CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/273,242, filed October 29, 2021, the disclosure of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The present disclosure relates to novel compounds which are relaxin family peptide receptor 1 (RXFP1) agonists, compositions containing them, and methods of using th em, for example in th e treatment of heart fai lure, fibroti c diseases, an d related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), and hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).

The human relaxin hormone (also called relaxin or H2 relaxin) is a 6-kDa peptide composed of 53 amino acids whose activity was initially discovered when Frederick Hisaw in 1926 injected crude extracts from swine corpus luteum into virgin guinea pigs and observed a relaxation of the fibrocartilaginous pubic symphysis joint (Hisaw FL., Proc. Soc. Exp. Biol. Med., 1926, 23, 661-663). Hie relaxin receptor was previously known as Lgr7 but is now officially termed the relaxin family peptide receptor 1 (RXFP1) and was deorphanized as a receptor for relaxin in 2002 (Hsu SY., et al. , Science, 2002, 295, 671-674). RXFP1 is reasonably well conserved between mouse and human with 85% amino acid identity and is essentially ubiquitously expressed in humans and in other species (Halls ML., etal, Br. J. Pharmacol, 2007, 150, 677-691). The cell signaling pathways for relaxin and RXFP1 are cell type dependent and quite complex (Halls ML., etal, Br. J. Pharmacol., 2007, 150, 677-691; Halls ML., etal. Ann. N Y Acad. Sci., 2009, 1160, 108-1 11; Halls ML., Ann NY Acad. Sci., 2007, 1160, 117-120). The best studied pathway is the relaxin-dependent increase in cellular levels of cAMP in which relaxin functions as an RXFP1 agonist to promote GDS coupling and activation of adenylate cyclase (Halls ML., et al, Mol. Pharmacol, 2006, 70, 214-226).

Since the initial discovery ⁷ of relaxin much experimental work has focused on delineating the role relaxin has played in female reproductive biology and the physiological changes that occur during mammalian pregnancy (Sherwood OD., Endocr. Rev., 2004, 25, 205-234). During human gestation, in order to meet the nutritional demands imposed upon it by the fetus, the female body undergoes a significant -30% decrease in systemic vascular resistance (SVR) and a concomitant -50% increase in cardiac output (Jeyabalan AC., K.P., Renal and Electolyte Disorders. 2010, 462-518), (Clapp IF. & Capeless E., ylm. J. Cardio., 1997, 80, 1469-1473). Additional vascular adaptations include an -30% increase in global arterial compliance that is important for maintaining efficient ventricular-arterial coupling, as well as an -50% increase in both renal blood flow (RBF) and glomerular filtration rate (GFR), important for metabolic waste elimination (Jeyabalan AC., K.P., Renal and Electolyte Disorders. 2010, 462-518), (Poppas A., et al., Circ., 1997, 95, 2407-2415). Both pre-clinical studies in rodents as well as clinical studies performed in a variety' of patient settings, provide evidence that relaxin is involved, at least to some extent, in mediating these adaptive physiological changes (Conrad KI’., Regul. Integr. Comp. Physiol., 2011, 301, R267-275), (Teichman SL., etal., Heart Fail. Rev., 2009, 14, 321-329). Importantly, many of these adaptive responses would likely be of benefit to HF patients in that excessive fibrosis, poor arterial compliance, and poor renal function are all characteristics common to heart failure patients (Mohammed SF., et al.., Circ., 2015, 131, 550-559), (Wohlfahrt P., etal,, Eur. J. Heart Fail., 2015, 17, 27-34), (Damman K., et al., Prog. Cardiovasc. Dis., 2011, 54, 144- 153).

Heart failure (HF), defined hemodynamically as “systemic perfusion inadequate to meet the body's metabolic demands as a result of impaired cardiac pump function”, represents a tremendous burden on today’s health care system with an estimated United States prevalence of 5.8 million and greater than 23 million worldwide (Roger VL., et al., Circ. Res., 2013, 113, 646-659). It is estimated that by 2030, an additional 3 million people in the United States alone will have HF, a 25% increase from 2010. The estimated direct costs (2008 dollars) associated with HF for 2010 was $25 billion, projected to grow to $78 B by ⁷ 2030 (Heidenreich PA., etal., Circ., 2011, 123, 933-944). Astoundingly, in the United States, 1 in 9 deaths has HF mentioned on the death certificate (Roger VL., et al., Circ., 2012, 125, e2-220) and, while survival after HF diagnosis lias improved over time (Matsushita K., et al,, Diabetes, 2010, 59, 2020-2026), (Roger VL., et al,, JAMA, 2004, 292, 344-350), the death rate remains high with -50% of people with HF dyeing within 5 years of diagnosis (Roger VL., etal., Circ., 2012, 125, e2-220), (Roger VL., et at, JAMA, 2004, 292, 344-350).

Hie symptoms of HF are the result of inadequate cardiac output and can be quite debilitating depending upon the advanced stage of the disease. Major symptoms and signs of HF include: 1) dyspnea (difficulty in breathing) resulting from pulmonary edema due to ineffective forward flow from the left ventricle and increased pressure in the pulmonary capillary bed; 2) lower extremity edema occurs when the right ventricle is unable to accommodate systemic venous return; and 3) fatigue due to the failing heart’s inability to sustain sufficient cardiac output (CO) to meet the body's metabolic needs (Kemp CD., & Conte JV., Cardiovasc. Pathol., 2011, 21, 365-371). Also, related to the severity of symptoms, HF patients are often described as “compensated” or “decompensated”. In compensated heart failure, symptoms are stable, and many overt features of fluid retention and pulmonary ⁷ edema are absent. Decompensated heart failure refers to a deterioration, which may present as an acute episode of pulmonary ⁷ edema, a reduction in exercise tolerance, and increasing breathlessness upon exertion (Millane T., etal., BMJ 2000, 320, 559-562).

In contrast to the simplistic definition of poor cardiac performance not being able to meet metabolic demands, the large number of contributory diseases, multitude of risk factors, and the many pathological changes that ultimately lead to heart failure make this disease exceedingly complex (Jessup M. & Brozena S., N. Engl. J. Med., 2003, 348, 3007-2018). Injurious events thought to be involved in the pathophysiology of HF range from the very acute such as myocardial infarction to a more chronic insult such as lifelong hypertension. Historically, HF was primarily described as “systolic HF” in which decreased left-ventricular (LV) contractile function limits the expulsion of blood and hence results in a reduced ejection fraction (EF is stroke volume/end diastolic volume), or “diastolic HF” in which active relaxation is decreased and passive stiffness is increased limiting LV filling during diastole, however overall EF is maintained (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). More recently, as it became understood that diastolic and systolic LV dysfunction was not uniquely specific to these two groups, new terminology was employed: “heart failure with reduced ejection fraction” (HFrEF), and “heart failure with preserved ejection fraction” (HFpEF) ( Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). Although these two patient populations have very similar signs and symptoms, whether HFrEF and HFpEF represent two distinct forms of HF or two extremes of a single spectrum sharing a common pathogenesis is currently under debate within the cardiovascular community (Borlaug BA. & Redfield MM., Circ., 2011, 123, 2006-2013), (De Keulenaer GW., & Brutsaert DL., Circ., 2011, 123, 1996- 2004).

Serelaxin, an intravenous (IV) formulation of the recombinant human relaxin peptide with a relatively short first-phase pharmacokinetic half-life of 0.09 hours, is currently being developed for the treatment of HF (Novartis, 2014). Serelaxin has been given to normal healthy volunteers (NHV) and demonstrated to increase RBF (Smith MC., et al., J. Am. Soc. Nephrol. 2006, 17, 3192-3197) and estimated GFR (Dahlke M., et al., J. Clin. Pharmacol., 2015, 55, 415-422). Increases in RBF were also observed in stable compensated HF patients (Voors AA., etal., Cir. Heart Fail., 2014, 7, 994-1002). In large clinical studies, favorable changes in worsening renal function, worsening HF, as well as fewer deaths, were observed in acute decompensated HF (ADHF) patients in response to an in-hospital 48 hour IV infusion of serelaxin (Teerlink JR., et al., Lancet, 2013, 381, 29-39), (Ponikowski P., et al., Eur. Heart, 2014, 35, 431-441). Suggesting that chronic dosing of serelaxin could provide sustained benefit to HF patients, improvement in renal function based on serum creatinine levels was observed in scleroderma patients given serelaxin continuously for 6 months using a subcutaneous pump (Teichman SL., et al., Heart Fail. Rev., 2009, 14, 321-329). In addition to its potential as a therapeutic agent for the treatment of HF, continuous subcutaneous administration of relaxin has also been demonstrated to be efficacious in a variety of animal models of lung (Unemori EN., etal., J. Clin. Invet., 1996, 98, 2739-2745), kidney (Garber SL., et al., Kidney Int., 2001, 59, 876-882), and liver injury' (Bennett RG., Liver Int., 2014, 34, 416-426).

In summary', a large body of evidence supports a role for relaxin-dependent agonism of RXFP1 mediating the adaptive changes that occur during mammalian pregnancy, and that these changes translate into favorable physiological effects and outcomes when relaxin is given to HF patients. Additional preclinical animal studies in various disease models of lung, kidney, and liver injury provide evidence that relaxin, when chronically administered, has the potential to provide therapeutic benefit for multiple indications in addition to HI’. More specifically, chronic relaxin administration could be of benefit to patients suffering from lung disease (e.g., idiopathic pulmonary' fibrosis), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., nonalcoholic steatohepatitis and portal hypertension).

SUMMARY OF THE INVENTION

The present invention provides novel substituted norbomyl compounds, their analogues, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as RXFP1 receptor agonists.

Hie present invention also provides processes and intermediates for making the compounds of the present invention.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used, for example, in the treatment and/or prophylaxis of heart failure, fibrotic diseases, and related diseases, such as: lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidneydisease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of heart failure.

The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).

These and other features of the invention will be set forth in expanded form as the disclosure continues.

DESCRIPTION OF HIE INVENTION

The invention encompasses compounds of Formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them. In a first aspect, the present invention provides, inter alia, compounds of Formula

(I):

R1 ,R ²

R ^{5 R} > L- R ³

Rt Z

O

,NH

O.

A (R ⁸ )0-4

(R ⁹ )0-2

(I) or pharmaceutically acceptable salts thereof, wherein:

L is O- or NH-;

Ring A is 5- to 15 -membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O) _P , N, and NR ¹⁶ ;

R ¹ is Ci-3 alkyl substituted with 1 aryl or C ₃ -r, cycloalkyl substituent;

R ² is H; or R ¹ and R ² are taken together to be =CR ⁶ R ⁷ , wherein is a double bond; or R ¹ and R ² together with the carbon atom to which they are both attached form a dioxolanyl substituted with 0-1 ary l substituent;

R ³ is Ci-8 alkyl substituted with 0-5 R ⁴ , -(CR ^d R ^d )n-C ₃ -io-carbocyclyl substituted with 0-5 R ⁴ or -(CR ^d R ^d )n-3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O) _P , N, NR ^4a , and substituted with 0-5 R ⁴ ;

R ⁴ is halo, CN, -OH, -SFs, -S(=O) _P R ^C , CM alkyl substituted with 0-5 halo -OH, or -OCM alkyl substituents, -OCM alkyl substituted with 0-5 halo substituents, -(CR ^d R ^d ) l>n- Ca-io carbocyclyl substituted with 0-5 R ^e , or -(CR ^d R ^d )n-4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O) _P , N, and NR ^4a ;

R ^4a is H CM alkyl, or -S(=O) ₂ CF ₃ ;

R ³ is H, halo, -OH, CM alkyl substituted with 0-5 halo substituents, or -OCM alkyl substituted with 0-5 halo substituents;

R ⁶ is H, halo, CN, C1-7 alkyl substituted with 0-3 R ^6a , C2-7 alkenyl substituted with 0-3 R ^6a , C2-7 alkynyl substituted with 0-3 R ^6a , -C(==O)OR ^6b , -CONR ^6b R ^6b , -(CH2)n-C ₃ - 10 carbocyclyl substituted with 0-5 R ¹⁴ , or 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O) _P , N, or NR ^14a , and substituted with 0-5 R ¹⁴ ; R ^6a is halo, -OIL -OCM alkyl, CM alkyl, aryl, or C.3-6 cycloalkyl substituted with 0-4 halo substituents;

R ^6b is H, C i-4 alkyl substituted with 0-1 aryl, or C3-6 cycloalkyl substituted with 0-4 halo substituents;

R ⁷ is H or CM alkyl;

R ⁸ is =0, Ci-4alkyl, or -OC1-6 alkyl substituted with 0-5 halo, -OH, -OCM alkyl, C3-6 cycloalkyl, aryl, or 3- to 6-membered heterocyclyl substituents;

R ⁹ is halo, CN, -C(=O)OR ^b , -C(=O)NR ¹⁷ R ¹⁷ , Ci-s alkyl substituted with 0-4 R ⁱ⁰ and 0-2 R ¹¹ , C2-8 alkenyl substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ , C2-8 alkynyl substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ , -(A)o-i-C3-6 carbocyclyl substituted with 0-3 R ¹⁰ and 0-2 R“, -(A)O-I-C6-9 spirocycloalkyl substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ , or -(A)o-i-3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, N, and NR ^{l la} , and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

A is -O-, -S-, -CH2O-, or -OCH2-;

R ¹⁰ is halo, CN, CM alkyl, =0, -OH, or -OCM alkyl;

R ¹¹ is CM alkyl substituted with 0-5 R ¹² and 0-2 R ¹³ , -OR ^b , -NR ^a R ^a , -NR ^a C(=O)R ^b , - NR ^a C(=O)OR ^b , -NR ^a C(=O)NR ^a R ^a , -NR ^a S(=O) _P R ^c , -C(=O)R ^b , -C(=O)OR ^b , -C(=O)NR ^a R ^a , -C(=O)NR ^a S(=O) _P R ^c , -OC(=O)R ^b , -S(=O) _P R ^C , -S(=O) _P NR ^a R ^a , C3-9 carbocyclyl substituted with 0-5 R ^e , aryl substituted with 0-5 R ^e , 3- to 12- membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O)p, N and NR ¹⁵ , and substituted with 0-5 R ^e ;

R ^lla is H, CM alkyl substituted with 0-4 R ^llb , -C(=O)R ^b , -C(=O)OR ^b , -C(=O)NR ^a R ^a , C3-6 cycloalkyl substituted with 0-5 R ^e , aryl substituted with 0-5 R ^e , 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O)p, N and NR ¹⁵ , and substituted with 0-5 R ^e ;

R ^llb is halo, -OH, -C(=O)OH, -C(=0)0CM alkyl, or aryl;

R ¹² is halo, -C(=O)OR ^b , -C(=O)NR ^a R ^a , -C(=O)NR ^a OR ^b , CM alkyl substituted with 0-3 halo or -OH substituents, or C3-6 cycloalkyl; S(=O) _P R ^C , -(CH2)n-C3-io carbocyclyl substituted with 0-3 R ^e , or -(CH2)n-3- to 12- membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O) _P , and N, and substituted with 0-3 R ^e ;

R ¹⁴ is halo, CN, Ci-4 alkyl substituted with 0-3 halo substituents, -OCi-4 alkyl substituted with 0-3 halo substituents, -(CH2)n-NR ^a R ^a , -(CH2)n-aryl substi tuted with 0-3 R ^e , -O-aryl substituted with 0-3 R ^e , or -(CH2)n- 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O) _P , and N, and substituted with 0-3 R ^e ;

R ^14a is H, C(=O)Ci-4 alkyl, C1-3 alkyl substituted with 0-3 Si(Ci-3 alkyl)3 or aryl substituted with 0-2 halo substituents;

R ¹⁵ is H, C1-4 alkyl, or aryl; substituted with 0-4 R ¹⁷ together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O) _P , N, and NR ^lla , and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

R ^a is H, -OC1-6 alkyl, C1-6 alkyl substituted with 0-5 R ^e , C2-6 alkenyl substituted with 0-5 R ^e , C2-6 alkynyl substituted with 0-5 R ^e , -(CH2)n-C3-io carbocyclyl substituted with 0-5 R ^e , or -(CH2)n-3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O) _P , and N, and substituted with 0-5 R ^e ; or R ^a and R ^a together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl selected from O, S(==O) _P , and N, and substituted with 0-5 R ^e ;

R ^b is H, C1-6 alkyl substituted with 0-5 R ^e , C2-6 alkenyl substituted with 0-5 R ^e , C2-6 alkynyl substituted with 0-5 R ^e , -(CH2)n-C3-io carbocyclyl substituted with 0-5 R ^e , or -(CH2)n-3- to 12 -membered heterocyclyl selected from O, S(=O) _P , and N, and substituted with 0-5 R ^e ;

R ^c is C1-6 alkyl substituted with 0-5 R ^e , C2-6 alkenyl substituted with 0-5 R ^e , C2-6 alkynyl substituted with 0-5 R ^e , C3-6 carbocyclyl, or 3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S( ^:::: O) _P , and N;

R ^d is H, CM alkyl, or C3-6 cycloalkyl; R ^e is halo, CN, NO2, =0, C1-6 alkyl substituted with 0-5 R ^g , C2-6 alkenyl substituted with 0-5 R ^g , C2-6 alkynyl substituted with 0-5 R ^g , -(CH2)n-C3-io carbocyclyl substituted with 0-5 R ^g , -(CH ₂ )n-3- to 12-membered heterocyclyl comprising 1 -5 heteroatoms selected from O, S(=O) _P , and N, and substituted with 0-5 R ^g , -(CH2)nOR ^f , - C(=O)OR ^f , -C(==O)NR ^f R ^f , -NR ^f C(=O)R ^f , -S(=O) _P R ^f , -S(==O) _P NR ^f R ^f , - NR ^f S(=O) _P R ^f , -NR ^f C(=O)OR ^f , -OC(=O)NR ^f R ^f , or -(CH ₂ )nNR ^f R ^f ;

R ¹ is H, C1-6 alkyl substituted with 0-2 OH or -OC1-4 alkyl substituents, C3-6 cycloalkyl, aryl, or 3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, and N; or R ^f and R ^f together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, and N;

R ^g is halo, CN, -OH, Ci-e alkyl, C3-6 cycloalkyl, or aryl; n is zero, 1, 2, or 3; and p is zero, 1 , or 2.

In a second aspect within the scope of the first aspect, the present invention provides compounds of Formula (II): or pharmaceutically acceptable salts thereof, wherein:

Ring A is 5- to 14-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O) _P , N, and NR ¹⁶ ;

R ⁴ is halo, Ci-4 alkyl substituted with 0-4 halo substituents, -OCi-t alkyl substituted with 0-4 halo, or -S(=O)pCi-4 alkyl substituted with 0-4 halo substituents;

R ⁶ is halo, Ci-7 alkyl substituted with 0-3 R ^6a , C3-6 cycloalkyl substituted with 0-3 R ¹⁴ , C3-

6 cycloalkenyl substituted with 0-3 R ¹⁴ , Ce-io aryl substituted with 0-3 R ¹⁴ , or 4- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S(=O)p, N, and NR ^14a , and substituted with 0-3 R ¹⁴ ;

R ^6a is halo, -OH, C3-6 cycloalkyl, or aryl;

R ⁷ is II or C1-3 alkyl;

R ⁸ is =0, or -OC1-4 alkyl substituted with 0-5 halo, -OH, -OC1-4 alkyl, or aryl substituents;

R ⁹ is halo, CN, -C(=O)OR ^b , -C(=O)NR ¹⁷ R ¹⁷ , C1-7 alkyl substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ , C2-7 alkenyl substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ , C2-7 alkynyl substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ , phenyl substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ or 3- to 12- membered heterocyclyl comprising 1-5 heteroatoms selected from O, S( ^:::: O)p, and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

R ¹⁰ is halo, CN, C1-4 alkyl, -OH, or -OC1-4 alkyl;

R ¹¹ is C1-3 alkyl substituted with 0-1 R ¹² and 0-1 R ¹³ , -OR ^b , -NR ^a R ^a , -C(=O)R ^b , -C(=O)OR ^b , -C(=O)NR ^a R ^a , -C(=O)NR ^a S(=O) _P R ^c , -OC(=O)R ^b , -S(=O) _P R ^C , -S(=O) _P NR ^a R ^a , C3-6 cycloalkyl substituted wdth 0-5 R ^c , 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O)p, N and NR ¹⁵ , and substituted with 0-5 R ^e ;

R ¹² is halo, -C(=O)OR ^b , -C(=O)NHR ^a , or C1-4 alkyd substituted with 0-3 halo or OH substituents;

R ¹⁴ is halo, CN, C1-4 alkyl substituted with 0-3 halo substituents, -OC1-4 alkyl substituted with 0-3 halo substituents;

R ^14a is H, -C(=O)Ci-4 alkyl, or C1-3 alkyl substituted with 0-3 aryl substituted with 0-2 halo substituents;

R ¹⁶ is H, C1-3 alkyl substituted with 0-4 R ^16a , or ary l substituted with 0-4 R ^16a ;

R ^16a is halo, C1-3 alkyl, OR ^b , C(=O)OR ^b or -S(=O) _P R ^C ;

R ¹⁷ is H or C1-3 alkyl; or R ¹⁷ and R ¹⁷ together with the nitrogen atom to which they are both attached form a 3- to 10-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, N, and NR ^lla , and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

R ^a is H, C1-5 alkyl substituted with 0-5 R ^e , C2-5 alkenyl substituted with 0-5 R ^e , C2-5 alkynyl substituted with 0-5 R ^e , -(CH2)n-C3-io carbocyclyl substituted with 0-5 R ^e , or -(CH0n-3- to 10-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, and N, and substituted with 0-5 R ^e ; or R ^a and R ^a together with the nitrogen atom to which they are both attached form a 3- to 10-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O) _P , and N, and substituted with 0-5 R ^e ;

R ^b is H, Ci-5 alkyl substituted with 0-5 R ^e , C2-5 alkenyl substituted with 0-5 R ^e , C2-5 alkynyl substituted with 0-5 R ^e , -(CH2)n-C3-io carbocyclyl substituted with 0-5 R ^e , or -(CH2)n- 3- to 10-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, and N, and substituted with 0-5 R ^e ;

R ^c is C1-5 alkyl substituted with 0-5 R ^e , C2-5 alkenyl substituted with 0-5 R ^e , C2-5 alkynyl substituted with 0-5 R ^e , C3-6 carbocyclyl, or 3- to 10-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, and N;

R ^e is halo, CN, =O, Ci-e alkyl substituted with 0-5 R ^g , C2-6 alkenyl substituted with 0-5 R ^g , C2-6 alkynyl substituted with 0-5 R ^g , -(CH2)n-C.3-6 carbocyclyl substituted with 0 5 R ^g , -(CH2)n- 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O)p, and N, and substituted with 0-5 R ^g , -(CH2)nOR ^f , -

R ^f is H, C1-5 alkyl, C3-6 cycloalkyl, or aryl; or R ^f and R ^f together with the nitrogen atom to which they are both attached form a heterocyclyl;

R ^g is halo, CN, -OH, C1-6 alkyl, C3-6 cycloalkyl, or aryl; n is zero, 1 , 2, or 3; and p is zero, 1, or 2.

In a third aspect within the scope of the second aspect, the present invention provides compounds of Formula (III): (HI) or pharmaceutically acceptable salts thereof, wherein:

R ⁴ is halo or C1-3 alkyl substituted with 0-4 halo substituents;

R ⁶ is halo, C1-4 alkyl substituted with 0-3 R ^6a , C.3-6 cycloalkyl, phenyl substituted with 0-3 R ¹⁴ , naphthyl, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;

R ^6a is halo, -OH, or C3-6 cycloalkyl;

R ⁷ is H;

R ⁸ is -OC1-4 alkyl substituted with 0-5 halo or -OH substituents;

R ⁹ is halo, substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ , C2-4 alkynyl substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ , or phenyl substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ , or 3- to 9-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O) _P , and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

R ¹⁰ is halo, CN, C1-4 alkyl, or -OH;

R ¹¹ is -OR ^b , -C(=O)OR ^b , -C(=O)NR ^a R ^a , C1-3 alkyl substituted with 0-1 R ¹² and 0-1 R ¹³ or C3-6 cycloalkyl substituted with 0-5 R ^e ;

R ¹² is halo, -C(=O)OR ^b , or C1-3 alkyl substituted with 0-3 halo or OH substituents;

R ¹⁷ and R ¹⁷ together with the nitrogen atom to which they are both attached form a 3- to 10-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S( ^: =O) _P , N, and NR ^lla , and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ; R ^a is H, C1-6 alkyl substituted with 0-5 R ^e , -(CH2)n-phenyl substituted with 0-5 R ^e , or -(CH2)n-heterocyclyl substituted with 0-5 R ^e ; or R ^a and R ^a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-5 R ^s ;

R ^b is H, C1-6 alkyl substituted with 0-5 R ^e , -(CH2.)O-I-C3-6 cycloalkyl substituted with 0-5 R ^e , -(CH2)o-i-phenyl substituted with 0-5 R ^e , or -(CHzJn-heterocyclyl substituted with 0-5 R ^e ;

R ^e is halo, CN, =0, C(=O)OH, C1-6 alkyl, (CH ₂ )nOR ^f or -S(=O) _P R ^f ;

R ^f is H or C1-3 alkyl and n is zero, 1, 2, or 3.

In a fourth aspect within the scope of the third aspect, the present invention provides compounds of Formula (III), or pharmaceutically acceptable salts thereof, wherein:

R ⁴ is halo or Ci-4 alkyl substituted with 0-4 F substituents;

R ⁶ is Ci-3 alkyl substituted with 0-3 R ^6a , C3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, S, and N;

R ^6a is halo; substituted with 0-4 halo or OH substituents; ¹ 5 ■

R ¹⁰ is halo;

R ¹¹ is -C(=O)OR ^b or C1-2 alkyl substituted with 0-1 R ¹² and 0-1 R ¹³ ;

R ¹² is halo, -C(=O)OR ^b , or C1-2 alkyl substituted with 0-3 halo or OH substituents;

R ¹³ is - OR ^b , -NR ^a R ^a , -OC(=O)NR ^a R ^a , or -S(=O) _P R ^C ;

R ^a is H, C1-5 alkyl substituted with 0-4 R ^e , -(CHzJn-phenyl substituted with 0-4 R ^e , or -(CH2)n-heterocyclyl substituted with 0-4 R ^e ; or R ^a and R ^a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-4 R ^e ;

R ^b is H, C1-5 alkyl substituted with 0-4 R ^e , -(CH2)n-phenyl substituted with 0-4 R ^e , or -(CH2)n-heterocyclyl substituted w ⁷ ith 0-4 R ^c ; R ^c is Ci-5 alkyl substituted with 0-4 R ^e ;

R ^e is halo, CN, =0, Ci-s alkyl; and n is zero, l, or 2.

In a fifth aspect within the scope of the fourth aspect, the present invention provides compounds of Formula (III), or pharmaceutically acceptable salts thereof, wherein:

R ⁴ is F or CF3;

R ⁶ is CF3, cyclopropyl, phenyl, or

R ⁸ is -OCi-4alkyl substituted with 0-2 OH substituents;

Rl°

R ⁹ is R ¹¹

R ¹⁰ is F;

R ¹¹ is -C(=O)O

R ¹² is halo, -C(

R ¹³ is -OH or -OC(=O)NR ^a R ^a ;

R ^a is H, Ci-4 alkyl, C3-6 cycloalkyl, or phenyl; and

R ^b is H or C1-3 alkyl.

In a sixth aspect within the scope of the second aspect, the present inven tion provides compounds of Formula (III):

or pharmaceutically acceptable salts thereof, wherein:

A (R ⁸ )0-2

(R ⁹ )0-2 is

R ⁴ is halo or Ci-4 alkyl substituted with 0-4 halo;

R ⁶ is Ci-4 alkyl substituted with 0-3 R ^6a , C3-6 cycloalkyl, phenyl substituted with 0-3 R ¹⁴ , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;

R ^6a is halo;

R ⁷ is H;

R ⁸ is -OC1-4 alkyl substituted with 0-5 halo or OH substituents;

R ⁹ is halo, CN, CM alkyl substituted with 0-3 R ¹⁰ , or phenyl substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

R ¹⁰ is halo, CN, or CM alkyl;

R ¹¹ is -C(=O)OR ^b ;R ¹⁶ is H, CM alkyl substituted with 0-4 R ^16a , or phenyl substituted with 0-4

R ^16a is halo,

R ^b is H or Ci -4 alkyl; and

R ^c is C1-3 alkyl. In a seventh aspect within the scope of the second aspect, the present invention provides compounds of Formula (III): or pharmaceutically acceptable salts thereof, wherein:

R ⁴ is halo or Ci-4 alkyl substituted with 0-4 halo substituents;

R ⁶ is Ci-4 alkyl substituted with 0-3 R ^6a , C3-6 cycloalkyl, phenyl substituted with 0-3 R ¹⁴ , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;

R ⁷ is H;

R ⁸ is -OC1-4 alkyl substituted with 0-5 halo or OH substituents;

R ⁹ is halo, CN, or C1-4 alkyl substituted with 0-3 R ¹⁰ ;

R ¹⁰ is halo;

R ¹⁶ is H, C1-4 alkyl substituted with 0-4 R ', or aryl substituted with 0-4 R ^16a ; and

R ^16a is halo, CM alkyl, or C(=O)OR ^b . In an eighth aspect within the scope of the second aspect, the present invention provides compounds of Formula (III): or pharmaceutically acceptable salts thereof, wherein:

A (R ⁸ )0-2

(R ⁹ )0-2 is

R ⁴ is halo or Ci-4 alkyl substituted with 0-4 halo substituents;

R ⁶ is Ci-4 alkyl substituted with 0-3 R ^6a , Ca-6 cycloalkyl, phenyl substituted with 0-3 R ¹⁴ , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;

R ⁷ is H;

R ⁸ is -OCi-4 alkyl substituted with 0-5 halo or OH substituents;

R ⁹ is halo or CN;

R ¹⁶ is H, Ci-4 alkyl, -S(=O) _P R ^C , or Ci-4 alkyl substituted with 0-4 R ^16a ; and

R ^16a is halo, Ci-4 alkyl, -OH, OC1-3 alkyl, or -S(=O)pCi-3 alkyl.

In a ninth aspect within the scope of the second aspect, the present invention provides compounds of Formula (III): A (R ⁸ )O-2

(R ⁹ )0-2

(HI) or pharmaceutically acceptable salts thereof, wherein:

R ⁴ is halo or Ci-4 alkyl substituted with 0-4 halo;

R ⁶ is Ci-4 alkyl substituted with 0-3 R ^6a , C3-6 cycloalkyl, phenyl substituted with 0-3 R ¹⁴ , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;

R ⁷ is H;

R ⁸ is -OC1-4 alkyl substituted with 0-5 halo or OH substituents;

R ⁹ is halo or CN;

R ¹⁶ is H or C1-4 alkyl substituted with 0-4 R ^16a ; and

R ^16a is halo.

In a tenth aspect within the scope of the third aspect, the present invention provides compounds of Formula (IV): or pharmaceutically acceptable salts thereof, wherein:

R ¹⁰ is halo, CN, C1-4 alkyl, or -OH;

R ¹¹ is -OR ^b , -C(=O)0R ^b , -C(=O)NR ^a R ^a , C1-3 alkyl substituted with 0-1 R ¹³ , or C3-6 cycloalkyl substituted with 0-5 R ^e ;

R ¹³ is -OH;

R ¹⁷ is II or C1-2 alkyl substituted with 0-3 R ⁱ⁰ and 0-2 R ¹¹ ; or R ¹⁷ and R ¹⁷ together with the nitrogen atom to which they are both attached form

R ^a is H or Ci-3 alkyl;

R ^b is H, Ci-3 alkyl substituted with 0-5 R ^e , or -(CH2)O-I-C3-6 cycloalkyl substituted with

0-5 R ^e ; and

R ^e is halo, CN, =0, C(=0)0H, Ci-e alkyl, CHzOH, or -S(=O) ₂ Ci-3 alkyl.

In an eleventh aspect within the scope of the first aspect, the present invention provides compounds of Fonnula (V):

R ^{7 RS} A

H N

R ³

O

NH

R ⁸

O' N

R ⁹

(V) or pharmaceutically acceptable salts thereof, wherein:

R ³ is C1-4 alkyl substituted with 0-3 R ⁴ , -(CHR ^d )n-C.3-6-carbocyclyl substituted with 0-3 R ⁴ ;

R ⁴ is halo, CN, or C1-4 alkyl substituted with 0-5 halo substituents;

R ⁶ is halo, C1-4 alkyl substituted with 0-3 R ^6a , C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N, and substituted with 0-5 R ¹⁴ ;

R ^6a is halo or OH;

R ⁷ is H;

R ⁸ is -OC1-3 alkyl;

(R ¹¹ )o-i (R ^1o )o.i (R ¹¹ ) ₀ -i (R ¹¹ )o-i , or

R ¹⁰ is halo, CN, Ci-4 alkyl, or -OH:

R ¹¹ is Ci-3 alkyl substituted with 0-3 R ¹² and 0-2 R ¹³ , CN, or OR ^b ;

R ¹² is halo;

R ¹³ is - OR ^b or C.3-6 carbocyclyl;

R ¹⁴ is halo, CN, or C1-4 alkyl substituted with 0-3 halo substituents;

R ^b is H or C1-3 alkyl substituted with 0-5 R ^e ;

R ^d is H or Ci-4 alkyl;

R ^e is halo or OH; and n is zero or 1 .

In a twelfth aspect within the scope of the first aspect, the present invention provides compounds of Formula (VI): or pharmaceutically acceptable salts thereof, wherein:

R ³ is Ci-4 alkyl substituted with 0-3 R ⁴ , -(CHR ^d )n-C.3-6-carbocyclyl substituted with 0-3 R ⁴ ; R ⁴ is halo, CN, or Ci-4 alkyl substituted with 0-5 halo substituents;

R ⁶ is halo, Ci-4 alkyl substituted with 0-3 R ^6a , C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N, and substituted wi th 0-5 R ¹⁴ ;

R ^6a is halo or -OH;

R ⁷ is H;

R ⁸ is C1-3 alkyl;

R ¹⁰ is halo, CN, C1-4 alkyl, or -OH;

R ¹¹ is C1-3 alkyl substituted with 0-3 R ¹² and 0-2 R ¹³ , CN, or OR ^b ;

R ¹² is halo;

R ¹³ is - OR ^b or C3-6 carbocyclyl;

R ¹⁴ is halo, CN, or C1-4 alkyl substituted with 0-3 halo substituents;

R ^b is H or Ci-3 alkyl substituted with 0-5 R ^e ;

R ^d is H or Ci-4 alkyl;

R ^e is halo or OH; and n is zero or 1 .

In a thirteenth aspect within the scope of the first aspect, the present invention provides compounds of Formula (VII): or pharmaceutically acceptable salts thereof, wherein:

R ³ is -(CHR ^d )n-C3-w-carbocyclyl substituted with 0-5 R ⁴ ;

R ⁴ is halo, CN, Ci-4 alkyl substituted with 0-5 halo or OH substituents, -OCi-4 alkyl substituted with 0-5 halo substituents, or -S(=O) _P R ^C ;

R ⁶ is Ci-4 alkyl substituted with 0-3 R ^6a or C3-6 cycloalkyl substituted with 0-5 R ¹⁴ ;

R ^6a is halo;

R ⁷ is H;

R ⁸ is C1-3 alkyl or -OC1-3 alkyl;

R ⁹ is -C(=O)NR ¹⁷ R ¹⁷ , C3-6 carbocyclyl substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ , or 5- to 12- membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(=O)p, N, and NR ^lla , and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

R ¹⁰ is halo, CN, C1-4 alkyl, =0, -OH, or -OC1-4 alkyl;

R ¹¹ is C1-4 alkyl substituted with 0-5 R ¹² and 0-2 R ¹³ , -S(=O) _P R ^C , C3-6 cycloalkyl substituted with 0-5 R ^e ;

R ^lla is H, Ci-4 alkyl substituted with 0-4 R ^{l lb} , -C(=O)R ^b , -C(=O)OR ^b , -C(=O)NR ^a R ^a , C3-6 cycloalkyl substituted with 0-5 R ^e , aryl substituted with 0-5 R ^e , 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O)p, N and NR ¹⁵ , and substituted with 0-5 R ^e ;

Rllb is halo, -OH, -C(=O)OH, -C(=O)OCi-4 alkyl, or aryl; R ¹² is halo, -C(=O)OR ^b , Ci-4 alkyl substituted with 0-3 halo or OH substituents, or C.i-6 cycloalkyl;

R ¹³ is -OR ^b , -NR ^a R ^a , -OC(=O)NR ^a R ^a ,;

R ¹⁴ is halo;

R ¹⁷ is H or Ci-4 alkyl substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ; or R ¹⁷ and R ¹⁷ together with the nitrogen atom to which they are both attached form a 3- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O) _P , N, and NR ^lia , and substituted with 0-3 R ¹⁰ and 0-2 R ¹¹ ;

R ^a is H, Ci -6 alkyl substituted with 0-5 R ^e , Ca-w carbocyclyl substituted with 0-5 R ^e ; or R ^a and R ^a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-5 R ^e ;

R ^b is H or Ci-4 alkyl substituted with 0-5 R ^e ;

R ^c is Ci-4 alkyl;

R ^d is H or Ci-3 alkyl;

R ^e is halo, CN, NO2, =0, Ci-e alkyl substituted with 0-5 R ^g , C3-6 cycloalkyl, or -S(=O) _P R ^f ;

R ^f is H or C1-4 alkyl,

R ^g is halo, CN, -OH, or Ci-4 alkyl; n is zero or 1; and p is zero, 1, or 2.

In a fourteenth aspect w'ithin the scope of the twelfth aspect, the present invention provides compounds of Formula (VII) or pharmaceutically acceptable salts thereof, wherein:

R ³ is -CHR ^d -C3-6 cycloalkyl substituted with 0-2 R ⁴ or phenyl substituted with 0-2 R ⁴ ; R ⁴ is F, CH3, or CF ₃ ;

R ⁶ is C1-4 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl substituted with 0- 3 halo substituents;

R ⁷ is H;

R ⁸ is -OCII3;

R ¹⁰ is halo;

R ¹¹ is Ci-4 alkyl substituted with 0-3 R ¹² and 0-2 R ¹³ , -S(=O) _P R ^C , or C3-6 cycloalkyl substituted with 0-3 R ^e ;

R ^lla is H or CM alkyl substituted with 0-3 R ^nb ;

R ^llb is -OH;

R ¹² is CM alkyl substituted with 0-3 halo substituents;

R ¹³ is -OC(=O)NR ^a R ^a ;

R ¹⁴ is halo;

R ¹⁷ is H or CM alkyl substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ ; or R ¹⁷ and R ¹⁷ together with the nitrogen atom to which they are both attached fonn a 3- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(=O)p, N, and NR ^lla , and substituted with 0-2 R ¹⁰ and 0-2 R ¹¹ ;

R ^a is H, Ci-4 alkyl substituted with 0-4 R ^e , C3-10 carbocyclyl substituted with 0-4 R ^e ; or R ^a and R ^a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-4 R ^e ;

R ^b is H or Ci -3 alkyl;

R ^c is C1-3 alkyl;

R ^d is C1-2 alkyl;

R ^e is CM alkyl, C3-6 cycloalkyl, or -S( ^:=: O)pR ^f ;

R ^f is CM alkyl; and p is zero, 1, or 2.

In one embodiment of Formula (I), R ¹ and R ² combined are =CR ⁶ R ⁷ , R ⁶ and R ⁷ are both methyl. In another embodiment of Formula (I), R ¹ and R ² combined are =CR ⁶ R ⁷ ; R ⁶ is CFa; R ⁷ is H.

In another embodim ent of Formula (I), R ¹ and R ² combined are =CR ⁶ R ⁷ ; R ⁶ is halo; R ⁷ is II.

In another embodiment of Fonnula (I), R ¹ and R ² combined are =CR ⁶ R ⁷ ; R ⁶ is phenyl substituted with 0-1 R ¹⁴ ; R ⁷ is H; R ¹⁴ is halo, -OCi-4 alkyl, or phenyl.

In another embodiment of Fonnula (I), R ¹ and R ² combined are =CR ⁶ R ⁷ ; R ⁶ is 5- membered heterocyclyl comprising 1-3 heteroatoms selected from O and N; R ⁷ is II.

In another embodiment of Formula (I), R ¹ and R ² combined are =CR ⁶ R ⁷ ; R ⁶ is C.3-

6 cycloalkyl; R ⁷ is H.

In another embodiment of Formula (I), R ¹ and R ² combined are =CR ⁶ R'; R ⁶ is - CH2-C3-6 cycloalkyl substituted with halo; R ⁷ is H.

In another embodiment of Formula (I), R ¹ and R ² combined are =CR ⁶ R ⁷ ; R ⁶ is cyclopropyl; R ⁷ is H.

In another embodiment of Formula (I), R ³ is Ci-e alkyl.

In another embodiment of Formula (I), R ³ is methyl, ethyl, propyl, or butyl, or pentyl.

H,C

In another embodiment of Fonnula (I), R ³ is .

In another embodiment of Formula (I), R ³ is C3-6 cycloalkyl substituted with 0-2

R ⁴ .

In ano ther embodiment of Formula (I), R ³ is C3-6 cycloalkenyl substituted with 0-2

R ⁴ .

In another embodiment of Fonnula (I), R ³ is

In another embodiment of Formula (I), R ³ is -(CR ^d R ^d )i-2-phenyl substituted with 0-2 R ⁴ ; R ⁴ is halo, CF3 or OCF3; R ^d is H or methyl. In another embodiment of Formula (I), R ³ is -(CHR ^d )-C3-6 cycloalkyl substituted with 0-2 R ⁴ ; R ⁴ is halo or C1-2 alkyl; Rd is H or C1-2 alkyl .

In another embodiment of Fonnula halo or C1-3 alkyl. b>

R ⁴

In another embodiment of Formula (I), R ³ is ; R ⁴ is C1-2 alkyl.

( ^R4 )O-I

In another embodiment of Formula (I), R ³ is ^1/Vx ' ^v V' ; R ⁴ is halo or CN.

In another embodiment of Formula (I), R ³ is -(CR ^d R ^d )i-2-5-membered heterocyclyl comprising 1 -2 heteroatoms selected from O and N; R ^d is II or methyl.

In another embodiment of Fonnula (I), R ⁴ is halo, CN, C1-2 alkyl substituted with 0-3 halo substituents.

In another embodiment of Fonnula (I), R ³ is cyclopropyl, cyclobutyl, cyclopentyl substituted with 0-1 R ⁴ , or cyclohexyl; R ⁴ is CN or C1-2 alkyl.

In one embodiment of Formula (I), R ⁵ is H, halo, or OH.

In one embodiment of Fonnula (I), R ⁶ is CH3 or CF3

In another embodiment of Formula (I), R ⁶ is C3-6 cycloalkyl substituted with 0-3 halo substituents.

In another embodiment of Formula (I), R ⁶ is 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S(=O)p, N, and NR ¹³ , and substituted with 0-3 R ¹⁴ ; R ¹⁴ is C1-3 alkyl substituted with 0-3 halo substituents.

In one embodiment of Formula (I), R ⁷ is H or CHs. In one embodiment of Formula (I), R ⁸ is halo or -OCFfe.In one embodiment of .( ^R4 ) ₂ R ¹⁴

N=<

Formula (V), R ³ is ; R ⁴ is halo, CF3, or -OCF3; R ⁶ is C3-6 cycloalkyl or C1-3 alkyl substituted with 0-3 R ^6a ; R ^6a is halo; R ¹⁴ is C1-2 alkyl substituted with 0-3 halo substituents; R ⁷ is H; R ⁸ is -OC1-3 alkyl substituted with 0-1 CF3 or -OCH3 substituent; R ⁹ is

N

/ N=Z

JR ¹¹ )O-I

° NC/S ^)l-2 x ₁ Z ^N '' _> O> 0-2

VxF “(R ¹⁰ )o-i -"O"(R ¹ °)0-2

(R ^1C )O-2 0-2 (R ¹¹ )o-i (R ¹ °)o..i (R ¹¹ )o-i _{; 0} r y-\ (R ^IO ) _O -2

N

^N 'r/^

( ^{R1 1} )O-I ; R ¹⁰ is Ci-4 alkyl, CN, or OH; R ¹¹ is C1-3 alkyl substituted with 0-3 R ¹ and 0-2 R ¹³ ; R ¹² is halo; and R ¹³ is OH or C3-6 cycloalkyl.

In one embodiment of Formula (V), R ³ is ; R ⁴ is halo, CF3, or -

R ¹⁴

N=^

OCF3; R ⁶ is C3-6 cycloalkyl or C1-3 alkyl substituted with 0-3 R ^6a ; R ^6a is halo; R ¹⁴ is C1-2 alkyl substituted with 0-3 halo substituents; R ⁷ is H; R ⁸ is -OC1-3 alkyl substituted with 0-1 CF3 or -OCH3 substituents; R ⁹ is

N 1 N=*

(R ¹¹ )o-i i

CX y N

X ^N ^0-2

~(R ¹ °)o-i

-~o (R ¹ °)O-2

(R ^1O )O-2 0-2

5 (R ¹¹ )o-i (R ^1O )O-I (R ¹¹ )o-i , or

(R ¹⁹ )O-2

N _x //x

N ' \

L^\O

(R ¹¹ )o-i ; R ¹⁰ is Ci-4 alkyl, CN, or OH; R ¹¹ is Ci-a alkyl substituted with 0-3 R 1 ¹ 2 and 0-2 R ¹³ ; R ¹² is halo; and R ¹³ is OH or Ca-e cycloalkyl.

In another embodiment of Formula (V), R ³ is R ^d or ; R ⁴ is

R ¹⁴ N=( .0 halo, CN, or C1-2 alkyl substituted with 0-3 halo; R ^d is C1-2 alkyl; R ⁶ is , Ca-e cycloalkyl substituted with 0-3 R ^6a , or Ci-a alkyl substituted with 0-3 R ^6a ; R ^6a is halo or OH; R ¹⁴ is Ci-2 alkyl substituted with 0-3 halo substituents; R ⁷ is H; R ⁸ is -OC1-2 alkyl substituted with 0-1 Ca-e cycloalkyl substituent; R ⁹ is alkyl or OH; R ¹¹ is Ci-a alkyl substituted with 0-3 R ¹² and 0-2 R ¹³ ; R ¹² is halo; and R ^L3 is OH or C.a-6 cycloalkyl.

For a compound of Formula (I), the scope of any instance of a variable substituent, including R ¹ , R ² , R ³ , R ⁴ , R ^4a , R ⁵ , R ⁶ , R ^6a , R ^6b , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^lla , R ^llb , R ¹² , R ¹³ , R ¹⁴ , R ^14a , R ¹⁵ , R ¹⁶ , R ^16a , R ¹⁷ , R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , and R ^g can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects.

Unless specified otherwise, these terms have the following meanings.

“Halo” includes fluoro, chloro, bromo, and iodo. “Alkyl” or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci to Cio alkyl" or "Ci-io alkyl" (or alkylene), is intended to include Ci, C2, C3, C4, C5, Ce, C7, Cs, Cs>, and Cio alkyl groups. Additionally, for example, "Ci to Ce alkyl" or "Ci-Ce alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, /-butyl), and pentyd (e.g., n-pentyl, isopentyd, neopentyl). When "Co alkyl" or "Co alkylene" is used, it is intended to denote a direct bond. "Alkyl" also includes deuteroalkyl such as CDs.

"Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carboncarbon double bonds that may ⁷ occur in any stable point along the chain. For example, "C2 to Ce alkenyl" or "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5, and Ce alkenyl groups; such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

"Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably ⁷ one to three, carboncarbon triple bonds that may occur in any stable point along the chain. For example, "C2 to Ce alkynyl" or "C2-6 alkynyl" (or alkynylene), is intended to include C2, Ci, C4, Cs, and Ce alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

"Carbocycle", "carbocyclyl", or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11 -, 12-, or 13 -membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocyclyl (e.g;, [2.2.2|bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge ahvays converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for tiie ring may also be present on the bridge. When the term "carbocyclyl" is used, it is intended to include "aryl," “cycloalkyl,” “spirocycloalkyl”, and “cycloalkenyl.” Preferred carbocyclyls, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.

“Cycloalkyl” is intended to mean cyclized alkyl groups, including mono-, bi- or multicyclic ring systems. "C3 to C? cycloalkyl" or "C3-7 cycloalkyl" is intended to include C3, C4, C5, Ce, and C? cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls include 1 -decalinyl, norbomyl and adamantyl.

"Cycloalkenyl" is intended to mean cyclized alkenyl groups, including mono- or multi-cyclic ring systems that contain one or more double bonds in at least one ring: although, if there is more than one, th e doubl e bonds cann ot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl," as defined herein). "C3 to C? cycloalkenyl" or "C.3-7 cycloalkenyl" is intended to include C3, C4, C5, Ce, and C7 cycloalkenyl groups.

"Spirocycloalkyl" is intended to mean hydrocarbon bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.

“Bicyclic carbocyclyl " or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

"Aryl" groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl .. Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley’s Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997).

“Benzyl" is intended to mean a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted with 1 to 5 groups, preferably 1 to 3 groups.

“Heterocycle”, "heterocyclyl" or "heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-., or 15-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N— >0 and S(O) _P , wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (z. e. , N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocyclyl may optionally be quatemized. It is preferred that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocyclyl is not more than 1. Bridged rings are also included in the definition of heterocyclyl. When the term "heterocyclyl" is used, it is intended to include heteroaryl.

Examples of heterocyclyls include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a/7-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2/7,677-1,5,2- dithiazinyl, dihydrofuro[2,3-6]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 177-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3 -oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2- pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4Zf-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 677-1,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocyclyls.

