOAc 1/1), to afford the title compound (187 mg, 80%) as a white solid. MS (ESI): m/z [M+Na] + 353.

A solution of hydrogen chloride (21 mg, 0.57 mmol) was added to Intermediate 125 (187 mg, 0.57 mmol). The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The product was used in the next step directly without further purification. MS (ESI): m/z [M+H] + 231.

Intermediate 126: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-((4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexylidene)methyl)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Step A. Intermediate 127: Methyl (1R,2S,3R,4S)-3-(5-bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylate

TEA (38.3 mL, 274.7 mmol) was added dropwise to Intermediate 8 (11.3 g, 54.9 mmol), Intermediate 114 (13.68 g, 54.94 mmol) and EDC (21.06 g, 109.88 mmol), HOBt (16.83 g, 109.88 mmol) in CHCl 3 (200 mL) at 20° C. over a period of 1 min under air. The resulting suspension was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with (1×150 mL, sat), NaHCO 3 (1×150 mL, sat), and H 2 O (1×150 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product. The residue was purified by preparative TLC (PE/EtOAc 5/1), to afford the title compound (13.0 g, 59.1%) as a colorless oil which solidified on standing. MS (ESI): m/z [M+H] + 400.

Step B. Intermediate 128: (1R,2S,3R,4S)-3-(5-Bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

A solution of LiOH (1.256 g, 52.47 mmol) in H 2 O (40.0 mL) was added dropwise to a stirred solution of Intermediate 127 (7 g, 17.5 mmol) in methanol (160 mL) cooled to 0° C., over a period of 1 minutes under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL). The H 2 O phase was acidified with 2 M HCl to pH 3, diluted with EtOAc (150 mL), and washed sequentially with sat NaHCO 3 (1×150 mL), brine (1×125 mL), and H 2 O (1×150 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (5.00 g, 74.0%). MS (ESI): m/z [M+H] + 386.

Intermediate 4 (1.0 g, 3.37 mmol) was dissolved in THF (10.12 mL) under N2 atmosphere and cooled to 0° C. Tebbe reagent (6.75 mL, 3.37 mmol, 0.5 M in toluene) was added and the reaction was allowed to reach ambient temperature (50 min). Et2O (20 mL) was added followed by 20 drops of NaOH (0.1 M, aq). Gas evolution was observed. Filtered through a phase separator and evaporate the solvents. The crude product was purified by flash chromatography using a gradient of 10-50% EtOAc in heptane as mobile phase to give the title compound (0.479 g, 48.2%) as a yellowish oil. 1 H NMR (400 MHz, CDCl 3 ) δ 1.19 (s, 3H), 1.28-1.39 (m, 2H), 2.01-2.23 (m, 6H), 4.59 (s, 2H), 5.59 (s, 2H), 7.46 (dd, 1H), 7.49-7.58 (m, 3H), 7.82-7.93 (m, 2H), 7.96-8.03 (m, 1H).

Step D. (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-((4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexylidene)methyl)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Intermediate 128 (628 mg, 1.63 mmol), tetrabutylammonium chloride (45.2 mg, 0.16 mmol) and PdCl 2 (dtbpf) (105 mg, 0.16 mmol) was diluted in DMA (7.26 mL) and placed under an N 2 -atmosphere. Intermediate 129 (479 mg, 1.63 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.87 mL, 4.07 mmol) was dissolved in small amount of DMA and added to the reaction mixture and the reaction was heated to 80° C. over 2 days. An additional amount of PdCl 2 (dtbpf) (105 mg, 0.16 mmol) was added after 24 h. The reaction was diluted with H 2 O/1 M KHSO 4 and EtOAc, rinsed with H 2 O/1 M KHSO 4 , filtered through phase separator. The organic phase was evaporated and the crude product was purified by Method PrepBasic-F to give the title compound (148 mg, 15%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.21 (d, 3H), 1.23-1.46 (m, 5H), 1.51-1.66 (m, 2H), 1.88 (d, 1H), 2.15 (d, 2H), 2.26 (dd, 4H), 2.35-2.46 (m, 1H), 2.54 (s, 1H), 2.81 (d, 1H), 3.78 (s, 3H), 4.46-4.63 (m, 1H), 5.53-5.7 (m, 2H), 6.03 (s, 1H), 6.42 (d, 1H), 7.41-7.6 (m, 4H), 7.87 (dd, 2H), 8.00 (dd, 2H), 8.38 (d, 1H). MS (ESI): m/z [M+H] + 231.

Intermediate 130: (1S,2R,3S,4R)-3-(5-(((1s,4R)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Step A. Intermediate 131: tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carboxylate

n-Butyllithium (28.6 mL, 71.5 mmol) was added dropwise to DIA (7.24 g, 71.5 mmol) in THF (100 mL) cooled to −78° C. under nitrogen. The resulting solution was stirred at −10° C. for 30 min and tert-butyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (15 g, 47.7 mmol) in THF (40 mL) was added dropwise to the former solution at −78° C. under nitrogen. The resulting solution was stirred at −78° C. for 3 h. Then MeI (4.17 mL, 66.8 mmol) in THF (40 mL) was added dropwise to the stirred mixture at −78° C. The resulting solution was stirred at −78° C. for 2 h. The reaction mixture was poured into NH 4 Cl (150 mL, sat), extracted with EtOAc (3×150 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to the title compound (15.50 g, 99%) as a pale yellow gum. 1 H NMR (300 MHz, DMSO-d6) δ 0.02 (d, 6H), 0.87 (d, 9H), 1.07 (d, 3H), 1.19 (m, 4H), 1.41 (d, 9H), 1.51 (d, 1H), 1.67 (d, 2H), 1.99 (d, 1H), 3.61 (m, 1H). (Major isomer).

TBAF (13.13 g, 50.22 mmol) was added in one portion to Intermediate 131 (15.0 g, 45.65 mmol) in THF (150 mL) at 20° C. over a period of min under air. The resulting solution was stirred at 20° C. for 20 h. The reaction mixture was evaporated to dryness and dissolved in EtOAc (200 mL), and washed sequentially with NH 4 Cl (1×100 mL, sat), brine (3×200 mL), and H 2 O (1×125 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product. The crude product was purified by flash chromatography using a gradient of 0-10% EtOAc in PE as mobile phase to give the title compound (6.50 g, 66.4%) as a pale yellow gum. 1 H NMR (300 MHz, DMSO-d6) δ 1.04 (d, 3H), 1.13 (m, 3H), 1.39 (d, 9H), 1.49 (d, 1H), 1.64 (t, 2H), 1.96 (d, 2H), 3.34 (m, 1H), 4.42 (dd, 1H). (Major isomer).

DIAD (13.61 mL, 69.99 mmol) was added dropwise to Intermediate 132 (12 g, 56 mmol), 4-nitrobenzoic acid (12.17 g, 72.79 mmol) and triphenylphosphine (18.36 g, 69.99 mmol) in THF (50 mL) at 50° C. The resulting solution was stirred at 60° C. for 16 h. The reaction mixture was concentrated and diluted with EtOAc (125 mL), and washed sequentially with H 2 O (2×150 mL), and brine (3×150 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the crude product. The crude product was purified by flash chromatography using a gradient of 5-10% EtOAc in PE as mobile phase to give the title compound (13.0 g, 63.9%) as a yellow solid.

Intermediate 133 (21 g, 57.8 mmol) was purified by preparative chiral-HPLC on a Chiralpak IB column, isocratic elution with 2% IPA in hexane (modified with 0.1% DEA) as eluent. The fractions containing the desired compound were evaporated to dryness to afford (1s,4s)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl 4-nitrobenzoate (2.30 g, 11.0%) as a yellow oil and Intermediate 134 (11.70 g, 55.7%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 1.17 (s, 3H), 1.44 (s, 9H), 1.52-1.64 (m, 2H), 1.67-1.95 (m, 6H), 5.14 (s, 1H), 8.20-8.27 (m, 2H), 8.34-8.40 (m, 2H).

LiOH (2.313 g, 96.59 mmol) was added in one portion to Intermediate 134 (11.7 g, 32.20 mmol) in THF (80 mL) and H 2 O (40.0 mL) at 20° C. over a period of 1 min under air. The resulting suspension was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (2×100 mL, sat), H 2 O (1×100 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (6.60 g, 96%) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 3H), 1.38 (s, 9H), 1.47 (dd, 6H), 1.62 (q, 2H), 3.57 (d, 1H), 4.38 (d, 1H).

