RXFP1 agonist

Abstract

The present invention relates to a compound represented by the formula (I) which is an RXFP1 receptor agonist. The present invention relates to a compound of formula (I): JPEG2024543013000344.jpg5038, compositions containing same, and methods of use thereof in the treatment of related diseases such as, for example, 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).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 273,370, filed October 29, 2021, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Background of the Invention The present invention relates to novel compounds that are relaxin family peptide receptor 1 (RXFP1) agonists, compositions containing same, and methods of using same 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).

[0003] Human relaxin hormone (also known as relaxin or H2 relaxin) is a 6-kDa peptide consisting of 53 amino acids. Its activity was first discovered in 1926 when Frederick Hisaw injected an extract from porcine corpora lutea into virgin guinea pigs and observed relaxation of the fibrocartilaginous symphysis pubis joint (Hisaw FL., Proc. Soc. Exp. Biol. Med., 1926, 23, 661-663). The relaxin receptor, formerly known as Lgr7, is now officially named relaxin family peptide receptor 1 (RXFP1) and was deorphanized as the 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 ubiquitously expressed in humans and other species (Halls ML., et al., Br. J. Pharmacol., 2007, 150, 677-691). The relaxin and RXFP1 cell signaling pathway is cell type dependent and quite 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., Ann NY Acad. Sci., 2007, 1160, 117-120). The most studied pathway is the relaxin-dependent increase in cAMP cellular levels, in which relaxin functions as an RXFP1 agonist to promote GαS coupling and activation of adenylate cyclase (Halls ML., et al., Mol. Pharmacol., 2006, 70, 214-226).

[0004] Since the initial discovery of relaxin, many studies have focused on delineating the role that relaxin plays 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 imposed by the fetus, the female body experiences a significant approximately 30% decrease in systemic vascular resistance (SVR) and a concomitant approximately 50% increase in cardiac output (Jeyabalan AC., KP, Renal and Electolyte Disorders. 2010, 462-518; Clapp JF. & Capeless E., Am. J. Cardio., 1997, 80, 1469-1473). Further vascular adaptations are an approximately 30% increase in global arterial compliance, which is important for maintaining efficient ventricular-arterial coupling, and an approximately 50% increase in both renal blood flow (RBF) and glomerular filtration rate (GFR), which are important for metabolic waste removal (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 trials conducted in various patient settings provide evidence that relaxin is involved, at least in part, in mediating these adaptive physiological 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 benefit patients with HF, as excessive fibrosis, impaired arterial compliance, and worsening renal function are all common features of patients with heart failure (Mohammed S F., 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).

[0005] Heart failure (HF), hemodynamically defined as "inadequate systemic perfusion to meet the body's metabolic demands as a result of cardiac pump dysfunction," represents a significant burden on today's healthcare system, with an estimated prevalence of 5.8 million in the United States and over 23 million worldwide (Roger VL., et al., Circ. Res., 2013, 113, 646-659). It is estimated that by 2030, an additional 3 million people in the United States alone will have HF, a 25% increase from 2010. The estimated direct costs associated with HF in 2010 (2008 dollars) were $25 billion and are expected to increase to $78 billion by 2030 (Heidenreich PA., et al., Circ., 2011, 123, 933-944). Alarmingly, 1 in 9 people in the United States have HF listed on their death certificate (Roger VL., et al., Circ., 2012, 125, e2-220), and although survival after HF diagnosis has 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 people dying from HF within 5 years of diagnosis (Roger VL., et al., Circ., 2012, 125, e2-220, Roger VL., et al., JAMA, 2004, 292, 344-350).

[0006] Symptoms of HF are the result of inadequate cardiac output and can be quite debilitating, depending on the stage of the disease. Cardiac symptoms and signs of HF include: 1) dyspnea (difficulty breathing) due to 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 supply venous return; and 3) fatigue due to the heart's inability to sustain sufficient cardiac output (CO) to meet the body's metabolic demands (Kemp CD., & Conte JV., Cardiovasc. Pathol., 2011, 21, 365-371). Furthermore, HF patients are often described as "compensated" or "decompensated" depending on the severity of their symptoms. In compensated heart failure, symptoms are stable and many of the hallmarks of fluid retention and pulmonary edema are absent. Decompensated heart failure refers to the worsening of pulmonary edema, which may present as an acute event, decreased exercise tolerance and increased shortness of breath on exertion (Millane T., et al., BMJ, 2000, 320, 559-562).