“Bicyclic heterocyclyl" "bicyclic heterocyclyl" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5 -membered heteroaryl ring, a 6- membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocyclyl, a 6-membered heterocyclyl or a carbocyclyl (provided the first ring is not benzo when the second ring is a carbocyclyl).

The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substi tuted on carbon or on a nitrogen atom if the resulting compotmd is stable. It is preferred that when the total number of S and O atoms in the heterocyclyl exceeds 1 , then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocyclyl is not more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, IH-indazolyl, benzimidazolyl, 1 ,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 5, 6,7,8- tetrahydroquinolinyl, 2,3 -dihydrobenzofuranyl , chromanyl, 1 ,2,3,4- tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.

“Heteroaryl” is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fiiryl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1 ,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaiyl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N-+O and S(O) _P , wherein p is 0, 1 or 2).

As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i. e. , within) of the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g. , mCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (NL.1O) derivative.

When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compotmd of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Throughout the specification and the appended claims, a given chemical formula or nam e shall encompass all stereo and optical isom ers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The tenn "diastereomer" refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.

The invention includes all tautomeric forms of the compounds, atropi somers and rotational isomers.

All processes used to prepare compotmds of the present invention and intermediates made therein are considered to be part of the present invention. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom(s). The isomeric descriptors "R" and "S" are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the li terature (TUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

The term "chiral" refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image. The term "homochiral" refers to a state of enantiomeric purity. The term "optical activity" refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light.

The invention is in tended to include all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³ C and ¹⁴ C. Isotopically- labeled compounds of the in vention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwi se employed . Such compounds may have a vari ety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

BIOLOGICAL METHODS

RXFP1 Cyclic Adenosine Monophosphate (cAMP) Assays. Human embiyonic kidney cells 293 (HEK293) cells and HEK293 cells stably expressing human RXFP1 , were cultured in MEM medium supplemented with 10% qualified FBS, and 300 L lg/ml hygromycin (Life Technologies). Cells were dissociated and suspended in assay buffer. The assay buffer was BBSS buffer (with calcium and magnesium) containing 20 mM HEPES, 0.05% BSA, and 0.5 mM IBMX. Cells (3000 cells per well, except 1500 cell per well for HEK293 cells stably expressing human RXFP1) were added to 384-well Proxiplates (Perkin-Elmer). Cells were immediately treated with test compounds in DMSO (2% final) at final concentrations in the range of 0.010 nM to 50 DM. Cells were incubated for 30 min at room temperature. The level of intracellular cAMP was determined using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to manufacturer’s instructions. Solutions of cryptate conjugated anti-cAMP and d2 fluorophore-labelled cAMP were made in a supplied lysis buffer separately. Upon completion of the reaction, the cells were lysed with equal volume of the d2-cAMP solution and anti-cAMP solution. After a 1 h room temperature incubation, time-resolved fluorescence intensity was measured using the Envision (Perkin-Elmer) at 400 nm excitation and dual emission at 590 nm and 665 nm. A calibration curve was constructed with an external cAMP standard at concentrations ranging from 2.7 DM to 0.1 pM by plotting the fluorescent intensity ratio from 665 nm emission to the intensity from the 590 nm emission against cAMP concentrations. The potency and activity of a compound to inhibit cAMP production was then determined by fitting to a 4-parametric logistic equation from a plot of cAMP level versus compotmd concentrations.

The examples disclosed below were tested in the human RXFP1 (hRXFPl) HEK293 cAMP assay described above and found to have agonist activity. Table 1 lists EC50 values in the hRXFPl HEK293 cAMP assay measured for the examples.

Table 1 cAMP hRXFPl HEK293

Example Assay

EC50 (nM)

1 710

2 660

3 440

4 5,000

5 1,100

6 1,100

7 1,200

8 1,300

9 1,400 cAMP hRXFPl HEK293

Example Assay EC50 (nM)

10 5,000

1 1 940

12 4,600

13 1,700

14 2,900

15 3,500

16 3,800

17 4,500

18 2,100

19 4,000

20 250

21 80

22 1,700

23 2,400

24 1,000

25 33

26 76

27 290

28 34

29 136

30 109

31 162

32 166

33 4,400

34 3,000

35 42 cAMP hRXFPl HEK293

Example Assay EC50 (nM)

36 63

37 95

38 63

39 110

40 39

41 770

42 8.1

43 9.4

44 360

45 560

46 65

47 200

48 880

49 153

50 129

51 1,300

52 1,300

53 1,600

54 1,200

55 360

56 2,800

57 3,900

58 3,000

59 870

60 210

61 3.7 cAMP hRXFPl HEK293

Example Assay EC50 (nM)

62 2,400

63 120

65 21

66 1.3

67 300

68 130

69 1.5

70 2.3

71 28

72 160

73 24

74 3.5

75 8.1

76 65

77 71

78 140

79 230

80 260

81 2,300

82 660

83 2,400

84 330

85 200

86 240

87 630

88 110 cAMP hRXFPl HEK293

Example Assay EC50 (nM)

89 230

90 2,400

91 4,700

92 4,800

93 1,700

94 1,200

95 1,600

96 1.4

97 3.1

99 3.2

TOO 3.4

101 1.6

102 2.5

103 3.4

104 4.0

105 1.2

106 1.8

107 2.6

108 3.5

109 2.7

110 3.5

111 3.6

112 3.9

113 4.3

114 1.2

115 2.1 cAMP hRXFPl HEK293

Example Assay EC50 (nM)

116 2.7

117 3.5

118 4.0

119 3.9

120 4.8

121 1.3

122 2.6

123 3.1

124 3.6

125 3.6

126 4.2

127 4.3

128 4.9

129 5.0

130 1.2

131 1.6

132 1.8

133 2.1

134 3.2

135 4.0

136 2.5

137 3.0

138 4.8

139 2.9

140 3.2

141 3.4 cAMP hRXFPl HEK293

Example Assay EC50 (nM)

142 2.2

143 2.9

144 2.0

145 3.0

146 3.5

147 3.8

148 0.5

149 2.7

150 5.3

151 3.5

152 9.0

153 4.6

154 4.1

155 6.8

156 1.3

157 5.6

158 7.8

159 6.1

160 8.4

161 9.0

162 4.6

163 1.0

164 1.4

165 1.2

166 2.5

167 1.7 cAMP hRXFPl HEK293

Example Assay EC50 (nM)

168 5.3

169 7.9

170 3.3

171 7.9

172 4.3

173 0.6

174 1.9

175 7.8

176 6.0

177 3.3

178 1.6

179 6.5

180 4.3

181 1.4

182 2.6

183 0.8

184 4.8

185 2.5

186 0.8

187 5.3

188 0.5

PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

The compounds of Formula (I) are RXFP1 receptor agonists and may find use in the treatment of medical indications such as heart failure (e.g., HFREF and HFpEF ), fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary' fibrosis or pulmonary hypertension), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension). The compounds of Formular (I) can also be used to treat 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.

Another aspect of the invention is a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.

Another aspect of the invention is a pharmaceutical composition comprising a compound of Formula (I) for the treatment of a relaxin-associated disorder and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating a cardiovascular disease comprising adm inistering an effective amount of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is a method of treating heart failure comprising administering an effective amount of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is a method of treating fibrosis comprising administering a therapeutically' effective amoimt of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is a method of treating a disease associated with fibrosis comprising administering a therapeutically effective amoimt of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is a method of treating idiopathic pulmonary' fibrosis comprising administering a therapeuti cally effective am ount of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is a method of treating a kidney disease (e.g., chronic kidney disease), comprising admini stering a therapeuticall y effecti ve amount of a compound of Formula (I) to a patient in need thereof. Another aspect of the invention is a method of treating or preventing kidney failure, comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is a method of improving, stabilizing or restoring renal function in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I) to the patient.

Another aspect of the invention is a method of treating a hepatic disease comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is a method of treating non-alcoholic steatohepatitis and portal hypertension comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.

Another aspect of the invention is use of a compound of Formula (I) for prophylaxis and/or treatment of a relaxin-associated disorder.

Another aspect of the invention is a compound of Formula (I) for use in tiie prophylaxis and/or treatment of a relaxin-associated disorder.

Unless otherwise specified, the following terms have the stated meanings.

The term "patient" or "subject" refers to any human or non-human organism that could potentially benefit from treatment with a RXFP1 agonist as understood by practitioners in this field. Exemplary subjects include human beings of any age with risk factors for cardiovascular disease. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arrhythmia, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS).

"Treating" or "treatment" cover the treatment of a disease-state as understood by practitioners in this field and include the following: (a) inhibiting the disease-state, i.e., arresting it development; (b) relieving the disease-state, i.e., causing regression of the disease state; and/or (c) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it.

"Preventing" or "prevention" cover the preventive treatment (i.e., prophylaxis and/or risk reduction) of a subclinical disease-state aimed at reducing the probability of the occurrence of a clinical disease-state as understood by practi tioners in this field. Patients are selected for preventative therapy based on factors that are known to increase ri sk of suffering a clinical disease state compared to the general population. "Prophylaxis" therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that lias not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state. "Risk reduction" or "reducing risk" covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.

"Therapeutically effecti ve amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination with other agents to treat disorders as understood by practitioners in this field. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.

“Disorders of the cardiovascular system” or “cardiovascular disorders” include for example the following disorders: hypertension (high blood pressure), peripheral and cardiac vascular disorders, coronary heart disease, stable and unstable angina pectoris, heart attack, myocardial insufficiency, abnormal heart rhythms (or ardiythmias), persistent ischemic dysfunction ("hibernating myocardium"), temporary postischemic dysfunction ("stunned myocardium"), heart failure, disturbances of peripheral blood flow, acute coronary syndrome, heart failure, heart muscle disease (cardiomyopathy), myocardial infarction and vascular disease (blood vessel disease).

“Heart failure” includes both acute and chronic manifestations of heart failure, as well as more specific or related types of disease, such as advanced heart failure, postacute heart failure, cardio-renal syndrome, heart failure with impaired kidney function, chronic heart failure, chronic heart failure with mid-range ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, heart failure associated with combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with cardiac storage disorders, diastolic heart failure, systolic heart failure, acute phases of worsening heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), chronic heart failure with reduced ejection fraction (HFrEF), chronic heart failure with preserved ejection fraction (HFpEF), post myocardial remodeling, angina, hypertension, pulmonary hypertension and pulmonary artery hypertension.

“Fibrotic disorders” encompasses diseases and disorders characterized by fibrosis, including among others tire following diseases and disorders: hepatic fibrosis, cirrhosis of the liver, NASH, pulmonary fibrosis or lung fibrosis, cardiac fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitreoretinopathy and disorders of the connective tissue (for example sarcoidosis).

Relaxin-associated disorders include but are not limited to disorders of tire cardiovascular system and fibrotic disorders.

The compounds of this invention can be administered by any suitable means, for example, orally, such as tablets, capsul es (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrastemal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. "Pharmaceutical composition" means a composition comprising a compound of tiie invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary' skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of adm inistration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary' skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L.V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

The dosage regimen for the compotmds of the present invention will, of course, vary' depending upon known factors, such as the ph armacodynamic characteristics of the particular agen t and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.01 to about 5000 mg per day, preferably between about 0.1 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.

Dosage forms (pharmaceutical compositions) suitable for administration may con tain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition. A typi cal capsule for oral admini stration contains at least one of the compounds of the present in vention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

The compounds may be employed in combination with other suitable therapeutic agents useful in the treatment of diseases or disorders including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, memoiy enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, and anti-inflammatory agents. The additional therapeutic agents may include ACE inhibitors, P-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine Al receptor agonists, partial adenosine Al receptor, dopamine P-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with biased agonism for select cell signaling pathways, combinations of angiotensin II receptor antagonists and neprilysin enzyme inhibitors, neprilysin enzyme inhibitors, soluble guanylate cyclase activators, myosin ATPase activators, rho-kinase 1 inhibitors, rho-kinase 2 inhibitors, apelin receptor agonists, nitroxyl donating compounds, calcium-dependent kinase II inhibitors, antifibrotic agents, galectin-3 inhibitors, vasopressin receptor antagonists, FPR2 receptor modulators, natriuretic peptide receptor agonists, transient receptor potential vanilloid-4 channel blockers, anti-arrhythmic agents, //"“funny current” channel blockers, nitrates, digitalis compounds, inotropic agents and p-receptor agonists, cell membrane resealing agents for example Poloxamer 188, anti-hyperlipidemic agents, plasma HDL-raising agents, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), LXR agonist, FXR agonist, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, anion exchange resins, quaternary amines, cholesty ramine, colestipol, low density lipoprotein receptor inducers, clofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrizol, vitamin B6, vitamin B12, anti-oxidant vitamins, anti-diabetes agents, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives, PCSK9 inhibitors, aspirin, and P2Y12 Inhibitors such as Clopidogrel.

The additional therapeutic agents may also include nintedanib, Pirfenidone, LPA1 antagonists, LPA1 receptor antagonists, GLP1 analogs, tralokinumab (IL- 13, AstraZeneca), vismodegib (hedgehog antagonist, Roche), PRM-151 (pentraxin-2, TGF beta-1, Promedior), SAR-156597 (bispecific Mab IL-4&IL-13, Sanofi), simtuzumab ((anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inh./pentoxifylline/NAC oral control, release, Pacific Ther.), omipalisib (oral PI3K/mT0R inhibitor, GSK), IW-001 (oral sol. bovine type V collagen mod., ImmuneWorks), STX-100 (integrin alpha V/ beta-6 ant, Stromedix/ Biogen), Actimmune (IFN gamma), PC-SOD (midismase; inhaled, LIT Bio-Pharma / CKD Pharm), lebrikizumab (anti-IL-13 SC humanized mAb, Roche), AQX-1125 (SHIP1 activator, Aquinox), CC-539 (JNK inhibitor, Celgene), FG-3019 (FibroGen), SAR-100842 (Sanofi), and obeticholic acid (OCA or INT-747, Intercept).

Hie above other therapeutic agents, when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, as in the patents set out above, or as otherwise determined by practitioners in the art.

Particularly when provided as a single dosage unit, the potential exi sts for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would invol ve the formulation of a combination product in which the one component is coated with a sustained and/or en teric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving RXFP1 . Such compounds may be provided in a commercial ki t, for example, for use in pharmaceutical research involving RXFP1. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. The compounds of the present invention may also be used in diagnostic assays involving RXFP1.

The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises a first therapeutic agent, compri sing a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemias and the sequelae thereof. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment of dyslipidemias and the sequelae thereof. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located witbin the first and second containers means that the respective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

Hie second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recites infonnation relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the arti cle of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g. , printed or applied).

CHEMICAL METHODS

The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.

It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007)).

Abbreviations are defined as follow's: " 1 x" for once, "2 x" for twice, "3 x" for thrice, " °C" for degrees Celsius, "aq" for aqueous, "eq" or “equiv.” for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "pL" for microliter or microliters, "N" for normal, "M" for molar, "nM" for nanomolar, “pM” for picomolar, "mol" for mole or moles. "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "cone." for concentrate, "aq" for "aqueous", "sat." for saturated, "MW" for molecular weight, "MS" or "Mass Spec" formass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "LC-MS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "NMR" for nuclear magnetic resonance spectroscopy, “SFC” for super critical fluid chromatography, "^H" for proton, "5 " for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, “MHz” for megahertz, and "a", "P", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

AcCl acetyl chloride

AcOH acetic acid

AIBN Azobisisobutyronitrile

Boc tert-butyloxycarbonyl

BuLi butyl lithium

DCE Dichloroethane

DCM Dichloromethane

DIEA diispropyl ethylamine

DMAP 4-dimethylamino pyridine

DMF Dimethylfonnamide

DPPA Diphenyl phosphoryl azide

Et?O diethyl ether

EtOAc Ethylacetate

EtOH Ethanol

HATH (l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate)

HMPA hexamethylphosphramide

IPA isopropanol i-Pr Isopropyl

KHMDS potassium bis(trimethylsilyl)amide\ LDA lithium diisopropyl amide

MeCN Acetonitrile

MeOH Methanol

Me Methyl

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

Pd/C palladium on carbon pTsOH p-toluenesulfonic acid

PyBroP Bromotripyrrolidinophosphonium hexafluorophosphate

T3P 2,4,6-Tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-tri oxide

TBAF tetra-n-butyl ammonium fluoride t-Bu tert-butyl

Teoc 2-(trimethyl silyl)ethyl

TFA trifluoro acetic acid

TFAA trifluoro acetic anhydride

THE Tetrahydrofuran

XPhos-Pd-G2 2nd generation XPhos precatalyst CAS no. 1310584-14-5

XPhos-Pd-G3 3rd generation XPhos precatalyst CAS no. 14445085-55-1

The following general methods were used in the exemplified examples, except where noted otherwise. Purification of intermediates and final products was carried out via either normal or reverse phase chromatography. Normal phase chromatography was carried out using prepacked SiO2 cartridges eluting with either gradients of hexanes and ethyl acetate or DCM and MeOH unless otherwise indicated. Reverse phase preparative HPLC was carried out using Cl 8 columns with UV 220 nm or prep LCMS detection eluting with gradients of Solvent A (90% water, 10% MeOH, 0.1% TEA) and Solvent B (10% water, 90% MeOH, 0.1% TFA) or with gradients of Solvent A (95% water, 5% ACN, 0.1% TFA) and Solvent B (5% water, 95% ACN, 0.1% TEA) or with gradients of Solvent A (95% water, 2% ACN, 0.1% HCOOH) and Solvent B (98% ACN, 2% water, 0.1% HCOOH) or with gradients of Solvent A (95% water, 5% ACN, 10 mM NH^OAc) and Solvent B (98% ACN, 2% water, 10 mM NH4OAC) or with gradients of Solvent A. (98% water, 2% ACN, 0.1% NII4OII) and Solvent B (98% ACN, 2% water, 0. 1%

NH4OH). Stereoisomer separations were achieved in > 95% ee or de.

LC/MS methods employed in characterization of examples are listed below.

Method A:

Instrument: Waters Acquity coupled with a Waters MICROMASS® ZQ Mass Spectrometer

Linear gradient of 2 to 98% B over 1 min, with 0.5 min hold time at 98% B

UV visualization at 220 nm

Column: Waters BEH Cl 8, 2.1 x 50 mm

Flow rate: 0.8 mL/min (Method A)

Mobile Phase A: 0.05% TFA, 100% water

Mobile Phase B: 0.05% TFA, 100% acetonitrile

Method B:

Instrument: Shimadzu Prominence HPLC coupled with a Shimadzu LCMS-2020

Mass Spectrometer

Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B

UV visualization at 220 nm

Column: Waters Xbridge Cl 8, 2.1 x 50 mm, 1.7 um particles

Flow rate: 1 mL/min

Mobile Phase A: 10 mM ammonium acetate, 95:5 water: acetonitrile

Mobile Phase B: 10 mM ammonium acetate, 5:95 water: acetonitrile

Method C:

Instrument: Shimadzu Prominence HPLC coupled with a Shimadzu LCMS-2020

Mass Spectrometer

Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B

UV visualization at 220 nm

Column: Waters Xbridge Cl 8, 2.1 x 50 mm, 1.7 um particles

Flow rate: 1 mL/min

Mobile Phase A: 0.1% TFA, 95:5 water: acetonitrile

Mobile Phase B: 0.1.% TFA, 5:95 wateracetonitrile

Method D:

Instrument: Waters Acquity coupled with a Waters MICROMASS® ZQ Mass Spectrometer

Linear gradient of 10% B to 98% B over 1 min, with 0.5 min hold time at 98% B

UV visualization at 220 nm

Column: Waters Acquity GEN C 18, 2.1 x 50 mm, 1.7 um particles

Flow rate: 1 mL/min

Mobile Phase A: 0.05% TFA, 100% water

Mobile Phase B: 0.05% TFA, 100% acetonitrile NMR Employed in Characterization of Examples. *H NMR spectra were obtained with Broker or JEOL® Fourier transform spectrometers operating at frequencies as follows: NMR.: 400 MHz (Bruker or JEOL®) or 500 MHz (Broker or JEOL®). Spectra data are reported in the format: chemical shift (multiplicity, coupling constants, number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (6 units, tetramethylsilane = 0 ppm) and/or referenced to solvent peaks, which in NMR spectra appear at 2.51 ppm for DMSO-de, 3.30 ppm for CD3OD, 1.94 ppm for CD3CN, and 7.24 ppm for CDCI3.

Syntheses of key norbomyl intermediates are outlined in Schemes I-XI. Norbomyl intermediates can be made with isopropylidene bridgehead substitution as described in Scheme 1, starting from 1-1. Diels-Alder cyclization with maleic anhydride furnished compound 1-2, which was reduced and anhydride opened with methanol to yield 1-3. Curtius reaction with DPP A on the free acid in the presence of trimethylsilylethanol produced 1-4. Enatiomers of 1-4 were separated and tiie trimethylsilylcarbamate was cleaved with TFA and the amine reprotected as the trifluoroacetamide 1-5. The methyl ester was converted to the amide via treatment with 4-fluoro-3 -trifluoromethylaniline and trime thyl aluminum to furnish 1-6. Deprotection of the trifluoroacetamide using K2CO3 and MeOH produced amine 1-7.

Scheme I

1-7

Intermediate 1-2: At 0 °C, into the reaction vessel was added Et2O (100 mL), 5- (propan-2-ylidene)cyclopenta-l,3-diene (10 g, 94 mmol), and furan-2, 5-dione (10 g, 100 mmol). Hie reaction mixture was stirred at 0 °C for 18 h, concentrated under reduced pressure and purified via silica gel chromatography to provide 1-2 (3.74 g, 18.3 mmol, 19.0% yield). Intermediate 1-2 is a known compound; please see: PCT Int. AppL, 2011163502, 29 Dec 2011.

Intermediate 1-3: Into the reaction vessel was added 1-2 (2.74 g, 13.4 mmol), EtOAc (100 mL), pyridine (0.540 mL, 6.71 mmol), and Pd/C (70 mg, 0.070 mmol). The reaction mixture was stirred at 23 °C under 1 atm Eb (Hz balloon) for 60 min filtered through Celite, and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) and heated at 50 °C for 12 h. The solution was concentrated under reduced pressure (azeotroped with toluene 3 x 15 mL) to produce 1-3 (3.21 g, 13.5 mmol, 100% yield) that was used without further purification.

Intermediate 1-4: Into the reaction vessel was added 1-3 (3.21 g, 13.5 mmol), EtsN (3.38 mL, 24.2 mmol), toluene (75 mL), and diphenylphosphoryl azide (4.35 mL, 20.2 mmol). The reaction mixture was stirred at 23 °C for 1 h and subsequently heated at 85 °C for 30 min. 2-(trimethylsilyl)ethanol (4.83 mL, 33.7 mmol) was added to the reaction mixture and, after stirring at 85 °C for 66 h, the reaction mixture was allowed to cool to 23 °C and purified via silica gel chromatography to provide racemic 1-4 (3.71 g, 10.5 mmol, 78% yield) LC-MS RT = 1.25 min; (M+H) = 354.1 . Method A. Racemic 1-4 was separated into individual enantiomers using chiral SEC. Preparative chromatographic conditions: Instrument: Thar 350 SEC; Column: Whelko-RR, 5 x 50 cm, 10 micron;

Mobile phase: 13% IPA/87% CO2; Flow conditions: 300 mL/min, 100 Bar, 35 °C;

Detector wavelength: 220 nm; Injections details: 4 injections of 3.5 mL of 59 g / 490 mL MeOELDCM (4:1) 120 mg/mL in IPA. Analytical chromatographic conditions:

Instrument: Thar analytical SEC; Column: Whelko-RR (0.46 x 25 cm, 5 micron; Mobile phase: 5% IPA/95% CO2; Flow conditions: 3 mL/min, 140 Bar, 40 °C; Detector wavelength: 200-400 nm UV; RT = 3.50 Peak #1, 4.42 Peak #2. Intermediate 1-4 product Peak #1 was collected and carried forward to produce chiral 1-5.

Intermediate 1-5: Peak #1 of intermediate 1-4 (2.87 g, 8.12 mmol) was dissol ved in 10: 1 DCM/TFA and stirred at rt for 72 h. Hie reaction mixture was concentrated under reduced pressure to generate (lR,2S,3R,4R)-methyl 3-amino-7-(propan-2- ylidene)bicyclo[2.2.1]heptane-2-carboxylate (1.699 g, 8.120 mmol, 100 % yield) which was used without further purification. To (lR,2S,3R,4R)-methyl 3-amino-7-(propan-2- ylidene)bicyclo[2.2.1]heptane-2-carboxylate (1.7 g, 8.1 mmol) was added DCM (41 mL) and the flask was cooled to 0 °C via an ice bath. TFAA (1.26 mL, 8.90 mmol) and DIEA (5.7 mL, 33 mmol) were added. Hie reaction mixture was allowed to warm to 23 °C and stirred for 30 min. Saturated NaHCOi (50 mL) was added to the reaction mixture and the solution extracted with EtOAc (3 x 50 mL). The combined organic portions were dried over Na2SO4 filtered and concentrated under reduced pressure to afford 1-5 (2.48 g, 8.12 mmol, 100% yield) that was used without further purification. LC-MS RT = 1.11 min; MS (ESI) m/z = 306.1 (M+H) ⁺ ; Method A.

Intermediate 1-6: To a solution of intermediate 1-5 (2.7 g, 8.8 mmol) in toluene (88 ml) was added trimethylaluminum (26.5 mmol) premixed with 4-fluoro- 3(trifluoromethyl)aniline (29.2 mmol) as a solution in toluene (0.275 M in amine, 0.25 M in trimethylaluminum). The reaction mixture was stirred at 60 °C for 30 min. On cooling to it, the reaction mixture was diluted with EtOAc (100 mL) and sat. Rochelle's salt (100 mL) added. Tire aqueous portion was extracted with EtOAc (3 x 75 mL). The combined organic portion was dried over Na?.SO4, filtered, concentrated under reduced pressure, and subjected to silica gel chromatography purification and the residue further purified by preparative reverse phase HPLC to yield (lR,2S,3R,4R)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-7-(propan-2-ylidene)-3-(2,2,2- trifluoroacetamido)bicyclo[2.2.1]heptane-2 -carboxamide 1-6 (2.5 g, 5.5 mmol, 63 % yield) as a yellow foam. LC-MS RT = 1 .20 min; MS (ESI) m/z = 453.0 (M+H)" ¹ "; Method A.

Intermediate 1-7: Intermediate 1-6 (133 mg, 0.290 mmol) was dissolved in water (2.9 mL) and MeOH (2.9 mL), then K2CO3 (2.03 g, 1.47 mmol) was added. The reaction mixture was stirred at 40 °C for 4 h, then partitioned between water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried overNazSCh filtered and concentrated under reduced pressure to afford 1-7 (105 mg, 0.290 mmol, 100% yield) that was used without further purification. LC-MS RT = 0.82 min: MS (ESI) m/z = 357.1 (M+H)" ¹ "; Method A.

Scheme la

The norbomyl intermediate IIa-8 could also be prepared by the general route shown in Scheme la from furan-2,5 -dione and ferrocenium hexafluorophosphate. Diels Alder condensation, followed by hydrolysis to IIa-2, Curtius rearrangement to the intermediate amine which was reduced tmder hydrogenation conditions and subsequently protected to generate intermediate Ila- 3. Cleavage of the benzyl ester and cross coupling to NHR1R2 generated intermediates with the general structure IIa-5. Conversion of the C7 hydroxygroup to the ketone followed by Wittig olefination generated major isomer intermediate IIa-8. The major isomer was separated from the minor isomer by chromatography and the racemate separated into enantiopure IIa-8 (-).

Ila -8 Ila -8 (-) Major Major

Minor

Scheme II utilizes elaboration via ozonolysis and Homer-Wadsworth Emmons

(although functionalizations could proceed with a variety of reagents such as alkyl lithium, alkyl magnesium, Wittig reaction, not limited to these) and a bridgehead substituted olefinic bromide that allows for Suzuki cross-coupling reactions on more advanced intermediates. This scheme demonstrates this process on more advanced intermediates that contain substituted heteroaryl functionality at the R ³ position.

Scheme II

Intermediate II-l Into the reaction vessel was added intermediate 1-6 (110 mg,

0.243 mmol) and EtOAc (2 mL). The reaction mixture was cooled to -78 °C and O3 was bubbled through the solution until the solution became pale purple/blue. N2 was subsequently bubbled through the solution at -78 °C to remove excess O3 (solution became colorless). Dimethyl sulfide (0.43 mL, 4.8 mmol) was subsequently added at -78

°C and the reaction mixture was allowed to warm to rt and stirred at it for 12h. After concentrating under reduced pressure, the residue was dissolved in EtOAc and filtered through silica gel to generate(lR,2S,3R,4S)-N-(4-fluoro-3-(trifluoromethyl)phenyl) -7- oxo-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1 ]heptane-2-carboxamide after removal of solvent under reduced pressure, (II-l, 101 mg, 0.237 mmol, 97.0 % yield). ^} H NMR (500

MHz, CDCh) 59.61 (br d, >6.3 Hz, 1H), 7.76 (dd, >5.9, 2.6 Hz, HI), 7.71 (dt, >8.9,

3.4 Hz, 1H), 7.66 (s, 1H), 7.23 (t, >9.4 Hz, 1H), 4.70 (dt, >10.3, 5.3 Hz, 1H), 3.33 (dd. J=10.5, 4.4 Hz, TH), 2.54 (t, J=4.3 Hz, 1H), 2.42 (t, J=4.1 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.06 - 1.99 (m, 1H), 1.96 - 1.81 (m, 2H).

Intermediate 11-2: Into the reaction vessel was added bromo(methyl)triphenylphosphorane (419 mg, 1.17 mmol) (fine powder by grinding the commercial material) and THF (7 mL). The reaction mixture was cooled to -78 °C and KHMDS (1.2 mL, 1.2 mmol) was added. The reaction mixture was allowed to stir vigorously at -78 °C for 30 min and II-l (100 mg, 0.24 mmol) was added at -78 °C. After stirring at -78 °C for a further 10 min, the reaction mixture was allowed to warm to 23 °C and stirred for a further 1.5 h. Hie reaction mixture was cooled to -40 °C and quenched by the addition of sat. NaHCOa. The resulting solution was extracted with EtOAc. The combined organic portion was dried over NaaSCh, filtered, concentrated under reduced pressure, and purified via silica gel chromatography to produce II-2 (71 mg, 0.17 mmol, 71% yield). LCMS RT = 1.16 min; (M+H) = 425.0; Method A.

Intermediates II-3 and 11-4: Into the reaction vessel was added II-2 (71 mg, 0.17 mmol), DCM (3 mL), and Bra (0.03 mL, 0.6 mmol). The reaction mixture was stirred at 23 °C for 20 min and concentrated under reduced pressure utilizing a trap with sat. NaaSaOa to quench excess Bra. The resulting dibromide was dissolved in THF (3 mL). After cooling to -78 °C, KHMDS (1.0 mL, 1.0 mmol) was added. Hie reaction mixture was kept at -78 °C for 12 h and -40 °C for 2 h, quenched by the addition of sat. NaHCOa at -40 °C, and the resulting solution extracted with EtOAc. The organic phase was collected, dried over NaaSCU, filtered, concentrated under reduced pressure, and purified via silica gel chromatography to produce II-4 (27 mg, 0.050 mmol, 32% yield) (peak2). LCMS RT = 1.19 min; (M+H) = 504.9; Method A. and the corresponding E-isomer II-3 (28 mg, 0.06 mmol, 33% yield) (peak 1).

Racemic II-4 (4 grams) was produced as outlined above and separated into individual enantiomers using chiral SFC. Preparative chromatographic conditions: Instrument: Thar 350 SFC; Column: Chiralcel OD-H, 5 x 50 cm, 5 micron; Mobile phase: 20% MeOH/80% COa; Flow conditions: 340 mL/min, 100 Bar, 35 °C; Detector wavelength: 220 nm; Injections details: 3.75 mL of 30 mg/mL in MeOH. Peak # 1 RT = 7.81 min, Peak #2 RT = 10.97 min. Peak #1 of 11-4 (1.9 grams) was collected and carried forward to produce chiral II-5. Intermediate II-5: Into the reaction was added MeOH (3 mL) and AcCl (0.3 mL, 4.2 mmol). After stirring for 5 min, chiral Peak #1 II-4 (75 mg, 0.15 mmol) was added and the reaction mixture was stirred at 40 °C for 48 h. The reaction mixture was concentrated under reduced pressure produced II-5 (67 mg, 0.16 mmol, 100%) that was used without further purification. LC-MS RT = 0.78 min; (M+H) == 408.9; Method A.

Scheme III demonstrates the diversification possible with a variety of reagents for example, alkyl lithium, alkyl magnesium, Wittig reaction, Homer-Wadsworth Emmons, but not limited to these.

Scheme III

HI-2

Intermediate 1II-1: hi to the reaction vessel was added diethyl benzylphosphonate (375 mg, 1.64 mmol) and THF (10 mL). The reaction mixture was cooled to -78 °C and KHMDS (1.6 mL, 1.6 mmol) was added. This reaction mixture was stirred at -78 °C for lOmin and intermediate II-l (140 mg, 0.328 mmol) was added. After 20 min, the reaction mixture was allowed to warm to rt and stirred at it for 2h. The reaction mixture was quenched by the addition of satNaHCCh and the solution extracted with EtOAc. The combined organic portion was dried over Na?.SO4, filtered, concentrated, and subjected to silica gel chromatography purification to the E-isomer byproduct (111 mg, 0.222 mmol, 67.5 % yield) and (lR,2S,3R,4R,Z)-7-benzylidene-N-(4-fluoro-3-

(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicy clo[2.2.1]heptane-2- carboxamide (III-l, 49 mg, 0.098 mmol, 30 % yield). RT = 1.23 min; MS (ESI) m/z = 501.1 (M+H) ⁺ ; Method A.

Intermediate III-2: To a vial containing MeOH (3 mL) cooled to 0 °C (ice/water bath) was added acetyl chloride (0.3 mL, 4 mmol) dropwise. The resulting solution was stirred at rt for 10 min, then was added to III-l (94 mg, 0.19 mmol). The reaction mixture was stirred at 40 °C for 48 h and concentration under reduced pressure afforded (lR,2S,3R,4R)-3-amino-7-((Z)-benzylidene)-N-(4-fluoro-3- (trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (HI-2, 73 mg, 0.18 mmol, 96 % yield). RT = 0.87 min; MS (ESI) m/z = 405.1 (M+H) ⁺ ; Method A which was used without further purification

Scheme IV demonstrates installation of cycloalkyl and heterocycle bridgehead functionality in similar manner as scheme II, in this example, isoxazole and cyclopropyl groups, but not limited to these groups.

Scheme IV

Intermediate IV-1: Into die reaction vessel containing II-4 (125 mg, 0.250 mmol) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (125 mg, 0.610 mmol), PdCh(dppf)-CH2C12 adduct (50.7 mg, 0.0620 mmol), and NaiCOa (1.5 mL, 3.00 mmol). The reaction mixture was degassed with nitrogen for 3 min, sealed, and stirred at 60 °C for 2 h. After cooling to 23 °C, the reaction mixture was extracted with EtOAc, dried over NaiSCU, concentrated tmder reduced pressure, and purified via silica gel chromatography to produce IV-1 (100 mg, 0.21 mmol, 83% yield). LC-MS RT = 1 .07 min; MS (ESI) m/z = 492.1 (M+H) ⁺ ; Method A.

Intermediate IV-2: Intermediate IV-2 was prepared from IV-1 in the same manner as intermediate I1I-2 in scheme III (67 mg, 0.16 mmol, 100% yield). RT = 0.76 min; MS (ESI) m/z = 396.0 (M+H) ⁺ ; Method A.

Intermediate IV-3: Intermediate IV-3 was prepared from II-4 in the same manner as intermediate IV-1 in scheme IV (5.1 mg, 0.01 mmol, 23% yield). RT = 1.21 min; MS (ESI) m/z = 465. 1 (M+H) ⁺ ; Method A.

Intermediate IV-4: Intermediate IV-4 was prepared from IV-3 in the same manner as intermediate 1-7 in scheme I (4.0 mg, 0.01 mmol, 100% yield). RT = 0.84 min; MS (ESI) m/z = 369.1 (M+H) ⁺ ; Method A.

Scheme V demonstrates functionalizing the C7 position with a trifluoromethyl group.

Scheme V

Intermediate V-1 : Intermediate V-1 was prepared from II-4. To a 250 mL round bottom flask charged with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.5 mL, 20 mmol) in anhydrous DMF (50 mL) was added dropwise via dropping funnel to a suspension of II-4 and Cui (2.3 g, 12 mmol) in anhydrous DMF (100 mL) and IIMPA (8.0 mL, 19 mmol) and the reaction mixture heated at 75 °C under an inert nitrogen atmosphere for 16 h. The cooled reaction mixture was filtered and purified by silica gel chromatography to produce V-1 (3.0 g, 6.1 mmol, 77% yield). 1H NMR (500 MHz, CDCh) 5 9.38 (br d, 1=6.1 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.46 (s, 1H), 7.24 (t, 1=9.1 Hz, HI), 5.62 (q, J=7.2 Hz, TH), 4.50 (dt, J=10.5, 5.3 Hz, 1H), 3.50 - 3.42 (m, 1H), 3.13 - 3.04 (m, 1H), 2.89 (t, >4.0 Hz, 1H), 2.02 - 1.90 (m, 2H), 1.76 - 1.60 (m, 2H).

Intermediate V-2: Intermediate V-2 was prepared from V-l .. MeOH (1.5 mL) and acetyl chloride (2. 1 mmol) were charged into a 2 dram vial and stirred at 23 °C for 5 min. V-l was added to the reaction vial and the contents heated at 40 °C for 24 h.

Concentration with a stream of nitrogen gave V-2 as the HC1 salt which was used without further purification. LC-MS RT = 0.75 min; MS (ESI) m/z = 397.1 (M+H) ⁺ ; Method A.

Scheme VI demonstrates a general method of preparing heterocyclic carboxylic acids for amide to coupling with intermediates for example, V-2 utilizing coupling agents such as HATU (not limited to). Additionally the carboxylic acids can be assembled in an alternate order or using an alternate protection strategy.

Scheme VI

Intermediate VI-1: A 20 mL vial was charged with methyl 5-bromo-2- methoxynicotinate (0.150 g, 0.610 mmol), 3-borono-4-fluorobenzoic (0.168 g, 0.910 mmol), Pd(OAc)2 (0.013 g, 0.061 mmol), K2CO3 (0.253 g, 1 .80 mmol), followed by water (0.120 mL), and DMF (6 mL). The reaction mixture was stirred for 18 h at 23 °C. After quenching the reaction mixture by the addition of HC1 (20 mL, 1.0 M) and extracting with ethyl acetate (3 x 20 mL), the combined organic portion was dried over NazSO4 filtered and concentrated under reduced pressure. The residue was purified via preparative RP-HPLC to produce intermediate VI- 1 (120 mg, 0.41 mmol, 67% yield). LC-MS RT = 0.82 min; MS (ESI) m/z = 306.1 (M+H) ⁺ ; Method A. Intermediate VI-2: To a 20 mL vial charged with VI-1 (0.120 mg 0.41 mmol) in toluene (4 mL), was added l,l-di-tert-butyoxy-N,N-dimethylmethanamine (0.49 mL, 2.0 mmol). The reaction mixture was heated at 40 °C for 2 days. The reaction mixture was concentrated under reduced pressure onto silica gel and purified by normal phase column chromatography to give VI-2 (110 mg, 0.31 mmol, 76%). LC-MS RT = 1.15 min; MS (ESI) m/z = 362.1 (M+H) ⁺ ; Method A.

Intermediate VI-3: To a vial containing VI-2 (56 mg, 0.16 mmol) in THE (0.89 mL)/water (0.44 mL)/MeOH (0.22 mL) was added a IN aqueous solution of lithium hydroxide (IN, 0.78 mL, 0.78 mmol) and the reaction mixture was stirred at rt for 18 hr, then diluted with IN HC1 (5 mL) and the solution extracted with EtOAc (3 x 5 mL). The combined organic portions were dried over NazSOi filtered and concentrated under reduced pressure to afford 5-(5-(tert-butoxycarbonyl)-2-fluorophenyl)-2- methoxynicotinic acid (54 mg, 0.16 mmol, 100 % yield). LC-MS RT = 1.02 min; MS (ESI) m/z = 348.1 (M+H) ⁺ ; Method A.

Alternatively various heteroaryl halides and aryl boronic acid or ester could be cross coupled by the general route shown in Scheme VI to yield aryl-pyrimidine and isomeric pyridines, for example but not limited to. In addition, cross coupling may be accomplished with aliphatic groups via Sonogashira conditions employing the appropriate alkyne, PdfPPhaK Cui, and triethylamine followed by subsequent reduction with Pd/C and hydrogen and hydrolysis with lithium hydroxide as demonstrated in scheme VII

Scheme VII

OMe

MeO ₂ C.

OMe N

MeO _z C. H Pd(PPh ₃ ) ₄ , Cui

VII-1

Et ₃ N, 80 °C

Br HO'

"OH

Intermediate VII-1: To a slurry of methyl 5-bromo-2 -methoxynicotinate (0.50 g, 2.0 mmol) in TEA (20 mL) was added propargyl alcohol (0.15 mL, 2.5 mmol), Pd(PPha)4 (0.047 g, 0.041 mmol), and Cui (3.9 mg, 0.020 mmol). The reaction mixture was degassed, and heated at 80 °C under N2 for 16 h. The reaction solution was partitioned between EtOAc and water and the organic layer was separated and dried over Na2SO4. The fluid was decanted and concentrated under reduced pressure and the residue purified by silica gel chromatography to furnish methyl 5-(3-hydroxyprop-l-yn-l-yl)-2- methoxynicotinate (300 mg, 1.4 mmol, 68 % yield): NMR. (500 MHz, CDCh) 8 8.40 (d, J=2.3 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 4.52 (d, .7=6.3 Hz, 2H), 4.08 (s, 3H), 3.93 (s, 3H), 1.69 (t, J=6.2 Hz, 1H). MS (ESI) m/z 222.2 (M+H).

Intermediate MI-2: To a solution of MI-1 (0.16 g, 0.72 mmol) dissolved in ethanol (7 mL) was added Pd-C 10% wt. (0.077 g, 0.072 mmol) and hydrogen introduced at ambient pressure via balloon for 16 h. The reaction solution was filtered and concentrated under reduced pressure to furnish methyl 5-(4-hydroxypropyl)-2- methoxynicotinate which is contaminated with over reduction product methyl 2-methoxy- 5 -propylnicotinate which used without further purification (0.65 g, 2.7 mmol, 65 % yield). MS (ESI) m/z 226.1 (M+H).

Intermdiate MI-3: To a solution of methyl MI-2 (0.022 g, 0.099 mmol) dissolved in THF (0.8 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (4 mg, 0.1 mmol) and stirred 16 h. The reaction was neutralized by the addition of IM HCl and extracted into EtOAc. The organic layer was separated, dried over Na?.SO4, and the fluid was decanted and concentrated under reduced pressure. The residue was used without further purification: 5-(3-hydroxypropyl)-2-methoxynicotinic acid (0.02 g, 0.1 mmol, 100 % yield). MS (ESI) m/z TlTl (M+H).

Scheme VIII

,R

Rlv ²

E ,F RL. R ²

,0 V

'F BoCoO, DMAP /'■F RNH - ₂ - *►

7xS F F DCM iPr ₂ NEt

H i o , DCM o NH ₂ H NH

Boc

VIII-1 VIII-2 1 ,R

R ~v ² 1 v ^R2

RVy R ² R ¹ -

£ HCI 1

__ HN-R R ³ COOH, HATU X H

HN-R - *- HN-R . X Dioxane o MeCN, DIEA

H ; O H NH H NH ₂ NH i Os Boc R ³ vm-3 VIII-4 examples

Scheme VIII demonstrates a general route to amides from generic aniline amide VIII-1 . Analogs were prepared by activating amine VIII-1 with B0C2C) in the presence of DMAP, and subsequently displacing the activated amide, VIII-2 with an amine. Further derivitizes are prepared by treatment of VIII-3 with acid, and subsequent amide bond formation is prepared between amine VIII-4 and a carboxyllic acid with cross coupling reagents, for example HATU, but not limited to.

Examples

Example 1

5 -bromo-N-[(2R,3 S)-3 - { [4-fluoro-3 -(trifluoromethyl)phenylj carbamoyl } -7 -(propan-2- yhdene)bicyclo[2.2.1]heptan-2-yl]-2-methoxypyridine-3-carbox amide: Into the reaction vessel was added intermediate 1-7 (12 mg, 0.077 mmol), 5-bromo-2-methoxynicotinic acid (18 mg, 0.077 mmol), MeCN (2.3 mL), DIEA (0.04 mL, 0.3 mmol), and HATU (53 mg, 0.14 mmol). The reaction mixture was stirred at RT for 3 hr, concentrated under reduced pressure, and subjected to HPLC purification to afford 1 (24 mg, 0.042 mmol, 60 % yield), hl NMR (500 MHz, DMSO-d6) 8 10.57 (br s, IH), 10.01 (br d, 1=6.7 Hz, IH), 8.44 (br d, J=2.4 Hz, 1H), 8.32 (br d, J=2.1 Hz, 1H), 8.23 - 8.17 (m, 1H), 7.83 - 7.76 (m, IH), 7.48 (brt, 1=9.6 Hz, IH), 4.34 - 4.25 (m, IH), 4.05 (s, 3H), 3.12 - 3.06 (m, IH), 3.06 - 3.00 (m, IH), 2.95 - 2.89 (m, IH), 1 .80 - 1 .63 (m, 8H), 1.40 - 1 .28 (m, 2H). LC-MS RT: 2.89 min; MS (ESI) m/z = 570.2 (M+H)+; Method B.

Example 20

Procedure for 4-(5 - { [(2R,3 S)-3 - { [4-fluoro-3 -(trifluoromethyl)phenyljcarbamoyl } -7- (propan-2-ylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-6-met hoxypyridin-3-yl)benzoic acid: To a vial was added example 1 (4.4 mg, 0.026 mmol), 4-boronobenzoic acid (4.4 mg, 0.026 mmol), 0.5 M aqueous K3PO4 (0.07 mL, 0.04 mmol), THF (0.3 mL), and Xphos Pd G2 (1.4 mg, 1.8 pmol). The reaction mixture was heated under microwave irradiation at 100 °C for 30 min, then cooled to RT, partitioned between water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic portions were dried over Na2SO4, filtered, concentrated and purified by HPLC to afford 20 (7.8 mg, 0.013 mmol, 71 % yield). ^] HNMR (500 MHz, DMSO-d6) 8 10.58 (br s, IH), 10.04 (br d, 1=6.9 Hz, 1H), 8.72 (br s, IH), 8.57 (br s, 1H), 8.24 (br d, J=3.9 Hz, IH), 8.03 (br d, J=8.1 Hz, 2H), 7.82 (br d, J=7.7 Hz, 3H), 7.49 (br t, J=9.7 Hz, 1H), 4.36 (br s, 1H), 4.13 (s, 3H), 3.12 (br d, 1=10.9 Hz, IH), 3.08 - 3.03 (m, IH), 2.98 - 2.93 (m, 1H), 1.85 - 1.78 (m, IH), 1.77 - 1.70 (m, TH), 1.41 - 1.31 (m, 2H). LC-MS RT: 2.11 min; MS (ESI) m/z = 612.2 (M+H)-t-; Method C.

Example 21

4-fl uoro-3 -(5 - { [(2R,3 S)-3 - { [4-fl uoro-3 -(tri fluoromethyl )phenyl]carbamoyl } -7 -(propan-2 - ylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-6-methoxypyridi n-3-yl)benzoic acid was prepared in a similar manner to example 20 substituting 3-borono-4-fluorobenzoic acid for 4-boronobenzoic acid. 21 (4.1 mg, 5.80 pmol, 30.1 % yield) JHNMR (500 MHz, DMSO-d6) 5 10.59 (br s, 1H), 10.06 (br d, >6.6 Hz, 1H), 8.56 (br s, 1H), 8.45 (br s, 1H), 8.23 (br d, >4.5 Hz, 1H), 8.13 - 8.04 (m, 1H), 8.03 - 7.98 (m, 1H), 7.87 - 7.79 (m, >2.9 Hz, 1H), 7.53 - 7.43 (m, 2H), 4.41 - 4.29 (m, 1H), 4.14 (s, 3H), 3.21 - 3.09 (m, 1H), 3.08 - 3.03 (m, 1H), 2.98 - 2.92 (m, 1H), 1.85 - 1.78 (m, 1H), 1.77 - 1.68 (m, TH), 1.41 - 1.32 (m, 2H). LC-MS RT: 2.1 1 min; MS (ESI) m/z = 630.5 (M+H)+; Method B.

Example 26

Intermediate 26-1

OMe O'

O

N.

F-

.OH

O

To a vial was added methyl 6-bromo-3-methoxypyrazine-2-carboxylate (0.10 g, 0.41 mmol), 3-borono-4-fluorobenzoic acid (0.10 g, 0.61 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), K2CO3 (0.170 g, 1.2 mmol) followed by H2O (0.080 mL, 4.5 mmol), and DMF (4 mL). The reaction was degassed with nitogren for 2 min, then stirred for 18 h at rt. The reaction mixture was diluted with water and extracted with EtOAc (3 x 10 mL). Hie combined organic layers were dried over Na2$O4, concentrated under reduced pressure, and the resulting residue was purified by HPLC to afford 4-fluoro-3-(5-methoxy-6- (methoxycarbonyl)pyrazin-2-yl)benzoic acid (37 mg, 0.12 mmol, 30 % yield). MS (ESI) m/z 307.0 (M+H) ⁺ .