Step F. Intermediate 136: Benzyl 5-(((1s,4s)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

DIAD (8.98 mL, 46.20 mmol) was added to Intermediate 135 (6.6 g, 30.8 mmol), Intermediate 117 (8.51 g, 30.80 mmol) and triphenylphosphane (12.12 g, 46.20 mmol) in THF (150 mL) at 60° C. over a period of 5 min under nitrogen. The resulting solution was stirred at 60° C. for 15 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with H 2 O (2×150 mL) and brine (2×150 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product. The crude product was purified by flash chromatography using a gradient of 5-10% EtOAc in PE as mobile phase to give the title compound (12.00 g, 82%) as a yellow solid. MS (ESI): m/z [M+Na] + 495.

Step G. Intermediate 137: Benzyl (1R,2R,3S,4S)-3-(5-(((1s,4R)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

DIPEA (6.17 mL, 35.30 mmol) was added to Intermediate 73 (2.7 g, 7.06 mmol), Intermediate 139 (3.1 g, 11.08 mmol) and HATU (8.05 g, 21.18 mmol) in DMF (150 mL) at 20° C. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with H 2 O (3×100 mL), and brine (3×100 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the crude product. The crude product was purified by flash chromatography using a gradient of 21-25% EtOAc in PE as mobile phase to give the title compound (3.50 g, 82%) as a yellow solid. MS (ESI): m/z [M+H] + 608.

Step H. (1S,2R,3S,4R)-3-(5-(((1s,4R)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Intermediate 137 (3.5 g, 5.76 mmol) and Pd—C (0.306 g, 0.29 mmol) in MeOH (150 mL) was stirred under an atmosphere of hydrogen at 1.5 atm and 20° C. for 1 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (2.99 g, 100%) as a white solid. MS (ESI): m/z [M+H] + 520.

Intermediate 138: tert-Butyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

DIEA (2.52 mL, 14.4 mmol) was added dropwise to Intermediate 130 (2.50 g, 4.81 mmol), (1-methylcyclobutyl)methanamine hydrochloride (0.653 g, 4.81 mmol) and HATU (9.15 g, 24.1 mmol) in DMF (150 mL) cooled to 0° C. in 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (1.0 L) and sequentially washed with saturated NaHCO 3 (250 mL), saturated brine (3×300 mL), and H 2 O (2×300 mL).

The organic layers were combined and dried over Na 2 SO 4 , filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in petroleum ether. Pure fractions were pooled and evaporated to dryness to afford the crude title compound, 2.6 g, as a pale yellow solid. The crude product was further purified by C18-flash chromatography, elution gradient 0 to 85% MeCN in H 2 O. Fractions containing product were evaporated to dryness to afford 2.1 g of the title compound as a white solid. The material was further purified by preparative chiral SFC (CHIRALPAK IF 20×250 mm ID, 5 μm, 86445S90IF0SCJ-RA002 column) using 70% CO 2 and 30% MeOH as mobile phase. Fractions containing the desired compound were pooled and evaporated to dryness to afford the title compound (1.50 g, 51.9%) as a white solid; MS (ESI): m/z, [M+H] + =601.4.

Intermediate 139: Benzyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

Step A. Intermediate 140: (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

MeOH (18.19 mL, 449.56 mmol) was added dropwise to (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione (24.6 g, 149.85 mmol) and quinine (48.6 g, 149.85 mmol) in toluene (150 mL) and CCl 4 (150 mL) cooled to −55° C. over a period of 1 min under nitrogen. The resulting suspension was stirred at −55° C. for 100 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (1200 mL), and washed sequentially with 2 M HCl (3×500 mL), sat brine (1×500 mL), and H 2 O (1×500 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the desired product (25.7 g, 87%) as a white solid.

Step B. Intermediate 141: Methyl (1R,2R,3S,4S)-3-(azidocarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate

Ethyl carbonochloridate (17.06 g, 157.18 mmol) was added dropwise to Intermediate 140 (25.7 g, 130.99 mmol) and TEA (19.88 g, 196.48 mmol) in acetone (450 mL) at 0° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 0° C. for 2 h. A solution of sodium azide (12.77 g, 196.48 mmol) in H 2 O (150 mL) was added dropwise to the stirred suspension of above at 0° C., over a period of 15 min under nitrogen. The resulting solution was stirred at 0° C. for 2 h followed by 14 h at 20° C. The reaction mixture was diluted with toluene (500 mL), and washed sequentially with brine (2×250 mL, sat), NaHCO 3 (2×250 mL, sat), and H 2 O (2×200 mL). The organic layer was dried over Na 2 SO 4 . The drying agent was filtered off and the solution was used in next step without any purification.

Intermediate 141 (29 g, 131.1 mmol) was added to toluene (500 mL) at 25° C. over a period of 1 min under air. The resulting solution was stirred at 100° C. for 1 h. The solvent was removed under reduced pressure to afford the title compound (25.3 g, 100%) as a yellow oil which was used in next step without further purification.

Step D. Intermediate 143: Methyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

A solution of hydrogen chloride (26.4 g, 724.63 mmol) in H 2 O (100 mL) was added dropwise to a stirred solution of Intermediate 142 (28 g, 144.93 mmol) in THF (250 mL) at 0° C., over a period of 5 min under air. The resulting solution was stirred at 25° C. for 14 h. The solvent was removed under reduced pressure to afford the title compound (30.0 g, 102%) as a beige oil, which solidified on standing.

Step E. Intermediate 144: Methyl (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

TEA (54.8 mL, 393.3 mmol) was added dropwise to Boc 2 O (45.7 mL, 196.65 mmol), and Intermediate 143 (26.7 g, 131.1 mmol) in THF (400 mL) at 0° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (500 mL), and washed sequentially with brine (1×250 mL, sat), H 2 O (1×200 mL), and NaHCO 3 (1×250 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated and the residue was crystallized from EtOAc/Et 2 O to afford crude title compound (42 g) as a white solid which was used without further purification.

Step F. Intermediate 145: (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

LiOH (9.41 g, 392.78 mmol) in H 2 O (180 mL) was added dropwise to Intermediate 144 (42.0 g, 157.11 mmol) in MeOH (360 mL) at 20° C. over a period of 10 min under air. The resulting suspension was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 2 by 0.5 M citric acid. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with brine (1×150 mL, sat), sat NaHCO 3 (1×150 mL), and H 2 O (1×150 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford pure product. The crude product was purified by crystallization from EtOAc/PE to afford the title compound (21.00 g, 52.8%) as a white solid.

Step G. Intermediate 146: Benzyl (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

TEA (9.63 mL, 69.1 mmol) was added dropwise to Intermediate 145 (5.0 g, 19.7 mmol), phenylmethanol (3.20 g, 29.61 mmol), EDC (8.33 g, 43.43 mmol) and HOBt (6.65 g, 43.43 mmol) in DMF (100 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The reaction mixture was poured into sat NaHCO 3 (350 mL), extracted with EtOAc (3×150 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford pale yellow oil. The crude product was purified by flash chromatography using a gradient of 0-5% EtOAc in PE as mobile phase to give the title compound (4.50 g, 66%) as a colorless gum. MS (ESI): m/z [M+Na] + 366.

Intermediate 146 (3.8 g, 11.07 mmol) was added dropwise to HCl (1.34 mL, 44 mmol) in 1,4-dioxane (100 mL) at 0° C. over a period of 1 min under air. The resulting solution was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure. The crude product was purified by crystallization from EtOAc/PE to afford the title compound (3.10 g, 100%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.42-1.52 (m, 1H), 2.03-2.10 (m, 1H), 2.63-2.71 (dd, 1H), 2.95-3.01 (d, 1H), 3.04-3.09 (s, 1H), 3.21-3.26 (s, 1H), 5.04-5.11 (d, 1H), 5.19-5.26 (d, 1H), 6.19-6.27 (dd, 1H), 6.29-6.36 (dd, 1H), 7.29-7.47 (m, 5H), 8.21-8.26 (s, 3H). MS (ESI): m/z [M+H] + 244.

Intermediate 147: 2-(Difluoromethoxy)-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

Intermediate 112 (3 g, 12.77 mmol) was added portion wise to HCl (7.29 mL, 240 mmol) in

MeOH (60 mL) at 20° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 78° C. for 48 h. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography using a gradient of 0-7% EtOAc in PE as mobile phase to give the title compound (1.50 g, 47.2%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 3.87 (s, 3H), 7.05 (d, 1H), 7.99 (d, 1H), 10.81 (s, 1H).

