RXFP1 agonist

Abstract

The present disclosure relates to compounds of formula (I), which are RXFP1 receptor agonists, to compositions containing them, and to methods of using them in the treatment of, for example, heart failure, fibrotic diseases, and related diseases such as pulmonary disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic kidney disease), or liver disease (e.g., nonalcoholic steatohepatitis and portal hypertension). TIFF2024540164001096.tif53139

Description

[Technical Field]

[0001] The present disclosure relates to novel compounds that are relaxin family peptide receptor 1 (RXFP1) agonists, compositions containing them, and methods of using them in the treatment of, for example, heart failure, fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), and liver disease (e.g., non-alcoholic steatohepatitis and portal hypertension). [Background technology]

[0002] Human relaxin hormone (also known as relaxin or H2 relaxin) is a 6-kDa peptide composed of 53 amino acids. Its activity was first discovered in 1926 by Frederick Hisaw, who observed relaxation of the fibrocartilaginous symphysis pubis joints when a crude extract from porcine corpora lutea was injected into virgin guinea pigs (Hisaw FL, Proc. Soc. Exp. Biol. Med., 1926, 23, 661-663). The relaxin receptor, formerly known as Lgr7, is now officially designated relaxin family peptide receptor 1 (RXFP1) and was de-orphanized as a relaxin receptor in 2002 (Hsu SY. et al., Science, 2002, 295, 671-674). RXFP1 is reasonably well conserved between mice and humans, with 85% amino acid identity, and is essentially ubiquitously expressed in humans and other species (Halls ML. et al., Br. J. Pharmacol., 2007, 150, 677-691). The relaxin and RXFP1 cell signaling pathways are cell type dependent and highly complex (Halls ML. et al., Br. J. Pharmacol., 2007, 150, 677-691; Halls ML. et al., Ann. NY Acad. Sci., 2009, 1160, 108-111; Halls ML. et al., Ann. NY Acad. Sci., 2007, 1160, 117-120). The most studied pathway is one in which relaxin functions as an RXFP1 agonist, promoting GαS coupling and adenylate cyclase activation, resulting in a relaxin-dependent increase in cellular levels of cAMP (Halls ML. et al., Mol. Pharmacol., 2006, 70, 214-226).

[0003] Since the initial discovery of relaxin, much experimental research has focused on clarifying its role in female reproductive biology and the physiological changes that occur during mammalian pregnancy (Sherwood OD., Endocr. Rev., 2004, 25, 205-234). During human pregnancy, to meet the nutritional demands of the fetus, the female body experiences a significant decrease in systemic vascular resistance (SVR) of approximately 30%, accompanied by an increase in cardiac output of approximately 50% (Jeyabalan AC., KP, Renal and Electrolyte Disorders. 2010, 462-518), (Clapp JF & Capeless E., Am. J. Cardio., 1997, 80, 1469-1473). Further vascular adaptations include an approximately 30% increase in systemic arterial compliance, which is important for maintaining effective ventricular-arterial coupling, and an approximately 50% increase in both renal blood flow (RBF) and glomerular filtration rate (GFR), which are important for the clearance of metabolic waste products (Jeyabalan AC., KP, Renal and Electrolyte Disorders. 2010, 462-518), (Poppas A. et al., Circ., 1997, 95, 2407-2415). Both preclinical studies in rodents and clinical studies conducted in various patient settings provide evidence that relaxin is involved, at least to some extent, in mediating these adaptive biological changes (Conrad KP., Regul Integr. Comp. Physiol., 2011, 301, R267-275), (Teichman SL. et al., Heart Fail. Rev., 2009, 14, 321-329).Importantly, many of these adaptive responses may be beneficial to patients with HF, in that excessive fibrosis, low arterial compliance, and reduced renal function are all common characteristics of patients with heart failure (Mohammed SF. et al., Circ., 2015, 131, 550-559), (Wohlfahrt P. et al., Eur. J. Heart Fail., 2015, 17, 27-34), (Damman K. et al., Prog. Cardiovasc. Dis., 2011, 54, 144-153).

[0004] Heart failure (HF), defined as a hemodynamic condition in which the cardiac pump function is impaired, resulting in inadequate systemic perfusion to meet the metabolic needs of the body, is prevalent in an estimated 5.8 million people in the United States and more than 23 million people worldwide, representing an enormous burden on today's healthcare systems (Roger VL et al., Circ. Res., 2013, 113, 646-659). It is estimated that an additional 3 million people will suffer from HF in the United States alone by 2030, a 25% increase from 2010. The estimated direct costs associated with HF in 2010 (in 2008 dollars) were $25 billion, projected to rise to $78 billion by 2030 (Heidenreich PA et al., Circ., 2011, 123, 933-944). Surprisingly, one in nine deaths in the United States is listed as having HF on the death certificate (Roger VL. et al., Circ., 2012, 125, e2-220), and although survival rates after a diagnosis of HF have improved over time (Matsushita K. et al., Diabetes, 2010, 59, 2020-2026) (Roger VL. et al., JAMA, 2004, 292, 344-350), mortality remains high, with approximately 50% of HF patients dying within five years of diagnosis (Roger VL. et al., Circ., 2012, 125, e2-220) (Roger VL. et al., JAMA, 2004, 292, 344-350).

[0005] Symptoms of HF are the result of insufficient cardiac output and can be quite debilitating depending on the stage of the disease. The primary signs and symptoms of HF include: 1) dyspnea (labored breathing) resulting from pulmonary edema caused by ineffective forward flow from the left ventricle and increased pressure in the pulmonary capillary bed; 2) lower extremity edema, which occurs when the right ventricle cannot accommodate systemic venous return; and 3) fatigue due to heart failure's inability to maintain sufficient cardiac output (CO) to meet the body's metabolic demands (Kemp CD. & Conte JV., Cardiovasc. Pathol., 2011, 21, 365-371). Furthermore, depending on the severity of symptoms, HF patients are often described as "compensated" or "decompensated." In compensated heart failure, symptoms are stable and many of the defining features, such as fluid retention and pulmonary edema, are absent. Decompensated heart failure refers to a deterioration that may present as acute episodes of pulmonary edema, decreased exercise tolerance, and increased shortness of breath on exercise (Millane T. et al., BMJ, 2000, 320, 559-562).

[0006] Contrary to the simple definition of a cardiac dysfunction resulting in an inability to meet metabolic demands, the numerous underlying causes, risk factors, and pathological changes that ultimately lead to heart failure make this disease extremely complex (Jessup M. & Brozena S., N. Engli. J. Med., 2003, 348, 3007-2018). The adverse events thought to be involved in the pathophysiology of HF range from very acute insults such as myocardial infarction to chronic insults such as lifelong hypertension. Historically, HF has been primarily described as either "systolic HF," in which reduced left ventricular (LV) systolic function limits blood ejection, resulting in a reduced ejection fraction (EF = stroke volume / end-diastolic volume), or "diastolic HF," in which active relaxation reduces LV filling during diastole and passive stiffness increases it, while overall EF is preserved (Borlaug, B.A. & Paulus, W.J., Eur Heart J., 2011, 32, 670-679). More recently, new terms have been adopted: "heart failure with reduced ejection fraction" (HFrEF) and "heart failure with preserved ejection fraction" (HFpEF), as it has become recognized that diastolic and systolic LV dysfunction are not unique or specific to these two groups (Borlaug, B.A. & Paulus, W.J., Eur Heart J., 2011, 32, 670-679). Although these two patient populations exhibit very similar signs and symptoms, it is currently under debate within the cardiovascular community whether HFrEF and HFpEF represent two distinct forms of HF or two extremes of a single spectrum that share a common pathology (Borlaug BA. & Redfield MM., Circ., 2011, 123, 2006-2013), (De Keulenaer GW. & Brutsaert DL., Circ., 2011, 123, 1996-2004).

[0007] Serelaxin, an intravenous (IV) formulation of the human recombinant relaxin peptide with a relatively short pharmacokinetic half-life of 0.09 hours, is currently in development for the treatment of HF (Novartis, 2014). Administration of serelaxin to healthy volunteers (NHVs) has been shown 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). Increased RBF was also observed in patients with stable, compensated HF (Voors AA. et al., Cir. Heart Fail., 2014, 7, 994-1002). In large-scale clinical trials, favorable changes in renal function, HF worsening, and reduced mortality were observed in patients with acutely decompensated heart failure (ADHF) in response to a 48-hour in-hospital intravenous 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 administration of serelaxin may provide sustained benefits for HF patients, improvements in renal function, based on serum creatine levels, were observed in patients with scleroderma who received serelaxin via subcutaneous pump for six months (Teichman SL. et al., Heart Fail. Rev., 2009, 14, 321-329). In addition to its potential as a therapeutic agent for treating HF, continuous subcutaneous administration of relaxin has also proven effective in various animal studies of lung injury (Unemori EN. et al., J. Clin. Invet. 1996, 98, 2739-2745), kidney injury (Garber SL. et al., Kidney Int., 2001, 59, 876-882), and liver injury (Bennett RG., Liver Int., 2014, 34, 416-426).

[0008] In summary, a large body of evidence supports the role of relaxin-dependent agonism of RXFP1 in mediating adaptive changes that occur during mammalian pregnancy and supports the positive physiological effects and outcomes of these changes when relaxin is administered to patients with HF. Further preclinical animal studies in various disease models of lung, kidney, and liver injury provide evidence that relaxin, when administered chronically, may provide therapeutic benefits for multiple indications in addition to HF. More specifically, chronic administration of relaxin may benefit patients with pulmonary disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic kidney disease), or liver disease (e.g., nonalcoholic steatohepatitis and portal hypertension). Summary of the Invention

[0009] The present invention provides novel substituted norbornyl compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, and analogs thereof, which are useful as RXFP1 receptor agonists. The 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 compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0010] The compounds of the invention may be used, for example, in the treatment and / or prevention of heart failure, fibrotic diseases, and pulmonary diseases (e.g., idiopathic pulmonary fibrosis), renal diseases (e.g., chronic renal disease), or liver diseases (e.g., non-alcoholic steatohepatitis and portal hypertension). The compounds of the invention may be used in therapy. The compounds of the present invention may be used in the manufacture of a medicament for the treatment and / or prevention of heart failure.

[0011] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one or two, other drugs. These and other features of the invention will be described in expanded form as the disclosure proceeds. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention encompasses compounds of formula (I), which are RXFP1 receptor agonists, compositions containing the compounds, and methods of using the compounds or compositions.

[0013] In a first aspect, the present invention provides, inter alia, a compound of formula (I): [ka] [In formula: L is -O- or -NH-; R 1 is C 1-3 Alkyl (0-1 aryl or C 3-6 substituted with a cycloalkyl substituent; R 2 is H; however, R 1 aryl or C 3-6 When substituted with a cycloalkyl substituent, R 9 is not absent; Alternatively, R 1 and R 2 are combined, =CR 6 R 7 or =NOC 1-4 alkyl, where "=" is a double bond; or R 1 and R 2 together with the carbon atom to which they are both attached form dioxolanyl (substituted with 0 to 1 aryl substituents); R 3 is C 1-8 Alkyl (0-5 halo, -CN, -OH, or -OC) 1-3 substituted with alkyl substituents), -(CR d R d ) n -C 3-10 -carbocyclyl (0 to 5 R 4 ), or -(CRd R d ) n -3 to 12-membered heterocyclyl (O, S(=O) p , N, and NR 4c and 0 to 5 R 4 ) and R 4 are halo, CN, -OH, -SF5, -S(=O) p R c , C 1-4 Alkyl (0-5 halo, -OH, or -OC) 1-4 substituted with alkyl substituents), OC 1-4 alkyl (substituted with 0 to 5 halo substituents), -(CR d R d ) n -C 3-10 Carbocyclyl (0 to 5 R e ), or -(CR d R d ) n - 4- to 6-membered heterocyclyl (O, S(=O) p , N, and NR 4c and 0 to 5 R e ) and R 4c is H, C 1-4 alkyl, or -S(=O)2CF3; R 5 are H, halo, -OH, and C, respectively. 1-4 alkyl (substituted with 0 to 5 halo substituents), or -OC 1-4 alkyl (substituted with 0-5 halo substituents); R 6 H, halo, CN, C 1-7 Alkyl (0 to 3 R 6a (substituted with), C 2-7 Alkenyl (0 to 3 R 6a (substituted with), C 2-7 Alkynyl (0 to 3 R 6a substituted with), -C(=O)O, -CONR 6b R 6b , -(CH2)n -C 3-10 Carbocyclyl (0 to 5 R 14 substituted with), or 3- to 12-membered heterocyclyl (O, S(=O) p , N, or NR 14a and 0 to 5 R 14 ) and R 6a Halo, -OH, -OC 1-4 Alkyl, C 1-4 Alkyl, aryl, or C 3-6 cycloalkyl (substituted with 0-4 halo substituents); R 6b is H, C 1-4 alkyl (substituted with 0-1 aryl substituents), or C 3-6 cycloalkyl (substituted with 0-4 halo substituents); R 7 is H or C 1-4 Is it alkyl; Or R 6 and R 7 together with the carbon atom to which they are attached form cyclopentadienyl, indanyl, or indenyl; R 8 H, halo, CN, -NR 7 R 7 , C 1-4 alkyl (substituted with 0-5 halo or -OH substituents), or -OC 1-4 Alkyl (0-5 halo, -OH, C 3-6 Cycloalkyl, aryl, 4- to 9-membered heterocyclyl (O, S(=O) p and N), or -OC 1-3 Alkyl (0 to 1 -OC) 1-3 substituted with alkyl substituents); R 9 is an aryl (0 to 3 R 10 and 0 to 2 R 11 substituted with) or 3- to 12-membered heterocyclyl (O, S(=O) p, N, and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 ) and R 10 Halo, CN, C 1-4 Alkyl, =O, -OH, or -OC 1-4 is alkyl; R 11 is C 1-5 Alkyl (0 to 4 R 12 and 0 to 2 R 13 (replaced with), -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 , C 3-9 Carbocyclyl (0 to 5 R e substituted with), or 3- to 12-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 5 R e ) and R 11a is H, C 1-5 Alkyl (0 to 4 R 11b substituted with -C(=O)R b, -C(=O)OR b , -C(=O)NR a R a , C 3-6 Cycloalkyl (0 to 5 R e substituted with aryl (0 to 5 R e substituted with), 4- to 6-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 5 R e ) and R 11b are halo, -OH, -C(=O)OH, -C(=O)OC 1-4 alkyl, or aryl; R 12 Halo, -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a OR b , C 1-4 alkyl (substituted with 0-3 halo or OH substituents), or C 3-6 is cycloalkyl; 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 , -NR a S(=O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , -S(=O) p R c, -(CH2) n -C 3-10 Carbocyclyl (0 to 3 R e substituted with), or (CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14 Halo, CN, C 1-4 Alkyl (substituted with 0-3 halo substituents), -OC 1-4 Alkyl (substituted with 0-3 halo substituents), -(CH2) n -NR a R a , -(CH2) n -aryl (0 to 3 R e substituted with 0 to 3 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14a is H, C(=O)C 1-4 Alkyl, or C 1-3 Alkyl (substituted with 0-2 halo substituents, 0-3 Si(C 1-3 alkyl) or aryl) substituted; R 15 is H, C 1-4 alkyl, or aryl; R a -H, -OC 1-6 Alkyl, C 1-6 Alkyl (0 to 5 R e (substituted with), C 2-6 Alkenyl (0 to 5 R e (substituted with), C 2-6 Alkynyl (0 to 5 R e (substituted with), (CH2) n C 3-10 Carbocyclyl (0 to 5 R esubstituted with), or (CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e or R a and R a and together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e (substituted with); R b is H, C 1-6 Alkyl (0 to 5 R e (substituted with), C 2-6 Alkenyl (0 to 5 R e (substituted with), C 2-6 Alkynyl (0 to 5 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R e substituted with), or (CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e ) and R c is C 1-6 Alkyl (0 to 5 R e (substituted with), C 2-6 Alkenyl (0 to 5 R e (substituted with), C 2-6 Alkynyl (0 to 5 R e (substituted with), C 3-6 Carbocyclyl (0 to 5 R e substituted with), or 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e ) and R d is H, C 1-4 Alkyl, or C3-6 is cycloalkyl; R e Halo, CN, NO2, =O, C 1-6 Alkyl (0 to 5 R g (substituted with), C 2-6 Alkenyl (0 to 5 R g (substituted with), C 2-6 Alkynyl (0 to 5 R g substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R g substituted with), -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R g substituted with), -(CH2) n OR 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 -(CH2) n NR f R f and; R f is H, C 1-6 Alkyl (0 to 2 -OH or -OC) 1-4 substituted with alkyl substituents), C 3-6 Cycloalkyl, aryl, or 3- to 12-membered heterocyclyl (O, S(=O) p and N) or R f and R fand together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) p and N) containing 1 to 4 heteroatoms selected from; R g Halo, CN, -OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0014] In a second aspect within the first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 3 But C 1-6 Alkyl (substituted with 0-4 halo or -OH substituents), -(CHR d ) 0-1 -C 3-6 Cycloalkyl (0 to 4 R 4 (substituted with), C 6-9 Spirocycloalkyl (0 to 4 R 4 (substituted with), C 6-10 Bicyclic carbocyclyl (0 to 4 R 4 substituted with), or 3- to 6-membered heterocyclyl (O, S(=O) p , N, and NR 4c and 0 to 4 R 4 ) and R 4 But halo or C 1-3 alkyl (substituted with 0-4 halo substituents); R 4c But H or C 1-4 is alkyl; R d C 1-3 is alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0015] In a third aspect within the first aspect, the present invention provides a compound of formula (II): [ka] [In formula: R 4 is halo, -S(=O) p C 1-4 Alkyl (substituted with 0-4 halo substituents), C 1-4 Alkyl (substituted with 0 to 4 halo substituents), -OC 1-4 alkyl (substituted with 0-4 halo substituents); R 5 is H or halo; R 6 Halo, CN, C 1-7 Alkyl (0 to 3 R 6a (substituted with), C 2-7 Alkenyl (0 to 3 R 6a (substituted with), C 2-7 Alkynyl (0 to 3 R 6a substituted with -C(=O)OR 6b ,CONR 6b R 6b , C 3-6 Cycloalkyl (0 to 3 R 14 (substituted with), C 3-6 Cycloalkenyl (0 to 3 R 14 substituted with aryl (0 to 3 R 14 substituted with), or 4- to 6-membered heterocyclyl (O, S(=O) p , N, and NR 14a and 0 to 3 R 14 ) and R 6a is halo, -OH, C 3-6 cycloalkyl, or aryl; R 6b is H, C 1-4 alkyl (substituted with 0-1 aryl substituents), or C 3-6 cycloalkyl (substituted with 0-4 halo substituents); R 7is H or C 1-3 is alkyl; R 8 is halo, CN, -N(C 1-2 Alkyl)2, C 1-4 alkyl (substituted with 0-5 halo or -OH substituents), or -OC 1-4 Alkyl (0-4 halo, -OH, aryl, or -OC 1-4 substituted with alkyl substituents; R 9 is a C6 aryl (0 to 3 R 10 and 0 to 2 R 11 substituted with), or 3- to 12-membered heterocyclyl (O, S(=O) p , N, and NR 11a and 0 to 3 R 10 and 0 to 1 R 11 ) and R 10 Halo, CN, C 1-4 Alkyl, =O, -OH, or -OC 1-4 is alkyl; R 11 is C 1-4 Alkyl (0 to 1 R 12 and 0 to 1 R 13 (replaced with), -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 , C 3-6 Cycloalkyl (0 to 5 R e substituted with), 4- to 12-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 5 R e ) and R 11a is H, C 1-4 Alkyl (0 to 2 R 11b substituted with -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , C 3-6 Cycloalkyl (0 to 5 R e substituted with), 4- to 6-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 5 R e ) and R 11b is —OH, —C(═O)OH, or aryl; R 12 Halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-3 halo or OH substituents); R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(=O) p NR a Ra , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , or -S(=O) p R c and; R 14 Halo, CN, C 1-4 Alkyl (substituted with 0-3 halo substituents), -OC 1-4 Alkyl (substituted with 0-3 halo substituents), -(CH2) 0-2 -NR a R a , -(CH2) 0-3 -aryl (0 to 3 R e substituted with 0 to 3 R e substituted with -(CH2) 0-3 -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14a is H, C(=O)C 1-4 Alkyl, or C 1-3 alkyl (substituted with 0-3, 0-2 halo substituents, aryl substituted); R 15 is H, C 1-3 alkyl, or aryl; R a is H, C 1-5 Alkyl (0 to 5 R e (substituted with), C 2-5 Alkenyl (0 to 5 R e (substituted with), C 2-5 Alkynyl (0 to 5 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O)p and N, and 0 to 5 R e or R a and R a and together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e (substituted with); R b is H, C 1-5 Alkyl (0 to 5 R e (substituted with), C 2-5 Alkenyl (0 to 5 R e (substituted with), C 2-5 Alkynyl (0 to 5 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e ) and R c is C 1-5 Alkyl (0 to 5 R e (substituted with), C 2-5 Alkenyl (0 to 5 R e (substituted with), C 2-5 Alkynyl (0 to 5 R e (substituted with), C 3-6 Carbocyclyl (0 to 5 R e substituted with), or 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e ) and R d is H or C 1-4 is alkyl; R e Halo, CN, =O, C 1-6Alkyl (0 to 5 R g (substituted with), C 2-6 Alkenyl (0 to 5 R g (substituted with), C 2-6 Alkynyl (0 to 5 R g substituted with), -(CH2) n -C 3-6 Cycloalkyl (0 to 5 R g substituted with), -(CH2) n -aryl (0 to 5 R g substituted with), -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R g substituted with), -(CH2) n OR f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f , -NR f C(=O)OR f , -OC(=O)NR f R f , or -(CH2) n NR f R f and; R f is H, C 1-5 Alkyl, C 3-6 cycloalkyl, or aryl; or R f and R f and together with the nitrogen atom to which they are both attached form a heterocyclyl; R g Halo, CN, -OH, C 1-5 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0016] In a fourth aspect within the first aspect, the present invention provides a compound of formula (III): [ka] [In formula: R 4a is a halo; R 4b is C 1-4 alkyl (substituted with 0-4 halo substituents); R 5 is H or F; R 6 Ha, Halo, C 1-4 Alkyl (0 to 3 R 6a (substituted with), C 2-4 Alkenyl (substituted with 0-1 phenyl or -OH substituents), -C(=O)OR 6b , C(=O)NHR 6b , C 3-6 Cycloalkyl (0 to 3 R 14 (substituted with), C 3-6 Cycloalkenyl (0 to 3 R 14 phenyl (substituted with 0 to 3 R 14 substituted with), naphthyl (substituted with 0 to 3 R 14 substituted with), or 5- or 6-membered heterocyclyl (O, S, N, and NR 14a and 0 to 3 R 14 ) and R 6a is halo, -OH, C 3-6 cycloalkyl, or phenyl; R 6b is H or C 1-4 is alkyl; R 7 is H or C 1-3 Is it alkyl; Or R 6 and R 7 together with the carbon atom to which they are attached form cyclopentadienyl, indanyl, or indenyl; R 8-N(C 1-4 alkyl)2 or -OC 1-4 Alkyl (0 to 1 -OC) 1-4 substituted with alkyl substituents; R 8a is a halo; R 14 Halo, CN, C 1-4 Alkyl (substituted with 0-3 halo substituents), -OC 1-4 Alkyl (substituted with 0-3 halo substituents), -(CH2) 0-2 -NR a R a , -(CH2) 0-2 -aryl (0 to 3 R e substituted with 0 to 3 R e substituted with -(CH2) 0-2 -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14a is H, C(=O)C 1-3 Alkyl, or C 1-3 alkyl (substituted with 0-3, 0-2 halo substituents, aryl substituted); R a is H, C 1-6 Alkyl (0 to 5 R e substituted with), -(CH2) n -phenyl (0 to 5 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e or R a and R a and together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e (substituted with); R b is H, C 1-6 Alkyl (0 to 5 R e substituted with), -(CH2) 0-1 -phenyl (0 to 5 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e ) and R e Halo, CN, =O, C 1-6 alkyl, or C(=O)OH; n is 0, 1, 2, or 3] or a pharmaceutically acceptable salt thereof.

[0017] In a fifth aspect within the first to third aspects, the present invention provides a compound of formula (IV): [ka] [In formula: R 4 Ha, Halo, C 1-4 alkyl (substituted with 0-3 halo substituents), or -OC 1-4 alkyl (substituted with 0-3 halo substituents); R 5 is H or F; R 6 Halo, CN, C 1-6 Alkyl (0 to 3 R 6a (substituted with), C 2-6 Alkenyl (0 to 3 R 6a (substituted with), C 2-6 Alkynyl (0 to 3 R 6a substituted with -C(=O)OR 6b , C(=O)NR 6b R 6b , C 3-6 Cycloalkyl (0 to 3 R 14 (substituted with), C 3-6 Cycloalkenyl (0 to 3 R14 phenyl (substituted with 0 to 3 R 14 substituted with), or 5- to 6-membered heteroaryl (O, S(=O) p , N, and NR 14a and 0 to 3 R 14 ) and R 6a Ha, Halo, C 3-6 cycloalkyl, or phenyl; R 6b is H, C 1-3 alkyl (substituted with 0-1 aryl substituents), or C 3-6 cycloalkyl (substituted with 0-4 halo substituents); R 7 is H or C 1-2 is alkyl; R 8 -OC 1-4 Alkyl (0-4 halo, -OH, aryl or -OC 1-4 substituted with alkyl substituents; R 10 Halo, CN, C 1-3 Alkyl, -OH, or -OC 1-4 is alkyl; R 11 is C 1-4 Alkyl (0 to 2 R 12 and 0 to 1 R 13 (replaced with), -OR b , -NR a R a , -NR a C(=O)R 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 , C 3-6 Cycloalkyl, 4- to 9-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 4 R e ) and R 12 Halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-3 halo or OH substituents); R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(=O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , or -S(=O) p R c and; R 14 Halo, CN, C 1-4 Alkyl (substituted with 0-3 halo substituents), -OC 1-4 Alkyl (substituted with 0-3 halo substituents), -(CH2) 0-2 -NR a R a , -(CH2) 0-2-aryl (0 to 3 R e substituted with 0 to 3 R e substituted with -(CH2) 0-2 -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14a is H, C(=O)C 1-3 Alkyl, C 1-3 alkyl (substituted with 0-2 aryl substituted with 0-2 halo substituents); R 15 is H, C 1-2 alkyl, or phenyl; R a is H, C 1-5 Alkyl (0 to 4 R e (substituted with), C 2-5 Alkenyl (0 to 4 R e (substituted with), C 2-5 Alkynyl (0 to 4 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 4 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e or R a and R a and together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e (substituted with); R b is H, C 1-5 Alkyl (0 to 4 R e (substituted with), C 2-5 Alkenyl (0 to 4 R e (substituted with), C 2-5Alkynyl (0 to 4 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 4 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e ) and R c is C 1-5 Alkyl (0 to 4 R e (substituted with), C 2-5 Alkenyl (0 to 4 R e (substituted with), C 2-5 Alkynyl (0 to 4 R e (substituted with), C 3-6 Carbocyclyl or 3- to 12-membered heterocyclyl (O, S(=O) p and N) containing 1 to 4 heteroatoms selected from; R e Halo, CN, NO2, =O, C 1-6 Alkyl (0 to 5 R g (substituted with), C 2-6 Alkenyl (0 to 5 R g (substituted with), C 2-6 Alkynyl (0 to 5 R g substituted with), -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N), -(CH2) n OR f , S(=O) p R f , C(=O)NR f R f , C(=O)OR f , N.R. f C(=O)R f , S(=O) p NR fR f , N.R. f S(=O) p R f , N.R. f C(=O)OR f , OC(=O)NR f R f , or -(CH2) n NR f R f and; R f is H, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; or R f and R f and together with the nitrogen atom to which they are both attached form a heterocyclyl; R g Halo, CN, -OH, C 1-5 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0018] In a sixth aspect within the fifth aspect, the present invention provides a compound of formula (V): [ka] [In formula: R 4a is halo or C 1-2 is alkyl; R 4b is C 1-4 alkyl (substituted with 0-4 halo substituents); R 5 is H or F; R 6 Halo, CN, C 1-4 Alkyl (0 to 3 R 6a (substituted with), C 2-4 Alkenyl (0 to 3 R 6a substituted with -C(=O)OR 6b , C(=O)ONR6b R 6b , C 3-6 Cycloalkyl (0 to 3 R 14 phenyl (substituted with 0 to 3 R 14 substituted with), or 5- to 6-membered heteroaryl (O, S(=O) p , N, and NR 14a and 0 to 3 R 14 ) and R 6a is halo, -OH, C 3-6 cycloalkyl, or phenyl; R 6b is H, C 1-3 alkyl (substituted with 0-1 aryl substituents), or C 3-6 is cycloalkyl; R 7 is H or C 1-2 is alkyl; R 8 Ha-OC 1-4 Alkyl (0-4 halo, -OH, -OC 1-4 substituted with alkyl, or aryl substituents; R 10 is halo or C 1-3 is alkyl; R 11 is C 1-4 Alkyl (0 to 2 R 12 and 0 to 1 R 13 substituted with), -OH, -OC 1-4 Alkyl, -NR a C(=O)R 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)Rb , -S(=O) p R c , -S(=O) p NR a R a , C 3-6 Cycloalkyl, 4- to 9-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 3 R e ) and R 12 Halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-3 halo or OH substituents); R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(=O) p NR a R a , -OC(=O)NR a R a , or -OC(=O)NR a OR b and; R 14 Halo, CN, C 1-4 Alkyl (substituted with 0-3 halo substituents), -OC 1-4 Alkyl (substituted with 0-3 halo substituents), -(CH2) 0-2 -NR a R a , -(CH2) 0-1 -aryl (0 to 3 R e substituted with 0 to 3 R e substituted with -(CH2) 0-1-3 to 9-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14a is H, C(=O)C 1-3 Alkyl, C 1-3 alkyl (substituted with 0-1 aryl substituted with 0-2 halo substituents); R 15 is H, C 1-2 alkyl, or phenyl; R a is H, C 1-4 Alkyl (0 to 5 R e (substituted with), C 2-4 Alkenyl (0 to 5 R e (substituted with), C 2-4 Alkynyl (0 to 5 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e or R a and R a and together with the nitrogen atom to which they are both attached form a 3- to 9-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e (substituted with); R b is H, C 1-4 Alkyl (0 to 5 R e (substituted with), C 2-4 Alkenyl (0 to 5 R e (substituted with), C 2-4 Alkynyl (0 to 5 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R esubstituted with -(CH2) n -3 to 9-membered heterocyclyl (O, S(=O) p and N, and 0 to 5 R e ) and R c is C 1-4 Alkyl (0 to 5 R e (substituted with), C 2-4 Alkenyl (0 to 5 R e (substituted with), C 2-4 Alkynyl (0 to 5 R e (substituted with), C 3-6 Carbocyclyl or 3- to 9-membered heterocyclyl (O, S(=O) p and N) containing 1 to 4 heteroatoms selected from; R e Halo, CN, =O, C 1-6 Alkyl (0 to 5 R g (substituted with), C 2-6 Alkenyl (0 to 5 R g (substituted with), C 2-6 Alkynyl (0 to 5 R g substituted with), -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n - 4- to 6-membered heterocyclyl (O, S(=O) p and N), -(CH2) n OR f , S(=O) p R f , C(=O)NR f R f , C(=O)OR f , N.R. f C(=O)R f , S(=O) p NR f R f , N.R. f S(=O) p R f , N.R. f C(=O)OR f, OC(=O)NR f R f , or -(CH2) n NR f R f and; R f is H, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; or R f and R f and together with the nitrogen atom to which they are both attached form a heterocyclyl; R g Halo, CN, -OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0019] In one embodiment of Formula (V), R 4a is F or CH3; R 4b is CF3; R 6 is phenyl or 5-membered heteroaryl (containing 1 to 2 heteroatoms selected from O and N); R 7 is H;R 8 Ha-OC 1-2 alkyl; R 10 is the halo; R 11 is -CH3, -CH2CH3, -CF3, -OCF3, -NHS(=O)2C 1-2 Alkyl, -C(=O)OH, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl (0 to 1 R e substituted with O, N, and R 15 and 0 to 3 R e substituted with R 15 is H, C 1-2 alkyl, or phenyl; R e is =O or C(=O)OH.

[0020] In a seventh aspect within the sixth aspect, the present invention provides a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein: R 4a is the halo; R 4b is CF3; R 6 C 1-4 Alkyl (substituted with 0-3 halo substituents) or C 3-6 cycloalkyl (substituted with 0-3 halo substituents); R 8 Ga-OC 1-4 is alkyl; R 10 is F; R 11 But -OH, -OC 1-4 Alkyl, -NR a C(=O)R b , -NR a S(=O) p R c , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , 4- to 9-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 5 R e ) and R 15 is H or C 1-2 is alkyl; R a is H or C 1-4 Alkyl (0 to 5 R e (replaced by); Or R a and R a Together [ka] and; Rb is H or C 1-4 Alkyl (0 to 5 R e ) and R c C 1-3 Alkyl (0 to 5 R e ) or C 3-6 is a carbocyclyl; R e But, halo, =O, C 1-4 Alkyl (0 to 5 R g substituted with), C(=O)OH, -OR f , or -NR f R f and; R f is H or C 1-6 alkyl; or R f and R f and together with the nitrogen atom to which they are both attached form a heterocyclyl; and R g is the halo, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0021] In an eighth aspect within the sixth aspect, the present invention provides a compound of formula (VI): [ka] [In formula: R 4a is a halo; R 4b is CF3; R 6 is C 1-4 Alkyl (substituted with 0-3 halo substituents) or C 3-6 cycloalkyl (substituted with 0-3 halo substituents); R 7 is H; R 8 Ha-OC 1-4 alkyl (substituted with 0-1 aryl substituents); R 10 is a halo; R 12-C(=O)OH, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl, -C(=O)NHOC 1-3 Alkyl, or C 1-3 alkyl (substituted with 0-3 halo substituents); R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(=O) p NR a R a , -OC(=O)NR a R a , or -OC(=O)NR a OR b and; R a is H, C 1-4 alkyl (substituted with 0-5 halo substituents), phenyl (substituted with 0-4 R e (substituted with), C 3-10 Cycloalkyl (0 to 4 R e substituted with 0 to 4 R e substituted with), or 3- to 9-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e or R a and R a and together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e (substituted with); R b is H, C 1-4 Alkyl (0 to 5 R e substituted with), -(CH2)n -phenyl (0 to 4 R e (substituted with), C 3-6 Cycloalkyl (substituted with 0-4 halo substituents), or 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e ) and R c is C 1-4 Alkyl (0 to 4 R e ) and R e Halo, CN, =O, C 1-5 Alkyl (0 to 5 R g (substituted with), C 3-6 Cycloalkyl, aryl, 4- to 6-membered heterocyclyl (O, S(=O) p and N), or -OR f and; R f is H, C 1-4 Alkyl, C 3-6 cycloalkyl, or aryl; R g is a halo; n is 0 or 1; p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0022] In a ninth aspect within the eighth aspect, the present invention provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein: R 4a is F; R 4b is CF3; R 6 is CF3 or C 3-6 is cycloalkyl; R 8 is -OCH3 or -OCH2-phenyl; R 10 is F; R 12-C(=O)OH, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl, -C(=O)NHOC 1-4 alkyl, CH3, CHF2, or CF3; R 13 -OH, -NR a R a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl, -OC(=O)NR a R a , or -OC(=O)NHOC 1-4 is alkyl; R a But H, C 1-4 alkyl (substituted with 0 to 4 F substituents); [ka] or R a and R a Together [ka] and; R b But H, C 1-4 Alkyl (0 to 5 R e substituted with), phenyl, or [ka] and; R e halo, ═O, aryl, 4- to 6-membered heterocyclyl (O, S(═O) p and N), or -OR f and; R f But H, C 1-3 Alkyl, C 3-6 cycloalkyl, or phenyl; The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0023] In a tenth aspect within the third aspect, the present invention provides a compound of formula (VII): [ka] [In formula: R 4a is a halo; R 4b is C 1-4 alkyl (substituted with 0-3 halo substituents), or -OC 1-4 alkyl (substituted with 0-3 halo substituents); R 5 is H or F; R 6 Halo, CN, C 1-6 Alkyl (0 to 3 R 6a (substituted with), C 2-6 Alkenyl (0 to 3 R 6a (substituted with), C 2-6 Alkynyl (0 to 3 R 6a (substituted with), C 3-6 Cycloalkyl (0 to 3 R 14 (substituted with), C 3-6 Cycloalkenyl (0 to 3 R 14 phenyl (substituted with 0 to 3 R 14 substituted with), or 5- to 6-membered heteroaryl (O, S(=O) p , N, and NR 14a and 0 to 3 R 14 ) and R 6a Ha, Halo, C 3-6 cycloalkyl, or phenyl; R 7 is H or C 1-2 is alkyl; R 8 is halo, CN, or -OC 1-4 Alkyl (0-4 halo, -OH, or -OC) 1-4 substituted with alkyl substituents; R 8a is halo or CN; R9 is a 3- to 12-membered heterocyclyl (O, S(=O) p , N, and NR 11a and 0 to 3 R 10 and 0 to 1 R 11 ) and R 10 ,Haro,CN,C 1-3 Alkyl, =O, -OH, or -OC 1-3 is alkyl; R 11 is C 1-3 Alkyl (0 to 1 R 12 and 0 to 1 R 13 (replaced with), -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 , C 3-6 Cycloalkyl (0 to 5 R e substituted with), 4- to 6-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 4 R e ) and R 11a is H, C 1-4 Alkyl (0 to 2 R11b substituted with -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 4 R e ) and R 11b is —OH, —C(═O)OH, or aryl; R 12 is -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-3 halo or OH substituents); R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(=O) p NR a R a , -OC(=O)NR a R a , -S(=O) p NR a R a , or -S(=O) p R c and; R 14 Halo, CN, C 1-4 Alkyl (substituted with 0-3 halo), -OC 1-4 Alkyl (substituted with 0-3 halo), -(CH2) 0-2 -NR a R a , -(CH2) 0-2 -aryl (0 to 3 Re substituted with 0 to 3 R e substituted with -(CH2) 0-2 -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14a is H, C(=O)C 1-3 Alkyl, or C 1-3 alkyl (substituted with 0-2 aryl substituted with 0-2 halo substituents); R 15 is H, C 1-2 alkyl, or phenyl; R a is H, C 1-5 Alkyl (0 to 4 R e (substituted with), C 2-5 Alkenyl (0 to 4 R e (substituted with), C 2-5 Alkynyl (0 to 4 R e substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 4 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e or R a and R a and together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e (substituted with); R b is H, C 1-5 Alkyl (0 to 4 R e (substituted with), C 2-5 Alkenyl (0 to 4 R e (substituted with), C 2-5 Alkynyl (0 to 4 Re substituted with), -(CH2) n -C 3-10 Carbocyclyl (0 to 4 R e substituted with -(CH2) n -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e ) and R c is C 1-5 Alkyl (0 to 4 R e (substituted with), C 2-5 Alkenyl (0 to 4 R e (substituted with), C 2-5 Alkynyl (0 to 4 R e (substituted with), C 3-6 Carbocyclyl or 3- to 12-membered heterocyclyl (O, S(=O) p and N) containing 1 to 4 heteroatoms selected from; R e Halo, CN, =O, C 1-6 Alkyl (0 to 4 R g (substituted with), C 2-6 Alkenyl (0 to 5 R g (substituted with), C 2-6 Alkynyl (0 to 5 R g substituted with), -(CH2) n -C 3-6 Cycloalkyl (0 to 4 R g substituted with), -(CH2) n -aryl (0 to 4 R g substituted with), -(CH2) n - 4- to 6-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R g substituted with), -(CH2) n OR f , C(=O)OR f , C(=O)NR f R f , N.R. f C(=O)R f , S(=O)p R f , N.R. f S(=O) p R f , N.R. f C(=O)OR f , OC(=O)NR f R f , or -(CH2) n NR f R f and; R f is H, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; R g Halo, CN, -OH, C 1-4 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0024] In an eleventh aspect within the tenth aspect, the present invention provides a compound of formula (VII): 1. A compound or a pharmaceutically acceptable salt thereof, wherein: R 4a is the halo; R 4b C 1-4 alkyl (substituted with 0-3 halo substituents); R 5 is H; R 6 C 1-2 Alkyl (substituted with 0-2 F substituents) or C 3-6 is cycloalkyl; R 8 Ga-OC 1-3 is alkyl; R 8a is F or CN; R 9 but [ka] and; R 10 But, Halo, CN, C 1-2 Alkyl, =O, -OH, or -OC 1-2 is alkyl; R 11 But C 1-3 Alkyl (0 to 1 R 12 and 0 to 1 R 13 (replaced with), -OR b , -NR a R a , -NR a C(=O)R b , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , or C 3-6 Cycloalkyl (0 to 5 R e ) and R 11a But H, -C(=O)R b , -C(=O)NR a R a , or C 1-4 Alkyl (0 to 1 R 11b ) and R 11b is —OH or aryl; R 12 But -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-2 halo or -OH substituents); R 13 But -OH, -OC 1-4 Alkyl (substituted with 0-2 -OH substituents), or -S(=O)2C 1-4 is alkyl; R a is H or C 1-6 alkyl or R a and R a and together with the nitrogen atom to which they are both attached form a 3- to 9-membered heterocyclyl (0 to 4 R e (substituted with); R b But H, C 1-4 Alkyl (0 to 1 R e ) or C 3-6 Cycloalkyl (0 to 1 R e ) and R e -OR f and; R f is H or C 1-4 is alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0025] In a twelfth aspect within the eleventh aspect, the present invention provides a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein: R 4a is the halo; R 4b is CF3; R 5 is H; R 6 is CF3 or C 3-6 is cyclopropyl; R 8 Ga-OC 1-3 is alkyl; R 9 but [ka] and; R 10 But C 1-2 Alkyl, -OH, or -OC 1-4 is alkyl; R 11 But C 1-2 Alkyl (0 to 1 R 12 and 0 to 1 R 13 substituted with -C(=O)OR b , or -C(=O)NR a R a and; R 12 -C(=O)OR b and; R13 is -OH; R a is H or C 1-4 is alkyl; R b is H or C 1-4 is alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0026] In a thirteenth aspect within the tenth aspect, the present invention provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein: R 4a is the halo; R 4b C 1-4 alkyl (substituted with 0-3 halo substituents); R 5 is H; R 6 C 1-3 Alkyl (substituted with 0-3 F substituents) or C 3-6 is cycloalkyl; R 8 Ga-OC 1-3 is alkyl; R 9 but [ka] and; R 10 But, Halo, C 1-3 Alkyl, -OH, or -OC 1-3 is alkyl; R 11 But C 1-3 Alkyl (0 to 1 R 12 and 0 to 1 R 13 substituted with) or -C(=O)NH2; R 11a But H, C 1-4 Alkyl (0 to 2 R 11b substituted with -C(=O)OC 1-4 is alkyl; R 11b is —OH, —C(═O)OH, or aryl; R 12 But C(=O)OR b or C 1-3 alkyl (substituted with 0-3 halo substituents); R 13 is -OH; R b is H or C 1-4 is alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment of Formula (VII), R 4a is F;R 4b is CF3; R 5 is H;R 6 is C 1-4 Alkyl (substituted with 0-3 F substituents) or C 3-6 is cycloalkyl; R 8 is -OCH3 or -OCH3(CH2)2OCH3; R 9 teeth [ka] and; R 11 is C 1-2 Alkyl (0 to 1 R 13 ) and R 11a is H, C 1-3 Alkyl (0 to 2 R 11b substituted with -C(=O)C 1-4 Alkyl (0 to 1 R 11b substituted with -C(=O)OC 1-4 alkyl; R 11b is —OH, —C(═O)OH, or aryl; R 13 is -OH.

[0028] In one embodiment of Formula (VII), R 4a is F;R 4b is CF3; R 5 is H;R 6 is C1-3 Alkyl (substituted with 0-3 F substituents) or C 3-6 is cycloalkyl; R 8 is -OCH3; R 9 teeth [ka] and; R 11a is H or C 1-2 Alkyl (0 to 1 R 11b substituted with R 11b is -C(=O)OH.

[0029] In a fourteenth aspect within the third aspect, the present invention provides a compound of formula (VIII): [ka] [In formula: R 4a is a halo; R 4b is C 1-4 alkyl (substituted with 0-4 halo substituents); R 6 is C 1-2 Alkyl (substituted with 0-2 F substituents), C 3-6 cycloalkyl, or aryl; R 7 is H; R 8 Ha-OC 1-3 is alkyl; R 9 teeth [ka] and; R 10 Halo, CN, C 1-4 Alkyl, =O, -OH, or -OC 1-4 is alkyl; R 11 is C 1-2 Alkyl (0 to 1 R 12 and 0 to 1 R 13 substituted with -NRa R a , -NR a C(=O)R b , -NR a C(=O)OR b , or -C(=O)OR b and; R 12 is -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-3 halo or OH substituents); R 13 is -OH or -NR a C(=O)R b and; R a is H or C 1-4 is alkyl; R b is H, C 1-4 Alkyl, or 3- to 9-membered heterocyclyl (O, S(=O) p and N). or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment of Formula (VIII), R 4a is F;R 4b is CF3; R 5 is H;R 6 is CF3 or cyclopropyl; R 8 is -OCH3; R 9 teeth [ka] is.