Intermediate 26-2

To a vial containing 26-1 (0.038 g, 0.12 mmol) suspended in toluene (1.3 mL) was added l,l-di-tert-butoxy-N,N-dimethylmethanamine (0.15 mL, 0.62 mmol). The reaction mixture was heated to 40 °C for 5 hr. The reaction was concentrated onto silica gel, then purified by silica gel chromatography to afford methyl 6-(5-(tert-butoxycarbonyl)-2- fluorophenyl)-3-methoxypyrazine-2-carboxylate (29 mg, 0.080 mmol, 65 % yield). MS (ESI) m/z 363.1 (M+H) \

Intermediate 26-3

OH O'

O Y ^N N.

F-

O

To a vial containing 26-2 (0.029 6g, 0.080 mmol) dissolved in THF (0.45 mL)/Water (0.2 mL)/MeOH (0.1 mL) was added lithium hydroxide (0.4 mL, IM, 0.4 mmol), and the reaction mixture was stirred at rt for 18 hrs, then partitioned between IN HQ (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to produce 6-(5-(tert-butoxycarbonyl)- 2-fluorophenyl)-3-methoxypyrazine-2-carboxylic acid (28 mg, 0.080 mmol, 100 % yield). MS (ESI) nVz 349.1 (M+HF.

Example 26: To a solution of IV-2 (10 mg, 0.025 mmol), 26-3 (11 mg, 0.030 mmol), MeCN (0.25 mL), and DIEA (0.02 mL, 0.09 mmol) was added HAITI (11 mg, 0.028 mmol). The reaction mixture was stirred at rt for 3 h, concentrated under reduced pressure and redissolved in 20% TEA in DCM (1 mL). The reaction was stirred at rt for 5 h, then concentrated under reduced pressure and purified by HPLC to afford 4-fluoro-3-(6- ((( 1R,2R, 3 S ,4R,Z)-3 -((4-fluoro-3 -(tri fluoromethyl )phenyl)carbamoyl)-7-(isoxazol -4- ylmethylene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-5-methoxypy razin-2-yl)benzoic acid (2.8 mg, 4.0 pmol, 16 % yield). IHNMR (500 MHz, DMSO-d6) 8 10.45 (s, 1H), 9.80 (br d, J=7.3 Hz, 1H), 8.96 (s, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.70 (s, 1H), 8.53 (dd, J=7.6, 1.8 Hz, 1H), 8.07 - 8.01 (m, 1H), 8.00 - 7.96 (m, 1H), 7.86 - 7.79 (m, 1H), 7.45 - 7.33 (m, 2H), 6.13 (s, 1H), 4.53 - 4.45 (m, 1H), 4.01 (s, 3H), 3.49 (br s, 1H), 3.30 - 3.24 (m, 1H), 2.92 (br s, 1H), 1.99 - 1.87 (m, 2H), 1.61 - 1.47 (m, 2H) LC-MS RT: 2.27 min; MS (ESI) m/z = 670.3 (M+H)+; Method C.

Example 33

Intermediate 33-1

Tert-butyl 3-formylbenzoate (0.10 g, 0.49 mmol) was dissolved in DCM (5 mL). To this solution was added hydroxylamine hydrochloride (34 mg, 0.49 mmol), followed by TEA (1 mL) and the reaction mixture was stirred at rt for 18h. The reaction mixture was diluted with water and the DCM layer was separated, dried (MgSO*) filtered and concentrated under reduced pressure to produce tert-butyl (E)-3- ((hydroxyimino)methyl)benzoate as an oil (126 mg, quant). TlNMR (500 MHz, CHLOROFORM-d) 5 8.17 (m, 2H), 8.03 (d, 1=7.7 Hz, 1H), 7.80 (dt, 1=7.7, 1.4 Hz, 1H), 7.57 - 7.42 (m, 2H), 1.70 - 1.48 (m, 9H). LCMS m/z 222.08 (M+H). The oil was was dissolved in DCM (5 mL) and to this solution was added NCS (0.066 g, 0.49 mmol) and the reaction mixture was stirred at rt for 18h. To this solution was added excess methylaciylate (2 mL) and followed by a sat. solution of NaHCO.3 (5 mL) and stirred at rt for 18h. The reaction mixture was diluted with water (50 mL), and the solution extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSOt), filtered and concentrated under reduced pressure to produce an oil which was purified via a 12g silica gel chromatography produce methyl 3-(3-(tert-butoxycarbonyl)phenyl)-4,5- dihydroisoxazole-5-carboxylate (140 mg, 0.46 mmol, 94%). NMR (500 MHz, CHLOROFORM-d) 5 8.20 (s, 1H), 8.06 (dt, 1=7.8, 1.4 Hz, 1H), 7.94 (d, 1=7.8 Hz, 1H), 7.49 (t, 1=7.5 Hz, 1H), 5.24 (dd, 1=11.0, 7.2 Hz, 1H), 3.90 - 3.80 (m, 3H), 3.78 - 3.65 (m, 2H), 1.76 - 1.55 (m, 9H). LCMS m/z = 306.1 (M+H).

Intermediate 33-2

OH

O-

O i N

O y

To a solution of 33-1 (0.085 g, 0.28 mmol) dissolved in MeOH (3 mL) was added LiOH (14 mg, 0.56 mmol) followed by the addition of water (3 mL) and the reaction mixture was stirred at rt for 18h. The reaction mixture was diluted with water (50 mL) and acidified (HC1, IN) and the solution extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSOt), filtered and evaporated under reduced pressure to produce 3-(3-(tert-butoxycarbonyl)phenyl)-4,5-dihydroisoxazole-5-car boxylic acid which was used without further purification, (79 mg, 0.27 mmol, 97%). Tl NMR (500 MHz, CHLOROFORM-d) 5 8.20 (t, 1=1.6 Hz, 1H), 8.07 (dt, 1=7.8, 1.4 Hz, 1H), 7.93 (dt, 1=8.0, 1.4 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 5.37 - 5.23 (m, 1H), 3.84 - 3.67 (m, 2H), 1.68 - 1.47 (m, 9H). LCMS m/z = 292.3 (M+H). Example 33: 3-(5-{[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]car bamoyl}-7- (2,2,2-trifluoroethyhdene)bicyclo[2.2.1]heptan-2-yl]carbamoy l}-4,5-dihydro-l,2-oxazol- 3-yl)benzoic acid was prepared by the coupling method described for example 1 using the trifluoromethyl norbomyl intennediate V-2 and 33-2 followed by deprotection with TEA as in the procedure to prepare example 26. (4.7 mg, 7.7 mmol, 20 % yield). NMR (500 MHz, DMSO-d6) 5 9.19 (br d, J=7.0 Hz, 1H), 8.23 (s, 1H), 8.05 (br d, J=6.4 Hz, 1H), 8.03 (br d, ,7=7.9 Hz, 1H), 7.88 (br d, ,7=7.3 Hz, 2H), 7.58 (brt, ,7=7.8 Hz, 1H), 7.51 (brt, ,7=9.6 Hz, 1H), 5.90 (q, .7=7.6 Hz, 1H), 5.23 (dd, ,7=11.7, 5.6 Hz, 1H), 4.30 (br s, 1H), 3.78 (br dd, J=17.2, 11.7 Hz, 1H), 3.22 (br d, ,7=10.4 Hz, 1H), 3.05 (br s, 1H), 2.96 (br s, 1H), 2.74 (s, 1H), 1.92 - 1.83 (m, 1H), 1.74 - 1.68 (m, 1H), 1.52 - 1.35 (m, 1H). MS (ESI) m/z = 614.0 (M+H). HPLC Purity: 100.0 %; RT= 2.13 min. Method C.

Example 34

Intermediate 34-1

Br

F.

.OH

CF ₃

Into die reaction vessel was added 3-bromo-4-fluorobenzaldehyde (240 mg, 1.2 mmol), DMF (3.5 mL), (trifluoromethyl)trimethylsilane (0.34 mL, 2.3 mmol), and K2CO3 (8 mg, 0.06 mmol). The reaction mixture was stirred at rt for 60 min and 2N HQ (3 mL) was added. After strirring at rt for Ih, the reaction mixture was diluted with EtOAc (15 mL), and the solution washed with sat NH4CI. The aqueous phase was extracted with additional EtOAc (10 mL x2). Tire organic portions were combined, dried over NazSO-s, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to produce l-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-l-ol (205 mg, 0.751 mmol, 64.9 % yield). ¹ HNMR (500 MHz, CDCh) 8 7.74 (dd, J=6.5, 2.1 Hz, 1H), 7.43 (ddd, .7=8.4, 4.8, 2.2 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 5.11 - 4.98 (m, 1H), 2.69 (d, J=4.4 Hz, 1H).

Intermediate 34-2

A solution of (S)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,l-b]thiazole (0.41 g, 1.6 mmol) and 34-1 (11 g, 40 mmol) in diisopropyl ether (130 mL) was cooled to -20 °C. The resulting solution was treated with isobutyric anhydride (4.0 mL, 24 mmol) and transferred to a freezer (-20 °C < t < 0 °C) for 16 h. Tire reaction mixture was diluted with MeOH (~ 1 mL) and the solution was extracted from phosphate buffer with EtOAc and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to furnish (S)-l-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan- l-ol (4.9 g, 18 mmol, 44 % yield).

Intermediate 34-3

To a solution of 34-2 (0.50 g, 1 .8 mmol) dissolved in 1,4-dioxane (4.6 ml) was added bis(pinacolato)diboron (0.93 g, 3.7 mmol), potassium acetate (0.54 g, 5.5 mmol), and PdCh(dppf)-DCM adduct (0.15 g, 0.18 mmol). The reaction mixture was heated at 110 °C for 2 h, allowed to cool and partitioned between EtOAc and water. The organic phase was separated, concentrated under reduced pressure, and purified via silica gel chromatography to furnish (S)-2,2,2-trifluoro-l-(4-fluoro-3-(4,4,5,5-tetramethyl-l,3,2 - dioxaborolan-2-yl)phenyl)ethan-l-ol (0.41 g, 1.3 mmol, 70 % yield) 'HNMR (500 MHz, CDCh) 5 7.84 (dd, .7=5.4, 2.4 Hz, 1H), 7.67 - 7.56 (m, 1H), 7.11 (t, J=8.7 Hz, HI), 5.05 (q, J=-6.6 Hz, 1H), 1.39 (s, 12H). MS (ESI) m/z 251.0 (M+H-pinacol).

Intermediate 34-4

To methyl 6-bromo-3-methoxypyrazine-2-carboxylate (40 mg, 0.16 mmol), 34-3 (57 mg, 0.18 mmol), 0.5 M aqueous K3PO4 (0.65 mL, 0.32 mmol), and THE (0.32 mL) in a flask was added Xphos-Pd-G2 (2.7 mg, 3.2 pmol) solution . The reaction mixture was stirred at rt for 16 h, then partitioned between EtOAc and water. The organic layer was separated, dried over NaiSO* decanted and concentrated under reduced pressure. The residue was purified via silica gel chromatography to furnish methyl (S)-6-(2-fluoro-5-(2,2,2- trifluoro-l-hydroxyethyl)phenyl)-3-methoxypyrazine-2-carboxy late (11 mg, 0.031 mmol, 19 % yield). MS (ESI) m/z 360.9 (M+H).

Intermediate 34-5

OH O'

O

F.

CF ₃

To a solution of 34-4 (11 mg, 0.031 mmol) dissolved in HIE (0.120 mL) was added water (0.030 mL) and lithium hydroxide monohydrate (1.3 mg, 0.031 mmol) and the reaction mixture stirred 16 h. The reaction mixture was diluted with water and EtOAc and neutralized by the addition of ~ 0.2 mL of IN HQ. Hie organic layer was separated and concentrated under reduced pressure to furnish (S)-6-(2-fluoro-5-(2,2,2-trifluoro-l- hydroxyethyl)phenyl)-3-methoxypyrazine-2-carboxylic acid (12 mg, quant.) which was used without further purification. MS (ESI) m/z 346.8 (M+H).

Example 34 was prepared from coupling 34-5 with V-2 under HATU conditions similar to example 1 to produce N-[(2R,3S,7Z)-3-{[4-fluoro-3-

(trifluoromethyl)phenyl] carbamoyl } -7 -(2,2,2-trifluoroethylidene)bicyclo [2.2.1 ]heptan-2- yl] -6- {2-fluoro-5-[( 1 S)-2,2,2-trifluoro- 1 -hydroxyethyl]phenyl } -3-methoxypyrazine-2- carboxamide (17 mg, 0.023 mmol, 68 % yield). NMR (500 MHz, DMSO-de) 89.85 - 9.73 (m, 1H), 8.84 - 8.71 (m, 1H), 8.09 (br d, J=7.2 Hz, 1H), 8.02 (br d, J-5.6 Hz, 1H),

7.93 - 7.82 (m, 1H), 7.69 - 7.59 (m, 1H), 7.53 - 7.39 (m, 1H), 7.32 - 7.21 (m, 1H), 6.95 (brt, J=7.3 Hz, 1H), 6.03 - 5.91 (m, HI), 5.30 - 5.16 (m, 1H), 4.60 - 4.47 (m, 1H), 4.10 -

3.94 (m, 3H), 3.30 - 3.21 (m, 1H), 3.07 - 2.96 (m, 1H), 2.04 - 1.91 (m, 2H), 1.58 - 1.44 (m, 2H). One aliphatic proton under solvent. LC-MS RT: 2.59 min: MS (ESI) m/z =

724.94 (M+H)+; Method C.

Example 35

(lS)-2,2,2-trifluoro-l-[4-fluoro-3-(6-{[(2R,3S,7Z)-3-{[4- fluoro-3- (trifluoromethyl)phenyl] carbamoyl } -7 -(2,2,2-trifluoroethylidene)bicyclo [2.2.1 ]heptan-2- yl] carbamoyl} -5 -methoxypyrazin-2-yl)phenyl] ethyl N-phenylcarbamate was prepared from carbamate formation with phenyl isocyanate: To a solution of example 35 (0.017 g, 0.023 mmol) dissolved in DCM (2.3 mL) was added pyridine (0.038 mL, 0.47 mmol) and phenyl isocyanate (0.013 mL, 0.117 mmol) and the reaction mixure stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and purified via reverse phase HPLC to furnish (S)-2,2,2-trifluoro-l-(4-fluoro-3-(6-(((lR,2R,3S,4R,Z)-3-((4 - fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2- trifluoroethyhdene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-5-me thoxypyrazin-2- yl)phenyl)ethyl phenylcarbamate (6.4 mg, 7.6 pmol, 32 % yield). NMR (500 MHz, DMSO-d6) 8 10.60 (s, 1H), 10.25 (br s, 1H), 9.77 (br d, 1=7.3 Hz, 1H), 8.79 (d, 1=2.1 Hz, 1H), 8.23 - 8.14 (m, 1H), 7.99 (dd, J=6.3, 2.3 Hz, 1H), 7.74 (br t, 1=9.2 Hz, 2H), 7.52 (dd, 1=10.8, 8.7 Hz, 1H), 7.42 (br d, J=7.6 Hz, 2H), 7.37 (br t J=9.8 Hz, 1H), 7.28 (br t, J=7.9 Hz, 2H), 7.03 (brt, 1=7.3 Hz, 1H), 6.42 (q, 1=7.1 Hz, 1H), 5.93 (q, J=7.6 Hz, 1H), 4.61 - 4.46 (m, 1H), 4.00 (s, 3H), 3.29 (br dd, J=11.0, 4.0 Hz, 1H), 3.24 (br s, 1H), 2.99 (br s, 1H), 2.05 - 1.87 (m, 2H), 1.48 (br d, J=8.2 Hz, 2H). LC-MS: 2.83 min; MS (ESI) m/z 844.28 (M+H); Method C.

Example 40

Intermediate 40-1

-0.

OMe O'

O' N

Br

To a solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-l-ol (0.17 mL, 1.3 mmol) dissolved in 1 mL of THE at 0 °C was added sodium hydride (0.051 g, 1.3 mmol) and the reaction mixture stirred for 45 min. The resulting solution was added to a precooled solution of methyl 5-bromo-2-fluoronicotinate (0.30 g, 1.3 mmol) dissolved in THF (26 mL) at 0 °C and the reaction mixture was allowed to warm to room temperature over 72 h. Tire reaction mixture was concentrated under reduced pressure and purified via silica gel chromatography to furnish methyl 5-bromo-2-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)nicotinate (0.20 g, 0.56 mmol, 43 % yield) MS (ESI) m/z 383.7 (M+Na).

Intermediate 40-2

O _x ,0 B

R

.OtBu

O

To a solution of 40-1 (1.0 g, 3.6 mmol) dissolved 1,4-dioxane (9.1 mL) was added bis(pinacolato)diboron (1.8 g, 7.3 mmol), potassium acetate (1.1 g, 11 mmol), and PdCh(dppf)-DCM adduct (0.30 g, 0.36 mmol) and the reaction was heated at 110 °C for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic phase separated, concentrated under reduced pressure and purified via silica gel chromatography to furnish tert-butyl 4-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzoate (1.0 g, 3.2 mmol, 88 % yield) ^! HNMR (500 MHz, CDCh) 8 8.40 (dd, .7=5.7, 2.4 Hz, 1H), 8.08 (ddd, J=8.6, 5.3, 2.4 Hz, 1H), 7.07 (t, .7=8.7 Hz, 1H), 1.62 (s, 9H), 1.39 (s, 12H)

Intermediate 40-3

.0.

OMe O'

O N

R

•OtBu

O

To 40-1 (0.053 g, 0.15 mmol), 40-2 (0.05 g, 0.2 mmol), 0.5 M aqueous K3PO4 (0.59 mL, 0.30 mmol), and THF (0.3 mL) in a flask was added Xphos-Pd-G2 (3 mg, 3 pmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer separated, dried over NaiSO* decanted and concentrated under reduced pressure. The residue was purified via silica gel chromatography to furnish methyl 5-(5-(tert-butoxycarbonyl)-2-fluorophenyl)-2-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (47 mg, 0.099 mmol, 67 % yield). MS (ESI) m/z 498.0 (M+Na).

Intermediate 40-4

.0.

OH O'

0 N

F.

•OtBu

O

To a solution of 40-3 (0.047 g, 0.099 mmol) dissolved in THE (0.4 mL) was added water (0.1 mL) and lithium hydroxide monohydrate (4.2 mg, 0.10 mmol) and the reaction mixture stirred for 16 h. The reaction mixture was diluted with water and EtOAc neutralized by the addition of - 0.2 mL of IN HQ. The organic layer was separated and concentrated under reduced pressure to furnish 5-(5-(tert-butoxycarbonyl)-2- fluorophenyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nic otinic acid (46 mg, 0.10 mmol, 100 % yield) which was used without further purification. MS (ESI) m/z 462.1 (M+H).

To a mixture of V-2 (0.043 g, 0.100 mmol), DIEA (0.052 mL, 0.299 mmol), and 40-4 (0.046 g, 0.10 mmol) slurried in MeCN (1 mL) was added HAITI (0.038 g, 0.100 mmol) and the reaction mixture stirred for 16 h. Water (0.1 mL) and TEA (0.23 mL) was added to the reaction mixture and the resulting solution stirred for 16 h. The reaction mixture concetrated under reduced pressure and the residue purified via preparative HPLC to fiimish 4-fluoro-3-(5-(((lR,2R,3S,4R,Z)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylid ene)bicyclo[2.2.1]heptan-2- yl)carbamoyl)-6-(2-hydroxyethoxy)pyridin-3-yl)benzoic acid (5 mg, 7 pmol, 7 % yield):

NMR (500 MHz, DMSO-de) 5 10.65 (s, 1H), 9.82 (br d, J=7.3 Hz, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.12 (br d, .7=4.3 Hz, 1H), 8.09 - 8.04 (m, 1H), 8.04 - 7.98 (m, 1H), 7.82 - 7.72 (m, 1H), 7.52 - 7.39 (m, 2H), 5.94 (q, J=7.6 Hz, HI), 4.75 - 4.64 (m, 1H), 4.65 - 4.53 (m, 2H), 4.03 - 3.83 (m, 2H), 3.29 (br dd, > 10.7, 4.3 Hz, 1H), 3.22 (br s, 1H), 3.01 (br s, HI), 2.05 (br d, .7=8.5 Hz, 2H), 1.53 (br d, .7=7,9 Hz, 2H). LC-MS: 2.27 min; MS (ESI) m/z 699.97 (M+H); Method C.

Example 42

F ₃ C F

HN •CF ₃

T‘t

O N

R

H

,.'O. ^N 'Ph

CF ₃ O

Intermediate 42-1

To a mixture of 40-1 (0.051 g, 0.14 mmol), 34-3 (0.050 g, 0.16 mmol), 0.5 M aqueous K3PO4 solution (0.57 mL, 0.284 mmol), and THE (0.28 mL) in a flask was added XPhos- Pd-G2 (2.4 mg, 2.8 pmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was separated, dried over NaiSCh decanted and concentrated under reduced pressure. The residue was purified via silica gel chromatography to furnish methyl 5-(2-fluoro-5-((S)-2,2,2- trifluoro-l-hydroxyethyl)phenyl)-2-(2-((tetrahydro-2H-pyran- 2-yl)oxy)ethoxy)nicotinate (0.031 g, 0.065 mmol, 46 % yield). MS (ESI) m/z 360.8 (M+H).

Intermediate 42-1 was hydrolyzed with aqueous LiOH in THF and coupled with amine as described in the general procedure for example 1 which was subsequently dissolved in DCM (1.6 mL). To this solution was added pyridine (0.025 mL, 0.31 mmol) and phenyl isocyanate (9 pL, 0.08 mmol) and the reaction mixture stirred for 16 h. The reaction solution was concentrated under reduced pressure and the residue dissolved in a mixture of 0.8 mL MeCN and 0.2 mb water with 0.1 mL TFA. After 1 h, the reaction solution was concentrated under reduced pressure and the residue purified by HPLC prep to furnish (S)-2,2,2-trifluoro-l-(4-fluoro-3-(5-(((lR,2R,3S,4R,Z)-3-((4 -fluoro-3- (trifhioromethyl)phenyl)carbamoyl)-7 -(2,2,2-trifhioroethylidene)bicyclo [2.2.1 ]heptan-2- yl)carbamoyl)-6-(2-hydroxyethoxy)pyridin-3-yl)phenyl)ethyl phenylcarbamate (3.2 mg, 3.7 pmol, 23 % yield): NMR (500 MHz, DMSO-de) 5 10.64 (s, 1H), 10.29 (br s, 1H), 9.85 (br d, J=7.3 Hz, 1H), 8.54 (br s, 1H), 8.46 (s, 1H), 8.13 (br d, J=4.0 Hz, 1H), 7.85 (br d, J=7.0 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.69 (br d, .7=4.9 Hz, 1H), 7.57 - 7.42 (m, 4H), 7.31 (br t, <7=7.8 Hz, 2H), 7.05 (brt, .7=7.3 Hz, 1H), 6.65 - 6.51 (m, 1H), 5.95 (q, .7=8,1 Hz, 1H), 4.81 (t, J=5.6 Hz, 1H), 4.74 - 4.65 (m, 1H), 4.61 (dt, J=10.8, 5.3 Hz, 2H), 4.05 - 3.84 (m, 2H), 3.22 (br s, 1H), 3.02 (br s, 1H), 2.04 (br d, .7=11.3 Hz, 2H), 1.53 (br d, .7=7.9 Hz, 2H). Analytical LC-MS: 2.95 min; MS (ESI) m/z 873.3 (M+H); Method C.

Example 49

Intermediate 49-1

OH OMe

O N

OH To a solution of VII- 1 (0.022 g, 0.10 mmol) dissolved in THF (0.8 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (4 mg, 0.1 mmol) and the reaction mixture stirred for 16 h. Hie reaction was neutralized to pH 6 by the addition of IM HC1 and extracted into EtOAc. The organic layer was separated, dried over NaiSO-t, and the fluid was decanted and concentrated under reduced pressure. The residue was used without further purification, : 5 -(3 -hydroxyprop- l-yn-l-yl)-2-methoxynicotinic acid (0.02 g, 0. 1 mmol, 100 % yield). MS (ESI) m/z 208.0 (M+H).

N-[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carb amoyl}-7-(2,2,2- trifluoroethylidene)bicyclo[2.2. l]heptan-2-yl] -5 -(3 -hydroxyprop- 1 -yn- 1 -yl)-2- methoxypyridine-3-carboxamide was prepared viaHATU coupling between 5-2 and 49-2 as described in the general procedure for example 1. (17 mg, 0.029 mmol, 29 % yield).1H NMR (500 MHz, DMSO-d6) 5 10.67 (s, 1H), 10.03 (d, J=6.7 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.27 - 8.17 (m, 2H), 7.84 - 7.76 (m, 1H), 7.50 (t, 1=9.8 Hz, 1H), 5.94 (q, 1=7.9 Hz, 1H), 4.55 - 4.43 (m, 1H), 4.32 (d, J=5.8 Hz, 2H), 4.10 (s, 3H), 3.28 (dd, 1=11.0, 4.0 Hz, 1H), 3.23 (br s, 1H), 3.00 (br s, 1H), 2.00 - 1.83 (m, 2H), 1.58 - 1.42 (m, 2H). Analytical LC-MS: 1.16 min; MS (ESI) m/z 586.20 (M+H); Method C.

Example 50

N-[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carb amoyl}-7-(2,2,2- trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]-5-(3-hydroxyp ropyl)-2-methoxypyridine- 3 -carboxamide was prepared via HATU coupling between V-2 and VII-3 as described by the general procedure for example 1. (21 mg, 0.035 mmol, 31 % yield). Tl NMR (500 MHz, DMS0-d6) 5 10.66 (s, 1H), 9.98 (d, 1=7.0 Hz, 1H), 8.21 (dd, 1=6.3, 2.3 Hz, 1H), 8.14 (dd, J=13.6, 2.3 Hz, 2H), 7.86 - 7.73 (m, 1H), 7.49 ft, J=9.6 Hz, 1H), 5.92 (q, J=7.6 Hz, 1H), 4.56 - 4.43 (m, 1H), 4.04 (s, 3H), 3.39 (t, 1=6.3 Hz, 1H), 3.26 (dd, J=1 1.0, 4.3 Hz, HI), 3.22 (br s, 1H), 2.99 (br s, 1H), 2.61 (t, 1=7.6 Hz, 2H), 2.03 - 1 .93 (m, HI), 1.90 - 1.79 (m, 1H), 1.73 - 1.63 (m, 2H), 1.49 (br d, 1=7.9 Hz, 2H). Analytical LC-MS: 2.36 min; MS (ESI) m/z 590.25 (M+H); Method C.

Example 51

N -[(2R,3 S,7Z)-3 - { [4-fluoro-3 -(trifluoromethyl)phenyl]carbamoyl } -7 -(2,2,2- trifluoroethylidene)bicyclo [2.2.1 ]heptan-2-yl] -2-methoxy-5 -propylpyridine-3 - carboxamide was isolate from example 50 as byproduct from over reduction product from the hydrogenation in the preparation of intermediate 50-1. (2.1 mg, 0.0032 mmol, 2.8 % yield). ^} H NMR (500 MHz, DMSO-d6) 5 10.66 (s, 1H), 9.98 (br d, 1=7.0 Hz, 1H), 8.23 (br dd, 1=6.3, 2.6 Hz, 1H), 8.18 - 8.06 (m, 2H), 7.84 - 7.72 (m, 1H), 7.50 (br t, 1=9.9 Hz, HI), 5.93 (q, 1=7.8 Hz, 1H), 4.58 - 4.41 (m, 1H), 4.05 (s, 3H), 3.33 - 3.17 (m, 2H), 3.00 (s, 2H), 2.05 - 1.76 (m, 2H), 1.64 - 1.40 (m, 4H), 0.86 (t, J=7.3 Hz, 3H). Analytical LC-MS: 2.87 min; MS (ESI) m/z 574.12 (M+H); Method C.

Example 53

Intermediate 53-1

To a solution of tert-butyl 3 -iodobenzoate (0.21 g, 0.71 mmol) dissolved in DMSO (4.7 mL) was added proline (11 mg, 0.094 mmol), ethyl 3-methoxy-lH-pyrazole-4- carboxylate (0.08 g, 0.5 mmol), K2CO3 (0.13 g, 0.94 mmol), and copper(I) iodide (9 mg, 0.05 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was partitioned between water and EtOAc and the organic layer was separated and dried over Na?.SO4. The fluid was decanted and concentrated under reduced pressure and the residue purified via silica gel chromatography to produce ethyl l-(3-(tert- butoxycarbonyl)phenyl)-3-methoxy-lH-pyrazole-4-carboxylate (92 mg, 0.27 mmol, 57 % yield). MS (ESI) m/z 347.3 (M+H).

3 -(4- { [(2R,3 S,7Z)-3 - { [4-fluoro-3 -(trifluoromethyl )phenyl]carbamoyl }-7-(2,2,2- trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-3-m ethoxy-lH-pyrazol-l- yl)benzoic acid was prepared via hydrolysis of the methyl ester 53-1 with LiOH followed by amide formation with V-2 under HATU conditions and deprotection as outlined example 26 to produce example 53. (8.8 mg, 0.14 mmol, 50 % yield). ^! HNMR (500 MHz, DMSO-d6) 5 10.66 (s, 1H), 8.99 (br d, J=7.0 Hz, 1H), 8.77 (br s, 1H), 8.46 - 8.16 (m, 2H), 8.04 (br d, J=7.3 Hz, 1H), 7.95 - 7.75 (m, 2H), 7.74 - 7.58 (m, 1H), 7.51 (br t, 1=9.6 Hz, 1H), 5.93 (q, 1=7.6 Hz, 1H), 4.57 - 4.43 (m, 1H), 4.10 (s, 3H), 3.26 (br dd, 1=11.1, 3.5 Hz, 1H), 3.18 (br s, 1H), 3.04 - 2.93 (m, 1H), 1.97 (br d, 1=9.5 Hz, HI), 1.92 - 1.83 (m, 1H), 1.57 - 1.42 (m, 2H). Analytical LC-MS: 2.44 min; MS (ESI) m/z 641.23 (M+H); Method C.

Example 55

Intermediate 55-1

1 . LHMDS, diethyloxalate. THF

2. hydrazine, AcOH. THF 85 ’C O,

OEt

3. NaH, Toluene/THF; difluoroethyltriflate 70 °C o

N

NC H

NC

Intermediate 55-1. To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.47 g, 2.8 mM) dissolved in THE (5 mL) was added LHMDS (4.1 mL, 4.1 mM) and diethyloxalate (0.40 g, 2.8 mM). Tire reaction mixture was stirred at rt 16 h, followed by tiie addition of AcOH (10 mL), and hydrazine (66 mg, 2.1 mmol). The reaction mixture was heated at 85 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 7-cyano-4,5-dihydro-lH-benzo[g]indazole-3-carboxylic acid which was redissolved in a mixture of toluene/THF (8:3, 15 mL) and Nall (60% wt in dispersion oil) (83 mg, 2.07 mmol) was added. The reaction mixture was stirred at rt for 1 h followed by the addition of the difluoroethyltriflate (440 mg, 2. 1 mmol). The reaction mixture was heated at 70 °C for 18h, allowed to cool. Water (25 mL) was added to the reaction mixture and the solution was extracted with EtOAc (2 x 25mL), the combined organic portions dried over MgSCh, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography to afford ethyl 2-(6-cyano-l-oxo- 1 ,2,3,4-tetrahydronaphthalen-2-yl)-2-oxoacetate (520 mg, 1.6 mmol 76 %). TI NMR (400 MHz, CDCh) 57.76 - 7.69 (m, 1H), 7.68 - 7.62 (m, 2H), 6.38 - 6.14 (tt, J=55.3, 4.6 Hz, 1H), 4.92 - 4.79 (m, 2H), 4.69 - 4.41 (m, 2H), 3.11 - 2.87 (m, 4H), 1.75 - 1.23 (m, 3H). MS (ESI) m/z = 332.08 (M+H).

Intermediate 55-2. The intermediate 55-1 (520 mg, 1.6 mmol) was dissolved in a solution of MeOH/THF (5: 1, 25 mL and water 5 mL). To this solution was added LiOH (75 mg, 3.2 mmol) and the stirred at rt for 16 h. The reaction was diluted with HC1 and extracted with EtOAc (2 x 100 mL), The conmbined organic portions were dried over MgSOt, filtered, and concetrated under reduced pressure to afford 55-2 (420 mg, 88 %). *HNMR (400 MHz, CDaOD) 5 7.90 (d, J=8.1 Hz, 1H), 7.80 - 7.71 (m, 2H), 6.40 (tt, N54.9, 4.0 Hz, 1H), 5.08 - 4.90 (m, 2H), 3.11 - 2.94 (m, 4H). MS (ESI) m/z = 304.08 (M+H).

Example 55. 7-cyano-l-(2,2-difluoroethyl)-N-((lR,2R,3S,4R,Z)-3-((4-fluor o-3- (trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylid ene)bicyclo[2.2.1]heptan-2- yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide was prepared by the general coupling method described for example 1 using the trifluoromethyl norbomyl intermediate V-2 and intermediate 55-2. (2.1 mg, 3.1 mmol, 48 % yield) ‘HNMR (500 MHz, DMSO-d6) 5 10.74 - 10.65 (m, 1H), 9.33 (br d, J=7.2 Hz, 1H), 8.16 (br s, 1H), 7.86 (br s, 2H), 7.81 (br s, 1H), 7.76 (br s, 1H), 7.57 - 7.45 (m, 1H), 6.49 (br s, 1H), 5.95 (br d, J=6.5 Hz, 1H), 5.05 (br t, J=14.5 Hz, 2H), 4.47 (br s, 1H), 3.27 (br d, J=9.8 Hz, 1H), 3.02 - 2.92 (m, 2H), 2.89 (br s, 2H), 1.99 - 1.80 (m, 2H), 1.52 (br d, J=1.1 Hz, 2H). MS (ESI) m/z = 682.3 (M+H). HPLC Purity: 99.2 %; Retention Time: 2.54 min. Method B.

Example 56 Intermediate 56-1:

OMe OMe

O N

Me

OtBu

O

Ethyl 5-(3-(tert-butoxycarbonyl)phenyl)-2-hydroxy-6-methylnicotina te (50 mg, 0.19 mmol), (3-(tert-butoxycarbonyl)phenyl)boronic acid (130 mg, 0.58 mmol) and Pd- XPhos G3 (12 mg, 0.014 mmol) were placed in a pressure vial. Then THF (2 mL) and phosphoric acid, potassium salt (0.5 M aq.) (0.77 mL, 0.38 mmol) were added, and the reaction mixture was degassed (3X, reduced pressure/Ar). The pressure vial was capped, and the reaction mixture was stirred at 120 °C for 30 min. The reaction mixture was filtered, diluted with EtOAc, washed with water, concetrated under reduced pressure and purified via silica gel chromatography to afford intermediate 56-1 (40 mg, 58%) as a white powder. MS (ESI) m/z = 358.2 (M+H).

A solution of 56-1 (40 mg, 0.34 mmol) in THF (1.0 mL) and water (0.34 mL) was treated with LiOH solution (1 M, 0.37 mL, 0.37 mmol). The solution was stirred at rt for 24 h. The reaction mixture was acidified by the addition of HC1 (1.0 M) to pH 1 then extracted with EtOAc. The organic layer was dried over NazSO* decanted and concentrated under reduced pressure to afford a clear oil which was dissolved in DMF (1.0 mL) and treated with V-2 (25 mg, 0.06 mmol), HATU (26 mg, 0.07 mmol), and DIEA (0.03 mL, 0.2 mmol). After 18 h, The reaction mixture was concentrated under reduced pressure then purified by prep HPLC to give 3-(5-(((lR,2R,3S,4R,Z)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)-7 -(2,2,2-trifluoroethylidene)bicyclo [2.2.1 ]heptan-2- yl)carbamoyl)-6-hydroxy-2-methylpyridin-3-yl)benzoic acid, example 56 (11.0 mg, 16.9 mmol, 24%). TlNMR (500 MHz, CD ₃ OD) 5 10.95 (d, .7=8.5 Hz, 1H), 8.28 (s, 1H), 8.06 (d, J=7.4 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.78 - 7.69 (m, 1H), 7.63 - 7.52 (m, 2H), 7.24 ft, .7=9.6 Hz, 1H), 5.76 (d, J=7.7 Hz, 1H), 4.79 (dd, .7=10.3, 4.8 Hz, 1H), 3.31 - 3.25 (m, 1H), 3.25 - 3.19 (m, 1H), 2.94 (t, ,7=3.9 Hz, 1H), 2.52 (t, .7=9.5 Hz, 1H), 2.36 (s, 3H), 2.17 (d, .7=4.1 Hz, 1H), 1.65 (t, .7=13.6 Hz, 2H). LCMS (Method: XBridge Phenyl 3.5 pm, 3.0x150 mm: Solvent A: 5% ACN, 95% water, 0.05% TFA; Solvent B: 5% water, 95% ACN, 0.05% TEA; 10 to 100% B over 15 min; flow rate: 1 .0 mL/min; detection at 220 nm and 254 nm.) Rt = 13.2 min, m/z ™ 652.08 (M+H).

Example 59

Boc

To a solution of IV-4 (0.10 g, 0.27 mmol) dissolved in DCM (2.7 mL) was added BOC2O (0.32 mL, 1.4 mmol), DIEA (0.24 mL, 1.4 mmol), and DMAP (17 mg, 0.14 mmol). The reaction mixture was stirred for 14h, concentrated under reduced pressure andthe residue purified with silica gel chromatography to afford tert-butyl ((lR,2S,3R,4R,Z)-3-((tert- butoxycarbonyl)amino)-7 -(cyclopropylm ethylene)bicyclo [2.2.1 ]heptane-2-carbonyl)(4- fluoro-3-(trifluoromethyl)phenyl)carbamate (0.11 g, 0.19 mmol, 71 % yield) LC-MS RT: 1.37 min; MS (ESI) m/z = 569.3 (M+H) ⁺ ; Method A.

Intermediate 59-1 Boc

To a solution of IX-1 (0.11 g, 0.19 mmol) dissolved in DCM (1.3 mL) was added 2,2- dimethylpropan-l-amine (0.14 g, 1.5 mmol). The reaction mixture was stirred overnight and concentrated under reduced pressure, then the residue was purified with silica gel chromatography to afford tert-butyl ((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3- (neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate (69 mg, 0.18 mmol, 95 % yield). LC-MS RT: 1 .21 min; MS (ESI) m/z = 377.3 (M+Hf; Method A.

Intermediate 59-2

To a flask containing 59-1 (69 mg, 0.18 mmol) was added a solution of HC1 (4 M in dioxane) (1.5 mL, 6.0 mmol) and the reaction mixture was stirred 1 h. The reaction mixture was concentrated under reduced pressure and azeotroped with hexanes under reduced pressure to afford (lR,2S,3R,4R,Z)-3-amino-7-(cyclopropylmethylene)-N- neopentylbicyclo[2.2.1]heptane-2-carboxamide (67 mg, 0.18 mmol, 100 % yield) as a hydrochloride salt, which was used without further manipulation. LC-MS RT: 0.87 min; MS (ESI) m/z = 277.1 (M+H) ⁺ ; Method A.

Intermediate 59-3

To a solution of methyl 5 -bromo-2-m ethoxynicotinate (1 .2 g, 4.9 mmol) dissolved in

DMF (24 mL) was added 2-isocyano-2-methylpropane (0.66 mL, 5.9 mmol), triethylsilane (0.78 mL, 4.9 mmol), 2-(dicyclohexylphosphino)biphenyl (68 mg, 0.20 mmol) and NaiCCh (520 mg, 4.9 mmol). The reaction mixture was degassed with nitrogen for 5 mins before Pd(OAc)2 (33 mg, 0.15 mmol) was added and the reaction mixture was heated to 65 °C for 18h. The reaction mixture was allowed to cool to room temperature, diluted with 10% LiCl aqueous solution and ethyl acetate, then extracted with ethyl acetate. The organic portions were dried over sodium sulfate, filtered and partially concentrated (~5 mL solvent left) under reduced pressure. To this solution was added 1 M HC1 (50 mL) and the resulting solution stirred for 2 hours, then quenched with 1 M sodium carbonate to pH 9. The reaction mixture was extracted with ethyl acetate (3 x 30 mL), the organic portions dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified with column chromatography to methyl 5- formyl-2-methoxynicotinate (390 mg, 2.0 mmol, 41% yield) as a white solid. ^! H NMR (500 MHz, CDCh) 5 10.04 (s, 1H), 8.81 (d, J=25 Hz, 1H), 8.64 (d, J=2.2 Hz, 1H), 4.18 (s, 3H), 3.96 (s, 3H). LC-MS RT: 0.73 min; MS (ESI) m/z = 196.1 (M+H) ⁺ ; Method A.

Intermediate 59-4

,OH vOMe

,N

H

59-3 (390 mg, 2.0 mmol) was dissolved in THF (8 mL) and water (2 mL) and lithium hydroxide monohydrate (110 mg, 2.6 mmol) were added and the reaction mixture stirred for 30 hours. The reaction mixture was neutralized with IN HQ and ethyl acetate added The resulting solution was extracted 3x with ethyl acetate. The combined organic portions were washed with brine, dried over NaiSCU and concentrated under reduced pressure to afford 5-formyl-2-methoxynicotinic acid (340 mg, 1.9 mmol, 96 % yield), which was used without further purification. LC-MS RT: 0.57 min; MS (ESI) m/z = 182.1 (M+H) ⁺ ; Method A.

Intermediate 59-5

N,N-dimethylformarnide di-tert-butyl acetal (2.5 mL, 11 mmol) was added dropwise to a solution of 59-4 (340 mg, 1.9 mmol) dissolved in toluene (0.5 mL). The solution was heated to 80 °C for 30h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (30 mL), dried over NaiSCh , filtered and then concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford tert-butyl 5-formyl- 2-methoxynicotinate (200 mg, 0.85 mmol, 45 % yield). ^] H NMR (500 MHz, CDCh) 8 10.03 (s, 1H), 8.77 (d, J=2.2 Hz, 1H), 8.54 (d, 1=2.2 Hz, 1H), 4.17 (s, 3H), 1.63 (s, 9H). LC-MS RT: 0.89 min; MS (ESI) m/z = 238.1 (M+Hf; Method A.

Intermediate 59-6

OH

N

O'

To a solution of 59-5 (200 mg, 0.85 mmol) dissolved in ethanol (8.5 mL) was added NaBHt (34 mg, 0.89 mmol) and the reaction mixture was stirred at it for 4 hours. The reaction mixture was partitioned between ethyl acetate & water and the organic portion was washed with brine, dried over NaiSOi and concentrated under reduced pressure to afford tert-butyl tert-butyl 5-(hydroxymetbyl)-2-methoxynicotinate (170 mg, 0.72 mmol, 85 % yield), which was used without further purification. Tl NMR (500 MHz, CDCh) 5 8.28 (d, >2.5 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 4.70 (d, 1=5.5 Hz, 2H), 4.07 (s, 3H), 1.69 (t, J=5.6 Hz, 1H), 1.62 (s, 9H). LC-MS RT: 0.81 min; MS (ESI) m/z = 240.3 (M+H) ⁺ ; Method A. Intermediate 59-7

Br

O'

C< O

To a solution of 59-6 (170 mg, 0.72 mmol) dissolved in DCM (3.6 mL) was added triphenylphosphine (280 mg, 1.1 mmol) and CBn (36 mg, 1.1 mmol). The reaction mixture was stirred at rt for 18h. The reaction mixture was concentrated under reduced pressure, then purified by silica gel chromatography to afford tert-butyl 5- (hydroxymethyl)-2-methoxynicotinate (180 mg, 0.60 mmol, 82 % yield). ^! H NMR (500 MHz, CDCla) 8 8.31 (d, 1=2.5 Hz, 1H), 8.12 (d, J=2.5 Hz, 1H), 4.50 (s, 2H), 4.06 (s, 3H), 1.62 (s, 9H). LC-MS RT: 1.06 min; MS (ESI) m/z = 302.1 (M+H) ⁺ ; Method A.

Intermediate 59-8

To a solution of methyl 1-hydroxycyclopropane-l-carboxylate (52 mg, 0.45 mmol) dissolved in THF (1.3 mL) cooled to 0 °C was added tetrabutylammonium iodide (10 mg, 0.03 mmol) and NaH (18 mg, 0.45 mmol). The reaction mixture was wanned to rt and stirred for another 15 min before a solution of 59-7 (80 mg, 0.27 mmol) dissolved in THF (1.3 mL) was added dropwise. Hie reaction was stirred at rt for 3 d. The reaction was diluted water, and the aqueous solution was extracted 3x with ethyl acetate. The organic portions were washed with brine, dried over NaiSCh and concentrated under reduced pressure to afford tert-butyl 2-methoxy-5-((I- (methoxycarbonyl)cyclopropoxy)methyl)nicotinate (87 mg, 0.26 mmol, 98% yield) which was used without further purification. LC-MS RT: 1.03 min; MS (ESI) m/z = 338.3 (M+H) ⁺ ; Method A. Intermediate 59-9

N

O'

To a solution of 59-8 (87 mg, 0.26 mmol) dissolved in a mixture of THF (2 mL) and water (0.67 mL) was added lithium hydroxide monohyrdate (16 mg, 0.36 mmol) and the reaction mixture was stirred at rt for 24 h. The reaction mixture was neutralized with IN

HC1 and extracted with ethyl acetate (3x). The organic portions were washed with brine, dried over NaiSCh and concentrated under reduced pressure to afford l-((5-(tert- butoxycarbonyl)-6-methoxypyridin-3-yl)methoxy)cyclopropane-l -carboxylic acid (76 mg, 0.24 mmol, 92 % yield) which was used without further purification. LC-MS RT: 0.91 min; MS (ESI) m/z = 324.2 (M+H) ⁺ ; Method A.

Intermediate 59-10

To a solution of 59-9 (76 mg, 0.24 mmol) dissolved in an THF (2.0 ml) and cooled to 0 °C was added borane (0.47 mL, 0.47 mmol, IM in THF) and stirred at rt for 18h. The reaction mixture was quenched with IN HC1 (0.5 mL) and then extracted with ethyl acetate (3x). The organic portions were washed with brine, dried overNaiSCh and concentrated under reduced pressure to afford tert-butyl 5-((l- (hydroxymethyl)cyclopropoxy)methyl)-2-methoxynicotinate (72 mg, 0.23 mmol, 99 % yield), which was used without purification. LC-MS RT: 0.89 min; MS (ESI) m/z = 310.3 (M+H) ⁺ ; Method A. Intermediate 59-11

To a solution of 59-10 dissolved in DCM (1.7 mL) was added TEA (0.6 mL) and stirred at rt for 18h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate, washed with IM potassium phosphate solution (pH 7.4) followed by brine, dried over NaiSCh. The aqueous portion was then brought to pH 1 with IN HC1, and extracted 3x with ethyl acetate and the organic portions were washed with brine, dried over NasSCh and combined with the other organics portions and concentrated to afford 5-((l-(hydroxymethyl)cyclopropoxy)methyl)-2-methoxynicotinic acid (57 mg, 0.22 mmol, 97% yield) which was used without further purification. LC-MS RT: 0.62 min; MS (ESI) m/z = 254.1 (M+H) ⁺ ; Method A.