(Bromodifluoromethyl)trimethylsilane (3.26 g, 16.06 mmol) in DCM (12 mL) was added slowly to Intermediate 148 (1 g, 4.02 mmol) and KOH (2.253 g, 40.15 mmol) in H 2 O (12 mL) at 0° C. over a period of 1 min under nitrogen. The resulting suspension was stirred at 0° C. for 2 h. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with NaHCO 3 (1×100 mL, sat), brine (1×100 mL, sat), and H 2 O (1×100 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the desired product (1.201 g, 100%) as a pale yellow residue. The product was used in the next step directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.40 (t, 1H), 7.52 (d, 1H), 8.18 (d, 1H).

Step C. Intermediate 150: Methyl 2-(difluoromethoxy)-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Potassium acetate (0.985 g, 10.03 mmol) was added slowly to Intermediate 149 (1.2 g, 4.01 mmol)), PdCl 2 (dppf)-DCM adduct (0.328 g, 0.40 mmol) and B 2 Pin 2 (2.038 g, 8.03 mmol) in 1,4-dioxane (30 mL) at 20° C. over a period of 1 min under nitrogen. The resulting suspension was stirred at 60° C. for 14 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×75 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product. The crude product was purified by preparative TLC (EtOAc/PE1/4), to afford the title compound (0.587 g, 42.3%) as a pale yellow gum.

NaBO 3 ×4 H 2 O (907 mg, 5.89 mmol) was added slowly to Intermediate 150 (510 mg, 1.47 mmol) in THF (20 mL) at 0° C. over a period of 1 min under air. The resulting solution was stirred at 20° C. for 12 h. A solution of ammonium chloride (788 mg, 14.74 mmol) in H 2 O (10 mL) was added slowly to the stirred solution obtained above at 0° C., over a period of 1 min under air. The resulting solution was stirred at 20° C. for 4 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×75 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/3), to afford the title compound (180 mg, 51.7%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 7.01 (t, 1H), 7.22 (d, 1H), 7.43 (d, 1H), 10.47 (s, 1H).

Step E. Intermediate 152: Methyl 2-(difluoromethoxy)-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

A solution of DBAD (280 mg, 1.22 mmol) in toluene (3 mL) was added dropwise to a stirred solution of triphenylphosphane (287 mg, 1.10 mmol), Intermediate 151 (115 mg, 0.49 mmol) and Intermediate 11 (153 mg, 0.51 mmol) in DCM (3 mL) cooled to 10° C., over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with brine (1×150 mL, sat), NaHCO 3 (1×150 mL, sat), and H 2 O (1×150 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product. which was purified by preparative TLC (EtOAc/PE 1/4), to afford the title compound (200 mg, 80%) as a pale yellow solid. MS (ESI): m/z [M+Na] + 539.

Step F. 2-(Difluoromethoxy)-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

A solution of LiOH (46.4 mg, 1.94 mmol) in H 2 O (8 mL) was added dropwise to a stirred solution of Intermediate 152 (200 mg, 0.39 mmol) in THF (10 mL) cooled to 0° C., over a period of 1 min under nitrogen. The resulting solution was stirred at ambient temperature for 2 h. The reaction mixture was adjusted to pH=3 by 0.1 M HCl, diluted with EtOAc (200 mL) and washed sequentially with NH 4 Cl (1×150 mL, sat), H 2 O (1×200). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (195 mg, 100%) as a pale yellow solid. MS (ESI): m/z [M+H] + 503.

Intermediate 153: (1R,2S,3R,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

Step A. Intermediate 154: tert-Butyl ((1R,2R,3S,4S)-3-((3-((trifluoromethyl)thio)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate

DIPEA (5.52 mL, 31.6 mmol) was added dropwise to Intermediate 19 (4.0 g, 15.8 mmol), 3-((trifluoromethyl)thio)aniline (3.05 g, 15.79 mmol) and T3P (30.1 g, 47.38 mmol) in butyl acetate (100 mL) at 20° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 120° C. for 5 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (1×200 mL, sat), NaHCO 3 (1×100 mL, sat), and H 2 O (1×100 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/1), to afford the title compound (3.20 g, 47.3%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.12 (s, 9H), 1.40 (d, 1H), 2.29 (d, 1H), 2.60 (d, 2H), 2.86 (s, 1H), 3.82 (1H, t), 6.21-6.31 (m, 2H), 6.64 d, (1H), 7.34 (d, 1H), 7.42 (t, 1H), 7.68 (m, 1H), 8.12 (s, 1H), 10.10 (s, 1H).

Step B. Intermediate 155: tert-Butyl ((1S,2R,3S,4R)-3-((3-((trifluoromethyl)thio)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

Intermediate 154 (1.8 g, 4.20 mmol) and Pd—C (2.235 g, 2.10 mmol) in MeOH (50 mL) was stirred under an atmosphere of hydrogen at 1.5 atm and 30° C. for 14 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (1.808 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07-1.12 (s, 9H), 1.12-1.20 (m, 3H), 1.32-1.39 (m, 1H), 1.42-1.47 (m, 1H), 1.50-1.55 (m, 1H), 2.02 (s, 1H), 2.12 (d, 1H), 2.31-2.36 (m, 1H), 3.86 (t, 1H), 6.62 (d, 1H), 7.32 (d, 1H), 7.42 (t, 1H), 7.66 (d, 1H), 8.08-8.14 (m, 1H), 10.04 (s, 1H). MS (ESI): m/z [M+Na] + 453.

Step C. Intermediate 156: tert-Butyl ((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

Sodium periodate (1.789 g, 8.36 mmol) was added portion wise to Intermediate 155 (1.8 g, 4.18 mmol) and ruthenium(III) chloride (0.087 g, 0.42 mmol) in MeCN (15 mL) and H 2 O (5.00 mL) at 20° C. over a period of 1 min under air. The resulting suspension was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with brine (3×25 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product which was purified by C18 flash chromatography using a gradient of 0-90% H 2 O in MeCN as mobile phase to give the title compound (1.93 g, 100%) as a yellow solid.

Step D. (1R,2S,3R,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

TFA (0.045 mL, 0.58 mmol) was added dropwise to Intermediate 156 (180 mg, 0.39 mmol) in DCM (25 mL) at 20° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with (1×125 mL, sat), NaHCO 3 (1×125 mL, sat), and H 2 O (1×125 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to the title compound (141 mg, 100%). MS (ESI): m/z [M+H] + 363.

Intermediate 157: (1R,2S,3R,4S)-3-(4′-(Ethoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid

PdCl 2 (dppf)-DCM adduct (1.743 g, 2.13 mmol) was added to Intermediate 115 (3.62 g, 10.67 mmol), (4-(ethoxycarbonyl)phenyl)boronic acid (2.485 g, 12.81 mmol) and K 2 CO 3 (3.69 g, 26.68 mmol) in 1,4-dioxane (30 mL) and H 2 O (7.50 mL). The resulting mixture was stirred at 70° C. for 1.5 h under nitrogen. The reaction mixture was diluted with EtOAc (1 L), and washed sequentially with brine (3×200 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the crude product which was purified by flash chromatography using a gradient of 0-30% EtOAc in PE as mobile phase to give the title compound (4.20 g, 96%) as a brown oil which solidified on standing. 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (t, 3H), 3.91 (s, 3H), 4.34 (q, 2H), 5.34 (s, 2H), 7.26 (d, 1H), 7.32-7.50 (m, 5H), 7.68 (d, 2H), 7.92 (d, 1H), 8.04 (d, J=8.4 Hz, 2H). MS (ESI): m/z [M+H] + 409.

Pd—C (10 mg, 0.09 mmol) was added to Intermediate 158 (4.1 g, 10.04 mmol) in MeOH (150 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure and the product (0.9 g, 28%) was used in the next step without further purification. MS (ESI): m/z [M+H] + 319.

Step C. Intermediate 160: Benzyl (1S,2S,3R,4R)-3-(4′-(ethoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

HATU (1.22 g, 3.20 mmol) was added portion wise to Intermediate 109 (0.715 mg, 2.94 mmol), Intermediate 159 (0.850 g, 2.67 mmol) and DIPEA (0.518 g, 4.01 mmol) in DMF (10 mL) at Rt. The resulting solution was stirred at 60° C. for 1.5 h. The reaction mixture was extracted with EtOAc (3×75 mL), the organic layer was washed with brine (2×100 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to the title compound (3.30 g) as a brown oil. The crude product was used in the next step directly without further purification. MS (ESI): m/z [M+H] + 544.