[0031] In a fifteenth aspect within the first aspect, the present invention provides a compound of formula (IX): [ka] [In formula: R 3 is C1-6 Alkyl, CF3, -(CR d R d ) 0-1 -C 3-6 Cycloalkyl (0 to 4 R 4 phenyl (substituted with 0 to 4 R 4 ) and R 4 is halo, CN, CH3, or CF3; R 5 is H; R 6 is C 1-5 Alkyl, CF3, or C 3-6 cycloalkyl (substituted with 0-2 F substituents); R 7 is H; R 8 is halo, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl (0 to 1 -OC) 1-4 substituted with alkyl substituents; R 9 teeth [ka] and; R 10 Ha, Halo, C 1-4 Alkyl, -OH, or -OC 1-4 is alkyl; R 11 is C 1-4 Alkyl (0 to 2 R 12 and 0 to 2 R 13 substituted with -C(=O)OR b , -C(=O)NR a R a , or C 3-6 Cycloalkyl (0 to 2 R e ) and R 11a is H, C 1-4 Alkyl (0 to 2 R 11b substituted with -C(=O)R b , or -C(=O)OC 1-4is alkyl; R 11b is -OH; R 12 is C 1-3 Alkyl (substituted with 0-3 halo substituents) or -C(=O)OR b and; R 13 is -OH; R a is H or C 1-3 is alkyl; R b is H or C 1-4 Alkyl (0 to 1 R e ) and R e HA-OR f and; R f is H or C 1-6 alkyl] or a pharmaceutically acceptable salt thereof.

[0032] In a sixteenth aspect within the first aspect, the present invention provides a compound of formula (X): [ka] [In formula: R 1 is C 1-2 Alkyl (C 3-6 cycloalkyl-substituted); R 2 Is H; Or R 1 and R 2 Together, these two make CR 6 R 7 Next; R 3 is C 1-6 Alkyl (0-5 halo, CN, or -OC) 1-3 substituted with alkyl substituents), -(CHR d ) n -C 3-10 Carbocyclyl (0 to 5 R 4 substituted with), or 5- to 6-membered heteroaryl (O, S(=O)p , N, and 0 to 3 R 4 ) and R 4 is halo, CN, S(=O)2CF3, or C 1-4 alkyl (substituted with 0-5 halo substituents); R 6 Ha, Halo, C 1-5 Alkyl (0 to 3 R 6a (substituted with), C 3-6 Cycloalkyl (0 to 3 R 14 substituted with), or 5- or 6-membered heterocyclyl (containing 1-3 heteroatoms selected from O, S, and N and 0-3 R 14 ) and R 6a is halo, -OH, or C 3-6 is cycloalkyl; R 7 is H; R 8 H, halo, CN, C 1-4 Alkyl, or -OC 1-4 Alkyl (0-5 halo, -OH, C 3-6 Cycloalkyl, or -OC 1-4 substituted with alkyl substituents; R 9 teeth [ka] and; R 10 Halo, CN, C 1-4 alkyl, or -OH; R 11 is C 1-3 Alkyl (0 to 3 R 12 and 0 to 1 R 13 (replaced with), -OR b , -NHC(=O)R b , or C(=O)OR b and; R 12 is a halo; R 13 HA-ORb or C 3-6 is a carbocyclyl; R 14 is halo, CN, or C 1-4 alkyl (substituted with 0-3 halo substituents); R b is H or C 1-3 Alkyl (0 to 5 R e ) and R d is H or C 1-4 is alkyl; R e is -OH; n is 0 or 1] or a pharmaceutically acceptable salt thereof.

[0033] In a seventeenth aspect within the first aspect, the present invention provides a compound of formula (XI): [ka] [In formula: R 3 is C 1-5 Alkyl, [ka] and; R 4 is halo, CN, -S(=O)2CF3, or C 1-4 alkyl (substituted with 0-5 halo substituents); R 6 is C 1-5 Alkyl (0 to 4 R 6a (substituted with), C 3-6 Cycloalkyl (0 to 2 R 14 substituted with 0-2 R 14 ) and R 6a is halo, -OH, or C 3-6 is cycloalkyl; R 7is H; R 8 Ha-OC 1-3 Alkyl (0-5 halo, -OH, C 3-6 Cycloalkyl, or -OC 1-3 substituted with alkyl substituents; R 8a is H, halo, CN, or C 1-3 is alkyl; R 9 teeth [ka] and; R 10 Halo, CN, C 1-4 alkyl, or -OH; R 11 is C 1-3 Alkyl (0 to 3 R 12 and 0 to 1 R 13 (replaced with), -OR b , -NHC(=O)R b , or -C(=O)OR b and; R 12 is a halo; R 13 HA-OR b or C 3-6 is a carbocyclyl; R 14 is halo or C 1-4 alkyl (substituted with 0-3 halo substituents); R b is H or C 1-3 Alkyl (0 to 5 R e ) and R d is H or C 1-2 is alkyl; n is 0 or 1] or a pharmaceutically acceptable salt thereof.

[0034] In compounds of formula (I), R 1 , R 2 , R 3 , R4 (R 4a , R 4b ), R 4c , R 5 , R 6 , R 6a , R 6b , R 7 , R 8 (R 8a ), R 9 , R 10 , R 11 , R 11a , R 11b , R 12 , R 13 , R 14 , R 14a , R 15 , R a , R b , R c , R d , R e , R f , and R g The exemplary ranges for any variable substituent, including R, can be used independently of the exemplary ranges for any other variable substituent. Thus, the present invention encompasses combinations of different embodiments. In particular, R 4a and R 4b is the variable group R 4 is a subset of R 8a is the variable group R 8 is a subset of .

[0035] In one embodiment of formula (XI), R 3 teeth [ka] and;R 4 is halo, CF3, or -OCF3; R 6 is C 3-6 Cycloalkyl or C 1-3 Alkyl (0 to 3 R 6a substituted with R 6a is the halo; R 7 is H;R 8 Ha-OC 1-3 alkyl (substituted with 0-1 CF3 or -OCH3 substituents); R 9 teeth [ka] and;R 10 is C 1-4 alkyl or -OH; R 11 is C 1-3 Alkyl (0 to 3 R 12 and 0 to 1 R 13 substituted with R 12 is a halo;R 13 is -OH.

[0036] In another embodiment of formula (XI), R 3 teeth [ka] and;R 4 is halo or C 1-2 alkyl (substituted with 0 to 3 halo substituents); R d is C 1-2 alkyl; R 6 teeth [ka] C 3-6 Cycloalkyl (0 to 3 R 6a ) or C 1-3 Alkyl (0 to 3 R 6a substituted with R 6a is halo or -OH; R 14 is C 1-2 alkyl (substituted with 0 to 3 halo substituents); R 7 is H;R 8 Ha-OC 1-2 Alkyl (0-1 C 3-6 substituted with cycloalkyl substituents; R 8a is H or halo; R 9 teeth [ka] and;R 10 is C 1-4alkyl or -OH; R 11 is C 1-3 Alkyl (0 to 3 R 12 and 0 to 1 R 13 substituted with R 12 is a halo;R 13 is -OH.

[0037] In one embodiment of formula (IX), R 3 is C 1-4 alkyl; R 6 is CF3 or cyclopropyl; R 7 is H;R 8 Ha-OC 1-2 alkyl; R 9 teeth [ka] and;R 10 is -OH or -OC 1-4 alkyl; R 11 is C 1-2 Alkyl (0 to 2 R 12 and 0 to 2 R 13 substituted with R 12 is C 1-3 Alkyl (substituted with 0-3 halo) or -C(=O)OR b And;R 13 is -OH.

[0038] In another embodiment of formula (IX), R 3 is cyclopentyl (0 to 1 R 4 substituted with R 4 is CN or C 1-2 alkyl; R 6 is CF3 or cyclopropyl; R 7 is H;R 8 Ha-OC 1-2 alkyl; R 9 teeth [ka] and;R 10 is -OH or -OC1-4 alkyl; R 11 is C 1-2 Alkyl (0 to 2 R 12 and 0 to 2 R 13 substituted with R 12 is C 1-3 Alkyl (substituted with 0-3 halo substituents) or -C(=O)OR b And;R 13 is -OH.

[0039] In another embodiment of formula (IX), R 3 is phenyl (0 to 2 R 4 substituted with R 4 is halo or CF3; R 6 is CF3 or cyclopropyl; R 7 is H;R 8 Ha-OC 1-2 alkyl; R 9 teeth [ka] and;R 11a is H, C 1-2 Alkyl (0 to 2 R 11b substituted with R 11b is -OH.

[0040] In another embodiment of formula (I), R 1 and R 2 together with the carbon atom to which they are both attached to form dioxolanyl. In another embodiment of formula (I), R 1 and R 2 The numbers combine to form =NOC 1-4 alkyl, where "=" is a double bond. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 where "=" is a double bond.

[0041] In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 and R 7 are both methyl. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is methyl, ethyl, propyl, or butyl, each of which is optionally substituted with —OH or halo; R 7 is H. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is CF3; R 7 is H. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is a halo;R 7 is H.

[0042] In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is phenyl (0 to 1 R 14 substituted with R 7 is H;R 14 Halo, -OC 1-4 alkyl, or phenyl. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6is a 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from O and N; R 7 is H. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is C(=O)NH-phenyl; R 7 is H. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is C(=O)OC 1-4 alkyl; R 7 is H.

[0043] In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is C(=O)N(Me)2; R 7 is H. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 is C 3-6 Cycloalkyl; R 7 is H. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 -CH2-C 3-6 Cycloalkyl (substituted with halo); R 7 is H.

[0044] In another embodiment of formula (I), R 1 and R 2are combined, =CR 6 R 7 Next;R 6 is cyclopropyl; R 7 is H. In another embodiment of formula (I), R 1 and R 2 are combined, =CR 6 R 7 Next;R 6 and R 7 together with the carbon atom to which they are both attached form a cyclopentadienyl, indanyl, or indenyl. In one embodiment of formula (I), R 3 is C 1-6 Alkyl (0 to 2 R 4 (which is replaced by ). In another embodiment of formula (I), R 3 is methyl, ethyl, propyl, or butyl, or pentyl.

[0045] In another embodiment of formula (I), R 3 teeth [ka] is. In another embodiment of formula (I), R 3 is C 3-6 Cycloalkyl (0 to 2 R 4 (which is replaced by ). In another embodiment of formula (I), R 3 is C 3-6 Cycloalkenyl (0 to 2 R 4 (which is replaced by ).

[0046] In another embodiment of formula (I), R 3 teeth [ka] is. In another embodiment of formula (I), R 3 teeth [ka] is. In another embodiment of formula (I), R 3 teeth [ka] is.

[0047] In another embodiment of formula (I), R 3 Ha-(CR d R d ) 1-2 -phenyl (0 to 2 R 4 substituted with R 4 is halo, CF3 or OCF3; R d is H or methyl. In another embodiment of formula (I), R 3 Ha-(CHR d )-C 3-6 Cycloalkyl (0 to 2 R 4 substituted with R 4 is halo or C 1-2 alkyl; R d is H or C 1-2 It is alkyl. In another embodiment of formula (I), R 3 teeth [ka] And;R 4 is halo or C 1-3 It is alkyl.

[0048] In another embodiment of formula (I), R 3 teeth [ka] And;R 4 is C 1-2 It is alkyl. In another embodiment of formula (I), R 3 teeth [ka] And;R 4 is halo or CN.

[0049] In another embodiment of formula (I), R 3 Ha-(CR d R d ) 1-2 - 5-membered heterocyclyl (containing 1 to 2 heteroatoms selected from O and N); R d is H or methyl. In another embodiment of formula (I), R 4 Halo, CN, C 1-2 alkyl (substituted with 0-3 halo); In another embodiment of formula (I), R 3 is cyclopropyl, cyclobutyl, cyclopentyl (0 to 1 R 4 substituted with), or cyclohexyl; R 4 is CN or C 1-2 It is alkyl. In another embodiment of formula (I), R 5 is H, halo, or -OH.

[0050] In another embodiment of formula (I), R 5 is H or -OH. In another embodiment of formula (I), R 6 is C 1-4 Alkyl (0 to 3 R 6a ) or C 3-6 Cycloalkyl (0 to 3 R 14 substituted with), or 5- or 6-membered heterocyclyl (O, S, N, and NR 14a and 0 to 3 R 14 substituted with R 6a is halo, -OH, or C 3-6 cycloalkyl (substituted with 0 to 3 halo substituents); R 14 is halo or C 1-3alkyl (substituted with 0-3 halo substituents);

[0051] In another embodiment of formula (I), R 6 is C 3-6 Cycloalkyl (0 to 3 R 14 substituted with R 14 is a halo substituent. In another embodiment of formula (I), R 6 is isopropyl. In another embodiment of formula (I), R 7 is H or C 1-2 It is alkyl. In another embodiment of formula (I), two R 8 There is a variable group. R 8 One of them is -OC 1-3 The other R is alkyl. 8 is sometimes R 8a It is called halo or CN.

[0052] In another embodiment of formula (I), R 9 is phenyl (0 to 3 R 10 and 0 to 2 R 11 (which is replaced by ). In another embodiment of formula (I), R 9 is phenyl (0 to 3 R 10 and 0 to 2 R 11 substituted with R 10 is the halo; R 11 is C 1-5 Alkyl (0 to 4 R 12 and 0 to 2 R 13 substituted with R 12 is halo or C(=O)OH; R 13 -OC(=O)NHR a and;R a is C 1-4 Alkyl, C 3-6 alkyl, or phenyl. In another embodiment of formula (I), R 9 is phenyl (0 to 3 R 10and 0 to 2 R 11 substituted with R 10 is the halo; R 11 is C 1-5 Alkyl (0 to 4 R 12 and 0 to 2 R 13 substituted with R 12 is halo or C(=O)OH; R 13 is -NHC(=O)R b and;R b is a 3- to 6-membered heterocyclyl (containing 1 to 3 heteroatoms selected from O, S, and N).

[0053] In another embodiment of formula (I), R 9 is phenyl (0 to 1 R 10 and 0 to 1 R 11 substituted with R 10 is the halo; R 11 is a 4- to 9-membered heterocyclyl (O, S(=O) p , N, and NR 15 and 0 to 3 R e substituted with R e -COOH or C 1-3 Alkyl (0 to 5 R g substituted with R g is -OH. In another embodiment of formula (I), R 9 is a 3- to 12-membered heterocyclyl (O, S(=O) p , N, and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 (which is replaced by ).

[0054] In another embodiment of formula (I), R 9 teeth [ka] and;R 10 is C 1-2 alkyl; R11 is C 1-3 alkyl (substituted with -OH substituents); R 11a is -C(=O)C 1-4 Alkyl (0 to 1 R 11b substituted with R 11b is -OH.

[0055] In another aspect, the present invention provides a compound of formula (IIIa): [ka] [In formula: R 4a is a halo; R 4b is C 1-4 alkyl (substituted with 0-4 halo substituents); R 6 Ha, Halo, C 1-4 Alkyl (0 to 3 R 6a (substituted with), C 2-4 Alkenyl (substituted with 0-1 phenyl or -OH), -C(=O)OR b , C(=O)NHR a , C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl (0 to 3 R 14 phenyl (substituted with 0 to 3 R 14 substituted with), naphthyl, or 5- or 6-membered heterocyclyl (O, S, N, and NR 14a and 0 to 3 R 14 ) and R 6a is halo, -OH, C 3-6 cycloalkyl, or phenyl; R 7 Is H; Or R 6 and R 7 together with the carbon atom to which they are attached form cyclopentadienyl, indanyl, or indenyl; R 14 Halo, CN, C 1-4Alkyl (substituted with 0-3 halo substituents), -OC 1-4 Alkyl (substituted with 0-3 halo substituents), -(CH2) 0-2 -NR a R a , -(CH2) 0-2 -aryl (0 to 3 R e substituted with 0 to 3 R e substituted with -(CH2) 0-2 -3 to 12-membered heterocyclyl (O, S(=O) p and N, and 0 to 3 R e ) and R 14a is H or C 1-3 is alkyl; R a is H or C 1-3 is alkyl; R b is H or C 1-3 is alkyl; p is 0 or 2] or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment of Formula (V), R 4a is F or CH3; R 4b is CF3; R 6 is phenyl or 5-membered heteroaryl (containing 1 to 2 heteroatoms selected from O and N); R 7 is H;R 8 Ha-OC 1-2 alkyl; R 10 is the halo; R 11 is -NHS(=O)2C 1-2 Alkyl, -C(=O)OH, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl (0 to 1 R e substituted with O, N, and R 15 and 0 to 3 R esubstituted with R 15 is H, C 1-2 alkyl, or phenyl; R e is =O or C(=O)OH.

[0057] In another aspect, the present invention provides a compound of formula (VIb): [ka] [In formula: R 4a is a halo; R 4b is CF3; R 8 Ha-OC 1-4 is alkyl; R 10 is a halo; R 12 -C(=O)OH, -C(=O)OC 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl, -C(=O)NHOC 1-3 Alkyl, or C 1-3 alkyl (substituted with 0-3 halo); R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(=O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , or -S(=O) p R c and; R a is H, C1-6 Alkyl (substituted with 0 to 5 halo substituents), phenyl, C 3-6 Cycloalkyl (0 to 4 R e substituted with 0 to 4 R e or R a and R a and together with the nitrogen atom to which they are both attached form a heterocyclyl (0 to 4 R e (substituted with); R b is H, C 1-6 Alkyl (0 to 5 R e substituted with), -(CH2) n -phenyl, C 3-6 Cycloalkyl (substituted with 0-4 halo substituents), or 3- to 9-membered heterocyclyl (O, S(=O) p and N, and 0 to 4 R e ) and R c is C 1-6 Alkyl (0 to 4 R e ) and R e Halo, CN, =O, C 1-5 Alkyl (0 to 5 R g (substituted with), C 3-6 cycloalkyl, aryl, 4- to 6-membered heterocyclyl, or -OR f and; R f is H, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; R g is a halo; n is 0 or 1; p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0058] In another embodiment, the present invention provides a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein: R 4a is F; R 4b is CF3; R 5 is H; R 6 C 1-3 Alkyl (substituted with 0-3 F substituents) or C 3-6 is cycloalkyl; R 8 is -OCH3; R 9 but [ka] and; R 11a But H, C 1-3 Alkyl (0 to 2 R 11b substituted with -C(=O)C 1-4 Alkyl (0 to 1 R 11b substituted with -C(=O)OC 1-4 is alkyl; R 11b is -OH, -C(=O)OH, or aryl; or a pharmaceutically acceptable salt thereof.

[0059] Unless otherwise specified, 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, "C1-C 10 Alkyl" or "C 1-10 "Alkyl" (or alkylene) is a group consisting of C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10Alkyl groups are intended to include alkyl groups. Additionally, for example, "C1-C6 alkyl" or "C1-C6 alkyl" refers to an alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted such that at least one hydrogen has been replaced with another chemical group. Exemplary 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, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to indicate a direct bond. "Alkyl" also includes deuterated alkyls such as CD3.

[0060] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either a straight or branched configuration having one or more, preferably one to three, carbon-carbon double bonds, which may occur at any stable point along the chain. For example, "C2-C6 alkenyl" or "C 2-6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups, such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl. "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either a straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds, which may occur at any stable point along the chain. For example, "C2-C6 alkynyl" or "C 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0061] "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 noted 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 connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. Note that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the 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.

[0062] "Cycloalkyl" is intended to mean a cyclized alkyl group, including monocyclic, bicyclic, or polycyclic ring systems. "C3-C7 cycloalkyl" or "C 3-7"Cycloalkyl" is intended to include C, C, C, C, and C cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyls include 1-decalinyl, norbornyl, and adamantyl.

[0063] "Cycloalkenyl" is intended to mean a monocyclic or polycyclic ring system containing one or more double bonds in at least one ring; provided that if there are more than one double bond, they cannot form a completely delocalized π-electron system throughout the ring (if they could, the group would be an "aryl" as defined herein). "C3-C7 cycloalkenyl" or "C 3-7 "Cycloalkenyl" is intended to include C3, C4, C5, C6, and C7 cycloalkenyl groups.

[0064] "Spirocycloalkyl" means a hydrocarbon bicyclic ring system in which both rings are connected through a single atom. The rings can be of different sizes and nature or of the same size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.

[0065] "Bicyclic carbocyclyl" or "bicyclic carbocyclic group" refers to a stable 9- or 10-membered carbocyclic ring system containing two fused rings and composed of carbon atoms. One of the two fused rings is a benzo ring fused to another ring, which is a 5- or 6-membered carbocyclic ring that is saturated, partially unsaturated, or unsaturated. A bicyclic carbocyclic group may be attached to its pendant group at any carbon atom that results in a stable structure. The bicyclic carbocyclic groups described herein may be substituted on any carbon, provided the resulting compound is stable. Examples of bicyclic carbocyclic groups include, but are not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0066] An "aryl" group refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and are described, for example, in Lewis, RJ (ed.), Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). "Benzyl" means a methyl group in which one of the hydrogen atoms is replaced by a phenyl group, wherein the phenyl group is optionally substituted with 1 to 5 groups, preferably 1 to 3 groups.

[0067] "Heterocycle," "heterocyclyl," or "heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered mono- or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and is intended to include any polycyclic group in which any of the above heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., [ka] and S(O) pwhere p is 0, 1, or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R, as defined, is H or another substituent). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in a heterocyclyl can optionally be quaternized. When the total number of S and O atoms in a heterocyclyl exceeds 1, then it is preferred that these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in a heterocyclyl is at most 1. Bridged rings are also included in the definition of heterocyclyl. When the term "heterocyclyl" is used, it is intended to include heteroaryl.

[0068] Examples of heterocyclyl include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetra ... tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl yl, 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, phteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl Pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,Heterocyclyls include 3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienoxazolyl, 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 the above heterocyclyls.

[0069] A "bicyclic heterocycle," "bicyclic heterocyclyl," or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system containing two fused rings and consisting of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. One of the two fused rings is a 5- or 6-membered monocyclic aromatic ring consisting of 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 saturated, partially unsaturated, or unsaturated 5- or 6-membered polycyclic ring consisting of a 5-membered heterocyclyl, a 6-membered heterocyclyl, or a carbocyclyl (provided that when the second ring is carbocyclyl, the first ring is a ring other than benzo).

[0070] Bicyclic heterocyclic groups can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure.The bicyclic heterocyclic groups described herein can be substituted on carbon or nitrogen atoms as long as the resulting compound is stable.If the total number of S and O atoms in the heterocyclyl exceeds 1, then it is preferred that these heteroatoms are not adjacent to each other.It is preferred that the total number of S and O atoms in the heterocyclyl is at most 1.

[0071] Examples of bicyclic heterocyclic groups include, but are not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-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.

[0072] "Heteroaryl" refers to stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups may be substituted or unsubstituted. Nitrogen atoms may be substituted or unsubstituted (i.e., N or NR, where R, as defined, is H or another substituent). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., [ka] and S(O) p where p is 0, 1, or 2).

[0073] As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a group other than hydrogen, provided that normal valence is maintained and the substitution results in a stable compound. When a substituent is keto (i.e., =0), then two hydrogens on the atom are replaced. Keto substituents are not present in aromatic moieties. When a ring system (e.g., a carbocyclic or heterocyclic ring system) is substituted with a carbonyl group or double bond, the carbonyl group or double bond is intended to be part of the ring (i.e., within the ring). As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0074] Where there are nitrogen atoms (e.g., amines) on the compounds of the invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the invention. Thus, a depicted and claimed nitrogen atom is a substituted or unsubstituted nitrogen atom, and its N-oxide is a substituted or unsubstituted nitrogen atom. [ka] It is believed that this applies to both the hydroxyl group and its derivatives.

[0075] 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 to 3 R groups, then that group may be optionally substituted with up to three R groups, where R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0076] When a bond to a substituent is shown across 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 to which such substituent is attached to the remainder of the compound of a given formula, then such substituent may be bonded through any atom of such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0077] The present invention encompasses all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are salts in which the counterion does not significantly contribute to the physiological activity or toxicity of the compound and, as such, acts as a pharmaceutical equivalent. These salts can be prepared using common organic techniques and commercially available reagents. Some anionic salt forms include acetate, acystolate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, vanzatin, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0078] Throughout the specification and appended claims, a given chemical formula or name encompasses all such stereoisomers and optical isomers, as well as racemates, where isomers exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present 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 non-superimposable. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The terms "racemate" or "racemic mixture" refer to a composition consisting of equimolar amounts of two enantiomeric species, wherein the composition lacks optical activity.

[0079] The present invention encompasses all tautomers, atropisomers and rotamers of the compounds. The term "counterion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate. All processes used to prepare compounds of the present invention and intermediates made along the way are considered to be part of the present invention. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" are used herein to indicate atomic configuration relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0080] 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 the state of being enantiomerically pure. The term "optically active" refers to the angle by which a homochiral molecule or a non-racemic mixture of chiral molecules rotates the plane of polarized light.

[0081] The present invention is intended to encompass all isotopes of atoms present in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of example, and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon are 13 C and 14 Isotopically labeled compounds of the present invention may generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, substituting an appropriately isotopically labeled reagent for an unlabeled reagent otherwise utilized. Such compounds may have a variety of potential uses, for example, as probes or reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to advantageously modify biological, pharmacological, or pharmacokinetic properties.

[0082] biological methods RXFP1 cyclic adenosine monophosphate (cAMP) assay Human embryonic kidney 293 (HEK293) cells and HEK293 cells stably expressing human RXFP1 were cultured in MEM medium supplemented with 10% qualified FBS and 300 μg / ml hygromycin (Life Technologies). Cells were dissociated and suspended in assay buffer, which consisted of HBSS buffer (containing calcium and magnesium) containing 20 mM HEPES, 0.05% BSA, and 0.5 mM IBMX. Cells (3,000 cells per well, except for HEK293 cells stably expressing human RXFP1, which were 1,500 cells per well) were added to 384-well Proxiplates (Perkin-Elmer). Cells were immediately treated with test compounds in DMSO (2% final) at final concentrations ranging from 0.010 nM to 50 μM. Cells were incubated at room temperature for 30 minutes. Intracellular cAMP levels were measured using the HTRF HiRange cAMP Assay Reagent Kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and d2 fluorescently labeled cAMP were prepared separately in the supplied lysis buffer. After the reaction was completed, cells were lysed with equal volumes of d2-cAMP solution and anti-cAMP solution. After 1 hour of incubation at room temperature, time-resolved fluorescence intensity was measured using an Envision (Perkin-Elmer) at an excitation wavelength of 400 nm and dual emission wavelengths of 590 nm and 665 nm. A calibration curve was constructed by plotting the ratio of the fluorescence intensity at 665 nm to the fluorescence intensity at 590 nm versus cAMP concentration using external cAMP solutions ranging from 2.7 μM to 0.1 pM. The potency and activity of compounds in inhibiting cAMP production were then determined by plotting cAMP levels versus compound concentration and fitting them to a four-parametric logistic equation.

[0083] The Examples disclosed below were tested in the human RXFP1 (hRXFP1) HEK293 cAMP assay described above and found to have agonist activity. Table 1 shows the EC agonist activity in the hRXFP1 HEK293 cAMP assay measured for the Examples. 50 Enumerate values.

[0084] Table 1 cAMP hRXFP1 HEK293 assay EC 50 (nM) [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0085] Pharmaceutical Compositions and Methods of Use The compounds of formula (I) are RXFP1 receptor agonists and are useful in treating heart failure (e.g., chronic heart failure with reduced ejection fraction (HF) R EF) or chronic heart failure with preserved ejection fraction (HF) PThe compounds of formula (I) may find use in the treatment of medical indications such as fibrotic diseases, pulmonary diseases (e.g., idiopathic pulmonary fibrosis or pulmonary hypertension), renal diseases (e.g., chronic kidney disease), or liver diseases (e.g., nonalcoholic steatohepatitis and portal hypertension), and related diseases. The compounds of formula (I) may also be used to treat disorders that result from or are caused by decreased arterial stiffness, arterial elasticity, arterial compliance, and distensibility, including hypertension, renal disease, peripheral arterial disease, carotid artery disease, and cerebrovascular disease (i.e., stroke and dementia), diabetes, microvascular diseases that result in end-organ damage, coronary artery disease, and heart failure. The compounds described herein may also be used to treat preeclampsia.

[0086] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for treating a relaxin-related disorder. Another aspect of the present invention is a method for treating a relaxin-associated disorder, comprising administering an effective amount of a compound of formula (I).

[0087] Another aspect of the present invention is a method for treating cardiovascular disease, comprising administering to a patient in need thereof an effective amount of a compound of formula (I). Another aspect of the present invention is a method for treating heart failure, comprising administering to a patient in need thereof an effective amount of a compound of formula (I). Another aspect of the present invention is a method for treating fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0088] Another aspect of the present invention is a method for treating a disease associated with fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). Another aspect of the present invention is a method of treating idiopathic pulmonary fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). Another aspect of the present invention is a method for treating kidney disease (e.g., chronic kidney disease), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0089] Another aspect of the present invention is a method for treating or preventing renal failure, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). Another aspect of the present invention is a method of improving, stabilizing or restoring renal function in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I). Another aspect of the present invention is a method of treating idiopathic pulmonary fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0090] Another aspect of the present invention is a method for treating renal disease (e.g., chronic renal disease), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). Another aspect of the present invention is a method for treating liver disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0091] Another aspect of the present invention is a method for treating non-alcoholic steatohepatitis and portal hypertension, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). Another aspect of the present invention resides in the use of compounds of formula (I) for the prevention and / or treatment of relaxin-related disorders. Another aspect of the present invention resides in compounds of formula (I) for use in the prevention and / or treatment of relaxin-related disorders.

[0092] Unless otherwise specified, the following terms have the meanings indicated. The term " patient " or " subject " refers to any human or non-human organism that may benefit from treatment with RXFP1 agonist, as substituted by those skilled in the art.Exemplary subjects include people of any age who have cardiovascular disease risk factors.Common risk factors include but are not limited to age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arrhythmia, or symptoms of insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovarian syndrome (PCOS).

[0093] "Treating" or "treatment," as understood by those skilled in the art, extends to the treatment of a condition and includes: (a) inhibiting the condition, i.e., preventing its onset; (b) alleviating the condition, i.e., causing regression of the condition; and / or (c) preventing the onset of the disease in a mammal, particularly when such mammal is predisposed to, but has not yet been diagnosed with, the condition.

[0094] "Preventing" or "prevention," as understood by those skilled in the art, refers to the prophylactic treatment of a subclinical condition (i.e., prevention and / or risk reduction) with the goal of reducing the likelihood of the clinical condition occurring. Patients are selected for prophylactic treatment based on factors known to increase the risk of developing the clinical condition compared to the general population. "Preventive" therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in subjects who have not yet developed a clinical condition, whereas secondary prevention is defined as preventing the secondary onset of the same or a similar clinical condition. "Risk reduction" or "risk reduction" refers to therapy that reduces the incidence of a clinical condition. Primary and secondary prevention therapy are themselves examples of risk reduction.

[0095] A "therapeutically effective amount" is intended to include an amount of a compound of the invention that is effective when administered alone or in combination with other agents to treat a disorder, as understood by one of ordinary skill in the art. When applied to a combination, the term refers to combined amounts of the active ingredients that result in a prophylactic or therapeutic effect, whether administered in combination, serially, or simultaneously.

[0096] "Cardiovascular system disorders" or "cardiovascular disorders" include, for example, the following disorders: hypertension (high blood pressure), peripheral vascular and cardiovascular disorders, coronary heart disease, stable and unstable angina, heart attack, myocardial failure, abnormal heart rhythm (or arrhythmia), persistent ischemic dysfunction ("hibernating myocardium"), transient post-ischemic dysfunction ("stunned myocardium"), heart failure, impaired peripheral blood flow, acute coronary syndromes, heart failure, myocardial disease (cardiomyopathy), myocardial infarction, and vascular diseases (vascular diseases).

[0097] "Heart failure" includes both acute and chronic forms of heart failure, as well as advanced heart failure, post-acute heart failure cardio-renal syndrome, heart failure with renal dysfunction, chronic heart failure, chronic heart failure with intermediate ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure secondary to congenital heart damage, valvular heart disease, heart failure secondary to valvular heart disease, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, aortic regurgitation, and complex heart failure. These include more specific or associated forms of the disease such as heart failure associated with valvular heart disease, 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 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), stenosis after myocardial remodeling, hypertension, pulmonary hypertension and pulmonary arterial hypertension.

[0098] "Fibrotic disorders" encompasses, inter alia, the following diseases and disorders characterized by fibrogenesis, including liver fibrosis, cirrhosis, NASH, pulmonary fibrosis, myocardial fibrosis, endocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic disorders due to diabetes, myelofibrosis and similar fibrotic disorders, scleroderma morphea, keloids, hypertrophic scars (even after surgery), nevi, diabetic retinopathy, proliferative vitreoretinopathy, and disorders of connective tissue (e.g., sarcoidosis). Relaxin-related disorders include, but are not limited to, cardiovascular disorders and fibrotic disorders.

[0099] The compounds of the present invention can be administered by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (for example, as a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories.The compounds can be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0100] " Pharmaceutical composition " refers to the composition comprising the compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. " Pharmaceutically acceptable carrier " refers to the medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, including adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the characteristics of dosage form.

[0101] Pharmaceutically acceptable carriers are formulated according to many factors well within the knowledge of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent to be formulated; the intended recipient of the drug-containing composition; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent, and such additional components are incorporated into the formulation for various reasons, such as stabilization of the active agent, binders, etc., as known to those skilled in the art. A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Allen, LV et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0102] The administration regimen for the compounds of the present invention will, of course, vary depending on known factors such as the pharmacological properties of the particular agent and its mode and route of administration; the species, age, sex, health, condition, and weight of the recipient; the nature and extent of symptoms; type of concurrent treatment; frequency of treatment; route of administration; the patient's renal and hepatic function; and the desired effect.

[0103] As a general guide, the daily oral dose of each active ingredient, when used to achieve the indicated effects, will range from about 0.01 to about 5000 mg per day, preferably from about 0.1 to about 1000 mg per day, and most preferably from about 0.1 to about 250 mg per day. For intravenous administration, the most preferred dose will be in the range of about 0.01 to about 10 mg / kg / minute via constant rate infusion. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily.

[0104] The compounds are typically administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected for the intended dosage form, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practice.

[0105] Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of about 0.1% to 95% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into a No. 1 gelatin capsule. A typical injectable formulation is produced by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically lyophilizing it, and sealing it. At the time of use, the contents of the vial are mixed with 2 mL of saline to produce an injectable formulation.

[0106] The compounds of the present invention may be utilized in combination with other suitable therapeutic agents useful in the treatment of diseases or disorders, including antiatherosclerotic agents, antilipidemic agents, antidiabetic agents, antihyperglycemic agents, antihyperinsulinemic agents, antithrombotic agents, antiretinopathy agents, antineuropathic agents, antinephropathic agents, antiischemic agents, antihypertensive agents, antiobesity agents, antihyperlipidemic agents, antihypertriglyceridemic agents, antihypercholesterolemic agents, antirestenosis agents, antipancreatic agents, lipid-lowering agents, anorexic agents, memory enhancers, antidementia agents, cognition enhancers, appetite suppressants, heart failure therapeutic agents, peripheral arterial disease therapeutic agents, malignant tumor therapeutic agents, and anti-inflammatory agents.

[0107] Additional therapeutic agents include ACE inhibitors, beta-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine A1 receptor agonists, partial adenosine A1 receptor, dopamine beta-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with agonist bias to select cell signaling pathways, angiotensin II receptor antagonists Combinations of steroids with 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, antifibrogenic agents, galectin-3 inhibitors, vasopressin receptor antagonists, RXFP1 receptor modulators, natriuretic peptide receptor agonists, transient receptor potential vanilloid-4 channel blockers, antiarrhythmic agents, provisional (I f ) "Funny current" channel s blockers, nitrates, digitalis compounds, cardiotonic and β-receptor agonists, cell membrane resealing agents, e.g., poloxamer 188, antihyperlipidemic agents, plasma HDL-raising agents, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (HMG CoA reductase inhibitors), LXR agonists, FXR agonists, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, anion exchange resins, quaternary amines, cholestyramine, colestipol, low density lipoprotein receptor inducers, clofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrizol, vitamin B6, vitamin B12, antioxidant vitamins, antidiabetic agents, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives, PCSK9 inhibitors, aspirin, and P2Y12 inhibitors such as clopidogrel.

[0108] Additional therapeutic agents also include nintedanib, pirfenidone, LPA1 antagonists, LPA1 receptor antagonists, GLP1 analogs, traloquinucab (IL-13, manufactured by AstraZeneca), vismodegib (hedgehog antagonist, manufactured by Roche), PRM-151 (pentraxin-2, TGF beta-1, manufactured by Promedior), SAR-156597 (bispecific Mab IL-4 & IL-13, manufactured by Sanofi), simtuzumab (anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, manufactured by Gilead), CKD-942, PTL-202 (PDE inhibitor / pentoxifylline / NAC oral controlled release, manufactured by Pacific These agents may also include omipalisib (oral PI3K / mTOR inhibitor, manufactured by GSK), IW-001 (oral solution, bovine type V collagen modified, manufactured by ImmuneWorks), STX-100 (integrin alpha V / beta-6 inhibitor, manufactured by Stromedix / Biogen), Actimun (IFN gamma), PC-SOD (midismase; inhaled, manufactured by LTT Bio-Pharma / CKD Pharm), lebrikizumab (anti-IL-13 SC humanized mAb, manufactured by Roche), AQX-1125 (SHIP1 activator, manufactured by Aquinox), CC-539 (JNK inhibitor, manufactured by Celgene), FG-3019 (manufactured by FibroGen), SAR-100842 (manufactured by Sanofi), and obeticholic acid (OCA or INT-747, manufactured by Intercept).

[0109] The other therapeutic agents described above, when utilized in combination with the compounds of the present invention, may be used in those amounts set forth in the Physicians' Desk Reference, e.g., as in the patents mentioned above, or in amounts otherwise determined by one skilled in the art.

[0110] Particularly when provided as a single dosage unit, there is a possibility of chemical interactions between the combined active ingredients. For this reason, when a compound of the present invention and another therapeutic agent are combined in a single dosage unit, the active ingredients are combined in a single dosage unit but are formulated to minimize (i.e., reduce) physical contact between the active ingredients. For example, one of the active ingredients may be enteric-coated. Enteric-coating one of the active ingredients not only minimizes contact between the combined active ingredients, but also modifies the release of one of the ingredients in the gastrointestinal tract so that one of the ingredients is released in the intestine rather than in the stomach. Alternatively, one of the active ingredients may be coated with a material that affects sustained release throughout the gastrointestinal tract and further serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-release component may be further enteric-coated so that its release occurs only in the intestine. Yet another solution would involve formulating a combination product in which one component is coated with a sustained-release and / or enteric polymer to further separate the active ingredients, and the other component is coated with a polymer such as a low viscosity grade of hydroxypropylmethylcellulose (HPMC) or other suitable material known in the art, the polymer coating serving to form an additional barrier to interaction with the other component.

[0111] The compounds of the present invention are also useful as control or control compounds, for example, as quality control or control compounds, in tests or assays involving RXFP1. Such compounds may be provided, for example, in commercially available kits for use in pharmaceutical research involving RXFP1 activity. For example, a compound of the present invention can be used as a control in an assay to compare its known activity with a compound of unknown activity. This allows experimental researchers to confirm that the assay is performed properly and provides a basis for comparison, especially when the test compound is a derivative of the control compound. When developing new assays or protocols, the compounds of the present invention can be used to test their effectiveness. The compounds of the present invention can also be used in diagnostic assays involving RXFP1.

[0112] The present invention also encompasses articles of manufacture. As used herein, "articles of manufacture" includes, but is not limited to, kits and packages. An article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition contained within the first container, the composition comprising a first therapeutic agent, the first therapeutic agent comprising 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 treating dyslipidemia and its sequelae. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent (as described above) for treating dyslipidemia and its sequelae. The article of manufacture may further comprise (d) a second container, in which components (a) and (b) are contained within the second container and component (c) is located inside or outside the second container. Being located within the first and second containers means that each container holds items within its boundaries.

[0113] A primary container is a container used to hold a pharmaceutical composition. This container may be for manufacturing, storing, and / or selling individually / in bulk. Primary container is also intended to extend to bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

[0114] The second container is used to hold the first container and, if desired, to hold the package insert.Examples of the second container include, but are not limited to, boxes (for example, cardboard boxes or plastic boxes), crates, cartons, bags (for example, paper bags or plastic bags), pouches and sacks.The package insert can be physically attached to the outside of the first container via tape, adhesive, staples or another attachment means, or can be fastened to the inside of the second container without being attached to the first container by any physical means.Alternatively, the package insert is located on the outside of the second container.When located on the outside of the second container, the package insert is preferably physically attached via tape, adhesive, staples or another attachment means.Alternatively, the package insert can be adjacent to or in contact with the outside of the second container without being physically attached.

[0115] The package insert is a label, tag, marker, etc. that provides information about the pharmaceutical composition located in the first container. The information provided will typically be determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) governing the region in which the product will be sold. Preferably, the package insert specifically describes the indications for which the pharmaceutical composition is approved. The package insert may be made of any material that allows a person to read the 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.) having the desired information formed thereon (e.g., printed or coated thereon).

[0116] chemical method The compounds of the present invention can be made by a variety of methods known in the art, including those described in the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are different 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 the present invention.

[0117] The present disclosure is not limited to the exemplary embodiments, which are to be considered in all respects as illustrative and not restrictive, and all changes which come within the meaning and range of equivalents of the claims are therefore intended to be embraced.

[0118] It will also be appreciated that another major consideration in planning any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functional groups present in the compounds described in this invention. An authoritative work describing the many options for those skilled in the art is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0119] Abbreviations are as follows: "1x" for 1 time, "2x" for 2 times, "3x" for 3 times, "°C" for degrees Celsius, "aq" for aqueous, "eq" or "equiv" for equivalents, "g" for gram, "mg" for milligram, "L" for liter, "mL" for milliliter, "μL" for microliter, "N" for normal, "M" for mole, "nM" for nanomole, "pM" for picomole, "mol" for mole, "mmol" for millimole, "min" for minute, "h" for hour, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrated, "aq" for aqueous, "sat." for saturated, "MW" for molecular weight, and "MS" or "Mass" for mass spectrometry. Spec,” for electrospray spectroscopy or mass spectrometry, “ESI,” for liquid chromatography-mass spectrometry, “LC-MS,” for high-pressure liquid chromatography, “HPLC,” for reversed-phase HPLC, “NMR,” for nuclear magnetic resonance spectroscopy, “SFC,” for supercritical fluid chromatography, and “ 1 "H", "δ" 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 "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to those skilled in the art.

[0120] [Table 11] [Table 12]

[0121] In the illustrated examples, the following methods were used unless otherwise noted. Purification of intermediates and final products was carried out via either normal-phase or reverse-phase chromatography. Normal-phase chromatography was carried out using pre-packed SiO2 cartridges eluting with a gradient of either hexane and ethyl acetate, or DCM and MeOH, unless otherwise noted. Reverse-phase preparative HPLC was performed using a C18 column with UV at 220 nm, or with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or with a gradient of solvent A (95% water, 5% ACN, 0.1% TFA) and solvent B (5% water, 95% ACN, 0.1% TFA), or with a gradient of solvent A (95% water, 2% ACN, 0.1% HCOOH) and solvent B (98% ACN, 2% water, 0.1% HCOOH), or with a gradient of solvent A (95% water, 5% ACN, 10 mM NHOAc) and solvent B (98% ACN, 2% water, 10 mM NHOAc). Preparative LCMS detection was performed eluting with a gradient of solvent A (98% water, 2% ACN, 0.1% NH4OH) and solvent B (98% ACN, 2% water, 0.1% NH4OH) with a gradient of 0.1% NH4OAc.

[0122] The LC / MS methods utilized for characterization of the examples are listed below. Method A: Equipment: Waters Acquity coupled with a Waters MICROMSS® ZQ mass spectrometer Run a linear gradient from 2 to 98% B over 1 min, hold at 98% B for 0.5 min UV visualization at 220 nm Column: Waters BEH C18, 2.1 x 50 mm Flow rate: 0.8mL / min (method A) Mobile phase A: 0.05% TFA, 100% water Mobile phase B: 0.05% TFA, 100% acetonitrile

[0123] Method B: Apparatus: Shimadzu Prominence HPLC coupled with a Shimadzu LCMS-2020 mass spectrometer Linear gradient from 0 to 100% B over 3 min, hold at 100% B for 0.75 min UV visualization at 220 nm Column: Waters Xbridge C18, 2.1 x 50 mm, 1.7 μm particles Flow rate: 1mL / min Mobile phase A: 10 mM ammonium acetate, 95:5 water:acetonitrile Mobile phase B: 10 mM ammonium acetate, 5:95 water:acetonitrile

[0124] Method C: Apparatus: Shimadzu Prominence HPLC coupled with a Shimadzu LCMS-2020 mass spectrometer Linear gradient from 0 to 100% B over 3 min, hold at 100% B for 0.75 min UV visualization at 220 nm Column: Waters Xbridge C18, 2.1 x 50 mm, 1.7 μm particles Flow rate: 1mL / min Mobile phase A: 0.1% TFA, 95:5 water:acetonitrile Mobile phase B: 0.1% TFA, 5:95 water:acetonitrile

[0125] Method D: Equipment: Waters Acquisition System coupled with a Waters Micromass® ZQ mass spectrometer Run a linear gradient from 10% B to 98% B over 1 min, then hold at 98% B for 0.5 min. UV visualization at 220 nm Column: Waters Acquity GEN C18, 2.1x50mm, 1.7µm particles Flow rate: 1mL / min Mobile phase A: 0.05% TFA, 100% water Mobile phase B: 0.05% TFA, 100% acetonitrile

[0126] Method E: Apparatus: Shimadzu Prominence HPLC coupled with a Shimadzu LCMS-2020 mass spectrometer Run a linear gradient from 0% B to 100% B over 1 minute, then hold at 100% B for 0.5 minutes. UV visualization at 220 nm Column: Waters Acquity BEH C18 2.1x50mm, 1.7µm particles Flow rate: 1mL / min Mobile phase A: 10 mM ammonium acetate, 95:5 water:acetonitrile Mobile phase B: 10 mM ammonium acetate, 5:95 water:acetonitrile

[0127] NMR used in the characterization of the examples 1 The H NMR spectrum shows the following frequencies: 1 H NMR: Obtained using a Bruker or JEOL® Fourier transform spectrometer operating at 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®). Spectral data are reported in the format: chemical shift (multiplicity, coupling constant, number of hydrogens). Chemical shifts are specified in ppm downfield of the internal coordinate system of tetramethylsilane (δ units, tetramethylsilane = 0 ppm) and / or 1 In the H NMR, the solvent peaks are referenced, which appear at 2.51 ppm for DMSO-d6, 3.30 ppm for CD3OD, 1.94 ppm for CD3CN, and 7.24 ppm for CDCl3.