[0007] Contrary to the overly simplistic definition of poor cardiac performance as an inability to meet metabolic demands, the disease is extremely complex due to the numerous contributing diseases, the large number of risk factors, and the many pathological changes that ultimately lead to heart failure (Jessup M. & Brozena S., N. Engl. J. Med., 2003, 348, 3007-2018). Adverse events thought to be involved in the pathophysiology of HF range from very acute ones, such as myocardial infarction, to more chronic insults, such as lifelong hypertension. Historically, HF was initially described as "systolic HF," in which reduced left ventricular (LV) systolic function limits blood ejection and therefore reduces the ejection fraction (EF = stroke volume / end-diastolic volume), or as "diastolic HF," in which active relaxation is reduced, passive stiffness is increased, and LV filling during diastole is limited, but overall EF is preserved (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). More recently, the new terms "heart failure with reduced systolic function" (HFrEF) and "heart failure with preserved systolic function" (HFpEF) have been used, as it has been recognized that diastolic and systolic LV dysfunction are not unique to these two groups (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). Although the signs and symptoms of these two patient populations are very similar, there is currently debate in the cardiovascular community as to whether HFrEF and HFpEF represent different forms of HF or two ends of a single spectrum with a common etiology (Borlaug BA. & Redfield MM., Circ., 2011, 123, 2006-2013, De Keulenaer GW., & Brutsaert DL., Circ., 2011, 123, 1996-2004).

[0008] Cerulacin, an intravenous (IV) formulation of recombinant human relaxin peptide with a relatively short phase 1 pharmacokinetic half-life of 0.09 hours, is currently under development for the treatment of heart failure (Novartis, 2014). Cerulacin has been given to normal volunteers (NHVs) and has been shown to increase RBF (Smith M.C., et al., J. Am. Soc. Nephrol. 2006, 17, 3192-3197) and estimated GFR (Dahlke M., et al., J. Clin. Pharmacol., 2015, 55, 415-422). Increases in RBF have also been observed in patients with stable, compensated heart failure (Voors A.A., et al., Cir. Heart Fail., 2014, 7, 994-1002). Large-scale clinical trials have observed a reduction in renal function deterioration, favorable changes in HF exacerbation, and mortality in patients with acutely decompensated HF (ADHF) in response to in-hospital 48-hour IV administration of Cerulaxin (Teerlink JR., et al., Lancet, 2013, 381, 29-39; Ponikowski P., et al., Eur. Heart, 2014, 35, 431-441). Chronic administration of Cerulaxin may provide sustained benefit to HF patients, with improved renal function based on serum creatinine levels observed in scleroderma patients who received Cerulaxin continuously via subcutaneous pump for 6 months (Teichman SL., et al., Heart Fail. Rev., 2009, 14, 321-329). In addition to its potential as a therapeutic agent for the treatment of HF, continuous subcutaneous administration of relaxin has also been shown to be effective in various animal models of pulmonary (Unemori EN., et al., J. Clin. Invet., 1996, 98, 2739-2745), renal (Garber SL., et al., Kidney Int., 2001, 59, 876-882) and liver injury (Bennett RG., Liver Int., 2014, 34, 416-426).

[0009] In summary, there is substantial evidence supporting the role of relaxin-dependent agonism of RXFP1 in mediating adaptive changes that occur during mammalian pregnancy and that these changes translate into favorable physiological effects 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, has the potential to provide therapeutic benefit for numerous indications in addition to HF. More specifically, chronic relaxin administration benefits 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

[0010] Summary of the Invention 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.

[0011] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0012] 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.

[0013] The compounds of the present invention may be used in the treatment and / or prevention of heart failure, fibrotic diseases and related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease) or liver disease (e.g., non-alcoholic steatohepatitis and portal hypertension).

[0014] The compounds of the present invention may be used in therapy.

[0015] The compounds of the present invention can be used for the manufacture of a medicament for the treatment and / or prevention of heart failure.

[0016] 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 to two, other drugs.

[0017] These and other features of the invention will be set forth in expanded form as the disclosure continues. DETAILED DESCRIPTION OF THE INVENTION

[0018] Description of the invention The present invention encompasses compounds of formula (I) that are RXFP1 receptor agonists, compositions containing same, and methods of use thereof.