Step D. (1R,2S,3R,4S)-3-(4′-(Ethoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid

Pd—C (0.626 g, 5.89 mmol) was added to Intermediate 160 (3.2 g, 5.89 mmol) in MeOH (150 mL). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound in mixture with the corresponding methyl ester due to some transesterification from the solvent. The crude product was used in the next step directly without purification. MS (ESI): m/z [M+H] + 456.3 (ethyl ester) and MS (ESI): m/z [M+H] + 442.3 (methyl ester).

Intermediate 161: 2-Amino-3,5-dimethyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride

Step A. Intermediate 162: tert-Butyl (2,4-dimethyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamate

2-((tert-Butoxycarbonyl)amino)-3,5-dimethylbenzoic acid (106 mg, 0.4 mmol) and HATU (304 mg, 0.80 mmol) was diluted in DCM (1.79 mL). DIPEA (210 μL, 1.20 mmol) and (1-methylcyclobutyl)methanamine hydrochloride (65.1 mg, 0.48 mmol) was added and the reaction was stirred overnight. DCM (1.79 mL) and NaHCO 3 (aq) was added and the phases was separated and the organic phase was evaporated. The crude product which was purified by flash chromatography using a gradient of 5-50% EtOAc in heptane as mobile phase to give the title compound (100 mg, 72.2%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.17 (s, 3H), 1.47 (s, 9H), 1.69-1.77 (m, 2H), 1.85-1.96 (m, 4H), 2.27 (s, 3H), 2.31 (s, 3H), 3.41 (d, 2H), 6.16 (s, 1H), 7.07 (s, 1H), 7.12 (s, 1H), 7.36 (s, 1H). MS (ESI): m/z [M+H] + 347.4.

Intermediate 162 (100 mg, 0.29 mmol) was diluted in dioxane (1 mL). 4 M HCl in dioxane (1 mL, 4.00 mmol) was added and the reaction was stirred at ambient temperature for 2 h, an additional 4 M HCl in Dioxane (1 mL, 4.00 mmol) was added and the stirring was continued for 2 h. The solvent and excess HCl was evaporated and the crude product was used as such in the next step. MS (ESI): m/z [M+H] + 247.3.

Intermediate 163: 2-Amino-4,5-dimethyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride

Step A. Intermediate 164: tert-Butyl (4,5-dimethyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamate

2-((tert-Butoxycarbonyl)amino)-4,5-dimethylbenzoic acid (106 mg, 0.4 mmol) and HATU (304 mg, 0.80 mmol) was diluted in DCM (1790 μL). DIPEA (210 μL, 1.20 mmol and (1-methylcyclobutyl)methanamine hydrochloride (65.1 mg, 0.48 mmol) was added and the reaction was stirred overnight. Diluted with DCM and NaHCO 3 (aq) separated the phases and evaporated the organic phase. The crude product was purified by flash chromatography using a gradient of 5-50% EtOAc in heptane as mobile phase to give the title compound (102 mg, 73.6%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ 1.20 (s, 3H), 1.51 (s, 9H), 1.73-1.8 (m, 2H), 1.93 (ddt, 4H), 2.23 (s, 3H), 2.29 (s, 3H), 3.43 (d, 2H), 6.09 (s, 1H), 7.13 (s, 1H), 8.17 (s, 1H), 10.06 (s, 1H). MS (ESI): m/z [M+H] + 347.4.

Intermediate 164 (102 mg, 0.29 mmol) was diluted in dioxane (1 mL). 4 M HCl in Dioxane (1 mL, 4.00 mmol) was added and the reaction was stirred at ambient temperature for 4 h, evaporated with a stream of N 2 . The solvent and excess HCl was evaporated and the crude product was used as such in the next step. MS (ESI): m/z [M+H] + 247.3.

Intermediate 165: Ethyl (1s,4s)-4-(5-carbamoyl-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

EDC (1.239 g, 6.46 mmol) was added slowly to Intermediate 111 (1 g, 2.94 mmol), NH 4 Cl (1.572 g, 29.38 mmol), HOBt (0.990 g, 6.46 mmol) and TEA (8.19 mL, 58.76 mmol) in DMF (20 mL) at 20° C. The resulting solution was stirred at 60° C. for 14 h. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with brine (2×150 mL, sat), NaHCO 3 (1×150 mL, sat), and H 2 O (1×150 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (0.900 g, 90%) as a yellow oil which solidified on standing. MS (ESI): m/z [M+H] + 340.2.

Intermediate 166: 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl trifluoromethanesulfonate

Step A. Intermediate 167: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxycyclohex-1-ene-1-carboxamide

DMAP (0.108 g, 0.88 mmol) was added to 4-fluoro-3-(trifluoromethyl)aniline (1.315 g, 7.34 mmol) and ethyl 2-oxocyclohexane-1-carboxylate (0.5 g, 2.94 mmol) in toluene (20 mL) at 20° C. The resulting solution was stirred at 130° C. for 15 h. The reaction mixture was poured into 2 M HCl (200 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the crude product as a yellow oil. The residue was purified by preparative TLC (EtOAc/PE 1/2), to afford the title compound (0.500 g, 56.1%) as a yellow gum. MS (ESI): m/z [M+H] + 304.1.

Step B. 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl trifluoromethanesulfonate

A solution of trifluoromethanesulfonic anhydride (4.23 g, 15.00 mmol) in DCM (10 mL) was added slowly to a stirred solution of Intermediate 167 (3.5 g, 11.54 mmol) and TEA (5.63 mL, 40.39 mmol) in DCM (10 mL) cooled to −78° C. under nitrogen. The resulting solution was stirred at −78° C. for 30 min. The temperature was increased to Rt and stirred overnight. The reaction mixture was poured into brine (200 mL, sat), extracted with EtOAc (3×75 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the crude product as a yellow oil. The crude product which was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (1.500 g, 29.9%) as an orange oil which solidified on standing. 1 HNMR (300 MHz, CDCl 3 ): δ 1.68-1.91 (m, 4H), 2.54 (m, 4H), 7.19 (d, 1H), 7.76 (dd, 1H), 7.82-7.86 (m, 1H). MS (ESI): m/z [M+H] + 436.3.

Intermediate 168: 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl trifluoromethanesulfonate

Step A. Intermediate 169: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxycyclopent-1-ene-1-carboxamide

DMAP (0.469 g, 3.84 mmol) was added to 4-fluoro-3-(trifluoromethyl)aniline (5.73 g, 32.01 mmol) and ethyl 2-oxocyclopentane-1-carboxylate (2 g, 12.81 mmol) in toluene (25 mL) under nitrogen. The resulting solution was stirred at 130° C. for 18 h. The reaction mixture was poured into 2 M HCl (200 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford the title compound (3.50 g, 94%) as a yellow gum. The product was used in the next step directly without further purification. MS (ESI): m/z [M+H] + 290.1.

Step B. 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl trifluoromethanesulfonate

A solution of trifluoromethanesulfonic anhydride (4.10 g, 14.52 mmol) in DCM (10 mL) was added slowly to a stirred solution of Intermediate 169 (3.5 g, 12.10 mmol) and TEA (5.06 mL, 36.30 mmol) in DCM (20 mL) cooled to −78° C. under nitrogen. The resulting solution was stirred at −78° C. for 30 min. The temperature was increased to room temperature. The reaction mixture was poured into brine (200 mL, sat), extracted with EtOAc (3×75 mL), the organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford a yellow oil. The crude product which was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (1.20 g, 24%) as a pale yellow oil which solidified on standing. 1 H NMR (400 MHz, CDCl 3 ): δ 2.08-2.16 (m, 2H), 2.83 (m, 2H), 2.90 (m, 2H), 7.20 (t, 1H), 7.70-7.76 (m, 1H), 7.78 (s, 1H), 7.87 (dd, 1H). MS (ESI): m/z [M+H] + 422.0.

Intermediate 170: 3-Amino-N-((1-methylcyclobutyl)methyl)-2-naphthamide 2,2,2-trifluoroacetate

Step A. Intermediate 171: tert-Butyl (3-(((1-methylcyclobutyl)methyl)carbamoyl)naphthalen-2-yl)carbamate

DIPEA (1.277 mL, 7.31 mmol) was added dropwise to 3-((tert-butoxycarbonyl)amino)-2-naphthoic acid (0.70 g, 2.44 mmol), (1-methylcyclobutyl)methanamine hydrochloride (0.330 g, 2.44 mmol) and HATU (2.78 g, 7.31 mmol) in DMF (20 mL) at 0° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (1×100 mL, sat), NH 4 Cl (1×100 mL, sat) and brine (1×100 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/3), to afford the title compound (0.350 g, 39%) as a white solid. MS (ESI): m/z [M+H] + 369.3.