[0128] Scheme I shows that the norbornyl examples are either commercially available or (R 1 =R 2═H) or as described in the scheme below. Starting with a protected amino ester such as I-1, the olefin can be reduced under hydrogenation conditions (e.g., Pd / C, H). The resulting Boc-protected amine I-2 can then be deprotected using TFA, followed by acylation with benzoic acid using a variety of amide bond-forming conditions (e.g., HATU or BOP-Cl with DIEA) to give I-3. Ester I-3 can then be directly converted to examples of general structure I by treatment with the appropriate amine and AlMe. Alternatively, the order of the amide bond-forming reactions can be reversed, starting with saponification of I-2, followed by treatment with T3P® and the appropriate amine to give I-4. Deprotection and acylation can then be carried out according to the conditions described above to give examples of general structure I. Additionally, the initial hydrogenation step can be delayed to any point in the reaction scheme without changing the outcome of the steps described in Scheme 1.

[0129] Scheme I [ka]

[0130] Scheme II illustrates the method for generating C7-substituted norbornyl analogs starting from II-1. Treatment of II-1 with malic anhydride gave II-2, which was selectively hydrogenated and subjected to solvolysis to generate II-3. II-3 was subjected to a Curtius reaction with DPPA in the presence of trimethylsilanol, leading to the formation of II-4. Deprotection of the Teoc group under standard conditions led to the formation of amine II-5, which could be directly elaborated into examples represented by general structure II. Alternatively, treatment of structure II with ozone gave ketone II-6, which could be subsequently functionalized via a variety of standard transformations, including, but not limited to, organometallic addition reactions (e.g., R-Li, R-MgBr), Wittig or Horner-Wadsworth-Emmons (HWE) olefination reactions, or acetal formation. These products could serve as examples of the general structures I or II, or alternatively, could serve as intermediates for further elaboration. Additionally, the ozonolysis step could be performed earlier in the synthetic pathway for strategic reasons without changing the outcome of the synthetic steps outlined in Scheme II.

[0131] Scheme II [ka]

[0132] Norbornyl intermediate IIa-8 can also be prepared from furan-2,5-dione and ferrocenium hexafluorophosphate via the general route shown in Scheme IIa. Diels-Alder condensation followed by hydrolysis to IIa-2 and Curtius rearrangement to the intermediate amine, which was reduced under hydrogenation conditions and subsequently protected to generate intermediate IIa-3. Cleavage of the benzyl ester afforded NHR. 1 R 2This was cross-coupled to afford the intermediate with the general structure IIa-5. The C7 hydroxy group was converted to a ketone, followed by Wittig olefination to afford the major isomer, intermediate IIa-8. The major isomer was separated from the minor isomer by chromatography, and the racemate was isolated to give enantiopure IIa-8(-).

[0133] Scheme IIa [ka]

[0134] Scheme III shows how the norbornyl nucleus can be fluorinated. Starting with II-4, the material was deprotonated with LDA, fluorinated with N-fluoro-bisbenzenesulfonimide, and then subsequently engineered to give examples of general structure III according to the route outlined in Scheme I. Alternatively, III-1 could be treated with ozone as shown in Scheme II to give III-2. Intermediate III-2 could then be subjected to Wittig or HWE conditions and worked up as shown in Scheme II to give examples of general structure III.

[0135] Scheme III [ka]

[0136] Scheme IV illustrates the preparation of a wide variety of C-7 methylidene-substituted norbornyl nuclei from a common intermediate bromide. II-4 was converted to IV-1 via standard Teoc-deprotection and TFA acylation procedures. Ester IV-1 was converted to amide IV-2 following the AlMe3 procedure outlined in Scheme I, and IV-2 was ozonolyzed to ketone IV-3 as shown in Scheme II. Wittig-type methylation afforded olefin IV-4, which was treated with bromine and KHMDS to afford IV-5 and IV-6 as a mixture of isomers, which were separated by silica gel chromatography. Isomer IV-6 was then subjected to chiral SFC purification to generate a single enantiomer of IV, which was then deprotected to give IV-7. Amine IV-7 could then be acylated according to the method outlined in Scheme 1 to afford IV-8. Vinyl bromides could also be further functionalized (e.g., using Suzuki, Negishi, and Semmelhack reaction conditions, among others) to lead to various examples of general structure IV or corresponding intermediates, which could then be further elaborated. Alternatively, the vinyl bromide functionalization step could be performed on IV-6, and the resulting material could be processed similarly to the examples of general structure IV.

[0137] Scheme IV [ka]

[0138] Scheme V illustrates the introduction of various amides into highly engineered norbornyl carboxylates. Intermediate V-1, prepared according to the methods described in Schemes I-IV, was treated with pivaloyl chloride, DMAP, and DIEA to afford V-2. The resulting imide could be directly displaced with an amine in the presence of AlMe to afford examples of general structure II. Alternatively, V-2 could be hydrolyzed using a hydroxide (e.g., LiOH, NaOH, etc.) to afford V-3, which could be further functionalized according to the methods outlined in Scheme I to afford examples of general structure II.

[0139] Scheme V [ka]

[0140] Scheme VI describes the synthesis of bicyclic benzoates (Ar = -Ar'-Ar'', where Ar = substituted phenyl, heteroaryl, or heterocyclic olefin) for use in Schemes I-IV. Aryl bromides VI-1 (where R can be H, Me, Bn, tBu, among others) were treated with aryl, heteroaryl, and heterocyclic vinylboronic acids (or esters) VI-2, a palladium catalyst (e.g., Pd(PPh) , PdCl(dppf), etc.), and a suitable base (e.g., NaCO , KPO , etc.) under Suzuki reaction conditions to afford bicycles VI-3. Alternatively, the coupling partners could be reversed utilizing arylboronic acids VI-4 and halides VI-5 under similar conditions to similarly afford VI-3. In VI-3, when R is not H, the benzoate could be cleaved using saponification conditions (e.g., LiOH, water when R = Me), acidic conditions (e.g., TFA / DCM when R = tBu), or hydrogenolysis conditions (e.g., Pd / C, H when R = Bn) to give VI-6. Benzoic acid VI-6 could then be coupled to a norbornyl nucleus as outlined in Schemes I-IV to give intermediates that could be further elaborated into examples shown in general structures I or II.

[0141] Scheme VI [ka]

[0142] Scheme VII outlines the synthesis of N-linked nitrogen heterobicyclic benzoates from benzoate intermediates VI-1 or VI-4. VI-1 was treated with amine VII-1 under either Hartwig-Buchwald (e.g., Pd(OAc)2, BINAP, Cs2CO3, among others) or Ullman (e.g., CuI, proline, Cs2CO3, among others) conditions to afford bicycle VII-2. Alternatively, VII-2 could be prepared from VO-4 following Chan-Evans-Lam conditions (e.g., Cu(OAc)2, TEA, O2, among others). Intermediate VII-2 could then be further functionalized, if desired, via ester cleavage in a manner similar to VI-3 in Scheme VI, and further manipulated either directly to examples shown in general structural formula I or II, or to intermediates that could be further elaborated to examples.

[0143] Scheme VII [ka]

[0144] Scheme VIII shows a general route to mandelic acid-based biaryl analogs. Commercially available VIII-1 was converted to the t-butyl ester VIII-2, which was then brominated to give VIII-3. Displacement of the bromide with acetic acid gave intermediate VIII-4, which then underwent a Suzuki reaction as described in Scheme VI to give VIII-5 (acetate cleavage was simultaneous with biaryl formation). The resulting acid was directly coupled with the norbornylamine intermediate VIII-6 as described in Scheme I to give VIII-7. The t-butyl ester VIII-7 could then be cleaved (with TEA / DCM) to give examples of general structure VIIIa. Alternatively, the hydroxyl group of VIII-7 could be elaborated either with an appropriate isocyanate or via a two-step carbamate formation protocol (e.g., nitrophenyl chloroformate, TEA, followed by an amine) to give VIII-8, which could then be cleaved (with TEA / DCM) to give examples of general structure VIIIb.

[0145] Scheme VIII [ka]

[0146] Scheme IX shows modifications to the steps in Scheme VIII that allow for the preparation of phenylglycine-based biaryl analogs. Treatment of intermediate VIII-3 with ammonia followed by acylation affords intermediate IX-1, which can be elaborated according to the methods outlined in Scheme VIII to afford examples of general structure IX.

[0147] Scheme IX [ka]

[0148] Scheme X describes how analogs bearing various aliphatic C-7 substituents can be prepared from intermediate X-1, which itself is prepared according to the route outlined in Scheme VIII. Treatment of intermediate X-1 with alkyl bromides under conditions outlined in MacMillan et al. (J. Am. Chem. Soc. 2016, 138, 8084-8087) followed by subsequent deprotection of the tBu ester led to examples of general structure X.

[0149] Scheme X [ka]

[0150] Scheme XI illustrates routes to analogs with various aliphatic aryl substituents (R) that can be prepared from Example 292. Example 292 was treated with alkyl bromides under conditions outlined in MacMillan et al. (J. Am. Chem. Soc. 2016, 138, 8084-8087) to give analogs of general structure XI.

[0151] Scheme XI [ka]

[0152] Scheme XII describes a route to prepare substituted isoxazoline analogs. Treatment of XII-1 with NaOCl followed by treatment with a substituted olefin, followed by saponification of the ester, afforded intermediates XII-2. These intermediates were coupled with norbornylamine according to the method outlined in Scheme 1 to afford examples of general structure XII.

[0153] Scheme XII [ka]

[0154] Scheme XIII describes a route to preparing analogs bearing various aryl substituents (Ar). Boronic acid VI-4 was treated with pinacol, followed by coupling with norbornyl amide (prepared according to the scheme described above) to give XIII-1. XIII-1 was treated with an aryl halide under standard anhydrous Suzuki reaction conditions, leading to the formation of analog XIII.

[0155] Scheme XIII [ka]

[0156] Example Example 5 [ka] [ka]

[0157] Intermediate II-2: To a reaction vessel at 0 °C was added EtO (100 mL), 5-(propan-2-ylidene)cyclopenta-1,3-diene (II-1, 10 g, 94 mmol), and furan-2,5-dione (10 g, 102 mmol). The reaction mixture was stirred at 0 °C for 18 hours, concentrated under reduced pressure, and purified via silica gel chromatography to give II-2 (3.74 g, 18.3 mmol, 19.0% yield). Intermediate II-2 is a known compound; see PCT International Application No. 2011163502, filed December 29, 2011.

[0158] Intermediate II-3: To a reaction vessel was added II-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 of H (H balloon) for 60 min, filtered through Celite, and concentrated under reduced pressure. The resulting intermediate was dissolved in methanol (50 mL) and heated at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure (azeotrope with toluene 3 x 15 mL) to afford II-3 (3.21 g, 13.5 mmol, 100% yield), which was used without further purification.

[0159] Intermediate II-4: To a reaction vessel was added II-3 (3.2 g, 13 mmol), EtN (3.38 mL, 24.3 mmol), toluene (75 mL), and diphenylphosphoryl azide (4.35 mL, 20.2 mmol). The reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was then heated at 85 °C for 30 min, and 2-(trimethylsilyl)ethanol (4.83 mL, 33.7 mmol) was added. After stirring at 85 °C for 66 h, the reaction mixture was cooled to 23 °C and purified via silica gel chromatography to give racemic II-4 (3.71 g, 10.5 mmol, 78.0% yield). LC-MS RT = 1.25 min; (M+H) = 354.1; Method A. Racemic II-4 was separated into its individual enantiomers using chiral SFC. Preparative chromatographic conditions: Apparatus: Thar 350 SFC; Column: Whelko-RR, 5x50cm, 10 micron; Mobile phase: 13%IPA / 87%CO2; Flow conditions: 300mL / min, 100 Bar, 35°C; Detector wavelength: 220nm; Injection details: 4 x 3.5mL injections of 59g / 490mL MeOH:DCM (4:1) at 120mg / mL in IPA. Analytical chromatographic conditions: Apparatus: Thar analytical SFC; Column: Whelko-RR (0.46 x 25 cm, 5 micron); Mobile phase: 5% IPA / 95% CO; Flow conditions: 3 mL / min, 140 Bar, 40 °C; Detector wavelength: 200-400 nm UV; Peak 1, RT = 3.496 min, >99% ee; Peak 2, RT = 4.417 min, >99% ee; Peak #1 of intermediate II-4 product was collected and carried forward to generate chiral 5-5.

[0160] Intermediate 5-5: To a reaction vessel was added chiral II-4 (3.71 g, 10.5 mmol), THF (80 mL), and TBAF (31.5 mL, 31.5 mmol). The reaction mixture was stirred at 23 °C for 12 h, diluted with EtOAc (15 mL), and the organic portion was washed with saturated NaHCO (15 mL). The organic phase was collected, dried over NaSO, concentrated under reduced pressure, and dissolved in DCM (50 mL). After cooling to 0 °C, DIEA (5.50 mL, 31.5 mmol) and 4,5-difluoro-2-methoxybenzoyl chloride (2.4 g, 12 mmol) were added. The reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to 23 °C, concentrated under reduced pressure, and the residue was purified via silica gel chromatography to give 5-5 (2.9 g, 7.7 mmol, 74% yield). LC-MS RT=1.13 min;(M+H)=380.1;Method A

[0161] Example 5-6: 4-Fluoro-3-(trifluoromethyl)aniline (4.87 g, 27.2 mmol), toluene (40 mL), and trimethylaluminum (13.59 mL, 27.20 mmol) were added to a reaction vessel. After stirring at 23° C. for 30 minutes, 5-6 (2.95 g, 7.76 mmol) in toluene (80 mL) was added. The reaction mixture was stirred at 65° C. for 30 minutes. After cooling to 23° C., the reaction mixture was diluted with EtOAc (50 mL) and washed with a saturated aqueous solution of Rochelle's salt. The organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified via silica gel chromatography to give Example 56 (3.23 g, 6.14 mmol, 79.0% yield). LCMS RT=1.23 min; (M+H)=527.1; Method A

[0162] Intermediate 5-6: To a reaction vessel was added Example 56 (110 mg, 0.210 mmol) and EtOAc (5 mL). The reaction mixture was cooled to -78 °C, and O3 was bubbled through the solution for 10 min (until a blue color appeared). After bubbling with N2 to remove excess O3, dimethyl disulfide (0.370 mL, 4.18 mmol) was then added, and the reaction mixture was allowed to warm to 23 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to yield the residue 5-6 (100 mg, 0.20 mmol, 96% yield), which was used without further purification. LC-MS RT = 1.08 min; (M+H) = 501.1; Method A

[0163] Procedure for Example 5: To a reaction vessel was added diethyl benzylphosphonate (0.290 mL, 1.40 mmol) and THF (10 mL). The mixture was cooled to -78 °C, and KHMDS (1.4 mL, 1.4 mmol) was added. The mixture was stirred at -78 °C for 15 minutes, and 5-6 was added at -78 °C. After stirring at -78 °C for 10 minutes, the mixture was allowed to warm to 23 °C, stirred at 23 °C for 1 hour, quenched with saturated NaHCO and extracted with EtOAc. The organic phases were collected, dried over NaSO, filtered, concentrated, and purified via silica gel chromatography to produce the E-isomer of Example 5 (59 mg, 0.10 mmol, 51% yield) and the Z-isomer of Example 6 (34 mg, 0.060 mmol, 29% yield). 1H NMR (400MHz, CDCl3) δ 9.53(d,J=7.7Hz,1H), 8.03(dd,J=11.2,9.5Hz,1H), 7.93(dd,J=6.1,2.5Hz,1H), 7.83(s,1 H), 7.55-7.47(m,1H), 7.37-7.21(m,5H), 7.10(t,J=9.4Hz,1H), 6.78(dd,J=11.6, 6.1Hz,1H ), 6.31(s,1H), 4.83-4.72(m,1H), 4.00(s,3H), 3.46-3.39(m,1H), 3.12(dd,J=10.7, 4.1Hz ,1H), 2.89(t,J=4.0Hz,1H), 2.31-2.20(m,1H), 1.94-1.84(m,1H), 1.79-1.65(m,2H); LC-MS RT:1.25 points;MS(ESI) m / z=575.2(M+H) + Method A

[0164] Example 6

change

[0165] The operation of Example 6 is the same as the by-products of Example 5 and the manufacturing process. 1 H NMR (400MHz, CDCl3) δ 9.51(d,J=7.7Hz,1H), 8.03(dd,J=11.4,9.5Hz,1H), 7.94(dd,J=6.2,2.6Hz,1H), 7.72(s,1H), 7.53(dt, J=8.5, 3.7Hz, 1H), 7.37-7.30 (m, 4H), 7.25-7.19 (m, 1H), 7.12 (t, J=9.4Hz, 1H), 6.78 (dd, J=11.7, 6.2Hz ,1H), 6.33(s,1H), 4.83(ddd,J=10.9,7.6,3.9Hz,1H), 3.99(s,3H), 3.49(br.s.,1H), 3.16(dd,J=10.8, 3.7Hz,1H), 2.87(br.s.,1H), 2.22(t,J=8.8Hz,1H), 1.91(t,J=8.7Hz,1H), 1.69(d,J=6.4Hz,2H); LC-MS RT:1.25 points;MS(ESI) m / z=575.2(M+H) + Method A

[0166] Example 11 [ka]

[0167] Procedure for Example 11: Example 11 was prepared from 5-6 utilizing bromo(bromomethyl)triphenylphosphorane according to the method described for Example 5. 1 H NMR (500MHz, CDCl3) δ 9.31(d,J=8.0Hz,1H), 8.01(dd,J=11.3, 9.4Hz,1H), 7.94-7.86(m,2H), 7.51(dt, J=8.7, 3.6Hz,1H), 7.10(t,J=9.4Hz,1H), 6.78(dd,J=11.6, 6.1Hz,1H), 5.98(s,1 H), 4.87-4.76(m,1H), 3.97(s,3H), 3.28(t,J=3.7Hz,1H), 3.16-3.09(m,1H), 2.9 3(t,J=3.7Hz,1H), 2.35-2.25(m,1H), 1.91-1.82(m,1H), 1.75-1.63(m,2H);LC-MS RT:1.22min;MS(ESI) m / z=578.9(M+H) + ;Method A

[0168] Example 12 [ka]

[0169] Procedure for Example 12: To a reaction vessel was added Example 11 (10 mg, 0.020 mmol), followed by furan-3-ylboronic acid (9.7 mg, 0.090 mmol), PdCl(dppf)-CHCl adduct (4.2 mg, 5.2 μmol), (2 mL of THF), and NaCO (0.5 mL, 1.00 mmol). The reaction mixture was degassed by bubbling N for 10 min, sealed, and stirred at 60 °C for 2 h. After cooling the reaction mixture to 23 °C, the reaction mixture was concentrated, and the residue was purified via preparative RP-HPLC to give Example 12 (7.7 mg, 0.010 mmol, 77% yield). 1 H NMR (500MHz, CDCl3) δ 9.54(d,J=7.4Hz,1H), 8.03(dd,J=11.3, 9.4Hz,1H), 7.94(dd,J=6.3, 2.8Hz,1H), 7.69(s,1H), 7.53(dt,J=8 .9, 3.4Hz,1H), 7.44(d,J=0.8Hz,1H), 7.39(t,J=1.7Hz,1H), 7.12(t,J=9.4Hz,1H), 6.79(dd,J=11.6, 6.3Hz ,1H), 6.54(d,J=1.1Hz,1H), 6.08(s,1H), 4.82-4.73(m,1H), 4.00(s,3H), 3.37(t,J=3.6Hz,1H), 3.12(dd,J LC-MS RT:1.22min;MS(ESI) m / z=565.0(M+H) + ;Method C

[0170] Example 13 [ka]

[0171] Procedure for Example 13: Example 13 was prepared from 5-6 (5.0 mg, 8.7 μmol) utilizing [1,1′-biphenyl]-4-ylboronic acid according to the method described for Example 12. When forming Example 13, no cross-coupling product was obtained, but a dehalogenated by-product was observed and isolated (2.3 mg, 4.6 μmol, 53%). 1 H NMR (500MHz, CDCl3) δ 9.44(d,J=6.6Hz,1H), 8.05(dd,J=11.3, 9.5Hz,1H), 7.99-7.93(m,1H), 7.76(bs,1) H), 7.58-7.50(m,1H), 7.13(t,J=9.3Hz,1H), 6.80(dd,J=11.6, 6.1Hz,1H), 4.86(s, 1H), 4.85(s,1H), 4.79-4.73(m,1H), 3.11(dd,J=10.8, 4.0Hz,1H), 2.83(br.s.,1H) ), 2.79(br.s.,1H), 2.24-2.15(m,1H), 1.88-1.80(m,1H), 1.69-1.63(m,2H);LC-MS RT:1.17min;MS(ESI) m / z=499.1(M+H) + ;Method C

[0172] Example 33 [ka]

[0173] Procedure for Example 33: To a reaction vessel was added 1H-indene (34.8 mg, 0.300 mmol) and THF (2 mL). The reaction mixture was cooled to -78 °C, and nBuLi (0.19 mL, 0.30 mmol) was added. After stirring at -78 °C for 10 minutes and at 23 °C for 10 minutes, the reaction mixture was cooled again to -78 °C, and 5-6 (15 mg, 0.030 mmol) was added. The reaction mixture was allowed to warm to 23 °C, stirred for 15 minutes, quenched by the addition of saturated NaHCO3, and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, concentrated, and dissolved in Et2O (2 mL). After adding Burgess reagent (14.3 mg, 0.0600 mmol) (1 equivalent added, followed by another equivalent after 3 hours), the reaction mixture was stirred at 45 °C for 12 hours. The resulting solution was concentrated and purified via silica gel chromatography to give the E-isomer of the product (3.4 mg, 5.6 μmol, 19% yield) and the Z-isomer of Example 33 (4.6 mg, 7.5 μmol, 25% yield). 1 H NMR (500MHz, CDCl3) δ 9.63(d,J=7.7Hz,1H), 8.07(dd,J=11.3, 9.4Hz,1H), 8.00(dd,J=6.2, 2.6Hz,1H), 7.87(d,J=7.4Hz,1H), 7.80(s,1H), 7 .57(dt,J=8.7, 3.5Hz,1H), 7.37(d,J=7.4Hz,1H), 7.32-7.26(m,1H), 7.25-7.21(m,1H), 7.17(t,J=9.4Hz,1H), 6.90(d, J=5.5Hz,1H), 6.83(dd,J=11.6, 6.1Hz,1H), 6.67(d,J=5.5Hz,1H), 4.94-4.86(m,1H), 4.04(s,3H), 3.98(t,J=4.0Hz,1 LC-MS RT:1.27min;MS(ESI) m / z=599.1(M+H) + ;Method A

[0174] Example 34 [ka] [ka]

[0175] Intermediate 34-1: Intermediate 34-1 was prepared from 5-6 and tert-butyl 2-(diethoxyphosphoryl)acetate in the same manner as the Wittig reaction in Example 5. LC-MS RT=1.25 min; (M+H)=599.1; Method A Intermediate 34-2: To a reaction vessel was added 34-1 (50 mg, 0.080 mmol), DCM (2 mL), and TFA (0.200 mL, 2.59 mmol). After stirring at 23 °C for 12 h, the reaction was concentrated under reduced pressure to give 34-2 (46 mg, 0.080 mmol, 98% yield), which was used without further purification. LC-MS RT = 1.08 min, (M+H) = 543.1; Method A

[0176] Procedure for Example 34: To a reaction vessel was added 34-2 (5 mg, 9 μmol), MeCN (1 mL), DIEA (5 μl, 0.03 mmol), and HATU (7 mg, 0.02 mmol). The reaction mixture was stirred at 23° C. for 3 hours, the solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give Example 34 (3.8 mg, 6.8 μmol, 74% yield). LC-MS RT: 1.18 min; MS(ESI) m / z=618.1 (M+H). + ;Method B

[0177] Example 51 [ka]

[0178] Intermediate III-1: To a reaction vessel was added II-4 (100 mg, 0.28 mmol) and THF (5 mL). After cooling to −78° C., LDA (prepared from BuLi (0.53 mL, 0.85 mmol) and diisopropylamine (0.12 mL, 0.85 mmol) at 0° C.) was added, and the reaction mixture was stirred at −78° C. for 15 minutes. Then, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (223 mg, 0.710 mmol) was added at −78° C. After stirring at −78° C. for 1 hour, the reaction mixture was quenched by adding saturated NaHCO, and the aqueous portion was extracted with EtOAc. The organic portions were combined, dried over NaSO, concentrated under reduced pressure, and purified via silica gel chromatography to yield III-1 (59.5 mg, 0.160 mmol, 57.0% yield) (first peak) along with the trans-isomer (17.5 mg, 0.0500 mmol, 17.0% yield) (second peak). LC-MS RT = 1.21 min, (M+H) = 372.1; Method A

[0179] Intermediate 51-2: To a reaction vessel was added III-1 (20 mg, 0.050 mmol), THF (1 mL), and TBAF (0.270 mL, 0.270 mmol). The reaction mixture was stirred at 23 °C for 3 h, diluted with EtOAc, and the organic portion was washed with saturated NaHCO. The organic phase was collected, dried over NaSO, concentrated under reduced pressure, and dissolved in DCM (1 mL). DIEA (0.02 mL, 0.11 mmol) and 4,5-difluoro-2-methoxybenzoyl chloride (16.7 mg, 0.0800 mmol) were then added. After stirring at 23 °C for 1 h, the reaction mixture was concentrated under reduced pressure and purified via silica gel chromatography to produce 51-2 (7.2 mg, 0.020 mmol, 34% yield). LC-MS RT = 1.11 min, (M+H) = 398.1; Method A

[0180] Intermediate 51-3: A reaction vessel was charged with 51-2 (7.5 mg, 0.020 mmol), THF (1 mL), water (0.5 mL), and lithium hydroxide monohydrate (4.0 mg, 0.090 mmol). The reaction mixture was stirred at 23 °C for 1 h, diluted with EtOAc (10 mL), and the organic portion was washed with 10 mL of saturated NH4Cl containing 0.1 mmol HCl. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 51-3 (7.5 mg, 0.020 mmol, 100% yield), which was used without further purification. LC-MS RT = 0.98 min, (M+H) = 384.1; Method A

[0181] Procedure for Example 51: To a reaction vessel was added 51-3 (7.0 mg, 0.020 mmol), 4-fluoro-3-(trifluoromethyl)aniline (6.5 mg, 0.040 mmol), MeCN (1 mL), DIEA (6 μl, 0.04 mmol), and HATU (14 mg, 0.040 mmol). The reaction mixture was stirred at 50° C. for 1 h, cooled to 23° C., concentrated under reduced pressure, and purified via silica gel chromatography to give Example 51 (4.7 mg, 8.3 μmol, 45% yield). 1 H NMR (500MHz, CDCl3) δ 9.21(d,J=8.3Hz,1H), 8.33(d,J=8.8Hz,1H), 8.09(dd,J=6.2, 2.6Hz,1H), 8.02(d d,J=11.3, 9.4Hz,1H), 7.54(dt,J=8.8, 3.4Hz,1H), 7.18(t,J=9.2Hz,1H), 6.78(d d,J=11.7, 6.2Hz,1H), 4.70-4.54(m,1H), 3.13(t,J=3.9Hz,1H), 2.98(dd,J=9.4, LC-MS RT:1.23min;MS(ESI) m / z=545.1(M+H) + ;Method A

[0182] Example 52 [ka]

[0183] Intermediate III-2: To a reaction vessel was added III-1 (50 mg, 0.14 mmol) and EtOAc (3 mL). The reaction mixture was cooled to -78 °C, and O was bubbled through the solution for 10 min. Dimethyl disulfide (0.24 mL, 2.7 mmol) was then added, and the reaction mixture was allowed to warm to 23 °C and stirred for 12 h. After concentration under reduced pressure, the residue was dissolved in EtOAc and filtered through silica gel. The filtrate was concentrated under reduced pressure to give III-2 (50.5 mg, 0.15) mmol, 100% yield), which was used without further purification. LCMS RT = 1.24 min, (M+H) = 346.0; Method A

[0184] Intermediate 52-2: To a reaction vessel was added diethyl benzylphosphonate (0.14 mL, 0.65 mmol) and THF (5 mL). The reaction mixture was cooled to -78 °C, and KHMDS (0.65 mL, 0.65 mmol) was added. The mixture was stirred at -78 °C for 20 minutes, and III-2 (45 mg, 0.13 mmol) was added at -78 °C. After stirring at -78 °C for 5 minutes and at 23 °C for 1 hour, the reaction mixture was quenched by adding saturated NaHCO3, and the aqueous portion was extracted with EtOAc. The organic portions were combined, dried over Na2SO4, concentrated under reduced pressure, and purified via silica gel chromatography to give 52-2 (17.4 mg, 0.0400 mmol, 31.0% yield, 1.45:1 mixture of olefin isomers). LC-MS RT = 1.27 min, (M+H-Et) = 406.0; Method A

[0185] Intermediate 52-3: Intermediate 52-3 was prepared utilizing the procedure described for the synthesis of intermediate 51-2.

[0186] Intermediate 52-4: Intermediate 52-4 was prepared utilizing the procedure described for the synthesis of intermediate 51-3. [ka]

[0187] Procedure for Example 52: Example 52 was prepared from 52-4 according to the method described for Example 51. 1 H NMR (500MHz, CDCl3) δ 9.25(d,J=8.0Hz,1H), 8.33(d,J=8.5Hz,1H), 8.10(dd,J=6.2, 2.6Hz,1H), 8.04(dd,J=11 .1, 9.5Hz,1H), 7.58-7.50(m,1H), 7.39-7.31(m,4H), 7.18(t,J=9.4Hz,1H), 6.79(dd,J= 11.6, 6.1Hz,1H), 6.56(s,1H), 4.92-4.73(m,1H), 4.00(s,3H), 3.41(dd,J=8.7, 3.4Hz,1 LC-MS RT:1.27min;MS(ESI) m / z=593.0(M+H) + ;Method A

[0188] Example 53 [ka]

[0189] Procedure for Example 53: Example 53 was prepared from 52-4 according to the method described for Example 51. 1H NMR (500MHz, CDCl3) δ 9.28(d,J=7.4Hz,1H), 8.33(d,J=8.3Hz,1H), 8.11(d,J=4.1Hz,1H), 8.02(t,J=10.3 Hz,1H), 7.55(d,J=7.7Hz,1H), 7.40-7.31(m,4H), 7.19(t,J=9.2Hz,1H), 6.79(dd,J =11.6, 6.1Hz,1H), 6.45(s,1H), 4.89-4.72(m,1H), 4.01(s,3H), 3.61(br.s.,1H), 2 .85(d,J=6.1Hz,1H), 2.25-2.13(m,1H), 1.85-1.76(m,1H), 1.75-1.58(m,3H);LC-MS RT:1.27min;MS(ESI) m / z=593.0(M+H) + ;Method A

[0190] Example 65 [ka]

[0191] Intermediate 65-1: Intermediate 65-1 was prepared from 5-6 and methyl 2-(dimethoxyphosphorylphosphoryl)acetate in a manner similar to the Wittig reaction described in Example 5.

[0192] Procedure for Example 65: To a reaction vessel was added 65-1 (5.0 mg, 9.0 μmol) and THF (1 mL). The reaction mixture was cooled to −78° C., and then methylmagnesium chloride (0.06 mL, 0.2 mmol) was added. The reaction mixture was allowed to warm to 23° C. and stirred at 23° C. for 2 hours. The reaction was quenched by adding saturated NaHCO, and the solution was extracted with EtOAc. The organic layer was dried over NaSO, filtered, concentrated under reduced pressure, and purified via preparative RP-HPLC purification to yield Example 65 (3.2 mg, 5.3 μmol, 59% yield). 1H NMR (500MHz, CDCl3) δ 9.46(d,J=7.7Hz,1H), 8.03-7.91(m,3H), 7.53(dt,J=8.6, 3.5Hz,1H), 7.10(t,J =9.4Hz,1H), 6.78(dd,J=11.6, 6.3Hz,1H), 5.49(s,1H), 4.77-4.67(m,1H), 3.98 (s,3H), 3.49(t,J=4.0Hz,1H), 3.07(dd,J=11.0, 4.1Hz,1H), 2.69(t,J=3.9Hz,1 LC-MS RT:1.14min;MS(ESI) m / z=557.0(M+H) + ;Method C

[0193] Example 76 [ka]

[0194] Intermediate 76-1: To a 20 mL vial containing II-4 (1.77 g, 5.00 mmol), DCM (20 mL) was added. TFA (2.02 mL, 26.3 mmol) was then added, and the reaction mixture was stirred at 23 °C for 48 h. The resulting solution was concentrated under reduced pressure and dried under high vacuum for 5 h. The residue was carried forward to the acylation step without further purification. 5-Bromo-2-methoxybenzoyl chloride was prepared in the following manner: To a 100 mL flask charged with 5-bromo-2-methoxybenzoic acid (1.39 g, 6.00 mmol), DCM (30 mL) was added, followed by oxalyl chloride (0.6 mL, 7 mmol) and DMF (0.05 mL, 0.6 mmol). The solution was stirred at 23° C. for 18 h and converted to the amide in a similar manner as described for intermediate 5-5 to give 76-1 (878 mg, 2.10 mmol, 56.0% yield). 1H NMR (500MHz, DMSO-d6) δ 9.49(d,J=7.0Hz,1H), 8.04-7.87(m,1H), 7.74-7.59(m,1H), 7.17(d,J=8.8Hz,1H), 4.26(br.s.,1H), 3.98(s,3H), 3.63(s,1H), 3. 51(br.s.,1H), 3.42(d,J=18.1Hz,3H), 3.13-3.01(m,1H), 2.92(d,J=13.5Hz,2H), 1.67(s,5H), 1.64-1.47(m,3H), 1.36(br.s.,2H)

[0195] Procedure for Example 76: Example 76 was prepared from 76-1 utilizing 4-fluoro-3-(trifluoromethyl)aniline following the method described for Example 56. 1 H NMR (500MHz, DMSO-d6) δ 10.52(s,1H), 9.88(d,J=7.0Hz,1H), 8.19(d,J=4.3Hz,1H), 7.97(d,J=2.7Hz,1H), 7.78(d ,J=8.5Hz,1H), 7.65(dd,J=8.7,2.6Hz,1H),7.47(t,J=9.8Hz,1H),7.16(d,J=8.9Hz,1H), 4.31(br.s.,1H), 3.98(s,3H), 3.55-3.40(m,3H), 3.09(dd,J=10.7, 4.0Hz,1H), 3.02(br. s.,1H), 2.91(br.s.,1H), 1.80(t,J=8.9Hz,1H), 1.75-1.62(m,7H), 1.33(d,J=6.1Hz,2H) LC-MS RT:2.69min;MS(ESI) m / z=569.1(MH)+;Method B

[0196] Example 77 [ka]

[0197] Intermediate 77-1: Intermediate 77-1 was prepared from Example 76 in the same general manner as described for Intermediate 5-6. LC-MS RT=1.0 min; (M+H)=544.0; Method A

[0198] Procedure for Example 77: Example 77 was prepared from 77-1 following the general method described in Example 5 utilizing diethyl benzylphosphonate. 1 H NMR (500MHz, DMSO-d6) δ 10.66-10.50(m,1H), 10.06-9.88(m,1H), 8.27-8.13(m,1H), 8.06-7.94(m,1H), 7.86-7.73(m ,1H), 7.71-7.59(m,1H), 7.53-7.43(m,1H), 7.43-7.31(m,4H), 7.31-7.21(m,1H), 7.21-7.09 (m,1H), 6.47-6.22(m,1H), 4.55-4.37(m,1H), 4.09-3.95(m,3H), 3.33-3.19(m,1H), 2.90-2. 76(m,1H), 2.02-1.88(m,1H), 1.87-1.71(m,1H), 1.64-1.42(m,2H), 1.06-0.91(m,1H);LC-MS RT:2.83min;MS(ESI) m / z=617.20(MH)+;Method B

[0199] Example 78 [ka]

[0200] Procedure for Example 78: Example 78 was prepared as a by-product in making Example 77. 1H NMR (500MHz, DMSO-d6) δ 10.66-10.50(m,1H), 10.06-9.88(m,1H), 8.27-8.13(m,1H), 8.06-7.94(m,1H), 7.86-7.73(m ,1H), 7.71-7.59(m,1H), 7.53-7.43(m,1H), 7.43-7.31(m,4H), 7.31-7.21(m,1H), 7.21-7.09 (m,1H), 6.47-6.22(m,1H), 4.55-4.37(m,1H), 4.09-3.95(m,3H), 3.33-3.19(m,1H), 2.90-2. 76(m,1H), 2.02-1.88(m,1H), 1.87-1.71(m,1H), 1.64-1.42(m,2H), 1.06-0.91(m,1H);LC-MS RT:2.82min;MS(ESI) m / z=617.35(MH)+;Method B

[0201] Example 79 [ka]

[0202] Procedure for Example 79: To a 0.5-2.0 mL microwave reaction vial charged with Example 77 (15 mg, 0.024 mmol), 4-boronobenzoic acid (6 mg, 0.04 mmol) was added, followed by a solution of THF (490 μL) and KPO (97 μL, 0.049 mmol) in water. Finally, XPhos-Pd-G (CAS 1310584-14-5) (2 mg, 0.002 mmol, small spatula tip) was added. The vial was capped and heated in a microwave at 100 °C for 30 min. The reaction was diluted with DMF to a total volume of 2 mL, filtered, and purified by preparative RP-HPLC to give Example 79 (5.2 mg, 0.01 mmol, 33% yield). 1H NMR (500 MHz, DMSO-d) δ 9.95(d,J=7.0Hz,1H), 8.26(d,J=4.3Hz,1H), 7.94(d,J=6.7Hz,1H), 7.81(b r.s.,1H), 7.50(t,J=8.2Hz,3H), 7.44-7.32(m,6H), 7.25(br.s.,2H), 7.18 (d,J=8.2Hz,1H), 7.04(t,J=7.5Hz,1H), 6.39(s,1H), 4.52(br.s.,1H), 3.2 8(br.s.,1H), 2.93(br.s.,1H), 2.02-1.79(m,3H), 1.53(br.s.,3H);LC-MS RT:2.2min;MS(ESI) m / z=659.4(MH)+;Method B

[0203] Example 107 [ka] [ka]

[0204] Intermediate IV-1: The same conditions as described in 76-1 were used to deprotect II-4 to intermediate IV-1. Introduction of the trifluoroacetyl protecting group was achieved as follows: II-4 was deprotected to the corresponding amine intermediate, and the amine (1.7 g, 8.1 mmol) was added in 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. After 5 min, the reaction flask was removed from the ice bath and stirred at 23 °C for 30 min. The reaction mixture was quenched with saturated NaHCO (50 mL) and extracted with EtOAc (3 × 50 mL). The organic portions were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give IV-1 (2.48 g, 8.12 mmol, 100% yield), which was used without further purification. LC-MS RT=1.11 min;MS(ESI) m / z=306.1(M+H) + ;Method A

[0205] Intermediate IV-2: Intermediate IV-2 was prepared from IV-1 in a similar manner as described for 5-6 (2.5 g, 5.5 mmol, 63% yield); LC-MS RT=1.20 min; MS(ESI) m / z=453.0 (M+H). + ;Method A

[0206] Intermediate 107-3: Intermediate IV-2 (133 mg, 0.290 mmol) was dissolved in water (2.9 mL) and MeOH (2.9 mL). K2CO3 (2.03 g, 1.47 mmol) was added, and the reaction mixture was stirred at 40 °C for 4 h. The reaction mixture was allowed to cool to room temperature, and then water (5 mL) was added. The resulting solution was extracted with EtOAc (3 x 10 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 107-3 (105 mg, 0.290 mmol, 100% yield), which was used without further purification. LC-MS RT = 0.82 min; MS (ESI) m / z = 357.1 (M+H). + ;Method A

[0207] Intermediate 107-4 was prepared from 107-3 using the sample procedure utilized for 76-1. Procedure for Example 107: Example 107 was prepared from 107-4 utilizing 3-borono-4-fluorobenzoic acid following the method described for Example 79. 1H NMR (500MHz, DMSO-d6) δ 10.64(s,1H), 10.34(brd,J=7.3Hz,1H), 8.23(dd,J=6.1,1.8Hz,1H), 7.99(brd,J=7.6Hz,1H), 7.93(s,1H ), 7.91-7.86(m,1H), 7.80(brd,J=8.2Hz,1H), 7.61(brd,J=8.2Hz,1H), 7.44(brt,J=9.8Hz,1H), 7.33(d, J=8.5Hz,1H), 7.24(brt,J=9.6Hz,1H), 4.46-4.38(m,1H), 3.13(brdd,J=10.4,4.0Hz,1H), 3.03(brs,1H) , 2.93(brs,1H), 2.71(s,6H), 1.94-1.87(m,2H), 1.84-1.75(m,1H), 1.71(s,6H), 1.45-1.30(m,2H); LC-MS RT:2.2 points;MS(ESI) m / z=642.2(M+H) + Method B

[0208] Example 108

change

change

[0209] Intermediate 108-1: To a vial were added 5-(3-bromo-4-fluorophenyl)-1H-tetrazole (50 mg, 0.21 mmol), 5-borono-2-methoxybenzoic acid (60.5 mg, 0.309 mmol), XPhos-Pd-G2 catalyst (32 mg, 0.042 mmol), and K3PO4 (131 mg, 0.617 mmol), followed by THF (1.8 mL) and water (257 μL). The reaction mixture was degassed with nitrogen for 2 minutes, then sealed and heated in a microwave oven at 150 °C for 2.5 hours. The reaction mixture was partitioned between 1N HCl (5 mL) and extracted with EtOAc (3 × 5 mL). The organic portions were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative RP-HPLC to give 108-1 (13 mg, 0.041 mmol, 20% yield). LC-MS RT=0.77 min; MS(ESI) m / z=315.1 (M+H). + ;Method A

[0210] Procedure for Example 108: To a reaction vessel was added 107-3 (10 mg, 0.03 mmol), 108-1 (13.2 mg, 0.0400 mmol), MeCN (1 mL), DIEA (0.02 mL, 0.1 mmol), and HATU (16 mg, 0.040 mmol). The reaction mixture was stirred at 23° C. for 3 h, concentrated under reduced pressure, and subjected to preparative RP-HPLC purification to give Example 108 (12.3 mg, 0.0200 mmol, 65.0% yield). 1H NMR (500MHz, DMSO-d6) δ 10.54(s,1H), 9.93(d,J=7.0Hz,1H), 8.26-8.19(m,2H), 8.17(brd,J=6.4Hz,1H), 8.09-8. 02(m,1H), 7.83-7.75(m,2H), 7.54(dd,J=10.2, 9.0Hz,1H), 7.47(t,J=9.8Hz,1H), 7.34(d ,J=8.5Hz,1H), 4.41-4.34(m,1H), 4.05(s,3H), 3.11(dd,J=10.8, 4.1Hz,1H), 3.05-3.02( LC-MS RT:2.17min;MS(ESI) m / z=653.6(M+H) + ;Method B

[0211] Example 110 [ka] [ka]

[0212] Intermediate 110-1: To a vial was added 5-borono-2-methoxybenzoic acid (100 mg, 0.51 mmol), ethyl 2-bromooxazole-4-carboxylate (75 mg, 0.34 mmol), PdCl(dppf)-CHCl adduct (28 mg, 0.030 mmol), KCO (470 mg, 3.40 mmol), toluene (1.7 mL), and ethanol (1.7 mL). The reaction mixture was heated at 120 °C for 3 h, after which it became a gel. The reaction mixture was diluted with DMF, filtered, and purified by preparative RP-HPLC to give 110-1 (24 mg, 0.080 mmol, 24% yield). RT = 0.73 min; MS (ESI) m / z = 292.1 (M+H). + ;Method A

[0213] Procedure for Example 110: Example 110 was prepared from 107-3 utilizing 110-1 according to the method described for Example 108. 1 H NMR (500MHz, DMSO-d6) δ 10.54(s,1H), 9.93(d,J=7.0Hz,1H), 8.88(s,1H), 8.58(d,J=2.4Hz,1H), 8.20(dd,J=6.4, 2.1Hz,1H), 8. 12(dd,J=8.7, 2.3Hz,1H), 7.81(brdd,J=8.4, 4.1Hz,1H), 7.48(t,J=9.8Hz,1H), 7.37(d,J=8.9Hz,1H), 4. 41-4.35(m,1H), 4.31(q,J=7.0Hz,2H), 4.08(s,3H), 3.12(brdd,J=10.7, 4.0Hz,1H), 3.07-3.02(m,1H), 2.98-2.93(m,1H), 1.86-1.79(m,1H), 1.78-1.69(m,7H), 1.38-1.33(m,2H), 1.31(t,J=7.0Hz,3H);LC-MS RT:2.61min;MS(ESI) m / z=630.5(M+H) + ;Method B

[0214] Example 113 [ka]

[0215] Procedure for Example 113: To a vial containing Example 110 (11.5 mg, 0.02 mmol) in THF (180 μL) / water (90 μL) / MeOH (90 μL) was added a 1.5 M solution of lithium hydroxide (61 μL, 0.09 mmol), and the reaction was stirred at 23° C. for 5 min. The reaction mixture was quenched by the addition of 1 N HCl (1 mL) and extracted with EtOAc (3×5 mL). The organics were combined, dried over NaSO, and concentrated under reduced pressure. The resulting crude product was purified via preparative RP-HPLC to give Example 113 (6.3 mg, 0.01 mmol, 56% yield). 1H NMR (500MHz, DMSO-d6) δ 10.57(s,1H), 9.93(d,J=7.3Hz,1H), 8.57(s,1H), 8.54(d,J=2.1Hz,1H), 8.18(dd,J=6.1, 2. 1Hz,1H), 8.10(dd,J=8.7, 2.3Hz,1H), 7.79(dd,J=8.1, 3.8Hz,1H), 7.46(t,J=9.8Hz,1H), 7.3 5(d,J=8.9Hz,1H), 4.41-4.30(m,1H), 4.06(s,3H), 3.10(dd,J=10.7, 4.0Hz,1H), 3.05-2.99( LC-MS RT:1.92min;MS(ESI) m / z=601.9(M+H) + ;Method B

[0216] Procedure for Example 114: Example 114 was prepared from 14-3 utilizing 5-cyano-2-fluorobenzoic acid following the method described for Example 108. 1 H NMR LC-MS RT:2.53min;MS(ESI) m / z=504.1(M+H) + ;Method C

[0217] Example 120 [ka] [ka]

[0218] Intermediate IV-3: Intermediate IV-3 was prepared from IV-2 in a similar manner to 5-6 (101 mg, 0.240 mmol, 97.0% yield). 1H NMR (500MHz, CDCl3) δ 9.61(brd,J=6.3Hz,1H), 7.76(dd,J=5.9, 2.6Hz,1H), 7.71(dt,J=8.9, 3.4Hz,1H), 7.66(s,1H), 7.23(t,J=9.4Hz,1H), 4.70(dt,J=10.3, 5.3 Hz,1H), 3.33(dd,J=10.5, 4.4Hz,1H), 2.54(t,J=4.3Hz,1H), 2.42(t,J=4.1Hz,1H), 2.20-2.10(m,1H), 2.06-1.99(m,1H), 1.96-1.81(m,2H)

[0219] Intermediate IV-4: Bromo(methyl)triphenylphosphorane (419 mg, 1.17 mmol) (fine powder obtained by grinding commercially available material) and THF (7 mL) were added to a reaction vessel. The reaction mixture was cooled to -78 °C, and KHMDS (1.2 mL, 1.17 mmol) was added. The reaction mixture was vigorously stirred at -78 °C for 30 minutes, and IV-3 (100 mg, 0.240 mmol) was added at -78 °C. After stirring at -78 °C for an additional 10 minutes, the reaction mixture was allowed to warm to 23 °C and stirred for 1.5 hours. The reaction mixture was cooled to -40 °C, and quenched by the addition of saturated NaHCO3. The solution was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified via silica gel chromatography to produce IV-4 (71 mg, 0.17 mmol, 71% yield). LCMS RT=1.16 min;(M+H)=425.0;Method A

[0220] Intermediates IV-5 and IV-6: To a reaction vessel was added IV-4 (71 mg, 0.17 mmol), DCM (3 mL), and Br (0.03 mL, 0.6 mmol). The reaction mixture was stirred at 23 °C for 20 min and concentrated under reduced pressure with a saturated NaSO trap to quench excess Br. The resulting dibromide was dissolved in THF (3 mL). The flask was cooled to -78 °C, and KHMDS (1.0 mL, 1.0 mmol) was added. The reaction mixture was kept at -78 °C for 12 h and at -40 °C for 2 h and quenched by the addition of saturated NaHCO at -40 °C. The resulting solution was extracted with EtOAc. The organic phases were collected, dried over NaSO, filtered, concentrated under reduced pressure, and purified via silica gel chromatography to produce IV-6 (27 mg, 0.050 mmol, 32% yield) (Z-isomer, peak 2; LCMS RT = 1.19 min; (M+H) = 504.9; Method A) and the corresponding E-isomer IV-5 (28 mg, 0.060 mmol, 33% yield) (peak 1). IV-6 was produced as a racemate as outlined above and separated into its individual enantiomers using chiral SFC. Preparative chromatographic conditions: Apparatus: Thar 350 SFC; Column: Chiralcel OD-H, 5x50cm, 5 micron; Mobile phase: 20% MeOH / 80% CO2; Flow conditions: 340mL / min, 100 Bar, 35°C; Detector wavelength: 220nm; Injection details: 3.75mL of 30mg / mL in MeOH; Peak 1, RT=7.81min, >99%ee; Peak 2, RT=10.97min, >99%ee; Peak #1 (1.9 grams) of intermediate IV-6 product was collected and carried forward to generate chiral IV-7.