Example 59: To a solution of 59-11 (13 mg, 0.051 mmol) and 59-2 hydrogen chloride salt (9.7 mg, 0.031 mmol) dissolved in DMF (0.4 mL) was added BOP (16 mg, 0.037 mmol) and DIEA (0.027 mL, 0.15 mmol) and stirred for 1.5 h. The reaction mixture was diluted with MeOH and filtered through a syringe filter and purified with HPLC to afford N-[(lR,2R,3S,4R,7Z)-7-(cyclopropylmethylidene)-3-[(2,2- dimethylpropyl)carbamoyl]bicyclo [2.2.1 ]heptan-2-yl] -5 - { [( 1 - hydroxycyclopropyl)methoxy]methyl}-2-methoxypyridine-3-carbo xamide (6.9 mg, 0.013 mmol, 43%). ^! HNMR (500 MHz, DMSO-de) 5 10.03 (br d, .7=7.0 Hz, 1H), 8.22 (d, ,7=2.1 Hz, 1H), 8.18 (d, .7=2.1 Hz, 1H), 8.00 - 7.92 (m, 1H), 4.77 (t, J=5.8 Hz, 1H), 4.63 (d, .7=9.8 Hz, 1H), 4.57 (s, 2H), 4.33 - 4.23 (m, 1H), 4.02 (s, 3H), 3.58 (d, J=5.8 Hz, 1H), 3.07 - 2.95 (m, 2H), 2.81 (brdd, J=13.0, 5.6 Hz, 1H), 1.90 - 1.81 (m, 1H), 1.76 - 1.67 (m, 1H), 1.51 - 1.42 (m, 1H), 1.33 (brt, J=9.8 Hz, 2H), 0.81 (s, 9H), 0.75 - 0.66 (m, 4H), 0.60 - 0.52 (m, 2H), 0.32 (br d, <7=2.7 Hz, 2H). LC-MS RT: 2.20 min; MS (ESI) m/z = 512.5 (M+H) ⁺ ; Method B. Example 61

Intermediate 61-1

O O

O N

A mixture of 5-bromo-6-methoxynicotinaldehyde (0.85 g, 3.9 mmol), TEA (0.5 mL, 3.9 mmol), Pd(OAc)2 (0.18 g, 0.80 mmol), dppf (0.65 g, 1.2 mmol) was slurried in DMSO (10 mL) and MeOH (7 mL) in steel reaction vessel. The reaction mixture was placed under CO (g) at 70 psi and heated to 80 °C for 18h. Tire reaction mixture was allowed to cool, then partitioned with water (20 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic portions were washed with brine (15 mL) and dried (MgSO*) and concetrated under reduced pressure. The resudue was purified with silica gel chromatography to afford methyl 5-formyl-2- methoxynicotinate (0.74 g, 3.8 mmol, 96 % yield). ’H NMR (500 MHz, CDCla) 5 10.03 (s, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.64 (d, J=2.3 Hz, 1H), 4.18 (s, 3H), 3.96 (s, 3H). LCMS (ESI) m/z\ 196.2 (M+H) ⁺

Intermediate 61-2

O O

O N

N

6H To a solution of 61-1 (0.59 g, 3.0 mmol) dissolved in DCM (15 mL) was added hydroxylamine hydrochloride (0.25 g, 3.6 mmol) followed by TEA (1.3 mL, 9.0 mmol) and the reaction mixture was stirred overnight. The reaction mixture was concetrated under reduced pressure and water (50 mL) was added. The resulting solid was collected by filtration and dried to afford methyl (£)-5-((hydroxyimino)methyl)-2- methoxynicotinate (0.43 g, 2.0 mmol, 68%) which was used without further purification. *HNMR (500 MHz, CDCh) 8 8.45 (s, 2H), 8.14 (s, 1H), 4.10 (s, 3H), 3.94 (s, 3H). LCMS (ESI) m/z\ 211.1 (M+Hf

Intermediate 61-3

O o

O N

Cl N OH

To a solution of 61-2 (0.24 g, 1.1 mmol) dissolved in DMF (3 mL) was added NCS (0.18 mg, 1.4 mmol) and the mixture was stirred overnight. The reaction mixture was diluted with water and the resultant solid was collected by filtration to afford methyl (Z)-5- (chloro(hydroxyimino)methyl)-2-methoxynicotinate (0.24 g, 1.0 mmol, 86%) which was used without purification. ⁱ H NMR (500 MHz, CDCh) 8 8.80 (d, .7=2.6 Hz, IH), 8.60 (d, J-1.6 Hz, IH), 7.88 (s, IH), 4.12 (s, 3H), 3.95 (s, 3H). LCMS(ESI) m/z\ 245.1 (M+H) ⁺

Intermediate 61-4

O 0

O N hr X o ,0

To 61-3 (200 mg, 0.82 mmol) in DCM (5 mL) was added 2,5 -dihydrofuran (0.57 g, 8.2 mmol) and TEA (0.34 mL, 2.5 mmol). After 24h, the solvent was removed under vacuum and the residue was purified by normal phase silica gel chromatography, using hexanes/EtOAc as eluents, to afford methyl 2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4- d]isoxazol-3-yl)nicotinate (160 mg, 0.56 mmol, 69 % yield). LCMS(ESI) m/z\ 279.1 (M+H) ⁺

Intennediate 61-5 (isomer 1), and 61-6 (isomer 2):

O O

0 N

N ' o .0

61-4 was subjected to chiral separtion SFC using the following conditions: Column: Chiralpak IA, 21 x 250 mm, 5 micron, Mobile Phase: 40%-60% MeOH / 60%-40% CO ₂ , Flow ⁷ Conditions: 90 mL/min, 150 Bar, 40°C,; Analytical method: Column Chiralpak IA, 4.6 x 250 mm, 3 micron, Mobile Phase: 25% MeOH / 75% CO2, Flow Conditions: 2 mL/min, 150 Bar, 40°C, to afford chiral peak-1, (RT=1.91 min., >99% ee), 61-5 (30 mg, 0.11 mmol, 13 % yield). ^] H NMR (500 MHz, CDCla) 5 8.53 (d, J=2.4 Hz, 1H), 8.50 (d, .7=2.4 Hz, 1H), 5.55 - 5.29 (m, 1H), 4.36 (d, .7=10.8 Hz, 1H), 4.31 (s, 1H), 4.16 (dd, .7=9.5, 1.1 Hz, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 3.90 (dd, .7=9,5, 6.7 Hz, 1H), 3.81 (dd, J=11.0, 3.8 Hz, 1H) and chiral peak-2, (RT=7.51 min., >99% ee), 61-6 (38 mg, 0.14 mmol, 17% yield). ^L H NMR (500 MHz, CDCh) 5 8.53 (d, .7=2.4 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 5.46 - 5.41 (m, 1H), 4.36 (d, .7=10.8 Hz, 1H), 4.31 (s, 1H), 4.16 (dd, J=9.5, 1.2 Hz, HI), 4.11 (s, 3H), 3.94 (s, 3H), 3.91 (d, .7=6.7 Hz, HI), 3.81 (dd, .7=10.8, 4.0 Hz, 1H).

Intennediate 61-7

To a solution of 61-6 (38 mg, 0.14 mmol) dissolved in THF (1 mL) and MeOH (0.5 mL) cooled to 0 °C was added 1 M aq. LiOH (0.41 mL, 0.41 mmol) and the reaction mixture was stirred for 14h. Hie reaction mixture was neutralized with IN HC1 and solvent volume reduced under reduced pressure. The resdiue was freeze-dried to afford 2- methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-7]isoxazol-3-yl)nico tinic acid (36 mg, 0.14 mmol, quant.) which was used without purification. *HNMR (500 MHz, DMSO-ck) 5 8.20 (s, 1H), 7.84 - 7.68 (m, 1H), 5.32 (dd, 7=9.2, 3.5 Hz, 1H), 4.61 - 4.37 (m, 1H), 4.09 (d, 7=10.7 Hz, 1H), 3.91 (d, 7=8.9 Hz, 1H), 3.83 (s, 3H), 3.77 (dd, 7=9.4, 6.9 Hz, 1H), 3.65 (dd, 7=10.5, 3.7 Hz, 1H). LCMS(ESI) m/z: 265.1 (M+H) ⁺

Example 61. To a solution of IV-4 (9.8 mg, 26 Dmol), 61-7 (7 mg, 26 Cmol), BOP (13 mg, 29 Dmol) dissolved in DMF (1 mL) was added DIEA (14 BL, 79 □mol. After 24h, the reaction mixture was purified by reverse phase HPLC to afford example 5- {3aH,4H,6H,6aH-furo[3,4-d][l,2]oxazol-3-yl}-N-[(lR,2R,3S,4R, 7Z)-7- (cyclopropylmethylidene)-3-{[4-fluoro-3- (trifluoromethyl)phenyl]carbamoyl}bicyclo[2.2.1]heptan-2-yl] -2-methoxypyridine-3- carboxamide (12 mg, 17 Dmol, 64 % yield). NMR (500 MHz, DMSO-de) 5 10.66 - 10.49 (m, 1H), 10.04 (d, 7=7.0 Hz, 1H), 8.68 - 8.46 (m, 2H), 8.23 (dd, J-6.5, 2.5 Hz, 1H), 7.80 (br dd, 7=7.8, 3.8 Hz, 1H), 7.49 (t, 7=9.8 Hz, 1H), 5.39 (dd, 7=9.2, 3.6 Hz, 1H), 4.70 (d, ,7=9.5 Hz, 1H), 4.55 (brt, 7=7.8 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.14 (s, 3H), 4.11 (d, 7=10.7 Hz, 1H), 3.96 (br d, 7=9.2 Hz, 1H), 3.77 (dd, 7=9.5, 6.8 Hz, 1H), 3.67 (dd, 7=10.9, 3.7 Hz, 1H), 3.17 (br dd, 7=11.1, 3.9 Hz, 1H), 3.12 (br s, 1H), 2.74 (br s, 1H), 1.86 - 1.67 (m, 2H), 1.59 - 1.47 (m, 1H), 1.44 - 1.29 (m, 2H), 0.89 - 0.66 (m, 2H), 0.45 - 0.21 (m, 2H). LCMS(ESI) m/z; 615.3 (M+H) ⁺ RT= 2.54 min., method B.

Example 65: Intermediate 65-1, 65-2, and 65-3:

O OMe

HO" N

N ^z

O' _ -NH ₂ O

Cyclopent-3-ene-l -carboxamide (1.2 g, 11 mmol) was added dropwise to a solution of methyl (Z)-5-(chloro(hydroxyimino)methyl)-2-methoxynicotinate 59-3 (0.88 g, 3.6 mmol) dissolved in DCM (36 mL) followed by addition of TEA (1.5 mL, 11 mmol). After 12h, the reaction mixture was concentrated under reduced pressure, then purified by normal phase chromatography. The residue was dissolved in THF/MeOH (1: 1, 10 mL) and treated with LiOH monohydrate (450 mg, 11 mmol) dissolved in H2O (3 mL). After 3h, the reaction mixture was made slightly acidic with LON HC1 solution and the solution was concentrated under reduced pressure. The remaining aqueous layer was extracted with EtOAc (3 x 20 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The benzoic acid 65-1 (85 mg, 0.28 mmol, 8.0 % yield) and was used withouth further purification. LC-MS RT = 1.079 min; (M+H) ⁺ = 329.1; Method B.

Individual chiral diastereomer nicotinic acid intermediates 65-2 and 65-3 were obtained by chiral SFC of diasteremeric mixture intermediate 65-1 (85 mg, 0.28 mmol). Chiral SFC Preparative chromatographic conditions: Instrument: PIC Solution SFC Prep-200; Column: Chiralpak AD-H, 21 x 250 mm, 5 micron; Mobile Phase: 35% MeOH / 65% CO2; Flow ⁷ Conditions: 45 mL/min, 150 Bar, 40°C; Detector Wavelength: 220 nm; Injection Details: L0 mL of~16.25mg/mL. Analytical Chromatographic Conditions: Instrument: Shimadzu Nexera SFC; Column: Chiralpak AD-H, 4.6 x 100 mm, 3 micron; Mobile Phase: 35% MeOH / 65% CO2; Flow Conditions: 2.0 mL/min, 150 Bar, 40°C; Detector Wavelength: 220 nm; Injection Details: 5 pL of ~lmg/mL in MeOH.

Intermediate 65-2 (Peak 1: >95%ee; chiral analytical RT = 1.70 min) was obtained as a film (25 mg, 0.080 mmol, 29%). ^! H NMR (500 MHz, DMSO-d6) 5 13.28 (br s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.30 (d, 1=2.1 Hz, 1H), 7.33 (br s, 1IT), 6.80 (br s, 1H), 5.16 (dd, J=8.7, 5.0 Hz, 1H), 4.31 (t, 1=8.8 Hz, 1H), 3.94 (s, 3H), 2.08 (dd, 1=13.8, 6.0 Hz, 1H), 2.04 - 1.86 (m, 4H).

Intermediate 65-3 (Peak 2; >95%ee; chiral analytical RT = 2.80 min) was obtained as a film (25 mg, 0.080 mmol, 29%). ^! H NMR (500 MHz, DMSO-d6) 8 8.50 (br s, 1H), 8.21 (br s, 1H), 7.36 (br s, 1H), 6.82 (br s, 1H), 5.18 (dd, J=8.5, 5.0 Hz, 1H), 4.32 (t, J=8.9 Hz, 1H), 3.94 (s, 3H), 2.60 - 2.53 (m, 1H), 2.10 (dd, J=13.8, 6.0 Hz, 1H), 2.06 - 1.89 (m, 4H).

Example 65 was prepared as described in example 59 using 65-2 (23 mg, 0.075 mmol) and IV-4 to afford 3-(5-(((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fhioro -3- (trifluoro-methyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl )carbamoyl)-6- methoxypyridin-3-yl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]is oxazole-5-carboxamide (isomer-1) (26 mg, 0.038 mmol, 50 % yield). ^} H NMR (500 MHz, DMSO-d6) 8 10.54 (s, 1H), 10.05 (d, 1=7.0 Hz, 1H), 8.61 - 8.57 (m, 2H), 8.23 (dd, 1=6.6, 2.6 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.50 (t, J=9.8 Hz, 1H), 7.34 (s, 1H), 6.82 (s, 1H), 5.19 (dd, 1=8.7, 5.0 Hz, HI), 4.70 (d, J=9.6 Hz, 1H), 4.43 (ddd, J=10.2, 6.3, 4.0 Hz, 1H), 4.33 (t, J=8.9 Hz, 1H), 4.14 (s, 3H), 3.17 (dd, J=10.6, 4.3 Hz, 1H), 3.12 (t, J=3.5 Hz, 1H), 2.74 (t, J=3.4 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.13 - 1.88 (m, 4H), 1.84 - 1.75 (m, 2H), 1.54 - 1.47 (m, 1H), 1.44 - 1.40 (m, 1H), 0.79 - 0.70 (m, 2H), 0.38 - 0.32 (m, 2H). LC-MS (M+H) = 656.3; HPLC RT = 1.34 min; Method A.

Example 71: Intermediate 71-1

O O

O'

Br

To a solution of sodium methoxide, 0.5 M in MeOH (3.4 mL, 1.7 mmol) was added methyl 2-bromo-5 -fluoroisonicotinate (0.33 g, 1.4 mmol) and the reaction mixture was stirred at rt for 18h. The reaction mixture was partitioned between EtOAc and water, and the organic portion was washed with brine, dried over Na2SOt, filtered and concentrated under reduced pressure to afford methyl 2-bromo-5 -methoxyisonicotinate (240 mg, 0.97 mmol, 69 % yield), which was used without further purification. NMR (500 MHz, CDCh) 5 8.21 (s, 1H), 7.76 (s, 1H), 4.01 (s, 3H), 3.96 (s, 311). LC-MS RT: 0.82 min; MS (ESI) m/z == 248.1 (M+H) ⁺ ; Method A.

Intermediate 71-2

Intermediate 71-2 was prepared from 71-1 according to the general method described for the preparation of 61-1 to afford methyl 2-formyl-5-methoxyisonicotinate (24 mg, 0.13 mmol, 27 % yield) LC-MS RT: 0.65 min; MS (ESI) m/z = 196.1 (M+H)+; Method A.

Intermediate 71-3

Intermediate 71-3 was prepared from 71-2 according to the general method described for the preparation of 61-7 to afford 5-methoxy-2-(3a,4,6,6a-tetrahydrofiiro[3,4-d]isoxazol-3- yl)isonicotinic acid (18 mg, 0.068 mmol, 54 % yield over 4 steps). LC-MS RT: 0.58 min;

MS (ESI) m/z = 265.1 (M+H) ⁺ ; Method A.

Intermediate 71-4

Intermediate 71-4 was prepared from 71-3 and 1V-4 according to the general method described forthe preparation of example 59 to afford a mixture of diastereomers N- ((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3- (trifhioromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl) -5-methoxy-2-(3a,4,6,6a- tetrahydrofuro[3,4-d]isoxazol-3-yl)isonicotinamide (30 mg, 0.048 mmol. 70 % yield) ^! H NMR. (500 MHz, DMSO-d6) 8 10.55 (s, 1H), 10.01 (dd, 1=6.8, 3.7 Hz, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 8.23 (br d, 1=6.1 Hz, 1H), 7.78 (br dd, 1=8.3, 4.1 Hz, 1H), 7.49 (t, 1=9.8 Hz, 1H), 5.38 (dt, J=9.2, 2.9 Hz, 1H), 4.70 (d, 1=9.5 Hz, 1H), 4.51 - 4.39 (m, 2H), 4.17 (s, 3H), 4.14 - 4.06 (m, 2H), 3.83 - 3.74 (m, 1H), 3.66 (dd, 1=10.8, 3.5 Hz, 1H), 3.17 (br dd, J=11.0, 4.3 Hz, 1H), 3.13 (br s, 1H), 2.74 (br s, 1H), 1.86 - 1.73 (m, 2H), 1.58 - 1.48 (m, 1H), 1.47 - 1.33 (m, 2H), 0.81 - 0.66 (m, 2H), 0.35 (br d, 1=4.0 Hz, 2H). LC-MS RT: 2.53 min: MS (ESI) m/z = 615.05 (M+H) ⁺ ; Method B.

Example 71 (isomer 1) and 72 (isomer 2)

71-4 was subjected to SFC-chiral chromatography with the following conditions: Column: Chiral AS 30 x 250 mm. 5 micron; Mobile phase: 65% CO2/ 35% MeOH w/0.1%DEA; Flow' conditions: 100 mL/min; Analytical chromatographic conditions: Column: Chiral AS, 4.6 x 100 mm, 5 micron; Mobile phase: 65% CO2/ 35% MeOH w/0.1%DEA; Flow conditions: 2 mL/min; Peak 1 (71), RT = 1.2 min, >95% ee, 1H NMR (500 MHz, DMSO-d6) 8 10.56 (s, 1H), 10.01 (br d, 1=6.7 Hz, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.27 - 8.19 (m, 1H), 7.85 - 7.74 (m, 1H), 7.49 (brt, 1=9.5 Hz, 1H), 5.39 (br dd, 1=9.3, 3.2 Hz, 1H), 4.71 (br d, J=9.8 Hz, 1H), 4.52 - 4.37 (m, 2H), 4.17 (s, 3H), 4.15 - 4.03 (m, 2H), 3.79 (br dd, 1=9.0, 7.2 Hz, 1H), 3.67 (br dd, J=10.4, 3.1 Hz, 1H), 3.18 (br dd, 1=10.7, 3.4 Hz, 1H), 3.13 (br s, 1H), 2.74 (br s, 1H), 1.87 - 1.71 (m, 2H), 1.59 - 1.48 (m, 1H), 1.46 - 1 .32 (m, 2H), 0.84 - 0.61 (m, 2H), 0.36 (br s, 2H), LC-MS RT: 2.44 min; MS (ESI) m/z = 614.9 (M+Hf; Method B.; Peak 2 (72), RT = 3.0 min, > 95% ee, 1H NMR (500 MHz, DMSO-d6) 5 10.57 (s, 1H), 10.02 (br d, J=6.7 Hz, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.23 (br d, 1=3.7 Hz, 1H), 7.79 (br d, 1=7.9 Hz, 1H), 7.50 (br t, 1=9.6 Hz, HI), 5.39 (br dd, 1=9.0, 2.9 Hz, 1H), 4.71 (br d, 1=10.1 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.17 (s, 3H), 4.16 - 4.05 (m, 2H), 3.85 - 3.74 (m, 1H), 3.71 - 3.63 (m, 1H), 3.18 (br dd, 1=10.2, 2.9 Hz, 1H), 3.13 (br s, 1H), 2.75 (br s, 1H), 1.80 (br dd, J=10.4, 9.2 Hz, 2H), 1.53 (br d, 1=5.8 Hz, HI), 1.43 (br s, 2H), 0.84 - 0.64 (m, 2H), 0.36 (br s, 2H), LC-MS RT: 2.43 min; MS (ESI) m/z = 614.9 (M+Hf; Method B.

Example 74:

Intermediate 74-1:

To a solution of example 78 (0.10 g, 0.17 mmol) dissolved in DCM (6 mL) was added TFA (0.26 mL, 3.3 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure to afford 5-(((lR,2R,3R,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)bicyclo [2.2.1 ]heptan-2-yl)carbamoyl)-6- methoxynicotinic acid (80 mg, 0.15 mmol, 88 % yield) which was used without further purification. LC-MS RT: 0.46 min, method E; MS (ESI) m/z = 548.2 (M+H)~.

Example 74 was prepared by the general procedure described for example 1 using 74-1 (20. mg, 0.037 mmol) and (l-(methylsulfonyl)cyclopropyl)methanamine hydrochloride (10. mg, 0.055 mmol) to afford N3-((lR,2R,3R,4R,Z)-7-(cyclopropylmethylene)-3-((4- fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo [2.2.1 Jheptan-2-yl)-2-methoxy-N5 - ((l-(methylsulfonyl)cyclopropyl)methyl)pyridine-3,5-dicarbox amide (6.5 mg, 9.2 pmol, 25 % yield). LC-MS RT: 2.3 min, method A. MS (ESI) m/z = 679.2 (M+Hf. 1H NMR (400 MHz, DMSO-d6) 5 10.54 (s, 1H), 10.03 (d, 1=7.1 Hz, 1H), 8.87 (t, 1=6.1 Hz, 1H), 8.81 - 8.76 (m, 1H), 8.76 - 8.66 (m, 1H), 8.23 (dd, 1=6.7, 2.6 Hz, 1H), 7.84 - 7.74 (m, 1H), 7.49 (t, J=10.0 Hz, 1H), 4.70 (d, J=9.5 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.14 (s, 3H), 3.83 (d, J=6.1 Hz, 2H),3.20 - 3.13 (m, 1H), 3.13 - 3.09 (m, 1H), 3.06 (s, 3H), 2.78 - 2.71 (m, 1H), 1.85 - 1.72 (m, 2H), 1.56 - 1.44 (m, 1H), 1.44 - 1.34 (m, 2H), 1.29 - 1.21(m, 3H), 1.17 - 1.11 (m, 2H), 0.79 - 0.68 (m, 2H), 0.36 (dd, J=4.4, 2.0 Hz, 2H). Example 77:

Intermediate 77-1:

To a solution of methyl 4-methoxy-lH-pyrazole-5-carboxylate (250 mg, 1.6 mmol) dissolved in DMF (10 mL) was added K2CO3 (660 mg, 4.8 mmol) followed by 1-chloro- 2-(methylsulfonyl)ethane (340 mg, 2.4 mmol). The reaction mixture was stirred at 70 °C for 5 h. The reaction mixture was diluted with EtOAc (20ml), filtered through celite, then tiie filtrate was concentrated under reduced pressure to afford mixture of regioisomers (250 mg, 0.95 mmol, 60 % yield). The mixture was used without further purification. LCMS RT: 0.53 min; method E; MS (ESI) m/z = 263.2 (M+H) ⁺ .

Intermediate 77-2:

OH

0

0

N ^/Z oj To a solution of 77-1. (0.2 g, 0.763 mmol) dissolved in MeOH (10 mL) cooled to 0 °C was added a solution of 2N aq LiOH (0.037 g, 1.5 mmol). Hie reaction mixture was allowed to warm to it. over 3 h thenconcentrated under reduced pressure and the residue was dissolved in water (5 mL). The aqueous portion was acidified with 1.5 N HQ and the resulting precipitate was filtered and dried under reduced pressure to yield a mixture of regioisomers (0.12 g, 0.37 mmol, 48 % yield). The mixture was used without further purification. LC-MS RT: 0.31 min; method E; MS (ESI) m/z = 249.2 (M+H) ⁺ .

Example 77 was prepared by the general procedure described for example 1 using 77-2 and IV-4 afford N-[(lR,2R,3S,4R,7Z)-7-(cyclopropylmethyhdene)-3-{[4-fluoro-3 - (trifhioromethyl)phenyl] carbamoyl }bicyclo [2.2.1 ]heptan -2-yl] - 1 -(2- methanesulfonylethyl)-4-methoxy-lH-pyrazole-3-carboxamide (5 mg, 8 pmol, 6 % yield). LC-MS RT: 3.47 min: method C; MS (ESI) m/z = 599.2 (M+H) ⁺ . 1HNMR (400 MHz, DMSO-d6) 8 ppm 10.51 (s, 1 H) 9.24 (d, 1=7.53 Hz, 1 H) 8.22 (dd, 1=6.53, 2.51 Hz, 1 H) 7.75 - 7.81 (m, 1 H) 7.58 (s, 1 H) 7.49 (t, 1=9.79 Hz, 1 H) 4.76 - 4.95 (m, 1 H) 4.42 (br s, 1 H) 3.92 (s, 3 H) 3.57 (t, 1=7.03 Hz, 1 H) 3.36 - 3.39 (m, 1 H) 3.22 - 3.29 (m, 1 H) 3.14 (dd, 1=10.79, 4.27 Hz, 2 H) 3.06 (br s, 1 H) 2.96 (s, 2 H) 2.68 - 2.73 (m, 1 H) 2.52 - 2.56 (m, 2 H) 2.34 - 2.47 (m, 2 H) 1.63 - 1.89 (m, 1 H) 1.46 - 1.58 (m, 2 H) 1.42 (br s, 2 H) 1.24 (s, 1 H).

Example 78: Intermediate 78-1:

O O

O N

O O

A solution of 6-methoxy-5-(methoxycarbonyl)nicotinic acid (3.5 g, 17 mmol) was dissolved in toluene (100 mL) and heated to 80 °C. To the solution was added 1,1-di-tert- butoxy-N,N-dimethylmethanamine (40 mL, 170 mmol) and the resulting solution stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (2x75 ml), and the combined organic portion washed with water (2 x 50 mL). The organic portion was dried over Na2$O4, filtered and concentrated under reduced pressure, then purified with silica gel chromatography eluted with 0 - 30 % EtOAc in petroleum ether to afford 5 -(tert-butyl) 3 -methyl 2- methoxypyridine-3,5-dicarboxylate which was used without further purification (3.7 g, 14 mmol, 84 % yield).LCMS RT = 1.90 min, method E, LCMS(ESI) m/z = 268.2 (M+H) ⁺ .

Intermediate 78-2:

OH o

O' N

O O

A solution of 78-1 (400 mg, 1.5 mmol) dissolved in THF (25 mL) was cooled to 0°C and IN aqueous solution of NaOH (3.0 mL, 3.0 mmol ) was added. The reaction mixture was allowed to warm to rt over 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (2ml) and the aqueous phase washed with diethyl ether (10ml). The aqueous portion was acidified with 1.5 N HQ to pH 4 and the resultant precipitate was filtered and dried under reduced pressure to afford 5-(tert- butoxycafbonyl)-2-methoxynicotinic acid (210 mg, 0.83 mmol, 55 % yield) which was used without further purification. LCMS RT = 0.80 min, method E. LCMS(ESI) m/z = 254.2 (M+H) ⁺ . Example 78 was prepared by the general coupling procedures described for example 1 using IV-4 (10 mg, 0.027 mmol) and 78-2 (6.87 mg, 0.027 mmol) to afford tert-butyl 5- (((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-

(trifluoromethyl)pheny l)carbamoy l)bicyclo [2.2.1 ]heptan-2-yl)carbamoyl)-6- methoxynicotinate (9.2 mg, 0.014 mmol, 53 % yield). LC-MS RT: 2.92 min; [A] MS (ESI) m/z = 604.2 (M+H). 1H NMR (400MHz, DMSO-d6) 5 = 10.54 (s, 1H), 10.02 (d, J=6.8 Hz, 1H), 8.80 (d, 1=2.4 Hz, 1H), 8.68 (d, J=2.2 Hz, 1H), 8.22 (dd, 1=2.7, 6.6 Hz, 1H), 7.84 -7.75 (m, 1H), 7.49 (t, 1=9.7 Hz, 1H), 4.70 (d, 1=9.5 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.15 (s, 3H), 3.20 - 3.14 (m, 1H), 3.13 - 3.09 (m, 1H), 2.76 - 2.71 (m, 1H),1.83 - 1.73 (m, 2H), 1.60 - 1.45 (m, 13H), 1.44 - 1.37 (m, 2H)

Example 81:

Intermediate 81-1

OH

F

O.

O

A solution of 2-bromoprop-2-en-l-ol (1.4 g, 10 mmol) dissolved in DMF (15 mL) was treated with (2-fluoro-5-(methoxycarbonyl)phenyl)boronic acid (2.0 g, 10 mmol), potassium phosphate (3.4 mL, 10 mmol), and chloro(2-dicyclohexylphosphino-2’,4’,6’- triisopropyl-l,l’-biphenyl)[2-(2’ -amino- l,r-biphenyl)]palladium(II) (0.08 g, 0.10 mmol) and the reaction mixture sparged with nitrogen for 10 min, sealed, and stirred at 65 °C for 3h. The reaction mixture was neutralized with IN HC1, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure, then purified with reverse phase purification to afford methyl 4-fluoro-3-(3-hydroxyprop-l-en-2-yl)benzoate (1.0 g, 4.7 mmol, 47 % yield). MS (ESI) m/z; 211.1 (M+H).

Intermediate 81-2

O. .0

O

0 o

F-

.0

O.

To a round bottom flask containing 81-1 (0.50 g, 2.4 mmol) and rhodium(II) acetate dimer (48 mg, 0.11 mmol) was added toluene (10 mL) and the reaction mixture heated at reflux. To the reaction mixture was added a solution of 1 -(tert-butyl) 3 -methyl 2- diazomalonate (0.43 g, 2.2 mmol) dissolved in Toluene (2 mL) over a period of 5 minutes and the resulting solution stirred for 30 min. The reaction mixture was concentrated under reduced pressure then purified with silica gel chromatography to afford 1 -(tert-butyl) 3- methyl 2-((2-(2-fluoro-5-(methoxycarbonyl)phenyl)allyl)oxy)malonate (610 mg, 1.6 mmol, 71 % yield). MS (ESI) m!z; 211.1 (M+Hf-

Intermediate 81-3

N Q / o

O O

Vx O

F-

O.

O To a solution of 81-2 (612 mg, 1.6 mmol) dissolved in DCM (10 mL) was added dimethylmethylideneammonium iodide (440 mg, 2.4 mmol) followed by TEA (0.34 mL, 2.4 mmol) and the reaction mixture stirred for 14h. The reaction mixture was concentrated under reduced pressure then purified with silica gel chromatography to afford 1 -(tert-butyl) 3-methyl 2-((dimethylamino)methyl)-2-((2-(2-fluoro-5- (methoxycarbonyl)phenyl)allyl)oxy)malonate (420 mg, 0.96 mmol, 57% yield). MS (ESI) m!z\ 440.2 (M+H) ⁺ .

Intermediate 81-4

N O. / O o

F.

.0.

O

To a solution of 81-3 (420 mg, 0.94 mmol) dissolved in acetone (10 mL) was added methyl iodide (0.089 mL, 1.4 mmol) and the reaction mixture stirred for 14h. Hie reaction mixture was concentrated tmder reduced pressure to afford 3-(tert-butoxy)-2-((2- (2-fluoro-5-(methoxycarbonyl)phenyl)allyl)oxy)-2-(methoxycar bonyl)-N,N,N-trimethyl- 3-oxopropan-l-aminium (430 mg, 0.94 mmol, quant.) which was used without further purification. ^] H NMR (400MHz, DMSO-de) 8 8.02 - 7.94 (m, 2H), 7.45 - 7.36 (m, 1H), 5.70 (s, 1H), 5.54 (s, 1H), 4.63 (s, 2H), 4.14 - 4.01 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.05 (s, 9H), 1.46 (s, 9H).

Intermediate 81-5

O. ,0 o

F. o

O.

To a solution of 81-4 (430 mg, 0.94 mmol) dissolved in DMSO (6 mL) was added a IM solution of sodium hydroxide (1.1 mL, 1 .1 mmol) and the reaction mixture stirred for 3 h at it. The reaction mixture was concentrated under reduced pressure then purified using silica gel chromatography to afford methyl 3-(3-((3-(tert-butoxy)-3-oxoprop-l-en-2- yl)oxy)prop-l-en-2-yl)-4-fluorobenzoate (210 mg, 0.62 mmol, 66% yield). MS (ESI) mlz\ 3313 (M+H) ⁺ .

Intermediate 81-6

O

0

F-

.0

O

To a solution of 81-5 (200 mg, 0.6 mmol) dissolved in DMSO (30 mL) was added (Ir[dF(CF3)ppy]2(dtbpy))-PF6 (7 mg, 6 pmol) and the reaction mixture was degassed under vacuum and backfilled with N2 3x. The reaction mixture was irradiated with blue

LED for 60 h. The reaction mixture was diluted with brine, extracted with ethyl acetate, the organic portion concentrated under reduced pressure, then purified with silica gel chromatography to afford tert-butyl 4-(2-fluoro-5-(methoxycarbonyl)phenyl)-2- oxabicyclo[2.1.1]hexane-l-carboxylate (120 mg, 0.36 mmol 57 % yield). MS (ESI) m/z'. 337.0 (M+H). Intermediate 81-7 o

7~OH

O

F.

.0.

O

To a solution of 81-6 (120 mg, 0.36 mmol) dissolved in DCM (2.4 mL) was added TEA (0.6 mL, 8 mmol) and the reaction mixture stirred at room temperature for 30 min. Tire reaction mixture was concentrated under reduced pressure to afford 4-(2-fluoro-5- (methoxycarbonyl)phenyl)-2-oxabicyclo [2. l.l]hexane-l -carboxy lie acid (100 mg, 0.36 mmol, quant.) which was used without further purification . MS (ESI) m!z\ 280.0 (M+H) ⁺ .

Intermediate 81-8:

81-8 was prepared from intermediate V-2 and intermediate 81-7 according to the general procedure outlined for Example 1 to afford methyl 4-fluoro-3-(l-(((lR,2R,3S,4R,Z)-3- ((4-fluoro-3 -(trifluoromethyl)phenyl)carbamoyl)-7 -(2,2,2- trifluoroethylidene)bicyclo[2.2. l]heptan-2-yl)carbamoyl)-2-oxabicyclo[2.1 . l]hexan-4- yl)benzoate (16 mg, 0.020 mmol, 38 % yield). MS (ESI) m!z; 659.3 (M+H) ⁺ .

Example 81 wasprepared from intermediate 81-8 as outlined in Example 26, then purified with HPLC to afford 4-fluoro-3-(l-(((lR,2R,3S,4R,Z)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylid ene)bicyclo[2.2.1]heptan-2- yl)carbamoyl)-2-oxabicyclo[2.1.1]hexan-4-yl)benzoic acid (6.9 mg, 0.01 mmol, 59% yield). ¹ HNMR (500MHz, DMSO-de) 8 10.65 (s, 1H), 9.05 (d, J=7.2 Hz, 1H), 8.04 - 7.97 (m, 1H), 7.95 - 7.88 (m, 1H), 7.87 - 7.79 (m, 2H), 7.51 (t, .7=9,7 Hz, 1H), 7.35 - 7.28 (m, III), 5.93 (q, ,7=7.8 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.03 (d, .7=5.5 Hz, 1H), 3.98 (d, .7=5.4 Hz, 1H), 3.23 (dd, J=10.7, 4.2 Hz, 1H), 3.14 (br. s., 1H), 2.97 (br. s., 1H), 2.37 (dd, .7=14.9, 7.0 Hz, 2H), 2.19 - 2.12 (m, 1H), 2.11 - 2.03 (m, 1H), 1.88 - 1.77 (m, 2H), 1.49 (d, .7=7.8 Hz, 2H); LC-MS (M+H) = 645.2; RT = 2.03 min; Method B.

Example 82:

H H .

F

H ''NH°OMe CF ₃

0

N Boc

Intermediate 82-1:

Bn

NBoc

To a solution of 6-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (5.0 g, 20 mmol) in DCM (100 mL) were added TEA (14 mL, 100 mmol), DMAP (0.25 g, 2.0 mmol) and Boc-anhydride (5.6 mL, 24 mmol) at 0 °C, then the reaction mixture was stirred at rt for 12h. The volatiles were removed under reduced pressure, the residue was diluted with EtOAc (2 x 100 mL), the organic portion washed with water, dried (Na^SO*), concentrated under reduced pressure, then purified with silica chromatography to afford tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (4.5 g, 14 mmol, 72 % yield). LCMS: MS (ES):m/z = 214.1 [M+2H-Boc],

Intermediate 82-2:

Pd2(dba)3 (1.5 g, 1.6 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.0 g, 2.4 mmol) were added to 82-2 (5.0 g, 16 mmol), methanol (6.5 mL, 160 mmol) and CS2CO3 (26 g, 80 mmol) dissol ved in dioxane (80 mL) at rt, degassed with nitrogen for 5 min, then stirred at 85 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, then purified with silica gel chromatography to afford tert-butyl 6-methoxy-3,4-dihydroisoquinoline-2(lH)-carboxylate (4.0 g, 15 mmol, 95 % yield). LCMS: MS (ES):/n/z = 164.1 [M+H-Boc],

Intermediate 82-3: o.

NBoc

Br

NBS (4.1 g, 23 mmol) was added to a solution of 82-2 (6.0 g, 23 mmol) dissolved in acetonitrile (100 mL) at rt and the reaction mixture was stirred for 5h. The reaction mixture was concentrated under reduced pressure and the residue was extracted with EtOAc. The organic portion was washed with water, dried over NaiSCh, concentrated, then purified with silica gel chromatography, elution with 25-45 % EtOAc in petroleum ether to afford tert-butyl 7-bromo-6-methoxy-3,4-dihydroisoquinoline-2(lH)-carboxylate (5.0 g, 15 mmol, 64 % yield). LCMS: MS (ESy.m/z = 288.0 [M+2H-tBu|.

Intermediate 82-4:

, ₀

O NBoc

.0

To a solution of 82-3 dissolved in methanol and degassed with bubbling nitrogen (70 mL) and DMF (70 mL) was added TEA (4.5 mL, 32 mmol), Pd(OAc)?. (0.14 g, 0.64 mmol) and dppf (0.54 g, 0.96 mmol) at rt. The reactionmixture was stirred at under CO (g) at 10 kg pressure and 100 °C in an autoclave for 16 h. The reaction mixture was concentrated under reduced pressure, the residue diluted with EtOAc, filtered through celite and the filter cakewashed with EtOAc. The filtrate was concentrated under reduced pressure, then purified by with silica chromatography, elution with 30-35 % EtOAc in petroleum ether to afford 2 -(tert-butyl) 7-methyl 6-methoxy-3,4-dihydroisoquinoline-2,7(lH)- dicarboxylate (520 mg, 1.6 mmol, 25% yield). LCMS: MS (ES):m<z == 322.2 [M+H],

Intermediate 82-5:

.0

0 NBoc

OH

To a solution of 82-4 (350 mg, 1.1 mmol) dissolved in MeOH (5.0 mL) and THF (5.0 mL) was added a solution of LiOH (260 mg, 11 mmol) dissolved in water (3.0 mL) and the reaction mixture was stirred at it for 5 h. The solution was concentrated under reduced pressure, the residue diluted with water (10 mL), and washed with 20% EtOAc in petroleum ether (20 mL).The aqueous layer was acidified with 0.1N HC1 and the resultant precipitate was filtered, washed with water and dried under reduced pressure to afford 2- (tert-butoxycarbonyl)-6-methoxy-l ,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (260 mg, 0.85 mmol, 78 % yield) which was used without further purification. LCMS: MS (ES):m/z == 306.1 [M-H],

Example 82

Prepared from intermediate 82-5 and IV-4 according to the general procedure described for Example 1 to afford tert-butyl 7-(((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4- fluoro-3-(trifluoromethyl)phenyl) carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6- methoxy-3,4-dihydroisoquinoline-2(lH)-carboxylate (180 mg, 67 % yield). 1HNMR (400 MHz, DMSO-d6) 5 = 10.49 (s, 1H), 9.78 (d, J== 7.1 Hz, 1H), 8.21 (dd, J = 2.7, 6.6 Hz, 1H), 7.83 - 7.74 (m, 1H), 7.69 (s, 1H), 7.47 (t, J= 9.8 Hz, 1H), 6.97 (s, 1H), 4.67 (d, J= 9.5 Hz, 1H), 4.50 - 4.33 (m, 3H), 3.96 (s, 3H), 3.53 (br t, .7= 5.7 Hz, 2H), 3.14 (dd, J == 4.4, 10.8 Hz, 1H), 3.07 (t, J = ^: 3.4 Hz, 1H), 2.80 (t, J = 5.9 Hz, 2H), 2.70 (t, J--- 3.9 Hz, 1H), 1.85 (br d, J= 9.8 Hz, 1H), 1.80 - 1.72 (m, 1H), 1.49 (br dd, J= 4.6, 9.5 Hz, 1H), 1.46 - 1.31 (m, 12H), 0.81 - 0.64 (m, 2H), 0.34 (dd, J= 2.1, 4.5 Hz, 2H); LCMS: RT = 2.788 min, MS (ES):m/z = 658.4 [M+H ⁺ ] method B. Example 83:

H H ,

F

H ■'/ o NH ^u OMe CF ₃

0'

N

H

Example 83: To a solution of Example 82 (200 mg, 0.30 mmol) dissolved in DCM (5.0 mL) was added TFA (0.11 mL, 1.5 mmol) at 0°C, then the reaction mixture was stirred at it for 4 h. The reaction mixture was concentrated under vacuum and was triturated with diethyl ether to generate N-((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl) bicyclo [2.2.1 ]heptan-2-yl)-6-methoxy- 1 ,2,3 ,4- tetrahydroisoquinoline-7-carboxamide (160 mg, 0.29 mmol, 97 % yield) as an off white solid. LCMS: MS (ES):m/z = 558.3 [M+IIJ. Ill NMR (400 MHz, DMSO-d6) 5 = 10.48 (s, 1H), 9.75 (d, J = 7.1 Hz, 1H), 8.22 (dd, J = 2.4, 6.6 Hz, 1H), 7.82 - 7.71 (m, 1H), 7.58 (s, 1H), 7.47 (t, J = 9.8Hz, 1H), 6.86 (s, 1H), 4.67 (d, J = 9.8 Hz, 1H), 4.47 - 4.34 (m, 1H), 3.94 (s, 3H), 3.80 (s, 2H), 3.13 (dd, J = 4.2, 10.8 Hz, 1H), 3.09 - 3.04 (m, 1H), 2.99 - 2.89(m, 2H), 2.76 - 2.66 (m, 3H), 1.89 - 1.81 (m, 1H), 1.79 - 1.70 (m, 1H), 1.55 - 1.44 (m, 1H), 1.44 - 1.30 (m, 2H), 0.82 - 0.66 (m, 2H), 0.34 (dd, J = 2.0, 4.6 Hz,2H)

Example 84:

H H .

F

H ^z NH°OMe CF ₃

O'

N cr

To a solution of Example 83 (20.0 mg, 0.036 mmol) and l-chloro-2- (methylsulfonyl)ethane (5.1 mg, 0.036 mmol) in DMF (1.0 ml) and THF (1.0 mL) solvent mixture was added TEA (0.015 mL, 0.11 mmol) at it, and the reaction mixture stirred for 14h. The reaction mixture was purified via preparative IIPLC to afford N- (( 1 R,2R,3 S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl) bicyclo [2.2.1 ]heptan-2-yl)-6-methoxy-2-(2- (methylsulfonyl)ethyl)-l,2,3,4-tetrahydroisoquinoline-7-carb oxamide (6.7 mg, 27%) as a white solid. HI NMR (400 MHz, DMSO-d6) 5 ppm 10.47 (s, 1H), 9.76 (d, J = 7.3 Hz, 1H), 8.21 (dd, J == 2.6, 6.5 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.63 (s, 1H), 7.47 ft, J = 9.8 Hz, 1H), 6.90 (s, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.09 (q, J = 5.4 Hz, 1H), 3.94 (s, 3H), 3.57 (s, 2H), 3.38 (s, 3H), 3.20 - 3.10 (m, 2H), 3.06 (br t, J = 3.8 Hz, 1H), 2.99 (s, 3H), 2.90 - 2.79 (m, 4H), 2.74 - 2.66 (m, 3H), 1.91 - 1.83 (m, 1H), 1.81 - 1.74 (m, 1H), 1.55 - 1.33 (m, 3H), 0.80 - 0.65 (m, 2H), 0.34 (dd, J = 2.1, 4.8 Hz, 2H). LCMS: RT = 2.491 min, MS (ES):iwZz = 664.3 [M+HJ method B.

Example 85:

To a solution of Example 83 and l-chloro-2-methylpropan-2-ol (3.9 mg, 0.036 mmol) in DMF (1.0 mL) and THE (1.0 mL) was added TEA (0.015 mL, 0. 11 mmol) at rt, then the mixture was heated at 80 °C for 14 h. The reaction mixture was allowed to cool, concentrated under reduced pressure and purified via preparative HPLC to afford N- ((lR,2R,3S,4R,Z)-7-(cyclopropyhnethylene)-3-((4-fluoro-3-(tr ifluoromethyl)phenyl) carbamoyl)bicyclo [2.2.1 ]heptan-2-yl)-2-(2-hydroxy-2-m ethylpropyl)-6-methoxy- 1 , 2,3 ,4- tetrahydroisoquinoline-7-carboxamide (1 mg, 5 % yield). 1H NMR (4OO MHz, DMSO- d6) 8 ppm 10.48 (s, 1H), 9.75 (d, J = 7.6 Hz, 1H), 8.22 (dd, J = 2.3, 6.5 Hz, 1H), 7.83 - 7.72 (m, 1H), 7.57 (s, 1H), 7.48 (t, J = 9.9 Hz, 1H), 6.88 (s, 1H), 4.67 (d, J = 9.8 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.15 (s, 1H), 3.94 (s, 3H), 3.63 (s, 2H), 3.19 - 3.09 (m, 1H), 3.08 - 3.02 (m, 1H), 2.87 - 2.74 (m, 4H), 2.68 (br d, J = 8.6 Hz, 1H), 2.35 (s, 2H), 1.90 - 1.82 (m, 1H), 1.79 - 1.72 (m, 1H), 1.54 - 1.45 (m, 1H), 1.44 - 1.34 (m, 2H), 1.10 (s, 6H), 0.79 - 0.70 (m, 2H), 0.41 - 0.27 (m, 2H). LCMS: RT = 2.573 min, MS (ES):w/z = 630.4 [M+H] method B.

Example 88:

To a solution of Example 83 (20 mg, 0.036 mmol), and 2-methylpropane-l -sulfonyl chloride (11 mg, 0.072 mmol) in DCM (2.0 mL) was added TEA (0.015 mL, 0.11 mmol) at 0 °C, then the reaction mixture was stirred at rt for 14 h. Tire reaction mixture concentrated under reduced pressure and purified via preparative HPLC to afford N- ((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(tr ifluoromethyl)phenyl) carbamoyl)bicyclo[2.2.1] heptan-2-yl)-2-(isobutylsulfonyl)-6-methoxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide (6.2 mg, 27% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 = 10.50 (s, 1H), 9.80 (d, J= 1A Hz, 1H), 8.22 (dd, J = 2.8, 6.7 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.71 (s, 1H), 7.48 (t, J= 9.8 Hz, 1H), 6.99 (s, 1H), 4.68 (d, J= 9.8 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.34 (s, 2H), 3.96 (s, 3H), 3.51 - 3.40 (m, 2H), 3.14 (dd, J = 4.5, 10.9 Hz, 1H), 3.07 (t, J= 3.9 Hz, 1H), 2.98 (d, J = 6.6 Hz, 2H), 2.92 (brt, J = 6.0 Hz, 2H), 2.70 (t, J = 3.7 Hz, 1H), 2.12 (td, J= 6.6, 13.4 Hz, 1H), 1.89 - 1.66 (m, 2H), 1.56 - 1.45 (m, 1H), 1.45 - 1.29 (m, 2H), 1.03 (d, J= 6.8 Hz, 6H), 0.81 - 0.68 (m, 2H), 0.34 (dd, J = 2.0, 4.6 Hz, 2H). LCMS: RT = 2.465 min, MS (ESy.m/z = 658.3 [M+H ⁺ ] method B.

Example 90:

Intermediate 90-1:

To tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (4.0 g, 13 mmol), Pdz(dba)3 (1 2 g, 1.3 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.82 g, 1.9 mmol), methanol (5.2 mL, 130 mmol) and CS2CO3 (21 g, 64 mmol) in dioxane (80.0 mL) was degassed for 5 min, then the reaction mixture was stirred at 85 °C for 12h. The reaction mixture was allowed to cool to rt and diluted with EtOAc The solid was filtered and the filtrate was concentrated under reduced pressure, then purified with silica gel chromatography eluted with 20-25 % EtOAc in to afford tert-butyl 7-methoxy-3,4- dihydroisoquinoline-2(lH)-carboxylate (3.0 g, 11 mmol, 89 % yield. LCMS: MS (ES):m/z = 164.1 [M+H-Boc],

Intermediate 90-2:

.0.

Br

NBS (2.2 g, 12 mmol) was added to a solution of 90-1 (3.2 g, 12 mmol) in acetonitrile (60 mL) at rt and the reaction mixture was stirred at rt for 5h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with water, dried over NaiSO4 and concentrated under reduced pressure, then purified with silica gel chromatography eluted with 25-35 % EtOAc in petroleum ether to afford tertbutyl 6-bromo-7-methoxy-3,4-dihydroisoquinoline-2(lH)-carboxylate (3.0 g, 8.8 mmol, 72 % yield) LCMS: MS (ES):m ^z z = 244.0 [M+2H-Boc],

Intermediate 90-3:

To a solution of 90-2 (2.0 g, 5.8 mmol) dissolved in methanol (70 mL) and DMF (70 mL) and degassed with nitrogen was added TEA (4.1 mL, 29 mmol), Pd(OAc)z (0.13 g, 0.58 mmol) and dppf (0.49 g, 0.88 mmol) at rt. The reaction mixture was stirred at under CO (g) at 10 kg pressure and 100 °C in an autoclave for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and the solid was filtered through celite. Tire filter cake was washed with EtOAc, and the filtrate concentrated under reduced pressure, then purified with silica gel chromatography eluted with 30-40 % EtOAc in petroleum ether to afford 2-(tert-butyl) 6-methyl 7-methoxy-3,4- dihydroisoquinoline-2,6(lH)-dicarboxylate (1.2 g, 3.7 mmol, 64 % yield). LCMS: MS (ES):m/z == 322.2 [M+HJ.

Intermediate 90-4:

.0

HO.

O

LiOH (0.75 g, 31 mmol) dissolved in w ⁷ ater (5.0 mL) was added to a solution of 90-3 (1.0 g, 3.1 mmol) dissolved in methanol (10. mL) and tetrahydrofuran (10. mL). The reaction mixture was stirred for 14 h thenconcentrated tmder reduced pressure. The residue was diluted with water (10 mL), washed with 20 % EtOAc in petroleum ether (20 mL), the aqueous layer was acidified with 0. IN HC1 and the resultant precipitate was filtered, washed with water and dried tmder reduced pressure to afford 2-(tert-butoxycarbonyl)-7- methoxy- 1,2, 3, 4-tetrahydroisoquinoline-6-carboxylic acid (760 mg, 2.5 mmol, 79 % yield) which was used without further purification. LCMS: MS (ES):m ^z z = 306.2 [M-H],

Intermediate 90-5:

Intermediate 34-5 was prepared from intermediate 90-4 and IV-4 according to the general procedure described for Example 1 to afford tert-butyl 6-(((lR,2R,3S,4R,Z)-7- (cyclopropylmethylene)-3 -((4-fluoro-3 - (trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl) carbamoyl)-7-methoxy-3,4- dihydroisoquinoline-2( lH)-carboxylate (150 mg, 56% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.48 (s, 1H), 9.77 (d, J= 13 Hz, 1H), 8.21 (dd, J= 2.6, 6.5 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.70 (s, 1H), 7.48 (t, J= 9.7 Hz, 1H), 7.01 (s, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.53 (br s, 2H), 4.43 (br s, 1H), 3.95 (s, 3H), 3.53 (br t, J = 6.0 Hz, 2H), 3.17 - 3.10 (m, 1H), 3.06 (br s, 1H), 2.76 - 2.67 (m, 3H), 1.90 - 1.82 (m, 1H), 1.79 - 1.71 (m, 1H), 1.53 - 1.46 (m, 1H), 1.45 - 1.29 (m, 11H), 0.79 - 0.64 (m, 2H), 0.34 (dd, J= 2.0, 4.6 Hz, 2H). LCMS: RT = 2.788 min, MS (ES):m/z = 658.3 [M+H] method B.