TFA (0.732 mL, 9.50 mmol) was added dropwise to Intermediate 171 (0.35 g, 0.95 mmol) in DCM (20 mL) at 10° C., over a period of 1 second under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure. The crude product was purified by crystallization from EtOAc/EtOH to afford the title compound (0.385 g) as a pale yellow solid. MS (ESI): m/z [M+H] + 269.3.

Intermediate 172: 2-Amino-5-methyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride

Step A. Intermediate 173: tert-Butyl (4-methyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamate

2-((tert-Butoxycarbonyl)amino)-5-methylbenzoic acid (300 mg, 1.19 mmol) was added to (1-methylcyclobutyl)methanamine (178 mg, 1.79 mmol), EDC (343 mg, 1.79 mmol), HOBt (242 mg, 1.79 mmol) and DIPEA (463 mg, 3.58 mmol) in DMF (10 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was concentrated, diluted with EtOAc (150 mL) and washed sequentially with NaHCO 3 (1×150 mL, sat), H 2 O (1×200 mL), and brine (1×200 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product. The residue was purified by preparative TLC (EtOAc/PE=1/3), to afford the title compound (260 mg, 65%) as a yellow solid. MS (ESI): m/z [M+H] + 333.3.

Hydrogen chloride (384 mg, 10.53 mmol) was added to Intermediate 173 (350 mg, 1.05 mmol) in MeOH (6 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The solvent was removed by distillation under vacuum and the residue was purified by preparative TLC (PE/EtOAc 3/1), to afford the title compound (210 mg, 74%) as a yellow solid. MS (ESI): m/z [M+H] + 233.3.

Intermediate 174: 2-Amino-N-((1-methylcyclobutyl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride

Step A. Intermediate 175: tert-Butyl (3-(((1-methylcyclobutyl)methyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate

2-((tert-Butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (300 mg, 1.08 mmol) was added to (1-methylcyclobutyl)methanamine (160 mg, 1.62 mmol), EDC (310 mg, 1.62 mmol, HOBt (219 mg, 1.62 mmol) and DIPEA (418 mg, 3.23 mmol) in DMF (10 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with NaHCO 3 (1×200 mL, sat), H 2 O (1×200 mL) and brine (1×200 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product which was purified by preparative TLC (PE/EtOAc 3/1), to afford the title compound (280 mg, 72%) as a yellow solid. MS (ESI): m/z [M+H] + 360.4.

Hydrogen chloride (203 mg, 5.56 mmol) was added to Intermediate 175 (200 mg, 0.56 mmol) in MeOH (6 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with H 2 O (1×200 mL), brine (1×200 mL, sat). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/1), to afford the title compound (130 mg, 79%) as a yellow solid. MS (ESI): m/z [M+H] + 260.3.

Intermediate 176: rac-(1R,2R,3S,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Step A: Intermediate 177: rac-Methyl (1R,2R,3S,4S)-3-(((benzyloxy)carbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylate

DIPEA (1.17 mL, 6.74 mmol) was added to a solution of rac-(1R,2R,3S,4S)-3-(methoxycarbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (900 mg, 4.50 mmol) in toluene and DPPA (1.16 mL, 5.40 mmol) was added dropwise, then the reaction mixture was stirred at rt for 1 hr. The reaction mixture was stirred at 90° C. for 10 min, then benzyl alcohol (0.56 mL, 5.39 mmol) was added and the reaction mixture was stirred for 1.5 hr. The reaction mixture was diluted with EtOAc and washed with H 2 O, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (1.33 g, 97%). MS (ESI) m/z 306.1 [M+H] +

Step B: Intermediate 178: rac-(1R,2R,3S,4S)-3-(((Benzyloxy)carbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

Intermediate 177 was dissolved in THF (11 mL) and H 2 O (5.5 mL), then the mixture was cooled to 0° C. LiOH was added and the reaction mixture was stirred at 0° C. for 1 h and rt for 3 hr. 1 M aq HCl was added to the reaction mixture until pH<2, then the reaction mixture was extracted with CHCl 3 twice and the combined organic layer was concentrated in vacuo to give titled compound which was used without further purification.

Step C: Intermediate 179: rac-Benzyl ((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

HATU (1.82 g, 4.79 mmol) was added to a solution of Intermediate 178 (1.27 g, 4.35 mmol), (1-methylcyclobutyl)methylamine hydrochloride (708 mg, 5.220 mmol) and DIPEA (1.69 g, 13.05 mmol) in DMF (11 mL) and the reaction mixture was stirred at rt for 1 hr. H 2 O was added to the reaction mixture and the mixture was extracted with EtOAc/Hexane (2/1), then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (671 mg, 41%). MS (ESI) m/z 373.1 [M+H] +

Step D: rac-(1R,2R,3S,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Palladium (10% Pd/C, moisture by 50% H 2 O, 100 mg) was added to a solution of Intermediate 179 (661 mg, 1.77 mmol) in MeOH (8.9 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 4 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®. The filtrate was concentrated in vacuo to give titled compound (524 mg, 100%). MS (ESI) m/z 239.2 [M+H] +

Intermediate 180: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide hydrochloride

Step A: Intermediate 181: rac-tert-Butyl ((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

EDC (121 mg, 0.63 mmol) and HOAt (86 mg, 0.63 mmol) were added to a solution of rac-(1R,2S,3R,4S)-3-((tert-butoxycarbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.486 mmol), (1-methylcyclobutyl)methylamine hydrochloride (86 mg, 0.634 mmol) and DIPEA (160 mg, 1.20 mmol) in DMF (5 mL) and the reaction mixture was stirred at rt for 12 hr. H 2 O was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo to give the title compound (169 mg, 100%). MS (ESI) m/z 339.1 [M+H] +

Step B: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide hydrochloride

A solution of Intermediate 181 in 4 M HCl in EtOH (2 mL) was stirred at rt for 12 h and the reaction mixture was concentrated in vacuo to give titled compound (144 mg, 100%). MS (ESI) m/z 239.3 [M+H] +

Intermediate 182: rac-tert-Butyl (1R,2R,3S,4S)-2-amino-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

The titled compound was prepared analogous to Intermediate 176, using rac-(1R,2R,3S,4S)-7-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid instead of rac-(1R,2R,3S,4S)-3-methoxycarbonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid. MS (ESI) m/z 338.2 [M+H] +

Intermediate 183: rac-(1R,2S)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclobutane-1-carboxamide

The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 184: rac-(1R,2S)-2-Amino-N-neopentylcyclobutane-1-carboxamide

The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 185: rac-(1R,2S)-2-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)cyclobutane-1-carboxamide

The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 335.0 [M+H] +

Intermediate 186: rac-(1R,2S)-2-Amino-N-((1-methylcyclobutyl)methyl)cyclobutane-1-carboxamide

The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178.

Intermediate 187: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.2]oct-5-ene-2-carboxamide hydrochloride

Step A: Intermediate 188: rac-tert-Butyl ((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamate

HATU (1.91 g, 5.02 mmol) was added to a solution of rac-(1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid (Compound 1) (1.22 g, 4.56 mmol), (1-methylcyclobutyl)methylamine hydrochloride (681 mg, 5.02 mmol) and DIPEA (2.37 g, 13.69 mmol) in DMF (11 mL) and the reaction mixture was stirred at rt for 10 min. H 2 O was added to the reaction mixture and the reaction mixture was stirred vigorously. The precipitate was collected by filtration and the crude material was dried under air to give titled compound (1.56 g, 98%). MS (ESI) m/z 349.3 [M+H] +

Step B: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.2]oct-5-ene-2-carboxamide hydrochloride

A solution of Intermediate 188 in 4 M HCl in cyclopentyl methyl ether (11 mL) was stirred at rt for 30 min and the reaction mixture was concentrated in vacuo to give titled compound (1.25 g, 98%). MS (ESI) m/z 249.2 [M+H] +

Intermediate 189: (1S,2R)-2-Amino-N-((1-methylcyclobutyl)methyl)cyclohexane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclohexane-1-carboxylic acid instead of Compound 1. MS (ESI) m/z 225.3 [M+H] + .

Intermediate 190: (1S,2R)-2-Amino-N-((1-methylcyclobutyl)methyl)cyclopentane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1. MS (ESI) m/z 211.3 [M+H] + .