[0221] Intermediate IV-7: To a reaction vial was added MeOH (3 mL) and AcCl (0.3 mL, 4.2 mmol). After stirring for 5 min, chiral IV-6 (first eluting peak from chiral SFC, 75 mg, 0.15 mmol) was added, and the reaction mixture was stirred at 40 °C for 48 h. The resulting solution was concentrated under reduced pressure to give IV-7 (67 mg, 0.16 mmol, 100%), which was used without further purification. LC-MS RT = 0.78 min; (M+H) = 408.9; Method A

[0222] [ka]

[0223] Intermediate 120-6: 5-Borono-2-methoxybenzoic acid (500 mg, 2.55 mmol), tert-butyl 3-bromo-4-fluorobenzoate (842 mg, 3.06 mmol), tert-butyl 3-bromo-4-fluorobenzoate (842 mg, 3.06 mmol), K2CO3 (1.76 g, 12.8 mmol), PdCl2(dppf)-CHCl2 adduct (313 mg, 0.380 mmol), and THF (22.3 mL) were added to a vial. The reaction mixture was degassed with nitrogen for 2 minutes and then heated at 80 °C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with 1N HCl (25 mL), and the solution was extracted with EtOAc (3 × 25 mL). The organic portions were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the resulting residue was dissolved in DMF and purified by preparative RP-HPLC to give 120-6 (586 mg, 1.69 mmol, 66.0% yield). LC-MS RT=1.02 min; (M+H)=347.1; Method A

[0224] The Suzuki reaction can also be carried out with alternative aryl halides and the remaining steps followed in a similar manner to give the biaryl analogs.

[0225] Intermediate 120-7: To a reaction vessel were added IV-7 (7 mg, 0.02 mmol) and 120-6 (6.6 mg, 0.020 mmol), MeCN (1 mL), DIEA (9.64 μL, 0.0600 mmol), and HATU (12.0 mg, 0.0300 mmol). The reaction mixture was stirred at 23 °C for 3 h, concentrated under reduced pressure, and purified via silica gel chromatography to produce 120-7 (10 mg, 0.014 mmol, 86% yield). LC-MS RT = 1.33 min; (M+H) = 735.2; Method A

[0226] Intermediate 120-8: Intermediate 120-8 was prepared from 120-7 in a similar manner to intermediate 34-2 (5 mg, 0.07 mmol, 100% yield). LC-MS RT=1.15 min; (M+H)=679.08; Method A

[0227] Procedure for Example 120: To a reaction vessel containing 120-8 (10 mg, 0.01 mmol) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (13.3 mg, 0.07 mmol), PdCl(dppf)-CHCl adduct (3 mg, 0.004 mmol, small spatula tip), and NaCO (0.5 mL, 1.0 mmol). The reaction mixture was degassed by bubbling N for 10 min, sealed, and stirred at 60 °C for 2 h. After cooling to 23 °C, the reaction mixture was concentrated under reduced pressure and purified via preparative RP-HPLC to yield the intermediate tert-butyl ester. Treatment of the ester with 10:1 DCM / TFA followed by purification by reverse phase HPLC gave Example 120 (7.0 mg, 0.01 mmol, 72% yield). 1H NMR (500MHz, CDCl3) δ 10.03(brd,J=6.3Hz,1H), 8.50(brs,1H), 8.43(brs,1H), 8.31(brs,1H), 8.21(brd,J=5.2Hz, 1H), 8.10-7.91(m,3H), 7.73(brd,J=8.3Hz,1H), 7.53(brd,J=3.9Hz,1H), 7.27-7.19(m,1H), 7 .19-7.08(m,2H), 6.06(s,1H), 4.86(brs,1H), 4.11(brs,3H), 3.31(brs,1H), 3.22(brd,J=7.2 Hz,1H), 2.93(brs,1H), 2.37-2.25(m,1H), 2.03(brd,J=11.8Hz,1H), 1.75-1.65(m,2H);LC-MS RT:1.14min;MS(ESI) m / z=668.3(M+H) + ;Method A

[0228] Example 121 [ka]

[0229] Procedure for Example 121: To a reaction vessel was added Example 87 (3 mg, 4.77 μmol), ethanesulfonamide (1.6 mg, 0.01 mmol), MeCN (1 mL), DIEA (3 μl, 0.017 mmol), and BOP-Cl (4 mg, 0.01 mmol). The reaction was stirred at 40° C. for 12 h, concentrated under reduced pressure, and purified by preparative RP-HPLC to afford only the primary amide by-product 121 (3.0 mg, 0.0040 mmol, 93% yield). 1H NMR (500MHz, CDCl3) δ 9.65(brd,J=8.0Hz,1H), 8.41(d,J=2.2Hz,1H), 7.96(dd,J=7.2, 2.2Hz,2H), 7.90-7.83(m,2H) , 7.73(dt,J=8.5, 2.2Hz,1H), 7.56(dt,J=8.7, 3.5Hz,1H), 7.25(dd,J=9.9, 8.8Hz,1H), 7.16-7. 06(m,2H), 6.69-6.68(m,1H), 4.72(brt,J=11.0Hz,1H), 4.08(s,3H), 3.06(brd,J=8.8Hz,3H), 2.21-2.14(m,1H), 1.84(brt,J=8.7Hz,1H), 1.76(s,3H), 1.75(s,3H), 1.64-1.54(m,2H);LC-MS RT:1.26min;MS(ESI) m / z=628.3(M+H) + ;Method A

[0230] Example 125 [ka] [ka]

[0231] Intermediate 125-1: Intermediate 125-1 was prepared from IV-3 in a similar manner as in Example 5 and purified via silica gel chromatography (49 mg, 0.10 mmol, 30% yield). RT=1.23 min; MS(ESI) m / z=501.1 (M+H). + ;Method A

[0232] Intermediate 125-2: Intermediate 125-2 was prepared from 125-1 in a similar manner to intermediate IV-7 (73 mg, 0.18 mmol, 96% yield). RT = 0.87 min; MS (ESI) m / z = 405.1 (M+H). + ;Method A

[0233] [ka]

[0234] Intermediate 125-3: To a reaction vessel was added methyl piperazine-1-carboxylate (103 mg, 0.710 mmol), DCE (1 mL), MeCN (1 mL), copper(II) acetate (130 mg, 0.71 mmol), (4-methoxy-3-(methoxycarbonyl)phenyl)boronic acid (50 mg, 0.24 mmol), and 4 Å molecular sieves (300 mg). The reaction mixture was stirred at 23 °C for 12 h (open to air), filtered, concentrated under reduced pressure, and purified via preparative RP-HPLC to yield 125-3 (37 mg, 0.12 mmol, 50% yield). LC-MS RT = 0.72 min; MS (ESI) m / z = 309.1 (M+H). + ;Method A

[0235] Intermediate 125-4: To a reaction vessel were added 125-3 (37 mg, 0.12 mmol), THF (1 mL), water (0.5 mL), and lithium hydroxide monohydrate (34.4 mg, 0.820 mmol). The reaction mixture was stirred at 23 °C for 2.5 h, diluted with EtOAc (10 mL), and washed with 10 mL of saturated NH4Cl containing 0.82 mmol HCl. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 125-4 (35.3 mg, 0.120 mmol, 100% yield), which was used without further purification. LC-MS RT = 0.62 min; MS (ESI) m / z = 295.0 (M+H). + ;Method A

[0236] Procedure for Example 125: Example 125 was prepared from 125-2 utilizing 125-4 according to the method described for Example 108. 1H NMR (500MHz, CDCl3) δ 9.63(brd,J=7.7Hz,1H), 7.96-7.84(m,3H), 7.59(dt,J=8.8, 3.4Hz,1H), 7.33(d,J=4.1Hz,4H), 7.29(dd,J=8.9, 3.2Hz,1H), 7.25-7.20(m,1H), 7.10(t,J=9.4Hz,1H), 6.95(d,J=9.1Hz,1H), 6.3 3(s,1H), 4.89-4.80(m,1H), 3.99(s,3H), 3.75(s,3H), 3.74-3.69(m,4H), 3.49(t,J=3.3Hz,1H) , 3.23-3.14(m,5H), 2.89(m,1H), 2.27-2.19(m,1H), 1.97-1.87(m,1H), 1.75-1.66(m,2H);LC-MS RT:1.16min;MS(ESI) m / z=681.3(M+H) + ;Method A

[0237] Example 126 [ka] [ka]

[0238] Intermediate 126-1: To a reaction vessel containing IV-6 (125 mg, 0.25 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (125 mg, 0.610 mmol), PdCl(dppf)-CHCl adduct (50.7 mg, 0.0620 mmol), and NaCO (1.5 mL, 3.0 mmol) were added. The reaction mixture was degassed by bubbling nitrogen through it for 3 minutes, sealed, and stirred at 60 °C for 2 hours. After cooling to 23 °C, the reaction mixture was extracted with EtOAc, and the organic portions were combined, dried over NaSO, filtered, concentrated under reduced pressure, and purified via silica gel chromatography to produce 126-1 (101 mg, 0.210 mmol, 83.0% yield). LC-MS RT=1.07min;MS(ESI) m / z=492.1(M+H) + ;Method A

[0239] Intermediate 126-2: Intermediate 126-2 was prepared from 126-1 in a similar manner to intermediate IV-7 (67 mg, 0.16 mmol, 100% yield). RT = 0.76 min; MS (ESI) m / z = 396.0 (M+H). + ;Method A

[0240] [ka]

[0241] Intermediate 126-3: To a reaction vessel was added methanesulfonamide (521 mg, 5.48 mmol), 3-bromo-4-fluorobenzoic acid (400 mg, 1.83 mmol), MeCN (3.7 mL), DIEA (1.1 mL, 6.40 mmol), and HATU (833 mg, 2.19 mmol). The reaction mixture was stirred at 40° C. for 12 hours, allowed to cool, concentrated under reduced pressure, and subjected to preparative RP-HPLC purification to produce 126-3 (450 mg, 1.52 mmol, 83% yield). LC-MS RT=0.76 min; (M+H)=297.7; Method A

[0242] Intermediate 126-4: To a reaction vessel containing 126-3 (200 mg, 0.68 mmol), 5-borono-2-methoxybenzoic acid (199 mg, 1.01 mmol), PdCl(dppf)-CHCl adduct (83 mg, 0.10 mmol), THF (6.7 mL), and 1 M NaCO (4.0 mL, 4.1 mmol) were added. The reaction mixture was degassed by bubbling nitrogen through for 10 min, sealed, and stirred at 70 °C for 2 h. After cooling to 23 °C, the reaction mixture was concentrated under reduced pressure and purified by preparative RP-HPLC to give 126-4 (158 mg, 0.430 mmol, 64.0% yield). LC-MS RT = 0.70 min; MS (ESI) m / z = 368.1 (M+H). + ;Method A

[0243] Procedure for Example 126: Example 126 was prepared from 126-2 utilizing 126-4 according to the method described for Example 108. 1 H NMR (500MHz, CDCl3) δ 10.32(brs,1H), 9.86(brd,J=7.7Hz,1H), 8.41(s,1H), 8.34(s,1H), 8.25(d,J=1.7Hz,1H), 8.10(brs,1H), 8.04(dd ,J=6.1, 2.5Hz,1H), 7.98(dd,J=7.3, 2.1Hz,1H), 7.89(ddd,J=8.5, 4.5, 2.2Hz,1H), 7.68(brd,J=8.8Hz,1H), 7.58(d t,J=8.6, 3.5Hz,1H), 7.19-7.06(m,3H), 5.95(s,1H), 4.72-4.63(m,1H), 4.08(s,3H), 3.45(s,3H), 3.25-3.20(m,1 LC-MS RT:1.09min;MS(ESI) m / z=745.2(M+H) + ;Method A

[0244] Example 127 [ka]

[0245] Intermediate 127-1: To a reaction vessel was added Example 6 (10 mg, 0.017 mmol), DCM (1 mL), DIEA (0.015 mL, 0.087 mmol), and DMAP (1.06 mg, 8.70 μmol). After stirring at 23° C. for 12 hours, the residue was purified via silica gel chromatography to produce 127-1 (10.5 mg, 0.0160 mmol, 92.0% yield). LC-MS RT=1.31 min; MS(ESI) m / z=659.3 (M+H). + ;Method A

[0246] Procedure for Example 127: To a reaction vessel was added 3-((trifluoromethyl)sulfonyl)aniline (24 mg, 0.11 mmol), toluene (0.5 mL), and trimethylaluminum (0.05 mL, 0.11 mmol). After stirring at 23° C. for 15 minutes, intermediate 127-1 (5 mg, 7.6 μmol) in toluene (0.5 mL) was added. The reaction was stirred at 23° C. for 1 hour, quenched with saturated Rochelle's salt, and extracted with EtOAc. The organic phase was dried over NaSO, concentrated, and purified by preparative RP-HPLC to give Example 127 (3.6 mg, 5.80 μmol, 76% yield). 1 H NMR (500MHz, CDCl3) δ 9.56(brd,J=7.7Hz,1H), 8.56-8.47(m,1H), 8.06-7.98(m,2H), 7.78-7.71(m,2H), 7.58 (t,J=8.0Hz,1H), 7.37-7.30(m,4H), 7.25-7.21(m,1H), 6.79(dd,J=11.7, 6.2Hz,1H), 6 .33(s,1H), 4.88-4.81(m,1H), 4.03(s,3H), 3.52-3.47(m,1H), 3.20(dd,J=10.7, 3.9Hz ,1H), 2.91-2.87(m,1H), 2.26-2.18(m,1H), 1.95-1.88(m,1H), 1.74-1.70(m,2H);LC-MS RT:1.25min;MS(ESI) m / z=621.2(M+H) + ;Method A

[0247] Example 130 [ka]

[0248] Intermediate 130-1: Intermediate 130-1 was prepared from Example 87 in a similar manner as described for 77-1 (19 mg, 0.030 mmol, 100% yield). LC-MS RT=1.06 min; MS(ESI) m / z=603.1 (M+H). + ;Method A

[0249] Procedure for Example 130: To a reaction vessel containing 130-1 (17 mg, 0.03 mmol), DCE (1.5 mL), DIEA (0.09 mL, 0.51 mmol), and O-ethylhydroxylamine·HCl (41.3 mg, 0.42 mmol) were added. The mixture was stirred at 40° C. and 23° C. for 24 h, concentrated under reduced pressure, and subjected to preparative RP-HPLC purification to give Example 130 as a mixture of Z / E isomers (15 mg, 0.023 mmol, 82% yield). LC-MS RT: 1.13 min; MS(ESI) m / z=464.2 (M+H). + ;Method A

[0250] Example 134 [ka]

[0251] Procedure for Example 134: To a reaction vessel was added Example 140 (6 mg, 10 μmol), DCM (1 mL), DIEA (6 μl, 0.03 mmol), and methyl chloroformate (2 μl, 0.02 mmol). After stirring at 23° C. for 30 min, the reaction mixture was concentrated under reduced pressure and purified by preparative RP-HPLC to give Example 134 (3.5 mg, 5.4 μmol, 51% yield). 1 H NMR (500MHz, CDCl3) δ 9.42-9.17(m,1H), 8.25-8.02(m,2H), 7.87(dd,J=6.1, 2.4Hz,1H), 7.62-7.53(m,1H), 7.43(brs ,1H), 7.07(t,J=9.5Hz,1H), 6.92(brd,J=8.6Hz,1H), 6.17(brs,1H), 4.78-4.66(m,1H), 4.38-4 .23(m,2H), 3.98(s,3H), 3.75(s,3H), 3.66-3.52(m,2H), 3.08-2.97(m,3H), 2.37-2.26(m,2H), 2.23-2.11(m,1H), 1.83-1.75(m,1H), 1.74-1.72(m,3H), 1.72(s,3H), 1.62-1.53(m,2H);LC-MS RT:1.25min;MS(ESI) m / z=630.3(M+H)+ ;Method B

[0252] Example 136 [ka] [ka]

[0253] Intermediate 136-1: To a reaction vessel was added methyl 5-bromo-2-methoxybenzoate (33.1 mg, 0.135 mmol), tert-butyl piperidine-3-carboxylate (25 mg, 0.14 mmol), toluene (1 mL), tert-butyl piperidine-3-carboxylate (25 mg, 0.14 mmol), BINAP (10.5 mg, 0.0200 mmol), and Pd2(dba)3 (6 mg, 0.01 mmol). The reaction mixture was degassed with nitrogen for 3 minutes, stirred at 100°C for 12 hours, cooled to 23°C, diluted with EtOAc, and the solution was washed with saturated NaHCO3 (2 x 10 mL). The organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative RP-HPLC to give 136-1 (39 mg, 0.084 mmol, 62% yield). LC-MS RT=0.82 min; MS(ESI) m / z=350.1 (M+H). + ;Method A

[0254] Intermediate 136-2: To a reaction vessel were added 136-1 (26 mg, 0.060 mmol), THF (1 mL), water (0.5 mL), and lithium hydroxide monohydrate (19.1 mg, 0.460 mmol). The reaction mixture was stirred at 23 °C for 3 h, diluted with EtOAc (10 mL), and washed with 10 mL of saturated NH4Cl containing 0.5 mmol HCl. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 136-2 (19 mg, 0.060 mmol, 100% yield), which was used without further purification. LC-MS RT = 0.74 min; MS (ESI) m / z = 336.1 (M+H). + ;Method A

[0255] Procedure for Example 136: Example 136 was prepared from 125-2 utilizing racemic 136-2 according to the method described for Example 108. Subsequent removal of the tert-butyl ester was accomplished similarly to the procedure for preparing Example 120. Example 136 (peak 1) was separated from its diastereomer (peak 2), Example 138, via SFC chromatography. Peak 1, RT=8.80 min, >99.5% ee; Peak 2, RT=9.97 min, >99.5% ee; Preparative Chromatography Conditions: Apparatus: Berger MG II; Column: Chiralpak IA, 30x250 mm, 5 micron; Mobile phase: 25% EtOH / 75% CO2; Flow conditions: 70 mL / min, 150 Bar, 40 °C; Detector wavelength: 220 nm; Injection details: 0.5 mL of approximately 3 mg / mL in ACN; Analytical Chromatography Conditions: Apparatus: Berger Analytical SFC; Column: Chiralpak IA, 4.6x250 mm, 5 micron; Mobile phase: 25% EtOH / 75% CO2; Flow conditions: 2.0 mL / min, 150 Bar, 40 °C; Detector wavelength: 220 nm; Injection details: 10 μL of concentrated sample / EtOH; LC-MS RT:1.07min;MS(ESI) m / z=666.3(M+H) + ;Method A

[0256] Example 140 [ka]

[0257] Intermediate 140-1: To a reaction vessel containing methyl 5-bromo-2-methoxybenzoate (47.6 mg, 0.190 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.16 mmol), PdCl(dppf)-CHCl adduct (19.8 mg, 0.0240 mmol), and NaCO (1 mL, 2 mmol) were added. The reaction mixture was degassed by bubbling nitrogen through for 3 minutes, sealed, and stirred at 65 °C for 2 hours. After cooling to 23 °C, the reaction mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified via silica gel chromatography to yield 140-1 (57.4 mg, 0.17 mmol, 100% yield). LC-MS RT = 1.04 min; MS (ESI) m / z = 348.0 (M+H). + ;Method A

[0258] Intermediate 140-2: A reaction vessel was charged with 140-1 (28 mg, 0.081 mmol), THF (1 mL), water (0.5 mL), and lithium hydroxide monohydrate (16.9 mg, 0.400 mmol). The reaction mixture was stirred at 23 °C for 1 h, diluted with EtOAc (10 mL), and the resulting solution was washed with 10 mL of saturated NH Cl containing 0.5 mmol HCl. The organic phase was dried over Na SO , filtered, and concentrated under reduced pressure to give 140-2 (25 mg, 0.080 mmol, 93% yield), which was used without further purification.

[0259] Intermediate 140-3: Intermediate 140-3 was prepared from 140-2 and 107-3 using the general amide coupling procedure utilized in Example 108 (67 mg, 0.16 mmol, 100% yield). RT = 1.32 min; MS (ESI) m / z = 672.3 (M+H). + ;Method A

[0260] Procedure for Example 140: To a reaction vessel was added 140-3 (11.4 mg, 0.02 mmol), DCM (1 mL), and TFA (0.1 mL, 1.30 mmol). After stirring at 23° C. for 3 h, the reaction was concentrated under reduced pressure to give Example 140 (3.7 mg, 5.13 μmol, 30% yield). 1 H NMR (500MHz, CDCl3) δ 9.29(brd,J=7.9Hz,1H), 8.59(brs,1H), 8.08(d,J=2.3Hz,1H), 7.94(brd,J=4.5Hz,1H), 7.67-7.57(m,1H), 7. 18(brd,J=8.3Hz,1H), 7.06(t,J=9.4Hz,1H), 6.82(d,J=8.6Hz,1H), 6.16(brs,1H), 4.75-4.60(m,1H), 3.97(s, 3H), 3.79-3.59(m,2H), 3.20-3.12(m,1H), 3.11-3.05(m,2H), 3.04-3.00(m,1H), 2.98-2.95(m,1H), 2.46-2.3 4(m,2H), 2.22(brt,J=8.7Hz,1H), 1.77(brt,J=8.7Hz,1H), 1.72(s,3H), 1.71(s,3H), 1.60-1.53(m,2H);LC-MS RT:0.98min;MS(ESI) m / z=572.4(M+H) + ;Method B

[0261] Example 144 [ka]

[0262] Procedure for Example 144: To a reaction vessel was added Example 114 (3.4 mg, 6.6 μmol), sodium azide (12.9 mg, 0.198 mmol), ammonium chloride (10.6 mg, 0.198 mmol), and DMF. The reaction mixture was stirred at 105° C. for 4 hours, cooled to 23° C., diluted with MeOH, filtered, and purified via preparative RP-HPLC to yield Example 144 (2.3 mg, 4.0 μmol, 60% yield). 1H NMR (500MHz, CDCl3) δ 10.01(d,J=9.4Hz,1H), 9.30(d,J=2.5Hz,1H), 8.51(dd,J=8.8, 2.5Hz,1H), 8.44(s,1H), 8.11(dd ,J=6.3, 2.8Hz,1H), 7.41(dt,J=8.7, 3.3Hz,1H), 7.25-7.22(m,1H), 7.08-6.99(m,1H), 4.96(td,J =9.8, 4.3Hz,1H), 4.21(s,3H), 3.31(dd,J=10.7, 3.9Hz,1H), 3.04(t,J=3.7Hz,1H), 2.88(t,J=4.0 Hz,1H), 2.51-2.44(m,1H), 1.87-1.80(m,2H), 1.67(s,3H), 1.60-1.50(m,2H), 1.48(s,3H);LC-MS RT:1.11min;MS(ESI) m / z=559.1(M+H) + ;Method A

[0263] Example 145 [ka]

[0264] Procedure for Example 145: Example 145 was prepared from 5-6 using 2-methyloxazole (24.9 mg, 0.300 mmol) and THF (1 mL). To a reaction vessel, 2-methyloxazole (24.9 mg, 0.300 mmol) and THF (1 mL) were added. The reaction mixture was cooled to -78 °C, and then KHMDS (0.30 mL, 0.30 mmol) was added. The mixture was stirred at -78 °C for 10 minutes, and additional 2-methyloxazole (24.9 mg, 0.300 mmol) was added. The mixture was allowed to warm to 23 °C, stirred at 23 °C for 3 hours, and quenched by the addition of saturated Na2CO3. The organic phase was dried over Na2SO4, filtered, concentrated, and purified via silica gel chromatography to afford the intermediate alcohol (17 mg, 0.029 mmol, 97% yield). The intermediate alcohol was dehydrated according to the method described in Example 33. 1H NMR (500MHz, CDCl3) δ 9.53(brd,J=7.4Hz,1H), 8.06-7.99(m,2H), 7.97(dd,J=6.2, 2.6Hz,1H), 7.63(s,1H), 7.53(dt,J=8.9, 3.4Hz,1H), 7.18-7.09(m,2H), 6.80(dd,J=11.6, 6.1Hz,1H), 6.28(s, 1H), 4.88-4.80(m,1H), 4.00(s,3H), 3.93(t,J=4.0Hz,1H), 3.19(dd,J=10.9, 3.7Hz,1 LC-MS RT:1.17min;MS(ESI) m / z=566.0(M+H) + ;Method A

[0265] Example 147 [ka]

[0266] Procedure for Example 147: To a reaction vessel was added 5-6 (10 mg, 0.020 mmol), benzene (1 mL), ethane-1,2-diol (24.81 mg, 0.4000 mmol), MgSO (200 mg, 1.66 mmol), and pTsOH monohydrate (3.8 mg, 0.020 mmol). After stirring at 50° C. for 12 h, the reaction mixture was filtered, concentrated under reduced pressure, and purified by preparative RP-HPLC to give Example 147 (2.1 mg, 3.8 μmol, 19% yield). 1H NMR (500MHz, CDCl3) δ 9.35(brd,J=7.8Hz,1H), 8.04(dd,J=11.4, 9.4Hz,1H), 7.93(dd,J=6.3, 2.6Hz,1H), 7.77(s,1H), 7.52(dt,J=8.7, 3.6Hz,1H), 7.12(t,J=9.4Hz,1H), 6.79(dd,J=11.6, 6 .1Hz,1H), 5.05-4.97(m,1H), 4.08-4.01(m,4H), 3.99(s,3H), 3.49-3.41(m,1H), 2. 23(t,J=4.0Hz,1H), 2.20-2.11(m,2H), 1.93-1.81(m,2H), 1.75-1.67(m,1H);LC-MS RT:1.14min;MS(ESI) m / z=545.1(M+H) + ;Method C

[0267] Example 150 [ka]

[0268] Procedure for Example 150: To a reaction vessel was added Example 87 (5 mg, 8 μmol), benzenesulfonamide (3.8 mg, 0.020 mmol), MeCN (1 mL), DIEA (5 μl, 0.03 mmol), and BOP-Cl (6.0 mg, 0.024 mmol). The reaction mixture was stirred at 40° C. for 12 h, concentrated under reduced pressure, and purified by preparative RP-HPLC to give Example 150 (2.2 mg, 2.7 μmol, 34% yield). 1H NMR (500MHz, CDCl3) δ 9.65(brd,J=8.0Hz,1H), 8.41(d,J=2.2Hz,1H), 7.96(dd,J=7.2, 2.2Hz,2H), 7.90-7.8 4(m,2H), 7.73(dt,J=8.5, 2.2Hz,1H), 7.56(dt,J=8.7, 3.5Hz,1H), 7.25(dd,J=9.9, 8.8 Hz,1H), 7.16-7.03(m,2H), 4.75-4.68(m,1H), 4.08(s,3H), 3.06(brd,J=8.8Hz,3H), 2. 21-2.14(m,1H), 1.87-1.81(m,1H), 1.76(s,3H), 1.75(s,3H), 1.63-1.56(m,2H);LC-MS RT:1.4min;MS(ESI) m / z=768.2(M+H) + ;Method C

[0269] Example 166 [ka]

[0270] Intermediate 166-1: Intermediate 166-1 was prepared from IV-6 in a similar manner to intermediate 126-1 (5.1 mg, 0.010 mmol, 23% yield). RT = 1.21 min; MS (ESI) m / z = 465.1 (M+H). + ;Method A

[0271] Intermediate 166-2: Intermediate 166-2 was prepared from 166-1 in a similar manner to intermediate IV-7 (4.0 mg, 0.010 mmol, 100% yield). RT = 0.84 min; MS (ESI) m / z = 369.1 (M+H). + ;Method A

[0272] [ka]

[0273] Intermediate 166-3: Intermediate 166-3 was prepared in a similar manner to Intermediate 140-1 from 3-bromo-4-fluoro-N-methylbenzamide and 5-borono-2-methoxybenzoic acid (28 mg, 0.080 mmol, 41% yield). LC-MS RT=0.99 min; MS(ESI) m / z=304.9 (M+H). + ;Method A

[0274] Procedure for Example 166: Example 166 was prepared from 166-2 utilizing 166-3 according to the method described for Example 108. 1 H NMR (500MHz, CDCl3) δ 9.73(brd,J=7.7Hz,1H), 8.39(d,J=1.9Hz,1H), 7.97(dd,J=6.2, 2.3Hz,1H), 7.90(s,1H), 7.85(dd,J=7.4, 2.2Hz,1H), 7.81(ddd,J=8.5, 4. 7, 2.2Hz,1H), 7.72(dt,J=8.8, 2.2Hz,1H), 7.56(dt,J=8.7, 3.4Hz,1H), 7.24-7.19(m,1H), 7.15-7.10(m,1H), 7.08(d,J=8.8Hz,1H), 6.47(b rs,1H), 4.85-4.76(m,1H), 4.66(d,J=9.6Hz,1H), 4.09(s,3H), 3.22(t,J=3.7Hz,1H), 3.10(dd,J=10.7, 3.3Hz,1H), 3.05(d,J=4.7Hz,3H), LC-MS RT:1.18min;MS(ESI) m / z=654.2(M+H) + ;Method A

[0275] Example 168 [ka]

[0276] Procedure for Example 168: Example 168 was prepared from 166-2 utilizing 120-6 according to the method described for Example 108. Cleavage of the tert-butyl ester was achieved by stirring with ZnBr (20 equiv.) in DCM (1 mL) at 23° C. for 12 hours. The reaction was quenched by adding HCl (1.0 M), and the resulting solution was extracted with ethyl acetate. The organic phase was then dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to yield Example 168. Analytical Data for Example 168: 1 H NMR (500MHz, CDCl3) δ 9.42(brd,J=7.7Hz,1H), 8.43(brs,1H), 8.30-8.21(m,1H), 8.12-8.02(m,1H), 7.96(brs,2H), 7.71(dt, J=8.7, 2.0Hz,1H), 7.54-7.47(m,1H), 7.26-7.21(m,1H), 7.13-7.06(m,2H), 4.95-4.85(m,1H), 4.66(d,J =9.6Hz,1H), 4.07(s,3H), 3.27-3.19(m,1H), 3.14(brdd,J=10.9, 3.2Hz,1H), 2.75(t,J=3.9Hz,1H), 2.3 2-2.23(m,1H), 1.94-1.87(m,1H), 1.74-1.63(m,2H), 1.54-1.48(m,1H), 0.76(m,2H), 0.36(m,2H);LC-MS RT:1.19min;MS(ESI) m / z=641.1(M+H) + ;Method A

[0277] Example 170 [ka] [ka]

[0278] Intermediate 170-1: To a 20 mL vial charged with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (volume ?, 0.15 mmol) in anhydrous DMF (0.5 mL), a suspension of IV-6 and CuI (mass ?, 0.07 mmol) in anhydrous DMF (1 mL) and HMPA (0.5 mL) was added dropwise via syringe at 75 °C under a nitrogen atmosphere over 30 min. The resulting mixture was stirred at the same temperature for 12 h. The reaction mixture was cooled, filtered through an HPLC filter, and purified by RP-HPLC to produce 170-1 (24 mg, 81% yield). 1 H NMR (500MHz, CDCl3) δ 9.38(brd,J=6.1Hz,1H), 7.77-7.69(m,2H), 7.46(s,1H), 7.24(t,J=9.1Hz,1H), 5.62(q,J=7.2Hz,1H), 4.50(dt,J= 10.5, 5.3Hz,1H), 3.50-3.42(m,1H), 3.13-3.04(m,1H), 2.89(t,J=4.0Hz,1H), 2.02-1.90(m,2H), 1.76-1.60(m,2H)

[0279] Intermediate 170-2: Intermediate 170-2 was prepared from 170-1. MeOH (1.5 mL) and acetyl chloride (2.1 mmol) were charged to a 2-dram vial and stirred at 23° C. for 5 min. 170-1 was added to the reaction vial and the contents were heated at 40° C. for 24 h. The reaction mixture was concentrated with a stream of nitrogen to give 170-2 as the HCl salt, which was used without further purification. LC-MS RT=0.75 min; MS(ESI) m / z=397.1 (M+H). + ;Method A

[0280] Procedure for Example 170: Example 170 was prepared from 170-2 using 120-6 according to the method described for Example 120. Analytical Data for Example 170: 1H NMR (500MHz, CDCl3) δ 9.28(brd,J=6.6Hz,1H), 8.41(brs,1H), 8.37(brs,1H), 8.27(brd,J=6.1Hz,1H), 8.08(brs,1H), 7.92(brs,1H), 7.80-7.70(m,1H), 7.47(dt,J=8.6, 3.7Hz,1H), 7.27-7.20(m,1H), 7.13-7.02(m, 2H), 5.60(q,J=7.3Hz,1H), 5.05-4.92(m,1H), 4.06(s,3H), 3.42(brs,1H), 3.25(brdd,J=10.6, 3 .4Hz,1H), 2.95(t,J=4.0Hz,1H), 2.61-2.50(m,1H), 2.05-1.97(m,1H), 1.82-1.72(m,2H);LC-MS RT:1.15min;MS(ESI) m / z=669.2(M+H) + ;Method A

[0281] Example 171 [ka]

[0282] Procedure for Example 171: Example 171 was prepared from Example 186. To a 1-dram vial charged with Example 186 (0.008 mmol), DCM (0.3 mL), and MeOH (0.1 mL) was added TMS-diazomethane (0.5 M in DCM, 0.34 mL, 0.17 mmol, 20 equiv.) and the reaction mixture was stirred at 23° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel normal phase chromatography to give 6.1 mg of Example 171. Analytical data for Example 171: 1H NMR (500MHz, CDCl3) δ 9.45(brd,J=8.0Hz,1H), 8.38-8.35(m,1H), 8.00-7.92(m,2H), 7.64(dt,J=8.7, 2.0Hz,1H), 7.54(dt,J=8.7, 3.5Hz,1H), 7.43(dd ,J=7.3, 2.3Hz,1H), 7.32(ddd,J=8.4, 4.5, 2.5Hz,1H), 7.17-7.03(m,3H), 6.59(brd,J=6.9Hz,1H), 5.61(d,J=6.9Hz,1H), 4.89-4 .81(m,1H), 4.65(d,J=9.6Hz,1H), 4.06(s,3H), 3.77(s,3H), 3.21(t,J=4.1Hz,1H), 3.15-3.08(m,1H), 2.73(t,J=4.0Hz,1H), 2.2 LC-MS RT:1.15min;MS(ESI) m / z=726.3(M+H) + ;Method A

[0283] Example 172 [ka]

[0284] Procedure for Example 172: Example 172 was prepared from Example 171. To an ice-bath cooled 1-dram vial charged with Example 171 (0.009 mmol) and THF (0.5 mL) was added LiBH (0.027, 3.0 equiv.). The reaction mixture was stirred at 0° C. for 5 minutes, then allowed to warm to 23° C. and stirred for an additional 30 minutes. The reaction mixture was diluted with ethyl acetate (10 mL). The solution was washed with saturated aqueous ammonium chloride solution (20 mL). The aqueous phase was extracted with EtOAc, and the organic portions were combined, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give Example 172. Analytical data for Example 172: 1H NMR (500MHz, CDCl3) δ 9.54(d,J=8.0Hz,1H), 8.29(d,J=1.7Hz,1H), 8.21(s,1H), 7.96(dd,J=6.1, 2.5Hz,1H), 7.57-7.47(m,2H), 7.32-7.29(m,1H) ), 7.23(ddd,J=8.3, 4.6, 2.5Hz,1H), 7.12-7.00(m,3H), 6.45(brd,J=6.9Hz,1H), 5.10-5.03(m,1H), 4.85-4.76(m,1H), 4.62 (d,J=9.4Hz,1H), 4.08(s,3H), 3.93-3.86(m,2H), 3.18(t,J=4.1Hz,1H), 3.13-3.06(m,1H), 2.71(t,J=4.0Hz,1H), 2.26-2.1 LC-MS RT:1.08min;MS(ESI) m / z=698.4(M+H) + ;Method A

[0285] Example 177 [ka] [ka]

[0286] Intermediate VIII-2: Intermediate VIII-2 was prepared using known conditions for similar substrates, except that the reaction temperature was maintained at 80°C for 12 hours (Ludwig, J.; Lehr, M. Syn. Comm. 2004, 34, 3691-3695). 1 H NMR (500MHz, CDCl3) δ 7.49(dd,J=6.6, 2.2Hz,1H), 7.20(ddd,J=8.3, 4.6, 2.2Hz,1H), 7.13-7.03(m,1H), 3.49(s,2H), 1.46(s,9H)

[0287] Intermediate VIII-3: To a 20 mL reaction vial charged with intermediate VIII-2 (266 mg, 0.920 mmol), NBS (196 mg, 1.10 mmol), carbon tetrachloride (10 mL), and AIBN (15 mg, 0.090 mmol) were added. The solution was stirred at 77 °C for 3 hours. The solution was concentrated under reduced pressure and purified by normal phase silica gel chromatography to give intermediate VIII-3 (308 mg, 0.840 mmol, 91.0% yield).

[0288] Intermediate VIII-4: To a 2-dram vial charged with intermediate VIII-3, ethyl acetate (2 mL), triethylamine (0.27 mL, 2.0 mmol), and acetic acid (0.1 mL, 2 mmol) were added. The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by normal phase silica gel chromatography to give intermediate VIII-4. 1 H NMR (500MHz, CDCl3) δ 7.70(dd,J=6.6, 2.2Hz,1H), 7.41(ddd,J=8.4, 4.7, 2.1Hz,1H), 7.15(t,J=8.4Hz,1H), 5.77(s,1H), 2.22(s,3H), 1.43(s,9H)

[0289] Intermediate VIII-5: Intermediate VIII-5 was prepared from intermediate VIII-4 using 5-borono-2-methoxybenzoic acid under the same conditions as used for intermediate 140-1. Half of the material was isolated as the O-acetate (85 mg, 0.60 mmol, 34%). 1 H NMR (500 MHz, CDCl3) δ 8.43-8.36 (m, 1H), 7.81 (dt, J = 8.7, 2.0 Hz, 1H), 7.56 (dd, J = 7.3, 2.3 Hz, 1H), 7.45 (ddd, J = 8.5, 4.6, 2.3 Hz, 1H), 7.23-7.16 (m, 2H), 5.84 (s, 1H), 4.17 (s, 3H), 2.23 (s, 3H), 1.45 (s, 9H). The other half was isolated as the free alcohol (70 mg, 0.19 mmol, 31%). 1H NMR (500 MHz, CDCl) δ 8.40 (d, J = 2.2 Hz, 1H), 7.82 (dt, J = 8.6, 2.2 Hz, 1H), 7.54 (dd, J = 7.4, 2.5 Hz, 1H), 7.41 (ddd, J = 8.4, 4.8, 2.2 Hz, 1H), 7.19-7.14 (m, 2H), 5.09 (s, 1H), 4.16 (s, 3H), 1.47 (s, 9H); racemic VIII-5 was separated into its individual enantiomers using chiral SFC. Preparative chromatographic conditions: Apparatus: Berger MG II; Column: Chiralpak ID, 21x250mm, 5 microns; Mobile phase: 25% IPA / 75% CO2; Flow conditions: 45mL / min, 120 Bar, 40°C; Detector wavelength: 220nm; Injection details: 8 injections of 0.36mL of approximately 20mg / mL (in IPA); Analytical chromatographic conditions: Apparatus: Waters UPC2 Analytical SFC; Column: Chiralpak ID 4.6x100mm, 3 microns; Mobile phase: 25% IPA / 75% CO2; Flow conditions: 2mL / min, 150 Bar, 40°C; Detector wavelength: 220nm; Peak 1, RT=3.89min, >99.5%ee; Peak 2, RT=5.44min, >99.5%ee; Peak #2 of the intermediate VIII-5 product was collected and carried forward to generate chiral intermediate 177-5.

[0290] Intermediate 177-5: Intermediate 177-5 was prepared from VIII-5 peak 2 according to the method described for Example 108. Intermediate 177-5 (14.2 mg, 0.0200 mmol, 79.0% yield); LC-MS RT=1.22 min; MS(ESI) m / z=727.1 (M+H). + ;Method A

[0291] Intermediate 177-6: To a 1-dram vial charged with 177-5 was added DCM (1 mL) and phenyl isocyanate (82 mg, 0.69 mmol). The solution was stirred at 23 °C for 4 days, concentrated under reduced pressure, and purified by RP-HPLC to give intermediate 177-6 (6.2 mg, 0.0070 mmol, 53% yield).