Intermediate 90-6:

H H .

F

H NH ^u OMe CF ₃

O

NH

Intennediate 34-6 was prepared from 90-5 according to general procedure described for

Example 82. N-((lR,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3- (trifluoromethyl )phenyl)carbamoyl) bicyclo [2.2.1 ]heptan-2-yl)-7 -methoxy- 1 ,2,3 ,4- tetrahydroisoquinoline-6-carboxamide (150 mg, 0.27 mmol, 98 % yield). LCMS: MS (ESy.m/z = 558.3 [M+H],

Example 90:

To Intermediate 90-6 (20 mg, 0.036 mmol) and 3-bromopropan-l-ol (5.0 mg, 0.036 mmol) dissolved in THE (1.0 mL) and DMF (1.0 ml) was added TEA (0.015 mL, 0.11 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and stirred at rt for 14 h. The reaction mixture was purified with preparative HPLC to afford N-((l R,2R,3S,4R_Z)- 7-(cyclopropylmethylene)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1 ] heptan-2-yl)-2-(3 -hydroxypropyl)-? - methoxy- 1,2, 3, 4-tetrahydroisoquinoline-6-carboxamide (10 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) 8 ppm 10.49 (s, 1H), 9.76 (d, J = 7.3 Hz, 1H), 8.22 (dd, J = 2.7, 6.6 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.66 (s, 1H), 7.48 (t, J = 9.8 Hz, 1H), 6.87 (s, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.53 - 4.32 (m, 2H), 3.93 (s, 3H), 3.57 (br s, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.18 - 3.11 (m, 1H), 3.08 - 3.02 (m, 1H), 2.77 - 2.59 (m, 5H), 1.85 (br d, J = 9.8 Hz, 1H), 1.81 - 1.58 (m, 3H), 1.53 - 1.28 (m, 3H), 0.82 - 0.65 (m, 2H), 0.41 - 0.30 (m, 2H). LCMS: RT = 1.86 min, MS (ES):/n/z = 616.4 [M+H] method B.

Compounds 2 -to 32, 57 and 58 in Table 2 were prepared by the general procedures described for Example 1, 20, 21, 26, and or 33

Compounds 36 -to 39 in Table 2 were prepared by the general procedures described for Example 34 to 35. Compounds 41 -to 48 in Table 2 were prepared by the general procedures described for Example 40 or 42. Compounds 52 in Table 2 were prepared by the general procedures described for Example 51.

Compounds 54 in Table 2 were prepared by the general procedures described for Example 53.

Compounds 60 to 70 in Table 3 were prepared by the general procedures described for Example 61 and 65.

Compounds 73 in Table 2 w ⁷ ere prepared by the general procedures described for Example 59.

Compounds 75 to 76 in Table 3 were prepared by the general procedures described for Example 74.

Compounds 79 to 80 in Table 3 were prepared by the general procedures described for Example 77.

Compounds 86 to 95 in Table 3 were prepared by the general procedures described for Examples 84, 85, and 88.

Table 2

LC RT ^a (min)

MS and (ESI)

Structure Name chiral (M+H NMR conditio ) ns when separat ed

¹ H NMR (500 MHz, DMSO-d6) 10.59 (s,

N-[(2R,3S)-3- 1H), 9.86 (br d, J=6.7 {[4-fluoro-3- Hz, 1H), 8.93 (br s, 1H),

.Me

Me (trifluoromethy 8.62 (br s, 1H), 8.20 (br l)phenyl]carba

H > d, 1=6.1 Hz, 1H), 7.85 - moyl}-7- 7.76 (m, 1H), 7.48 (br t, 2.27

F (propan-2-

492.0 1=9.6 Hz, 1H), 7.34 (br Method

'NH° OMe ylidene)bicyclo

CF ₃ d, >4.3 Hz, 1H), 4.37 - B [2.2.1]heptan-

O 2-yl]-4- 4.29 (m, 1H), 4.09 (s,

N methoxypyridi 3H), 3.15 - 3.08 (m, ne-3- 1H), 3.07 - 3.01 (m, carboxamide 1H), 2.98 - 2.90 (m, 1H), 1.83 - 1.62 (m, 8H), 1.43 - 1.27 (m, 2H) ^! H NMR (500 MHz, DMSO-d6) 10.49 (s,

N-[(2R,3S)-3- 1H), 9.38 (d, J=7.0 Hz, { [4-fluoro-3- 1H), 8.22 (d, J=4.6 Hz, (trifluor 1H), 7.99 (d, J=3.4 Hz,

Me«< omethy l)phenyl]carba 1H), 7.80 - 7.72 (m,

H z. moyl}-7- 1H), 7.47 (L J=9.8 Hz, z X NHX (propan-2 1H), 6.75 (d, J=3.4 Hz, 2.50 o U OX F -

497.2 Method Me ylidene)bicyclo 1H), 4.35 - 4.22 (m,

CF ₃ B [2.2.1]heptan- 1H), 3.91 (s, 3H), 3.06

0 2-yl]-4- (dd, 1=10.5, 3.8 Hz,

■s ^z methoxythioph 1H), 3.03 - 2.97 (m, ene-3- 1H), 2.91 - 2.82 (m, carboxamide 1H), 1.86 - 1.78 (m, 1H), 1.75 - 1.62 (m, 7H), 1.41 - 1.26 (m, 2H) ti NMR CSOO MHz,

N-[(2R,3S)-3- DMSO-d6) 10.57 (s, {[4 -fluoro-3- 1H), 9.88 (br d, J=7.0 (trifluoromethy Hz, 1H), 8.98 (s, 1H),

Me«<

3 l)phenyl]carba 8.90 (s, 1H), 8.20 (d,

H , moyl}-7- 1=4.3 Hz, 1H), 7.85 -

2.34

F (propan-2- 7.78 (m, 1H), 7.48 (t,

493.4 Method

NH° OMe CF ₃ ylidene)bicyclo J=9.8 Hz, 1H), 4.35 -

B

O' N [2.2.1]heptan- 4.27 (m, 1H), 4.12 (s, 2-yl]-4- 3H), 3.10 (dd, 1=10.7,

N methoxypyrimi 4.3 Hz, 1H), 3.06 - 3.02 dine-5- (m, 1H), 2.96 - 2.91 (m, carboxamide 1H), 1.79 - 1.69 (m, 8H), 1.42 - 1.28 (m, 2H)

5-chloro-N- ¹ H NMR (500 MHz, [(2R,3S,7Z)-3- DMSO-d6) 5 8.38 (d, {[4-fluoro-3- 1=2.4 Hz, 1H), 8.28 - (trifluorome 8.16 (m, 2H), 7.78 (br d,

^F,c thy l H > l)phenyl]carba J=8.5 Hz, 1H), 7.49 (br moyl}-7- t, J=9.6 Hz, 1H), 5.93

F x o (q, J=7.7 Hz, 1H), 4.53 - NFT OMe (2,2,2-

CF ₃ 566.3 2.81 trifluoroethylid 4.38 (m, 1H), 4.06 (s, o N ene)bicyclo[2. 3H), 3.48 (br d, J=7.6 2. l]heptan-2- Hz, 1H), 3.33 - 3.14 (m,

Cl ylJ-2- 2H), 2.99 (br s, 1H), methoxypyridi 1.98 - 1.76 (m, 2H), ne-3- 1.48 (br d, J=5.2 Hz, carboxamide 2H) ^! H NMR (500 MHz, DMSO-d6) 8 10.60 (s,

N-[(2R,3S,7Z)- 1H), 8.75 (d, J=7.3 Hz, 3-{[4-fluoro-3- 1H), 8.24 (dd, J=6.4, 2.1 (trifluoromethy Hz, 1H), 7.91 (s, 1H),

^F3C l)phenyl]carba 1 7.82 - 7.70 (m, 1H),

H z.- moyl}-7- 7.50 (t, J=9.8 Hz, 1H),

F (2,2,2-

'• o 5.92 (q, 1=7.8 Hz, 1H),

OMe CF ₃ trifluoroethylid 535.2 2.23

4.50 - 4.33 (m, 1H), o ene)bicyclo[2. 2. l]h 4.02 - 3.87 (m, 3H),

(^, ^N eptan-2-

^N . ylj-3-meth 3.70 (s, 3H), 3.22 (br dd,

Me oxy- 1 -methyl- 1H- J=10.7, 4.0 Hz, 1H), pyrazole-4- 3.13 (br s, 1H)' 2.96 (br carboxamide s, 1H), 2.06 - 1.93 (m, 1H), 1.89 - 1.79 (m, 1H), 1,58 - 1,41 (m, 2H)

5-chloro-7- ¹ H NMR (500 MHz, (difluoromethy DMSO-d6) 8 10.73 (s, 1)-N- 1H), 9.79 (br d, J=6.7

F ₃ C- [(2R,3S,7Z)-3- Hz, 1H), 8.34 (br d,

H , { [4-fluoro-3- J=4.9 Hz, lH), 8.17 (s, (trifluoromethy 1H), 7.70 (br s, 1H),

F l)phenyl]carba 7.53 - 7.45 (m, 2H), "NH° CF ₃ moyl}-7- 625.3 7.51 (brt, J=52.9 Hz, 2.65

O' (2,2,2- 1H), 7.12 (s, 1H), 5.95

L ' trifluoroethylid (q, 1=7.6 Hz, 1H), 4.47

1 CHF ₂ ene)bicyclo[2. (br s, 1H), 3.23 (br s, cr 2.1]heptan-2- 1H), 3.04 - 2.98 (m, yl]pyrazolo[l,5 1H), 1.88 (br d, J=7.9 -a]pyridine-3- Hz, 2H), 1.52 (br d, carboxamide 1=8.2 Hz, 2H) _

¹ H NMR (500 MHz, DMSO-d6) 8 10.66 (s,

N-[(2R,3S,7Z)- 1H), 9.42 (br d, J=7.2 3-{[4-fluoro-3- Hz, 1H), 9.11 (d, J=1.9

^F SC^ (trifluoromethy Hz, 1H), 8.67 (d, 1=2.0 l)phenyl]carba

H , Hz, 1H), 8.09 (br d, moyl}-7-

F J=4.0 Hz, 1H), 7.89 - (2,2,2-

NH o ^U 7.75 (m, 1H), 7.66 -

CF ₃ trifluoroethylid 582.3 2.03 7.58 (m, 2H), 7.50 (t, o N ene)bicyclo[2. J=9.8 Hz, 1H), 7.33 (d,

.OMe 2.1]heptan-2- yl]-8- 1=7.1 Hz, 1H), 5.97 (q, methoxyquinol J=7.9 Hz, 1H), 4.72 - ine-3- 4.53 (m, 1H), 4.00 (s, carboxamide 3H), 3.33 (br dd, J=10.6, 4.6 Hz, 1H), 3.04 (br s, 1H), 2,14 (brt, 1=8,9 Hz, 1H), 2.02 (brt, >9.0 Hz, 1H), 1.55 (br d, 1=7.3 Hz, 2H) ’H NMR (500 MHz, DMSO-d6) 5 10.73 (d, J=7.9 Hz, 1H), 10.40 (s,

N-[(2R,3S,7Z)- 1H), 8.76 (s, 1H), 8.04 3-{[4-fluoro-3- (dd, 3=6.4, 2.1 Hz, 1H), (trifluoromethy 7.96 (d, 1=7.0 Hz, 1H),

^F,c l l)phenyl]carba 7.78 (t, J=7.9 Hz, 1H),

H , moyl}-7- 7.74 (d, 1=8.1 Hz, 1H),

F (2,2,2- 7.65 (d, J=8.5 Hz, 1H),

NH° O trifluoroethylid

CF ₃ 582.2 7.44 (t, J=9.2 Hz, 1H), 2.44 ene)bicyclo[2.

O' N' ^Me 7.37 (t, J=7.5 Hz' 1H), 2.1]heptan-2-

5.94 (q, 1=7.7 Hz, 1H), yl] -1 -methyls¬

4.81 - 4.63 (m, 1H), oxo- 1,2- 3.73 (s, 3H), 3.26 - 3.14 dihydroquinoli ne-3- (m, 1H), 2.98 (br s, 1H), carboxamide 2.32 (brt, 3=9.2 Hz, 1H), 1.99 (brt, 1=8.9 Hz, 1H), 1.63 - 1.46 (m, 2H) _ lHNMR (500 MHz,

N-[(2R,3S,7Z)- DMSO-d6) 88.21 (br d, 3-{[4-fluoro-3- J=4.8 Hz, 1H), 8.08 (d,

F ₃ C, (trifluoromethy J=7.9 Hz, 1H), 7.91 (t,

H , l)phenyl]carba 1=7.9 Hz, 1H), 7.88 - movl} 7.85 (m, 1H), 7.62 -

F -7-

2.48 "NH° (2,2,2- 7.50 (m, 3H), 6.82 (s,

569.3 Method

.o ^CF = trifluoroethylid 1H), 6.05 - 5.92 (m,

O' B ene)bicyclo[2. 1H), 4.42 (br s, 1H), o. 2.1]heptan-2- 3.51 (br s, lH), 3.26 (br yl]-4-oxo-4H- s, 1H), 3.06 (br s, 1H), chromene-2- 1.95 (br d, J=10.9 Hz, carboxamide 1H), 1.90 - 1.82 (m, 1H), 1.54 (br s, 2H) 1HNMR (500 MHz,

6-chloro-N-

^F,c DMSO-d6) d 10.61 (s, l [(2R,3S,7Z)-3-

H 1H), 9.40 (brd, J=6.7 {[4-fluoro-3-

,,^ ^N Hz, 1H), 9.16 (s, 1H),

F (trifluoromethy 'NH° 8.69 (s, 1H), 8.22 (s,

CF ₃ l)phenyl]carba

586.1 1H), 8.11 (d, J=8.7 Hz, 2.61 o N moyl}-7- 1H), 8.07 - 8.04 (m, (2,2,2- 1H), 7.90 - 7.80 (m, trifluoroethylid 2H), 7.48 (brt, J=9.8 ene)bicyclo[2. ci 2.1]heptan-2- Hz, 1H), 5.96 (q, 1=7.7 Hz, 1H), 3.39 (br s. 1H), yl]quinoline-3- 3.36 - 3.27 (m, 1H), carboxamide 3.23 (br s, 1H), 2.18 - 2.09 (m, 1H), 2.07 - 1.96 (m, HI), L54 (br d, J=7.6 Hz, 2H) _

¹ HNMR (500 MHz, DMSO-d6) 5 10.52 (d, J=8.2 Hz, 1H), 10.25 (s,

5-bromo-N- 1H), 8.38 (d, J=2.7 Hz, [(2R,3S,7Z)-7- 1H), 8.20 (d, >2.7 Hz, (cyclopropylm 1H), 7.99 (d, 1=6.7 Hz, ethylidene)-3- 1H), 7.80 - 7.64 (m, {[4-fluoro-3- 1H), 7.44 (t, 1=9.8 Hz, (trifluoromethy 1H), 4.66 (d, J=9.5 Hz,

F l)phenyl]carba 1H), 4.58 - 4.44 (m,

'NH°O 581.9 2.35 moyl}bicyclo[ 1H), 3.56 (s, 3H), 3.08 2.2.1]heptan-2- (dd, 1=10.5, 3.8 Hz, yl] -1 -methyl -2- 1H), 3.03 - 2.93 (m,

Br oxo- 1,2- 1H), 2.67 (br s, 1H), dihydropyridin 2.12 (brt, J=9.0 Hz, e-3- 1H), 1.88 - 1.68 (m, carboxamide 1H), 1.60 - 1.44 (m, 2H), 1.25 (m, 1H), 0.79 - 0.66 (m, 2H), 0.34 (br DMSO-d6) d 10.66 (d, 1=8.5 Hz, 1H), 10.29 (s, 1H), 8.76 (s, 1H), 8.02

N-[(2R,3S,7Z)- (d, J=6.6 Hz, 1H), 7.97 7- (d, 1=7.8 Hz, 1H), 7.85 - (cyclopropylm 7.70 (m, 2H), 7.65 (d, ethylidene)-3- 1=8.5 Hz, 1H), 7.43 (t, {[4-fluoro-3- J=9.7 Hz, 1H), 7.37 (t, (trifluoromethy J=7.6 Hz, 1H), 4.68 (d, l)phenyl]carba 1=9.8 Hz, 1H), 4.64 -

'NH°O 554.0 2.52

>? ^CF 3 moyl}bicyclo[ 4.43 (m, 1H), 3.74 (s,

O' N' ^Me 2.2.1]heptan-2- 3H), 3.12 (brdd, 1=11.1, yl]-l-methyl-2- 3.8 Hz, 1H), 3.05 (t, oxo- 1,2- 1=4.1 Hz, 1H), 2.79 - dihydroquinoli 2.63 (m, 1H), 2.16 (brt, ne-3- J=8.7 Hz, 1H), 2.03 - carboxamide 1.83 (m, 1H), 1.56 - 1.47 (m, 2H), 1.43 (br d, 1=13.1 Hz, 1H), 0.84 - 0.64 (m, 2H), 0.41 - 0.31 (m, 2H) 4-(6- ¹ HNMR (500 MHz, {[(2R,3S)-3- DMSO-d6) 5 10.59 (s,

Me { [4-fluoro-3- 1H), 9.98 (brd, J=7.0

1 (triflu Hz. 1H), 8.35 - 8.26 (m,

H oromethy 2H), 8.20 (d, 1=8.9 Hz, l)phenyl]carba moyl}-7- 1H), 8.05 (d, J=4.0 Hz,

NH °OMe 1H), 7.99 - 7.88 (m,

CF ₃ (propan-2- 3H),

O' ylidene)bicyclo 612.2 7.73 (d, J=8.5 Hz, 2.15 [2.2.1]heptan- 1H), 7.52 - 7.40 (m, 2- 1H), 4.32 - 4.21 (m, yl] carbamoyl }- 1H), 3.88 (s, 3H), 3.19 -

5- 3.11 (m, 1H), 3.08 - 3.02 (m, 1H), 2.98 -

CO ₂ H methoxypyridi n-2-yl)benzoic 2.91 (m, 1H), 1.83 - 1.66 (m, 8H), 1.44 - acid 1.28 (m, 2H)

4-Fluoro-3-(6- ’H NMR (500 MHz, {[(2R,3S)-3-

Me DMSO-d6) 8 10.49 (br {[4-fluoro-3- s, 1H), 9.66 (br d, J=6.7 1

, H (trifluoromethy N-V Hz, 1H), 8.64 - 8.48 (m, l)phenyl]carba

7'X 1H), 8.06 - 7.87 (m, 1 F moyl}-7- NH ^u OMe 3H), 7.82 - 7.64 (m,

CF ₃ (propan-2- 2.00 2H), 7.48 - 7.29 (m,

O' ylidene)bicyclo 630.1 Method 2H), 4.34 - 4.23 (m, [2.2.1]heptan- B 1H), 3.79 (s, 2H), 3.12 - 2-

F. 3.05 (m, 1H), 3.04 - yl J carbamoyl }-

-OH 5- 2.98 (m, 1H), 2.97 - methoxypjTi 2.91 (m, 1H), 1.85 -

O di n-2-yl)benzoic 1.64 (m, 8H), 1.43 - acid 1.26 (m, 2H) lHNMR (500 MHz,

4-Fluoro-3-(6- DMSO-d6) 10.49 (s, {[(2R,3S)-3-

Me 1H), 9.82 (d, J=7.3 Hz,

Me' {[4-fluoro-3- 1H), 8.80 (d, 1=2.1 Hz,

H (trifluoromethy 1H), 8.57 (dd, 1=7.5, 2.0 , ,N-V l)phenyl]carba Hz, 1H), 8.10 - 8.01 (m, z^F moyl}-7-

NH °OMe 2H), 7.85 (brdd, J=8.2,

CF ₃ (propan-2- 2.12 4.0 Hz, 1H), 7.50 (dd,

O' Il ? ylidene)bicyclo 631.5 Method 1=10.7, 8.9 Hz, 1H), [2.2.1]heptan- B 7.40 (t, J=9.8 Hz, 1H), 2-

R 4.38 - 4.32 (m, 1H), yl] carbamoyl }-

.OH 4.01 (s, 3H), 3.12 (dd, met 1=10.7, 4.3 Hz, 1H),

O hoxypyrazi n-2-yl)benzoic 3.08 - 3.04 (m, 1H), acid 2.99 - 2.95 (m, 1H), 1.83 - 1.77 (m, 2H), 1.75 (s, 3H), 1.73 (s, 3H), 1.44 - 1.28 (m, 2H)

¹ HNMR (500 MHz, DMSO-d6) 5 13.19 (br s, 1H), 10.63 (s, 1H), 10.16 (d, 1=6.9 Hz, 1H),

4-Fluoro-3-(5- 8.58 (dd, 1=2.2, 1.4 Hz,

Ph*. {[(2R,3S,7Z)- 1H), 8.48 (dd, 1=2.3, 1.2

A 3-{[4-fluoro-3-

H Hz, 1H), 8.27 (dd, (trifluoromethy 1=6.5, 2.6 Hz, 1H), 8.09

1 F l)phenyl]carba (dd, 1=7.7, 2.2 Hz, 1H), 'NH °OMe moyl}-7-

CF ₃ 8.02 (ddd, 1=8.5, 4.7, o (phenylmethyli N 678.2 2.2 Hz, 1H), 7.84 (dt, 2.70 dene)bicyclo[2 1=8.4, 3.6 Hz, 1H), 7.55 .2. l]heptan-2-

F. - 7.45 (m, 2H), 7.39 (d, yl] carbamoyl }- 1=4.4 Hz, 4H), 7.26

■OH 6- (quin, 1=4.3 Hz, 1H), methoxypyridi

O n-3-yl)benzoic 6.40 (s, 1H), 4.64 - 4.46 acid (m, 2H), 4.16 (s, 3H), 3.45 - 3.40 (m, 1H), 2.99 - 2.93 (m, 1H), 1.96 - 1.85 (m, 2H), 1.62 - 1.50 (m, 2H)

¹ HNMR (500 MHz,

4-Fluoro-3-(6- DMSO-d6) 8 10.57 (s, {[(2R,3S,7Z)- p- 1H), 9.73 (brd, 1=7.6 3-{[4-fhioro-3-

Nc Hz, 1H), 9.05 (s, 1H), (trifluoromethy

8.78 (s, 1H), 8.65 - 8.61 l)phenyl]carba (m, 1H), 8.06 - 8.01 (m,

? 'X I F moyl}-7-[(l,2- 1=4.6 Hz, 2H), 7.99 (br ''NH °OMe oxazol-4-

CF _S d, 1=7.9 Hz, 1H), 7.85 -

O' yl)methylidene 669.2 2.09

7.79 (m, 1H), 7.77 (d, |bicyclo[2.2.1 | 1=8.9 Hz, 1H), 7.49 - heptan-2-

F- 7.37 (m, 2H), 6.15 (s, yl] carbarn oyl}-

•OH 5- 1H), 4.54 - 4.41 (m, meth 1H), 3.91 (s, 3H), 3.32 -

O oxypyridi n-2-yl)benzoic 3.24 (m, 2H), 2.97 - acid 2.91 (m, 1H), 2.03 - 1.87 (m, 2H) ¹ HNMR(500MHz,

4-Fluoro-3-(5- DMSO-d6) 810.66 (s, {[(2R,3S,7Z)- 1H), 10.08 (brd, J=6.7

F ₃ C 3-{[4-fhioro-3- Hz, 1H), 8.57 (s, 1H),

\\ (trifluoromethy 8.46 (s, 1H), 8.24 (brd, l)phenyl]carba J=4.3 Hz, 1H), 8.08 (br

1 F moyl}-7- d, J=7.0Hz, 1H), 8.01 'NH°OMe

CF ₃ (2,2,2- (brd, J=4.9Hz, 1H),

O' N trifluoroethylid 670.0 7.85 - 7.77 (m, 1H), 2.53 ene)bicyclo[2. 7.56 - 7.43 (m, 2H),

F. 2.1]heptan-2- 5.95 (q, >7.7 Hz, 1H), yl] carbamoyl }- 4.52 (brd, J=4.0Hz,

•OH 6- lH),4.14(s, 3 H), 3.00 o methoxypyridi (brd, J=5.8Hz, 1H), n-3-yl)benzoic 2.02 - 1.83 (m, 2H), acid 1.50 (brd, 1=3.7 Hz, 2H)

¹ HNMR(500MHz,

3-(5- DMSO-d6) 810.67 (s, {[(2R,3S,7Z)- 1H), 10.09 (brd, 1=6.7

F ₃ C. 3-{[4-fhioro-3- Hz, 1H), 8.70 (d, J=2.1 (trifluoromethy Hz, 1H), 8.55 (d, 1=2.1 l)phenyl]carba Hz, 1H), 8.24 (brd,

F moyl}-7-

'NH°OMe J=4.3 Hz, 1H), 8.17 (s,

CF ₃ (2,2,2- 1H), 7.96 (brt, 1=6.7

O' N trifluoroethylid 652.2 2.48 Hz, 2H), 7.81 (brd, ene)bicyclo[2. 1=8.5 Hz, 1H), 7.62 (t,

2.1]heptan-2- 1=7.6 Hz, 1H), 7.50 (br yl] carbarn oyl}-

-OH t, 1=9.8 Hz, 1H), 5.95 6- o (q, 1=7.9 Hz, 1H), 4.54 methoxypyridi n-3-yl)benzoic (br s, 1H),4.14 (s, 3H), acid 3.00 (brd, J=8.2 Hz. 1H)

¹ HNMR(500 MHz,

4-Fluoro-3-(4- DMSO-d6) 810.69 (s, {[(2R,3S,7Z)- 1H), 10.03 (brd,J=6.7

^F3C 1 H 3-{[4-fluoro-3- Hz, 1H), 8.77 (s, 1H),

T 'NHx (trifluoromethy 1 8.55(brd,J=7.3Hz, l)phenyl|carba °OMe 1H), 8.31 -8.15 (m,

CF ₃ moyl}-7- 2H), 8.00 (brs, 1H),

O' (2,2,2- 670.0 2.33

N 7.83 - 7.71 (m, 1H), trifluoroethylid 7.55 - 7.33 (m, 2H),

F- ene)bicyclo[2. 5.93 (q, N7.5 Hz, 1H), 2.1]heptan-2-

.OH 4.51 (brs, lH),4.18(s, yl] carbamoyl }-

O 3H), 3.35 -3.20 (m, methoxypyridi 2H),3.00 (brs, 1H), 2.03 - 1.82 (m, 2H), n-2-yl)benzoic 1.50 (br d, J=5.2 Hz, acid 2H)

¹ HNMR (500 MHz,

3-(4- DMSO-d6) 5 10.70 (s, {[(2R,3S,7Z)- 1H), 10.05 (br d, J=6.7

F ₃ C- 3-{[4-fluoro-3- Hz, 1H), 8.72 (s, 1H), (trifluo 8.57 (s, 1H), 8.30 (s,

H romethy l)phenyl]carba 1H), 8.27 - 8.16 (m,

1 F moyl}-7- 2H), 8.03 - 7.91 (m, 'NH °OMe

CF ₃ (2,2,2- 1H), 7.80 (brd, J=8.2

O' trifluoroethylid 652.0 Hz, 1H), 7.60 (t, 1=7.6 2.38

N ene)bicyclo[2. Hz, 1H), 7.50 (br t, 2.1]heptan-2- 1=9.8 Hz, 1H), 5.95 (q, yl] carbamoyl }- 1=7.8 Hz, 1H), 4.54 (br

•OH 5- s, 1H), 4.17 (s, 3H), 3.35

O methoxypyridi - 3.25 (m, 1H), 3.01 (br n-2-yl)benzoic s, 1H), 2.00 - 1.83 (m, acid 2H), 1.50 (brd, 1=5.5 Hz, 2H)

^T H NMR (500 MHZ,

4-Fluoro-3-(4- DMSO-d6) 5 10.62 (s, {[(2R,3S,7Z)- 1H), 9.79 (d, J=7.2 Hz, 3-{[4-fluoro-3- 1H), 8.98 (s, 1H), 8.63

^F3C \ „ H (trifluoromethy (dd, J=7.4, 2.0 Hz, 1H),

N-V l)phenyl]carba

1 8.17 - 8.02 (m, 2H), moyl}-7- 'NH °OMe 7.85 - 7.72 (m, 1H),

CF ₃ (2,2,2- 7.51 - 7.35 (m, 2H),

O'

Tl trifluoroethylid 671.1 2.23 N. N 5.95 (q, J=7.8 Hz, 1H), ene)bicyclo[2. 4.51 (dt, 1=10.7, 5.3 Hz,

F. 2.1]heptan-2- 1H), 4.01 (s, 3H), 3.28 yl J carbamoyl }-

■OH (dd, 1=10.6, 4.4 Hz,

5-

O methoxypyrimi lH), 3.23 (br s, 1H), din-2- 3.00 (s, 1H), 2.O3 - 1.86 yl)benzoic acid (m, 2H), 1.51 (br d, J=8.1 Hz, 2H)

(lS)-2,2,2- ^} H NMR (500 MHz,

F ₃ C. F trifhioro-l-[4- DMSO-d6) 5 10.59 (s, fluoro-3-(4- 1H), 10.30 (br s, 1H),

__ HN ■CF 7; ''NHx ₃ {[(2R,3S,7Z)- 9.69 (br d, J=7.3 Hz, ° OMe 3-{[4-fluoro-3- 1H), 8.99 (s, 1H), 8.25

O' (trifluoromethy (br d, J=5.5 Hz, 1H),

T 1 844.3 2.62

N^N l)phenyl]carba 8.08 (dd, J=6.3' 2.3 Hz,

R moyl}-7- 1H), 7.77 (brdd, 1=4.6, (2,2,2-

. ,,O- ,NHPh 2.7 Hz, 2H), 7.54 - 7.38 I Y trifluoroethylid (m, 4H), 7.30 (t, J=7.9 CF ₃ O ene)bicyclo[2. Hz, 2H), 7.04 (brt, 2.1]heptan-2- 1=7.3 Hz, 1H), 6.62 - ^! H NMR (500 MHz,

(lS)-2,2,2- DMSO-d6) 8 10.59 (s, trifluoro-1 -[4- 1H), 10.23 (br s, 1H), fluoro-3-(6- 9.61 (br d, 1=7.6 Hz, {[(2R,3S,7Z)- 1H), 8.24 fbrd, J=5.5 3-{[4-fluoro-3- Hz, 1H), 8.02 - 7.90 (m,

F ₃ C. r==^V ^F (trifluoromethy 2H), 7.81 - 7.63 (m, l)phenyl]carba

-CF ₃ 3H), 7.54 - 7.44 (m, moyl}-7- 1H), 7.41 (brd, J=8.2

NH ^u OMe (2,2,2- Hz, 2H), 7.35 (brt,

O’ trifluoroethylid

843.1 J=9.6 Hz, 1H), 1.T1 (br 2.74 ene)bicyclo[2. t, 1=7.9 Hz, 2H), 7.03

F- 2.1]heptan-2- (brt, J=7.3 Hz, 1H), yl] carbamoyl }-

. ,'O^NHPh 6.46 - 6.33 (m, 1H), u 5.92 (q, J=7.8 Hz, 1H), methoxypyridi n-2- 4.50 (brt, 1=6.7 Hz, yl)phenyl]ethyl 1H), 3.89 (s, 3H), 3.34 - N- 3.17 (m, 2H), 2.98 (br s, phenylcarbama 1H), 1.99 (brd, J=10.1 te Hz, 2H), 1.60 - 1.37 (m, 2H)

¹ HNMR (500 MHz, DMSO-d6) 8 10.62 (s,

5-bromo-N- 1ID, 9.79 (brd, J=7.0 [(2R,3S,7Z)-3- Hz, 1H), 8.44 (d, J=2.4 {[4-fluoro-3- Hz, 1H), 8.31 (d, J=2.4

F ₃ C< F (trifluoromethy Hz, 1H), 8.17 - 8.04 (m, l)phenyl]carba 1H), 7.86 - 7.73 (m, s _ HN' ■CF ₃ moyl}-7- 1H), 7.48 (brt, 1=9.6 (2, Hz, 1H), 5.95 (q, J=8.0

'"NH°O-^/° ^H 2,2-

640.1 2.48 trifluoroethylid Hz, 1H), 4.78 (t, J=5.5 ene)bicyclo[2. Hz, 1H), 4.67 - 4.39 (m, 2.1]heptan-2- 3H), 3.99 - 3.76 (m,

Br yl]-2-(2- 2H), 3.27 (brdd, J=10.7, hydroxyethoxy 3.7 Hz, lH), 3.19 (br s, )pyridine-3- 1H), 3.OO (br s, 1H), carboxamide 2.01 (br d, J=8.2 Hz, 2H), 1.52 (brd, J=8.2 Hz, 2H) (lS)-2,2,2- ¹ HNMR (500 MHz, trifluoro-l-[4- DMSO-d6) 5 10.63 (s, fluoro-3-(5- 1H), 9.85 (brd, 1=7.3 {[(2R,3S,7Z)- Hz, 1H), 8.53 (s, 1H), 3-{[4-fhioro-3-

F 8.44 (s, 1H), 8.19 - 8.07

FgC- (trifluoromethy (m, 2H), 7.84 - 7.72 (m,

HN ‘CF ₃ l)phenyl]carba 2H), 7.60 (br s, 1H), moyl}-7- 7.48 (brt, J=9.6 Hz,

Wo— ^OH (2,2,2- 2H), 6.45 - 6.32 (m,

O' N trifluoroethylid

851.1 1H), 6.01 - 5.88 (m, 2.66 ene)bicyclo[2. 1H), 4.81 (t, J=5.6 Hz, 2.1]heptan-2-

F. 1H), 4.74 - 4.65 (m, yl] carbarn oyl}- 1H), 4.61 (dt, J=10.7, 6 (2-

1 T CF ₃ 0 hydroxyethoxy 5.3 Hz, 2H), 4.00 - 3.82 )pyridin-3- (m, 3H), 3.22 (br s, 1H), yl)phenyl]ethyl 3.02 (br s, 1H), 2.27 - N- 2.00 (m, 4H), 1.98 - cyclobutylcarb 1.81 (m, 2H), 1.69 - amate 1.45 (m, 4H) tiNMR fSOO MHz, DMSO-d6) 5 10.62 (s,

4-Fluoro-3-(4- 1H), 9.76 (brd, 1=7.3 {[(2R,3S,7Z)- Hz, 1H), 8.83 (s, 1H),

F ₃ C. F 3-{[4-fluoro-3- 8.57 (dd, 1=7.9, 2.1 Hz, (trifluoromethy 1H), 8.21 (s, 1H), 8.12 -

'CF ₃ l)phenyl]carba 8.07 (m, 1H), 8.06 - moyl}-7- 7.95 (m, 1H), 7.81 -

'"NH°O^/° ^H (2,2,2- 7.68 (m, 1H), 7.55 -

O' trifluoroethylid 700.3 7.39 (m, 2H), 5.95 (q, 2.08

N ene)bicyclo[2. 1=8.0 Hz, 1H), 4.67 -

F- 2.1]heptan-2- 4.55 (m, 1H), 4.55 - yl] carbamoyl }- 4.44 (m, 2H), 4.04 -

-OH

5-(2- 3.84 (m, 2H), 3.29 (br

O hydroxyethoxy dd, 1=10.7, 3.7 Hz, 1H), )pyridin-2- 3.23 (br s, 1H), 3.05 - yl)benzoic acid 2.95 (m, 1H), 2.14 -

1.96 (m, 2H), 1.59 - 1.41 (m, 2H)

2-Brom

F ₃ c- F o-N- ¹ HNMR (500 MHz, [(2R,3S,7Z)-3- DMSO-d6) 5 10.62 (s, {[4-fluoro-3- 1H), 9.70 (brd, J=7.3 (trifluoromethy Hz, 1H), 8.46 (s, HD,

\H°O— ^OH l)phenyl]carba 640.3 2.23 8.17 - 8.00 (m, 1H),

O' moyl}-7- 7.82 - 7.69 (m, 2H),

N (2,2,2- 7.47 (brt, J=9.8 Hz, trifluoroethylid

Br ene)bicyclo[2. 1H), 5.93 (q, J=7.8 Hz, 2. l]heptan-2- 1H), 4.93 (t, 1=5.5 Hz, yl]-5-(2- 1H), 4.60 - 4.46 (m, hydroxyethoxy 1H), 4.46 - 4.31 (m, )pyridine-4- 2H), 4.00 - 3.75 (m, carboxamide 2H), 3.26 (brdd, J=10.7, 4.0 Hz, 1H), 3.21 - 3.14 (m, 1H), 2.99 (br s, 1H), 2.05 - 1.90 (m, 2H), 1.51 (br d, J=7.9 Hz, 2H)

(lS)-2,2,2- trifhioro-l-[4- ¹ HNMR (500 MHz, fluoro-3-(4- DMSO-J6) 5 10.63 (s, {[(2R,3S,7Z)- 1H), 9.77 (brd, >7.3 3-{[4-fluoro-3- Hz, 1H), 8.82 (s, 1H), (trifluoromethy

^F3C 1 8.22 - 8.04 (m, 3H), l)phenyl]carba

HN' ■CF ₃ 7.76 (br dd, 1=8.5, 3.7 moyl}-7- Hz, 1H), 7.65 - 7.56 (m, "-NH°o^ ^OH (2,2,2- 1H), 7.52 - 7.36 (m,

O' trifluoroethylid

851.3 2H), 6.36 (q, J=6.7 Hz, 2.52 x-N ene)bicyclo[2. 1H), 5.96 (q, J=7.5 Hz, 2.1]heptan-2-

F. 1H), 4.95 (brt, 1=5.2 vl] carbarn ovl}-

. .xO^NH Hz, 1H), 4.67 - 4.43 (m, 5 (2- T T CF ₃ 0 3H), 4.03 - 3.84 (m, hydroxyethoxy )pyridin-2- 2H), 3.24 (br s, 1H), yl)phenyl]ethyl 3.01 (br s, 1H), 2.19 - N- 1.83 (m, 5H), 1.63 - cyclobutylcarb 1.45 (m, 3H) am ate

’H NMR (500 MHz,

4-Fluoro-3-(6- DMSO-d6) 59.85 (d, {[(2R,3S,7Z)- 1=7.3 Hz, 1H), 8.57 (dd,

F 3-{[4-fluoro-3- 1=7.4, 1.4 Hz, 1H), 8.08

^F,c l (trifluoromethy (br dd, J =6.0, 2.7 Hz,

HN ^x/ CF ₃ l)phenyl]carba 1H), 8.03 (brd, 1=4.2

7"'^ moyl}-7- Hz, 1H), 7.89 - 7.78 (m, 'Wo^ ^OH (2,2,2- 1H), 7.55 - 7.47 (m,

O' trifluoroethylid 701.2 1H), 7.41 (t, 1=9.8 Hz, 2.10 ene)bicyclo[2. 1H), 6.03 - 5.90 (m,

F- 2.1]heptan-2- 1H), 4.52 (qd, 1=11.7, vl J carbamoyl }- 5.9 Hz, 3H), 3.86 - 3.70

-OH

5-(2- (m, 2H), 3.26 (br s, 1H),

O hydroxyethoxy 3.01 (br s, 1H), 2.11 - )pyrazin-2- 2.01 (m, 1H), 1.99 - yljbenzoic acid 1.90 (m, 1H), 1.52 (br d, J=6.3 Hz, 2H) ¹ HNMR (500 MHz, DMSO-d6) 8 10.64 (s,

6-Bromo-N- 1H), 9.63 (d, 1=7.4 Hz, [(2R,3S,7Z)-3- 1H), 8.56 (s, 1H), 8.13 {[4-fluoro-3- (br d, J=5.7 Hz, 1H),

F ₃ C. F (trifluoromethy 7.82 - 7.73 (m, 1H), l)phenyl]carba 7.49 (t, 1=9.8 Hz, 1H),

HN CF ₃ moyl}-7- 5.94 (q, 1=7.6 Hz, 1H),

V '^ "-NH° O— °H (2,2,2- 4.96 - 4.80 (m, 1H),

640.9 2.25 trifluoroethylid 4.57 - 4.37 (m, 3H), ene)bicyclo[2. 3.75 (quin, J=5.2 Hz,

N_s#J 2.1]heptan-2- 2H), 3.58 - 3.46 (m,

Br yl]-3-(2- 1H), 3.27 (br dd, J=10.6, hydroxyethoxy 4.2 Hz, 1H), 3.20 (br s, )pyrazine-2- 1H), 3.00 (br s, 1H), carboxamide 2.05 - 1.88 (m, 2H),

1.51 (br d, 1=7.7 Hz,

2H) _

^! H NMR (500 MHz, DMSO-d6) 8 10.65 (s, 1H), 9.84 (d, 1=7.0 Hz,

N-[(2R,3S,7Z)- 1H), 8.29 (s, 1H), 8.25 3-{[4-fluoro-3- (dd, J=6.4, 2.1 Hz, 1H),

F (trifluoromethy 7.80 - 7.67 (m, 1H),

^F3C 1 l)phenyl]carba 7.49 (t, 1=9.6 Hz, 1H),

> _ HN "CF ₃ movl}-7- 6.02 - 5.88 (m, 1H), (2,2,2-

4.52 - 4.40 (m, 1H),

NH ^u OMe trifluoroethylid

575.1 3.92 (s, 3H), 3.46 (s, 2.51 ene)bicyclo[2. 1H), 3.28 (dd, J=11.0,

2.1]heptan-2-

4.3 Hz, 1H), 3.21 (br s, yl]-3-methoxy- lH), 3.00 (br s, 1H), 6- propylpyrazine 2.71 (td, J-7.3, 2.4 Hz, -2- 2H), 2.00 - 1.83 (m, carboxamide 2H), 1.74 (sxt, J=7.2 Hz, 2H), 1.57 - 1.43 (m, 2H), 0.88 (t, J=7.3 Hz, 3H) _

Ph. F 3-(4- ^! HNMR (500MHz, {[(2R,3S,7Z)- DMSO-d6) 8 10.48 (s,

_ HN "CF _a 3-{[4-fluoro-3- 1H), 8.96 (d, J=7.3 Hz,

71 (trifluoromethy 1H), 8.72 (s, 1H), 8.31

"NH° < 2.13 l)phenyl]carba (s, 1H), 8.22 (d, 1=4.4

641.2 Method

O' moyl}-7- Hz, 1H), 8.02 (d, J=8.0

C ^N B ‘"N (phenylmethyli Hz, 1H), 7.88 - 7.80 (m,

OH dene)bicyclo[2 2H), 7.57 (t, J=7.9 Hz, ,2.1]heptan-2- 1H), 7.47 (t, 1=9.8 Hz, o yl] carbamoyl }- 1H), 7,37 (d, 1=4.3 Hz, 3 -meth oxy- 1 H- 4H), 7.29 - 7.21 (m, pjTazol-1- 1H), 6.38 (s, 1H), 4.50 yl)benzoic acid (br. s., 1H), 4.10 (s, 3H), 2.93 (br. s„ 1H), 2.05 - 1.85 (m, 2H), 1.61 - 1.48 (m, 2H) _

1- ¹ H NMR (500 MHz, (difluoromethy DMSO-d6) 5 10.67 (s, 1)- 1H), 9.64 - 9.57 (m,

F N-

^F,c 1H) \ |(2R,3S,7Z)-3- , 8.10 - 8.04 (m,

HN ■CF ₃ {[4-fluoro-3- 2H), 7.83 - 7.78 (m,

M (trifluoromethy 1H), 7.50 (brt, J=9.5 l)phenyl]carba Hz, 1H), 7.37 - 7.34 (m,

NH

O=/ moyl}-7- 1H), 7.10 - 7.06 (m,

Z^N (2,2,2- 679.3 1H), 5.96 (q, 1=8.0 Hz, 2.55

F trifluoroethylid 1H), 4.76 - 4.73 (m,

\=/ _F ene)bicyclo[2. 1H), 4.56 - 4.50 (m, o. 2.1]heptan-2- 1H), 3.84 - 3.81 (m, yl]-6-(2- 2H), 3.44 - 3.40 (m, hydroxy-2-

OH 2H), 3.05 - 3.00 (m, methylpropoxy 1H), 1.93 - 1.85 (m, )-lH-indazole- 2H), 1.53 (br d, 1=7.6 3 -carboxamide Hz, 2H), 1.23 (s, 6H) 1H NMR (500 MHz, DMSO-de) 8 10.46 (s, 1H), 9.28 (br d, J=7.1

5-bromo-N- Hz, 1H), 8.12 (br d, [(2R,3S,7Z)-3- J=4.8 Hz, 1H), 7.79 (br {[4-fluoro-3-

F d, J=8.6 Hz, 1H), 7.68

Ph*. (trifluoromethy

1 (s, 1H), 7.56 (s, 1H), l)phenyl]carba

HN •CF ₃ 7.46 (t, J=9.8 Hz, 1H), moyl}-7- 5.90 (q, J=7.8 Hz, 1H), (2,2,2-

'NH° ( O 622.0 4.82 (q, J=8.8 Hz, 1H), 2.75 trifluoroethylid 4.65 (q, .7=8.7 Hz, 1H), ene)bicyclo[2. 4.53 (br s, 1H), 3.46 (br 2.1 |heptan-2- s, 1H), 3.36 (br s, 1H),

Br yI]-2,3- 3.26 - 3.12 (m, 1H), dihydro-1- 2.98 (br d, .7=3.9 Hz, benzofuran-7- 1H), 2.57 - 2.53 (m, carboxamide 4H), 2.13 - 1.99 (m, 1H), 1.97 - 1.84 (m, 1H), 1.51 (br s, 2H)

(a) All LC retention times are based on Method C unless otherwise specified, (b) 1-3 protons were not accounted for in these samples due to overlap with solvent residue and/or artifacts of water suppression. LC RT ^a (min) and

MS

Ex.

Structure Name (ESI) chiral

No !H NMR ^b (M+H) conditions when separated

{3aH,4H,6H,6a {3aH,4H,6H,6aH- H-furo[3,4- fiiro[3,4-

F d][1.2]oxazol-3- d][l,2]oxazol-3- yl}-N- yl}-N-

HN ■CF ₃ 1(1R,2R,3S,4R,7 [(1R,2R,3S,4R,7Z) Z)-7- -7-

NH° OMe 2.54/B (cyclopropylmet (cyclopropylmethy

615.3

O' N hylidene)-3-{[4- lidene)-3-{[4-

From 61-6 fluoro-3- fluoro-3- (trifluoromethyl) (trifluoromethyl)p

N X ^z phenyljcarbamo henyljcarbamoyl} o ,o yl}bicyclo[2.2.1] bicyclo[2.2.1]hept heptan-2-yl |-2- an-2-yl]-2- methoxypyridine methoxypyridine- -3-carboxamide 3 -carboxamide 1HNMR (5OO 2.27/C MHz, DMSO-d6) Peak 1 5- 5 10.55 (s, 1H), (3a, 4, 6,6a- 9.43 (brd, 1=7.3 tetrahydrofur Hz, 1 o[3,4-

5- H), 9.02 (s, 1H), 8.97 (s, 1H) d]isoxazol-3- {3aII,4H,6H,6a , 8.34 (s, 1H), 8. yl)nicotinic H-furo[3,4- 08 (b acid-

F d][l,2]oxazol-3- r d, J=4.3 Hz, 1H), RT=1.54 yl}-N- 7.90 - 7.70 min., >99% ... HN 'CF ₃ |(1R,2R,3S,4R,7 (m, 1H), 7.49 (br t, 7"^ de)- SFC Z)-7- 1=9.8 Hz, 1H),

"NH° Column: (cyclopropylmet 5.47 (dd, J=8.9,

585.1 Chiralpak

O' N hylidene)-3-{[4- 3.4 Hz, 1H), 4.71 AD-H, 21 x fluoro-3- (br d, 1=9.8 Hz, 250 mm, 5 (trifluoromethyl) 1H), 4.63 (brt,

N I" micron, phenyljcarbamo J=7.6 Hz, 1H), o ,o Mobile yl}bicyclo[2.2.1] 4.50 - 4.40 (m, Phase: 30% heptan-2- 1H), 4.15 (br d, IPA-0.1% yl]pyridine-3- 1=11.0 Hz, 1H), DEA / 70% carboxamide 4.00 (brd, J=9.5 CO2, Flow Hz, 1H), 3.75 (br Conditions: dd, J=9.3, 6.9 Hz, 45 mL/min, lH), 3.69 (br dd, 150 Bar, 1=10.8, 3.5 Hz, 40°C,; 1H), 3.19 (br dd, Analytical >10.2, 4.1 Hz, method:Colu 1H), 3.10 (br s, mn 1H), 2.77 (br s, Chiralpak 1H), 1.99 - 1.92 AD-H, 4.6 x (m, 1H), 1.85 - 250 mm, 3 1.74 (m, 1H), 1.60 micron. - 1.50 (m, 1H), Mobile 1.46 - 1.36 (m, Phase: 20% 1H), 0.82 - 0.67 IPA-0.1% (m, 2H), 0.37 (br s, DEA / 80% 2H) CO2, Flow Conditions: 2 mL/min, 150 Bar, 40°C, to afford chiral (Peak-1, RT=1.54 min., >99% de) and chiral (Peak- 2, RT=3.07 min., >99% de). lH NMR (500 2.27/C MHz, DMSO-d6) Peak-25- 5 10.53 (s, 1H), (3a,4,6,6a- 9.39 (brd, J=7.0 tetrahydrofur

5- Hz, 1H), 9.02 (br o[3,4- {3aH,4H,6H,6a s, 1H), 8.96 (br s, d]isoxazol-3- H-furo[3,4- 1H), 8.34 (br s, yl)nicotinic

F d][l,2]oxazol-3- 1H), 8.14 - 8.04 acid, yl}-N- (m, 1H), 7.89 - RT=3.07

... HN 'CF ₃ |(1R,2R,3S,4R,7 TX 7.75 (m, 1H), 7.49 min., >99% Z)-7- "NH° (br t, >9.6 Hz, de). Column: (cyclopropylmet

585.1 1H), 5.46 (br dd, Chiralpak

O' N hylidene)-3-{[4- >9.2, 3.1 Hz, III), AD-H, 21 x fluoro-3- 4.71 (brd, >9.5 250 mm, 5 (trifluoromethyl)

N I ^z Hz, 1H), 4.61 (brt, micron, phenyljcarbamo o- .0 >7.6 Hz, 1H), Mobile yl}bicyclo[2.2.1] 4.49 - 4.3 Phase: 30% heptan-2- 8 (m, 1H), 4.15 (br d, IPA-0.1% yl]pyridine-3- >10.7 Hz, 1H), DEA / 70% carboxamide 4.03 (brd, >9.5 CO2, Flow Hz, 1H), 3.84 - Conditions: 3.74 (m, 1H), 3.69 45 mL/min, (br dd, >10.7, 3.4 150 Bar, Hz, lH), 3.19 (br 40°C; dd, 1=9.9, 4.1 Hz, Analytical 1H), 3.11 (br s, method:Colu 1H), 2.77 (br s, mn 1H), 2.02 - 1.89 Chiralpak (m, 1H), 1.85 - AD-H, 4.6 x 1.75 (m, 1H), 1.65 250 mm, 3 - 1.50 (m, 1H), micron, 1.48 - 1.34 (m, Mobile 2H), 0.84 - 0.68 Phase: 20% (m, 2H), 0.37 (br s, IPA-0.1% 2H) DEA / 80% CO2, Flow Conditions: 2 mL/min, 150 Bar, ' 40°C, to afford chiral (Peak-1, RT=1.54 min., >99% de) and chiral (Peak- 2, RT=3.07 min., >99% de).