Intermediate 191: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

Step A: Intermediate 192: rac-Methyl (1R,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylate

AgO (231 mg, 1.00 mmol) and iodomethane (0.09 mL, 1.36 mmol) were added to a solution of rac-methyl (1S,2R,4S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-cyclopentanecarboxylate (Compound 2) (132 mg, 0.453 mmol) in MeCN (5 mL) and the reaction mixture was stirred at 50° C. for 3 hr. Iodomethane (0.38 mL, 6.07 mmol) was added and the reaction mixture was stirred at 40° C. for 20 hr. The reaction mixture was cooled at ambient temperature and filtered with Celite®, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-60% EtOAc in hexane as mobile phase to give the title compound (130 mg, 91%). MS (ESI) m/z 308.3 [M+H] + .

Step B: Intermediate 193: rac-(1R,2S,4R)-2-(((Benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylic acid

LiOH (51 mg, 2.11 mmol) was added to a solution of Intermediate 192 (130 mg, 0.42 mmol) in THF (3 mL) and H 2 O (1 mL), then the reaction mixture was stirred at rt for 19 hr. 1 M aq HCl was added to a reaction mixture to neutralize and the mixture was extracted with EtOAc three times, then the combined organic layer was concentrated in vacuo to give titled compound (125 mg, 100%). MS (ESI) m/z 294.1 [M+H] + .

Step C: Intermediate 194: rac-Benzyl ((1R,2S,4S)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

T3P (1.7 M in EtOAc, 0.54 mL, 0.91 mmol) and DIPEA (0.20 mL, 1.13 mmol) were added to a solution of Intermediate 193 (122 mg, 0.42 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (85 mg, 0.38 mmol) in MeCN (4 mL), then the reaction mixture was stirred at rt for 20 hr. Sat aq NaHCO 3 was added to a reaction mixture and the mixture was extracted with EtOAc three times, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-2% MeOH in CHCl 3 as mobile phase to give the title compound (133 mg, 71%). MS (ESI) m/z 501.1 [M+H] + .

Step D: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

Palladium (10% Pd/C, moisture by 50% H 2 O, 38 mg) was added to a solution of Intermediate 194 (130 mg, 0.26 mmol) in MeOH (3 mL) and THF (6 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 5 hr. The hydrogen in the reaction vessel was replaced with argon, and the reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% MeOH in CHCl 3 as mobile phase to give the title compound (46 mg, 48%). MS (ESI) m/z 367.1 [M+H] + .

Intermediate 195: rac-(1R,2S,4S)-2-Amino-4-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

The titled compound was prepared analogous to Intermediate 191, using rac-methyl (1S,2R,4R)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-cyclopentanecarboxylate instead of Compound 2. MS (ESI) m/z 367.4 [M+H] + .

Intermediate 196: rac-(1R,2R)-2-Amino-1-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

Step A: Intermediate 197: Methyl (1R,2R)-2-(benzyl((R)-1-phenylethyl)amino)-1-fluorocyclopentane-1-carboxylate

n-BuLi (2.6 M in Hexane, 0.73 mL, 1.90 mmol) was added dropwise to −78° C. cooled solution of (1R)—N-benzyl-1-phenyl-ethanamine (502 mg, 2.38 mmol) in THF (4 mL) and the reaction mixture was stirred at −78° C. for 20 min. Methyl cyclopentene-1-carboxylate (200 mg, 1.59 mmol) was added dropwise to a reaction mixture was stirred at −78° C. for 30 min. N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (1.0 g, 3.17 mmol) in THF (4 mL) was added to a reaction mixture and the mixture was stirred at rt for 30 min. Sat aq NH 4 Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give the title compound (210 mg, 37%). MS (ESI) m/z 356.2 [M+H] + .

Step B: Intermediate 198: (1R,2R)-2-(Benzyl((R)-1-phenylethyl)amino)-1-fluorocyclopentane-1-carboxylic acid

LiOH (142 mg, 5.91 mmol) was added to a solution of Intermediate 197 (210 mg, 0.59 mmol) in THF (3 mL) and H 2 O (1.5 mL), then the reaction mixture was stirred at rt for 7 days. 1 M aq HCl was added to a reaction mixture to neutralize and the mixture was extracted with CHCl 3 twice, then the combined organic layer was concentrated in vacuo give titled compound (60 mg, 30%) which was used without further purification.

Step C: Intermediate 199: (1R,2R)-2-(Benzyl((R)-1-phenylethyl)amino)-1-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

HATU (73 mg, 0.19 mmol) and DIPEA (0.09 mL, 0.53 mmol) were added to a solution of Intermediate 198 (60 mg, 0.18 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (44 mg, 0.19 mmol) in DMF (1 mL), then the reaction mixture was stirred at rt for 24 hr. H 2 O was added to a reaction mixture and the mixture was extracted with CHCl 3 twice, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-25% EtOAc in hexane as mobile phase to give the title compound (43 mg, 45%). MS (ESI) m/z 549.5 [M+H] + .

Step D: rac-(1R,2R)-2-Amino-1-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

Palladium (10% Pd/C, moisture by 50% H 2 O, 10 mg) was added to a solution of Intermediate 199 (43 mg, 0.078 mmol) in MeOH (1.5 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 20 hr. The hydrogen in the reaction vessel was replaced with argon, and the reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo to give titled compound (27 mg, 97%). MS (ESI) m/z 355.3 [M+H] + .

Intermediate 200: rac-(1R,2R,3S)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

Step A: Intermediate 201: rac-Benzyl (3aR,4R,6R,6aR)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-4-carboxylate

NBS (336 mg, 1.89 mmol) was added to a solution of rac-benzyl (1S,2R)-2-(tert-butoxycarbonylamino)cyclopent-3-ene-1-carboxylate (500 mg, 1.58 mmol) in THF (7.9 mL) and H 2 O (0.79 mL), and the reaction mixture was stirred at rt for 3 days. H 2 O was added to the reaction mixture and the mixture was extracted with CHCl 3 twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (361 mg, 67%). MS (ESI) m/z 340.2/342.2 [M+H] + .

Step B: Intermediate 202: rac-Benzyl (3aR,4R,6aS)-2-oxohexahydro-2H-cyclopenta[d]oxazole-4-carboxylate

AIBN (17 mg, 0.11 mmol) was added to a solution of Intermediate 201 (359 mg, 1.05 mmol) and tributylstannane (338 mg, 1.16 mmol) in toluene (3 mL), then the reaction mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (216 mg, 78%). MS (ESI) m/z 262.1 [M+H] + .

Step C: Intermediate 203: rac-4-Benzyl 3-(tert-butyl) (3aR,4R,6aS)-2-oxotetrahydro-2H-cyclopenta[d]oxazole-3,4(3aH)-dicarboxylate

Boc 2 O (193 mg, 0.88 mmol) and 4-(dimethylamino)pyridine (10 mg, 0.08 mmol) were added to a solution of Intermediate 202 (210 mg, 0.80 mmol) in MeCN (4 mL), then the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo to give titled compound (310 mg, 107%) which was used without further purification.

Step D: Intermediate 204: rac-(3aR,4R,6aS)-3-(tert-Butoxycarbonyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-4-carboxylic acid

Palladium (10% Pd/C, moisture by 50% H 2 O, 30 mg) was added to a solution of Intermediate 203 (262 mg, 0.73 mmol) in MeOH (3.6 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 4 hr. The hydrogen in the reaction vessel was replaced with argon, and CHCl 3 and MeOH were added to the reaction mixture to dissolve precipitated product. The reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo to give titled compound (196 mg, 100%). MS (ESI) m/z 270.3 [M−H]−

Step E: Intermediate 205: rac-tert-Butyl (3aR,4R,6aS)-2-oxo-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-cyclopenta[d]oxazole-3(3aH)-carboxylate

T3P (1.7 M in EtOAc, 910 mg, 1.43 mmol) and pyridine (113 mg, 1.43 mmol) were added to a solution of Intermediate 204 (194 mg, 0.72 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (177 mg, 0.79 mmol) in EtOAc (1.8 mL), then the reaction mixture was stirred at rt for 15 h. CHCl 3 and H 2 O were added to a reaction mixture and the mixture was extracted with EtOAc twice, then the combined organic layer was concentrated in vacuo. The crude product was triturated with IPA to give titled compound (164 mg, 48%). MS (ESI) m/z 477.4 [M−H]−

Step F: Intermediate 206: rac-tert-Butyl ((1R,2S,5R)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate hydrochloride

LiOH (80 mg, 3.34 mmol) was added to a solution of Intermediate 205 (160 mg, 0.33 mmol) in THF (3.3 mL) and H 2 O (0.84 mL), and the reaction mixture was stirred at rt for 3 hr. H 2 O was added to the reaction mixture and the reaction mixture was extracted with EtOAc twice and the combined organic layer was concentrated in vacuo to give titled compound (116 mg, 77%). MS (ESI) m/z 451.3 [M−H]−

Step G: rac-(1R,2R,3S)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

Intermediate 206 (70 mg, 0.15 mmol) was dissolved in 2 M HCl in EtOH (1.6 mL) and the reaction mixture was stirred at rt for 5 hr. The reaction mixture was concentrated in vacuo to give titled compound (62 mg, 103%). MS (ESI) m/z 353.1 [M+H] + .