[0292] Procedure for Example 177: Example 177 was prepared from 177-6 by utilizing the tert-butyl ester cleavage method described in Example 168. Analytical Data for Example 177: 1 H NMR (500MHz, CDCl3) δ 9.74(brd,J=8.0Hz,1H), 8.22(d,J=2.2Hz,1H), 8.06-7.97(m,2H), 7.73(brs,1H), 7.65(td,J=8.7, 2.1Hz,2H), 7.46( dt,J=8.8, 3.4Hz,1H), 7.41-7.33(m,3H), 7.24(t,J=7.8Hz,2H), 7.09-6.98(m,4H), 6.15(s,1H), 4.84-4.74(m,1H), 4 .59(d,J=9.6Hz,1H), 4.04(s,3H), 3.16(t,J=4.0Hz,1H), 3.09(brdd,J=10.6, 3.7Hz,1H), 2.67(brt,J=3.7Hz,1H), 2. 21-2.14(m,1H), 1.91-1.82(m,1H), 1.68-1.52(m,2H), 1.51-1.41(m,1H), 0.79-0.69(m,2H), 0.36-0.29(m,2H);LC-MS RT:1.26min;MS(ESI) m / z=790.4(M+H) + ;Method A

[0293] Example 178 [ka]

[0294] Procedure for Example 178: Example 178 was prepared from 34-1. To a 2-dram vial charged with 34-1, DCM (1.5 mL), and DIEA (0.12 mL, 0.70 mmol, 30 equiv.) was added acetyl chloride (0.03 mL, 0.5 mmol, 20 equiv.) and stirred at 23° C. for 1 hour. The reaction was quenched by the addition of MeOH (1 mL), and the tert-butyl ester was removed according to the method described for Example 168. Analytical data for Example 178: 1H NMR (500MHz, CDCl3) δ 9.82(d,J=8.3Hz,1H), 8.45(s,1H), 8.36(s,1H), 8.29(s,1H), 8.26(d,J=2.5Hz,1H), 8.00(dd,J=6.3, 2.5H z,1H), 7.70(dt,J=8.5, 2.2Hz,1H), 7.62(dd,J=7.4, 2.2Hz,1H), 7.46(ddd,J=8.5, 4.3, 2.6Hz,2H), 7.14(dd ,J=10.0, 8.7Hz,1H), 7.08-7.00(m,2H), 5.98(s,1H), 5.98(s,1H), 4.88-4.79(m,1H), 4.06(s,3H), 3.25-3 .19(m,2H), 2.91-2.86(m,1H), 2.40-2.33(m,1H), 2.19(s,3H), 2.00-1.93(m,1H), 1.72-1.60(m,2H);LC-MS RT:1.11min;MS(ESI) m / z=740.1(M+H) + ;Method A

[0295] Example 179 [ka] [ka]

[0296] Intermediate 179-1: To a 20 mL vial charged with 177-5 was added DCM (4 mL), 4-nitrophenyl carbonochloridate (volume or mass, 0.43 mmol), and DMAP (mass, 0.04 mmol). The reaction solution was stirred at 23 °C for 12 h. Methylamine (0.85 mmol) was added, and the reaction solution was stirred for an additional 1 h. The reaction solution was concentrated under reduced pressure and purified by RP-HPLC to give intermediate 179-1 (65 mg, 0.083 mmol, 97%). LC-MS RT = 1.24 min; MS (ESI) m / z = 784.4 (M+H). + ;Method A

[0297] Procedure for Example 179: Example 179 was prepared from 179-1 following the tert-butyl ester cleavage method as described in Example 168. Analytical Data for Example 179: 1 H NMR (500MHz, CDCl3) δ 9.70(brd,J=8.0Hz,1H), 8.28(d,J=1.9Hz,1H), 8.19(s,1H), 8.01(dd,J=6.2, 2.6Hz,1H), 7.68(dt,J=8.6, 2.2Hz,1H), 7.60(b rd,J=5.5Hz,1H), 7.52-7.45(m,1H), 7.45-7.37(m,1H), 7.15-7.00(m,3H), 6.05(s,1H), 5.38-5.28(m,1H), 4.82-4.75(m,1H), 4.60(d,J=9.4Hz,1H), 4.07(s,3H), 3.16(t,J=4.1Hz,1H), 3.10(dd,J=10.5, 3.3Hz,1H), 2.85(brd,J=3.3Hz,3H), 2.71-2.67(m ,1H), 2.25-2.20(m,1H), 1.92-1.86(m,1H), 1.68-1.53(m,2H), 1.49-1.42(m,1H), 0.78-0.69(m,2H), 0.36-0.30(m,2H);LC-MS RT:1.13min;MS(ESI) m / z=728.3(M+H) + ;Method A

[0298] Example 182 [ka] [ka]

[0299] Intermediate 182-1: To a 1-dram vial charged with intermediate VIII-3 was added ammonia (0.5 mL, 4 mmol, 7 M in MeOH). The solution was stirred at 23 °C for 12 h. The solution was concentrated under reduced pressure, and the residue was treated with acetic anhydride (7.2 μL, 0.076 mmol) in DCM (1 mL) and stirred at 23 °C for 1 h. The resulting residue was purified by normal phase silica gel chromatography to give intermediate 182-1 (26 mg, 0.074 mmol, 97% yield). LC-MS RT = 0.92 min; MS (ESI) m / z = 346.1 (M+H). + ;Method A

[0300] Intermediate 182-2: Intermediate 182-2 was prepared using similar conditions as described for Intermediate 140-1, except the reaction was carried out at a temperature of 65° C. for 18 hours. 1H NMR (500 MHz, CDCl) δ 8.37 (d, J = 1.9 Hz, 1H), 7.81 (dt, J = 8.5, 2.1 Hz, 1H), 7.45 (dd, J = 7.3, 2.3 Hz, 1H), 7.35 (ddd, J = 8.5, 4.6, 2.3 Hz, 1H), 7.21-7.13 (m, 2H), 6.74 (brd, J = 6.9 Hz, 1H), 5.51 (d, J = 6.9 Hz, 1H), 4.17 (s, 3H), 2.12 (s, 3H), 1.45 (s, 9H); racemic 182-2 was separated into its enantiomers using chiral SFC. Preparative Chromatography Conditions: Instrument: Berger MG II; Column: Chiralpak ID, 21x250mm, 5 micron; Mobile Phase: 20%IPA / 80%CO2; Flow Conditions: 45mL / min, 120 Bar, 40°C; Detector Wavelength: 215nm; Injection Details: 3 injections of 15mg / mL in MeOH; Analytical Chromatography Conditions: Instrument: Aurora Infinity analytical SFC; Column: Chiralpak AD-H, 4.6x100mm, 3 micron; Mobile Phase: 20%IPA / 80%CO2; Flow Conditions: 2mL / min, 150 Bar, 40°C; Detector Wavelength: 220nm; Peak 1, RT=3.49min, >99.5%ee; Peak 2, RT=4.43min, >99.5%ee; Peak #2 of the intermediate 182-2 product was collected and carried forward to generate Example 182.

[0301] Procedure for Example 182: Example 182 was prepared from 166-2 using 182-2 (peak 2, isomer 2) according to the method described for Example 108. Subsequent removal of the tert-butyl ester was accomplished similarly to the procedure for preparing Example 168. Analytical Data for Example 182 (Isomer 1): 1H NMR (500MHz, CDCl3) δ 10.14(d,J=7.7Hz,1H), 8.72(brd,J=9.1Hz,1H), 8.46(d,J=2.5Hz,1H), 8.00(dd,J=6.1, 2.8Hz,1H), 7.80-7.7 0(m,2H), 7.61(s,1H), 7.46-7.38(m,2H), 7.11-7.01(m,2H), 6.98(d,J=8.8Hz,1H), 5.96(d,J=9.1Hz,1H), 4.73 -4.65(m,2H), 4.04(s,3H), 3.18(brt,J=3.7Hz,1H), 3.03(dd,J=10.6, 4.0Hz,1H), 2.69(brt,J=3.7Hz,1H), 2.1 3(s,3H), 2.06-1.98(m,1H), 1.88-1.80(m,1H), 1.64-1.49(m,3H), 0.89-0.76(m,2H), 0.44-0.34(m,2H).LC-MS RT:1.11min;MS(ESI) m / z=712.2(M+H) + ;Method A

[0302] Example 183 [ka] [ka]

[0303] Intermediate 183-1: Intermediate 183-1 was prepared from VIII-3 according to the method described for Intermediate 182-1, using BocO instead of AcO. LC-MS RT=1.14 min; MS(ESI) m / z=406.0 (M+H). + ;Method A

[0304] Intermediate 183-2: Intermediate 183-2 was prepared using the same conditions as used for intermediate 140-1, except the temperature was 60° C. for 18 hours. 1H NMR (500 MHz, CDCl) δ 8.38 (d, J = 1.9 Hz, 1H), 7.80 (dt, J = 8.7, 2.0 Hz, 1H), 7.46 (dd, J = 7.4, 2.5 Hz, 1H), 7.36 (dddd, J = 8.8, 4.4, 2.2, 1.1 Hz, 1H), 7.19-7.13 (m, 2H), 5.67 (brd, J = 5.2 Hz, 1H), 5.25 (brd, J = 6.3 Hz, 1H), 4.16 (s, 3H), 1.46 (brs, 9H), 1.44 (s, 9H); racemic 183-2 was separated into its individual enantiomers using chiral SFC. Preparative Chromatography Conditions: Apparatus: Berger MG II; Column: Chiralpak ID, 21x250 mm, 5 micron; Mobile phase: 20% MeOH / 80% CO2; Flow conditions: 45 mL / min, 120 Bar, 40°C; Detector wavelength: 209 nm; Injection details: 49 injections in MeOH; Analytical Chromatography Conditions: Apparatus: Waters UPC2 Analytical SFC; Column: Chiralpak IC, 4.6x100 mm, 3 micron; Mobile phase: 25% MeOH / 75% CO2; Flow conditions: 2 mL / min, 150 Bar, 40°C; Detector wavelength: 220 nm; Peak 1, RT = 4.22 min, 95.7% ee; Peak 2, RT = 5.11 min, >99% ee.; Peak #2 of the intermediate 183-2 product was collected and carried forward to produce intermediate 183-3.

[0305] Intermediate 183-3: Intermediate 183-3 was prepared from 183-2 according to the method described for Example 108. Subsequent removal of the tert-butyl ester was achieved in a similar manner to the procedure for preparing Example 120. LC-MS RT=0.99 min; MS(ESI) m / z=698.3 (M+H). + ;Method A

[0306] Procedure for Example 183: Example 183 was prepared from 183-3. A 2-dram vial was charged with 183-3, DIEA (0.06 mmol, 5 eq.), and 4-chlorobenzoyl chloride (0.035 mmol, 3.0 eq.). The solution was stirred at 23° C. for 30 minutes and then quenched with MeOH. The reaction was concentrated under reduced pressure to give the crude product, which was purified via preparative RP-HPLC to give Example 183. Analytical data for Example 183: 1 H NMR (500MHz, CDCl3) δ 9.98(brd,J=8.0Hz,1H), 8.77-8.68(m,1H), 8.49(d,J=2.5Hz,1H), 7.96(dd,J=6.3, 2.5Hz,1H), 7.91-7.84(m,2H), 7.77-7.71(m,1H) ), 7.69(t,J=1.7Hz,1H), 7.60(d,J=8.0Hz,1H), 7.55(ddd,J=8.3, 4.3, 2.2Hz,1H), 7.43-7.39(m,1H), 7.37-7.31(m,1H), 7.27-7.24( m,1H), 7.08(dd,J=10.6, 8.7Hz,1H), 7.01-6.95(m,2H), 6.21(d,J=8.5Hz,1H), 5.61(q,J=7.4Hz,1H), 4.83-4.74(m,1H), 4.04(s,3H) , 3.41(brs,1H), 3.14(dd,J=10.5, 4.1Hz,1H), 2.88(t,J=3.9Hz,1H), 2.30-2.22(m,1H), 2.01-1.95(m,1H), 1.73-1.62(m,2H);LC-MS RT:1.21min;MS(ESI) m / z=836.3(M+H) + ;Method A

[0307] Example 192 [ka]

[0308] Procedure for Example 192: Example 192 was prepared from Example 120 using BHFFT as the coupling reagent. To a 2-dram pressure-controlled vial charged with Example 120 (0.043 mmol, 1.3 eq) was added BHFFT (0.049 mmol, 2.0 eq), followed by DCM (1 mL) and DIEA (0.15 mmol, 4.5 eq). The reaction mixture was stirred at 23° C. for 30 minutes and then heated at 80° C. for 18 hours. The reaction mixture was cooled to 23° C., the contents of the vial were dissolved in DMF (1.5 mL), and the residue was purified by RP-HPLC. Analytical data for Example 192: LC-MS RT: 2.41 min; MS (ESI) m / z=735.1 (M+H). + ;Method C

[0309] Example 199 [ka] [ka]

[0310] Intermediate 199-1: Intermediate 199-1 was prepared using the same conditions as Intermediate 140-1, except the temperature was 65° C. for 18 hours. 1 H NMR (500MHz, CDCl3) δ 10.87(s,1H), 8.11-8.04(m,2H), 7.95(ddd,J=8.5, 4.8, 2.3Hz,1H), 7.68(dt,J=8.5, 1.9Hz,1 LC-MS RT=1.20min;MS(ESI) m / z=347.1(M+H) +

[0311] Intermediate 199-2: To a 1-dram vial charged with intermediate 199-1 was added potassium carbonate (53.5 mg, 0.39 mmol), DMF (0.4 mL), and 1-bromo-2-(2-methoxyethoxy)ethane (70.8 mg, 0.39 mmol). The reaction mixture was stirred at 23 °C for 18 hours and then heated at 40 °C for an additional 18 hours. The reaction mixture was concentrated with a stream of nitrogen gas, the residue was diluted with ethyl acetate and water, and the resulting solution was extracted with ethyl acetate (3 × 10 mL). The organic portions were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 199-2 (80 mg, 0.18 mmol, 92% yield). 1 H NMR (500 MHz, CDCl3) δ 8.08(dd,J=7.7, 2.2Hz,1H), 8.00(dd,J=2.2, 1.1Hz,1H), 7.94(ddd,J=8.5, 4.8, 2.3Hz,1H), 7.66(dt,J=8.7, 2.0Hz,1H), 7.17(dd,J=10.0, 8.7Hz,1H), 7 .09(d,J=8.8Hz,1H), 4.28(t,J=5.1Hz,2H), 3.97-3.93(m,2H), 3.91(s,3H), 3.81-3.77(m,2H), 3.61-3.57(m,2H), 3.44-3.39(m,3H), 1.61(s,9H);LC-MS RT=1.11 min;MS(ESI) m / z=449.1(M+H) + ;Method A

[0312] Intermediate 199-3: Intermediate 199-3 was prepared in a similar manner to intermediate 3-3 by subjecting intermediate 199-2 to hydrolysis with lithium hydroxide. LC-MS RT=1.02 min; MS(ESI) m / z=348.1 (M+H). + ;Method A

[0313] Procedure for Example 199: Example 199 was prepared from 125-2 utilizing 199-3 according to the method described for Example 108. Subsequent removal of the tert-butyl ester was accomplished similarly to the procedure for preparing Example 120. Analytical data for Example 199: LC-MS RT: 1.15 min; MS(ESI) m / z=765.2 (M+H).+ ;Method A

[0314] Example 201 [ka] [ka]

[0315] Intermediate 201-1: Intermediate 201-1 was prepared from 166-2 utilizing 120-6 according to the method described for Example 108. 1 H NMR (500MHz, CDCl3) δ 9.40(brd,J=8.0Hz,1H), 8.40(d,J=1.1Hz,1H), 8.08(dd,J=7.7, 2.2Hz,1H), 8.02-7.93(m,3H), 7.64(dt,J=8.6, 1.9Hz ,1H), 7.49(dt,J=8.6, 3.5Hz,1H), 7.18(dd,J=10.0, 8.7Hz,1H), 7.12-7.03(m,2H), 4.89-4.81(m,1H), 4.63(d,J=9.4Hz) ,1H), 4.05(s,3H), 3.20(t,J=3.9Hz,1H), 3.10(dd,J=10.6, 3.2Hz,1H), 2.72(t,J=3.9Hz,1H), 2.24-2.16(m,1H), 1.93 LC-MS RT=1.30min;MS(ESI) m / z=697.3(M+H) + ;Method A

[0316] Intermediate 201-2: To a 2-dram vial charged with intermediate 201-1 (88 mg, 0.126 mmol), DCM (1.25 mL) was added, followed by BocO (0.51 mmol), DMAP (0.06 mmol), and DIEA (0.51 mmol). The solution was stirred at 23 °C for 18 hours and then concentrated under reduced pressure. The resulting crude material was purified by normal phase silica gel chromatography to give intermediate 201-2 (94 mg, 0.12 mmol, 93% yield). LC-MS RT = 1.34 min; MS (ESI) m / z = 797.5 (M+H). + ;Method A

[0317] Procedure for Example 201: Example 201 was prepared from 201-2. To a 1-dram vial charged with 201-2 (0.013 mmol) was added DCM (0.3 mL) and cyclopentylamine (0.125 mmol, 10 equiv.). The solution was stirred at 23° C. for 18 hours and concentrated under reduced pressure to give the crude intermediate. Subsequent removal of the tert-butyl ester was achieved in a manner similar to that used to prepare Example 120. Analytical data for Example 201: 1 H NMR (500MHz, DMSO-d6) δ 9.78(brd,J=7.0Hz,1H), 7.85-7.75(m,3H), 7.74-7.67(m,1H), 7.48(brd,J=8.5Hz,1H), 7.16 (brt,J=9.5Hz,1H), 7.05(d,J=8.9Hz,1H), 4.36(d,J=9.5Hz,1H), 4.04(dt,J=10.0, 5.2Hz,1H ), 3.81-3.73(m,4H), 2.83-2.76(m,1H), 2.66-2.60(m,1H), 1.69-1.45(m,4H), 1.40-1.29(m, LC-MS RT:2.33min;MS(ESI) m / z=547.4(M+H) + ;Method C

[0318] Example 206 [ka]

[0319] Intermediate 206-2: To a reaction vessel were added 3-bromo-4-fluorobenzaldehyde (206-1, 235 mg, 1.15 mmol), DMF (3.5 mL), (trifluoromethyl)trimethylsilane (0.34 mL, 2.3 mmol), and K2CO3 (8.0 mg, 0.058 mmol). The reaction mixture was stirred at room temperature for 60 minutes, and 2N HCl (3 mL) was added. After stirring at room temperature for an additional hour, the reaction mixture was diluted with EtOAc (15 mL), and the solution was washed with saturated NH4Cl. The aqueous phase was extracted with additional EtOAc (10 mL x 2). The organic portions were combined, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to produce 206-2 (205 mg, 0.751 mmol, 64.9% yield). 1 H NMR (500MHz, CDCl3) d 7.74(dd,J=6.5, 2.1Hz,1H), 7.43(ddd,J=8.4, 4.8, 2.2Hz,1H), 7.19(t,J=8.4Hz,1H), 5.11-4.98(m,1H), 2.69(d,J=4.4Hz,1H) Intermediate 206-3: To a reaction vessel containing 206-2 (100 mg, 0.366 mmol), 5-borono-2-methoxybenzoic acid (93 mg, 0.48 mmol), PdCl(dppf)-CHCl adduct (45 mg, 0.055 mmol), NaCO (155 mg, 1.46 mmol), and HO (1 mL) were added. The reaction mixture was degassed by bubbling N for 10 min, sealed, and stirred at 65 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched by adding 1 N HCl, and the solution was extracted with EtOAc, dried over NaSO, filtered, concentrated, and purified by HPLC to produce 206-3 (50.5 mg, 0.147 mmol, 40.1% yield). 1H NMR (500MHz, CDCl3) δ 8.39(d,J=1.9Hz,1H), 7.83(dt,J=8.7, 2.1Hz,1H), 7.59(dd,J=7.3, 2.1Hz,1H), 7.53-7.45(m ,1H), 7.23(dd,J=10.2, 8.8Hz,1H), 7.18(d,J=8.5Hz,1H), 5.11(q,J=6.6Hz,1H), 4.17(s,3H)

[0320] Intermediate 206-4: Racemic 206-3 was separated into its individual enantiomers using chiral SFC. Preparative chromatographic conditions: Apparatus: Berger MG II; Column: Kromasil 5-CelluCoat, 21x250mm, 5 micron; Mobile phase: 15% IPA-ACN (0.1% DEA) / 85% CO2; Flow conditions: 45mL / min, 120 Bar, 40°C; Detector wavelength: 220nm; Injection details: 0.4mL of approximately 15mg / mL (ACN-IPA (1:1)) injected; Peak #2 was collected to give intermediate 206-4. Analytical chromatographic conditions: Instrument: Aurora Infinity Analytical SFC; Column: Cromadil 5-Cellcoat, 4.6 x 250 mm, 5 micron; Mobile phase: 20% IPA-ACN (0.1% DEA) / 80% CO2; Flow conditions: 2 mL / min, 150 Bar, 40 °C; Detector wavelength: 220 nm; Peak 1, RT = 9.12 min, 99% ee; Peak 2, RT = 10.19 min, 98% ee

[0321] Example 245: To a reaction vessel was added intermediate 166-2 (7.0 mg, 0.017 mmol), intermediate 206-4 (6.2 mg, 0.018 mmol), MeCN (1 mL), DIEA (9.1 μl, 0.052 mmol), and HATU (7.2 mg, 0.019 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and subjected to preparative HPLC purification to produce Example 245 (9.5 mg, 0.014 mmol, 78% yield). 1H NMR (500MHz, CDCl3) δ 9.57(d,J=7.7Hz,1H), 8.33(dd,J=2.2, 0.8Hz,1H), 8.05(s,1H), 7.99(dd,J=6.3, 2.5Hz,1H), 7.66(dt,J=8.7, 2.0Hz,1H), 7.57(dd, J=7.3, 2.1Hz,1H), 7.56-7.52(m,1H), 7.45-7.40(m,1H), 7.17(dd,J=10.2, 8.5Hz,1H), 7.11-7.04(m,2H), 5.11-5.04(m,1H), 4.77-4 .70(m,1H), 4.57(d,J=9.4Hz,1H), 4.06(s,3H), 3.42(brs,1H), 3.19(t,J=4.1Hz,1H), 3.08(ddd,J=10.7, 4.1, 1.2Hz,1H), 2.67(t,J= LC-MS RT:1.38min;MS(ESI) m / z695.3(M+H) + ;Method A

[0322] Example 246: Prepared from the enantiomer of intermediates 166-2 and 206-4 (peak 1 from chiral SFC purification) following the procedure for synthesizing Example 246. 1H NMR (500MHz, CDCl3) δ 9.53(d,J=7.7Hz,1H), 8.34(dd,J=2.5, 0.8Hz,1H), 8.01(s,1H), 7.97(dd,J=6.2, 2.6Hz,1H), 7.66(dt,J=8.7, 2.0Hz,1H) , 7.57-7.50(m,2H), 7.48-7.40(m,1H), 7.18(dd,J=10.2, 8.5Hz,1H), 7.12-7.02(m,2H), 5.13-5.03(m,1H), 4.81-4.71(m, 1H), 4.60(d,J=9.6Hz,1H), 4.06(s,3H), 3.19(t,J=3.7Hz,2H), 3.09(ddd,J=10.8, 4.1, 1.1Hz,1H), 2.70(t,J=4.0Hz,1H) , 2.19-2.11(m,1H), 1.92-1.84(m,1H), 1.70-1.60(m,2H), 1.51-1.42(m,1H), 0.77-0.70(m,2H), 0.36-0.30(m,2H);LC-MS RT:1.38min;MS(ESI) m / z695.3(M+H) + ;Method A

[0323] Example 206: To a reaction vessel was added Example 245 (6.0 mg, 8.6 μmol), DCM (1 mL), pyridine (7.0 μL, 0.086 mmol), 4-nitrophenyl carbonochloridate (8.7 mg, 0.043 mmol), and DMAP (1.0 mg, 8.6 μmol). After stirring at room temperature for 2 hours, bicyclo[1.1.1]pentan-1-amine (7.2 mg, 0.086 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and subjected to preparative HPLC purification to yield 1-(3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethylbicyclo[1.1.1]pentan-1-ylcarbamate (Example 206, 3.8 mg, 4.7 μmol, 54% yield). 1H NMR (500MHz, DMSO-d6) δ 10.54(s,1H), 9.95(brd,J=6.3Hz,1H), 8.55(brs,1H), 8.24(brd,J=4.2Hz,1H), 8.13(brs,1H), 7.86-7.75(m,1H) , 7.69(brt,J=9.4Hz,2H), 7.58-7.38(m,3H), 7.33(d,J=8.8Hz,1H), 6.43-6.30(m,1H), 4.69(d,J=9.6Hz,1H), 4.5 1-4.41(m,1H), 4.06(s,3H), 3.16(brdd,J=10.1, 3.8Hz,1H), 3.11(brs,1H), 2.72(brs,1H), 2.39-2.34(m,1H), 2. 02-1.89(m,6H), 1.88-1.77(m,2H), 1.54-1.47(m,1H), 1.45-1.36(m,2H), 0.79-0.69(m,2H), 0.35(brs,2H);LC-MS RT:1.27min;MS(ESI) m / z804.5(M+H) + ;Method A

[0324] Example 222 [ka]

[0325] Example 222: To a reaction vessel was added Example 246 (11 mg, 0.017 mmol), DCM (1 mL), pyridine (8.0 μL, 0.099 mmol), and isocyanatobenzene (9.9 mg, 0.083 mmol). After stirring at room temperature for 12 hours, the reaction mixture was concentrated and subjected to preparative HPLC purification to produce 1-(3′-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)ethylphenylcarbamate (Example 222, 11.8 mg, 0.0160 mmol, 94.0% yield). 1H NMR (500MHz, DMSO-d6) δ 10.52(s,1H), 9.92(brd,J=7.3Hz,1H), 9.72(brs,1H), 8.22(brd,J=4.9Hz,1H), 8.14(s,1H), 7.81-7.75(m,1H), 7.70(brd,J=8. 2Hz,1H), 7.54(brd,J=6.7Hz,1H), 7.50-7.38(m,4H), 7.35-7.27(m,2H), 7.25(brt,J=7.8Hz,2H), 6.96(t,J=7.5Hz,1H), 5.89-5 .80(m,1H), 4.69(d,J=9.5Hz,1H), 4.49-4.41(m,1H), 4.05(s,3H), 3.16(brdd,J=10.8, 3.5Hz,1H), 3.11(brs,1H), 2.72(brs,1H) ), 1.92-1.74(m,2H), 1.56(brd,J=6.1Hz,3H), 1.53-1.47(m,1H), 1.45-1.35(m,2H), 0.82-0.66(m,2H), 0.39-0.29(m,2H);LC-MS RT:1.26min;MS(ESI) m / z760.5(M+H) + ;Method A

[0326] Example 230 [ka]

[0327] Intermediate 230-1: To a reaction vessel were added 206-1 (577 mg, 2.84 mmol), DMF (15 mL), (difluoromethyl)trimethylsilane (530 mg, 4.26 mmol), and CsF (216 mg, 1.42 mmol). After stirring at 50 °C for 12 h, the reaction mixture was diluted with EtOAc (15 mL), and the solution was washed with saturated NH Cl. The aqueous phase was extracted with additional EtOAc (10 mL x 2). The organic portions were combined, dried over Na SO , filtered, concentrated, and purified by silica gel chromatography to give 1-(3-bromo-4-fluorophenyl)-2,2-difluoroethan-1-ol (230-1, 98 mg, 0.38 mmol, 13% yield). 1H NMR (500MHz, CDCl3) δ 7.67(dd,J=6.6, 2.1Hz,1H), 7.36(ddd,J=8.4, 4.6, 2.1Hz,1H), 7.16(t,J=8.4Hz,1H), 5.87-5.57(m,1H), 4.86-4.78(m,1H), 2.50(brs,1H)

[0328] Intermediate 230-2: To a reaction vessel containing 230-1 (220 mg, 0.863 mmol), 5-borono-2-methoxybenzoic acid (220 mg, 1.12 mmol), PdCl(dppf)-CHCl adduct (106 mg, 0.129 mmol), NaCO (366 mg, 3.45 mmol), and HO (3.5 mL) were added. The reaction mixture was degassed by bubbling N for 10 min, sealed, and stirred at 65 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched by adding 1N HCl, and the resulting solution was extracted with EtOAc, dried over NaSO, filtered, concentrated, and subjected to preparative HPLC purification to give 5'-(2,2-difluoro-1-hydroxyethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid (230-2, 186 mg, 0.570 mmol, 66.1% yield). 1 H NMR (400MHz, CDCl3) δ 8.37(d,J=1.8Hz,1H), 7.82(dt,J=8.7, 2.0Hz,1H), 7.53(dd,J=7.4, 2.1Hz,1H), 7.45-7.3 9(m,1H), 7.24-7.14(m,2H), 6.01-5.59(m,1H), 4.89(td,J=10.1, 4.7Hz,1H), 4.15(s,3H)

[0329] Intermediate 230-3: Racemic 230-2 was separated into its individual enantiomers using chiral SFC. Preparative chromatographic conditions: Apparatus: PIC Solution SFC Prep-200; Column: Chiralpak IC, 30x250mm, 5 micron; Mobile phase: 10% MeOH / 90% CO2; Flow conditions: 85mL / min, 150 Bar, 40°C; Detector wavelength: 220nm; Injection details: 10µL of approximately 1mg / mL (in MeOH) was injected; Peak #2 was collected to give intermediate 230-3. Analytical chromatographic conditions: Instrument: Aurora Infinity Analytical SFC; Column: Chiralpak ID, 4.6 x 250 mm, 5 micron; Mobile phase: 10% MeOH / 90% CO2; Flow conditions: 2 mL / min, 150 Bar, 40 °C; Detector wavelength: 220 nm; Peak 1, RT = 11.85 min, 96% ee; Peak 2, RT = 13.65 min, >99.5% ee

[0330] Intermediate 230-4: To a reaction vessel was added intermediate 166-2 (20 mg, 0.054 mmol), intermediate 230-3 (18 mg, 0.057 mmol), MeCN (1 mL), DIEA (0.028 mL, 0.16 mmol), and HATU (23 mg, 0.060 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and subjected to silica gel chromatography purification to yield (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-3-(5'-(2,2-difluoro-1-hydroxyethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (230-4, 25 mg, 0.037 mmol, 68% yield). 1H NMR (400MHz, CDCl3) δ 9.49(brd,J=7.7Hz,1H), 8.40-8.33(m,1H), 8.01(s,1H), 7.98-7.91(m,1H), 7.66(dt,J=8.7, 2.0Hz,1H), 7.57-7.48(m,2H), 7.38 (dq,J=6.4, 4.2Hz,1H), 7.18(ddd,J=10.2, 8.6, 1.2Hz,1H), 7.11-7.01(m,2H), 6.03-5.59(m,1H), 4.91-4.83(m,1H), 4.81-4.73( m,1H), 4.61(d,J=9.5Hz,1H), 4.06(s,3H), 3.19(t,J=3.7Hz,1H), 3.09(dd,J=10.8, 3.3Hz,1H), 2.82(brd,J=12.5Hz,1H), 2.70(t ,J=3.9Hz,1H), 2.22-2.12(m,1H), 1.95-1.85(m,1H), 1.72-1.61(m,2H), 1.50-1.41(m,1H), 0.79-0.69(m,2H), 0.39-0.28(m,2H)

[0331] Example 230: To a reaction vessel was added intermediate 230-4 (6.0 mg, 8.9 μmol), DCM (1 mL), pyridine (7.2 μl, 0.089 mmol), 4-nitrophenyl carbonochloridate (8.9 mg, 0.044 mmol), and DMAP (1.1 mg, 8.9 μmol). After stirring at room temperature for 2 hours, cyclobutanamine (6.3 mg, 0.089 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and subjected to preparative HPLC purification to yield 1-(3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-2,2-difluoroethyl cyclobutylcarbamate (Example 230, 4.5 mg, 5.8 μmol, 66% yield). 1H NMR (500MHz, DMSO-d6) δ 10.55(s,1H), 9.94(brd,J=7.2Hz,1H), 8.19(brd,J=5.1Hz,1H), 8.09(s,1H), 7.94(brd,J=7.8Hz,1H), 7.80-7.71(m,1H), 7 .68(brd,J=8.8Hz,1H), 7.53(brd,J=6.7Hz,1H), 7.48-7.39(m,2H), 7.38-7.27(m,2H), 6.49-6.13(m,1H), 5.93-5.81(m,1H) ), 4.67(d,J=9.6Hz,1H), 4.48-4.38(m,1H), 4.03(s,3H), 3.94-3.85(m,1H), 3.19-3.11(m,1H), 3.08(brs,1H), 2.70(brs,1 LC-MS RT:1.22min;MS(ESI) m / z774.3(M+H) + ;Method A

[0332] Example 233 [ka] Example 233: To a reaction vessel was added 230-4 (6.0 mg, 8.9 μmol), DCM (1 mL), pyridine (0.014 mL, 0.17 mmol), and isocyanatobenzene (5.3 mg, 0.044 mmol). After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure and subjected to preparative HPLC purification to produce 1-(3′-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)-2,2-difluoroethylphenylcarbamate (Example 233, 4.9 mg, 5.9 μmol, 67% yield). 1H NMR (500MHz, DMSO-d6) δ 10.54(s,1H), 10.07(brs,1H), 9.93(brd,J=7.0Hz,1H), 8.17(brd,J=4.6Hz,1H), 8.10(s,1H), 7.79-7.59(m,3 H), 7.50(brs,1H), 7.47-7.34(m,4H), 7.34-7.24(m,3H), 7.01(brt,J=7.2Hz,1H), 6.55-6.25(m,1H), 6.08-5. 98(m,1H), 4.68(d,J=9.5Hz,1H), 4.48-4.39(m,1H), 4.02(s,3H), 3.19-3.10(m,1H), 3.08(brs,1H), 2.72-2.6 7(m,1H), 1.87-1.72(m,2H), 1.53-1.45(m,1H), 1.44-1.34(m,2H), 0.77-0.65(m,2H), 0.37-0.26(m,2H);LC-MS RT:1.23min;MS(ESI) m / z796.2(M+H) + ;Method A

[0333] Example 238: [ka]

[0334] Intermediate 238-1: To a reaction vessel was added 166-2 (75 mg, 0.19 mmol), 183-2 (92 mg, 0.20 mmol), MeCN (5 mL), DIEA (0.097 mL, 0.56 mmol), and HATU (77 mg, 0.200 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography purification to yield tert-butyl 2-((tert-butoxycarbonyl)amino)-2-(3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)acetate (238-1, 147 mg, 0.178 mmol, 96.0% yield). 1H NMR (400MHz, CDCl3) δ 9.42(brd,J=7.9Hz,1H), 8.41(dd,J=2.2, 1.3Hz,1H), 8.09-8.04(m,1H), 8.06(s,1H), 8.00(dd,J=6.3, 2.5Hz,1H), 7.67-7.61(m,1H), 7 .55-7.48(m,1H), 7.44(dd,J=7.3, 2.4Hz,1H), 7.36-7.31(m,1H), 7.20-7.04(m,3H), 5.66(brd,J=6.6Hz,1H), 5.24(brd,J=7.0Hz,1H), 4 .92-4.82(m,1H), 4.65(d,J=9.5Hz,1H), 4.07(s,3H), 3.22(t,J=3.9Hz,1H), 3.13(dd,J=10.5, 3.6Hz,1H), 2.74(t,J=3.7Hz,1H), 2.27- 2.16(m,1H), 1.95-1.86(m,1H), 1.74-1.66(m,2H), 1.46(brs,9H), 1.43(s,9H), 1.39-1.34(m,1H), 0.81-0.72(m,2H), 0.43-0.33(m,2H)

[0335] Intermediate 238-2: To a reaction vessel was added 238-1 (147 mg, 0.178 mmol), DCM (10 mL), sodium bicarbonate (112 mg, 1.33 mmol), and zinc bromide (1200 mg, 5.34 mmol). After stirring for 24 h, the reaction mixture was quenched by adding 1N HCl, and the solution was extracted with EtOAc. The organic portions were combined, dried over Na2SO4, filtered, concentrated, and subjected to preparative HPLC purification to yield 2-amino-2-(3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)acetic acid·TFA (238-2, 62 mg, 0.079 mmol, 44% yield). MS(ESI) m / z 670.4 (M+H).

[0336] Example 238: To a reaction vessel was added 238-2 (9 mg, 0.01 mmol), MeCN (1 mL), pyridine (2.8 μl, 0.034 mmol), and tetrahydro-2H-pyran-4-carbonyl chloride (1.7 mg, 0.012 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was quenched by the addition of MeOH, concentrated under reduced pressure, and the residue was subjected to preparative HPLC purification to give 2-(3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)acetic acid (Example 238, 8.9 mg, 0.011 mmol, 99% yield). 1 H NMR (500MHz, CDCl3) δ 9.89(brd,J=7.7Hz,1H), 8.26(d,J=2.2Hz,1H), 7.99(dd,J=6.2, 2.3Hz,1H), 7.84(s,1H), 7.74-7.62(m,2H), 7.54(dd,J=7.3, 2.3Hz,1H), 7 .49-7.42(m,1H), 7.37-7.31(m,1H), 7.12-7.05(m,1H), 7.02-6.94(m,2H), 5.80(d,J=8.0Hz,1H), 4.77-4.69(m,1H), 4.64(d,J=9.4Hz,1H), 4.06(s,3H), 4.03-3.90(m,2H), 3.49-3.36(m,2H), 3.14-3.09(m,1H), 3.06(dd,J=10.6, 4.0Hz,1H), 2.73-2.66(m,1H), 2.57-2.48(m,1H), LC-MS RT:1.26min;MS(ESI) m / z782.5(M+H) + ;Method A

[0337] Example 249: [ka]

[0338] Intermediate 249-1: To a reaction vessel was added tert-butyl 5-bromo-2-fluorobenzoate (120 mg, 0.436 mmol), morpholine (0.19 mL, 2.2 mmol), and toluene (2 mL). After stirring at 90° C. for 12 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to produce tert-butyl 5-bromo-2-morpholinobenzoate (249-1, 117 mg, 0.342 mmol, 78.0% yield). 1 H NMR (400MHz, CDCl3) δ 7.69(d,J=2.4Hz,1H), 7.49(dd,J=8.7, 2.5Hz,1H), 6.91(d,J=8.8Hz,1H), 3.89-3.85(m,4H), 3.07-3.03(m,4H), 1.62(s,9H). Intermediate 249-2: To a reaction vessel containing 249-1 (30 mg, 0.088 mmol), 5-borono-2-methoxybenzoic acid (25.8 mg, 0.131 mmol), PdCl(dppf)-CHCl adduct (14 mg, 0.018 mmol), and NaCO (46 mg, 0.44 mmol) were added. The reaction mixture was degassed by bubbling N for 10 min, sealed, and stirred at 65 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC purification to produce 3'-(tert-butoxycarbonyl)-4-methoxy-4'-morpholino-[1,1'-biphenyl]-3-carboxylic acid (249-2, 40 mg, 0.097 mmol, 110% yield). MS(ESI) m / z 414.0(M+H)

[0339] Example 251: To a reaction vessel was added intermediate 166-2 (15 mg, 0.037 mmol), 249-2 (20 mg, 0.048 mmol), MeCN (1 mL), DIEA (0.02 mL, 0.1 mmol), and HATU (18 mg, 0.048 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography purification to give tert-butyl 3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4'-methoxy-4-morpholino-[1,1'-biphenyl]-3-carboxylate (Example 251, 12 mg, 0.016 mmol, 42% yield). 1 H NMR (500MHz, CDCl3) δ 9.87(brd,J=7.7Hz,1H), 8.31(d,J=2.2Hz,1H), 8.22(s,1H), 8.04(dd,J=6.3, 2.5Hz,1H), 7.94(d,J=2.2Hz,1H), 7.76(brdd,J=8.3, 1.9Hz, 1H), 7.60(dd,J=8.7, 2.3Hz,1H), 7.56(dt,J=8.7, 3.4Hz,1H), 7.47(brd,J=8.0Hz,1H), 7.11(t,J=9.4Hz,1H), 7.03(d,J=8.8Hz,1H), 4.62( d,J=9.6Hz,2H), 4.07(s,3H), 4.07-4.04(m,4H), 3.50-3.38(m,4H), 3.17(t,J=3.9Hz,1H), 2.97(dd,J=10.7, 3.9Hz,1H), 2.69(t,J=3.9Hz, LC-MS RT:1.23min;MS(ESI) m / z764.3(M+H) + ;Method A

[0340] Example 249: To a reaction vessel was added Example 251 (12 mg, 0.016 mmol), CHCl (2 mL), sodium bicarbonate (13.2 mg, 0.157 mmol), and zinc bromide (142 mg, 0.628 mmol). After stirring at 35° C. for 3 hours, the reaction mixture was quenched by the addition of 1N HCl, and the solution was extracted with EtOAc. The organic portions were combined, dried over NaSO, filtered, concentrated, and subjected to preparative HPLC purification to yield 3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4'-methoxy-4-morpholino-[1,1'-biphenyl]-3-carboxylic acid·TFA (Example 249, 5.2 mg, 6.2 μmol, 40% yield). 1 H NMR (500MHz, CDCl3) δ 9.71(brd,J=7.7Hz,1H), 8.53(d,J=2.2Hz,1H), 8.41(d,J=2.5Hz,1H), 7.96(dd,J=6.1, 2.5Hz,1H), 7.91-7.84(m,2H), 7.76(dd,J=8. 7, 2.6Hz,1H), 7.59(dt,J=8.7, 3.5Hz,1H), 7.54(d,J=8.3Hz,1H), 7.13(t,J=9.4Hz,1H), 7.09(d,J=8.8Hz,1H), 4.83-4.74(m,1H), 4. 67(d,J=9.6Hz,1H), 4.09(s,3H), 4.02(brs,4H), 3.23(brt,J=4.0Hz,1H), 3.17(brs,4H), 3.10(brdd,J=10.9, 3.4Hz,1H), 2.74(t,J= LC-MS RT:1.15min;MS(ESI) m / z708.4(M+H) + ;Method A

[0341] Example 253: [ka]

[0342] Intermediate 253-1: To a reaction vessel was added 1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol (100 mg, 0.366 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (126 mg, 0.494 mmol), and 1,4-dioxane (3 mL). PdCl(dppf)-CHCl adduct (29.9 mg, 0.037 mmol) and potassium acetate (90 mg, 0.91 mmol) were then added, and the reaction mixture was degassed by bubbling N through it for 10 minutes. The reaction mixture was stirred at 65 °C for 5 hours, cooled to room temperature, and the solution was extracted with EtOAc. The organic portions were combined, dried over NaSO, filtered, and concentrated. The resulting material (253-1) was used in the next step without further purification.

[0343] Intermediate 253-2: To a reaction vessel was added methyl 5-bromo-2-hydroxybenzoate (200 mg, 0.866 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (217 mg, 1.039 mmol), acetone (3 mL), and KCO (239 mg, 1.73 mmol). After stirring at 50 °C for 12 h, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to produce methyl 5-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (253-2, 112 mg, 0.312 mmol, 36.0% yield). 1H NMR (500MHz, CDCl3) δ 7.90(d,J=2.6Hz,1H), 7.55(dd,J=8.9, 2.6Hz,1H), 6.94(d,J=8.9Hz,1H), 4.76(t,J=3.5Hz,1H), 4.30-4.16(m,2H), 4.08(dt,J=1 1.5, 4.6Hz,1H), 3.94-3.84(m,5H), 3.59-3.52(m,1H), 1.88-1.79(m,1H), 1.79-1.71(m,1H), 1.67-1.60(m,2H), 1.58-1.50(m,2H)

[0344] Intermediate 253-3: To a reaction vessel containing 253-2 (80 mg, 0.22 mmol), 253-1 (93 mg, 0.29 mmol), PdCl(dppf)-CHCl adduct (27 mg, 0.033 mmol), NaCO (94 mg, 0.89 mmol), and HO (0.5 mL) were added. The reaction mixture was degassed by bubbling N for 10 min, sealed, and stirred at 65 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched by adding water, and the solution was extracted with EtOAc. The EtOAc portions were combined, dried over NaSO, filtered, concentrated, and subjected to silica gel chromatography purification to yield methyl 2'-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-5'-(2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-carboxylate (253-3, 66 mg, 0.14 mmol, 62% yield). 1H NMR (500MHz, CDCl3) δ 7.95(dd,J=2.4, 1.0Hz,1H), 7.64(dt,J=8.7, 1.8Hz,1H), 7.52(dd,J=7.3, 2.1Hz,1H), 7.47-7 .40(m,1H), 7.19(dd,J=10.2, 8.5Hz,1H), 7.09(d,J=8.7Hz,1H), 5.10-5.03(m,1H), 4.77(t,J= 3.5Hz,1H), 4.31-4.25(m,2H), 4.15-4.08(m,1H), 3.95-3.87(m,5H), 3.60-3.52(m,1H), 2.98( brd,J=3.5Hz,1H), 1.89-1.81(m,1H), 1.79-1.71(m,1H), 1.67-1.61(m,2H), 1.59-1.51(m,2H)

[0345] Intermediate 253-4: 253-3 (66 mg, 0.14 mmol) was dissolved in THF (4 mL) and a solution of lithium hydroxide monohydrate (31.7 mg, 0.754 mmol) in water (2 mL) was added. The reaction mixture was stirred at room temperature for 12 h, diluted with EtOAc (10 mL), and quenched by adding 1.0 equivalent of 1 N HCl. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2'-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-5'-(2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-carboxylic acid (253-4, 64 mg, 0.14 mmol, 100% yield), which was used in the next step without further purification.