1H NMR: (500 MHz, DMSO-d6) 5 10.54 (s, 1H),

5-{5-carbamoyl- 10.04 (d, 1=6.9 Hz, 3aH,4H.5H,6H,6 1H), 8.61 - 8.58 all- (m, 2H), 8.23 (dd,

F cyclopenta[d][l, J=6.4, 2.6 Hz, 1H), 2]oxazol-3-yl}- 7.82 - 7.78 (m,

HN 'CF _S N- 1H), 7.50 (t, 1=9.8

[(1R,2R,3S,4R7 Hz, 1H), 7.34 (s,

'NH° OMe Z)-7- 1H), 6.82 (s, 1H), 2.29/C o N (cyclopropylmet 656.2 5.19 (dd, J=8.5, From 65-3 hylidene)-3-{[4- 5.0 Hz, 1H), 4.70 fluoro-3-

N ^z (d, J=9.6 Hz, 1H), p (trifluoromethyl) o- 4.43 (ddd, 1=10.2, phenyljcarbamo

NH2 yl}bicyclo[2.2.1] 6.4, 4.3 Hz, 1H), heptan-2-yl |-2- 4.34 (t, 1=9.0 Hz, methoxypyridine 1H), 4.14 (s, 3H), -3-carboxamide 3.17 (dd, 1=10.8, 4.3 Hz, 1H), 3.12 1H), 2.58 - 2.52 (m, 1H), 2.14 - 1.88 (m, 4H), 1.85 - 1.75 (m, 2H), 1.54 - 1.46 (m, 1H), L42 (br s, 1H), 0.79 - 0.69 (m, 2H), 0.39 - 0.33 (m, 2H)

2.41/C Prepared from 5-(5- (hydroxymet hyl)-

1H NMR: (500 3a,5,6,6a- MHz, DMSO-d6) tetrahydro- 5 10.54 (s, 1H), 4H- 10.06 - 10.01 (m, cyclopentafd 1H), 8.58 (dd, ]isoxazol-3-

N- 1=15.6, 2.3 Hz, yl)-2- [(1R,2R,3S,4R,7 2H), 8.26 - 8.20 methoxynico Z)-7- (m, 1H), 7.84 - tinic acid (cyclopropylmet 7.76 (m, 1H), 7.49 (Peak 1; hylidene)-3-{[4- (t, 1=9.7 H >99%de;

F z, 1H), fluoro-3- 5.15 (dd, 1=8.7, chiral (trifluoromethyl) CF ₃ 5 analytical RT

_ HN ■ .2 Hz, 1H), 4.70 phenyljcarbamo = 1.14 min); (d, 1=9.6 Hz, 1H),

NH ^u OMe yl}bicyclo[2.2.1] Preparative 4.47 - 4.40 (m, heptan-2-yl]-5- 643.1 Chiral SFC

O' N 1H), 4.26 (br t, [5- conditions :C J=8.9 Hz, 1H), (hydroxymethyl) olumn: 4.13 (s, 3H), 3.36

N" Chiralpak

,0H 3aH,4H,5 (qd, J=10.7, 6.0 o- H,6H,6 AD-H, 21 x aH- Hz, 2H), 3.17 (br 250 mm, 5 cyclopenta[d][l, dd, 1=10.7, 4.1 Hz, micron 2]oxazol-3-yl]-2- 1H), 3.12 (br s, Mobile methoxypyridine 1H), 2.73 (br s, Phase: 30% -3-carboxamide 1H), 2.02 - 1.75 MeOH/ 70% (m, 5H), 1.70 - CO2; Flow 1.46 (m, 3H), 1.42 Conditions: (br s, 2H), 0.78 - 45 mL/min, 0.69 (m, 2H), 0.39 150 Bar, - 0.31 (m, 2H) 40°C; Injection Details: 0.5 mL of ~22.5mg/mL in MeOH 2.40/C Prepared from 5-(5- (hydroxymet hyl)- 3a,5,6,6a- tetrahydro-

1H NMR: (500 4H- MHz, DMSO-d6) cyclopenta[d 5 10.56 - 10.53 (m, |isoxazol-3- 1H), 10.07 - 10.01

N- yi)-2- (m, 1H), 8.61 - methoxynico [(1R,2R,3S,4R,7 8.56 (m, 2H), 8.25 tinic acid Z)-7- - 8.20 (m, 1H), (Peak 4; (cyclopropyhnet 7.82 - 7.77 (m, >99%de; hylidene)-3-{[4-

F 1H), 7.52 - 7.45 chiral fluoro-3- (m, 1H), 5.21 - analytical RT (trifluoromethyl)

... HN •CF

T ₃ 5.15 (m, 1H), 4.72 = 6.240 phenyljcarbamo

-

NHV 4.68 (m, 1H), min); u OMe yl} bicyclo [2.2.1] 4.46 - 4.40 (m, Preparative heptan-2-yl]-5- 643.1

O' N 1H), 4.20 - 4.11 Chiral SFC [5- (m, 4H), 3.30 - conditions: (hydroxymethyl)

3.15 (m, 3H), 3.14 Column:

- 3. Chiralpak

,OH 3a 07 (m, 1H),

O- H,4H,5H,6H,6

2.76 - 2. AD-H, 21 x aH- 70 (m, 1H), 2.25 - 2.09 250 mm, 5 cyclopenta[d][l, (m, 3H), micron

2]oxazol-3-yl]-2- 1.84 - Mobile methoxypyridine 1.76 (m, 2H), 1.67 boxamide - 1.6 Phase: 30% -3-car 0 (m, 1H), 1.53 - 1.38 (m, MeOH/ 70% 4H), 0.80 - 0.69 CO2; Flow (m, 2H), 0.39 - Conditions: 0.31 (m, 2H) 45 mL/min, 150 Bar, 40°C; Injection Details: 0.5 mL of ~22.5mg/mL in MeOH Z)-7- j=9.6 Hz, 1H),

F (cyclopropylmet 4.79 (t, J=5.8 Hz, hylidene)-3-{[4- 1H), 4.71 (br d,

HN ■CF _S T't fluoro-3- J=9.8 Hz, 1H), NH° OMe (trifluoromethyl) 4.60 (s, 2H), 4.49 - phenyljcarbamo 4.40 (m, 1H), 4.09

O' N 604.4 2.53/B yl}bicyclo[2.2.1J (s, 3H), 3.61 (br d, heptan-2-vlJ-5- J=5.5 Hz, 2H), o {[1- 3.18 (br dd, (hydroxymethyl) J=10.7, 4.0 Hz, vS cyclopropoxyjm 1H), 3.14 - 3.07 OH ethyl} -2- (m, 1H), 2.75 (br s, methoxypyridine 1H), 1.89 - 1.73 -3-carboxamide (m, 2H), 1.57 - 1.47 (m, 1H), 1.47 - 1.38 (m, 2H), 0.82 - 0.69 (m, 4H), 0.63 - 0.55 (m, 2H), 0.43 - 0.29 (m, 2H)

1HNMR (4OO MHz, DMSO-d6)

N- 5 10.53 (s, 1H), [(1R,2R,3S,4R,7 10.02 (d, J=7.3 Hz, Z)-7- 1H), 8.58 (d, >=2.4

F (cyclopropyhnet Hz, 1H), 8.51 (d, hylidene)-3-{[4- J=2.4 Hz, 1H),

HN •CF ₃ fluoro-3- 8.22 (dd, j=6.2, 2.3 H ° OMe (trif z,lH), 7.80

NH l luoromethyl) phenyljcarbamo 603.2 (dt, J=8.7, 3.7 Hz, 2.15/A

O' N yl}bicyclo[2.2.1] 1H), 7.49 (t, J=9.8 heptan-2-yl]-5- Hz, 1H), 5.77 (d,

O N (3- J=5.9 Hz, 1H),

"OH hydroxyazetidine 4.70 (d, >=9.5 Hz, -l-carbonyl)-2- 1H), 4.56 - 4.46 methoxypyridine (m, 2H), 4.46 - -3-carboxamide 4.38 (m, 1H),4.3O - 4.22 (m, 1H), 4.11 - 4.11 (m, 1H), 4.16 - 4.01 (m, 3H), 3.85 - 3.76 (m, 1H), 3.20 - 3.14 (m, 1H), 3.11 (brt, J=2.9 Hz, 1H), 2.73 (t, J=3.3 Hz,lH), 1.87

- 1.70 (m, 2H), 1.56 - 1.45 (m, 1H), 1.45 - 1.34 (m, 2H), 0.80 - 0.66 (m, 2H), 0.42

- 0.28 (m, 2H) 1HNMR (4OO MHz, DMSO-d6) 5 10.53 (s, 1H), 10.02 (d, 1=6.8 Hz, 1H), 8.57 (d, 1=2.4

N- Hz, 1H), 8.50 (d, [(1R,2R,3S,4R,7 1=2.4 Hz, 1H), Z)-7- 8.22 (dd, J=6.6,

F (cyclopropylmet 2.2 Hz,lH), 7.84 - hylidene)-3-{[4- 7.75 (m, 1H), 7.49

HN ■CF ₃ fluoro-3- (t, 1=9.7 Hz, 1H), (trifluoromethyl) 4.73 - 4.63 (m, H),

'NH° OMe phenyljcarbamo 4.52 (br s, 2H),

629.2 2.26/A

O' N yl}bicyclo[2.2.1] 4.42 (br s, 1H), heptan-2-yl ]-2- 4.22 (brd, 1=0.7 methoxy-5-{2- Hz, 2H), 4.14 (s, o N oxa-6- 3H), 3.20 -3.13

■o azaspiro[3.3]hept (m, 1H), 3.11 (br t, ane-6- J=2.4 Hz, 1H), carbonyl}pyridin 2.73 (brd, J=3.2 e-3-carboxamide Hz, 1H), 1.86 -

1.73 (m, 2H), 1.54

- 1.35 (m, 3H), 0.80 - 0.68 (m, 2H), 0.35 (dd, 1=4.6, 1,7Hz, 2H) 1HNMR(4OO MHz, DMSO-d6) 5 ppm 10.48 (s, 1 H) 9.13 (d, J=7.53

N- Hz, 1 H) 8.21 (dd, [(1R,2R,3S,4R,7 1=6.53, 2.51 Hz, 1

F Z)-7- H) 7.73 - 7.79 (m, (cyclopropyhnet 1H) 7.46 -7.51

HN "CF ₃ hylidene)-3-{[4- (m, 2 H) 4.53 - fluoro-3- 4.72 (m, 3 H) 4.40

’NH° < OMe (trifluoromethyl) (brt, J=10.54 Hz,

551.2 3.30/C

O' phenyljcarbamo 1 H) 3.90 (s, 3 H)

Tl T

N-N yl}bicyclo[2.2.1] 3.60 (t, 1=5.77 Hz, heptan-2-ylj-4- 2H)3.11 -3.17 methoxy-l-(2- (m, 4 H) 3.05 (t,

/° methoxyethyl)- 1=3.76 Hz, 1 H) lH-pyrazole-3- 2.69 - 2.86 (m, 1 carboxamide H) 2.52 - 2.61 (m, 2H) 1.67-1.91 (m,2H) 1.34- 1.55 (m, 3 H) 0.68 - 0.79 (m, 2 H)

1HNMR(4OO MHz, DMSO-d6) 5 ppm 10.53 (s, 1 H) 9.15 (d, J=7.53 Hz, 1 H) 8.22 (dd,

N- 1=6.53, 2.51 Hz, 1 [(1R,2R,3S,4R,7 H) 7.77 (brd, Z)-7- 1=9.04 Hz, 1 H)

F (cyclopropvlmet 7.45-7.51 (m, 2 hylidene)-3-{[ H) 4.68 (d, J=9.54

HN ■CF ₃ 4- fluoro-3- Hz, 1 H) 4.35 -

NH° OMe (trifluoromethyl) 4.55 (m, 1 H) 3.90 phenyljcarbamo 551.3 (s,3H)3.41 (brd, 3.27/C

O' Tl yl}bicyclo[2.2.1] J=19.58 Hz, 1 H)

N~N heptan-2-yl]-l- 3.10- 3.27 (m, 2 (3- H) 2.91 - 3.08 (m, hydroxypropyl)- 1H) 2.67 -2.81

HO 4-methoxy-lH- (m, 2 H) 2.53 (br s, pyrazole-3- 1 H) 2.33 - 2.44 carboxamide (m,2H) 1.68- 1.91 (m, 2 H) 1.58 (brs, 1 H) 1.33-

1.55 (m, 2 H) 1.24 (s, 1H) 0.73 (brt, 1=8.78 Hz, 2 H) 2.75 (br dd, 4.5, 13.8 Hz, , 2.36 (s, 2H), 1.85 (br d, J ■■■ 9.3 Hz, IH), 1.81 - 1.72 (m, IH), 1.55 - 1.46 (m, IH), 1.46 - 1.31 (m , 2H), 1.11 (s, 6H), 0.80 - 0.64 (m, 2H), 0.40 _ _ _ - 0,25 (m, 2H) LC retention times are based on Method C unless otherwise specified, (b) 1-3 tons were not accounted for in these samples due to overlap with solvent due and/or artifacts of water suppression.

Table 4

LC RT ^a

MS (min) and (ESI) tructure Name chiral (M+ IH NMR conditions H) when separated MHz, 10.62 (s, IH), 10.04 (d, J =

N- 7.3 Hz, lH), 9.12 (d, ((1R,2R,3S,4R,Z) J == 2.0 Hz, IH), 8.62 -3-((4-fluoro-3- - 8.51 (m, 2H), 8.25 (trifluoromethyl )p (dd, J = 2.5, 6.5 Hz, henyl)carbam oyl)

H , IH), 7.89 - 7.76 (m, -7-(thiazol-4- IH), 7.57 (d, J - 1.8

F ylmethylene)bicy Hz, IH), 7.50 (t, J =

'NH° OMe CF ₃ clo[2.2.1]heptan-

686.2 9.6 Hz, IH), 6.43 (s, 2.19, A

O' N 2-yl)-5-(5- (hydroxymethyl)- IH), 5.21 - 5.07 (m, IH), 4.57 - 4.46 (m, 3a,5,6,6a-

N ' tet 2H), 4.22 - 4.08 (m, X o ,OH rahydro-4H- cyclopenta[d] isox 4H), 4.00 - 3.92 (m, azol-3-yl)-2- IH), 3.90 (s, IH), methoxynicotina 3.30 - 3.17 (m, 3H), mide 2.93 (br s, IH), 2.27 - 2.04 (m, 3H), 1.99 - 1.78 (m, 2H), 1.65 (br dd, J = 6.4, 10.9 Hz, 1H), 1.58 - 1.42 (m, 3H)

1H NMR (400 MHz, DMSO-d6) 5 = 10.61 (s, 1H), 10.03 (d, J = 7.3 Hz, 1H), 9.12 (d,

N- 1.5 Hz, 1H), 8.60 ((1R,2R,3S,4R,Z) , J = 2.5 Hz, 1H), -3-((4-fluoro-3- 8.56 (d, J = 2.5 Hz, (trifluoromethyl)p 1H), 8.25 (dd, J = 2.5,

O N henyl)carbamoyl) 6.5 Hz, 1H), 7.86 -

H , -7-(thiazol-4- 7.79 (m, 1H), 7.57 (d,

^~F ylmethylene)bicy J = 2.0 Hz, 1H), 7.50

-NH° OMe CF ₃ clo[2.2.1]heptan- (t, J = 9.8 Hz, 1H),

686.2 2.19, A o' N 2-yl)-5-(5- 6.43 (s, 1H), 5.15 (hydroxymethyl)- (dd, J = 5.1, 8.9 Hz, 3a,5,6,6a- 1H), 4.50 (q, 1 = 5.1

N ^z tetrahydro-4H- Hz, 2H), 4.30 - 4.23 o .OH cyclopenta[d] i sox (m, 1H), 4.13 (s, 3H), azol-3-yl)-2- 3.95 (br s, 1H), 3.36 methoxynicotina (br d, J = 8.8 Hz, 2H), mide 3.29 (br d, J = 6.3 Hz, 1H), 2.96 - 2.89 (m, 1H), 2.03 - 1.73 (m, 5H), 1.72 - 1.43 (m, 4H)

1H NMR (400 MHz, DMSO-d6) 6 = 10.25 (d, J = 6.8 Hz, 1H),

5-(5- 8.59 (d, J = 2.5 Hz, (hydroxymethyl)- 1H), 8.51 (d, J = 2.3 3a,5,6,6a- Hz, 1H), 8.03 (d, J = s tetr

3- ahydro-4H- 8.5 Hz, 1H), 7.29 (s, cyclopenta[d]isox 1H), 6.27 (s, 1H), azol-3-yl)-2- 5.16 fdd, J = 5.1, 8.9 methoxv-N- Hz, 1H), 4.50 (t, J =

'l)IH ^O OMe ((1R,2R,3S,4R,Z)

620.3 5.4 Hz, 1H), 4.38 - 2.00, A -3-(((R)-l-(l-

4.31 (m, 1H), 4.27 (t, methylcyclopropy J = 8.8 Hz, 1H), 4.1O l)ethyl)carbamoyl

N ^z

,OH )-7-( (s, 3H), 3.83 (t, J =

O' (2- methylthiazol-4- 3.3 Hz, 1H), 3.53 - yl)methylene)bicy 3.46 (m, 1H), 3.41 - clo[2.2.1]heptan- 3.36 (m, 3H), 3.06 2-yl)nicotinamide (dd, J = 4.4, 10.9 Hz, 1H), 2.72 (br s, 1H), 2.66 (s, 3H), 2.05 - 1.87 (m, 3H), 1.84 - 1.74 (m, 2H), 1.72 -

1.54 (m, 2H), 1.48 -

1.39 (m, 2H), 1.05 (d, J = 7.0 Hz, 3H), 1.01 (s, 3H), 0.62 - 0.53 (m, IH), 0.42 - 0.32 (m. IH), 0.25 - 0.15 (m, 2H)

1HNMR(4OO MHz, DMSO-d6) 5 ppm 10.27 (d, 1=6.75 Hz, 1 H) 8.60 (d, 1=2.25 Hz, 1 H) 8.52 (d, J=2.50 Hz, 1 H) 8.06 (d, 1=8.51 Hz, 1 H)

N- 7.81 (s, 1H)7.19- ((1R,2R,3S,4R,Z) 7.52 (m, 1 H) 6.40 (s, -7-((2- IH) 5.39 (dd, 1=9.51, (difluorome 3.50 Hz, IH) 4.52- n thyl)t hiazol-4- 4.61 (m, 1 H) 4.37

F H (ddd, 1=10

N-V ) yl)methylene)-3- .76, 6.63, (((R)-l-(l- 4.63 Hz, 1 H)4.11 (s,

'"NH l ^! °OMe methylcyclopropy 4 H) 3.96 (d, J=9.26

628.2 2.18, A li N l)ethyl)carbamoyl Hz, 1 H) 3.72-3.82 )bicyclo[2.2.1]he (m, 2 H) 3.67 (dd, ptan-2-yl)-2- 1=10.76, 3.75 Hz, 1

^N . b- ,o methoxy-5- H) 3.46 - 3.54 (m, 1 (3a,4,6,6a- H)3.09 (dd, 1=11.01, tetrahydrofuro[3, 4.50 Hz, 1 H) 2.78 4-d]isoxazol-3- (br s, 1 H) 1.98 (brt, yl)nicotinamide J=8.76Hz, IH) 1.80 - 1.88 (m, IH) 1.47

(brd, 1=6.75 Hz,2H) 1.05 (d, J=6.75 Hz, 3 H) 0.55 - 0.60 (m, 1 H) 1.01 (s,3H)0.32 -0.40(m, 1 H)0.17- 0.26 (m, 2 H)

1H NMR (400 MHz, DMSO-d6) 5 = 10.56 (s, 1H), 10.00 (d, J = 6.9 Hz, 1H), 8.58 (dd,

N- J = 2.4, 13.7 Hz, 2H), ((1R,2R,3S,4R,Z) 8.24 (dd, J = 2.4, 6.6 -7- Hz, 1H), 7.82 -7.71 (cyclopentyhneth (m, 1H), 7.49 (t, J = ylene)-3-((4- 9.8 Hz, 1H), 5.24 -

H , fluoro-3- 5.07 (m, 2H), 4.50 (br (trifluoromethyl)p

F t, J = 4.8 Hz, 1H),

'NH° OMe henyl)carbamoyl)

CF ₃ 4.42 - 4.32 (m, 1H), bicyclo[2.2.I]hept 671.3 2.53, B

O' N 4.26 (t, J = 8.7 Hz, an-2-yl)-5-(5- (hydroxymethyl)- lH), 4.13 (s, 3H),3.I7 z 3a (dd, J = 4.2, 10.7 Hz,

N ,5,6,6'a-

, 1H), 3.01 (br s, 1H), o- OH tetrahydro-4H- cyclopenta[d] isox 2.73 (br d, J = 3.4 Hz, azol-3-yl)-2- 1H), 2.65 - 2.56 (m, methoxynicotina 1H), 2.01 (br dd, J = mide 5.6, 13.6 Hz, 1H), 1.95 - 1.70 (m,7H), 1.69 - 1.52 (m, 6H), 1.39 (br s, 2H), 1.33 -

1,22 (m, 2H) 1H NMR (400 MHz, DMSO-d6) 5 = 10.57 (s, 1H), 10.06 (br d, 1=6.7 Hz, 1H), 8.41

N- (d, 1=2.1 Hz, 1H), ((1R,2R,3S,4R,Z) 8.32 (d, 1=2.1 Hz, -7- 1H), 8.23 (br d, 1=4.3 (cyclopropylmeth Hz, 1H), 7.86 - 7.75 ylene)-3-((4-

H , (m, 1H), 7.49 (brt, fluoro-3-

F J=9.5 Hz, 1H), 7.04 (trifluoromethyl)p

NH° OMe (s, 1H), 4.71 (d, 1=9.5

CF ₃ henyl)carbamoyl)

640.2 Hz, 1H), 4.50 - 4.39 2.06

O' N bicyclo[2.2. IJhept (m, 1H), 4.18 (br s, an-2-yl)-5-(6- hydroxy-5, 6,7,8- 1H), 4.12 (s, 3H),

N t 4.05 (br dd, 1=1 1.9,

•OH etrahydroimidazo N=( [l,2-a]pyridin-3- 3.1 Hz, 1H), 3.71 (br yi)-2- dd, 1=12.4, 3.8 Hz, methoxynicotina 1H), 3.17 (br dd, mide 1=10.7, 4.3 Hz, 1H), 3.12 (br s, 1H), 2.96 - 2.85 (m, 1H), 2.84 - 2.72 (m, 2H), 1.94 (br d, 1=5.8 Hz, 2H), 1.86 - 1.74 (m, 2H), 1.57 - 1.35 (m, 3H), 0.74 (quin, J=9.8 Hz, 211), 0.35 (br s, 214) THNM^ DMSO-d6) 5 10.65 - 10.59 (m, 114), 10.06 (br d, 4=5.8 Hz, 1H),

8.42 (s, 1H), 8.36 - 8.31 (m, 1H), 8.29 -

N- 8.22 (m, 1H), 7.85 - ((1R,2R,3S,4R,Z) 7.80 (m, 1H), 7.50 (br .7. t, 1=9.6 Hz, 1H), 7.09

(cyclopropylmeth - 7.02 (m, 1H), 4.75 - ylene)-3-((4- 4.68 (m, 1H), 4.49 -

H > fluoro-3- 4.42 (m, lH), 4.17 (br

F (trifluoromethyl)p d, 1=5.2 Hz, 114),

'NH° OMe CF ₃ henyl)carbamoyl) 4.14 (s, 3H), 4.08 -

640.2 2.05

O N bicyclo[2.2.1]hept 4.01 (m, 1H), 3.78 - an-2-yl)-5-(6- 3.69 (m, 1H), 3.22 - hydroxy-5, 6,7,8- 3.17 (m, 1H), 3.15 -

N •OH tetrahydroimidazo 3.11 (m, 1H), 2.97 -

N=( [l,2-a]pyridin-3- 2.87 (m, 1H), 2.84 - yl)-2- 2.77 (m, 1H), 2.78 - methoxynicotina 2.72 (m, 1H), 2.00 - mide 1.90 (m, 2H), 1.88 - 1.79 (m, 2H), 1.78 - 1.74 (m, 1H), 1.56 - 1.47 (m, 1H), 1.46 - 1.37 (m, 2H), 0.81 - 0.69 (m, 2H), 0.41 -

0.32 (m, 2H) 1HNMR (500 MHz,

N- DMSO-d6) 8 10.58 ((1R,2R,3S,4R,Z) (s, 1H), 10.07 (br d, -7- 1=7.0 Hz, 114), 8.45 (cyclopropylmeth

H , (d, J=1.8 Hz, 1H), ylene)-3-((4- 8.36 (d, 1=1.8 Hz, fluoro-3-

'NH° OMe 1H), 8.24 (br d, 4=4.3

CF ₃ (trifluoromethyl)p

640.2 Hz, 1H), 7.87 - 7.77 2.06

O' N henyl)carbamoyl) (m, 1H), 7.50 (brt, bicyclo[2.2.1]hept an-2-yl)-5-(6- 1=9.8 Hz, 1H), 7.29

N hydroxy-5, 6,7,8 (s, 1H), 4.71 (d, 4=9.8 N •OH - =Z tetrahydroimidazo Hz, 114), 4.51 - 4.39 [l,2-a]pyridin-3- (m, 1H), 4.21 (br s, yi)-2- 1H), 4.14 (s, 3H), 4,07 (br dd, J=12.5, methoxynicotina 3.1 Hz, 1H), 3.77 (br mide dd, 1=12.1, 4.1 Hz, 1H), 3.18 (br dd, 1=10.4, 4.0 Hz, 1H), 3.14 - 3.07 (m, 1H), 3.03 - 2.93 (m, 1H), 2.93 - 2.84 (m, 1H), 2.75 (br s, 1H), 1.97 (br d, J=4.3 Hz, 2H), 1.88 - 1.76 (m, 2H), 1.56 - 1.35 (m, 3H), 0.82 - 0.68 (m, 2H), 0.36 (br s, 2H) 1HNMR (5OO MHz, DMSO-d6) 8 10.21 (br d, J=6.7 Hz, 1H), 8.51 (d, 1=2.4 Hz, 1H), 8.45 (d, 1=2.4 Hz, 1H), 7.92 (br d,

N- J=8.5 Hz, 1H), 5.10 ((1R,2R,3S,4R,Z) (br dd, J=8.7, 5.0 Hz, -7- 1H), 4.58 (d, 1=9.5 (cyclopropylmeth Hz, 1H), 4.20 (brt, vlene)-3-(((R)-l- J=8.4 Hz, 2H), 4.02 (1- (s, 3H), 3.58 - 3.46 m ethylcycl opropy (m, 1H), 3.44 - 3.24

'NH° OMe l)ethyl)carbamoyl (m, 2H), 3.00 (br s, )bicyclo[ 563.0 2.27 o- N 2.2.1]he 1H), 2.90 (br dd, ptan-2-yl)-5-(5- J=10.5, 3.8 Hz, 1H), (hydroxymethyl)-

N' 3a,5,6 1.99 - 1.82 (m, 2H),

,OH ,6a- b- tetrahydro-4H- 1.80 - 1.56 (m, 4H)' cyclopenta[d] isox 1.55 - 1.46 (m, 1H), azol-3-yl)-2- 1.45 - 1.36 (m, 1H), methoxynicotina 1.34 - 1.23 (m, 2H), mide 0.97 (d, J=6.7 Hz, 3H), 0.92 (s, 3H), 0.71 - 0.57 (m, 2H), 0.47 (br dd, J=8.4, 3.5 Hz, 1H), 0.32 - 0.21 (m, 3H), 0.18 - 0.06 (m, 2H) 1HNMR (500 MHz, DMSO-d6) 5 10.34 - 10.25 (m, 1H), 8.61 -

N- 8.56 (m, III), 8.49 - ((1R,2R,3S,4R,Z) 8.44 (m, 1H), 7.95 (br -7- d, 1=8.5 Hz, 1H), (cyclopropylmeth 5.88 - 5.77 (m, 1H), ylene)-3-(((R)-l- 4.63 (d, J=9.5 Hz, (1- 1H), 4.29 - 4.22 (m, methylcyclopropy 1H), 4.12 - 4.05 (m, l)ethyl)carbamoyl 3H), 3.34 - 3.26 (m, )bicyclo[2.2.1]he 1H), 3.22 - 3.15 (m, ptan-2-vl)-5- 564.4 2.24 1H), 3.06 (br s, 1H), ((6S,7aR)-6- 2.98 - 2.87 (m, 1H), (hydroxymethyl)-

2.35 - 1.93 (m, 3H), 5,6,7,7a- 1.86 - 1.67 (m, 2H), tetrahydropyrrolo 1.51 - 1.42 (m, 1H), [1,2- ' d][l,2,41oxadiazo 1.35 (br s, 2H), 1.02 l-3-yl)-2- (br d, J=6.8 Hz, 3H), methoxynicotina 0.97 (s, 3H), 0.75 - mide 0.65 (m, 2H), 0.57 - 0.48 (m, 1H), 0.36 - 0.27 (m, 3H), 0.23 - 0,12 (m, 2H)

1HNMR (500 MHz, DMSO-d6) 8 10.36 -

N- 10.24 (m, 1H), 8.65 -

((1R,2R,3S,4R,Z) 8.56 (m, 1H), 8.53 - -7- 8.41 (m, 1H), 7.95 (br (cyclopropylmeth d, 1=7.9 Hz, 1H), ylene)-3-(((R)-l- 5.90 - 5.77 (m, 1H), (1- 4.70 - 4.58 (m, 2H), methylcyclopropy 4.26 (br s, 1H), 4.16 - l)ethyl)carbamoyl 4.04 (m, 3H), 3.52 - )bicyclo[2.2.1]he 3.42 (m, 1H), 3.41 - ptan-2-yl)-5- 564.3 2.24 3.31 (m, 1H), 3.06 (br ((6S,7aS)-6- s, 1H), 3.01 - 2.86 (hydroxymethyl)- (m, 2H), 2.33 - 1.93 5,6,7,7a- (m, 3H), 1.88 - 1.66 tetrahydropvrrolo (m, 2H), 1.55 - 1.42 [1,2- d][l,2,4]oxadiazo (m, 1H), 1.41 - 1.29 l-3-yl)-2- (m, 2H), 1.09 - 0.94 methoxynicotina (m, 6H), 0.79 - 0.65 mide (m, 2H), 0.60 - 0.48 (m, 1H), 0.32 (br s, 3H), 0,18 (br s, 2H) 1HNMR (500 MHz, DMSO-d6) 8 10.21 (br d, J=6.7 Hz, IH), 8.92 (s, IH), 8.61 (d,

N- J=2.4 Hz, 1H), 8.56 ((1R,2R,3S,4R,Z) (d, J=2.1 Hz, IH), -3-((3- 5.19 (dd, J=8.5, 5.2 cyanobicyclo[l.l. Hz, IH), 4.62 (d, l]pentan-l- J=9.8 Hz, IH), 4.31 yl)carbamoyl)-7- (brt, J=9.3 Hz, IH), (cyclopropylmeth 4.27 - 4.22 (m, 1H), ylene)bicyclo[2.2. 4.14 (s, 3H), 3.99 - 1 ]heptan-2-yl)-2- 640.2 3.90 (m, 1H), 3.06 (br 2.13 methoxy-5-(5- s, IH), 2.83 (br dd, (2,2,2-trifhioro- 1 - J=10.8, 4.1 Hz, IH), hydroxyethyl)- 2.53 - 2.50 (m, 6H) 3a,5,6,6a- ' (overlaps DMSO), tetrahydro-4H- 2.07 - 1.89 (m, 3H), cyclopenta[d]isox 1.86 - 1.76 (m, 2H), azol-3- 1.68 (br d, J=11.6 Hz, yl)nicotinamide 2H), 1.50 - 1.40 (m, 1H), 1.34 (br d, 1=8.5 Hz, 2H), 0.71 (quin, J=8.9 Hz, 2H), 0.32 (br d, J=4.0 Hz, 2H) 1HNMR (5OO MHz, DMSO-d6) 8 10.60 - 10.51 (m, IH), 10.04

N- (br d, J=7.0 Hz, IH),

((1R,2R,3S,4R,Z) 8.59 (s, IH), 8.58 (s, .7. IH), 8.24 (br d, J=4.3

(cyclopropylmeth Hz, IH), 7.92 - 7.71 ylene)-3-((4- (m, IH), 7.50 (t, fluoro-3- J=9.8 Hz, IH), 5.14

(trifluorometbyl)p (br dd, J=8.7, 4.4 Hz, henyl)carbamoyl) 2H), 4.71 (d, J=9.5 bicyclo[2.2.1]hept 671.3 2.46, B Hz, IH), 4.54 - 4.45 an-2-yl)-5-(5-(2- (m, IH), 4.34 - 4.20 hydroxypropan-2- (m, 2H), 4.17 - 4.07 yl)-3a,5,6,6a- tetrahydro-4H- (m, 3H), 3.21 - 3.10 cyclopenta[d]isox (m, 2H), 2.74 (br s, azol-3-yl)-2- IH), 1.98 - 1.91 (m, methoxynicotina IH), 1.87 - 1.76 (m, mide 3H), 1.67 (br d, J=7.6 Hz, IH), 1.56 - 1.49 (m, IH), 1.47 - 1.38 (m, 2H), 1.06 (s, 3H), 1.03 (s, 3H), 0.82 -

0.63 (m, 3H), 0.50 - 0.23 (m, 2H)

1HNMR (4OO MHz, CD3OD) 8 10.43 (br d, J=7.2 Hz, 1H), 10.23 - 10.10 (m, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.19

N- (dd, J=6.3, 2.3 Hz, ((1R,2R,3S,4R,Z) 1H), 7.78 (dt, >8.8, -7- 3.5 Hz, 1H), 7.31 (t, (cyclopropylmeth 1=9.6 Hz, 1H), 5.23 ylene)-3-((4- (dd, J=8.9, 5.0 Hz,

,CF ₃ fluoro-3- 1H), 4.76 (d, N9.4

F (trifluoromethyl)p Hz, 1H), 4.63 - 4.45

NH° OMe henyl)carbamoyl) (m, 1H), 4.26 (s, 3H), bicyclo[2.2.1]hept 657.4 3.61 (t, J=6.4 Hz, 2.47, A an-2-yl)-5-(5-(l- 1H), 3.28 - 3.23 (m, hydroxyethyl)- lH), 3.18 (dd, J=10.9,

N' b- ,OH 3a,5,6,6a- 4.4 Hz, 1H), 2.75 (t, tetrahydro-4H- J=3.3 Hz, 1H), 2.31 cyclopenta[d J isox (dd, 1=13.7, 5.7 Hz, azol-3-yl)-2- 1H), 2.06 - 1.98 (m, methoxynicotina 1H), 1.94 - 1.86 (m, mide 2H), 1.85 - 1.81 (m, 2H), 1.76 - 1.66 (m, 1H)' 1.60 - 1.50 (m, 3H), 1.15 (d, 1=6.5 Hz, 3H), 0.78 (dd, J=8.1, 1.7 Hz, 2H), 0.38 (br dd, J=4.6, 2.6 Hz, 2H)

5-(5- lHNMR (500 MHz, (cyclopropy 1 (hydr DMSO-d6) 8 10.37 oxy)me (s, 1H), 9.87 (br d,

,CF ₃ thyl)- 3a,5,6,6a- J=7.0 Hz. 1H), 8.41

F tetrahydro-4H- (s, 1H), 8.40 (s, 1H),

-NH° OMe cyclopenta[d]isox 8.12 - 8.01 (m, 1H), o- N azol-3-yl)-N- 683.2 7.70 - 7.57 (m, 1H), 2.60, B ((1R,2R,3S,4R,Z) 7.31 (t, 1=9.6 Hz,

N ^z -7- 1H), 5.08 - 4.89 (m, b- ,OH (cyclopropylmeth 1H), 4.52 (d, 1=9.5 ylene)-3-((4- Hz, 1H), 4.38 - 4.23 fluoro-3- (m, 2H), 4.00 - 3.90 (trifluorometiiyl)p (m, 4H), 2.99 (br dd, henyl)carbamoyl) 1=10.4, 4.0 Hz, 1H), bicyclo[2.2.1]hept 2.94 (br s, 1H), 2.56 an-2-yl)-2- (br s, 1H), 2.52 - 2.45 methoxynicotina (m, 1H), 2.19 - 2.09 mide (m, 1H), 2.05 - 1.98 (m, 1H), 1.96 - 1.86 (m, 1H), 1.69 - 1.56 (m, 2H), 1.53 - 1.44 (m, 1H), 1.40 - 1.30 (m , 2H), 1.24 (br s, 2H), 0.65 - 0.47 (m, 3H), 0.26 - 0.16 (m, 3H), 0.15 - 0.08 (m' 1H), 0.01 (br d, J=3.7 Hz, 2H) 1HNMR (500 MHz, DMSO-d6) 5 10.56 (s, 1H), 10.05 (br d, J=6.7 Hz, 1H), 8.60 (d, 1=2.4 Hz, 1H),

N- 8.57 (d, J=2.4 Hz, ((1R,2R,3S,4R,Z) 1H), 8.30 - 8.15 (m, -7- 1H), 7.87 - 7.73 (m, (cyclopropylmeth 1H), 7.49 (t, 1=9.6 ylene)-3-((4- Hz, 1H), 5.15 (dd,

,CF ₃ fluoro-3- 1=8.5, 4.9 Hz, 1H),

■F (trifluoromethyl)p 4.71 (d, J=9.8 Hz,

'NH° OMe henyl)carbamoyl) 1H), 4.49 - 4.39 (m, bicyclo[2.2. IJhept 657.4 2.47, B 1H), 4.25 (br t, J=8.4 an-2-yl)-5-(5-(l- Hz, 1H), 4. 13 (s, 3H), hydroxyethyl)-

N ^z 3.65 - 3.36 (m, 1H), b- ,OH 3a,5,6,6a- tetrahydro-4H- 3.19 - 3.13 (m, 1H), cyclopenta[d] i sox 3.12 (br s, 1H), 2.74 azol-3-yl)-2- (br s, 1H), 1.96 - 1.71 methoxynicotina (m, 5H), 1.64 - 1.57 mide (m, 1H), 1.52 - 1.45 (m, 1H), 1.44 - 1.33 (m, 2H), 1.03 (d, J=6.1 Hz, 3H), 0.82 - 0.66 (m, 2H), 0.36 (br s, 2H). 1HNMR (500 MHz, DMSO-d6) 5 10.57 (s, 1H), 10.05 (br d, >7.0 Hz, 1H), 8.59 (br s, 1H), 8.58 (br s, 1H), 8.24 (br d, >4.9 Hz, 1H), 7.96 - 7.71

N- (m, 1H), 7.58 - 7.43 ((1R,2R,3S,4R,Z) (m, 1H), 5.15 (br dd, -7- >8.7, 4.7 Hz, 1H), (cyclopropylmeth 4.72 (d, >9.5 Hz, ylene)-3-((4- 1H), 4.48 (d, >5.8

H , ,CF ₃ fluoro-3- Hz, 1H), 4.46 - 4.41

F (trifluoromethyl)p (m, 1H), 4.29 - 4.23

'NH ° OMe henyl)carbamoyl) (m, 1H), 4.14 (s, 3H),

N bicyclo[2.2.1]hept 671.2 3.28 - 3.17 (m, 1H), 2.59 an-2-yl)-5-(5-(l- 3.13 (br s, 1H), 2.75 hydroxypropyl)-

N ^z (br s, 1H), 2.16 - 2.02 b- ,0H 3a,5,6,6a- (m, 1H) 1.90 - 1.73 tetrahydro-4H- (m, 4H), 1.65 (br dd, cyclopenta[d]isox >10.7, 6.1 Hz, 2H), azol-3-yl)-2- 1.57 - 1.49 (m, 1H), methoxynicotina 1.45 - 1.39 (m, 2H), mide 1.38 - 1.29 (m, 1H),

1.28 - 1.17 (m, 1H), 0.83 (br t, >7.3 Hz, 3H), 0.78 - 0.64 (m, 2H), 0.50 - 0.30 (m, 2H). Some protons are obscured by water suppression

N- lHNMR (500 MHz, ((1R,2R,3S,4R,Z) DMSO-d6) 5 10.53 -3-((4-fluoro-3- (s, 1H), 9.94 (br d,O- (trifluoromethyl)p >6.8 Hz, 1H), 8.57 henyl)carbamoyl) (s, 1H), 8.54 (br s,

,CF _a 1H), 8.22 (br d, >4.3

F hydroxypropylide Hz, 1H), 7.80 (br s,

NH° OMe ne)bicyclo[2.2.1] 1H), 7.48 (brt, >9.6

633.1 2.55

O' N heptan-2-yl)-5-(5- Hz, 1H), 5.15 (dd, (hydroxymethyl)- >8.6, 5.5 Hz, 1H), 3a,5,6,6a- 4.59 (br s, 1H), 4.25

^N o, -- ,OH tetrahydro-4H- (brt, >8.8 Hz, 1H), cyclopenta[d]isox 4.12 (s, 3H), 3.41 - azol-3-yl)-2- 3.30 (m, 1H), 3.25 (br methoxynicotina d, >10.4 Hz, 1H), mide 2.99 (s, 1H), 2.49 - 2.33 (m, 1H), 2.29 (br s, 1H), 2.00 (br dd, J=13.7, 5.5 Hz, 1H), 1.93 - 1.74 (m, 3H), 1.72 - 1.53 (m, 4H), 1.51 - 1.33 (m, 6H), 0.97 (br t, J=6.7 Hz, _ 3H) _ 1HNMR (5OO MHz, DMSO-d6) 5 10.11 (br d, 1=6.4 Hz, 1H), 8.39 (d, 1=2.1 Hz, 1H), 8.31 (d, 1=2.1 Hz, 1H), 7.91 (br d, J=8.9 Hz, 1H), 5.68

5-(5- (q, J=7.9 Hz, 1H), (hydroxymetbyl)- 4.96 (br dd, 1=8.4, 3a,5,6,6a- 5.0 Hz, 1H), 4.45 - tetrahydro-4H-C. 4.28 (m, 1H), 4.13 (br cyclopenta[d]isox s, 1H), 4.06 (brt, azol-3-yl)-2- J=8.7 Hz, 1H), 3.89 methoxy’-N-

''NH°OMe (s, 3H), 3.43 - 3.25 ((1R,2R,3S,4R,Z)

591.2 (m, 1H), 3.25 - 3.09 2.22 -3-(((R)-l-(l- (m, 1H), 3.00 (br s, methylcyclopropy 1H), 2.87 (br dd,

^N l)ethvl)carbamovl . b- ,OH )-7-(2,2,2- J=10.5, 4.4 Hz, 1H), trifluoroethyliden 2.63 (br s, 1H), 1.85 - e)bicyclo[2.2.1]he 1.65 (m, 3H), 1.65 - ptan-2- 1.54 (m, 2H), 1.51 - yl)nicotinamide 1.29 (m, 2H), 1.24 (br s, 2H), 1.05 (br d,

J=6.7 Hz, 1H), 0.84 (d, J=7.0 Hz, 3H), 0.79 (s, 3H), 0.34 (br d, J=5.2 Hz, 1H), 0.24 - 0.08 (m, 1H), 0,04 - -0.12 (m, 2H)

N- 1HNMR (500 MHz, ((1R,2R,3S,4R,Z) DMSO-d6) 8 10.31 ^C 1 -3-(((lR)-l-(2,2- (br d, 1=6.4 Hz, 1H), difluoro-1- 8.61 (d, J=2.1 Hz,

'NH°OMe methylcyclopropy 1H), 8.57 - 8.49 (m,

627.2 2.14 l)ethvl)carbamovl 1H), 8.23 (br d, J=7.9 )-7-(2,2,2- Hz, 1H), 5.91 (q, trifluoroethyliden J=8.0 Hz, 1H), 5.17 o . ,0H e)bicyclo[2.2.1]he (br dd, J=8.5, 5.2 Hz, ptan-2-yl)-5-(5- 1H), 4.44 - 4.32 (m, (hydroxymethyl)- 1H), 4.28 (brt, 1=8.9 3a,5,6,6a- Hz, 1H), 4.11 (s, 3H), tetrahydro-4H- 3.87 - 3.72 (m, 1H), cyclopenta[d]isox 3.22 (br s, 1H), 3.11 azol-3-yl)-2- (br dd, 1=10.5, 4.1 methoxynicotina Hz, HI), 2.84 (br s, mide 1H), 2.01 (br dd, 1=13.7, 5.8 Hz, 1H),

1.96 - 1.75 (m, 4H), 1.74 - 1.53 (m, 2H), 1.48 - 1.29 (m, 3H), 1.20 (br s, 1H), 1.15 (br d, J=7.3 Hz, 6H) 1HNMR (5OO MHz, DMSO-d6) 8 10.56 (s, 1H), 10.01 (br d,

N- 1=6.7 Hz, 1H), 8.56 ((1R,2R,3S,4R,Z) (s, 2H), 8.23 (br d, -7- J=4.6 Hz, 1H), 7.79

(cyclobutylm ethyl (br s, 1H), 7.49 (brt, ene)-3-((4-fluoro- J=9.8 Hz, 1H), 5.38

,CF ₃ 3- (d, J=8.5 Hz, 1H),

(trifluoromethyl)p

F 5.18 (br s, 1H), 4.34

-NH° OMe henyl)carbamoyl) (br s, 1H), 4.32 - 4.21 bicyclo[2.2.1]hept 643.2 2.47

N (m, 1H), 4.13 (s, 3H), an-2-yl)-5-(5- hydroxy- 3.45 (br s, 1H), 3.30 -

N ^y 3a,5,6,6a- 3.13 (m, 1H), 3.10 (br b- 'OH tetrahydro-4H- d, 1=7.6 Hz, 1H), cyclopenta[d]isox 2.97 (br s, 1H), 2.72 azol-3-yl)-2- (br s, 1H), 2.24 - 2.07 methoxynicotina (m, 2H), 2.06 - 1.96 mide (m, 1H), 1.96 - 1.78 (m, 6H), 1.75 (br d, J=8.2 Hz, 2H), 1.37

(br s, 2H)

N- lHNMR (500 MHz,

F ((1R,2R,3S,4R,Z) DMSO-d6) 8 10.28 -3-((( (br d, J=6.4 Hz, 1H), ^C lR)-l-(2,2- 1 difluoro-1- 8.58 (d, J=2.1 Hz, methylcyclopropy HI), 8.52 (s, 1H), l°OMe l)ethyl)carbamoyl 8.47 (br d, J=7.9 Hz,

627.2 2.22

O' li N )-7-(2,2,2- 1H), 5.88 (q, 1=8.0 trifluoroethyliden Hz, 1H), 5.16 (br dd, e)bicyclo[2.2.1]he 1=8.7, 5.0 Hz, 1H),

N ^z b- ,OH ptan-2-yl)-5-(5- 4.63 (br t, 1=5.2 Hz, (hydroxymethyl)- 1H), 4.36 (br d, J=5.5 3a,5,6,6a- Hz, 1H), 4.25 (br t, tetrahydro-4H- 1=8.9 Hz, 1H), 4.08 cyclopenta[d] isox (s, 3H), 3.94 - 3.78 azol-3-yl)-2- (m, 1H), 3.64 - 3.47 methoxynicotina (m, 2H), 3.47 - 3.29 mide (m, 1H), 3.25 - 3.15 (m, 1H), 3.10 (br dd, J=10.7, 4.3 Hz, 1H), 2.85 (br s, 1H), 2.00 (br dd, 1=13.7, 5.5