[0019] In a first aspect, the present invention relates to, inter alia, a compound of formula (I): [ka] [During the ceremony, L is -O- or -NH-; R 1 is one aryl or C 3-6 C substituted with cycloalkyl substituents 1-3 is alkyl; R 2 is H; or R 1 and R 2 are united =CR 6 R 7 where "=" is a double bond; or R 1 and R 2 together with the carbon atom to which they are both attached form a dioxolanyl substituted with 0 to 1 aryl substituents; R 3 is 0 to 5 halo, -CN, -OH or -OC 1-3 C substituted with alkyl substituents 1-8 Alkyl, 0 to 5 R 4 -(CR d R d ) n -C 3-10 -Carbocyclyl or O, S(=O) p, N, NR 4a and 0 to 5 R 4 -(CR d R d ) n -3 to 12-membered heterocyclyl; R 4 are halo, CN, -OH, -SF5, -S(=O) p R c , 0 to 5 halo, -OH or -OC 1-4 C substituted with alkyl substituents 1-4 Alkyl, substituted with 0-5 halo substituents -OC 1-4 Alkyl, 0 to 5 R e -(CR d R d ) n -C 3-10 Carbocyclyl or O, S(=O) p , N and NR 4a -(CR d R d ) n -4 to 6-membered heterocyclyl; R 4a is H, C 1-4 alkyl or -S(=O)2CF3; R 5 is H, halo, -OH, C substituted with 0-5 halo substituents 1-4 -OC substituted with alkyl or 0-5 halo substituents 1-4 is alkyl; R 6 H, halo, CN, 0-3 R 6a C is replaced by 1-7 Alkyl, 0 to 3 R 6a C is replaced by 2-7 Alkenyl, 0 to 3 R 6a C is replaced by 2-7 Alkynyl, -C(=O)OR 6b , -CONR 6b R 6b , 0 to 5 R 14 Substituted with -(CH2) n -C 3-10Carbocyclyl or O, S(=O) p , N or NR 13 and 0 to 5 R 14 3-12 membered heterocyclyl substituted with; R 6a is halo, -OH, -OC 1-4 Alkyl, C 1-4 C substituted with alkyl, aryl or 0-4 halo substituents 3-6 is cycloalkyl; R 6b is H, C substituted with 0-1 aryl substituents 1-4 C substituted with alkyl or 0-4 halo substituents 3-6 is cycloalkyl; R 7 is H or C 1-4 is alkyl; R 8 H, halo, CN, -NR 7 R 7 or 0 to 5 halo, -OH, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, aryl or O, S(=O) p and N, substituted with a 4- to 9-membered heterocyclyl substituent containing 1 to 4 heteroatoms selected from -OC 1-4 is alkyl; R 9 is -C(=O)OR 15 , -C(=O)NR 15 R 15 , -S(=O) p NR 15 R 15 , -S(=O) p R c , -NR 17 R 17 , 0 to 4 R 10 and 0 to 2 R 11 C is replaced by 1-8 Alkyl, 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 2-8 Alkenyl, 0 to 2 R 10 and 0 to 2 R11 C is replaced by 2-8 Alkynyl, 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 3-9 Cycloalkyl, 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 3-9 Cycloalkenyl, 0 to 2 R 10 and 0 to 2 R 11 fused C substituted with 3-6 Cycloalkyl, 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 6-9 Spirocycloalkyl, 0 to 2 R 10 and 0 to 2 R 11 AC is replaced by 3-6 Carbocyclyl or O, S(=O) p , N and NR 18 and 0 to 2 R 10 and 0 to 2 R 11 A- is a 4- to 9-membered heterocyclyl substituted with; A is -O-, -S-, -CHO-, or -OCH-; R 10 is halo, CN or 0-4 R 11 C is replaced by 1-6 is alkyl; R 11 is halo, -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 , -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 , -OC(=O)OR b , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p R c , -S(=O) p NR a R a , 0 to 5 R e C is replaced by 3-9 Carbocyclyl or O, S(=O) p , N and NR 12 and 0 to 5 R e 3-12 membered heterocyclyl substituted with; R 12 is H, 0-4 halo, or OR b C substituted with a substituent 1-4 is alkyl or aryl; R 13 is H, C(=O)C 