[0346] Intermediate 253-5: To a reaction vessel was added intermediate 166-2 (25 mg, 0.068 mmol), 253-4 (31 mg, 0.068 mmol), MeCN (1 mL), DIEA (0.036 mL, 0.20 mmol), and HATU (28.4 mg, 0.0750 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was subjected to preparative HPLC purification to yield (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2'-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-5'-(2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-carboxamide)bicyclo[2.2.1]heptane-2-carboxamide (253-5, 39 mg, 0.049 mmol, 72% yield). MS(ESI) m / z 809.2 (M+H).

[0347] Example 253: To a reaction vessel was added 253-5 (15 mg, 0.019 mmol), DCM (1 mL), pyridine (0.015 mL, 0.19 mmol), 4-nitrophenyl carbonochloridate (19 mg, 0.093 mmol), and DMAP (2.3 mg, 0.019 mmol). After stirring at room temperature for 2 hours, cyclobutanamine (13.2 mg, 0.185 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was subjected to preparative HPLC purification to produce the corresponding carbamate. This product was unstable due to the presence of TFA. Standing at room temperature for 12 hours followed by concentration and preparative HPLC purification gave 1-(3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-(2-hydroxyethoxy)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethylcyclobutylcarbamate (Example 253, 11.0 mg, 0.0130 mmol, 70.0% yield). 1H NMR (500MHz, CDCl3) δ 9.54(brd,J=8.5Hz,1H), 8.29(d,J=2.0Hz,1H), 7.76-7.67(m,2H), 7.57-7.47(m,3H), 7.43-7.36(m,1H), 7.21-7.14(m,2H), 7. 10(brd,J=8.9Hz,1H), 6.11-6.05(m,1H), 5.32(brd,J=8.2Hz,1H), 4.93-4.85(m,1H), 4.69(d,J=9.6Hz,1H), 4.49-4.43(m,1H) , 4.32-4.24(m,2H), 4.17-4.09(m,2H), 3.17(t,J=4.1Hz,1H), 3.13(dd,J=10.5, 3.8Hz,1H), 2.75(t,J=4.0Hz,1H), 2.42-2.24( LC-MS RT:1.33min;MS(ESI) m / z822.1(M+H) + ;Method A

[0348] Example 256: [ka]

[0349] Intermediate 256-1: To a reaction vessel was added 3-bromo-4-fluorobenzaldehyde (1670 mg, 8.25 mmol), 2-methylpropane-2-sulfinamide (500 mg, 4.13 mmol), DCM (2 mL), MgSO (2483 mg, 20.63 mmol), and PPTS (52 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 24 h, loaded onto a silica cartridge, and subjected to silica gel chromatography purification to produce (£)-N-(3-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (256-1, 1220 mg, 3.98 mmol, 97% yield). 1H NMR (500MHz, CDCl3) δ 8.51(s,1H), 8.11(dd,J=6.6, 2.2Hz,1H), 7.77(ddd,J=8.5, 4.7, 1.9Hz,1H), 7.24(t,J=8.4Hz,1H), 1.28(s,9H)

[0350] Intermediate 256-2: To a reaction vessel were added 256-1 (200 mg, 0.653 mmol), DMF (3 mL), (trifluoromethyl)trimethylsilane (0.19 mL, 1.3 mmol), and K2CO3 (45 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 60 minutes, and 2 N HCl (15 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with EtOAc (30 mL), and the organic portion was washed with saturated NH4Cl. The aqueous phase was extracted with additional EtOAc (10 mL x 2). The organic portions were combined, dried over Na2SO4, concentrated, filtered, and purified by silica gel chromatography to produce N-(1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (256-2, 163 mg, 0.433 mmol, 66% yield). 1 H NMR (500MHz, CDCl3) δ 7.65(dd,J=6.3, 2.1Hz,1H), 7.42-7.37(m,1H), 7.18(t,J=8.4Hz,1H), 4.81(quin,J=7.1Hz,1H), 3.58(brd,J=6.6Hz,1H), 1.27(s,9H)

[0351] Intermediate 256-3: To a reaction vessel containing 256-2 (50 mg, 0.13 mmol), 5-borono-2-methoxybenzoic acid (31 mg, 0.16 mmol), PdCl(dppf)-CHCl adduct (16 mg, 0.020 mmol), NaCO (56 mg, 0.53 mmol), and HO (0.5 mL) were added. The reaction mixture was degassed by bubbling N for 10 min, sealed, and stirred at 65 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched by the addition of 1N HCl, the solution was extracted with EtOAc, and the organic portions were combined, dried over Na2SO4, filtered, concentrated, and subjected to preparative HPLC purification to give 5'-(1-((tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid (256-3, 47 mg, 0.10 mmol, 79% yield). MS (ESI) m / z 448.1 (M+H).

[0352] Example 256: To a reaction vessel was added 166-2 (10 mg, 0.027 mmol), 256-3 (12 mg, 0.027 mmol), MeCN (1 mL), DIEA (0.014 mL, 0.081 mmol), and HATU (11 mg, 0.030 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was subjected to preparative HPLC purification to yield (1R,2S,3R,4R,Z)-3-(5′-(1-((tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-2′-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamide)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (Example 256, 7.5 mg, 9.3 μmol, 34% yield). 1H NMR (500MHz, DMSO-d6) δ 10.55(s,1H), 9.95(brd,J=6.4Hz,1H), 8.27-8.19(m,1H), 8.16(s,1H), 7.87-7.74(m,2H), 7.70(brd,J=8. 8Hz,1H), 7.66-7.58(m,1H), 7.48(brt,J=9.7Hz,1H), 7.40-7.29(m,2H), 6.51(d,J=9.6Hz,1H), 5.39-5.27 (m,1H), 4.68(d,J=9.7Hz,1H), 4.51-4.41(m,1H), 4.05(s,3H), 3.19-3.14(m,1H), 3.11(brs,1H), 1.88-1. 75(m,2H), 1.56-1.46(m,1H), 1.44-1.35(m,2H), 1.14(s,9H), 0.79-0.68(m,2H), 0.39-0.30(m,2H);LC-MS RT:1.25min;MS(ESI) m / z798.1(M+H) + ;Method A

[0353] Example 258: [ka]

[0354] Intermediate 258-1: To a reaction vessel was added intermediate 166-2 (15 mg, 0.041 mmol) and THF (1 mL). After cooling to 0 °C, LiAlH (0.5 mL, 0.500 mmol) was added. After stirring at 0 °C for 5 minutes, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 20 minutes. The reaction mixture was diluted with EtOAc. After washing the organic solution with saturated NaHCO, the organic phase was dried over NaSO and concentrated under reduced pressure to give (1R,2R,3R,4R,Z)-7-(cyclopropylmethylene)-3-(((4-fluoro-3-(trifluoromethyl)phenyl)amino)methyl)bicyclo[2.2.1]heptan-2-amine (258-1, 7.0 mg, 0.020 mmol, 49% yield). This material was used in the next step without further purification. MS(ESI) m / z 355.3(M+H)

[0355] Example 258: To a reaction vessel was added 258-1 (7.0 mg, 0.020 mmol), 120-6 (6.5 mg, 0.019 mmol), MeCN (1 mL), DIEA (9.4 μl, 0.054 mmol), and HATU (7.5 mg, 0.020 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography purification to give a residue that was treated with 2:1 DCM / TFA at room temperature for 30 minutes. The resulting solution was concentrated and the residue was purified by HPLC to give 3'-(((1R,2R,3R,4R,Z)-7-(cyclopropylmethylene)-3-(((4-fluoro-3-(trifluoromethyl)phenyl)amino)methyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (Example 258, 6.5 mg, 8.4 μmol, 47% yield). 1 H NMR (500MHz, CDCl3) δ 8.59(brd,J=7.4Hz,1H), 8.41(d,J=1.4Hz,1H), 8.23(dd,J=7.6, 2.1Hz,1H), 8.09(ddd,J=8.5, 4.6, 2.1Hz,1H), 7.7 1(brd,J=8.8Hz,1H), 7.26-7.22(m,1H), 7.08-7.02(m,2H), 6.99-6.94(m,2H), 4.65(d,J=9.6Hz,1H), 4.63-4.57(m ,1H), 4.03(s,3H), 3.32(dd,J=11.4, 2.9Hz,1H), 3.09(t,J=4.1Hz,1H), 3.04-2.97(m,1H), 2.59-2.52(m,2H), 1.83 LC-MS RT:1.31min;MS(ESI) m / z683.5(M+H) + ;Method A

[0356] Example 259 [ka] Intermediate 259-1: 259-1 was prepared from intermediates 166-2 and 140-2 according to the procedures described in Example 168. 1 H NMR (500MHz, CDCl3) δ 9.58-9.15(br.s,1H), 8.20(d,J=2.2Hz,1H), 8.17-7.93(m,1H), 7.90(dd,J=6.1, 2.5Hz,1H), 7.56(dt,J=8.9, 3.4Hz,1H), 7.41(dd,J =8.5, 2.5Hz,1H), 7.08(t,J=9.4Hz,1H), 6.92(brd,J=7.7Hz,1H), 6.16(dt,J=4.0, 2.1Hz,1H), 4.87-4.79(m,1H), 4.63(d,J=9.6Hz,1H) ), 4.32-4.18(m,2H), 3.99(s,3H), 3.55(brs,2H), 3.18(t,J=3.7Hz,1H), 3.11-3.06(m,1H), 2.71(t,J=3.7Hz,1H), 2.31(brd,J=2.8H) z,2H), 2.23-2.12(m,1H), 1.91-1.80(m,1H), 1.71-1.61(m,2H), 1.50(s,9H), 1.49-1.42(m,1H), 0.77-0.70(m,2H), 0.40-0.30(m,2H)

[0357] Intermediate 259-2: To a reaction vessel were added 259-1 (13 mg, 0.019 mmol), DCM (1.5 mL), DIEA (0.012 mL, 0.067 mmol), and zinc bromide (150 mg, 0.665 mmol). After stirring at room temperature for 12 hours, the reaction mixture was quenched by adding saturated NaHCO3, and the solution was extracted with EtOAc. The organic portions were combined, dried over Na2SO4, filtered, and concentrated to yield (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(1,2,5,6-tetrahydropyridin-3-yl)benzamido)bicyclo[2.2.1]heptane-2-carboxamide (259-2, 12 mg, 0.021 mmol, 110% yield). This intermediate was used in the next step without further purification. MS (ESI) m / z 584.4 (M+H).

[0358] Example 259: To a reaction vessel was added 259-2 (11 mg, 0.019 mmol), MeCN (1 mL), 2-bromoacetic acid (1.5 mg, 0.011 mmol), and DIEA (9.9 μL, 0.057 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC followed by SFC purification to yield 2-(5-(3-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenyl)-3,6-dihydropyridin-1(2H)-yl)acetic acid (Example 259, 4.1 mg, 5.4 μmol, 28% yield). 1 H NMR(500MHz, CD3OD) δ 10.31(brd,J=7.2Hz,1H), 10.12(s,1H), 8.15(dd,J=6.2, 2.6Hz,1H), 8.05(d,J=2.5Hz,1H), 7.78-7.68 (m,1H), 7.59(dd,J=8.8, 2.5Hz,1H), 7.28(t,J=9.6Hz,1H), 7.23-7.17(m,1H), 6.38-6.32(m,1H), 4.74 (d,J=9.4Hz,1H), 4.60-4.52(m,1H), 4.25(brs,4H), 4.09(s,3H), 3.25-3.19(m,1H), 3.17-3.11(m,1H) , 2.77-2.68(m,3H), 2.01-1.89(m,2H), 1.59-1.47(m,3H), 0.80-0.71(m,2H), 0.41-0.29(m,2H);LC-MS RT:0.94min;MS(ESI) m / z642.3(M+H) + ;Method A

[0359] Example 265 [ka] Intermediate 265-1: To a vial containing 260-2 (10 mg, 0.013 mmol) in THF (1.3 mL) was added LiOH (63 μL, 0.063 mmol) as a 1 M solution in water. The reaction mixture was stirred at room temperature for 18 h and then diluted with 1 N HCl. The resulting mixture was diluted with EtOAc (3 × 5 mL). The organics were combined, dried over NaSO, filtered, and concentrated to give (1R,2S,3R,4R,Z)-3-(5'-(tert-butoxycarbonyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxamido)-7-(cyclopropylmethylene)bicyclo[2.2.1]heptane-2-carboxylic acid, which was used without further purification (7.0 mg, 0.013 mmol, 100% yield). H-NMR (500 MHz, DMSO-d) δ 10.05(brs,1H), 8.12(s,1H), 8.01-7.97(m,1H), 7.96-7.92(m,1H), 7.74(d,J=8.9Hz,1H), 7.4 5(t,J=9.5Hz,1H), 7.33(d,J=8.9Hz,1H), 4.66(d,J=9.5Hz,1H), 4.34-4.25(m,1H), 4.04(s,3H) ), 3.15-3.09(m,1H), 2.99(dd,J=10.8, 3.8Hz,1H), 2.68-2.61(m,1H), 1.76-1.63(m,2H), 1.56 (s,9H), 1.47(dt,J=8.7, 4.2Hz,1H), 1.42(s,2H), 0.84-0.60(m,2H), 0.44-0.23(m,2H);LC-MS RT:1.17min;MS(ESI) m / z536(M+H) + ;Method D

[0360] Example 265: To a reaction vessel was added 265-1 (4.0 mg, 0.022 mmol), MeCN (1 mL), DIEA (10 μl, 0.060 mmol), and HATU (6.8 mg, 0.018 mmol). The reaction mixture was stirred at room temperature for 12 hours, then concentrated under reduced pressure, and the residue was dissolved in 1:2 TFA / DCM and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO, and purified by HPLC to give 3'-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (3.4 mg, 5.3 μmol, 35% yield). H-NMR (500 MHz, DMSO-d) δ 10.41(s,1H), 9.98(d,J=6.7Hz,1H), 8.21-8.09(m,2H), 8.05-7.99(m,1H), 7.99-7.90(m,1H), 7.77-7.70(m ,1H), 7.64(dd,J=7.8, 1.1Hz,1H), 7.45-7.36(m,2H), 7.33(d,J=8.5Hz,1H), 4.69(d,J=9.5Hz,1H), 4.55-4. 36(m,1H), 4.06(s,3H), 3.19-3.13(m,1H), 3.13-3.08(m,1H), 2.78-2.66(m,1H), 2.37(s,3H), 1.90-1.84(m ,1H), 1.83-1.76(m,1H), 1.55-1.47(m,1H), 1.47-1.37(m,2H), 0.84-0.60(m,2H), 0.42-0.23(m,2H);LC-MS RT:2.21min;MS(ESI) m / z653(M+H) + ;Method A

[0361] Example 310 [ka]

[0362] Intermediate 310-1 A solution of 5-borono-2-methoxybenzoic acid (0.200 g, 1.02 mmol) in EtOAc (10 mL) was treated with pinacol (0.121 g, 1.02 mmol), and the resulting solution was stirred at room temperature overnight. The reaction mixture was then concentrated, and the resulting solid was used without further manipulation as 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.284 g, 1.02 mmol, 100% yield). This solid was prepared according to the same procedure as in Example 108. Coupling with intermediate 170-2 gave intermediate 310-1.

[0363] The reaction mixture of 310-1 (50 mg, 0.076 mmol), PdCl(dppf) (5.6 mg, 7.6 μmol), 3-bromopyridine (0.1 mL), and KPO (48.5 mg, 0.229 mmol) was heated to 80 °C. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was concentrated, and the residue was purified by reverse-phase HPLC to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(pyridin-3-yl)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (11.4 mg, 0.019 mmol, 24% yield). 1H NMR (500MHz, DMSO-d6) δ 10.68(s,1H), 9.99(brd,J=6.8Hz,1H), 8.85(s,1H), 8.55(brd,J=3.4Hz,1H), 8.24(brd,J=2. 3Hz,2H), 8.07-8.00(m,1H), 7.90(dd,J=8.6, 2.4Hz,1H), 7.83-7.73(m,1H), 7.56-7.45(m,2H) ), 7.34(d,J=8.8Hz,1H), 6.05-5.92(m,1H), 4.60-4.51(m,1H), 4.06(s,3H), 3.47(s,1H), 3.0 0(brs,1H), 2.74(s,1H), 2.02-1.95(m,1H), 1.94-1.87(m,1H), 1.51(brd,J=6.6Hz,2H);LC-MS RT2.47min;MS(ESI) m / z=608.3(M+H) + ;Method C

[0364] Example 320 was prepared in a manner similar to Example 253 via the following intermediates:

[0365] Example 320 [ka]

[0366] Intermediate 320-1 [ka]

[0367] To a solution of methyl 5-bromo-2-hydroxybenzoate (750 mg, 3.25 mmol) and 4-(2-bromoethyl)morpholine (756 mg, 3.90 mmol) in DMF (12 mL) was added K2CO3 (1346 mg, 9.74 mmol) and heated at 70 °C for 4 h. The reaction mixture was diluted with EtOAc, and the solution was washed with water and brine solution. The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica column to give methyl 5-bromo-2-(2-morpholinoethoxy)benzoate (320-1, 0.800 g, 2.32 mmol, 71.6% yield). MS, m / z: 343.9 (M+2H).

[0368] Intermediate 320-2 [ka]

[0369] To a solution of 320-1 (300 mg, 0.872 mmol) and tert-butyl 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (309 mg, 0.959 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added tripotassium phosphate (555 mg, 2.61 mmol), and the resulting mixture was purged with nitrogen for 5 minutes. PdCl(dppf)-CHCl adduct (71 mg, 0.087 mmol) was added, and the reaction mixture was purged with nitrogen for 2 minutes and then heated in a sealed test tube at 85 °C for 16 hours. The reaction mixture was filtered through Celite. The filtrate was diluted with EtOAc, and the organic phase was washed with water and brine solution. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography to give 3'-(tert-butyl) 3-methyl 6'-fluoro-4-(2-morpholinoethoxy)-[1,1'-biphenyl]-3,3'-dicarboxylate (320-2, 0.310 g, 0.675 mmol, 77% yield). MS, m / z: 460.2 (M+H).

[0370] Intermediate 320-3 [ka]

[0371] To a solution of 320-2 (100 mg, 0.218 mmol) in THF (2 mL) was added NaOH solution (0.87 mL, 2.2 mmol) and stirred at 50 °C for 30 min. THF was removed under vacuum, 1 mL of water was added, and the mixture was acidified to pH 4 with 1.5 N HCl. The aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with water and brine solution, dried over NaSO, filtered, and concentrated under reduced pressure to give 5'-(tert-butoxycarbonyl)-2'-fluoro-4-(2-morpholinoethoxy)-[1,1'-biphenyl]-3-carboxylic acid (40 mg, 0.090 mmol, 41% yield). MS, m / z: 446.2 (M+H).

[0372] Intermediate 320-4 [ka]

[0373] To a solution of 320-3 (30 mg, 0.076 mmol) and 170-2 (334 mg, 0.0760 mmol) in DMF (2 mL), DIPEA (0.07 mL, 0.4 mmol) and HATU (57.6 mg, 0.151 mmol) were added and stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and washed with water and brine solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The remaining product was purified by silica gel chromatography to give tert-butyl 6-fluoro-3'-(((1R,2R,3S,4R,Z)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4'-(2-morpholinoethoxy)-[1,1'-biphenyl]-3-carboxylate (320-4, 50 mg, 0.061 mmol, 80% yield). MS, m / z: 824.3 (M+H).

[0374] To a solution of 320-4 (50 mg, 0.061 mmol) in DCM (2 mL) was added TFA (0.094 mL, 1.2 mmol) at 0° C. and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give 6-fluoro-3′-(((1R,2R,3S,4R,Z)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4′-(2-morpholinoethoxy)-[1,1′-biphenyl]-3-carboxylic acid (20 mg, 0.025 mmol, 42% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ ppm 13.27-13.08(m,1H), 10.47-10.37(m,1H), 10.02-9.81(m,1H), 8.91-8.75(m,1H), 8.16-7.9 4(m,3H), 7.89-7.79(m,1H), 7.76-7.60(m,2H), 5.82-5.67(m,1H), 4.68-4.61(m,1H), 4.61-4 .43(m,1H), 4.01-3.83(m,2H), 3.75-3.61(m,2H), 3.58-3.48(m,3H), 2.84-2.78(m,2H), 2.7 0-2.63(m,5H), 2.02-1.85(m,2H), 1.81-1.65(m,2H), 1.62-1.45(m,2H);MS, m / z:768.2(M+H)

[0375] Example 323 [ka]

[0376] Intermediate 323-1 [ka]

[0377] To 120-4 (0.05 g, 0.1 mmol) dissolved in MeOH (0.5 mL) and THF (0.5 mL) was added Hunig's base (0.021 mL, 0.12 mmol), triphenylphosphine (0.8 mg, 3 μmol), and bis(triphenylphosphine)palladium(II) chloride (2 mg, 3 μmol). The vessel was pressurized to 60 psi with carbon monoxide and heated at 70 °C for 36 h. The reaction solution was concentrated in vacuo and purified by flash chromatography to give methyl (Z)-2-((1R,2S,3R,4R)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptan-7-ylidene)acetate 323-1. 1H NMR (500MHz, CDCl3) δ 9.49(brd,J=6.9Hz,1H), 7.96(s,1H), 7.86-7.72(m,2H), 7.23(t,J=9.4Hz,1H), 5.76(s,1H), 4.51(dt,J=10.5, 5.3Hz,1H) , 3.93(t,J=4.1Hz,1H), 3.86-3.75(m,3H), 3.18-3.05(m,1H), 2.89(t,J=4.0Hz,1H), 2.06-1.87(m,2H), 1.78-1.64(m,2H)

[0378] Intermediate 323-2 [ka]

[0379] To MeOH (0.8 mL) was added AcCl (0.080 mL, 1.1 mmol) and stirred for 5 min. 323-1 (0.029 g, 0.060 mmol) was added and the reaction mixture was stirred for 32 h. The reaction mixture was concentrated in vacuo to give methyl (Z)-2-((1R,2R,3S,4R)-2-amino-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-7-ylidene)acetate hydrochloride (323-2, 0.025 g, 0.060 mmol, 100% yield), which was used without further purification. MS(ESI) m / z 387.0 (M+H)

[0380] Intermediate 323-3 [ka]

[0381] To a solution of 323-2 and 120-6 (0.025 g, 0.072 mmol) in MeCN (0.6 mL) was added DIEA (0.03 mL, 0.2 mmol), followed by HATU (0.034 g, 0.090 mmol). The reaction mixture was stirred for 16 h, concentrated in vacuo, and purified by flash chromatography to give tert-butyl 6-fluoro-3'-(((1R,2R,3S,4R,Z)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(2-methoxy-2-oxoethylidene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylate (323-3, 0.028 g, 0.039 mmol, 65% yield). MS(ESI) m / z 715.3(M+H)

[0382] Intermediate 323-4 [ka]

[0383] To 323-3 (0.028 g, 0.040 mmol) dissolved in THF (1 mL) was added water (0.5 mL) and lithium hydroxide monohydrate (2 mg, 0.05 mmol), followed by stirring for 16 h. The reaction mixture was diluted with water, neutralized with 1 M HCl, and extracted into EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give (Z)-2-((1R,2R,3S,4R)-2-(5'-(tert-butoxycarbonyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxamido)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-7-ylidene)acetic acid (323-4, 0.025 g, 0.036 mmol, 90% yield). 1H NMR (500 MHz, CDCl3) δ 8.43(s,1H), 8.30-8.18(m,1H), 8.16-8.06(m,1H), 8.02-7.94(m,1H), 7.71(brd,J=8.5Hz,1H), 7.25-7.13(m,2H), 7.00(brd,J=8.8Hz,1H), 5. 82(s,1H), 4.85-4.65(m,1H), 4.29(brs,1H), 3.97(s,3H), 3.16-2.96( m,2H), 2.22-2.09(m,1H), 2.04-1.86(m,2H), 1.75-1.58(m,9H)MS(ESI) m / z701.3(M+H)

[0384] Example 323 was prepared from intermediate 323-4 by first preparing the amide according to the procedure of Example 34, followed by removal of the t-butyl group according to the procedure of Example 120. 1 H NMR (500MHz, DMSO-d6) δ 10.67(s,1H), 9.85(brd,J=7.0Hz,1H), 8.24(brd,J=4.3Hz,1H), 8.11(brs,1H), 8.01(brd,J=7.0Hz,1 H), 7.93(brs,1H), 7.80(brd,J=8.2Hz,1H), 7.72(brd,J=8.2Hz,1H), 7.48(brt,J=9.5Hz,1H), 7.37(b rt,J=9.5Hz,1H), 7.31(brd,J=8.9Hz,1H), 6.14(s,1H), 4.58-4.44(m,1H), 4.06(s,3H), 3.54(brs,1H) ), 3.05(s,3H), 2.99(s,1H), 2.88(s,4H), 2.03-1.95(m,1H), 1.90-1.73(m,1H), 1.45(brs,2H);LC-MS RT:2.19min;MS(ESI) m / z=627.14(MH)+;Method C

[0385] Example 325 [ka]

[0386] Intermediate 325-1 [ka]

[0387] To 120-4 (0.05 g, 0.1 mmol) slurried in triethylamine (0.2 mL) was added ethynyltrimethylsilane (0.02 mL, 0.1 mmol), bis(triphenylphosphine)palladium(II) chloride (3 mg, 5 μmol), and copper(I) iodide (2 mg, 10 μmol). The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was partitioned between EtOAc and pH 7.4 buffer and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, decanted, concentrated in vacuo, and the residue was purified by flash chromatography to give (1R,2S,3R,4R,Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)-7-(3-(trimethylsilyl)prop-2-yn-1-ylidene)bicyclo[2.2.1]heptane-2-carboxamide (325-1, 40 mg, 0.077 mmol, 77% yield). 1 H NMR (500MHz, CDCl3) δ 9.39(brd,J=6.9Hz,1H), 7.78-7.67(m,2H), 7.33(s,1H), 7.26-7.18(m,1H), 5.45(s,1H), 4.60-4.41(m,1H), 3.32(t,J=4.1Hz,1H), 3.05( ddd,J=10.5, 4.4, 1.4Hz,1H), 2.81(t,J=4.1Hz,1H), 1.98-1.90(m,1H), 1.90-1.81(m,1H), 1.76-1.59(m,2H), 0.31-0.17(m,9H);MS(ESI) m / z 521.0(M+H)

[0388] Intermediate 325-2 [ka]

[0389] To 325-1 (40 mg, 0.077 mmol) dissolved in THF (0.8 mL) was added 1 M TBAF in THF (0.2 mL, 0.2 mmol), and the reaction was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(prop-2-yn-1-ylidene)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide (325-2, 38 mg, 0.084 mmol, quantitative yield); MS(ESI) m / z 499.0 (M+H).

[0390] Intermediate 325-3 [ka]

[0391] To a solution of 325-2 (0.017 g, 0.038 mmol), (azidomethyl)trimethylsilane (0.011 mL, 0.076 mmol) in DMF (0.3 mL) and water (0.1 mL), copper(II) sulfate pentahydrate (7 mg, 0.03 mmol), and sodium ascorbate (8 mg, 0.04 mmol) were added and stirred for 3 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed 2x with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)-7-((1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)methylene)bicyclo[2.2.1]heptane-2-carboxamide (325-3), which was used without further purification. MS(ESI) m / z 578.1(M+H).

[0392] Intermediate 325-4 [ka]

[0393] To MeOH (0.5 ml) was added AcCl (0.050 ml, 0.70 mmol), and the reaction mixture was stirred for 5 minutes. 325-3 (0.022 g, 0.038 mmol) was added, and the reaction mixture was stirred at 40° C. for 48 hours. The reaction mixture was concentrated under reduced pressure, and the remaining solvent was removed under high vacuum to give (1R,2S,3R,4R,Z)-3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-((1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)methylene)bicyclo[2.2.1]heptane-2-carboxamide (325-4, 0.018 g, 0.038 mmol, 100% yield), which was used without further purification. MS (ESI) m / z 482.2 (M+H)

[0394] Intermediate 325-5 [ka]

[0395] Intermediate 325-5 was prepared from 325-4 and 120-6 according to the procedure of Example 108.

[0396] Example 325 was prepared from 325-5 according to the procedure of Example 120. 1H NMR (500MHz, DMSO-d6) δ 10.53(s,1H), 9.85(brd,J=7.0Hz,1H), 8.15(brd,J=4.6Hz,1H), 8.05(brs,1H), 7.99-7.81(m,3 H), 7.71(brs,1H), 7.65(brd,J=8.2Hz,1H), 7.40(brt,J=9.6Hz,1H), 7.33(brt,J=9.6Hz,1H), 7 .24(brd,J=8.5Hz,1H), 6.18(s,1H), 4.44(brs,1H), 3.98(s,3H), 3.90(s,2H), 3.48(brs,1H), 3 .27-3.09(m,1H), 2.83(brs,1H), 1.96-1.72(m,2H), 1.41(brd,J=5.8Hz,2H), 0.00(s,9H);LC-MS RT: 2.54 points; MS(ESI) m / z=754.36(MH)+; Method C

[0397] Example 329

change

[0398] Intermediate 329-1

change

[0399] To a solution of methyl 5-iodo-2-methoxybenzoate (500 mg, 1.71 mmol) and piperidin-3-ylmethanol (394 mg, 3.42 mmol) in DMSO (10 mL) was added KCO (710 mg, 5.14 mmol), CuI (98 mg, 0.51 mmol), and L-proline (59 mg, 0.51 mmol). The resulting solution was degassed with N for 10 minutes and then heated at 90 °C for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl 5-(3-(hydroxymethyl)piperidin-1-yl)-2-methoxybenzoate (329-1, 350 mg, 1.25 mmol, 73.2% yield). MS(ESI) m / z 280.2(M+H)

[0400] Intermediate 329-2 [ka]

[0401] To a solution of 329-1 (350 mg, 1.253 mmol) in MeOH (5 mL), THF (5 mL), and water (3 mL) was added LiOH (150 mg, 6.26 mmol) and stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure, the aqueous layer was acidified with HCl to a pH of approximately 4 to 5, and the resulting precipitate was filtered and dried to give 5-(3-(hydroxymethyl)piperidin-1-yl)-2-methoxybenzoic acid (300 mg, 1.13 mmol, 90% yield) as a white solid. MS (ESI) m / z 266.2 (M+H).

[0402] Example 329 was prepared from intermediates 166-2 and 329-2 according to the procedure of Example 108. The stereoisomers were separated on a preparative HPLC column, Chiralcel OD-H (250x4.6) mm, 5μ, to give (1R,2R,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-(hydroxymethyl)piperidin-1-yl)-2-methoxybenzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (2.1 mg, 3.231 μmol, 3.51% yield). MS (ESI) m / z 644.2 (M+H); 1 H NMR (400MHz, DMSO-d6) δ ppm 10.43(s,1H), 8.41(d,J=6.5Hz,1H), 8.12(dd,J=2.5, 6.5Hz,1H), 7.88-7.75(m,1H), 7.48(t,J=9.8Hz,1H ), 7.20(d,J=2.5Hz,1H), 7.11-6.95(m,2H), 5.82-5.64(m,1H), 4.65-4.56(m,1H), 4.52(t,J=5.3Hz,1H), 3.83(s,3H), 3.51(brs,1H), 3.44-3.41(m,1H), 3.25-3.20(m,2H), 2.78(d,J=4.0Hz,1H), 2.58-2.55(m,3 H), 2.32-2.27(m,1H), 1.92(td,J=4.7, 12.2Hz,1H), 1.80-1.65(m,6H), 1.56(brs,2H), 1.09-0.94(m,1H)

[0403] Example 346 [ka]

[0404] Intermediate 346-1 [ka]

[0405] To a solution of 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol) in THF (100 mL) at −78° C., n-butyllithium (25.5 mL, 40.8 mmol) was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The mixture was then cooled back to −78° C., and a solution of diethyl oxalate (2.8 mL, 20 mmol) in THF (2.5 mL) was added and stirred for 20 minutes. The reaction mixture was quenched by the addition of saturated ammonium chloride, and the solution was extracted with ethyl acetate. The organic layer was collected, concentrated under reduced pressure, and purified using silica gel chromatography to give 346-1 (496 mg, 20.6%). MS (ESI) m / z: 168.9 (M+H).

[0406] Intermediate 346-2 [ka] To a solution of 346-1 (150 mg, 0.892 mmol) in acetonitrile (5 mL) was added DMAP (10.90 mg, 0.089 mmol), di-tert-butyl dicarbonate (0.249 mL, 1.07 mmol), followed by TEA (0.149 mL, 1.07 mmol). The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and purified using silica gel chromatography to give 346-2 (185 mg, 73.4%). MS (ESI) m / z: 269.1 (M+H).

[0407] Intermediate 346-3 [ka]

[0408] A solution of 346-2 (185 mg, 0.690 mmol), sodium acetate (62.2 mg, 0.759 mmol), and hydroxylamine hydrochloride (86 mg, 1.241 mmol) in ethanol (3 mL) was heated at reflux for 1 h. The reaction mixture was then concentrated in vacuo and diluted with ethyl acetate. The organic layer was washed with 5% HCl solution to give 346-3 (190 mg, 88%), which was used without further purification. MS (ESI) m / z: 183.9 (M+H-Boc).

[0409] Intermediate 346-3 [ka]

[0410] To a degassed solution of 346-3 (190 mg, 0.671 mmol) in ethanol (5 mL) was added palladium on carbon (143 mg, 0.134 mmol) and degassed with nitrogen. The reaction mixture was stirred under a hydrogen balloon for 1.5 hours. The reaction mixture was filtered through a Celite pad to give 346-4 (181 mg, 100%). MS (ESI) m / z: 270.1 (M+H).

[0411] Intermediate 346-5 [ka]

[0412] To a solution of 346-4 (181 mg, 0.672 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (87 mg, 0.672 mmol) in anhydrous DMF (2 mL) was added DIEA (0.587 mL, 3.36 mmol), followed by BOP (327 mg, 0.739 mmol). The reaction mixture was stirred at room temperature for 1 hour and filtered. The residue was concentrated under reduced pressure and purified using silica gel chromatography to give 346-5 (120 mg, 44.5%). MS (ESI) m / z: 382.3 (M+H).

[0413] Intermediate 346-6 [ka]

[0414] To a solution of 346-5 (120 mg, 0.315 mmol) in DCM (4 mL) was added TFA (1.5 mL, 19.47 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 346-6 (125 mg, 90%). MS (ESI) m / z: 282.2 (M+H).

[0415] Intermediate 346-7 [ka]

[0416] To a solution of 5-borono-2-methoxybenzoic acid (87 mg, 0.444 mmol), 346-6 (125 mg, 0.444 mmol), and boric acid (82 mg, 1.3 mmol) degassed under N was added copper(II) acetate (81 mg, 0.44 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified using silica gel chromatography. MS (ESI) m / z: 432.3 (M+H).

[0417] Example 346 was prepared from 170-2 and 346-7 in a manner similar to Example 108. 1H NMR (500MHz, DMSO-d6) δ 10.66(s,1H), 10.03(d,J=6.7Hz,1H), 8.59-8.51(m,1H), 8.46(br.s.,1H), 8.32(br.s.,1H), 8.24(d,J=4.6Hz,1 H), 7.98-7.88(m,1H), 7.79(br.s.,1H), 7.72(s,1H), 7.50(t,J=9.8Hz,1H), 7.33(d,J=8.8Hz,1H), 6.00-5.88(m ,1H), 5.38(d,J=6.4Hz,1H), 4.54(br.s.,1H), 4.17-4.09(m,2H), 4.05(s,3H), 3.36-3.20(m,2H), 3.00(br.s.,1 HPLC RT=2.44 minutes; Method B

[0418] Example 348 [ka]

[0419] Intermediate 348-1: [ka]

[0420] A mixture of furan-2,5-dione (10 g, 102 mmol) and phenylmethanol (31.7 mL, 306 mmol) in toluene (50 mL) was heated at 80° C. for 24 hours. The reaction mixture was then concentrated under reduced pressure and purified using silica gel chromatography to give 348-1 (15.5 g, 73%). MS (ESI) m / z: 206.9 (M+H).

[0421] Intermediate 348-2 [ka]

[0422] To a solution of 348-1 (3.6 g, 17 mmol) in MeCN (40 mL) and water (0.400 mL), ferronium hexafluorophosphate (11.6 g, 34.9 mmol) was added and stirred under an open atmosphere for 18 hours. The reaction mixture was concentrated under reduced pressure and diluted with DCM. The reaction mixture was treated with 1N HCl (40 mL) for 30 minutes. The organic layer was then separated, and the aqueous layer was washed with DCM and separated. The organic layers were combined and washed with brine. The organic layer was concentrated under reduced pressure and purified using silica gel chromatography to give 348-2 (1.8 g, 35%). MS (ESI) m / z: 289.1 (M+H).

[0423] Intermediate 348-3 [ka]

[0424] To a three-neck round-bottom flask, 348-2 (1.99 g, 6.90 mmol) and toluene (45 mL) were added, followed by TEA (2.1 mL, 15 mmol) and diphenylphosphoryl azide (1.26 mL, 5.87 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. To this reaction mixture, 2-(trimethylsilyl)ethan-1-ol (3.94 mL, 28.3 mmol) was added, and the resulting reaction mixture was heated at 80° C. for 28 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and purified using silica gel chromatography to give 348-3 (1.52 g, 51.8%). MS (ESI) m / z: 403.9 (M+H).

[0425] Intermediate 348-4 [ka]

[0426] To a solution of 348-3 (1.52 g, 3.77 mmol) in THF (24 mL) and water (8.0 mL), LiOH (5.65 mL, 11.3 mmol) was added and the solution was stirred at room temperature for 1 hour. The reaction mixture was acidified and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure to give 348-4 (1.1 g, 92%). MS (ESI) m / z: 313.9 (M+H).

[0427] Intermediate 348-5 [ka]

[0428] To a solution of 348-4 (680 mg, 2.17 mmol) in anhydrous DMF (12 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (0.28 mL, 2.2 mmol), 1-hydroxybenzotriazole hydrate (515 mg, 3.36 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (624 mg, 3.25 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was purified using silica gel chromatography to give 348-5 (260 mg, 25%). MS(ESI) m / z: 474.9 (M+H).

[0429] Intermediate 348-6 [ka]

[0430] In a flask under N2, DMSO (4 mL) and sulfur trioxide pyridine (279 mg, 1.75 mmol) were added to a solution of 348-5 (260 mg, 0.548 mmol) and TEA (0.61 mL, 4.4 mmol) in DMSO (4 mL) at 0 °C. The reaction mixture was stirred for 1 h, diluted with EtOAc, and the organic phase was washed with brine. The organic layer was concentrated under reduced pressure, and the residue was purified using silica gel chromatography to give 348-6 (280 mg, 100%). MS (ESI) m / z: 473.0 (M+H).

[0431] Intermediate 348-7 [ka]

[0432] To a round-bottom flask was added (bromomethyl)triphenylphosphonium bromide (388 mg, 0.889 mmol) and THF (5.0 mL). The reaction mixture was cooled to −78° C., followed by the dropwise addition of a 1 M solution of NaHMDS in THF (0.89 mL, 0.89 mmol) over 2 minutes, while maintaining the internal temperature below −70° C. The resulting light yellow suspension was stirred at −78° C. for 1 hour. This reaction mixture was added over 2 minutes to a solution of 348-6 (280 mg, 0.593 mmol) in anhydrous THF (1.0 mL), previously treated with NaHMDS (1.12 mL, 1.12 mmol), while maintaining the internal temperature below −70° C. The resulting reaction mixture was stirred at −78° C. for 3 hours. The reaction mixture was then quenched by the slow addition of water (6 mL), followed by ethyl acetate (6 mL). The resulting reaction mixture was stirred for 5 minutes and then diluted with EtOAc. The organic portions were combined, washed with brine, and purified using silica gel chromatography. The residue was subjected to chiral separation using a Chiralpak OD-H 21x250 mm, 5 micron column with a mobile phase of 5% MeOH / CAN / 95% CO2 at a flow rate of 45 mL / min and 150 Bar. The separation was performed at 40°C and monitored at a wavelength of 240 nm. The chiral separation yielded four peaks with retention times of 9.29 minutes (>99.9% ee), 11.16 minutes (>99.9% ee), 13.98 minutes (>99.9% ee), and 15.30 minutes (>81.0% ee). The desired product was found at 11.16 min with an ee of >99.9% and confirmed by 2D NMR analysis (peak 2 from chiral SFC), yielding 348-7 (82 mg, 25.16%). MS(ESI) m / z: 473.1 (M+H).

[0433] Intermediate 348-8 [ka]

[0434] To a suspension of 348-7 (83 mg, 0.15 mmol) and CuI (43.2 mg, 0.227 mmol) in anhydrous DMF (1 mL) and HMPA (1.2 mL, 7.0 mmol) under N at 75 °C, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.048 mL, 0.38 mmol) in anhydrous DMF (0.5 mL) was added dropwise over 10 min. The resulting suspension was stirred at 75 °C under nitrogen for 12 h. The reaction mixture was cooled to room temperature and quenched by the addition of NaHCO (20 mL), and the solution was extracted with EtOAc. The organic layer was concentrated and subjected to silica gel chromatography to give 348-8 (52 mg, 61%). MS (ESI) m / z: 539.1 (M+H).

[0435] Intermediate 348-9 [ka]

[0436] To a solution of 348-8 (52 mg, 0.097 mmol) in 1,4-dioxane (1.5 mL) was added DCM (1.6 mL) and TFA (0.4 mL). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure to give 348-9, which was used without further purification (49 mg, 95%). MS (ESI) m / z: 394.9 (M+H).