Hz, 1H), 1.95 - 1.74 (m, 4H), 1.70 - 1.49 (m, 3H), 1.44 (br s, 2H), 1.22 (br s, 1H), 1.14 - 1.07 (s, 6H)

1H NMR (400 MHz, DMSO-d6) 5 = 10.30 (d, J = 6.5 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.97 (s,

2-methoxy-N- HI), 6.44 (s, 1H), ((1R,2R,3S,4R,Z) 5.39 (dd, J = 3.4, 9.1 -3-(((R)-l-(l- Hz, 1H), 4.62 - 4.53 methylcyclopropy (m, 1H), 4.43 - 4.31 l)ethyl)carbamovl (m, 1H), 4.14 - 4.09 )-7-((2- (m, 4H), 3.96 (d, J = (trifluoromethyl)t 9.8 Hz, 1H), 3.80 - hiazol-4- 646.2 2.37, B 3.72 (m, 2H), 3.67 yl)methylene)bicy (dd, 1 = 3.5, 10.8 Hz, clo[2.2.1]heptan- 2-yl)-5- 1H), 3.53 - 3.47 (m, (3a,4,6,6a- 1H), 3.10 (dd, J = 4.3, tetrahydrofuro[3, 11.0 Hz, 1H), 2.80 4-d]isoxazol-3- (br d, J = 1.0 Hz, 1H), yl)nicotinamide 2.02 - 1.95 (m, 1H), 1.88 - 1.82 (m, 1H), 1.51 - 1.45 (m, 2H), 1.05 (d, J = 7.0 Hz, 3H), 1.02 (s, 3H), 0.63 - 0.52 (m, 1H), 0.42 - 0.31 (m, 1H), 0.27 - 0.16 (m, 2H) 1HNMR (500 MHz, DMSO-d6) 5 10.60 (s, 1H), 10.00 (br d, 1=7.0 Hz, 1H), 8.57

N- (dd, 1=13.3, 2.0 Hz, ((1R,2R,3S,4R,Z) 2H), 8.22 (br d, J=4.0 -7- Hz, 1H), 7.83 - 7.78 (cyclobutylmethyl (m, 1H), 7.49 (br t, ene)-3-((4-fluoro- J=9.8 Hz, 1H), 6.34

H , ,CF, 3- (br d, 1=7.0 Hz, 1H), (trifluoromethyl )p

F 5.32 (br t, J=7.2 Hz, henyl)carbamoyl)

'NH° OMe 1H), 5.14 (br dd, bicyclo[2.2.1]hept 0 ^< Tl 725.1 1=8.9, 4.3 Hz, 1H), 2.45 an-2-yl)-2- 4.42 (brt, 1=10.4 Hz, methoxy-5-(5- 1H), 4.23 (br t, J=9.0 b- ,0H (2,2,2-trifluoro-l- hydroxyethyl)- Hz, 1H), 4.13 (s, 3H),

CFg 3a,5,6,6a- 4.04 - 3.92 (m, 1H), tetrahydro-4H- 3.18 (br dd, 1=10.4, cyclopenta[d J isox 3.7 Hz, 1H), 2.98 (br azol-3- s, 1H), 2.78 (br s, yl )nicotinamide 1H), 2.44 - 2.26 (m, 2H), 1.98 - 1.63 (m, 6H), 1.47 - 1.32 (m, 2H), 1.04 (br d, DMSO-d6) 5 10.56 (s, 1H), 10.01 (br d,

N- J=6.7 Hz, 1H), 8.58 ((1R,2R,3S,4R,Z) (dd, J=15.6, 2.1 Hz, .7. 2H), 8.29 - 8.19 (m,

(cyclopentylmeth 1H), 7.84 - 7.75 (m, ylene)-3-((4- 1H), 7.49 (t, 1=9.8

\\ H , ,CF ₃ fluoro-3- Hz, 1H), 5.25 - 5.07 (trifluoromethyl)p T '• ‘< O NH ^u OA F (m, 2H), 4.43 - 4.34 Me henyl)carbamoyl) (m, 1H), 4.26 (brt, bicyclo[2.2.1]hept 671.1 2.68

O' N J=8.5 Hz, 1H), 4.13 an-2-yl)-5-(5- (hydroxymethyl)- (s, 3H), 3.17 (br dd, 1=10.7, 4.3 Hz, 1H),

N ^z 3a,5,6,6a- b- ,OH tetrahydro-4H- 3.01 (br d, J=4.0 Hz, cyclopenta[d]isox 1H), 2.73 (br s, 1H), azol-3-yl)-2- 2.65 - 2.58 (m, 1H), methoxynicotina 2.51 (br s, 3H), 2.01 mide (br dd, 1=13.6, 5.3 Hz, 1H), 1.97 - 1.88 (m, 1H), 1.87 - 1.70 (m, 5H), 1.69 - 1.52 (m, 6H), 1.39 (br s, 2H), 1.32 - 1.20 (m,

2H) lHNMR (500 MHz, DMSO-d6) 5 10.60 (s, 1H), 10.03 (brd, 1=7.0 Hz, HI), 8.66 - 8.50 (m, 2H), 8.25 (br

N- d, J=4.3 Hz, 1H), ((1R,2R,3S,4R,Z) 7.88 - 7.78 (m, 1H), -3-((4-fluoro-3- 7.50 (brt, 1=9.8 Hz, (trifluoromethyl)p 1H), 5.30 (br t, J=6.7 henyl)carbamoyl) Hz, 1H), 5.15 (br dd, -7-(4,4,4-

1=8.5, 4.6 Hz, 1H), trifluorobutyliden

4.50 (br d, J=5.2 Hz, e)bicyclo[2.2.1]he

713.2 1H), 4.44 - 4.34 (m, 2.51 ptan-2-yl)-5-(5- 1H), 4.26 (brt, J=7.8 ( 1 -hydroxyethyl)- Hz, 1H), 4.14 (s, 3H), 3a,5,6,6a- H 3.47 - 3.35 (m, 1H), tetrahydro-4H- cyclopenta[d]isox 3.19 (brdd, 1=11.1, azol-3-yl)-2- 3.8 Hz, 1H), 3.02 (br methoxynicotina s, 1H), 2.78 (br s, mide 1H), 2.45 - 2.26 (m, 4H), 2.16 - 2.05 (m, 1H), 1.96 - 1.53 (m, 6H), 1.48 - 1.36 (m, 2H), 1.01 (br d, J=6.1 Hz, 3H)

1HNMR (500 MHz, DMSO-d6) 8 10.55

N- (s, 1H), 10.05 (brd, ((1R,2R,3S,4R,Z) J=6.9 Hz, 1H), 8.86 -7- (s, 1H), 8.64 (d, J=2.2 (cyclopentylmeth Hz, 1H), 8.56 (d, ylene)-3-((4- j=2.1 Hz, 1H), 8.29 - fluoro-3- 8.19 (m, 1H), 7.86 - (trifluoromethyl)p 7.76 (m, 1H), 7.49 (br henyl)carbamoyl)

657.2 t, 1=9.8 Hz, 1H), 5.20 2.74 bicyclo[2.2.1]hept (d, J=8.8 Hz, 1H), an-2-yl)-2- 4.44 - 4.32 (m, 1H), methoxy-5- 4.16 (s, 3H), 3.45 - (3a, 5,6,7a- tetrahydro-4H- 3.41 (m, 1H), 3.17 (br pyrano[3,2- dd, 1=11.1, 3.5 Hz, d]isoxazol-3- 2H), 3.02 (br s, 1H), yl )nicotinamide 2.73 (br s, 1H), 2.59 (br d, 1=7.3 Hz, 2H), 1.90 - 1.73 (m, 4H), 1HNMR (500 MHz, DMS0-d6) 5 10.57 (s, 1H), 10.01 (br d, J=6.7 Hz, 1H), 8.58

N- (br d, J=9.5 Hz, 2H), ((1R,2R,3S,4R,Z) 8.24 (br d, 1=5.5 Hz, -7- 1H), 7.86 - 7.77 (m, (cyclopentylmeth 1H), 7.49 (brt, J=9.6 ylene)-3-((4- Hz, 1H), 5.20 (brd, fluoro-3- 1=8.9 Hz, 1H), 5.15 (trifluoromethyl)p (br dd, J=8.4, 4.7 Hz, henyl)carbamoyl) 1H), 4.37 (br d, 1=6.7 bicyclo[2.2.1]hept 685.3 Hz, 1H), 4.28 - 4.21 2.72 an-2-yl)-5-(5-(l- (m, 1H), 4.17 - 4.08 hydroxyethyl)- (m, 3H), 3.91 (s, 1H), 3a,5,6,6a- 3.17 (brdd, J=10.2, tetrahydro-4H- 3.8 Hz, 1H), 3.01 (br cyclopenta[d]isox s, 1H), 2.73 (br s, azol-3-yl)-2- 1H), 2.64 - 2.57 (m, methoxynicotina 1H), 2.16 - 2.07 (m, mide 1H), 1.89 - 1.53 (m, 12H), 1.46 - 1.35 (m, 2H), 1.33 - 1.18 (m, 3H), 1.00 (br d, J=5.8 Hz, 3H) 1HNMR (5OO MHz, DMSO-d6) 5 10.59

N- (br s, 1H), 10.02 (br ((1R,2R,3S,4R,Z) s, 1H), 8.66 - 8.52 -3-((4-fluoro-3- (m, 2H), 8.21 (br s, (trifluorometbyl)p 1H), 7.80 (br d, J=2.7 henyl)carbamoyl) Hz, 1H), 7.54 - 7.42 -7-(4 _; 4 _; 4. (m, 1H), 5.32 (br d, 3 trifluoro-3- J=1.8 Hz, 1H), 5.22 - hydroxybutyliden 5.12 (m, 1H), 4.44 - e)bicyclo[2.2.1]he 4.36 (m, 1H), 4.33 -

783.0 2.46 ptan-2-yl)-2- 4.24 (m, 1H), 4.12 (br methoxy-5-(5- d, J=3.1 Hz, 3H), (2,2,2-trifhioro-l - 4.04 - 3.88 (m, 2H), H hydroxyethyl)- 3.21 - 3.13 (m, 1H), 3 3a,5,6,6a- 2.99 (br s, 1H), 2.78 tetrahydro-4H- (br s, 1H), 2.48 - 2.36 cyclopenta[d] i sox (m, 2H), 2.36 - 2.24 azol-3- (m' 1H), 2.10 - 1.90 yl)nicotinamide (m, 4H), 1.85 - 1.71 (m, 4H), 1.41 (br s, 2H) , , , -

N- 8.60 (m, 1H), 8.59 - ((1R,2R,3S,4R,Z) 8.55 (m, 1H), 8.25 - -7- 8.21 (m, 1H), 7.80 (br (cyclopropylmeth dd, 1=7.9, 3.6 Hz, ylene)-3-((4- 1H), 7.48 (t, J=9.7 n ,CF ₃ fluoro-3- Hz, 1H), 5.18 (dd, (trifluoromethyl)p

F J=8.7, 4.9 Hz, 1H),

'NH° OMe henyl)carbamoyl) 4.73 - 4.67 (m, 1H), bicyclo[2.2.1]hept

711.2 4.46 - 4.39 (m, 1H), 2.53, B an-2-yl)-2-

4.30 (t, 1=8.9 Hz, methoxy-5-(5- 1H), 4.13 (s, 3H),

^N / ,0H (2,2,2-trifluoro-l-

O -- hydroxyethyl)- 3.99 - 3.91 (m, 1H),

CF ₃ 3a,5,6,6a- 3.19 - 3.14 (m, 1H), tetrahydro-4H- 3.13 - 3.08 (m, 1H), cyclopenta[d J isox 2.73 (br s, 1H), 2.05 - azol-3- 1.88 (m, 3H), 1.86 - yl)nicotinamide 1.75 (m, 4H), 1.54 - 1.45 (m, 1H), 1.44 - 1.34 (m, 2H), 0.80 - 0.69 (m, 2H), 0.39 -

0.30 (m, 2H) 1HNMR (400 MHz, DMSO-d6) 8 10.54

N- (s, 1H), 10.05 (d, ((1R,2R,3S,4R,Z) J=7.0 Hz, 1H), 8.66 - -7- 8.61 (m, 1H), 8.58 (d, (cyclopropylmeth 1=2.3 Hz, 1H), 8.24 ylene)-3-((4- (dd, 1=6.5, 2.5 Hz,

,CF ₃ fluoro-3- 1H), 7.81 (dt, J=8.4, (trifluoromethyl)p 3.7 Hz, 1H), 7.50 (t,

F

- 1=9.8 Hz, 1H), 5 NH° OMe henyl)carbamoyl) .19 bicyclo[2.2.1]hept (dd, 1=8.8, 4.9 Hz, o- N 711.2 2.57, B an-2-yl)-2- HI), 4.71 (d, 1=9.4 m ethoxy-5 -(5 - Hz, 1H), 4.44 (ddd,

, (2,2,2-trifluoro-I - J=10.4, 6.6, 4.2 Hz, b- 0H hydroxyethyl)- 1H), 4.32 (t, J=8.6

CF ₃ 3a,5,6,6a- Hz, 1H), 4.14 (s, 3H), tetrahydro-4H- 4.01 - 3.90 (m, 1H), cyclopenta[d] i sox 3.18 (dd, 1=10.8, 4.3 azol-3- Hz, 1H), 3.14 - 3.09 yl)nicotinamide (m, 1H), 2.74 (br s, 1H), 2.08 - 1.89 (m, 3H), 1.87 - 1.75 (m, 1.94 (m, 2H), 1.86 -

1.70 (m, 5H), 1.69 -

1.51 (m, 5H), 1.44 - 1.34 (m, 211), 1.30 -

1.23 (m, 2H) 1HNMR (5OO MHz, DMSO-J6) 5 10.55 (s, 1H), 10.08 - 10.03 (m, 1H), 8.60 - 8.56

5-((6S,7aS)-6- (m, 1H), 8.52 - 8.48 cyano-5,6,7,7a- (m, 1H), 8.22 (dd, tetrahydropyrrolo >6.1, 1.8 Hz, 1H), [1,2- ' 7.82 - 7.76 (m, 1H), d][l,2,4]oxadiazo 7.52 - 7.45 (m, 1H),

,CF ₃ l-3-yl)-N- 5.91 - 5.87 (m, 1H), ((1R,2R,3S,4R,Z)

F 4.70 (d, >9.8 Hz,

-NH° OMe -7- 1H), 4.46 - 4.39 (m, (cyclopropylmeth 639.2 2.50, B

O^N 1H), 4.15 (s, 3H), ylene)-3-((4- fluoro-3- 3.75 (dd, >11.4, 7.2

N Hz, 1H), 3.38 - 3.25 l^ 5N ¹ - (trifluorometiiyl)p o— x 'GN henyl)carbamoyl) (m, 1H), 3.19 - 3.09 bicyclo[2.2.1]hept (m, 2H), 2.73 (br s, an-2-yl)-2- 1H), 2.54 - 2.51 (m, methoxynicotina 2H), 1.84 - 1.74 (m, mide 2H), 1.55 - 1.46 (m, 1H), 1.45 - 1.36 (m, 2H), 0.80 - 0.67 (m' 2H), 0.39 - 0.31 (m, _ 2H) _

N- 1H NMR (400 MHz, ((1R,2R,3S,4R,Z) DMSO-d6) 5 10.54 .7. (s, 1H), 10.06 - 9.99

(cyclopropylmeth (m, 1H), 8.63 - 8.55 ylene)-3-((4- (m, 2H), 8.23 (dd, ft ft ,CF ₃ fluoro-3- >6.5, 2.3 Hz, 1H),

(trifluoromethyl )p 7.83 - 7.77 (m, 1H),

7'?"( F - 7.48 NH° OMe henyl)carbamoyl) (t, >9.8 Hz, bicyclo[2.2.1]hept 1H), 5.19 - 5.14 (m,

O' N 711.2 2.57, B an-2-yl)-2- 1H), 4.69 (d, >9.4 methoxy-5-(5- Hz, 1H), 4.46 - 4.39

^N / (2,2,2-trifluoro-l- (m, 1H), 4.31 (brt, 0-- OH hydroxyethyl)- >8.8 Hz, 1H), 4.15 -

CF ₃ 3a,5,6,6a- 4.10 (m, 3H), 4.00 - tetrahydro-4H- 3.90 (m, 1H), 3.19 - cyclopenta[d J isox 3.09 (m, 2H), 2.75 - azol-3- 2.71 (m, 1H), 2.06 - yl)nicotinamide 1.95 (m, 2H), 1,94 - 1.86 (m, 1H), 1.85 - 1.73 (m, 4H), 1.55 - 1.46 (m, 1H), 1.44 - 1.35 (m, 211), 0.79 - 0.68 (m, 2H), 0.40 - 0.28 (m, 2H)

1H NMR (400 MHz, DMSO-d6) 5 = 10.55 (s, 1H), 10.00 (d, J = 6.9 Hz, 1H), 8.66 - 8.54 (m, 2H), 8.24 (dd, J = 2.4, 6.6 Hz,

N- 1H), 7.86 - 7.71 (m, ((1R,2R,3S,4R,Z) 1H), 7.49 (t, J = 9.8 -7- Hz, 1H), 5.39 (dd, J = (cyclopentylmeth 3.5, 9.3 Hz, 1H), 5.20

,CF ₃ ylene)-3-((4- (d, J = 8.9 Hz, 1H), fluoro-3-

F 4.55 (brt, J = 7.4 Hz, o NH OMe (tri fluoromethyl )p 1H), 4.43 - 4.29 (m, henyl)carbamoyl) 643.2 2.64, A 1H), 4.17 - 4.06 (m, bicyclo[2.2.1]hept 4H), 3.96 (d, J = 9.1 an-2-yl)-2-

N Hz, 1H), 3.76 (d t ^z methoxy-5- d, J = o ,o (3a, 4, 6,6a- 6.8, 9.6 Hz, 1H), 3.67 tetrahydrofuro[3, (dd, J = 3.6, 10.8 Hz, 4-d]isoxazol-3- 1H), 3.20 - 3.12 (m, yl)nicotinamide 1H), 3.01 (br s, 1H),

2.73 (br s, 1H), 2.63 -

2.56 (m, 1H), 1.88 - 1.72 (m, 4H), 1.70 -

1.53 (m, 4H), 1.39 (br s, 2H), 1.27 (dt, J

4.3, 8.3 Hz, 2H

N- 1H NMR (400 MHz, ((1R,2R,3S,4R,Z) DMSO-d6) 5 = 10.27 -7- (d, J = 6.8 Hz, 1H), (cyclopropylmeth 8.72 - 8.45 (m, 2H), vlene)-3-(((R)-l- 7.95 (d, J = 8.5 Hz, (1- lH), 5.39 (dd, J = 3.4,

'NH° OMe methylcyclopropy 9.1 Hz, 1H), 4.65 (d, l)ethyl) 535.2 2.21, A

O' N carbamoyl 1 = 9.5 )bicyclo[2.2.1]he Hz, 1H), 4.62 - 4.52 ptan-2-yl)-2-

N ^z methoxy-5- (m, 1H), 4.33 - 4.22 b- ,o (3a,4,6,6a- (m, 1H), 4.15 - 4.07 tetrahyd rofuro [3 , (m, 4H), 3.96 (br d, J 4-d]isoxazol-3- = 9.3 Hz, 1H), 3.77 yl)nicotinamide (dd, J = 6.8, 9.5 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.54 -

3.43 (m, 1H), 3.09 - 3.05 (m, ill), 3.04 - 3.01 (m, 1H), 2.96 (dd, J = 4.4, 11.1 Hz, 1H), 2.55 (br s, 2H), 1.93 - 1.70 (m, 2H), 1.53 - 1.44 (m, 1H), 1.42 - 1.32

(m, 2H), 1.06 - 1.01 (m, 4H), 0.99 (s, 2H), 0.78 - 0.67 (m, 2H), 0.61 - 0.51 (m, 1H), 0.39 - 0.30 (m, 3H), 0,25 - 0,13 (m, 2H) 1HNMR (4OO MHz, DMSO-d6) 5 = 10.54 (s, 1H), 10.04 (d, J = 6.8 Hz, 1H), 8.57 (s,

N- 2H), 8.23 (dd, J = 2.3, ((1R,2R,3S,4R,Z) 7.0 Hz, 1H), 7.84 - -7- 7.75 (m, 1H), 7.50 (cyclopropylmeth (t, J = 9.6 Hz, HI), ylene)-3-((4- 5.22 - 5.13 (m, 1H),

-OF, fluoro-3- 4.87 (d, J = 4.3 Hz, (trifluoromethyl)p

F 1H), 4.71 (d, J = 9.5 i°OMe henyl)carbamoyl) Hz, 1H), 4.49 - 4.41 bicyclo[2.2. l]hept 629.2 2.37, A

O' (m, 1H), 4.32 - 4.25 an-2-yl)-5-(5- (m, 1H), 4.14 (s, 4H), hydroxy- 3.20 - 3.15 (m, 1H), 3a,5,6,6a- b- OH tetrahydro-4H- 3.13 - 3.09 (m, 1H), cyclopenta[d] i sox 2.75 (br d, J = 4.3 Hz, azol-3-yl)-2- 1H), 2.02 - 1.88 (m, methoxynicotina 3H), 1.85 - 1.76 (m, mide 3H), 1.56 - 1.47 (m, 1H), 1.44 - 1.35 (m, 2H), 0.82 - 0.65 (m, 2H), 0.40 - 0.31 (m, 2H) 1HNMR (500 MHz, DMSO-d6) 8 10.59 (s, 1H), 10.02 (d, 1=6.9 Hz, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.56 (d, 1=2.4 Hz,

N- 1H), 8.28 - 8.18 (m, ((1R,2R,3S,4R,Z) 1H), 7.86 - 7.75 (m, -3-((4-fluoro-3- 1H), 7.49 (t, J=9.7 C- (trifluoromethyl)p Hz, 1H), 5.28 (t, henyl)carbamoyl)

,CF ₃ J=6.9 Hz, 1H), 5.16 -7-(4,4,4-

,N- (dd, 1=8.6, 5.0 Hz,

F trifluorobutyliden 1H), 4.59 - 4.48 (m,

NH ^u OMe e)bicyclo[2.2.1]he

699.2 1H), 4.44 - 4.35 (m, 2.45

O ¹ N ptan-2-yl)-5-(5- 1H), 4.26 (br t, J=9.0 (hydroxymethyl)- Hz, 1H), 4.13 (s, 3H), 3a,5,6,6a-

N" tetrahydro-4H 3.18 (br dd, J=10.6,

,0H - o- cyclopenta[d]isox 4.5 Hz, 1H), 3.01 (br azol-3-yl)-2- s, 1H), 2.77 (br s, methoxynicotina 1H), 2.44 - 2.24 (m, mide 4H), 2.00 (br dd, J=13.5, 6.0 Hz, 1H), 1.95 - 1.72 (m, 4H), 1.72 - 1.62 (m, 1H), 1.62 - 1.52 (m, 1H), 1.40 (br d, J=6.0 Hz, _ 2H) _ 1HNMR (500 MHz, DMSO-d6) 3 9.93 (br

N- d, 1=6.4 Hz, 1H), ((1R,2R,3S,4R,Z) 8.33 (d, J=2.1 Hz, -7- 1H), 8.27 (d, J=2.1 (cyclopropylmeth Hz, 1H), 7.86 (br d, ylene)-3-(((R)-l- J=9.2 Hz, 1H), 4.91 (3,3-difluoro-l- (br dd, 1=8.4, 5.3 Hz, methylcyclobutyl) 1H), 4.40 (br d, 1=9.5 ethyl)carbamoyl)

'NH° OMe Hz, 1H), 4.1 1 - 3.97 bicyclo[2.2.1]hept 613.3 2.26 (m, 2H), 3.85 (s, 3H), an-2-yl)-5-(5- 3.79 (quin, 1=7.2 Hz, (hydroxymethyl)- 1H), 3.20 - 3.04 (m,

^N 3a,5,6,6a-

Q/._. ,0H tetrahydro-4H- 1H), 2.82 (br s, 1H), cyclopenta[d]isox 2.74 (br dd, J=10.5, azol-3-yl)-2- 4.1 Hz, 1H), 2.46 - methoxynicotina 2.33 (m, 1H), 2.24 - mide 2.07 (m, 1H), 2.03 - 1.81 (m, 2H), 1.76 (br dd, J=13.6, 6.0 Hz, 1H), 1.71 - 1.59 (m, 1H), 1.58 - 1.38 (m, 4H), 1.37 - 1.27 (m, 1H), 1.26 - 1.17 (m, 1H), 1.17 - 1.02 (m, 2H), 0.89 (s, 3H), 0.70 (br d, >7.0 Hz, 3H), 0.53 - 0.41 (m, 2H), 0.07 (br d, 1=3.1

Hz, 2H)

1HNMR (500 MHz, DMSO-d6) 59.91 (br d, 1=6.7 Hz, 1H), 8.33 (d, J=2.4 Hz,

N- 1H), 8.27 (d, 1=2.1 ((1R,2R,3S,4R,Z) Hz, 1H), 7.90 (brd, -7- 1=8.5 Hz, 1H), 4.91 (cyclopropylmeth (br dd, 1=8.5, 5.5 Hz, ylene)-3-(((R)-l- 1H), 4.40 (d, J=9.5 (1- Hz, 1H), 4.09 - 3.97 (trifluoromethyl)c (m, 2H), 3.93 - 3.80 yclopropyl)ethyl) (m, 3H), 2.82 (br s, carbamoyl)bicycl 1H), 2.76 - 2.69 (m,

617.5 2.29 o[2.2.1]heptan-2- 1H), 1.76 (br dd, yl)-5-(5- J=13.3, 5.3 Hz, 1H), (hydroxymethyl)- 1.70 - 1.60 (m, 2H), 3a,5,6,6'a- 1.59 - 1.38 (m, 4H), tetrahydro-4H- 1.37 - 1.28 (m, 1H), cyclopenta[d]isox 1.27 - 1.17 (m, 1H), azol-3-yl)-2- 1.16 - 1.03 (m, 2H), methoxynicotina 0.87 (br d, J=7.0 Hz, mide 3H), 0.74 (br d, 1=11.0 Hz, 1H), 0.67 - 0.57 (m, 2H), 0.56 - 0.40 (m, 3H), 0.07 (br d, J=3.7 Hz, 2H)

N- (400 MHz, DMSO- |(1R,2R,3S,4R,7Z d6) 8 = 10.43 (br s, )-7- 1H), 8.12 - 8.09 (m, (cyclopentylmeth 1H), 8.03 (d, J = 7.0 ylidene)-3-{[4- Hz, 1H), 7.87 - 7.83 fluoro-3- 764.3 (m, 2H), 7.70 (s, 1H), 2.65, B (trifluoromefhyl)p 7.46 (t, J = 9.8Hz, henyl]carbamoyl} 1H), 5.26 (dd, 1 = 6.1, bicyclo[2.2.1]hept 8.9 Hz, 1H), 5.O2 (d, an-2-yl]-5-[5- J = 8.9 Hz, 1H), 4.59 hydroxy-5- - 4.55 (m, 1H), 4.40 - (trifluoromethyl )- 4.34 (m, lH), 3.I7 (br

3aH,4H,5H,6H,6a d, J = 3.3 Hz, 2H), H- 2.97 (t, J =3.4 Hz, cyclopenta[d][l,2 III), 2.58 (br s, 2H),

]oxazol-3-yl]-2,2- 2.31 - 2.22 (m, 5H), dimethyl-2,3- 2.00 - 1.94 (m, 2H), dihydro-1- 1.81 - 1.70 (m, 6H), benzofuran-7- 1.63 - 1.49 (m, 19H), carboxamide 1.26 - 1.22 (m, 3H)

(400 MHz, DMSO- d6) 8 = 10.53 (s, 1H),

(1R,2S,3R,4R,7Z) 10.31 (s, 1H), 9.89 -7- (d, J = 7.1 Hz, 1H), (cyclopentylmeth 8.30 - 8.17 (m, 1H), ylidene)-N-[4- 7.91 - 7.71 (m, 1H), fluoro-3- 7.53 - 7.39 (m, 1H),

HN- ■F (trifluoromethyl)p 7.33 - 7.15 (m, 1H),

W henyl]-3-{5-[5- 6.02 - 5.86 (m, 1H),

NH° O' V- C ^p 3 hydroxy-5- 5.36 - 5.23 (m, 1H),

O^ Ti ¹ (trifluoromethyl)- 724.2 5.20 (d, J = 8.9 Hz, 2.67, B 3aH,4H,5H,6H,6a 1H), 4.43 - 4.37 (m, H-

N ^y HI), 4.04 (s, 1H), X _/ V O' ^{C F} 3 cyclopenta[d][l,2 3.51 - 3.36 (m, 9H), ]oxazol-3-yl|-2- 2.56 - 2.53 (m, 2H),

Isomer 2 methoxybenzami 2.41 (br d, J = 4.9 Hz, do}bicyclo[2.2.1] 1H), 2.34 - 2.24 (m, heptane-2- 2H), 1.82 - 1.72 (m' carboxamide 1H), 1.68 - 1.52 (m, 2H), 1.25 (br d, J =

8.4 Hz, 1H)

N- 1HNMR (4OO MHz, |(1R,2R,3S,4R,7Z DMSO-d6) 8 ppm )-7- 10.33 - 10.62 (m, 1 (cyclopropylmeth H) 9.48 - 9.69 (m, 1 ylidene)-3-{[4- H) 8.31 - 8.47 (m, 1 fluor H) 7.81 - 7.98 (m, 1

_ HN' ■F o-3- H) 7.59 - 7.74 (

•"NH° o M (trifluoromethyl)p m, 2

V- C ^p 3 henyl]carbamoyl} H) 7.39 - 7.54 (m, 1 bicyclo[2.2.1]hept 682.3 H) 5.01 - 5.21 (m, 1 3.93, C

O' an-2-yl]-5-[5- H) 4.65 - 4.77 (m, 1 (hydroxymethyl)- H) 4.38 - 4.52 (m, 2 3aH,4H,5H,6H,6a H) 4.01 - 4.24 (m, 1

N X ^z H- o ,0H H) 2.98 - 3.21 (m, 4 cyclopenta[d][L2 H) 2.61 - 2.83 (m, 2 ]oxazol-3-yl |-2,2- H) 2.10 - 2.27 (m, 1 dimethyl-2,3- H) 1.70 - 2.02 (m, 5 dihydro-1- H) 1.58 - 1.68 (m, 4 benzofuran -7- 3H), 1.83 - 1.74 (m, carboxamide 2H), 1.65 (br dd, J =

9.3, 12.0 Hz, 1H), 1.57 (d, J = 10.5 Hz, 7H), 1.50 - 1.42(m, 1H), 1.40 - 1.27 (m, 2H), 0.86 - 0.77 (m, 10H), 0.71 (br t, J = 8.9 Hz, 2H), 0.32 (br d, J = 3.0 Hz, 2H)

(400 MHz, DMSO- d6) 8 = 10.46 (s, 1H), 9.60 (d, J = 7.5 Hz, 1H), 8.39 (dd, J = 2.5,

6.6 Hz, 1H), 7.93 (d,

5- 1.9 Hz, 1H), 7.70 {3aH,4H,6H,7H,7 , J = 1.8Hz, 1H), aH-pyrano[3,4- 7.63 (td, J = 3.9, 8.0 d]| l,2]oxazol-3- Hz, 1H), 7.46 (t, J = yl}-N- 9.8 Hz, 1H), 4.69 (d, [(1R,2R,3S,4R,7Z J = 9.6 Hz, 1H), 4.61

HN- F )-7- (td, J = 3.5, 7.2 Hz, (cyclopropylmeth 1H), 4.54 - 4.41 (m,

'NH° O ylidene)-3-{[4- lH), 3.98(dd, 1 = 6.7,

668.3 2.65, A

O’ fluoro-3- 11.6 Hz, 1H), 3.81 - (trifluoromethyl)p 3.63 (m, 2H), 3.47 henyl]carbamoyl } (dt, J = 3.3, 11.5 Hz,

N'

O bicyclo[2.2.1]hept 1H), 3.21 - 3.10 (m, o- an-2-yl]-2,2- 4H), 3.09 - 3.02 (m, dimethyl-2,3- 1H), 2.75 - 2.69 (m, dihydro-1- 1H), 2.10 -2.00 (m, benzofuran-7- 1H), 1.97 - 1.85 (m, carboxamide 2H), 1.84 - 1.75 (m,

1H), 1.62 (s, 3H), 1.53 - 1.29 (m, 5H), 0.82 - 0.64 (m, 2H), 0.35 (dd, J = 2.2, 4.6 Hz, 2H)

(a) All LC retention times are based on Method C unless otherwise specified, (b) 1 -3 protons were not accounted for in these samples due to overlap with solvent residue and/or artifacts of water suppression.

Table 5 LC RT ^a

MS (min) and

Ex. (ESI)

Structure Name chiral

No. (M+ !ll NMR conditions

H) when separated

1H NMR (500 MHz, DMSO-d6) 8 10.12 (br d, J=6.6 Hz, 1H), 8.34 (s, 1H), 8.24 (d, 1=1.1 Hz, 1H), 7.96 (br d, 1=7.8 Hz, 1H),

(S)-l-(3-(5- 7.81 (br d, J=8.5 Hz, (((1R,2R,3S,4R, 1H), 7.58 (br d, 1=7.1 Z)-7-((3,3- Hz, 1H), 7.42 (br d, difluorocyclobut 1=2.7 Hz, 1H), 7.35 - vl)methvlene)-3 - 7.23 (m, 1H), 6.18 (q, (((R)-l -(l- J=6.9 Hz, 1H), 5.16 methylcycloprop (d, 1=8.3 Hz, 1H), yl)ethyl)carbamo 4.12 - 3.98 (m, 1H), yl)bicyclo[2.2.1]

763.4 3.92 (s, 3H), 3.81 - 2.89 heptan-2- 3.70 (m, 1H), 2.84 - yl)carbamoyl)-6- 2.56 (m, 5H), 2.41 (br methoxypyridin- 3-yl)-4- s, 1H), 2.29 - 2.12 fluorophenyl)- (m, 2H), 2.06 - 1.84 2,2,2- (m, 2H), 1.80 - 1.62 trifluoroethyl (m, 3H), 1.60 - 1.50 cyclobutylcarba (m' 1H), 1.46 - 1.29 mate (m, 2H), 1.22 - 1.06 (m, 2H), 0.85 (d, 1=6.9 Hz, 3H), 0.80 (s, 3H), 0.42 - 0.30 (m, 1H), 0.21 - 0.10 (m, 1H), 0.07 - -0.06 (m, 2H)

N3- 599.3 1H NMR (400 MHz, 2.13, A [(1R,2R,3S,4R,7 DMSO-d6) 8 = 10.27 Z)-7- (d, J = 6.6 Hz. 1H), (cyclopropylmet 8.87 (t. J = 6.1 Hz, hylidene)-3- 1H), 8.77 (d, J = 2.5 {[(1R)-1-(1- Hz, 1H), 8.71 (d, J = methylcycloprop 2.5 Hz, 1H), 7.96 (d, y l)ethy 1] carbamo J = 8.5 Hz, 1H), 4.65 yl}bicyclo[2.2.1] (d. J = 9.5 Hz, 1H), heptan-2-yl]-N5- 4.34 - 4.18 (m, 1H), [(1- 4.10 (s. 3H), 3.83 (d, methanesulfonyl J = 6.0 Hz, 2H), 3.47 cyclopropyl)met (dd, J = 6.9, 8.4 Hz, hyl]-2- 1H), 3.11 - 3.04 (m, methoxypyridine 4H), 3.01 - 2.92 (m, 1H), 2.55 (br d, J = dicarboxamide 3.6 Hz, 1H), 1.90 - 1.79 (m, 1H), 1.77 - 1.59 (m, 1H), 1.52 - 1.44 (m, 1H), 1.35 (br d, J = 7.8 Hz, 2H), 1.28 - 1.21 (m, 2H), 1.16 - 1.12 (m, 2H), 1.03 (d, J = 6.9 Hz, 3H), 0.99 (s, 3H), 0.78 - 0.69 (m, 2H), 0.59 - 0.48 (m, 1H), 0.39 - 0.29 (m, 3H), 0,25 - 0,11 (m, 2H)

N- 668.3 1H NMR (400 MHz, 2.73, A [(1R,2R,3S,4R,7 DMSO-d6) 8 = 10.52 Z)-7- (s, 1H), 9.97 (d, J = (cyclopentylmet 7.0 Hz, 1H), 8.27 - hylidene)-3-{[4- 8.18 (m, 2H), 8.16 (d, fluoro-3- J = 2.6 Hz, HI), 7.84 (trifluoromethyl) - 7.72 (m, 1H), 7.49 phenyl]carbamo (t, J = 9.8 Hz, 1H),

,CF ₃ yl}bicyclo[2.2.1] 5.20 (d, J = 8.9 Hz,

^ heptan-2-yl o U^ 1 ^NH O5 ■F ]-2- 1H), 4.83 (s, 2H), methoxy-5-{2- 4.39 (ddd, J = 3.7, methyl- 6.7, 10.5 Hz. 1H), z°- V u

N^-Z 4H,6H,7H- 4.09 (d, J = 12.4 Hz,

/ ^N pyrazolo[3,2- TH), 3.20 - 3.12 (m, c][ 1,4] oxazin-3 - 1H), 3.01 (br s, 1H), yl}pyridine-3- 2.73 (br s, 1H), 2.64 - carboxamide 2.56 (m, 1H), 2.21 (s, 3H), 1.91 - 1.72 (m, 4H), 1.70 - 1.53 (m, 4H), 1.48 - 1.20 (m, 5H)

N- 585.6 ^HNM^OO M^ 2.03, A [(1R,2R,4R,7Z)- DMSO-d6) 8 = 10.29 7- (d, J = 6.5 Hz, 1H), (cyclopropylmet 8.61 (d, J = 2.4 Hz, hvlidene)-3- 1H), 8.48 (d, J = 2.5

NH

Ck _ / V ^S ~O {[(1R)-1-(1- Hz, 1H), 7.96 (d, J = z°-f N r—fl methylcycloprop 8.5 Hz, 1H), 4.81 - N- yl)ethyl] carbamo 4.61 (m, 2H), 4.51 (br

6 yl}bicyclo[2.2.1] d, J = 5.5 Hz, 1H), heptan-2-vl]-5- 4.43 - 4.20 (m, 4H), (3- 4.11 (s, 3H), 3.50 - methanesulfonyl 3.43 (m, 1H), 3.07 (s, azetidine- 1- 4H), 2.96 (dd, J = 4.3, carbonyl)-2- 10.9 Hz, 1H), 2.55 methoxypyridine (br d, J = 3.8 Hz, 1H), -3 -carboxamide 1.92 - 1.63 (m, 2H), 1.48 (dt, J = 4.1, 8.4 Hz, 1H), 1.42 - 1.29 (m, 2H), 1.06 - 0.91 (m, 6H), 0.79 - 0.64 (m, 2H), 0.54 (dd, J = 3.9, 8.3 Hz, 1H), 0.43 - 0.25 (m, 3H), 0.24 -

0.13 (m, 2H)

N- 588.3 1HNMR (4OO 2.27, A [(1R,2R,3S,4R,7 MHz, DMSO-d6) 8 = Z)-7- 9.69 (d, J = 7.0 Hz, (cyclopropylmet 1H), 7.91 - 7.77 (m, hvlidene)-3- 2H), 7.68 (s, 1H), 5.17 - 4.99 (m, 2H), methylcycloprop 4.63 (d, J = 9.5 Hz, yl)ethyl] carbamo 1H), 4.49 (t,J = 5.3 yl}bicyclo[2.2.1] Hz, 1H), 4.38 - 4.25 heptan-2-vl]-5- (m, 1H), 4.17 (t, J =

■7-Z [5 8.9 Hz, 1H), 3.47 - ? ,NH t -

Hl

O; (hydroxymethyl) 3.38 (m, 3H), 3.02 (br s, 1H), 2.97 - 2.83

O— 3aH,4H,5H,6H,6 (m, 2H), 2.04 - 1.85

\\ I N"*O aH- (m, 3H), 1.84 -1.72 cyclopenta[d][l, (m, 2H), 1.70 - 1.43 2]oxazol-3-yl]-2- (m, 6H), 1.35 (br s, methyl-2,3- 2H), 1.00 (d, J = 6.9 dihydro-1- Hz, 3H), 0.97 (s, 3H), benzofuran-7- 0.77 - 0.63 (m, 2H), carboxamide 0.58 - 0.46 (m, 1H), 0.39 - 0.25 (m,3H), 0.22 - 0,09 (m, 2H).

N- 588.3 1HNMR (4OO MHz, 2.28, A [(1R,2R,3S,4R,7 DMSO-d6) 8 = 9.76 Z)-7- (d, J = 7.0 Hz, 1H), (cyclopropylmet 7.91 - 7.79 (m, 2H), hylidene)-3- 7.68 (s, 1H), 5.26 -

? t ,NH Hl

O; {[(1R)-1-(1- 5.17 (m, 1H), 5.10 methylcycloprop (dd, J = 5.1, 8.6 Hz,

O- yl)ethyl] carbamo 1H),4.63 (d, J = 9.5

\\ I N"*O yl}bicyclo[2.2.1] Hz, 1H), 4.49 (t, J = heptan-2-yl]-5- 5.2 Hz, 1H), 4.38 - [5- 4.26 (m, 1H), 4.17 (t, (hydroxymethyl) J = 9.1 Hz, 1H), 3.46 - 3.38 (m, 3H), 3.00

3aH,4H,5H,6H,6 (br s, 1H), 2.96 - 2.80 aH- (m,2H), 2.03 - 1.84 cyclopenta[d][l, (m, 3H), 1.83 - 1.72 2]oxazol-3-yl]-2- (m, 2H), 1.70 - 1.61 methyl-2,3- (m, 1H), 1.58 - 1.42 dihydro-1- (m, 5H), 1.40 - 1.26 benzofuran-7- (m, 2H), 1.03 - 0.90 carboxamide (m, 6H), 0.72 (quin, J = 8.7Hz, 2H), 0.60 - 0.48 (m, 1H), 0.41 - 0.26 (m, 3H), 0.24 - 0.10 (m, 2H),

N- 654.3 1HNMR (4OO 2.38, A [(1R,2R,3S,4R,7 MHz, DMSO-d6) 8 = Z)-7- 10.50 (s, 1H), 9.55 (cyclopropylmet (d, J = 7.4 Hz, 1H), hylidene)-3-{[4- 8.35 (dd, J = 2.5, 6.5 fluoro-3- Hz, 1H), 7.90 (d, J = (trifluoromethyl) 1.8 Hz, 1H), 7.72 - phenyl]carbamo 7.56 (m,2H), 7.47 (t, yl}bicyclo[2.2.1] J = 9.8 Hz, HI), 5.34 heptan-2-yl]-5- - 5.19 (m, 1H), 5.08 {5-hydroxy- (ddd, J = 2.4, 6.9, 9.7 3aH,4H,5H,6H,6 Hz, 1H), 4.70 (d, J = aH- 9.5 Hz, 1H), 4.55 - cyclopenta[d][l, 4.45 (m, 1H), 4.43 (br 2]oxazol-3-yl}- s, 1H),4.14 (br s, 1H), 2-methyl-2,3- 4.07 (dt, 1 = 3.8, 9.5 dihydro-1- Hz, 1H), 3.47 (br dd, benzofiiran-7- J = 8.9, 16.2 Hz, 1H), carboxamide 3.16 (dd, J = 4.3, 10.8 Hz, 1H), 3.06 (br s, 1H), 2.88 (dd, J = 6.9,16.0 Hz, 1H), 2.77 - 2.69 (m, 1H), 2.15 - 2.00 (m, 2H), 1.94 - 1.67 (m, 4H)'

1.57 - 1.32 (m, 6H), 0.83 - 0.63 (m, 2H), 0.36 (dd, J = 2.1, 4.4 Hz, 2H). N- 654.3 H NMR. (400 MHz, [(1R,2R,3S,4R,7 DMSO-d6) 8 = 10.46 Z)-7- (s, 1H), 9.52 (d, J = (cyclopropylmet 7.3 Hz, 1H), 8.27 (dd, hylidene)-3-{[4- J = 2.4, 6.6 Hz, TH), fluoro-3- 7.87 (d, J = 1.5 Hz, (trifluoromethyl) 1H), 7.77 - 7.69 phenyl]carbamo (m,lH), 7.68 (s, 1H), yl}bicyclo[2.2.1] 7.48 (t, J = 9.8 Hz, heptan-2-yl]-5- 1H), 5.20 - 4.99 (m, {5-hydroxy- 2H), 4.84 (d, J - 4.3 3aH,4H,5H,6H,6 Hz, 1H), 4.70 (d, J = all- 9.6 Hz, 1H), 4.51 - cyclopenta[d][l, 4.37 (m, 1H), 4.18 2]oxazol-3-yl}- (dt J =4.3, 9.2 Hz, 2-methyl-2,3- 1H), 4.13 - 4.00 (m, dihydro-1- 1H), 3.41 (br dd, J = benzofuran-7- 8.6, 16.3 Hz, 1H), carboxamide 3.15 (dd, J = 3.8, 10.5 Hz, 1H), 3.10 (br s, 1H), 2.93 (dd, J = 7.8, 15.8 Hz,lH), 2.71 (br d, J = 3.4 Hz, 1H), 2.04 - 1.84 (m, 4H), 1.83 - 1.71 (m, 2H), 1.58 (d, J = 6.3 Hz, 3H), 1.54 - 1.28 (m, 3EQ, 0.82 - 0.64 (m, 2H), 0.44 -0.23 (m, 2H).

N- 750.2 lHNMR (400 MHz, 2.80, A [(1R,2R,3S,4R,7 DMSO-d6) 8 = 10.47 Z)-7- (s, 1H), 9.53 (d, J = (cyclopentylmet 7.4 Hz, 1H), 8.35 (dd, hylidene)-3-{[4- J = 2.6, 6.6 Hz, 1H), fluoro-3- 7.89 (d, J = 1.8 Hz, (trifluoromethyl) 1H), 7.75 - 7.59 phenyl]carbamo (m,2H), 7.46 (t, J = yl}bicyclo[2.2.1J 9.8 Hz, 1H), 5.91 (s, heptan-2-yl]-5- 1H), 5.33 - 5.15 (m, [5-hydroxy-5- 3H), 4.43 (ddd, J = (trifluoromethyl) 3.8, 7.4, 10.8 Hz, 1H), 4.36 (brt, J =

3aH,4H,5H,6H,6 9.7 Hz, 1H), 3.51 - aH- 3.44 (m,lH), 3.15 cyclopenta[d][l, (dd, J = 4.1, 10.7 Hz,

2]oxazol-3-yl]-2- 1H), 2.96 (br s, 1H), methyl-2,3- 2.88 (dd, J = 6.8, 16.1 dihydro- 1 - Hz, 1H), 2.71 (br s, benzofuran-7- 1H), 2.63 - 2.56 (m, carboxamide 1H), 2.31 - 2.20 (m, 3H), 1.98(brd, J = 13.9 Hz, 1H), 1.91 - 1.74 (m, 4H), 1.70 - 1.53 (m, 5H), 1.47 (d, J = 6.3 Hz, 3H), 1.40 (brd, J = 6.0 Hz, 2H), 1.34 - 1.15 (m, 3H).

N- 617.3 1HNMR(4OO 2.33, A [(1R,2R,3S,4R,7 MHz, DMSO-d6) 5 = Z)-7- 10.54 (s, 1H), 10.03 (cyclopropylmet (d, J = 6.9 Hz. 1H), hylidene)-3-{[4- 8.57 (d, J = 2.4 Hz. fluoro-3- 1H), 8.52 (d, J = 2.4 (trifluoromethyl) Hz, 1H), 8.23 (dd, J = phenyljcarbamo 2.4, 6.6 Hz, 1H), 7.90 yl}bicyclo[2.2.1] - 7.70 (m, 1H), 7.49 heptan-2-ylj-5- (t J = 9.8 Hz, 1H), [5- 5.11 (t, J = 5.7 Hz, (hydroxymethyl) 1H), 4.70 (d, J = 9.6 -5-methyl-4,5- Hz, 1H), 4.49 - 4.35 dihydro-1,2- (m, 1H), 4.13 (s, 3H), oxazol-3-yl]-2- 3.47 -3.40 (m, 2H), ' methoxypyridine 3.17 (dd, J = 4.6, 10.4 -3 -carboxamide Hz, 1H), 3.14 - 2.95 (m, 2H), 2.74 (br s, 1H), 1.91 - 1.70 (m, 2H), 1.57 - 1.37 (m, 3H), 1.33 (s, 3H), 0.86 - 0.66(m, 2H), 0.43 - 0.24 (m, 2H).