Intermediate 207: rac-(1R,2R,3R)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

Step A: Intermediate 208: rac-tert-Butyl ((1R,2S,3S,5S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)-6-oxabicyclo[3.1.0]hexan-2-yl)carbamate

3-((Trifluoromethyl)sulfonyl)aniline (1.33 g, 5.91 mmol) was added to a suspension of NaH (60% in oil suspension, 236 mg, 5.91 mmol) in THF (7.9 mL), then the reaction mixture was stirred at rt for 10 min. The reaction mixture was cooled to 0° C. and rac-tert-butyl (1R,2S,4R,6R)-7-oxo-3-oxa-8-azatricyclo[4.2.0.02,4]octane-8-carboxylate (888 mg, 3.94 mmol) in THF (4 mL) was added to the reaction mixture and the reaction mixture was stirred at rt for 3 hr. Sat aq NH 4 Cl was added to the reaction mixture and the mixture was filtered to give titled compound (809 mg, 46%). The filtrate was extracted with EtOAc twice and the combined organic layer was concentrated in vacuo. The crude product was triturated with IPA to give additional titled compound (549 mg, 31%). MS (ESI) m/z 449.4 [M−H]−

Step B: Intermediate 209: rac-tert-Butyl ((1R,2S,3S,5R)-3-bromo-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

Lithium bromide (289 mg, 3.33 mmol) was added to a solution of Intermediate 208 (300 mg, 0.67 mmol) in acetic acid (4.2 mL) at 0° C., then the reaction mixture was stirred at 0° C. for 1 h and rt for 5 hr. H 2 O was added to the reaction mixture and filtered to give titled compound (218 mg, 62%). MS (ESI) m/z 529.2/531.2 [M−H]−

Step C: Intermediate 210: rac-tert-Butyl ((1R,2R,5R)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

AIBN (14 mg, 0.09 mmol) was added to a solution of Intermediate 209 (455 mg, 0.86 mmol) and tributylstannane (300 mg, 1.03 mmol) in toluene (1.7 mL), then the reaction mixture was stirred at 90° C. for 4 hr. Additional tributylstannane (150 mg, 0.51 mmol) and AIBN (14 mg, 0.09 mmol) was added to the reaction mixture, then the reaction mixture was stirred at 90° C. for 1.5 hr. The reaction precipitate was collected by filtration and washed with toluene to give titled compound (335 mg, 87%). MS (ESI) m/z 451.2 [M−H]−

Step D: rac-(1R,2R,3R)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

Intermediate 210 (120 mg, 0.27 mmol) was dissolved in 2 M HCl in EtOH (3 mL) and the reaction mixture was stirred at rt for 5 hr. The reaction mixture was concentrated in vacuo to give titled compound (107 mg, 103%). MS (ESI) m/z 353.1 [M+H] + .

Intermediate 211: rac-(1R,2R,3R)-2-Amino-3-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

Step A: Intermediate 212: rac-tert-Butyl ((1R,2R,5R)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

Silver oxide (131 mg, 0.57 mmol) and iodomethane (0.26 mL, 4.23 mmol) were added to a solution of Intermediate 210 (137 mg, 0.26 mmol) in MeCN (2.6 mL), then the reaction mixture was stirred at 50° C. for 6 hr. Additional silver oxide (48 mg, 0.21 mmol) and iodomethane (0.06 mL, 0.93 mmol) were added to the reaction mixture, then the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The crude product was triturated with Et 2 O to give titled compound (65 mg, 43%). The filtrate was concentrated in vacuo and the residual powder was triturated with THF-hexane to give additional titled compound (50 mg, 33%). MS (ESI) m/z 465.3 [M−H]−

Step B: rac-(1R,2R,3R)-2-Amino-3-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

Intermediate 212 (115 mg, 0.20 mmol) was dissolved in 2 M HCl in EtOH (3 mL) and the reaction mixture was stirred at rt for 18 hr. The reaction mixture was concentrated in vacuo and the crude product was triturated with IPA to give titled compound (79 mg, 89%). MS (ESI) m/z 367.2 [M+H] + .

Intermediate 213: rac-(1R,2R,3S,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 361.2 [M+H] + .

Intermediate 214: rac-(1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 379.0 [M+H] + .

Intermediate 215: rac-(1R,2R,3S,4S)-3-Amino-N-(3-fluoro-5-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 3-fluoro-5-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 373.2 [M+H] + .

Intermediate 216: rac-(1R,2S)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 337.0 [M+H] + .

Intermediate 217: (1S,2R)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 337.2 [M+H] + .

Intermediate 218: (1S,2R)-2-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopentane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 349.1 [M+H] + .

Intermediate 219: (1R,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 375.1 [M+H] + .

Intermediate 220: (1R,2S,3R,4S)-3-Amino-N-((1-(trifluoromethyl)cyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using (1-trifluoromethylcyclobutyl)methylamine hydrochloride instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 221: (1S,2S,3R,4R)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1.

Intermediate 222: (1S,2S,3R,4R)-3-Amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 223: (1R,2S,3R,4S)-3-Amino-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 239.2 [M+H] + .

Intermediate 224: (1R,2S,3R,4S)-3-Amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 225.3 [M+H] + .

Intermediate 225: (1R,2S,3R,4S)-3-Amino-N-(3,3,3-trifluoro-2,2-dimethylpropyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-methyl-3-trifluoromethylpropylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 279.2 [M+H] + .

Intermediate 226: (1R,2S,3R,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 363.2 [M+H] + .

Intermediate 227: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 379.0 [M+H] + .

Intermediate 228: (1S,2R)-2-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopentane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 291.0 [M+H] + .

Intermediate 229: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 315.0 [M+H] + .

Intermediate 230: (1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 315.1 [M+H] + .

Intermediate 231: rac-(1R,2R,3S,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 363.1 [M+H].

Intermediate 232: (1S,2S,3R,4R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 363.1 [M+H] + .

Intermediate 233: rac-(1R,2R,3S,4S)-3-Amino-N-(3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 357.0 [M+H] + .

Intermediate 234: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 373.1 [M+H] + .

Intermediate 235: rac-(1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-(pentafluoro-6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 375.1 [M+H] + .

Intermediate 236: rac-(3R,4R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-4-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 353.3 [M+H] + .

Intermediate 237: rac-(3R,4R)-3-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)tetrahydro-2H-pyran-4-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 238: (2S,3R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 196 Step B, using methyl (2S,3R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate instead of Intermediate 197.

Step B: (2S,3R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (2S,3R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 239: rac-(1R,2S)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cycloheptane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2S)-2-(tert-butoxycarbonylamino)cycloheptane-1-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 240: rac-(3R,4R)-4-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-3-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4R)-4-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-3-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methyl cyclobutyl)methylamine hydrochloride.

Intermediate 241: (2S,3R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydrofuran-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using (2S,3R)-3-(tert-butoxycarbonylamino)tetrahydrofuran-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 242: rac-(3R,4S)-4-Amino-N-((1-methylcyclobutyl)methyl)tetrahydrofuran-3-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1. MS (ESI) m/z 213.2 [M+H] + .

Intermediate 243: rac-(3R,4S)-4-Amino-N-neopentyltetrahydrofuran-3-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 244: rac-(3R,4S)-4-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydrofuran-3-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 245: rac-(3R,4S)-4-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)tetrahydrofuran-3-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 246: rac-(1R,2S,4S)-2-Amino-4-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

The titled compound was prepared analogous to Intermediate 176 Step B-D, using rac-methyl (1S,2R,4R)-2-(((benzyloxy)carbonyl)amino)-4-hydroxycyclopentane-1-carboxylate instead of rac-methyl (1R,2R,3S,4S)-3-(((benzyloxy)carbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylate and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 247: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-neopentylcyclopentane-1-carboxamide

The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylic acid instead of Intermediate 178 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 248: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-((1-methylcyclobutyl)methyl)cyclopentane-1-carboxamide

The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylic acid instead of Intermediate 178. MS (ESI) m/z 241.2 [M+H] + .