[0437] Intermediate 348-10 [ka]

[0438] 348-10 was prepared according to the procedure of Example 230. MS (ESI) m / z: 818.2 (M+H)

[0439] Example 348 [ka]

[0440] To a solution of 348-10 (35 mg, 0.043 mmol) in acetone (1 mL) was added N-methylmorpholine N-oxide (10 mg, 0.086 mmol), followed by OsO / t-butanol (0.054 mL, 4.2 μmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, and the solution was washed with sodium thiosulfate. The organic layer was separated and concentrated under reduced pressure, and the residue was purified using preparative reverse-phase HPLC to give Example 348 (14.6 mg, 38.0%). 1 H NMR(400MHz, CD3OD) δ 10.41(s,1H), 10.15(d,J=7.3Hz,1H), 8.27(d,J=1.3Hz,1H), 8.19(dd,J=6.3, 2.5Hz,1H), 7.84-7.72(m,2H), 7.69-7 .61(m,1H), 7.56-7.48(m,1H), 7.38-7.24(m,3H), 6.18(q,J=7.0Hz,1H), 5.94(q,J=7.5Hz,1H), 4.70(ddd,J=10.9, 7. 1, 4.2Hz,1H), 4.55(d,J=6.4Hz,1H), 4.45(d,J=6.4Hz,1H), 4.13(s,3H), 4.12-3.99(m,1H), 3.42(d,J=1.5Hz,1H), 3 .38(s,1H), 2.90(d,J=4.0Hz,1H), 2.39-2.19(m,2H), 2.09-1.90(m,2H), 1.78-1.63(m,2H);LC-MS(M+H)=852.1;HPLC RT=11.48 minutes; Method C

[0441] A solution of 351-5 (120 mg, 0.176 mmol) and LiOH (21.05 mg, 0.879 mmol) in MeOH (2 mL), THF (2 mL), and water (1 mL) was stirred at ambient temperature for 12 hours. The reaction was concentrated and acidified with 1.5 N HCl. The reaction was extracted with DCM, and the organic layer was concentrated. The residue was purified by preparative reverse-phase HPLC to give 4-fluoro-3'-(1R,2R,3R,4R,Z)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (11.5 mg, 0.016 mmol, 9% yield). 1 H NMR; MS(E-) m / z: 669.2 (M+H)

[0442] Example 352 [ka]

[0443] Intermediate 352-1 [ka]

[0444] Intermediate 352-1 was prepared from 120-5 and 177-4 according to the method described for Example 108. LC-MS (M+H) = 767.1; HPLC RT = 1.25 min; Method A

[0445] 352-1 (0.038 g, 0.050 mmol), Na2CO3 (5.30 mg, 0.0500 mmol), (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-κ] N ) Phenyl-κ CA slurry of iridium(III)·PF₆ (0.515 mg, 0.500 μmol), NiCl₂-ethylene glycol dimethyl ether complex (0.549 mg, 2.50 μmol), 4,4'-di-t-butyl-2,2'-bipyridine (0.551 mg, 2.50 μmol), (TMS)₃SiH₃ (0.03 mL), and 3-(bromomethyl)-1,1-difluorocyclobutane (0.019 g, 0.10 mmol) in DME was degassed with N₂ and illuminated with a blue LED for 96 h. The reaction mixture was diluted with EtOAc, filtered through silica gel, and concentrated under reduced pressure. The residue was dissolved in DCM (0.4 mL) and treated with TFA (0.08 mL). After 15 min, the solution was diluted with toluene and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC to give 2-(3'-(((1R,2R,3S,4R,Z)-7-(2-(3,3-difluorocyclobutyl)ethylidene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-hydroxyacetic acid (2.6 mg, 3.2 μmol, 6.5% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.56(brs,1H), 9.92(brdd,J=15.4, 7.2Hz,1H), 8.18(brt,J=4.9Hz,1H), 8.08(brd,J=11.0Hz,1H) , 7.81-7.61(m,2H), 7.52-7.35(m,3H), 7.32-7.13(m,2H), 5.26-5.13(m,1H), 4.92(brd,J=1.8Hz,1H ), 4.38(brd,J=4.3Hz,1H), 4.02(s,1H), 3.89-3.71(m,3H), 3.19-3.09(m,1H), 2.88(s,1H), 2.72(s, 2H), 2.64(brs,2H), 2.32-2.06(m,5H), 1.89-1.66(m,2H), 1.38(brs,2H);LC-MS(M+H)=734.24;HPLC RT=2.48 minutes; Method C

[0446] Example 360 [ka]

[0447] Example 292 (0.025 g, 0.041 mmol), NaCO (4.35 mg, 0.0410 mmol), (4,4'-di-t-butyl-2,2'-bipyridine) bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-κ] N ) Phenyl-κ C A slurry of ]Ir(III)·PF₆ (0.423 mg, 0.410 μmol), NiCl₂ethylene glycol dimethyl ether complex (0.451 mg, 2.05 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.551 mg, 2.50 μmol), (TMS)₃SiH₂ (0.03 mL), and 3-bromotetrahydrofuran (0.012 g, 0.082 mmol) in DME (1.641 mL) was degassed, blanketed under N₂, and illuminated with a blue LED. After 96 h, the reaction mixture was diluted with EtOAc, filtered through silica gel, and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(tetrahydrofuran-3-yl)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (3.5 mg, 5.5 μmol, 13% yield) as a mixture of diastereomers. 1H NMR (500MHz, DMSO-d6) δ 10.55(s,1H), 9.78(brd,J=5.8Hz,1H), 8.14(brd,J=4.6Hz,1H), 7.81-7.65(m,2H), 7.49-7.2 8(m,2H), 7.04(brd,J=8.5Hz,1H), 5.84(q,J=7.9Hz,1H), 4.43(brs,1H), 3.95-3.78(m,5H), 3 .74-3.64(m,1H), 3.37-3.07(m,2H), 2.89(brs,1H), 2.81(s,1H), 2.71-2.62(m,1H), 2.24-2. 11(m,1H), 1.99-1.87(m,1H), 1.83-1.71(m,2H), 1.50-1.26(m,2H);LC-MS(M+H)=601.16;HPLC RT=2.58 minutes; Method C

[0448] Example 378 [ka] [ka]

[0449] Preparation of Intermediate 378-1: Methyl (E)-5-((hydroxyimino)methyl)-2-methoxybenzoate Commercially available methyl 5-formyl-2-methoxybenzoate (1.16 g, 5.97 mmol) was dissolved in DCM (5 mL). To this solution was added hydroxylamine·HCl (415 mg, 5.97 mmol), followed by TEA (1 mL). The reaction mixture was stirred at room temperature for 18 h. Water (100 mL) was added, and the solution was extracted with EtOAc (2 × 25 mL). The organic portions were combined, dried (MgSO), filtered, and evaporated under reduced pressure to give 378-1 (1.19 g, 95% yield). 1 H NMR (400MHz, CDCl3) δ 8.13(s,1H), 8.03(d,J=2.4Hz,1H), 7.78-7.67(m,1H), 7.03(d,J=8.8Hz,1H), 3.97(s,3H), 3.93(s,3H):MS(ESI) m / z=210.1(M+H)

[0450] Preparation of Intermediate 378-2: Methyl 5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoate Intermediate 378-1 (55 mg, 0.26 mmol) was dissolved in DMF (2 mL). NCS (35 mg, 0.26 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 4 h. Water was added, and the solution was extracted with EtOAc (2 × 25 mL). The organic portions were combined, dried (MgSO), filtered, and concentrated under reduced pressure. The residue was immediately redissolved in DCM (5 mL). Allyl alcohol (61 mg, 1.05 mmol) was added to the solution, followed by TEA (0.5 mL). The resulting reaction mixture was stirred at room temperature for 18 h. Water (20 mL) was added, and the solution was extracted with EtOAc (2 × 20 mL). The organic portions were combined, dried (MgSO), filtered, and purified by normal phase chromatography eluting with hexane / EtOAc to give 378-2 (58 mg, 85% yield). 1 H NMR (500MHz, CDCl3) δ 8.05(d,J=2.4Hz,1H), 7.89(dd,J=8.8, 2.4Hz,1H), 7.05(d,J=8.9Hz,1H), 4.90(dddd,J=10.8, 7.7, 4.6, 3.2Hz ,1H), 4.08-3.85(ss,6H), 3.81-3.68(m,1H), 3.46-3.36(m,1H), 1.89(brt,J=6.2Hz,1H), 1.57(s,2H):MS(ESI) m / z=266.1(M+H)

[0451] Intermediate 378-3: 378-2 (58 mg, 0.22 mmol) was dissolved in THF (2 mL) and LiOH (6.3 g, 0.26 mmol) was added, followed by water (2 mL) and methanol (1 mL) and stirred at room temperature for 4 h. After quenching with dilute HCl (1 N) to pH 7, the solution was extracted with EtOAc (2 x 25 mL), and the organic portions were combined, dried (MgSO), filtered, and evaporated to give 378-3. 1H NMR (500MHz, CDCl3) δ 8.28(d,J=2.3Hz,1H), 8.14(dd,J=8.8, 2.4Hz,1H), 7.28-7.14(m,1H), 4.92(dddd,J=10.8, 7.7, 4.6, 3.1Hz,1H), 4.16(s,3H), 4. 09-3.89(m,1H), 3.72(dd,J=12.4, 4.6Hz,1H), 3.48-3.39(m,1H), 3.38-3.29(m,1H), 1.94-1.72(m,1H), 1.60(brs,1H):MS(ESI) m / z=252.3(M+H)

[0452] Intermediates 378-4 and 378-5: 378-3 was purified by the following preparative procedure: Apparatus: Berger MG II; Column: Chiralpak IC, 21x250mm, 5 micron; Mobile phase: 20% methanol / 80% CO2; Flow conditions: 2mL / min, 150 Bar, 40°C; Detector wavelength: 220nm; Injection details: 0.7mL of approximately 35mg / mL in MeOH was injected and subjected to chiral SFC separation to give 378-4 (Peak 1, >99% de, analytical RT=5.6min) and 378-5 (Peak 2, 99% de, analytical RT=6.6min). Analytical chromatographic conditions: Apparatus: Shimadzu Nexera SFC (CTR-L410-SFC3), Column: Chiralpak IC, 4.6x100mm, 3 micron, Mobile phase: 20% methanol / 80% CO2; Flow conditions: 2.0mL / min, 150 Bar, 40°C, Detector wavelength: 220nm; Injection details: 5µL of approximately 1mg / mL (in MeOH) was injected.

[0453] (1R,2S,3R,4R,Z)-7-(cyclobutylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide 378 (diastereomeric mixture) was prepared by coupling intermediate 378-3 (4.6 mg, 0.018 mmol) with cyclobutylnorbornyl intermediate 369-1 (7 mg, 0.02 mmol) in the presence of BOP reagent (8.1 mg, 0.018 mmol) and Hunig's base (0.05 mL) in DMF. Purification by reverse-phase HPLC afforded 378 (5 mg, 44% yield) as a solid. 1 H NMR (500MHz, DMSO-d6) δ 10.55(s,1H), 9.89(dd,J=7.1, 2.8Hz,1H), 8.26-8.17(m,2H), 7.84-7.73(m,2H), 7 .48(brt,J=9.7Hz,1H), 7.26(d,J=8.8Hz,1H), 5.37(d,J=8.4Hz,1H), 4.78-4.65(m ,1H), 4.35(brs,1H), 4.03(s,3H), 3.63(brs,1H), 3.22-3.05(m,3H), 2.96(brs,1H) ), 2.70(brs,1H), 2.23-2.06(m,3H), 1.91-1.70(m,7H), 1.43-1.22(m,2H):MS(ESI) m / z=616.1(M+H); HPLC purity: 100%; Retention time: 2.54 min; Method C

[0454] Example 379 [ka]

[0455] Example 379: (1R,2S,3R,4R,Z)-7-(cyclobutylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide (homochiral isomer-2) was prepared using cyclobutylnorbornyl intermediate 369-1 and intermediate 378-5 using the coupling method described in Example 378 (49% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.54(s,1H), 9.88(brd,J=7.0Hz,1H), 8.22(s,1H), 8.23(d,J=7.0Hz,1H), 7.79(brd,J=8.2Hz,2H ), 7.49(brt,J=9.6Hz,1H), 7.27(d,J=8.5Hz,1H), 5.38(brd,J=8.5Hz,1H), 4.70(brd,J=3.1Hz,2H ), 4.36(brs,1H), 4.04(s,3H), 3.51(brs,1H), 3.37(brs,2H), 3.22-3.04(m,2H), 2.97(brs,1H), 2 .71(brs,1H), 2.19(brd,J=5.8Hz,1H), 2.14(brs,1H), 1.92-1.71(m,6H), 1.37(brs,2H):MS(ESI) m / z=616.1(M+H); HPLC purity: 100%; Retention time: 2.54 min; Method C

[0456] Example 384 [ka]

[0457] Intermediates 384-1 (racemic), 384-2 (homochiral peak-1), and 384-3 (homochiral peak-2) [ka]

[0458] Intermediate 384-1: The intermediate 5-(5-(tert-butoxycarbonyl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoic acid was prepared from the product of 378-1 via ester hydrolysis and treatment with NCS in DMF as described in 378-2 to give 5-(chloro(hydroxyimino)methyl)-2-methoxybenzoic acid, which was then treated with excess t-butyl acrylate to give the desired intermediate 5-(5-(tert-butoxycarbonyl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoic acid (384-1) in 76% yield. 1 H NMR (500MHz, CDCl3) δ 8.25(d,J=2.3Hz,1H), 8.19(dd,J=8.8, 2.4Hz,1H), 7.16(d,J=8.9Hz,1H), 5.10(d d,J=9.9, 8.7Hz,1H), 4.16(s,3H), 3.67-3.60(m,2H), 1.74-1.51(m,9H):MS(ESI) m / z=322.1(M+H)

[0459] Intermediates 384-2 and 384-3: The chiral intermediates of 384-1 were separated by chiral SFC using the following preparative chromatographic method: Apparatus: Berger MG II; Column: Chiralpak IC, 21x250mm, 5 micron; Mobile phase: 20% methanol / 80% CO2; Flow conditions: 2mL / min, 150 Bar, 40°C; Detector wavelength: 220nm; Injection details: 0.7mL injection of approximately 35mg / mL (in MeOH) to give 384-2 (Peak 1, >99% de, analytical RT=7.93min) and 384-3 (Peak 2, >99% de, analytical RT=9.65min). Analytical chromatographic conditions: Apparatus: Shimadzu Nexera SFC (CTR-L410-SFC3); Column: Chiralpak IC, 4.6 x 100 mm, 3 micron; Mobile phase: 20% methanol / 80% CO2; Flow conditions: 2.0 mL / min, 150 Bar, 40 °C; Detector wavelength: 220 nm; Injection details: 5 μL of approximately 1 mg / mL (in methanol) was injected.

[0460] 3-(3-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenyl)-4,5-dihydroisoxazole-5-carboxylic acid (mixture of diastereomers) was prepared using the coupling method described in Example 378 with norbornyl intermediate 166-2 and intermediate 384-1 (7% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.56(s,1H), 9.92(d,J=7.0Hz,1H), 8.32-8.20(m,2H), 7.87-7.75(m,2H), 7.49(t,J=9.8Hz,1 H), 7.34-7.22(m,1H), 5.15(dd,J=11.6, 6.7Hz,1H), 4.70(d,J=9.5Hz,1H), 4.45(brs,1H), 4.05 (s,3H), 3.74(dd,J=17.1, 11.6Hz,1H), 3.23-3.13(m,2H), 3.11(brs,2H), 2.86-2.64(m,1H), 1 .88-1.68(m,2H), 1.62-1.46(m,1H), 1.42(brs,2H), 0.88-0.68(m,2H), 0.36(brs,2H):MS(ESI) m / z=616.3(M+H); HPLC purity: 100%; Retention time: 2.38 min; Method C

[0461] Example 385 [ka]

[0462] Homochiral isomer-1 of 3-(3-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenyl)-4,5-dihydroisoxazole-5-carboxylic acid was prepared by coupling intermediate 384-2 (13.9 mg, 0.04 mmol) with intermediate 166-2 (16 mg, 0.04 mmol) in DMF in the presence of BOP reagent (19 mg, 0.04 mmol) and Hunig's base (0.05 mL). The reaction mixture was concentrated under reduced pressure, water (25 mL) was added, and the solution was extracted with EtOAc (2×25 mL). The organic portions were combined, dried (MgSO), filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL), TFA (0.2 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The solution was concentrated under reduced pressure, redissolved in DMF (1 mL), and purified by reverse-phase HPLC to give 385, 3-(3-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenyl)-4,5-dihydroisoxazole-5-carboxylic acid (homochiral) as a solid (12 mg, 99% yield). 1H NMR (500MHz, DMSO-d6) δ 10.62(s,1H), 9.92(brd,J=7.0Hz,1H), 8.24(brs,2H), 7.88-7.76(m,2H), 7.49(brt,J=9.5Hz,1H), 7.2 7(d,J=8.9Hz,1H), 5.01-4.84(m,1H), 4.69(d,J=9.5Hz,1H), 4.45(brs,1H), 4.05(s,3H), 3.67-3.43(m ,1H), 3.18(brd,J=7.3Hz,1H), 3.12(brs,1H), 2.73(brs,1H), 1.92(s,1H), 1.88-1.66(m,2H), 1.51(br d,J=4.3Hz,1H), 1.42(brs,2H), 0.89-0.68(m,2H), 0.35(brs,2H); HPLC purity: 100%; Analytical LC-MS: 2.33 min; (ESI) m / z=616.28(M+H) + , method C

[0463] Example 390 [ka]

[0464] Intermediate 390-1 [ka]

[0465] Intermediate 390-1 was prepared in a similar manner as described for intermediate 378-3, in this case using tert-butyl but-3-ynoate instead of allyl alcohol (71% yield). 1H NMR (400MHz, CDCl3) δ 10.40(brs,1H), 8.29-8.25(m,1H), 8.18(dd,J=8.8, 2.4Hz,1H), 7.16(d,J=8.8Hz,1H), 5.21-5.09(m,1H), 4.23-4.12(m,3H), 3.58(dd,J =16.8, 10.5Hz,1H), 3.17(dd,J=16.7, 7.5Hz,1H), 2.82(dd,J=15.8, 5.9Hz,1H), 2.61(dd,J=15.8, 7.5Hz,1H), 1.52-1.43(m,9H):MS(ESI) m / z=336.1(M+H)

[0466] Intermediates 390-2 and 390-3: The chiral intermediate of 390-1 was separated by chiral SFC using the following preparative chromatography method: Apparatus: PIC Solution SFC Prep 200, Column: Chiralpak, 30x250mm, 5 micron; Mobile phase: 15% MeOH / 85% CO2; Flow conditions: 85mL / min, 150 Bar, 40°C Detector wavelength: 227nm, Injection details: 0.5mL injection of approximately 53mg / mL (in MeOH) to give 390-2 (Peak 1, 100% de, analytical RT=11.3min) and 390-3 (Peak 2, 93.8% de, analytical RT=12.6min). Analytical chromatography conditions: Instrument: Aurora Infinity SFC; Column: Chiralpak IC, 4.6x250mm, 3 micron; Mobile phase: 20% MeOH / 80% CO2; Flow conditions: 2.0mL / min, 150 Bar, 40°C; Detector wavelength: 220nm; Injection details: Inject 5µL of approximately 1mg / mL (in MeOH).

[0467] The homochiral isomer-2 of 2-(3-(3-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenyl)-4,5-dihydroisoxazol-5-yl)acetic acid 390 was prepared using cyclopropylnorbornyl intermediate 166-2 and intermediate 390-3 via the coupling method described in Example 378, followed by deprotection with TFA (47% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.55(s,1H), 9.92(brd,J=7.2Hz,1H), 8.26-8.19(m,2H), 7.84-7.77(m,2H), 7.49(t,J=9. 6Hz,1H), 7.28(d,J=8.9Hz,1H), 5.04-4.90(m,1H), 4.70(d,J=9.5Hz,1H), 4.46(brs,1H), 4 .05(s,3H), 3.22-3.09(m,2H), 2.73(brs,1H), 2.70-2.59(m,2H), 2.55(s,2H), 1.89-1.71( m,2H), 1.51(brd,J=4.9Hz,1H), 1.42(brs,2H), 0.87-0.69(m,2H), 0.36(brs,2H):MS(ESI) m / z=630.3(M+H); HPLC purity: 100%; Retention time: 2 minutes; Method B

[0468] Example 397 [ka]

[0469] Intermediate 397-1 [ka]

[0470] Intermediate 397-1 was prepared in a similar manner as described for intermediate 378-3, in this case using tert-butyl 3,3-dimethyl-2-methylenebutanoate instead of allyl alcohol (81% yield).1 H NMR(500MHz, CD3OD) δ 8.12(d,J=2.3Hz,1H), 7.88(d,J=8.5Hz,1H), 7.22(d,J=8.9Hz,1H), 4.06-3.88(s,3H), 3.62(q,J=18.0Hz,2H), 1.61-1.39(m,9H):MS(ESI) m / z=378.3(M+H)

[0471] A diastereomeric mixture of 5-(tert-butyl)-3-(3-(((1R,2R,3S,4R,Z)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenyl)-4,5-dihydroisoxazole-5-carboxylic acid 397 was prepared using trifluoromethylnorbornyl intermediate 170-2 and intermediate 397-1 via the coupling method described in Example 378, followed by treatment with TFA (54% yield). 1 H NMR (500 MHz, DMSO-d) δ 10.74-10.63(m,1H), 9.98-9.88(m,1H), 8.21(brd,J=5.2Hz,1H), 7.79(brs ,1H), 7.50(brt,J=9.2Hz,1H), 7.26(brs,1H), 7.08(brs,1H), 5.99-5.86(m, 1H), 4.50(brs,1H), 4.03(s,3H), 3.51(brs,3H), 3.24(brs,1H), 2.99(s,1H) ), 2.11-1.90(m,1H), 1.86(brs,1H), 1.49(brs,1H), 0.99(brs,9H):MS(ESI) m / z=700.3(M+H); HPLC purity: 98.8%; Retention time: 2.07 min; Method B

[0472] Example 406 [ka]

[0473] Intermediate 406-1 [ka]

[0474] Intermediate 406-1 was prepared in a similar manner as described for intermediate 378-3, in this case cyclopent-3-en-1-ol was used as a diastereomeric mixture in place of allyl alcohol (31% yield). 1 H NMR (600MHz, CDCl3) δ 8.04(d,J=2.3Hz,1H), 7.85(dd,J=8.8, 2.3Hz,1H), 7.03(d,J=8.8Hz,1H), 5.30(ddd,J=9.4, 6.2, 2.9Hz,1H), 4. 50(quin, J=5.9Hz,1H), 4.19(td, J=9.3, 4.7Hz,1H), 3.92(s,3H), 2.33-2.27(m,1H), 2.18-2.06(m,3H):MS(ESI) m / z=292.0(M+H)

[0475] Intermediates 406-2 to 406-5 (chiral) The chiral intermediates of 406-1 were separated by chiral SFC using the following preparative chromatography method: Apparatus: Berger SFC (LVL-L4021 Lab); Column: IC 25x3 cm ID, 5 μm, Temperature: 40 °C; Flow rate: 85 mL / min; Mobile phase: Gradient 75 / 25 CO2 / MeOH for 12 min, then 45% MeOH; Detector wavelength: 235 nm; Injection volume: 1000 μL to give chiral 406-2 (Peak-1, >99% de, analytical RT = 8.80 min), chiral 406-3 (Peak-2, >95% de, analytical RT = 9.86 min), chiral 406-4 (Peak-3, >99% de, analytical RT = 13.53 min), and chiral 406-5 (Peak-4, >99% de, analytical RT = 16.67 min). Analytical chromatographic conditions: Instrument: Agilent SFC (LVL-L4021 Lab), Column: IC 250x4.6mm ID, 5μm, Temperature: Ambient, Flow rate: 2.0mL / min, Mobile phase: Gradient 75 / 25 CO2 / MeOH 12 min then 45% MeOH.

[0476] A diastereomeric mixture of (1R,2S,3R,4R,Z)-7-(cyclobutylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-hydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamide)bicyclo[2.2.1]heptane-2-carboxamide 406 was prepared by coupling cyclobutylnorbornyl intermediate 369-1 and intermediate 406-1 as described in Example 378 (74% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.56(s,1H), 9.89(d,J=7.3Hz,1H), 8.21(brs,2H), 7.78(brd,J=8.7Hz,2H), 7.48(brt,J=9.6H z,1H), 7.26(brd,J=8.8Hz,1H), 5.37(d,J=8.3Hz,1H), 5.10(brt,J=7.2Hz,1H), 4.34(brs,1H), 4 .15(brs,1H), 4.12-4.05(m,1H), 4.03(s,3H), 3.72-3.56(m,3H), 3.20-3.02(m,2H), 2.95(brs,1 H), 2.70(brs,1H), 2.16(brs,1H), 2.13-2.01(m,2H), 1.92-1.70(m,6H), 1.36(brs,2H):MS(ESI) m / z=642.1(M+H); HPLC purity: 100%; Retention time: 2.49 min; Method C

[0477] Example 413 [ka]

[0478] Intermediate 413-1 (mixture of diastereomers) [ka]

[0479] Intermediate 413-1 was prepared in a similar manner as described for intermediate 378-3, in this case using (1R,3S)-cyclopent-4-ene-1,3-diol as a diastereomeric mixture in place of allyl alcohol. 1 H NMR (400MHz, CDCl3) δ 8.09-7.91(m,1H), 7.30(s,1H), 7.11-7.01(m,1H), 5.46-5.21(m,1H), 4.45-4.23(m,1H), 4.04- 3.88(ss,6H), 3.02-2.98(m,1H), 2.92(d,J=0.7Hz,1H), 2.45-2.35(m,1H), 2.02(s,2H):MS(ESI) m / z=294.1(M+H)

[0480] Intermediate 413-2 (mixture of diastereomers) [ka]

[0481] 413-2 was prepared from intermediate 413-1 via a two-step reaction scheme by protection using excess TBDMS triflate (2.64 g, 9.99 mmol) and 2,6-lutidine (1.61 g, 14.9 mmol) in DCM (5 mL), followed by hydrolysis of the ester with LiOH / THF / MeOH / water (1:1:1, 5 mL). 1 H NMR (500 MHz, CDCl3) δ 8.48-8.46(m,1H), 8.04-8.00(m,1H), 7.10-7.05(m,1H), 5.06-5.02(m,1 H), 4.33-4.29(m,1H), 4.23-4.18(s,3H), 4.15-4.13(m,1H), 4.12-4.10(m ,1H), 4.00-3.94(m,1H), 1.29-1.24(m,1H), 0.93(ss,18H), 0.12(s,3H), 0.12-0.03(m,3H), 0.03(s,1H), 0.02(s,3H), -0.05-0.06(m,3H):MS(ESI) m / z 522.5 (M+H)

[0482] A diastereomeric mixture of (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-3-(5-(4,6-dihydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide 413 was prepared (36% yield) using the coupling method described in Example 378 using cyclopropylnorbornyl intermediate 166-2 and intermediate 413-2, followed by deprotection with tetrabutylammonium fluoride (1 M in THF, 1 mL). 1 H NMR (500MHz, DMSO-d6) δ 10.55(s,1H), 9.90(brd,J=7.3Hz,1H), 8.43-8.37(m,1H), 8.21(brd,J=6.1Hz,1H), 7.89(dd,J=8.7, 2.3Hz,1H), 7.83-7.66(m,1H), 7.48(t,J=9.6Hz,1H), 7.29(d,J=8.9Hz,1H), 4.96(dd,J=10.2, 2.0Hz,1H), 4.70(d,J=9.5Hz, 1H), 4.45(brs,1H), 4.05(s,3H), 3.54(brs,1H), 3.21-3.07(m,2H), 3.00(s,1H), 2.54(s,1H), 2.85-2.64(m,1H) , 1.92-1.76(m,3H), 1.76-1.62(m,1H), 1.52(brs,1H), 1.42(brs,2H), 0.85-0.68(m,2H), 0.36(brs,2H):MS(ESI) m / z=644.4(M+H); HPLC purity: 100%; Retention time: 2.36 min; Method C

[0483] Example 414 [ka]

[0484] Intermediate 414-3 (racemic), Chiral 414-4 (Chiral Peak-1), Chiral 414-5 (Chiral Peak-2), Chiral 414-6 (Chiral Peak-3), Chiral 414-7 (Chiral Peak-4) [ka]

[0485] Intermediate 414-1: Commercially available methyl 5-formyl-2-methoxybenzoate (948 mg, 4.88 mmol) was dissolved in EtOH (10 mL). To this solution was added NMeNHOH·HCl (408 mg, 4.88 mmol), followed by KCO (675 mg, 4.88 mmol). The reaction mixture was stirred at room temperature for 1 h. Water (100 mL) was added, and the solution was extracted with EtOAc (2×25 mL). The combined organic portions were dried (MgSO) and evaporated to dryness under reduced pressure. The solid was transferred to a vial, and toluene (7 mL) was added, followed by methyl acrylate (3 mL). The vial was sealed. The reaction mixture was heated at 95° C. for 18 h. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by silica gel chromatography. 414-3 was isolated as an oil (200 mg, 13%). 1 H NMR (400MHz, CDCl3) δ 7.96(m,1H), 7.88(m,1), 7.02(d,J=8.8Hz,1H), 4.01-3.84(mss,8H), 3.79-3 .71(m,3H), 3.17-3.01(m,3H), 2.92-2.67(m,1H), 2.07-1.81(m,2H):MS(ESI) m / z=310.0(M+H)

[0486] Intermediate 414-2: The product 414-1 (49 mg, 0.158 mmol) was dissolved in methanol (5 mL) in a Parr flask, to which Pd / C 10% (20 mg) was added and subjected to hydrogenation at 60 psi for 5 h. The reaction mixture was filtered through a Celite pad and evaporated under reduced pressure to give methyl 5-(4-hydroxy-1-methyl-5-oxopyrrolidin-2-yl)-2-methoxybenzoate (35 mg, 79%) as an oil. 1H NMR(500MHz, CD3OD) δ 7.71(d,J=2.4Hz,1H), 7.50(dd,J=8.7, 2.4Hz,1H), 7.18(d,J=8.7Hz,1H), 4.51-4.42(m,1H), 4.38(t,J=8.5Hz,1H) , 3.90(s,3H), 3.86(s,3H), 2.84(ddd,J=13.1, 8.4, 6.9Hz,1H), 2.58(s,3H), 1.74(dt,J=13.0, 8.5Hz,1H):MS(ESI) m / z=280.2(M+H)

[0487] Intermediate 414-3: The product 414-2 (30 mg) was dissolved in MeOH (1 mL), and LiOH was added to the solution, followed by water (1 mL), and the mixture was stirred at room temperature for 5 hours. Dilute HCl was added, and the resulting solution was concentrated under reduced pressure to a gummy solid. Methanol was added, and the reaction mixture was filtered and concentrated under reduced pressure to give 414-3 (20 mg, 71% yield). MS m / z = 266.08 (M+H).

[0488] Chiral intermediate 414-(4-7): 414-3 was separated by SFC under the following preparative conditions: Instrument: Berger SFC (LVL-L4021 Lab), Column: IG 25x3 cm ID, 5 μm; Temperature: 40 °C, Flow Rate: 85 mL / min; Mobile Phase: 82 / 18 CO2 / MeOH-0.1% DEA, Detector Wavelength: 220 nm; Injection Volume: 1200 μL to give chiral 414-4 (Peak-1, >99% de, Analytical RT = 15.56 min), chiral 414-5 (Peak-2 >95% de, Analytical RT = 18.09 min), chiral 414-6 (Peak-3, >99% de, Analytical RT = 26.38 min), and chiral 414-7 (Peak-4, >95% de, Analytical RT = 29.29 min). Analytical chromatographic conditions: Apparatus: Agilent SFC (LVL-L4021 Lab); Column: IG 250x4.6mm ID, 5µm; Temperature: Ambient; Flow rate: 2.0mL / min; Mobile phase: 80 / 20 CO2 / MeOH-0.1%DEA

[0489] Homochiral isomer-1 of (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(4-hydroxy-1-methyl-5-oxopyrrolidin-2-yl)-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide, 414, was prepared using cyclopropylnorbornyl intermediate 166-2 and intermediate 414-4 via the coupling method described in Example 378 (48% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.54(s,1H), 9.89(d,J=7.3Hz,1H), 8.23(dd,J=6.6, 2.3Hz,1H), 7.89(d,J=2.1Hz,1H), 7.84-7.67(m,1H) , 7.49(t,J=9.2Hz,1H), 7.44(d,J=8.3Hz,1H), 7.24(d,J=8.5Hz,1H), 4.70(d,J=9.8Hz,1H), 4.34(m,1H), 4 .20(brs,1H), 4.02(s,3H), 3.16(brdd,J=10.7, 4.0Hz,1H), 3.09(brs,1H), 2.80-2.63(m,2H), 2.50-2.39( m,2H), 1.94-1.74(m,2H), 1.65-1.45(m,1H), 1.45-1.24(m,2H), 0.88-0.67(m,2H), 0.36(brs,2H):MS(ESI) m / z=616.2(M+H); HPLC purity: 100%; retention time: 2.12 min; method C

[0490] Example 416 [ka]

[0491] Intermediate 416-1: (racemic) and chiral 416-2 (Chiral Peak-1), 416-3 (Chiral Peak-2) [ka]

[0492] Intermediate 416-1 was prepared in the same manner as described for Intermediate 378-1 (50% yield). 1 H NMR (500MHz, CDCl3) δ 7.98(d,J=2.3Hz,1H), 7.86(dd,J=8.8, 2.4Hz,1H), 7.04(d,J=8.7Hz,1H), 5.38(dd,J=9.2, 3.9Hz,1H), 4.3 4-4.26(m,2H), 4.20-4.09(m,1H), 3.96(s,3H), 3.91(s,3H), 3.83-3.76(m,1H), 2.92-2.70(m,1H):MS(ESI) m / z=278.3(M+H)

[0493] 416-2&416-3: The following chiral intermediates were separated from racemic DP39-1 by the following preparative chromatographic method: Apparatus: Berger MG II; Column: Chiralpak IA, 21x250mm, 5 micron; Mobile phase: 20% MeOH / 80% CO2, Flow conditions: 45mL / min, 150 Bar, 40°C, Detector wavelength: 220nm to give chiral 416-2 (Peak-1, >99% de, analytical RT=3.80min) and chiral 416-3 (Peak-2, >98% de, analytical RT=7.43min). Analytical chromatographic conditions: Apparatus: Shimadzu Nexera SFC; Column: Chiralpak IA, 4.6x100mm, 3 micron; Mobile phase: 20% MeOH / 80% CO2; Flow conditions: 2.0mL / min, 150 Bar, 40°C; Detector wavelength: 220nm; Injection details: Inject 5µL of approximately 1mg / mL (in MeOH)

[0494] The homochiral isomer-2 of (1R,2S,3R,4R,Z)-7-(cyclobutylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzamide)bicyclo[2.2.1]heptane-2-carboxamide, 416, was prepared using cyclobutylnorbornyl intermediate 369-1 and intermediate 416-2 by the method described in Example 378 (62% yield). 1H NMR (500MHz, DMSO-d6) δ 10.56(s,1H), 9.93(dd,J=10.8,7.2Hz,1H), 8.25-8.20(m,2H), 7.84-7.76(m,2H), 7.48(t,J=9.8Hz,1H), 7.28( d,J=8.9Hz,1H), 5.35(dd,J=9.0,3.2Hz,1H), 4.70(d,J=9.5Hz,1H), 4.54-4.41(m,2H), 4.12-4.02(m,3H), 3.90( brd, J = 9.5 Hz, 1H), 3.84-3.73 (m, 1H), 3.50 (brs, 1H), 3.16 (brdd, J = 10.8, 4.4 Hz, 1H), 3.11 (brs, 1H), 2.73 (brs, 1H), 2.56 (s, 4H), 1.91-1.71 (m, 2H), 1.50 (brs, 1H), 1.42 (brs, 2H), 0.87-0.68 (m, 2H), 0.35 (brs, 2H): MS (ESI) m / z = 614.2 (M+H); HPLC purity: 100%; retention time: 2.42 min; Method C

[0495] Example 419

change

[0496] Intermediate 419-5(キラルピーク-1)および419-6(キラルピーク-2)

change

[0497] Intermediate 419-1: To a solution of methyl 4-fluoro-5-formyl-2-methoxybenzoate (0.15 g, 0.68 mmol) (prepared as described in Chen, Xiao-Yang, Sorensen, Eric, J. JACS, 2018, 140, 2789-2792) and NHOH·HCl (48 mg, 0.68 mmol) in DCM (10 mL) was added DIEA (0.12 mL, 0.68 mmol). After 24 h, the reaction mixture was diluted with water, and the white solid methyl (E)-4-fluoro-5-((hydroxyimino)methyl)-2-methoxybenzoate (0.15 g, 96%) was collected by filtration, dried, and used as is. 1 H NMR (400MHz, CDCl3) δ 8.53-8.37(m,1H), 8.33-8.22(m,2H), 6.79-6.61(m,1H), 3.94(s,3H), 3.91(s,3H):MS(ESI) m / z228.2(M+H) +

[0498] Intermediate 419-2: To intermediate 419-1 (0.15 g, 0.66 mmol) and DMF (1 mL) was added NCS (88 mg, 0.66 mmol). After 24 hours, the reaction mixture was partitioned between water (20 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with brine (15 mL), and dried (NaSO) to give a solid. To the solid in DCM (3 mL) was added 2,5-dihydrofuran (0.46 g, 6.6 mmol) and TEA (0.1 mL, 0.66 mmol). After 24 hours, the reaction mixture was quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The organic layers were combined, washed with brine (15 mL), and dried (MgSO). The residue was purified by silica gel chromatography using hexane / EtOAc as eluent to give methyl 4-fluoro-2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoate (0.13 g, 66%) as a tan solid. MS(ESI) m / z=296.2 (M+H). +

[0499] Chiral intermediates 419-3 and 419-4: Intermediate 419-2 was separated on a Jusco SFC Prep using a Chiralpak IA, 21x250mm column, eluting with 20% MeOH / 80% CO2 at 45mL / min, 150 Bar, 40°C, detector wavelength: 267nm, to give 419-3 (33mg, 0.11mmol, 17% yield) (Peak-1, 99%ee, analytical RT=1.693min); 1 H NMR (400 MHz, CDCl) δ 8.45 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 13.2 Hz, 1H), 5.39 (dd, J = 9.1, 3.9 Hz, 1H), 4.40 (dt, J = 4.6, 2.3 Hz, 1H), 4.34 (d, J = 10.8 Hz, 1H), 4.11 (brd, J = 9.7 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.86 (dd, J = 9.7, 6.8 Hz, 1H), 3.79 (dd, J = 10.8, 4.0 Hz, 1H); 419-4 (32 mg, 0.11 mmol, 16% yield) (peak-2, 99% ee, analytical RT = 5.463 min); 1 H NMR (400MHz, CDCl3) δ 8.45(d,J=8.6Hz,1H), 6.75(d,J=13.4Hz,1H), 5.39(dd,J=9.5, 4.0Hz,1H), 4.46-4.38(m,1H), 4.34(d,J=11.0Hz) ,1H), 4.16-4.09(m,1H), 3.97(s,3H), 3.91(s,3H), 3.86(dd,J=9.7, 6.8Hz,1H), and 3.79(dd,J=10.8, 4.0Hz,1H) were obtained. Analytical chromatographic conditions: Apparatus: Shimadzu Nexera SFC; Column: Chiralpak IC, 4.6 x 100 mm, 3 micron; Mobile phase: 20% methanol / 80% CO2; Flow conditions: 2.0 mL / min, 150 Bar, 40°C, Detector wavelength: 220 nm

[0500] Intermediate 419-5: To a mixture of 419-3 (33 mg, 0.11 mmol) in THF (2 mL) / MeOH (0.1 mL) cooled to 0 °C was added 2 M aqueous solution of LiOH (0.17 mL, 0.34 mmol). After stirring for 18 h, the reaction was quenched with dilute HCl (10 mL) and extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with brine (15 mL), dried (MgSO), filtered, and concentrated to give 419-5 (31 mg, 0.11 mmol, 99% yield) as a white solid. 1 H NMR (600MHz, DMSO-d6) δ 12.90(brs,1H), 8.07(d,J=8.7Hz,1H), 7.17(d,J=13.8Hz,1H), 5.34(dd,J=9.2, 3.7Hz,1H), 4.49-4.42(m,1H), 4.09(d,J LCMS (ESI) m / z=282.2(M+H) +

[0501] Intermediate 419-6: 419-6 (30 mg, 0.11 mmol, 96% yield) was prepared in a similar manner to 419-5, using 419-4 instead of 419-3. 1 H NMR (400MHz, CDCl3) δ 8.62(d,J=8.6Hz,1H), 6.86(d,J=12.5Hz,1H), 5.40(dd,J=9.2, 4.0Hz,1H), 4.55-4.28(m,2H), 4.11(s,3H), 4.08(s,1H), 3.87(dd,J=9.7, 6.8Hz,1H), 3.79(dd,J=10.8, 4.0Hz,1H);LCMS(ESI) m / z=282.2(M+H) +

[0502] Example 419 (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-3-(4-fluoro-2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide 419 was prepared in a similar manner to Example 378 by using cyclopropylnorbornyl intermediate 20-4 and intermediate 419-5 (5.9 mg, 67% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.67-10.38(m,1H), 9.89(brd,J=7.0Hz,1H), 8.33(brd,J=8.9Hz,1H), 8.20(brd,J=4.0Hz,1H), 7.85-7.71(m,1H), 7.48(brd,J=9.8Hz) ,1H), 7.22(brd,J=13.1Hz,1H), 5.35(brdd,J=9.5, 3.4Hz,1H), 4.69(brd,J=9.5Hz,1H), 4.52-4.36(m,2H), 4.10(brd,J=10.7Hz,1H), 4 .05(s,3H), 3.77-3.66(m,1H), 3.66-3.54(m,2H), 3.22-3.12(m,1H), 3.09(brs,1H), 2.72(brs,1H), 1.90-1.79(m,1H), 1.79-1.66(m,1 H), 1.50(brdd,J=8.5, 4.3Hz,1H), 1.45-1.32(m,2H), 0.87-0.61(m,2H), 0.35(brd,J=2.7Hz,2H); HPLC purity 98%; Analytical LC-MS: 2.48 min; MS(ESI) m / z=631.9(M+H) + ;Method B

[0503] Example 423 [ka]

[0504] Intermediate 423-1 [ka]

[0505] Intermediate 423-1 was prepared in the same manner as described for intermediate 378-3, in this case using propargyl alcohol instead of allyl alcohol. 1 H NMR(500MHz, CD3OD) δ 8.28(d,J=2.3Hz,1H), 8.01(dd,J=8.7, 2.3Hz,1H), 7.27(d,J=8.7Hz,1H), 6.75(s,1H), 4.91-4.82(m,5H), 4.73(s,2H), 4.00-3.96(m,3H):MS(ESI) m / z=250.3(M+H)

[0506] (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(hydroxymethyl)isoxazol-3-yl)-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide 423 was prepared using norbornyl intermediate 20-4 and intermediate 423-1 via the coupling method described in Example 378 (77% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.56(s,1H), 9.95(brd,J=7.0Hz,1H), 8.40(d,J=1.8Hz,1H), 8.19(brd,J=4.3Hz,1H), 7.97(dd,J=8.5, 2.1Hz,1H), 7.77(brd,J=8.9Hz,1H), 7.46(brt,J=9.8Hz,1H), 7.32(d,J=8.5Hz,1H), 6.84(s,1H), 4.69( d,J=9.8Hz,1H), 4.61(d,J=5.8Hz,2H), 4.45(brs,1H), 4.05(s,3H), 3.21-3.06(m,2H), 2.72(brs,1H), 1 .92-1.73(m,2H), 1.62-1.45(m,1H), 1.41(brs,2H), 0.84-0.67(m,2H), 0.35(brd,J=4.3Hz,2H):MS(ESI) m / z=600.1(M+H); HPLC purity: 100%; Retention time: 2.39 min; Method B

[0507] Example 427 [ka] [ka]

[0508] Preparation of methyl 5-(5-fluoro-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoate (diastereomeric mixture) To a mixture of 406-1 ester (0.1 g, 0.3 mmol) in DCM (2 mL) was added DAST (0.05 mL, 0.412 mmol). After 24 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the corresponding fluoride (66 mg, 0.23 mmol, 66% yield) as a clear film. 1 H NMR (400MHz, CDCl3) δ 8.06(d,J=2.4Hz,1H), 7.88(dd,J=8.7, 2.3Hz,1H), 7.06(d,J=8.8Hz,1H), 5.53-5.38(m,1H), 4.25(dd,J=9.5, 2.0 Hz,1H), 4.01-3.97(m,4H), 3.94-3.92(m,3H), 2.76-2.47(m,2H), 2.33-2.12(m,1H), 2.10-1.90(m,1H);LCMS(ESI) m / z=294.2(M+H) +

[0509] Preparation of Intermediate 427-2: 5-(5-fluoro-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid To intermediate 427-1 (14 mg, 0.048 mmol) in THF (1 mL) was added a 2 M aqueous solution of LiOH (72 μl, 0.14 mmol). After 24 h, dilute HCl (10 mL) was added and the solution was extracted with EtOAc (3×30 mL). The organic layers were combined, washed with brine (15 mL), dried (MgSO), filtered, and concentrated under reduced pressure to give 427-2 (13 mg, 0.047 mmol, 98% yield). 1H NMR (400MHz, CDCl3) δ 8.28(d,J=2.2Hz,1H), 8.13(dd,J=8.8, 2.4Hz,1H), 7.20-7.12(m,1H), 5.95-5.83(m,1H), 5.45(ddd,J=10.0, 6.8, 4.7Hz,1H), 5 .38-5.18(m,1H), 4.28(td, J=9.4, 7.5Hz,1H), 4.16(s,3H), 2.75-2.55(m,2H), 2.32-2.17(m,1H), 2.06-1.92(m,1H);LCMS(ESI) m / z=280.2(M+H) +

[0510] A diastereomeric mixture of (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-fluoro-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide 427 was prepared in a similar manner to Example 378 using cyclopropylnorbornyl intermediate 20-4 and intermediate 427-2 (5.7 mg, 9.1 μmol, 67% yield). 1H NMR (500MHz, DMSO-d6) δ 10.69-10.39(m,1H), 9.92(brt,J=7.0Hz,1H), 8.49-8.08(m,2H), 7.91-7.71(m,2H), 7.50(brt,J=9.6Hz,1H), 7.29(d,J=8.9Hz,1H) , 5.45-5.26(m,1H), 4.71(brd,J=9.2Hz,1H), 4.46(brs,1H), 4.39-4.30(m,1H), 4.06(d,J=2.4Hz,3H), 3.41(brs,1H), 3.18(brdd,J= 10.8, 3.5Hz,1H), 3.12(brs,1H), 2.74(brs,1H), 2.51-2.35(m,2H), 2.17-2.06(m,1H), 2.06-2.00(m,1H), 1.92-1.84(m,1H), 1.80(b rd,J=11.3Hz,1H), 1.61-1.50(m,1H), 1.49-1.36(m,2H), 0.86-0.68(m,2H), 0.37(brs,2H); HPLC purity: 100%; Analytical LC-MS: 2.65 minutes; MS(ESI) m / z=630.3(M+H) + ;Method B

[0511] 428 was prepared in a similar manner to the example by using cyclopropylnorbornyl intermediate 20-4 and intermediate 428-1 (6.1 mg, 69% yield). 1 H NMR; HPLC purity: 100%; Analytical LC-MS: 2.84 min; MS(ESI) m / z=638.2(M+H) + ;Method B

[0512] Example 429 [ka]

[0513] Preparation of Intermediate 429-1: Methyl 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoate [ka]

[0514] Intermediate 429-1 was prepared in the same manner as described for intermediate 378-3 (75% yield), in this case using cyclopent-3-en-1-ylmethanol instead of allyl alcohol.

[0515] Preparation of Intermediate 429-2: 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid [ka]

[0516] Methyl 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoate (58 mg, 0.22 mmol) was dissolved in THF (1 mL) / MeOH (1 mL) and treated with LiOH monohydrate (36 mg, 0.86 mmol) / HO (1 mL) at room temperature. After 3 h, the reaction mixture was diluted with HO (5 mL) and the organics were liberated. The pH of the remaining aqueous layer was adjusted to pH 7 with 1 M HCl, extracted with EtOAc (2 x 25 mL), washed with brine, dried (NaSO), filtered, and evaporated to give intermediate 429-2 (62 mg, 74.2%). The carboxylic acid was carried forward to the next reaction without further purification. MS (ESI) m / z = 292.3 (M+H).