1-4 Alkyl, 0-3 Si(C 1-3 C substituted with alkyl)3 1-3 is an aryl substituted with alkyl or 0-2 halo substituents; R 14 is halo, CN, C substituted with 0-3 halo substituents 1-4 Alkyl, substituted with 0-3 halo substituents -OC 1-4 Alkyl, -(CH2) n -NR a R a , 0 to 3 R e Substituted with -(CH2) n -aryl, 0 to 3 R e -O-aryl or O, S(=O) substituted with pand N, and 0 to 3 R e Substituted with -(CH2) n -3 to 12-membered heterocyclyl; R 15 is H, 0 to 5 R e C is replaced by 1-6 Alkyl, 0 to 5 R e C is replaced by 2-6 Alkenyl, 0 to 5 R e C is replaced by 2-6 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p , N and NR 16 and 0 to 5 R e Substituted with -(CH2) n -3 to 12-membered heterocyclyl; or R 15 and R 15 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 16 and 0 to 5 R e forming a 3- to 12-membered heterocyclyl substituted with; R 16 is H, 0 to 5 R e C is replaced by 1-6 Alkyl, -C(=O)R f , -C(=O)OR f , -C(=O)NR f R f , -S(=O) p R f or -S(=O) p NR f R f and; R 17 is H, 0 to 5 R e C is replaced by 1-6 Alkyl, 0 to 5 R e C is replaced by 2-6 Alkenyl, 0 to 5 R eC is replaced by 2-6 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p , N and NR 18 and 0 to 5 R e Substituted with -(CH2) n -4 to 12-membered heterocyclyl; R 18 is H, C substituted with 0-4 halo or -OH substituents 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(=O) p R c , -S(=O) p NR a R a , 0 to 5 R e aryl substituted with 0 to 5 R e C is replaced by 3-6 Cycloalkyl or O, S(=O) p and N, and 0 to 5 R e 4-6 membered heterocyclyl substituted with; R a is H, 0 to 8 R e C is replaced by 1-6 Alkyl, 0 to 5 R e C is replaced by 2-6 Alkenyl, 0 to 5 R e C is replaced by 2-6 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p and N, and 0 to 5 R e Substituted with -(CH2) n -3 to 12-membered heterocyclyl; or R a and Ra are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N, and 0 to 5 R e forming a 3- to 12-membered heterocyclyl substituted with; R b is H, 0 to 5 R e C is replaced by 1-6 Alkyl, 0 to 5 R e C is replaced by 2-6 Alkenyl, 0 to 5 R e C is replaced by 2-6 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p and N, and 0 to 5 R e Substituted with -(CH2) n -3 to 12-membered heterocyclyl; R c is 0 to 5 R e C is replaced by 1-6 Alkyl, 0 to 5 R e C is replaced by 2-6 Alkenyl, 0 to 5 R e C is replaced by 2-6 Alkynyl, 0 to 5 R e C is replaced by 3-6 Carbocyclyl or O, S(=O) p and N, and 0 to 5 R e 3-12 membered heterocyclyl substituted with; R d is H, C 1-4 Alkyl or C 3-6 is cycloalkyl; R e Halo, CN, NO2, =O, 0-5 R g C is replaced by 1-6 Alkyl, 0 to 5 R g C is replaced by 2-6 Alkenyl, 0 to 5 Rg C is replaced by 2-6 Alkynyl, 0 to 5 R g Substituted with -(CH2) n -C 3-10 Carbocyclyl, O, S(=O) p and N, and 0 to 5 R g Substituted with -(CH2) n -3 to 12-membered heterocyclyl, -(CH2) n OR f , -C(=O)R 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, C 3-6 Cycloalkyl, aryl or O, S(=O) p and N; or R f and R f are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N to form a 3- to 12-membered heterocyclyl containing 1-4 heteroatoms selected from; R g Halo, CN, OH, OC 1-6 Alkyl, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0, 1, 2, or 3; and p is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