Intermediate 249: (1R,2S,3R,4S,5S,6R)-3-Amino-5,6-dihydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

Step A: Intermediate 250: tert-Butyl ((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate

T3P (1.7 M in EtOAc, 2.30 mL, 3.90 mmol) and DIPEA (1.02 mL, 5.90 mmol) were added to a solution of (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (500 mg, 1.97 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (489 mg, 2.17 mmol) in EtOAc (5 mL), then the reaction mixture was stirred at rt for 7 hr. Sat aq NaHCO 3 was added to a reaction mixture and the mixture was extracted with EtOAc three times, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using CHCl 3 as mobile phase to give the title compound (493 mg, 54%). MS (ESI) m/z 405.1 [M+H-tBuH]+

Step B: Intermediate 251: tert-Butyl ((1S,2R,3S,4R,5R,6S)-5,6-dihydroxy-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

OsO4 (microcapsulated, 273 mg, 0.107 mmol) and N-methylmorpholine N-oxide (0.9 mL, 4.40 mmol) were added to a solution of Intermediate 250 (493 mg, 1.07 mmol) in MeCN (3 mL) and acetone (3 mL), and the reaction mixture was stirred at rt for 24 hr. Iodomethane (0.38 mL, 6.07 mmol) was added and the reaction mixture was stirred at 40° C. for 20 hr. The reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl 3 as mobile phase to give the title compound (498 mg, 94%). MS (ESI) m/z 439.1 [M+H-tBuH]+

Step C: (1R,2S,3R,4S,5S,6R)-3-Amino-5,6-dihydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

4 M HCl in EtOAc (3 mL) was added to a solution of Intermediate 251 (498 mg, 1.00 mmol) in MeOH (2 mL), and the reaction mixture was stirred at rt for 18 hr. The reaction mixture was concentrated in vacuo to give titled compound (434 mg, 100%).

Intermediate 252: rac-(1R,2R,3S,4R)-2-Amino-3,4-dihydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 249, using rac-(1S,2R)-2-(tert-butoxycarbonylamino)cyclopent-3-ene-1-carboxylic acid instead of (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.

Intermediate 253: rac-(1R,2S)-2-Amino-4,4-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopentane-1-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2R)-2-(tert-butoxycarbonylamino)-4,4-difluoro-cyclopentanecarboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

Intermediate 254: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1. MS (ESI) m/z 237.2 [M+H] + .

Intermediate 255: rac-(1R,2R,3S,4S)-3-Amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 237.2 [M+H] + .

Intermediate 256: (1S,2S,3R,4R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

The titled compound was prepared analogous to Intermediate 207 Step D, using Intermediate 250 instead of Intermediate 210. MS (APCI) m/z 361.0 [M+H] + .

Intermediate 257: Ethyl 1-(cyanomethyl)-4-hydroxycyclohexane-1-carboxylate

n-BuLi (2.6 M in hexane, 3.87 mL, 10.3 mmol) was added dropwise to 0° C. cooled solution of DIA (1.14 g, 11.2 mmol) in THF (12 mL) and the reaction mixture was stirred at 0° C. for 30 min. Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (2 g, 9.33 mmol) in THF (3 mL) was added dropwise to a reaction mixture was stirred at −78° C. for 1 hr. 2-Bromoacetonitrile (1.68 g, 14.0 mmol) was added to a reaction mixture and the mixture was stirred at rt for 4 hr. Sat aq NH 4 Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (900 mg, 38%). MS (ESI) m/z 254.1 [M+H] + .

2 M aq HCl (5 mL) was added to a solution of Intermediate 258 (900 mg, 3.55 mmol) in acetone (5 mL) and the reaction mixture was stirred at rt for 20 hr. The reaction mixture was concentrated in vacuo, and H 2 O and EtOAc were added and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was dissolved in EtOH (7 mL) and NaBH 4 (161 mg, 4.26 mmol) was added portionwise to 0° C. cooled solution of mixture. The reaction mixture was stirred at 0° C. for 1 hr. Sat aq NH 4 Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-60% EtOAc in hexane as mobile phase to give the title compound (649 mg, 87%) as cis/trans mixture. MS (ESI) m/z 194.1 [M+H−H 2 O] +

Intermediate 259: tert-Butyl (1s,4s)-4-hydroxy-1-(trifluoromethyl)cyclohexane-1-carboxylate

A mixture of tert-butyl 2-(trifluoromethyl)prop-2-enoate and trimethyl(1-methyleneallyloxy)silane was stirred at 140° C. for 6 hr. THF (5 mL) and 0.1 M aq HCl (5 mL) were added to the reaction mixture and the mixture was stirred at rt for 16 hr. H 2 O was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was washed with sat aq NaHCO 3 and was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (880 mg, 65%).

NaBH 4 (150 mg, 3.97 mmol) was added portionwise to 0° C. cooled solution of Intermediate 260 (880 mg, 3.30 mmol) in EtOH (5 mL). The reaction mixture was stirred at 0° C. for 1 hr. Sat aq NH 4 Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (869 mg, 98%).

Di-2-methoxyethyl azodicarboxylate (869 mg, 4.86 mmol) in THF (10 mL) was added dropwise to a solution of p-nitrobenzoic acid (812 mg, 4.86 mmol), Intermediate 261 (869 mg, 3.24 mmol) and triphenylphosphine (1.27 g, 4.84 mmol) at 0° C., and the reaction mixture was stirred at rt for 7 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H 2 O twice, then the organic layer was concentrated in vacuo to give crude p-nitrobenzoate derivative. Potassium carbonate (1.04 g, 7.52 mmol) in H 2 O (2 mL) was added to a mixture of above crude product in MeOH (8 mL) and the reaction mixture was stirred at reflux for 3 hr. After being concentrated the solvent, H 2 O was added to the reaction mixture and then the mixture was extracted with CHCl 3 , then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give the title compound (630 mg, 72%).

Intermediate 262: Benzyl (1s,4s)-4-hydroxy-1-methoxycyclohexane-1-carboxylate

NaBH 4 (204 mg, 5.39 mmol) was added portionwise to −78° C. cooled solution of benzyl 1-methoxy-4-oxo-cyclohexane-1-carboxylate (705 mg, 2.69 mmol) in EtOH (5 mL). The reaction mixture was stirred at 0° C. for 4 hr. Sat aq NH 4 Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-60% EtOAc in hexane as mobile phase to give the title compound (536 mg, 75%). MS (ESI) m/z 265 [M+H] + .

Intermediate 263: Benzyl (1r,4r)-1-((benzyloxy)methyl)-4-hydroxycyclohexane-1-carboxylate

4 M aq NaOH (13.2 mL, 52.8 mmol) was added to a solution of ethyl 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (5.89 g, 17.6 mmol) in MeOH (15 mL). The reaction mixture was stirred at reflux for 6 hr. The reaction mixture was concentrated in vacuo and 6 M aq HCl was added to the mixture, and the mixture was extracted with CHCl 3 twice. The combined organic layer was concentrated in vacuo. The crude product was dissolved in DMF (20 mL). Potassium carbonate (3.65 g, 26.4 mmol) and benzyl bromide (2.20 mL, 18.5 mmol) were added to mixture, and the mixture was stirred at rt for 3 hr. H 2 O was added to the mixture and the mixture was extracted with Et2O twice. The combined organic layer was washed with H 2 O twice and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in hexane as mobile phase to give the title compound (6.92 g, 99%). MS (ESI) m/z 397.5 [M+H] + .

2 M aq HCl (70 mL) was added to a solution of Intermediate 264 (6.92 g, 17.5 mmol) in acetone (20 mL) and the reaction mixture was stirred at rt for 8 hr. The reaction mixture was concentrated in vacuo, and H 2 O and EtOAc were added and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was dissolved in MeOH (10 mL) and THF (10 mL), and NaBH 4 (1.98 g, 52.3 mmol) was added portionwise to −78° C. cooled solution of mixture. The reaction mixture was stirred at −40° C. for 2 hr. Sat aq NH 4 Cl was added to the reaction mixture and the mixture was extracted with CHCl 3 twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-50% EtOAc in hexane as mobile phase to give the title compound (5.22 g, 84%). MS (ESI) m/z 355.4 [M+H] + .

Di-2-methoxyethyl azodicarboxylate (5.17 g, 22.1 mmol) in THF (20 mL) was added dropwise to a solution of p-nitrobenzoic acid (3.69 g, 22.1 mmol), Intermediate 265 (5.22 g, 14.7 mmol) and triphenylphosphine (5.79 g, 22.1 mmol) in THF (10 mL) at 0° C., and the reaction mixture was stirred at rt for 3 hr. The reaction mixture was diluted with EtOAc and the mixture was washed w