[0517] Example 429 was prepared by coupling intermediate 429-2 (3.95 mg, 0.014 mmol) with intermediate 166-2 (5 mg, 0.014 mmol) dissolved in anhydrous DMF (2 mL) in the presence of DIEA (0.012 mL, 0.068 mmol) and BOP (6.60 mg, 0.015 mmol). After 3 h, the reaction mixture was filtered and purified by reverse-phase preparative HPLC to give the desired product 429 (5.1 mg, 0.0079 mmol, 58% yield) of a diastereomeric mixture of (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamide)bicyclo[2.2.1]heptane-2-carboxamide. 1 H NMR (500MHz, DMSO-d6) δ 10.53(s,1H), 9.90(brd,J=6.4Hz,1H), 8.23-8.17(m,2H), 7.81-7.74(m,2H), 7.46(brt,J=9.8Hz,1H), 7.26 (d,J=8.9Hz,1H), 5.15-5.07(m,1H), 4.68(brd,J=9.5Hz,1H), 4.42(brs,1H), 4.20-4.14(m,1H), 4.02(s,3H) ), 3.58-3.47(m,2H), 3.39-3.18(m,2H), 3.17-3.06(m,2H), 2.73-2.68(m,1H), 1.99-1.73(m,5H), 1.66-1.5 9(m,1H), 1.56-1.37(m,4H), 0.78-0.68(m,2H), 0.38-0.29(m,2H); HPLC purity: 99.2%; Analytical LC-MS: 2.53 min; MS(ESI) m / z=642.2(M+H);Method B

[0518] Example 430 [ka]

[0519] Intermediates 429-4 (chiral peak-1), 429-6 (chiral peak-2), 429-8 (chiral peak-3) and 429-10 (chiral peak-4) [ka]

[0520] The individual chiral diastereomeric ester intermediates 429-4A, 429-6A, 429-8A, and 429-10A were obtained by subjecting the diastereomeric mixture of intermediate 429 (524.9 mg, 1.72 mmol) to chiral SFC. Chiral SFC preparative chromatography conditions: Apparatus: Berger MG II (SFC); Column: Chiralpak AD-H, 21x250mm, 5 micron; Mobile phase: 15% MeOH / 85% CO2; Flow conditions: 45mL / min, 150 Bar, 40°C; Detector wavelength: 210nm; Injection details: 0.5mL injected at approximately 35mg / mL in MeOH; Analytical chromatography conditions: Apparatus: Shimadzu Nexera SFC; Column: Chiralpak AD-H, 4.6x100mm, 3 micron; Mobile phase: 15% MeOH / 85% CO2; Flow conditions: 2.0mL / min, 150 Bar, 40°C; Detector wavelength: 220nm; Injection details: 5µL injected at approximately 1mg / mL in MeOH

[0521] Intermediate 429-4A (Peak-1, >99% de, analytical RT=4.02 min) was obtained as a film (152.8 mg, 29.1%). 1 H NMR (600MHz, CDCl3) δ 8.04(d,J=2.3Hz,1H), 7.87(dd,J=8.7, 2.3Hz,1H), 7.01(d,J=8.8Hz,1H), 5.23(dd ,J=8.8, 5.1Hz,1H), 4.10(t,J=8.7Hz,1H), 3.94(s,3H), 3.90(s,3H), 3.72-3.66(m ,1H), 3.61(dt,J=10.5, 5.2Hz,1H), 2.30-2.16(m,2H), 2.05(dd,J=13.0, 6.1Hz,1H ), 1.76(ddd,J=12.9, 11.5, 9.4Hz,1H), 1.68-1.62(m,1H), 1.39(brt,J=4.8Hz,1H)

[0522] Intermediate 429-4 (104.4 mg, 78%) was prepared in a similar manner to intermediate 429-2 by hydrolysis of intermediate 429-...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: L is —O— or —NH—; R １ is C １－３ alkyl (0-1 aryl or C ３－６ substituted with a cycloalkyl substituent; R ２ is H; provided that R １ is C １－３ Alkyl (0 aryl or C ３－６ substituted with cycloalkyl), then R ９ is not absent; Or, R １ and R ２ The numbers combine to form = CR ６ R ７ or = NOC １－４ alkyl, where "=" is a double bond; or R １ and R ２ taken together with the carbon atom to which they are both attached form dioxolanyl (substituted with 0 to 1 aryl substituents); R ３ is C １－８ Alkyl (0-5 halo, CN, —OH, or —OC １－３ substituted with alkyl substituents), -(CR ｄ R ｄ ) ｎ -C ３－１０ -carbocyclyl (0 to 5 R ４ substituted with -(CR ｄ R ｄ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ , N, and NR ４ｃ and 0 to 5 R ４ substituted with R ４ is halo, CN, -OH, SF ５ , -S(=O) ｐ R ｃ , C １－４ alkyl (0-5 halo, —OH, or —OC １－４ substituted with alkyl substituents), —OC １－４ alkyl (substituted with 0 to 5 halo substituents), —(CR ｄ R ｄ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CR ｄ R ｄ ) ｎ - 4 to 6 membered heterocyclyl (O, S(=O) ｐ , N, and NR ４ｃ and 0 to 5 R ｅ substituted with R ４ｃ is H, C １－４ Alkyl, or -S(=O) ２ CF ３ and R ５ are H, halo, —OH, and C, respectively. １－４ alkyl (substituted with 0 to 5 halo substituents), or —OC １－４ alkyl (substituted with 0-5 halo substituents); R ６ H, halo, CN, C １－７ Alkyl (0 to 3 R ６ａ substituted with), C ２－７ Alkenyl (0 to 3 R ６ａ substituted with), C ２－７ Alkynyl (0 to 3 R ６ａ substituted with), —C(═O)OR ６ｂ , —C(═O)NR ６ｂ R ６ｂ , -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R １４ substituted with), or 3- to 12-membered heterocyclyl (O, S(═O) ｐ , N, or NR １４ａ and 0 to 5 R １４ substituted with R ６ａ is halo, -OH, -OC １－４ Alkyl, C １－４ Alkyl, aryl, or C ３－６ cycloalkyl (substituted with 0-4 halo substituents); R ６ｂ is H, C １－４ alkyl (substituted with 0-1 aryl substituents), or C ３－６ cycloalkyl (substituted with 0-4 halo substituents); R ７ is H or C １－４ Is alkyl; or R ６ and R ７ together with the carbon atom to which they are both attached form cyclopentadienyl, indanyl, or indenyl; R ８ is H, halo, CN, -NR ７ R ７ , C １－４ alkyl (substituted with 0-5 halo or —OH substituents), or —OC １－４ Alkyl (0-5 halo, —OH, C ３－６ Cycloalkyl, aryl, 4- to 9-membered heterocyclyl (O, S(=O) ｐ and N), or —OC １－４ Alkyl (0 to 1 -OC １－３ substituted with alkyl substituents); R ９ is an aryl (0 to 3 R １０ and 0 to 2 R １１ substituted with) or 3- to 12-membered heterocyclyl (O, S(=O) ｐ , N, and NR １１ａ and 0 to 3 R １０ and 0 to 2 R １１ substituted with R １０ Halo, CN, C １－４ Alkyl, ═O, —OH, or —OC １－４ is alkyl; R １１ is C １－４ Alkyl (0 to 4 R １２ and 0 to 2 R １３ substituted with), -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 , C ３－６ Carbocyclyl (0 to 5 R ｅ substituted with), or 3- to 12-membered heterocyclyl (O, S(═O) ｐ , N, and NR １５ and 0 to 5 R ｅ substituted with R １１ａ is H, C １－５ Alkyl (0 to 4 R １１ｂ substituted with), —C(═O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , C ３－６ Cycloalkyl (0 to 5 R ｅ aryl (substituted with 0 to 5 R ｅ substituted with), 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N, and NR １５ and 0 to 5 R ｅ substituted with R １１ｂ is halo, -OH, -C(=O)OH, -C(=O)OC １－４ alkyl, or aryl; R １２ is halo, -C(=O)OR ｂ , —C(═O)NR ａ R ａ , —C(═O)NR ａ OR ｂ , or C １－４ alkyl (substituted with 0-3 halo or OH substituents), or C ３－６ is cycloalkyl; R １３ is -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 , -NR ａ S (= O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ , -OC(=O)NR ａ OR ｂ , -S(=O) ｐ NR ａ R ａ , -S(=O) ｐ R ｃ , -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 3 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with R １４ Halo, CN, C １－４ alkyl (substituted with 0 to 3 halo substituents), —OC １－４ alkyl (substituted with 0 to 3 halo substituents), —(CH ２ ) ｎ -NR ａ R ａ , -(CH ２ ) ｎ -aryl (0 to 3 R ｅ substituted with), —O-aryl (substituted with 0 to 3 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with R １４ａ is H, C(=O)C １－４ Alkyl, or C １－３ Alkyl (0-3 Si(C １－３ alkyl) ３ aryl (substituted with 0-2 halo substituents); R １５ is H, C １－４ alkyl, or aryl; R ａ is H, -OC １－６ Alkyl, C １－６ Alkyl (0 to 5 R ｅ substituted with), C ２－６ alkenyl (0 to 5 R ｅ substituted with), C ２－６ Alkynyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ or R ａ and R ａ and together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with; R ｂ is H, C １－６ Alkyl (0 to 5 R ｅ substituted with), C ２－６ alkenyl (0 to 5 R ｅ substituted with), C ２－６ Alkynyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with R ｃ is C １－６ Alkyl (0 to 5 R ｅ substituted with), C ２－６ alkenyl (0 to 5 R ｅ substituted with), C ２－６ Alkynyl (0 to 5 R ｅ substituted with), C ３－６ Carbocyclyl (0 to 5 R ｅ substituted with), or 3- to 12-membered heterocyclyl (O, S(═O) ｐ and N, and 0 to 5 R ｅ substituted with R ｄ is H, C １－４ Alkyl, or C ３－６ is cycloalkyl; R ｅ Ha, Halo, CN, NO ２ , =O,C １－６ Alkyl (0 to 5 R ｇ substituted with), C ２－６ alkenyl (0 to 5 R ｇ substituted with), C ２－６ Alkynyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｇ substituted with), -(CH ２ ) ｎ OR 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 ) ｎ NR ｆ R ｆ and R ｆ is H, C １－６ Alkyl (0 to 2 —OH or —OC １－４ substituted with alkyl substituents), C ３－６ Cycloalkyl, aryl, or 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N); or R ｆ and R ｆ and together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N; R ｇ is halo, CN, -OH, C １－６ Alkyl, C ３－６ cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

2. R ３ But C １－６ alkyl (substituted with 0 to 4 halo or —OH substituents), —(CHR ｄ ) ０－１ -C ３－６ Cycloalkyl (0 to 4 R ４ substituted with), C ６－９ Spirocycloalkyl (0 to 4 R ４ substituted with), C ６－１０ Bicyclic carbocyclyl (0 to 4 R ４ substituted with), or 3- to 6-membered heterocyclyl (O, S(=O) ｐ , N, and NR ４ｃ and 0 to 4 R ４ substituted with R ４ is halo or C １－３ alkyl (substituted with 0-4 halo substituents); R ４ｃ is H or C １－４ alkyl; R ｄ is C １－３ is alkyl, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. Formula (II): 【Chemistry 2】 [In the formula: R ４ is halo, -S(=O) ｐ C １－４ alkyl (substituted with 0 to 4 halo substituents), C １－４ alkyl (substituted with 0 to 4 halo substituents), or —OC １－４ alkyl (substituted with 0-4 halo substituents); R ５ is H or halo; R ６ Halo, CN, C １－７ Alkyl (0 to 3 R ６ａ substituted with), C ２－７ Alkenyl (0 to 3 R ６ａ substituted with), C ２－７ Alkynyl (0 to 3 R ６ａ substituted with), C(=O)OR ６ｂ , —C(═O)NR ６ｂ R ６ｂ , C ３－６ Cycloalkyl (0 to 3 R １４ substituted with), C ３－６ Cycloalkenyl (0 to 3 R １４ aryl (substituted with 0 to 3 R １４ substituted with), or 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N, and NR １４ａ and 0 to 3 R １４ substituted with R ６ａ is halo, -OH, C ３－６ cycloalkyl, or aryl; R ６ｂ is H, C １－４ alkyl (substituted with 0-1 aryl substituents), or C ３－６ cycloalkyl (substituted with 0-4 halo substituents); R ７ is H or C １－３ is alkyl; R ８ is halo, CN, -N(C １－２ alkyl) ２ , C １－４ alkyl (substituted with 0-5 halo or —OH substituents), or —OC １－４ alkyl (0-4 halo, —OH, aryl or —OC １－４ substituted with alkyl substituents; R ９ is an aryl (0 to 3 R １０ and 0 to 2 R １１ substituted with), or 3- to 12-membered heterocyclyl (O, S(═O) ｐ , N, and NR １１ａ and 0 to 3 R １０ and 0 to 1 R １１ substituted with R １０ Halo, CN, C １－４ Alkyl, ═O, —OH, or —OC １－４ is alkyl; R １１ is C １－４ Alkyl (0 to 3 R １２ and 0 to 1 R １３ substituted with), -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 , C ３－６ Cycloalkyl (0 to 5 R ｅ substituted with), 4- to 12-membered heterocyclyl (O, S(═O) ｐ , N, and NR １５ and 0 to 5 R ｅ substituted with R １１ａ is H, C １－４ Alkyl (0 to 2 R １１ｂ substituted with), —C(═O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , C ３－６ Cycloalkyl (0 to 5 R ｅ substituted with), 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N, and NR １５ and 0 to 5 R ｅ substituted with R １１ｂ is —OH, —C(═O)OH, or aryl; R １２ is halo, -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－４ alkyl (substituted with 0-3 halo or OH substituents); R １３ is -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , -NR ａ S (= O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ , -OC(=O)NR ａ OR ｂ , -S(=O) ｐ NR ａ R ａ , or -S(=O) ｐ R ｃ and R １４ Halo, CN, C １－４ alkyl (substituted with 0 to 3 halo substituents), —OC １－４ alkyl (substituted with 0 to 3 halo substituents), —(CH ２ ) ０－３ -NR ａ R ａ , -(CH ２ ) ０－３ -aryl (0 to 3 R ｅ substituted with), —O-aryl (substituted with 0 to 3 R ｅ substituted with -(CH ２ ) ０－２ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with R １４ａ is H, C(=O)C １－４ Alkyl, or C １－３ alkyl (substituted with 0-3, 0-2 halo substituents, aryl substituted); R １５ is H, C １－３ alkyl, or aryl; R ａ is H, C １－５ Alkyl (0 to 5 R ｅ substituted with), C ２－５ alkenyl (0 to 5 R ｅ substituted with), C ２－５ Alkynyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ or R ａ and R ａ and together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with; R ｂ is H, C １－５ Alkyl (0 to 5 R ｅ substituted with), C ２－５ alkenyl (0 to 5 R ｅ substituted with), C ２－５ Alkynyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with R ｃ is C １－５ Alkyl (0 to 5 R ｅ substituted with), C ２－５ alkenyl (0 to 5 R ｅ substituted with), C ２－５ Alkynyl (0 to 5 R ｅ substituted with), C ３－６ Carbocyclyl (0 to 5 R ｅ substituted with), or 3- to 12-membered heterocyclyl (O, S(═O) ｐ and N, and 0 to 5 R ｅ substituted with R ｄ is H or C １－４ is alkyl; R ｅ Halo, CN, =O, C １－６ Alkyl (0 to 5 R ｇ substituted with), C ２－６ alkenyl (0 to 5 R ｇ substituted with), C ２－６ Alkynyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -C ３－６ Cycloalkyl (0 to 4 R ｇ substituted with), -(CH ２ ) ｎ -aryl (0 to 4 R ｇ substituted with), -(CH ２ ) ｎ - 4 to 6 membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｇ substituted with), -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -NR ｆ C(=O)R ｆ , -S(=O) ｐ R ｆ , -NR ｆ C(=O)OR ｆ , -OC(=O)NR ｆ R ｆ , or -(CH ２ ) ｎ NR ｆ R ｆ and R ｆ is H, C １－５ Alkyl, C ３－６ cycloalkyl, or aryl; or R ｆ and R ｆ and together with the nitrogen atom to which they are both attached form a 3- to 9-membered heterocyclyl; R ｇ is halo, CN, -OH, C １－５ Alkyl, C ３－６ cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2.

2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

4. Formula (III): 【Transformation 3】 [In the formula: R ４ａ is a halo; R ４ｂ is C １－４ alkyl (substituted with 0-4 halo substituents); R ５ is H or F; R ６ Ha, Halo, C １－４ Alkyl (0 to 3 R ６ａ substituted with), C ２－４ alkenyl (substituted with 0-1 phenyl or —OH substituents), —C(═O)OR ６ｂ , C(=O)NHR ６ｂ , C ３－６ Cycloalkyl (0 to 3 R １４ substituted with), C ３－６ Cycloalkenyl (0 to 3 R １４ phenyl (substituted with 0 to 3 R １４ substituted with), naphthyl, or 5- to 6-membered heterocyclyl (substituted with O, S, N, and NR １４ａ and 0 to 3 R １４ substituted with R ６ａ is halo, -OH, C ３－６ cycloalkyl, or phenyl; R ６ｂ is H or C １－４ is alkyl; R ７ is H or C １－３ Is alkyl; Or R ６ and R ７ together with the carbon atom to which they are both attached form cyclopentadienyl, indanyl, or indenyl; R ８ is -N(C １－４ alkyl) ２ or -OC １－４ Alkyl (0 to 1 -OC １－４ substituted with alkyl substituents; R ８ａ is a halo; R １４ Halo, CN, C １－４ alkyl (substituted with 0 to 3 halo substituents), —OC １－４ alkyl (substituted with 0 to 3 halo substituents), —(CH ２ ) ０－２ -NR ａ R ａ , -(CH ２ ) ０－２ -aryl (0 to 3 R ｅ substituted with), —O-aryl (substituted with 0 to 3 R ｅ substituted with -(CH ２ ) ０－２ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with R １４ａ is H, C(=O)C １－３ Alkyl, or C １－３ alkyl (substituted with 0-3, 0-2 halo substituents, aryl substituted); R ａ is H, C １－６ Alkyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -phenyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ or R ａ and R ａ and together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with; R ｂ is H, C １－６ Alkyl (0 to 5 R ｅ substituted with), -(CH ２ ) ０－１ -phenyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with R ｅ Ha, Halo, CN, NO ２ , =O,C １－６ alkyl, or C(=O)OH; n is 0, 1, 2, or 3.

2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

5. Formula (IV): 【Chemistry 4】 [In the formula: R ４ Ha, Halo, C １－４ alkyl (substituted with 0 to 3 halo substituents), or —OC １－４ alkyl (substituted with 0-3 halo substituents); R ５ is H or F; R ６ Halo, CN, C １－６ Alkyl (0 to 3 R ６ａ substituted with), C ２－６ Alkenyl (0 to 3 R ６ａ substituted with), C ２－６ Alkynyl (0 to 3 R ６ａ substituted with), —C(═O)OR ６ｂ , C(═O)NR ６ｂ R ６ｂ , C ３－６ Cycloalkyl (0 to 3 R １４ substituted with), C ３－６ Cycloalkenyl (0 to 3 R １４ phenyl (substituted with 0 to 3 R １４ substituted with), or 5- to 6-membered heteroaryl (O, S(=O) ｐ , N, and NR １４ａ and 0 to 3 R １４ substituted with R ６ａ Ha, Halo, C ３－６ cycloalkyl, or phenyl; R ６ｂ is H, C １－３ alkyl (substituted with 0-1 aryl substituents), or C ３－６ cycloalkyl (substituted with 0-4 halo substituents); R ７ is H or C １－２ is alkyl; R ８ Ha-OC １－４ alkyl (0-4 halo, —OH, aryl, or —OC １－４ substituted with alkyl substituents; R １０ Halo, CN, C １－３ Alkyl, —OH, or —OC １－４ is alkyl; R １１ is C １－４ Alkyl (0 to 2 R １２ and 0 to 1 R １３ substituted with), -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R 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 , C ３－６ Cycloalkyl, 4- to 9-membered heterocyclyl (O, S(=O) ｐ , N, and NR １５ and 0 to 4 R ｅ substituted with R １２ is halo, -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－４ alkyl (substituted with 0-3 halo or OH substituents); R １３ is -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , -NR ａ S (= O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ , -OC(=O)NR ａ OR ｂ , -S(=O) ｐ NR ａ R ａ , or -S(=O) ｐ R ｃ and R １４ Halo, CN, C １－４ alkyl (substituted with 0 to 3 halo substituents), —OC １－４ alkyl (substituted with 0 to 3 halo substituents), —(CH ２ ) ０－２ -NR ａ R ａ , -(CH ２ ) ０－２ -aryl (0 to 3 R ｅ substituted with), —O-aryl (substituted with 0 to 3 R ｅ substituted with -(CH ２ ) ０－２ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with R １４ａ is H, C(=O)C １－３ Alkyl, C １－３ alkyl (substituted with 0-2 aryl, which are substituted with 0-2 halo substituents); R １５ is H, C １－２ alkyl, or phenyl; R ａ is H, C １－５ Alkyl (0 to 4 R ｅ substituted with), C ２－５ alkenyl (0 to 4 R ｅ substituted with), C ２－５ Alkynyl (0 to 4 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 4 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ or R ａ and R ａ and together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ substituted with; R ｂ is H, C １－５ Alkyl (0 to 4 R ｅ substituted with), C ２－５ alkenyl (0 to 4 R ｅ substituted with), C ２－５ Alkynyl (0 to 4 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 4 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ substituted with R ｃ is C １－５ Alkyl (0 to 4 R ｅ substituted with), C ２－５ alkenyl (0 to 4 R ｅ substituted with), C ２－５ Alkynyl (0 to 4 R ｅ substituted with), C ３－６ Carbocyclyl, or 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N; R ｅ Ha, Halo, CN, NO ２ , =O,C １－６ Alkyl (0 to 5 R ｇ substituted with), C ２－６ alkenyl (0 to 5 R ｇ substituted with), C ２－６ Alkynyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -C ３－６ Cycloalkyl, -(CH ２ ) ｎ -aryl, -(CH ２ ) ｎ - 4 to 6 membered heterocyclyl (O, S(=O) ｐ and N), -(CH ２ ) ｎ OR ｆ , S(=O) ｐ R ｆ , C(═O)NR ｆ R ｆ , C(=O)OR ｆ , N.R. ｆ C(=O)R ｆ , S(=O) ｐ NR ｆ R ｆ , N.R. ｆ S (= O) ｐ R ｆ , N.R. ｆ C(=O)OR ｆ , OC(=O)NR ｆ R ｆ , or -(CH ２ ) ｎ NR ｆ R ｆ and R ｆ is H, C １－６ Alkyl, C ３－６ cycloalkyl, or aryl; or R ｆ and R ｆ and together with the nitrogen atom to which they are both attached form a heterocyclyl; R ｇ is halo, CN, -OH, C １－５ Alkyl, C ３－６ cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2.

4. The compound of claim 3, wherein: or a pharmaceutically acceptable salt thereof.

6. Formula (V): 【Transformation 5】 [In the formula: R ４ａ is halo or C １－２ is alkyl; R ４ｂ is C １－４ alkyl (substituted with 0-4 halo substituents); R ５ is H or F; R ６ Halo, CN, C １－４ Alkyl (0 to 3 R ６ａ substituted with), C ２－４ Alkenyl (0 to 3 R ６ａ substituted with), —C(═O)OR ６ｂ , C(═O)NR ６ｂ R ６ｂ , C ３－６ Cycloalkyl (0 to 3 R １４ phenyl (substituted with 0 to 3 R １４ substituted with), or 5- to 6-membered heteroaryl (O, S(=O) ｐ , N, and NR １４ａ and 0 to 3 R １４ substituted with R ６ａ is halo, -OH, C ３－６ cycloalkyl, or phenyl; R ６ｂ is H, C １－３ alkyl (substituted with 0-1 aryl substituents), or C ３－６ is cycloalkyl; R ７ is H or C １－２ is alkyl; R ８ Ha-OC １－４ Alkyl (0-4 halo, —OH, —OC １－４ substituted with alkyl, or aryl substituents; R １０ is halo or C １－３ is alkyl; R １１ is C １－４ Alkyl (0 to 2 R １２ and 0 to 1 R １３ substituted with), —OH, —OC １－４ Alkyl, —NR ａ C(=O)R 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 , C ３－６ Cycloalkyl, 4- to 9-membered heterocyclyl (O, S(=O) ｐ , N, and NR １５ and 0 to 3 R ｅ substituted with R １２ is halo, -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－４ alkyl (substituted with 0-3 halo or OH substituents); R １３ is -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , -NR ａ S (= O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ or —OC(═O)NR ａ OR ｂ and R １４ Halo, CN, C １－４ alkyl (substituted with 0 to 3 halo substituents), —OC １－４ alkyl (substituted with 0 to 3 halo substituents), —(CH ２ ) ０－２ -NR ａ R ａ , -(CH ２ ) ０－１ -aryl (0 to 3 R ｅ substituted with), —O-aryl (substituted with 0 to 3 R ｅ substituted with -(CH ２ ) ０－１ -3 to 9-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with R １４ａ is H, C(=O)C １－３ Alkyl, C １－３ alkyl (substituted with 0-1 aryl, which is substituted with 0-2 halo substituents); R １５ is H, C １－２ alkyl, or phenyl; R ａ is H, C １－４ Alkyl (0 to 5 R ｅ substituted with), C ２－４ alkenyl (0 to 5 R ｅ substituted with), C ２－４ Alkynyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ or R ａ and R ａ and together with the nitrogen atom to which they are both attached form a 3- to 9-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with; R ｂ is H, C １－４ Alkyl (0 to 5 R ｅ substituted with), C ２－４ alkenyl (0 to 5 R ｅ substituted with), C ２－４ Alkynyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 5 R ｅ substituted with R ｃ is C １－４ Alkyl (0 to 5 R ｅ substituted with), C ２－４ alkenyl (0 to 5 R ｅ substituted with), C ２－４ Alkynyl (0 to 5 R ｅ substituted with), C ３－６ Carbocyclyl, or 3- to 9-membered heterocyclyl (O, S(=O) ｐ and N; R ｅ Halo, CN, =O, C １－６ Alkyl (0 to 5 R ｇ substituted with), C ２－６ alkenyl (0 to 5 R ｇ substituted with), C ２－６ Alkynyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -C ３－６ Cycloalkyl, -(CH ２ ) ｎ -aryl, -(CH ２ ) ｎ - 4 to 6 membered heterocyclyl (O, S(=O) ｐ and N), -(CH ２ ) ｎ OR ｆ , -S(=O) ｐ R ｆ , —C(═O)NR ｆ R ｆ , -C(=O)OR ｆ , -NR ｆ C(=O)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 ) ｎ NR ｆ R ｆ and R ｆ is H, C １－６ Alkyl, C ３－６ cycloalkyl, or aryl; or R ｆ and R ｆ and together with the nitrogen atom to which they are both attached form a heterocyclyl; R ｇ is halo, CN, -OH, C １－６ Alkyl, C ３－６ cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2.

6. The compound of claim 5, wherein: or a pharmaceutically acceptable salt thereof.

7. R ４ａ is a halo; R ４ｂ is CF ３ and R ６ But C １－４ alkyl (substituted with 0-3 halo substituents) or C ３－６ cycloalkyl (substituted with 0-3 halo substituents); R ８ Ga-OC １－４ is alkyl; R １０ is F; R １１ But -OH, -OC １－４ Alkyl, —NR ａ C(=O)R ｂ , -NR ａ S (= O) ｐ R ｃ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , —C(═O)NR ａ S (= O) ｐ R ｃ , or 4- to 9-membered heterocyclyl (O, S(=O) ｐ , N, and NR １５ and 0 to 5 R ｅ substituted with R １５ is H or C １－２ is alkyl; R ａ is H or C １－４ Alkyl (0 to 5 R ｅ is replaced by; Or R ａ and R ａ Together 【Transformation 6】 Next; R ｂ is H or C １－４ Alkyl (0 to 5 R ｅ substituted with R ｃ But C １－３ Alkyl (0 to 5 R ｅ substituted with) or C ３－６ is carbocyclyl; R ｅ But halo, =O, C １－４ Alkyl (0 to 5 R ｇ substituted with), C(═O)OH, —OR ｆ , or -NR ｆ R ｆ and R ｆ is H or C １－６ alkyl; or R ｆ and R ｆ and together with the nitrogen atom to which they are both attached form a heterocyclyl; and R ｇ is the halo, 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof.

8. Formula (VI): 【Transformation 7】 [In the formula: R ４ａ is a halo; R ４ｂ is CF ３ and R ６ is C １－４ alkyl (substituted with 0-3 halo substituents) or C ３－６ cycloalkyl (substituted with 0-3 halo substituents); R ７ is H; R ８ Ha-OC １－４ alkyl (substituted with 0-1 aryl substituents); R １０ is a halo; R １２ is -C(=O)OH, -C(=O)OC １－４ Alkyl, —C(═O)NHC １－４ Alkyl, —C(═O)NHOC １－３ Alkyl, or C １－３ alkyl (substituted with 0-3 halo substituents); R １３ is -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , -NR ａ S (= O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ or —OC(═O)NR ａ OR ｂ and R ａ is H, C １－４ alkyl (substituted with 0-5 halo substituents), phenyl (substituted with 0-4 R ｅ substituted with), C ３－１０ Cycloalkyl (0 to 4 R ｅ substituted with 0 to 4 R ｅ substituted with), or 3- to 9-membered heterocyclyl (O, S(═O) ｐ and N, and 0 to 4 R ｅ or R ａ and R ａ and together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ substituted with; R ｂ is H, C １－４ Alkyl (0 to 5 R ｅ substituted with), -(CH ２ ) ｎ -phenyl (substituted with 0 to 4 halo substituents), C ３－６ cycloalkyl (substituted with 0-4 halo substituents), or 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ substituted with R ｃ is C １－４ Alkyl (0 to 4 R ｅ substituted with R ｅ Halo, CN, =O, C １－５ Alkyl (0 to 5 R ｇ substituted with), C ３－６ Cycloalkyl, aryl, 4- to 6-membered heterocyclyl (O, S(=O) ｐ and N), or —OR ｆ and R ｆ is H, C １－４ Alkyl, C ３－６ cycloalkyl, or aryl; R ｇ is a halo; n is 0 or 1; p is 0, 1, or 2.

7. The compound of claim 6, wherein: or a pharmaceutically acceptable salt thereof.

9. R ４ａ is F; R ４ｂ is CF ３ and R ６ is CF ３ or C ３－６ is cycloalkyl; R ８ Ga-OCH ３ or -OCH ２ -phenyl; R １０ is F; R １２ is -C(=O)OH, -C(=O)OC １－４ Alkyl, —C(═O)NHC １－４ Alkyl, —C(═O)NHOC １－３ Alkyl, CH ３ , CHF ２ , or CF ３ and R １３ But -OH, -NR ａ R ａ , -NHC(=O)R ｂ , -NHS(=O) ｐ C １－４ Alkyl, —OC(═O)NR ａ R ａ , or —OC(═O)NHOC １－４ is alkyl; R ａ But H, C １－４ alkyl (substituted with 0-4 F substituents); 【Transformation 8】 Is it; or R ａ and R ａ Together, 【Chemistry 9】 Or; R ｂ But H, C １－４ Alkyl (0 to 5 R ｅ substituted with), phenyl, or 【Chemistry 10】 and R ｅ is halo, ═O, aryl, 4- to 6-membered heterocyclyl (O, S(═O) ｐ and N), or —OR ｆ and R ｆ But H, C １－３ Alkyl, C ３－６ cycloalkyl, or phenyl; 9. The compound of claim 8 or a pharmaceutically acceptable salt thereof.

10. Formula (VII): 【Chemistry 11】 [In the formula: R ４ａ is a halo; R ４ｂ is C １－４ alkyl (substituted with 0 to 3 halo substituents), or —OC １－４ alkyl (substituted with 0-3 halo substituents); R ５ is H or F; R ６ Halo, CN, C １－６ Alkyl (0 to 3 R ６ａ substituted with), C ２－６ Alkenyl (0 to 3 R ６ａ substituted with), C ２－６ Alkynyl (0 to 3 R ６ａ substituted with), C ３－６ Cycloalkyl (0 to 3 R １４ substituted with), C ３－６ Cycloalkenyl (0 to 3 R １４ phenyl (substituted with 0 to 3 R １４ substituted with), or 5- to 6-membered heteroaryl (O, S(=O) ｐ , N, and NR １４ａ and 0 to 3 R １４ substituted with R ６ａ Ha, Halo, C ３－６ cycloalkyl, or phenyl; R ７ is H or C １－２ is alkyl; R ８ is halo, CN, or -OC １－４ alkyl (0-4 halo, —OH, or —OC １－４ substituted with alkyl substituents; R ８ａ is halo or CN; R ９ is a 3- to 12-membered heterocyclyl (O, S(=O) ｐ , N, and NR １１ａ and 0 to 3 R １０ and 0 to 1 R １１ substituted with R １０ Halo, CN, C １－３ Alkyl, ═O, —OH, or —OC １－３ is alkyl; R １１ is C １－３ alkyl (0 to 1 R １２ and 0 to 1 R １３ substituted with), -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 , C ３－６ Cycloalkyl (0 to 5 R ｅ substituted with), 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N, and NR １５ and 0 to 4 R ｅ substituted with R １１ａ is H, C １－４ Alkyl (0 to 2 R １１ｂ substituted with), —C(═O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , C ３－６ Cycloalkyl, 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N, and NR １５ and 0 to 4 R ｅ substituted with R １１ｂ is —OH, —C(═O)OH, or aryl; R １２ is -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－４ alkyl (substituted with 0-3 halo or OH substituents); R １３ is -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , -NR ａ S (= O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ , -S(=O) ｐ NR ａ R ａ , or -S(=O) ｐ R ｃ and R １４ Halo, CN, C １－４ alkyl (substituted with 0 to 3 halo substituents), —OC １－４ alkyl (substituted with 0 to 3 halo substituents), —(CH ２ ) ０－２ -NR ａ R ａ , -(CH ２ ) ０－２ -aryl (0 to 3 R ｅ substituted with), —O-aryl (substituted with 0 to 3 R ｅ substituted with), or -(CH ２ ) ０－２ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with R １４ａ is H, C(=O)C １－３ Alkyl, or C １－３ alkyl (substituted with 0-2 aryl, which are substituted with 0-2 halo substituents); R １５ is H, C １－２ alkyl, or phenyl; R ａ is H, C １－５ Alkyl (0 to 4 R ｅ substituted with), C ２－５ alkenyl (0 to 4 R ｅ substituted with), C ２－５ Alkynyl (0 to 4 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 4 R ｅ substituted with), or -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ or R ａ and R ａ and together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ substituted with; R ｂ is H, C １－５ Alkyl (0 to 4 R ｅ substituted with), C ２－５ alkenyl (0 to 4 R ｅ substituted with), C ２－５ Alkynyl (0 to 4 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 4 R ｅ substituted with), or -(CH ２ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｅ substituted with R ｃ is C １－５ Alkyl (0 to 4 R ｅ substituted with), C ２－５ alkenyl (0 to 4 R ｅ substituted with), C ２－５ Alkynyl (0 to 4 R ｅ substituted with), C ３－６ Carbocyclyl, or 3- to 12-membered heterocyclyl (O, S(=O) ｐ and N; R ｅ Halo, CN, =O, C １－６ Alkyl (0 to 4 R ｇ substituted with), C ２－６ alkenyl (0 to 4 R ｇ substituted with), C ２－６ Alkynyl (0 to 4 R ｇ substituted with), -(CH ２ ) ｎ -C ３－６ Cycloalkyl (0 to 4 R ｇ substituted with), -(CH ２ ) ｎ -aryl (0 to 4 R ｇ substituted with), -(CH ２ ) ｎ - 4 to 6 membered heterocyclyl (O, S(=O) ｐ and N, and 0 to 4 R ｇ substituted with), -(CH ２ ) ｎ OR ｆ , C(=O)OR ｆ , C(═O)NR ｆ R ｆ , N.R. ｆ C(=O)R ｆ , S(=O) ｐ R ｆ , N.R. ｆ S (= O) ｐ R ｆ , N.R. ｆ C(=O)OR ｆ , OC(=O)NR ｆ R ｆ , or -(CH ２ ) ｎ NR ｆ R ｆ and R ｆ is H, C １－６ Alkyl, C ３－６ cycloalkyl, or aryl; R ｇ is halo, CN, -OH, C １－４ Alkyl, C ３－６ cycloalkyl, or phenyl; n is 0, 1, 2, or 3; p is 0, 1, or 2.

4. The compound of claim 3, wherein: or a pharmaceutically acceptable salt thereof.

11. R ４ａ is a halo; R ４ｂ is C １－４ alkyl (substituted with 0-3 halo substituents); R ５ is H; R ６ is C １－２ alkyl (substituted with 0-2 F substituents) or C ３－６ is cycloalkyl; R ８ Ga-OC １－３ is alkyl; R ８ａ is F or CN; R ９ but 【Chemistry 12】 and R １０ But, Haro, CN, C １－２ Alkyl, ═O, —OH, or —OC １－２ is alkyl; R １１ But C １－３ alkyl (0 to 1 R １２ and 0 to 1 R １３ substituted with), -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -C(=O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , or C ３－６ Cycloalkyl (0 to 5 R ｅ substituted with R １１ａ is H, -C(=O)R ｂ , —C(═O)NR ａ R ａ , or C １－４ alkyl (0 to 1 R １１ｂ substituted with R １１ｂ is —OH or aryl; R １２ is -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－４ alkyl (substituted with 0-2 halo or —OH substituents); R １３ But -OH, -OC １－４ alkyl (substituted with 0-2 —OH substituents), or —S(═O) ２ C １－４ is alkyl; R ａ is H or C １－４ alkyl or R ａ and R ａ and together with the nitrogen atom to which they are both attached form a 3- to 9-membered heterocyclyl (0 to 4 R ｅ substituted with; R ｂ But H, C １－４ alkyl (0 to 1 R ｅ substituted with), or C ３－６ Cycloalkyl (0 to 1 R ｅ substituted with R ｅ Ga-OR ｆ and R ｆ is H or C １－４ is alkyl, 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof.

12. R ４ａ is a halo; R ４ｂ is CF ３ and R ５ is H; R ６ is CF ３ or C ３－６ is cyclopropyl; R ８ Ga-OC １－３ is alkyl; R ９ but 【Chemistry 13】 and R １０ But C １－２ Alkyl, —OH, or —OC １－２ is alkyl; R １１ But C １－３ alkyl (0 to 1 R １２ and 0 to 1 R １３ substituted with), —C(═O)OR ｂ or —C(═O)NR ａ R ａ and R １２ -C(=O)OR ｂ and R １３ is —OH; R ａ is H or C １－４ alkyl; R ｂ is H or C １－４ is alkyl, 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof.

13. R ４ａ is a halo; R ４ｂ is C １－４ alkyl (substituted with 0-3 halo substituents); R ５ is H; R ６ is C １－３ alkyl (substituted with 0-3 F substituents) or C ３－６ is cycloalkyl; R ８ Ga-OC １－３ is alkyl; R ９ but 【Chemistry 14】 and R １０ But, Halo, C １－３ Alkyl, —OH, or —OC １－３ is alkyl; R １１ is C １－３ alkyl (0 to 1 R １２ and 0 to 1 R １３ substituted with R １１ａ But H, C １－４ Alkyl (0 to 2 R １１ｂ substituted with -C(=O)OC １－４ is alkyl; R １１ｂ is —OH, —C(═O)OH, or aryl; R １２ -C(=O)OR ｂ or C １－３ alkyl (substituted with 0-3 halo substituents); R １３ is —OH; R ｂ is H or C １－４ is alkyl, 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof.

14. Formula (VIII): 【Chemistry 15】 [In the formula: R ４ａ is a halo; R ４ｂ is C １－４ alkyl (substituted with 0-4 halo substituents); R ６ is C １－２ alkyl (substituted with 0-2 F substituents), C ３－６ cycloalkyl, or aryl; R ７ is H; R ８ Ha-OC １－３ is alkyl; R ９ teeth 【Chemistry 16】 and R １０ Halo, CN, C １－４ Alkyl, ═O, —OH, or —OC １－４ is alkyl; R １１ is C １－２ alkyl (0 to 1 R １２ and 0 to 1 R １３ substituted with —NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ or -C(=O)OR ｂ and R １２ is -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－４ alkyl (substituted with 0-3 halo or OH substituents); R １３ is -OH or -NR ａ C(=O)R ｂ and R ａ is H or C １－４ alkyl; R ｂ is H, C １－４ Alkyl, or 3 to 9 membered heterocyclyl (O, S(=O) ｐ and N).

4. The compound of claim 3, wherein: or a pharmaceutically acceptable salt thereof.

15. Formula (IX): 【Chemistry 17】 [In the formula: R ３ is C １－５ Alkyl, CF ３ , -(CR ｄ R ｄ ) ０－１ -C ３－６ Cycloalkyl (0 to 4 R ４ phenyl (substituted with 0 to 4 R ４ substituted with R ４ Halo, CN, CH ３ , or CF ３ and R ６ is C １－６ Alkyl, CF ３ , or C ３－６ cycloalkyl (substituted with 0-2 F substituents); R ７ is H; R ８ is halo, -N(C １－３ alkyl) ２ , -OC １－３ Alkyl (0 to 1 -OC １－４ substituted with alkyl substituents; R ９ teeth [Chemistry 18] and R １０ Ha, Halo, C １－４ Alkyl, —OH, or —OC １－４ is alkyl; R １１ is C １－４ Alkyl (0 to 2 R １２ and 0 to 2 R １３ substituted with), —C(═O)OR ｂ , —C(═O)NR ａ R ａ , or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with R １１ａ is H, C １－４ Alkyl (0 to 2 R １１ｂ substituted with), —C(═O)R ｂ or -C(=O)OC １－４ is alkyl; R １１ｂ is —OH; R １２ is C １－３ alkyl (substituted with 0-3 halo substituents) or —C(═O)OR ｂ and R １３ is —OH; R ａ is H or C １－３ is alkyl; R ｂ is H or C １－４ alkyl (0 to 1 R ｅ substituted with R ｅ Ha-OR ｆ and R ｆ is H or C １－６ alkyl] 2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

16. Formula (X): 【Chemistry 19】 [In the formula: R １ is C １－２ Alkyl (C ３－６ substituted with a cycloalkyl substituent; R ２ is H; Or R １ and R ２ Combined with this = CR ６ R ７ Next; R ３ is C １－６ Alkyl (0-5 halo, CN, or —OC １－３ substituted with alkyl substituents), -(CHR ｄ ) ｎ -C ３－１０ -carbocyclyl (0 to 5 R ４ substituted with 0-3 R ４ substituted with R ４ is halo, S(=O) ２ CF ３ , CN, or C １－４ alkyl (substituted with 0-5 halo substituents); R ６ Ha, Halo, C １－５ Alkyl (0 to 3 R ６ａ substituted with), C ３－６ Cycloalkyl (0 to 3 R １４ substituted with 0-3 R １４ substituted with R ６ａ is halo, —OH, or C ３－６ is cycloalkyl; R ７ is H; R ８ H, halo, CN, C １－４ Alkyl, or —OC １－４ Alkyl (0-5 halo, —OH, C ３－６ cycloalkyl, or —OC １－４ substituted with alkyl substituents; R ９ teeth 【Chemistry 20】 and R １０ Halo, CN, C １－４ alkyl, or —OH; R １１ is C １－３ Alkyl (0 to 3 R １２ and 0 to 1 R １３ substituted with), -OR ｂ , -NHC(=O)R ｂ or -C(=O)OR ｂ and R １２ is a halo; R １３ Ha-OR ｂ or C ３－６ is carbocyclyl; R １４ is halo, CN, or C １－４ alkyl (substituted with 0-3 halo substituents); R ｂ is H or C １－３ Alkyl (0 to 5 R ｅ substituted with R ｄ is H or C １－４ is alkyl; R ｅ is —OH; n is 0 or 1.

2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

17. Formula (XI): 【Chemistry 21】 [In the formula: R ３ is C １－５ Alkyl or 【Chemistry 22】 and R ４ is halo, CN, -S(=O) ２ CF ３ , C １－４ alkyl (substituted with 0-5 halo substituents); R ６ is C １－５ Alkyl (0 to 2 R ６ａ substituted with), C ３－６ Cycloalkyl (0 to 2 R １４ substituted with 0-2 R １４ substituted with R ６ａ is halo, —OH, or C ３－６ is cycloalkyl; R ７ is H; R ８ Ha-OC １－３ Alkyl (0-5 halo, —OH, C ３－６ cycloalkyl, or —OC １－３ substituted with alkyl substituents; R ８ａ is H, halo, CN, or C １－３ is alkyl; R ９ teeth 【Chemistry 23】 and R １０ Halo, CN, C １－４ alkyl, or —OH; R １１ is C １－３ Alkyl (0 to 3 R １２ and 0 to 1 R １３ substituted with), -OR ｂ , -NHC(=O)R ｂ or -C(=O)OR ｂ and R １２ is a halo; R １３ Ha-OR ｂ or C ３－６ is carbocyclyl; R １４ is halo or C １－４ alkyl (substituted with 0-3 halo substituents); R ｂ is H or C １－３ Alkyl (0 to 5 R ｅ substituted with R ｄ is H or C １－２ alkyl; n is 0 or 1.

17. The compound of claim 16, wherein: or a pharmaceutically acceptable salt thereof.

18. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. 19. The pharmaceutical composition of claim 18 for treating a relaxin-related disease.

20. 20. The pharmaceutical composition of claim 19, wherein the disease is selected from the group consisting of angina, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and cardiac ectopic damage.

21. 21. The pharmaceutical composition of claim 20, wherein the disease is heart failure.

22. 20. The pharmaceutical composition of claim 19, wherein the disease is fibrosis.

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