[3-(2- 762.3 lHNMR (500 MHz, 2.88, B {[(2R,3S,7Z)-7- DMSO-d6) 8 10.60 (cyclopropylmet (s, 1H), 10.49 - 10.40 hylidene)-3-{[4- (m, 1H), 9.59 - 9.47 fluoro-3- (m, 1H), 8.45 - 8.21 (trifluoromethyl) (m, 1H), 7.89 (s, 1ID- phenyljcarbamo 7.70 (brdd, J=4.4, yl}bicyclo[2.2.1] 3.5 Hz, 1H), 7.49 (br heptan-2- t, J=9.5 Hz, 1H), 7.42 yl]carbamoyl}-6- (br d, J=7.9 Hz, 2H), methoxypyridin- 7.32 - 7.19 (m, 3H), 4-yl)- 6.97 (brt, J=7.3 Hz, 3aH,4H,5H,6H,6 1H), 5.29 (brdd, aH- J=8.7, 5.0 Hz, 2H), cyclopenta[d][l. 4.72 (br d, J=9.8 Hz, 2]oxazol-5- 1H), 4.49 - 4.26 (m, yljmethyl N- 2H), 4.10 - 3.93 (m, phenylcarbamate 2H), 3.57 - 3.29 (m, 2H), 3.26 - 3.14 (m, 1H), 2.89 - 2.67 (m, III), 2.27 - 2.02 (m, 2H), 1.97 - 1.85 (m, 1H), 1.85 - 1.62 (m, 4H), 1.60 - 1.49 (m, 1H), 1.48 - 1.35 (m, 2H), 0.92 - 0.67 (m, 2H), 0.37 (br s, 211) One H is hidden under water/solvent peak

N- 577.3 1HNMR (500 MHz, 2.34 [(1R,2R,3S,4R,7 DMSO-d6) 5 10.08 Z)-7- (br d, 1=7.0 Hz, 1H), (cyclopropyhnet 8.39 (br s, 1H), 8.34 hylidene)-3- (s, 1H), 7.85 - 7.72 {[(1R)-1-(1- (m, 1H), 7.09 - 6.74 methylcycloprop (m.2H), 5.11 - 4.91 yl)ethyl]carbamo (m, 2H), 4.47 (br d, yl}bicyclo[2.2.1] 1=10.1 Hz, 1H), 4.15 heptan-2-yl]-5- - 4.02 (m, 2H), 3.90 [5-(l- (s, 3H), 3.34 - 3.21 hydroxyethyl)- (m, 1H), 3.19 - 3.06 3aH,4H,5H,6H,6 (m, 3H), 2.98 - 2.85 aH- (m, lH), 2.78 (br dd, cyclopenta[d][l, 1=13.0, 4.4 Hz, 1H), 2]oxazol-3-yl]-2- 1.99 - 1.86 (m, 1H), methoxypyridine 1.73 - 1.64 (m, 1H), -3 -carboxamide 1.61 - 1.54 (m, 2H), 1.50 - 1.41 (m, 2H), 1.33 - 1.25 (m, 1H), 1.22 - 1.14 (m, 2H), 0.84 (br dd, 1=13.0, 6.6 Hz, 6H), 0.59 - 0.49 (m, 2H), 0.36 (br dd, J=9.9, 3.5 Hz, 1H), 0.23 - 0.10 (m, 3H), 0.07 - -0.10 (m, 3H) cyclopropyl[3- 852.3 1HNMR (500 MHz, 2.81 (5-{[(2R,3S,7Z)- DMSO-d6) 5 10.57 7-[(3,3- (s, 1H), 10.02 (d, difluorocyclobut J=6.9 Hz, 1H), 9.53 - yl)methylidene]- 9.39 (m, III). 8.60 (d. 3-{[4-fluoro-3- J=2.4 Hz, 1H), 8.56 (trifluoromethyl) (d, 1=2.4 Hz. 1H), phenyl]carbamo 8.21 (dd, 1=6.5, 2.3 yl}bicyclo[2.2.1] Hz, 1H), 7.78 (br dd, heptan-2- J=8.3, 3.3 Hz, 1H). yl]carbamoyl}-6- 7.48 (t, 1=9.8 Hz, methoxypyridin- 1H), 7.39 (brd, 1=8.0 3-yl)- Hz, 2H), 7.28 - 7.19 3aH,4H,5H,6H,6 (m, 2H), 6.95 (t, aH- J=7.4 Hz, 1H), 5.39 cyclopenta[d][l, (d, J=8.5 Hz, 1H), 2]oxazol-5- 5.19 (dd, J=8.7, 4.8 yijmethyl N- Hz, 1H), 4.38 - 4.33 phenylcarbamate (m, 1H), 4.32 - 4.26 (m, 1H), 4.14 - 4.07 (m, 4H), 3.52 - 3.43 (m' 1H), 3.20 - 3.11 (m, 1H), 2.99 (br s, 1H), 2.96 - 2.90 (m, HI). 2.87 - 2.79 (m, 2H), 2.79 - 2.73 (m, 1H), 2.47 - 2.38 (m, 2EQ, 2.20 - 2.10 (m, 2H), 1.90 - 1.81 (m' 2H), 1.78 - 1.70 (m, 2H), 1.42 - 1.33 (in, 2H), 1.02 - 0.93 (m, 1H), 0.58 - 0.53 (m, 1H), 0.46 - 0.40 (m, 1H), 0.38 - 0.31 (m, 2H), cvclopropyl[3- 830.1 lHNMR (500 MHz, 2.84 (5-{[(2R,3S,7Z)- DMSO-d6) 5 10.35 7-[(3,3- (s, 1H), 9.78 (d, J=6.9 difluorocyclobut Hz, 1H), 8.36 (d, yl)methylidene]- 1=2.4 Hz, 1H), 8.31

3-{[4-fluoro-3- (d, J=2.4 Hz, 1H), (trifluoromethyl) 7.97 (dd, J=6.4, 2.5 phenyl]carbamo Hz, 1H), 7.64 - 7.51 yl}bicyclo[2.2.1] (m, 1H), 7.24 (t, heptan-2- J=9.8 Hz, 1H), 7.06 - yl]carbamoyl}-6- 6.96 (m, lH), 5.16 (d, methoxypyridin- 1=8.5 Hz. 1H), 4.92 3-yl)- (dd, J=8.7, 4.9 Hz, 3aH,4H,5H,6H,6 1H), 4.21 - 4.08 (m, aH- 1H), 4.04 - 3.97 (m, cyclopenta[d][l, 1H), 3.88 (s, 3H), 2]oxazol-5- 3.74 - 3.68 (m. 1H), yl]methyl N- 3.67 - 3.58 (m, 1H), cyclobutylcarba 3.33 - 3.21 (m, 1H), mate 2.97 - 2.85 (m, 1H), 2.79 - 2.67 (m, 2H), 2.65 - 2.55 (m, 2H), 2.21 - 2.07 (m, 2H), 1.82 (brd, 1=8.5 Hz, 4H), 1.65 - 1.43 (m, TH), 1.32 - 1.25 (m, 2H), 1.20 - 1.11 (m' 2H), 0.71 - 0.57 (m, 1H), 0.29 - 0.22 (in, 1H), 0.17 - 0.10 (m, 1H), 0.06 - -0.07 (m, 2H)

[3-(5- 830.3 lHNMR (500 MHz, 3.11, B {[(2R,3S,7Z)-7- DMSO-d6) 5 10.54 (cyclopentylmet (s, 1H), 10.01 (d, hylidene)-3-{[4- 1=6.8 Hz, 1H), 9.47 fluoro-3- (s, 1H), 8.61 (d, 1=2.4 (trifluoromethyl) Hz, 1H), 8.57 (d, phenyl]carbamo 1=2.4 Hz, 1H), 8.23 yl}bicyclo[2.2.1] (dd, J=6.4, 2.5 Hz, heptan-2- 1H), 7.79 (br dd, yl]carbamoyl}-6- 1=8.4, 3.5 Hz, 1H),

F methoxypyridin- 7.57 - 7.45 (m, 1H),

FX-CF ₃ 3-yl)- 7.40 (s, 1H), 7.32 - 3aH,4H,5H,6H,6 7.18 (m, 2H), 6.96 (t,

NH o aH- J=7.3 Hz, 1H), 5.24 - o (Ar V H ^Ph cyclopenta[d][l, 5.10 (m, 2H), 4.50 -

OssZ

\ \ 2]oxazol-5- 4.33 (m, 1H), 4.33 -

A ylj(cyclopropyl) 4.23 (m, 1H), 3.50 -

N=s/ \\ /

N-0 methyl N- 3.36 (m, 1H), 3.23 - phenylcarbamate 3.10 (m, 1H), 3.00 (br s, 1H), 2.72 (br s, 1H), 2.62 - 2.55 (m, 5H), 2.21 - 2.11 (m, 2H), 1.91 - 1.70 (m, 7H), 1.69 - 1.60 (m, 2EQ, 1.58 - 1.49 (m, 1H), 1.48 - 1.35 (m' 2H), 1.28 - 1.19 (m, 2H), 1.02 - 0.89 (m, 1H), 0.61 - 0.52 (m, 1H), 0.48 - 0.41 (m, 1H), 0.36 (br s, 2H),One H is hidden under water/solvent _ peak _

N- 724.5 lHNMR (500 MHz, 2.93 [(1R,2R,3S,4R,7 DMSO-d6) 5 10.56 Z)-7- (s, 1H), 10.03 (br d, (cyclopentylmet 1=6.9 Hz, 1H), 8.53 hylidene)-3-{[4- (br s, 1H), 8.46 (br s, fluoro-3- 1H), 8.24 (br d, J=3.7 (trifluoromethyl) Hz, 1H), 7.84 - 7.76 phenyl Jcarbamo (m, 1H), 7.69 (br d, yl}bicyclo[2.2.1] 1=6.6 Hz, 1H), 7.58

F heptan-2-yl]-5- (br d, J=3.4 Hz, 1H),

■CF ₅ {2-fluoro-5- 7.53 - 7.34 (m, 2H),

1

,NH [(lS)-2,2,2- 5.28 (br d, 1=6.3 Hz,

- o trifluoro-1- 1H), 5.20 (br d, J=8.8 Ose/ hydroxyethyljph Hz, 1H), 4.39 (br s, enyl}-2- lH), 4.14 (s, 3H), methoxypyridine 3.17 (br dd, 1=10.3, -3 -carboxamide 3.4 Hz, 1H), 3.02 (br s, 1H), 2.73 (br s, 1H), 2.64 - 2.58 (m, 1H), 1.92 - 1.74 (m, 4H), 1.70 - 1.50 (m, 4H), 1.40 (br d, J=1.5 Hz, 2H), 1.32 - 1.20 (m, 2H) proton missing due to water suppression

(lS)-l-[3-(5- 807.1 1HNMR (500 MHz, 3.14 {[(1R,2R,3S,4R, DMSO-d6) 5 10.56 7Z)-7- (s, 1H), 10.03 (br d, (cyclopentylmet J=6.6 Hz, 1H), 8.59 -

F hylidene)-3-{[4- 8.40 (m, 2H), 8.29 - /rA-CF ₃ fluoro-3- 8.16 (m, 1H), 8.01 (br

NH (trifluoromethyl) d, 1=2.3 Hz, 1H),

O phenyljcarbamo 7.85 - 7.71 (m, 2H),

0=/ ^! HN yl}bicyclo[2.2.1] 7.67 - 7.56 (m, 1H),

F

\ ₃ C o-^ A- .0-^0 heptan-2- 7.54 - 7.39 (m, 2H),

Ns yl]carbamoyl}-6- 6.38 (q, J=7.2 Hz,

> methoxypyridin- lH), 5.19 (d, J=8.8 3-yl)-4- Hz, 1H), 4.46 - 4.34 fluorophenyl]- (m, 1H), 4.14 (s, 3H), 2,2,2- 3.49 (br d, 1=2.0 Hz, trifluoroethyl N- 1H), 3.24 - 3.10 (m, cyclopropylcarba 1H), 3.01 (br s, 1H), mate 2.73 (br s, 1H), 2.63 - 2.58 (m, 1H), 1.88 - 1.72 (m, 4H), 1.71 - 1.52 (m, 4H), 1.45 - 1.33 (m, 2H), 1.30 - 1.17 (m, 2H), 0.65 -

0.55 (m, 2H), 0.52 -

0.35 (m, 2H)

(lS)-2,2,2- 835.2 lHNMR (500 MHz, 2.89 trifluoro-l-[4- DMSCM6) 8 10.36 fluoro-3-(5- (s, 1H), 9.83 (brd, {[(1R,2R,3S,4R, J=6.7 Hz, 1H), 8.32 7Z)-3-{[4- (s, 1H), 8.25 (s, 1H), fluoro-3- 8.07 - 7.99 (m. 1H). (trifluoromethyl) 7.79 (br s, 1H), 7.64 -

F phenyl]carbamo 7.51 (m, 2H), 7.38 (brC- [I V-CF3 yl}-7-(4,4,4- d, 1=2.4 Hz, 1H),

1 trifluorobutylide 7.28 - 7.20 (m, 2H),

71 ne)bicyclo[2.2.1] 6.18 (q, J=5.9 Hz, ,NH

Oe, HN ¹ ^ heptan-2- 1H), 5.11 - 4.97 (m,

F _S C

\ J yl]carbamoyl}-6- 1H), 4.24 - 4.17 (m. -o-^ ⁰

N- methoxypyridm- 1H), 3.93 (s, 3H),

3 F 3- 2.97 (br dd, 1=11.1, yl)phenyl]ethyl 4.0 Hz, 1H), 2.80 (br N- s, 1H), 2.56 (br s, cyclopropylcarba 1H), 2.23 - 2.04 (m, mate 5H), 1.66 - 1.53 (m, 2H), 1.26 - 1.15 (m. 2H), 0.37 (br s, 2H), 0.24 - 0.16 (m.2H)

(l.S)-2,2,2- 781.2 lHNMR (500 MHz, 3.06 trifluoro-l-[4- DMSO-d6) 8 10.32 fluoro-3-(5- (s, 1H), 9.78 (brd, {[(1R,2R,3S,4R, J=6.9 Hz, 1H), 8.29

F 7Z)-3-{[4- (s, 1H), 8.22 (d, J=1.4

A-CF, fluoro-3- Hz, 1H), 8.05 - 7.97

1 (trifluoromethyl) (m, 1H), 7.77 (brd, phenyl]carbamo J=2.4 Hz, 1H), 7.62 - yl}-7-(2- 7.47 (m, 2H), 7.44 - methylpropylide 7.30 (m, 1H), 7.29 - ne)bicyclo[2.2.1] 7.15 (m, 2H), 6.26 - heptan-2- 6.08 (m, 1H), 4.87 (d, yl]carbamoyl}-6- J=8.9 Hz, 1H), 4.22 - methoxypyridin- 4.10 (m, 1H), 3.9O (s, 3- 3H), 3.19 - 3.10 (m, yl)phenyl]ethyl 1H), 2.93 (brdd, N- J=10.7, 4.3 Hz, 1H), cyclopropylcarba 2.80 - 2.75 (m, 1H), mate 2.47 (br s, 1H), 2.24 -

2.18 (m, 1H), 1.66 - 1.44 (m, 2H), 1.25 - 1.08 (m, 2H), 0.86 - 0.68 (m, 6H), 0.41 - 0.29 (m, 2H), 0.26 - 0.11 (m, 2H)

(lS)-l-[3-(5- 829.2 1HNMR (500 MHz, 2.86 {[(IR,2R,3S,4R, DMSO-d6) 5 10.36 7Z)-7-[(3,3- (s, 1H), 9.83 (brd, difluorocyclobut J=6.7 Hz, 1H), 8.33 yl)methylidene] - (s, 1H), 8.25 (d, J=1.0 3-{[4-fluoro-3- Hz, 1H), 8.08 - 7.99 (trifluoromethyl) (m, 1H), 7.80 (br s, phenyl]carbamo 1H), 7.63 - 7.53 (m, yl}bicyclo[2.2.1] 2H), 7.39 (br s, 1H),

F _x 6. heptan-2- 7.29 - 7.21 (m, 2H),

•CF, yl]carbamoyl}-6- 6.18 (brd, J=7.4 Hz,

1 methoxypyridin- lH), 5.19 (d, J=8.5

■r 3-yl)-4- Hz, 1H), 4.24 - 4.15

,RIH o

H fluorophenyl]- (m, 1H), 3.93 (s, 3H),

F ₃ C N

^S O 2,2,2- 3.20 - 3.12 (m, 1H),

Ni=/ trifluoroethyl N- 2.97 (br dd, 1=11.1,

\\ F ^Z cyclopropylcarba 4.0 Hz, 1H), 2.81 (br mate s, 1H), 2.77 - 2.59 (m, 2H), 2.57 (br s, 1H), 2.26 - 2.12 (m, 2H), 1.67 - 1.53 (m, 2H), 1.19 (br s, 2H), 0.83 (d, 1=6.1 Hz, 1H), 0.37 (brd, J=1.9 Hz, 2H). 0.27 - 0.16 (m, 2H)

(lS)-2,2,2- 849.2 lHNMR (500 MHz, 2.97 trifluoro-l-[4- DMSO-d6) 5 10.60 fluoro-3-(5- (s, 1H), 10.05 (br d,

F {[(2R,3S,7Z)-3- J=6.9 Hz, 1H), 8.55 C- 0 -CF ₃ {[4-fluoro-3- (s, 1H), 8.48 (d, 1=1.5

1

NH (trifluoromethyl) Hz, 1H), 8.25 (dd, phenyl]carbamo 1=6.3, 2.1 Hz, 1H),

O

,NH yl}-7-(4,4,4- 8.15 (d, J=7.7 Hz,

^F =c trifluorobutylide 1H), 7.88 - 7.76 (m,

-0^°

N=sZ 3 ne)bicyclo[2.2.1] 2H), 7.61 (br s, 1H),

V heptan-2- 7.55 - 7.41 (m, 2H), yl]carbamoyl}-6- 6.39 (q, J=7.2 Hz, methoxypyridm- 1H), 5.29 (t, 1=6.9 3- Hz, 1H). 4.50 - 4.36 yl)phenyl]ethyl (m, 1H), 4.16 (s, 3H), N- 3.99 - 3.87 (m, 1H), cyclobutylcarba 3.20 (dd, J=10.9, 4.3 mate Hz, 1H), 3.03 (br s, 1H), 2.78 (br s, 1H), 2.45 - 2.30 (m, 4H), 2.19 - 2.06 (m, 2H), 2.01 - 1.78 (m, 4H), 1.64 - 1.53 (m, 2H), 1.51 - 1.37 (m, 2H)

(lS)-l-[3-(5- 843 1HNMR (500 MHz, 3.03 {[(2R_3S,7Z)-7- DMSO-d6) 5 10.58 [(3,3- (s, 1H), 10.15 - 9.91 difluorocyclobut (m, 1H), 8.55 (s, 1H), yl)methylidene]- 8.46 (d, J=1.3 Hz, 3-{[4-fluoro-3- HI), 8.25 (dd, J=6.2, (trifluoromethyl) 2.0 Hz, 1H), 8.15 (d, phenyl]carbamo J=7.8 Hz, 1H), 7.86 - yl}bicyclo[2.2.1] 7.72 (m, 2H), 7.61 (br heptan-2- dd, 1=5.9, 2.1 Hz, yl]carbamoyl}-6- 1H), 7.52 - 7.44 (m, methoxypyridin- 2H), 7.22 (s, 1H), 3-yl)-4- 7.12 (s, 1H), 7.02 (s, fluorophenyl]- 1H), 6.38 (brd, J=7.I 2,2,2- Hz, 1H), 5.41 (d, trifluoroethyl N- J=8.6 Hz, 1H), 4.51 - cyclobutylcarba 4.36 (m, 1H), 4.15 (s, mate 3H), 3.98 - 3.93 (m, 1H), 3.23 - 3.15 (m. 1H), 3.03 (br s, 1H), 2.91 - 2.85 (m, 1H), 2.81 - 2.75 (m, 1H)' 2.45 - 2.37 (m, 1H), 2.18 - 2.10 (m, 1H), 1.97 - 1.80 (m, 4H), 1.66 - 1.52 (m, 2H), 1.48 - 1.37 (m, 2H)

N- 681.1 lHNMR (500 MHz, 2.61

[(1R,2R,3S,4R.7 DMSO-d6) Shift

Z)-7-[(3,3- 10.25 (br d, J=6.4 Hz, difluorocyclobut 1H), 8.60 - 8.50 (m, yl)methylidene] - 2H), 7.97 (brd, 1=8.5 3-{[(lR)-l-(l- Hz, 1H), 6.27 (br d, methylcycloprop J=6.7 Hz, 1H), 5.35 - yl)ethyl]carbamo 5.30 (m, lH), 5.17 (br yl}bicyclo[2.2.1] dd, J=8.4, 5.0 Hz, heptan-2-yl]-2- 1H), 4.29 (brt, J=8.9 methoxy-5-[5- Hz, 1H), 4.19 (br d, (2,2,2-trifluoro- 1=3.7 Hz, 1H), 4.10 - 1-hydroxyethyl)- 4.03 (m, 3H), 3.98 - 3aH,4H,5H,6H,6 3.89 (m, 1H), 2.86 - aH- 2.73 (m, 2H), 2.42 - cyclopenta[d][l, 2.31 (m, 2H), 2.03 - 2]oxazol-3- 1.89 (m, 3H), 1.87 - yl]pyridine-3- 1.77 (m, 3H), 1.73 - carboxamide 1.67 (m, 1H), 1.38 - 1.25 (m, 4H), 1.05 - 0.92 (m, 7H), 0.56 - 0.50 (m, 1H), 0.35 - 0.29 (m, 1H), 0.22 -

0.14 (m, 2H) l-[3-(5- 808.2 lHNMR (500 MHz, 2.97

{[(2R,3S,7Z)-7- DMSO-d6) d 10.54 (cyclopropylmet (s, 1H), 10.03 (d, hylidene)-3-{[4- 1=6.8 Hz, 1H), 8.62 fluoro-3- (d, 1=2.4 Hz, 1H), (trifluoromethyl) 8.57 (d, J=2.4 Hz, phenyljcarbamo 1H), 8.22 (dd, J=6.4, yl}bicyclo[2.2.1] 2.5 Hz, 1H), 7.86 (d, heptan-2- J=7.9 Hz, 1H), 7.81 - yl]carbamoyl}-6- 7.77 (m, 1H), 7.48 (t, methoxypvridin- J=9.8 Hz, 1H), 5.29 - 3-yl)- 5.22 (m, 1H), 5.19

3aH,4H,5H,6H,6 (dd, J=8.7, 4.9 Hz,

H , ,Cr ₃ aH- 1H), 4.70 (d, J=9.5 t o ^N "( •F cyclopenta[d][l, Hz, 1H), 4.42 (ddd,

,NH F ₃ C 2]oxazol-5-yl]- 1=10.6, 6.8, 3.9 Hz,

>- ^N H 2,2 1H), 4.34 (brt, 1=9.1

/°" ,2-

V N=sZ S

» b trifluoroethyl N- Hz, 1H), 4.14 - 4.11 N-0 I cyclobutylcarba (m, 3H), 3.97 - 3.88 mate (m, 1H), 3.16 (dd, J=10.6, 4.0 Hz, 1H), 3.10 (br s, 1H), 2.76 - 2.71 (m, 1H), 2.17 - 2.04 (m, 4H), 1.91 - 1.76 (m' TH), 1.59 - 1.52 (m, 2H), 1.51 -

1.47 (m, 1H), 1.41 (br d, 1=2.5 Hz, 2H), 0.78 - 0.69 (m, 2H), 0.38 - 0.33 (m, 2H) N- 671.1 1HNMR (500 MHz, 2.67 [(1R,2R,3S,4R,7 DMSO-d6) Shift Z)-7- 10.54 (s, 1H), 10.00 (cyclopentylmet (d, >=7.0 Hz, 1H), hylidene)-3-{[4- 8.57 (dd. 1=16.1, 2.4 fluoro-3- Hz, 2H), 8.23 (dd, (trifluoromethyl) 1=6.6, 2.6 Hz, 1H), phenyl]carbamo 7.82 - 7.77 (m, 1H), yl}bicyclo[2.2.1] 7.48 (t, J=9.7 Hz, heptan-2-yl]-5- 1H), 5.21 - 5.13 (m, [5- 2H), 4.52 (t, 1=5.2 (hydroxymethyl) Hz. 1H). 4.40 - 4.34 (m, 1H), 4.25 (brt,

3aH,4H,5H,6H,6 1=9.3 Hz, 1H), 4.12 aH- (s, 3H), 3.16 (dd, cyclopenta[d][l, 1=10.4, 4.0 Hz, 1H), 2]oxazol-3-yl]-2- 3.00 (br d, J=3.3 Hz, methoxypyridine 1H), 2.72 (br s, 1H), -3 -carboxamide 2.61 - 2.56 (m. 1H), 2.00 (br dd, 1=13.3, 5.7 Hz, 1H), 1.93 - 1.69 (m, 7H), 1.68 - 1.53 (m, 6H), 1.43 - 1.35 (m, 2H), 1.31 - 1.22 (m, 2H)

N- 739.2 lH NMR (500 MHz, 2.82 [(1R,2R,3S,4R,7 DMSO-d6) Shift Z)-7- 10.57 - 10.54 (m, (cyclopentylmet 1H). 10.00 (br d, hylidene)-3-{[4- 1=6.8 Hz, 1H), 8.62 - fluoro-3- 8.56 (m, 2H), 8.23 (trifluoromethyl) (dd, J=6.4, 2.3 Hz, phenyljcarbamo 1H), 7.81 - 7.77 (m, yl}bicyclo[2.2.1] 1H), 7.48 (t, >=9.8 heptan-2-yl]-2- Hz, 1H), 5.21 - 5.16 methoxy-5-[5- (m, 2H), 4.40 - 4.34 (2,2,2-trifluoro- (m, 1H), 4.32 - 4.27

1 -hydroxyethyl)- (m, 1H), 4.12 (s, 3H), 3aH,4H,5H,6H,6 4.00 - 3.91 (m, 1H), aH- 3.16 (br dd, J=10.4, cyclopenta[d]| 1, 4.3 Hz, 1H), 3.03 - 2]oxazol-3- 2.98 (m, 1H), 2.72 (br yl]pyridine-3- s, 1H), 2.64 - 2.56 carboxamide (m, 1H), 2.04 - 1.90 (m, 3H), 1.86 - 1.69 (m' 7H), 1.68 - 1.54 (m.4H), 1.42 - 1.35 (m, 2H), 1.31 - 1.22 (m, 2H) l-[3-(5- 858.2 lHNMR (500 MHz, 2.72 {[(1R,2R,3S,4R, DMSCM6) 8 10.54 7Z)-7- (s, 1H), 10.04 - 9.97 (cyclopentyhnet (m, 2H), 8.63 (d, hylidene)-3-{[4- >2.4 Hz. 1H), 8.58 fluoro-3- (d, 1=2.4 Hz. 1H), (trifluoromethyl) 8.24 (dd, 1=6.4, 2.4 phenyl]carbamo Hz, 1H), 7.81 - 7.77 yl}bicyclo[2.2.1] (m, 1H), 7.51 - 7.41 heptan-2- (m, 3H), 7.29 (t, yl]carbamoyl}-6- J=7.9 Hz, 2H), 7.03

H z~- ,CF ₃ methoxypyridin- (t, J=7.3 Hz, 1H),

■F 3-yl)- 5.50 - 5.42 (m. 1H),

⁰ F^ 3aH,4H,5H,6H,6 5.24 - 5.17 (m, 2H),

•O Ph >NH aH- 4.37 (brt, 1=8.8 Hz, 0 cyclopenta[d][l, 2H), 4.12 (s, 3H),

\\ N-0 I 2Joxazol-5-vl]- 3.18 - 3.13 (m, 1H), 2,2,2- 3.03 - 2.97 (m, 1H), trifluoroethyl N- 2.75 - 2.71 (m, 1H), phenylcarbamate 2.63 - 2.56 (m. 1H), 2.28 - 2.19 (m, 1H), 2.16 - 2.07 (m, 1H), 2.03 - 1.72 (m, 7H), 1.69 - 1.61 (m, 2H), 1.60 - 1.52 (m, 2H), 1.44 - 1.33 (m, 2H), 1.32 - 1.23 (m, 2H)

N- 696.4 lHNMR (400 MHz, 2.59, A |(1R,2R,3S,4R,7 DMSO-d6) 8 = 10.46 Z)-7- (s, 1H), 9.59 (d, J = (cyclopropylmet 7.5 Hz, 1H), 8.39 (dd, hylidene)-3-{[4- J = 2.3, 6.5 Hz, 1H), fluoro-3- 7.90 (s, 1H), 7.69 (s, (trifluoromethyl) 1H), 7.66 - 7.58

,CF ₃ phenyl]carbamo (m,lH). 7.46 (t, J = yl}bicyclo| 2.2.1] 9.8 Hz, 1H), 5.09 (td,

7 ^ ,NH

O: heptan-2-vl]-5- J = 6.5, 10.3 Hz, 1H),

■OH [5-(l- 4.69 (d, J = 9.5 Hz, p- 1 hydroxyethyl)- 1H), 4.54 - 4.31 (m,

» N-0 I 3aH,4H,5H,6H,6 2H), 4.11 - 4.00 (m' aH- 1H), 3.47 - 3.41 (m, cyclopenta[d]| 1, 1H),3.19 - 3.O2 (m, 2]oxazol-3-yl]- 4H), 2.71 (br s, 1H),

2.2-dimethyl- 2.27 (td, J = 6.9, 13.3

2.3-dihydro-l- Hz, 1H), 2.16 - 2.04 (m, 1H), 1.95 - 1.75 benzofuran-7- (m, 3H), 1.61 (s, 3H), carboxamide 1.56 - 1.22 (m, 9H), 0.98(d, J = 6.1 Hz, 3H), 0.81 - 0.61 (m, 2H), 0.40 - 0.19 (m, _ 2H) _

N- 616.5 1HNMR (4OO MHz, 2.46, A [(1R,2R,3S,4R,7 DMSO-d6) 5 = 9.81 Z)-7- (d, J = 7.1 Hz, 1H), (cyclopropylmet 7.90 - 7.78 (m, 2H), hylidene)-3- 7.68 (d, J = 1.6 Hz, {[(1R)-1-(1- 1H), 5.09 (td, J = 6.7, methylcycloprop 10.2 Hz, 1H), 4.63 (d, yl)ethyl]carbamo J= 9.6 Hz, 1H), 4.46 yl}bicyclo[2.2.1] (d, J = 5.0 Hz, 1H), heptan-2-yl]-5- 4.36 - 4.21 (m, 1H), [5-(l- 4.12 - 3.98 (m, 1H), hydroxyethyl)- 3.46 - 3.41 (m, 2H), 3aH,4H,5H,6H,6 3.15 - 3.05 (m, 2H), aH- 3.03 - 2.98 (m, 1H), cyclopenta[d][l, 2.93(dd, J = 4.3, 11.1 2]oxazol-3-yl]- Hz, 1H), 2.30 - 2.23

2.2-dimethyl- (m, 1H), 2.18 - 2.08

2.3-dihydro-l- (m, 1H), 2.00 - 1.84 benzofuran-7- (m, 2H), 1.81 - 1.73 carboxamide (m, 1H), 1.55 (d, J = 18.9 Hz, 6H), 1.40 - 1.27(m, 3H), 1.02 - 0.98 (m, 6H), 0.97 (s, 3H), 0.78 - 0.65 (m, 2H), 0.61 - 0.55 (m, 1H), 0.40 - 0.26 (m' 3H), 0.22 - 0.12 (m, _ 2H) _

N- 577.3 1H NMR (400 MHz, 2.31, A [(1R,2R,3S,4R,7 DMSO-d6) d = 10.27 Z)-7- (d, J = 6.5 Hz, 1H), (cyclopropylmet 8.54 (dd, J = 2.4, 14.4 hvlidene)-3- Hz, 2H), 7.95 (d, J = {[(IR)-l-(l- 8.4 Hz, HI), 5.20 methylcycloprop (ddd, J = 3.2, 6.7, 9.8 yl)ethyl] carbamo Hz, 1H), 4.75 (t, J = yl}bicyclo[2.2.1] 5.4 Hz, 1H), 4.65 (d, heptan-2-yl]-5- J = 9.5 Hz, 1H), 4.25 [5- (dq, J = 5.4, 10.0 Hz, (hydroxymethyl) 2H), 4.09 (s, 3H), -5 -methyl - 3.52 - 3.45 (m, 1H), 3aH,4H5H,6H,6 3.16 (d, J = 5.4 Hz, aH- 2H), 3.07 (br s, 1H), cyclopenta[d][l, 2.96 (dd, J = 4.4, 10.8 2]oxazol-3-yl]-2- Hz, 1H), 2.55 (br d, J methoxypyridine = 3.4 Hz, 1H), 2.24 - -3 -carboxamide 2.03 (m, 2H), 1.91 - 1.80 (m, 1H), 1.78 - 1.70 (m, 1H), 1.61 (dd, 1 = 2.9, 13.8 Hz, 1H), 1.47 (ddd, J = 4.3, 8.5, 12.9 Hz, 1H), 1.42 - 1.28 (m, 3H), 1.11 - 0.96 (m, 6H), 0.92 (s, 3H), 0.80 - 0.63 (m, 2H), 0.60 -0.48 (m, 1H), 0.41 - 0.28 (m, 3H), 0.25 - 0,05 (m, 2H)

N- 674.2 1H NMR (400 MHz, 2.79, A [(1R,2R,3S,4R,7 DMSO-d6) d = 10.51 Z)-7- (s, 1H), 9.62 (d, J = (cyclopropylmet 7.3 Hz, 1H), 8.12 (dd, hylidene)-3-{[4- J = 2.6, 6.4 Hz, 1H), fluoro-3- 7.97 (s, 1H), 7.85 - (trifluoromethyl) 7.66 (m, 2H), 7.48 phenyl]carbamo (t,J = 9.8 Hz, 1H), yl}bicyclo[2.2.1] 5.20 (d, J = 8.9 Hz, heptan-2-yl]-5- 1H), 4.68 (td, J = 3.6, [5-(2- 7.3 Hz, 1H), 4.41 methanesulfonyl (ddd, J = 3.9, 6.9, ethyl)- 10.6 Hz, 1H), 4.08 (d, 3aH,4H,5H,6H,6 J = 2.8 Hz, 3H), 4.01 aH-pyrrolo[3,4- (dd, J =6.6, 11.6 Hz, dj[l,2joxazol-3- 1H), 3.84 - 3.69 (m, yi]-2- 2H), 3.52 - 3.45 (m, methoxypyridine 1H), 3.22 - 3.10 (m, -3 -carboxamide 2H), 3.00 (br s, 1H), 2.73 (br s, 1H), 2.63 - 2.55 (m, 1H), 2.12 - 2.00 (m,lH), 1.97 - 1.89 (m, 1H), 1.88 - 1.73 (m, 4H), 1.69 - 1.50 (m, 4H), 1.48 - 1.33 (m, 2H), 1.32 - 1.15 (m, 2H) N- 724,3 1H NMR (400 MHz, 2.85, A [(1R,2R,3S,4R,7 DMSO-d6) d = 10.46 Z)-7- (s, 1H), 9.56 (d, J = (cyclopropylmet 7.6 Hz, HI), 8.40 (dd, hylidene)-3-{[4- J = 2.4, 6.4 Hz, 1H), fluoro-3- 7.89 (s, 1H), 7.69 (s, (trifluoromethyl) 1H), 7.65 - 7.56 phenyl]carbamo (m,lH), 7.54 - 7.35 yl}bicyclo[2.2.1] (m, 1H), 5.28 - 5.07

% H ,CF ₃ heptan-2-yl]-5- (m, 2H), 4.74 (t, J = ,N'

1 [5-(2-hydroxy-2- 5.4 Hz, 1H), 4.51 - i o ,NH methylpropyl)-

O: 4.30 (m, 1H), 4.13 3aH,4H,5H,6H,6

~N OH (dt, J = 5.2, 9.8 Hz,

P" 1 aH-pyrrolo[3,4- lH), 3.14 (br dd, J =

» N-0 I d][l,2]oxazol-3- 4.9, 11.4Hz, 5H), y 1] -2,2-dimethyl- 2.96 (br s, 1H), 2.71 2,3 -dihydro- 1 - (br s, 1H), 2.62 - 2.56 benzofuran-7- (m, 1H), 2.19 - 1.99 carboxamide (m, 2H), 1.95 - 1.72 (m, 4H), 1.70 - 1.53

(m, 8H), 1.50 (s, 3H), 1.43 - 1.16(m, 5H), 0.91 (s, 3H)

N- 725,3 1H NMR (400 MHz, 2.61, A [(1R,2R,3S,4R,7 DMSO-d6) d = 10.46 Z)-7- (s, 1H), 9.61 (d, J = (cyclopropylmet 7.5 Hz, 1H), 8.40 (dd, hylidene)-3-{[4- J = 2.5, 6.6 Hz, 1H), fluoro-3- 7.88 (d, J = 1.8 Hz, (trifluoromethyl) 1H), 7.68 (d, J = phenyl]carbamo 1.6Hz, 1H), 7.66 - yl}bicyclo[2.2.1] 7.55 (m, 1H), 7.47 (t, heptan-2-ylj-2-

1 ,CF ₃ J = 9.8 Hz, 1H), 5.O8 methoxy-5-[5- (dd, J = 4.3, 9.6 Hz,

7 ■F (3,3,3-trifluoro- 1H), 4.69 (d, J = 9.6

,NH^ PH 2- Hz, 1H), 4.56 - 4.38

\ °y 3- a •N CF ₃ hydroxypropyl)- (m, 1H), 4.23 (t, J =

N=aZ \\ I 3aH,4H,5H,6H,6 N-0 8.1Hz, 1H), 4.03 (s, aH-pyrrolo[3,4- 1H), 3.23 - 3.10 (m, d][l,2]oxazol-3- 4H), 3.09 - 2.97 (m, yl]pyridine-3- 2H), 2.75 - 2.66 (m, carboxamide 1H), 2.48 - 2.41 (m, 1H), 2.32 - 2.18 (m, 2H), 1.94 - 1.86 (m' 1H),1.85 - 1.76 (m, 1H), 1.61 (s, 3H), 1.56 - 1.34 (m, 6H), 1.02 (s, 3H), 0.96 (s, 3H), 0.81 - 0.66 (m, 2H), 0.35 (dd, J = 2.0,

4.5 Hz, 2H)

(lS)-l-[3-(5- 775.1 lHNMR (500 MHz, 2.87, B {[(2R,3S,7Z)-7- (M+ DMSO-d6) 8 10.56 (cyclopropylmet Na)+ (s, 1H), 10.07 (d, hylidene)-3-{[4- J=6.9 Hz, 1H), 8.60 - fluoro-3- 8.45 (m, 2H), 8.24 (trifluoromethyl) (dd, J=6.4, 2.3 Hz, phenyljcarbamo 1H), 7.84 - 7.75 (m, yl}bicyclo[2.2.1] 2H), 7.74 - 7.68 (m, heptan-2- 1H), 7.64 - 7.58 (m, yl]carbamoyl}-6- 1H), 7.53 - 7.44 (m, methoxypyridin- 2H), 6.43 - 6.37 (m, 3-yl)-4- 1H), 4.71 (d, >9.5 fluorophenyl]- Hz, 1H), 4.52 - 4.42 2,2,2- (m, 1H), 4.15 (s, 3H), trifluoroethyl N- 3.21 - 3.17 (m, 1H), methylcarbamate 3.13 (br d, 1=3.1 Hz, 1H), 2.75 (br s, 1H), 2.61 (d, J=4.6 Hz, 3H), 1.91 - 1.76 (m, 2H), 1.57 - 1.35 (m, 3H), 0.82 - 0.67 (m, 2H), 0.41 - 0.31 (m, 2H)

(lS)-l-[3-(5- 822.2 1H NMR (500 MHz, 2.93, B {[(2R,3S,7Z)-7- DMSO-d6) 8 10.31 (cyclopropylmet (s, 1H), 9.79 (d, J=6.9 hylidene)-3-{[4- Hz, 1H), 8.31 - 8.17 fluoro-3- (m, 2H), 7.98 (dd, (trifluoromethyl) 1=6.5, 2.4 Hz, 1H), phenyljcarbamo 7.59 - 7.51 (m, 2H), yl}bicyclo[2.2.1] 7.43 - 7.35 (m, 1H), heptan-2- 7.29 - 7.15 (m, 2H), yl]carbamoyl}-6- 6.19 (q, J=6.7 Hz, methoxypyridm- 1H), 4.45 (d, 1=9.6 3-yl)-4- Hz, 1H), 4.25 - 4.15 fluorophenyl]- (m, 1H), 3.90 (s, 3H), 2,2,2- 2.93 (dd, J= 10.5, 4.3 trifluoroethyl 4- Hz, 1H), 2.87 (br s, methylpiperazine 1H), 2.49 (br s, 1H), -1 -carboxylate 2.30 (s, 4H), 2.10 - 1.98 (m, 4H), 1.92 (s, 3H), 1.64 - 1.50 (m, 2H), 1.32 - 1.11 (m, 3H), 0.49 (brt, 1=9.3 Hz, 2H), 0.15 - 0.06 (m, 2H)

(lS)-l-[3-(5- 815.1 lH NMR (500 MHz, 3.02, B {[(2R,3S,7Z)-7- (M+ DMSO-d6) 5 10.55 (cyclopropylmet Na)+ (s, 1H), 10.07 (br d, hylidene)-3-{[4- 1=7.0 Hz, HI), 8.57 - fluoro-3- 8.41 (m, 2H), 8.24 (trifluoromethyl) (dd, 1=6.4, 2.3 Hz, phenyl]carbamo 1H), 8.14 (d, J=7.9 yl}bicyclo[2.2.1] Hz, 1H), 7.84 - 7.74 heptan-2- (m, 2H), 7.65 - 7.57

1 ,CF ₃ yl]carbamoyl}-6- (m, 1H), 7.48 (td,

F methoxypyridin- J=9.6, 6.4 Hz, 2H),

,Nrl 3-yl)-4- 6.43 - 6.34 (m, 1H),

' X ^F3< L fluorophenyl]- 4.71 (d, 1=9.5 Hz, 2,2,2- 1H), 4.48 - 4.42 (m, trifluoroethyl N- lH), 4.15 (s, 3H), cyclobutylcarba 3.98 - 3.89 (m, 1H), mate 3.18 (dd, 1=10.7, 4.3 Hz, 1H), 3.13 (br s, 1H), 2.75 (br s, 1H), 2.21 - 2.04 (m, 2H), 1.97 - 1.77 (m, 4H), 1.65 - 1.37 (m, 5H), 0.81 - 0.66 (m, 2H), 0.40 - 0.30 (m, 2H)

(lS)-l-|3-(5- 843.1 1H NMR (500 MHz, 2.88, B {[(2R,3S,7Z)-7- (M+ DMSCM6) 8 10.55 (cyclopropylmet Na)+ (s, 1H), 10.06 (d, hylidene)-3-{[4- J=7.1 Hz, 1H), 8.58 - fluoro-3- 8.45 (m, 2H), 8.24 (trifluoromethyl) (dd, J=6.3, 2.3 Hz, phenyljcarbamo 1H), 7.86 - 7.73 (m,

,CF ₃ yl}bicyclo[2.2.1] 2H), 7.66 - 7.58 (m,

F heptan-2-

; O 1H), 7.53 - 7.43 (m,

O<s/ yl]carbamoyl}-6-

F ₃ C 2H), 6.43 - 6.34 (m, methoxypyridm-

>o HI), 4.75 - 4.59 (m,

°Y )

N=»/ 3-yl)-4-

3 So 5H), 4.50 - 4.41 (m, ,N

F fluorophenyl]- 1H), 4.36 - 4.24 (m, 2,2,2-

O' 2H), 4.15 (s, 3H), trifluoroethyl 2-

4.11 (br d, J=11.4 Hz, oxa-6- lH), 3.18 (dd, 1=10.6, azaspiro[3.3]hept

4.5 Hz, 1H), 3.15 - ane-6-

3.11 (m, 1H), 2.75 (br carboxylate s, 1H), 1.89 - 1.77 (m, 2H), 1,55 - 1.39 (m, 3H), 0.81 - 0.67

(m, 2H), 0.36 (br d, J=1.8 Hz, 2H)

(lS)-l-[3-(5- 845.1 1H NMR (500 MHz, 2.79, B {[(2R,3S,7Z)-7- (M+ DMSO-d6) 5 10.31 (cyclopropylmet Na)+ (s, 1H), 9.83 (brd, hylidene)-3-{[4- J=7.0 Hz, HI), 8.36 - fluoro-3- 8.18 (m, 2H), 8.00 (trifluoromethyl) (dd, J=6.4, 2.4 Hz, phenyl]carbamo 1H), 7.68 (d, J=7.6 yl}bicyclo[2.2.1] Hz, 1H), 7.61 - 7.52 heptane(m, 2H), 7.42 - 7.35 yl] carbamoyl} -6- (m, 1H), 7.29 - 7.19 methoxypyridin- (m, 2H), 6.17 (br d, 3-yl)-4- 1=6.8 Hz, 1H), 4.47 fluorophenyl]- (d, J=9.5 Hz, 1H), 2,2,2- 4.26 - 4.16 (m, 1H), trifluoroethyl N- 3.92 (s, 3H), 3.61 - (oxan-4- 3.50 (m, 2H), 3.13 (br yl)carbamate s, 1H), 3.05 (br d, J=2.3 Hz, 1H), 2.99 - 2.85 (m, 2H), 2.51 (br s, 1H), 1.64 - 1.46 (m, 3H), 1.42 (brd, J=11.7 Hz, 1H), 1.29 - 1.08 (m, 5H), 0.57 - 0.43 (m, 2H), 0.17 - 0.07 (m, 2H)

(lS)-l-[3-(5- 837.1 1H NMR (500 MHz, 3.02, B {[(2R,3S,7Z)-7- (M+ DMSO-d6) 8 10.31 (s, (cyclopropylmet Na)+ 1H), 10.04 (br s, 1H), hylidene)-3-{[4- 9.83 (d, J=6.9 Hz, 1H), fluoro-3- 8.35 - 8.19 (m, 2H), (trifluoromethyl) 8.00 (dd, 1=6.4, 2.4 Hz, ,NH phe 1H), 7.67 - 7.53 (tn,

F ₃ C nyl]carbamo y 2H), 7.45 (brdd, J=3.6,

⁰ l}bicyclo[2.2.1]

NS:Z J ^- heptan-2- 2.9 Hz, 1H), 7.31 - 7.18

3 "O zZ HN F^ Ph (m, 4H), 7.06 (t, 1=7.9 yl]carbamoyl}-6- Hz, 2H), 6.80 (t, 1=7.3 methoxypyridin- Hz, 1H), 6.33 (brd, 3-yl)-4- J=6.9 Hz, 1H), 4,47 (d, fluorophenyl]- J=9.5 Hz, 1H), 4.25 -

2,2,2- 4.16 (m, 1H), 3.91 (s, trifluoroethyl N- 3H), 2.96 - 2.86 (m, phenylcarbamate 2H), 2.50 (br d, 1=3.2 Hz, 1H), 1.62 - 1.53 (m, 2H), 1.31 - 1.13 (m, 3H), 0.56 - 0.44 (m, 2H), 0.16 - 0.06 (m, _ 2H) _

(lS)-l-[3-(5- 879.1 1H NMR (500 MHz, 2.80, B {[(2R,3S,7Z)-7- (M+ DMSO-d6) 5 10.57 (s, (cyclopropylmet Na)+ 1H), 10.06 (d, 1=7.0 hylidene)-3-{[4- Hz, 1H), 8.58 - 8.45 fluoro-3- (m, 2H), 8.25 (dd, (trifluoromethyl) 1=6.5, 2.6 Hz, 1H), phenyljcarbamo 7.90 - 7.85 (m, 1H), yl}bicyclo[2.2.1] 7.84 - 7.76 (m, 1H), heptan-2- 7.72 - 7.66 (m, 1H), 7.56 - 7.42 (m, 2H), yl]carbamoyl}-6- 6.48 (br d, 1=6.6 Hz, methoxypyridin-

1H), 4.71 (d, 1=9.5 Hz,

3-yl)-4- 1H), 4.50 - 4.42 (m, fluorophenyl]- 1H), 4.16 (s, 3H), 4.05 2,2,2- (br s, 1H), 3.74 - 3.74 trifluoroethyl (m, 1H), 3.91 (s, 2H), 1, 1 -dioxo- IX ⁶ - 3.18 (d, 1=4.8 Hz, 5H), thiomorpholine- 3.13 (br s, 1H), 2.79 -

4-carboxylate 2.72 (m, 1H), 1.87 - 1.76 (m, 2H), 1.56 - 1.37 (m, 3H), 0.82 - 0.67 (m, 2H), 0.41 - 0.34 (m, 2H)

(500 MHz, DMSO-d6) 5

10.12 (br d, J=6.6 Hz, 1H), 8.34 (s, 1H), 8.24 (d, J=l.l Hz, 1H), 7.96 (br d, 1=7.8 Hz, 1H), 7.81 (br d, 1=8.5 Hz, 1H), 7.58 (br d, j=7.1 Hz, 1H),

(lS)-l-[3-(5- 7.42 (br d, J=2.7 {[(1R,2R,3S,4R,7Z) Hz, 1H), 7.35 - -7-[(3,3- 7.23 (m, 1H), 6.18 difluorocyclobutyl) (q, 1=6.9 Hz, 1H), methylidene] -3- 5.16 (d, 1=8.3 Hz, {[(1R)-1-(1- 1H), 4.12 - 3.98 methylcyclopropyl)e (m, 1H), 3.92 (s, 2.89,88 thyl Jcarbamoyl }bicy 763.4 3H), 3.81 - 3.70 C clo[2.2.1]heptan-2- (m, 1H), 2.84 - yl]carbamoyl}-6- 2.56 (m, 5H), 2.41 methoxypyridin-3 - (br s, 1H), 2.29 - HcyBu yl)-4-fluorophenyl] -

2.12 (m, 2H), 2.06 2,2,2-trifluoroethyl

- 1.84 (m, 2H), N- 1.80 - 1.62 (m, cyclobutylcarbamate 3H), 1.60 - 1.50 (m, 1H), 1.46 - 1.29 (m, 2H), 1.22

- 1.06 0.85 ( 3H), 0.80 (s, 3H), 0.42 - 0.30 (m, 1H), 0.21 - 0.10 (m, 1H), 0.07 - - 0.06 (m, 2H)

(a) All LC retention times are based on Method C unless otherwise specified, (b) 1-3 protons were not accounted for in these samples due to overlap with solvent residue and/or artifacts of water suppression . It will be evident to one skilled in the art that the present disclosure is not limited to tiie foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.