[0020] In a second aspect within the first aspect, the present invention provides a compound of formula (II): [ka] [During the ceremony, R 4 is halo, C substituted with 0 to 3 halo substituents 1-4 -OC substituted with alkyl or 0-3 halo substituents 1-4 is alkyl; R 6 is halo, CN, 0-3 R 6a C is replaced by 1-6 Alkyl, 0 to 3 R 6a C is replaced by 2-6 Alkenyl, 0 to 3 R 6a C is replaced by 2-6 Alkynyl, 0 to 3 R 14 C is replaced by 3-6 Cycloalkyl, 0 to 3 R 14 C is replaced by 3-6 Cycloalkenyl, 0 to 3 R 14 Phenyl or O, S(=O) substituted with p , N and NR 13 and 0 to 3 R 14 is a 5- to 6-membered heterocyclyl substituted with; R 7 is H or C 1-2 is alkyl; R 6a Halo, -OC 1-4 Alkyl, C 3-6 is cycloalkyl or phenyl; R 8 is H, halo, CN or 0 to 4 halo, OH or -OC 1-4 Alkyl-substituted -OC 1-4 is alkyl; R9 is 0 to 3 R 10 and 0 to 2 R 11 C is replaced by 1-7 Alkyl, 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 2-7 Alkenyl, 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 2-7 Alkynyl, 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 3-9 Cycloalkyl or 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 6-9 Spirocycloalkyl, 0 to 2 R 10 and 0 to 2 R 11 -CH2-O-C6 carbocyclyl substituted with 0-2 R 10 and 0 to 2 R 11 -OC is substituted with 3-6 is cycloalkyl; R 10 is halo, CN or C substituted with 0-4 halo or -OH substituents 1-5 is alkyl; R 11 HA-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 , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NRa S(=O) p R c , -OC(=O)R b , -OC(=O)NR a R a , -S(=O) p R c , -S(=O) p NR a R a , 0 to 4 R e aryl substituted with 0 to 4 R e C is replaced by 3-6 Cycloalkyl or O, S(=O) p , N and NR 12 and 0 to 4 R e 4-6 membered heterocyclyl substituted with; R 12 is H, C 1-2 is alkyl or phenyl; R 13 is H, C(=O)C 1-3 C substituted with 0-2 aryl substituted with alkyl or 0-2 halo substituents 1-3 is alkyl; R 14 is halo, CN, C substituted with 0-3 halo substituents 1-4 Alkyl, substituted with 0-3 halo substituents -OC 1-4 Alkyl, -(CH2) 0-2 -NR a R a , 0 to 3 R e Substituted with -(CH2) 0-2 -aryl, 0 to 3 R e -O-aryl or -(CH2) 0-2 -O, S(=O) p and N, and 0 to 3 R e is a 4- to 9-membered heterocyclyl substituted with; R a is H, 0 to 4 R e C is replaced by 1-5 Alkyl, 0 to 4 R eC is replaced by 2-5 Alkenyl, 0 to 4 R e C is replaced by 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or -(CH2) n -O, S(=O) p and N, and 0 to 4 R e or R a and R a are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N, and 0 to 4 R e forming a 4- to 9-membered heterocyclyl substituted with; R b is H, 0 to 4 R e C is replaced by 1-5 Alkyl, 0 to 4 R e C is replaced by 2-5 Alkenyl, 0 to 4 R e C is replaced by 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or -(CH2) n -O, S(=O) p and N, and 0 to 4 R e is a 4- to 9-membered heterocyclyl substituted with; R c is 0 to 4 R e C is replaced by 1-5 Alkyl, 0 to 4 R e C is replaced by 2-5 Alkenyl, 0 to 4 R e C is replaced by 2-5 Alkynyl, 0 to 4 R e C is replaced by 3-6 Carbocyclyl or O, S(=O) pand N, and 0 to 4 R e is a 4- to 9-membered heterocyclyl substituted with; R e is halo, CN, =O, 0-5 R g C is replaced by 1-6 Alkyl, 0 to 5 R g C is replaced by 2-6 Alkenyl, 0 to 5 R g C is replaced by 2-6 Alkynyl, 0 to 5 R g Substituted with -(CH2) n -C 3-6 Carbocyclyl, O, S(=O) p and N, and 0 to 5 R g , -(CH2) n OR f Substituted with -(CH2) n -4-9 membered heterocyclyl, -C(=O)OR f , S(=O) p R f , C(=O)NR f R 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 or -(CH2) n NR f R f and; R f is H, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; or R f and R f are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N to form a 4- to 9-membered heterocyclyl containing 1 to 4 heteroatoms selected from; R g is halo, CN, OH, C1-4 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0, 1, 2, or 3; and p is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

[0021] In a third aspect within the second aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or C substituted with 0-3 halo substituents 1-3 is alkyl; R 6 is 0 to 3 R 6a C is replaced by 1-5 Alkyl, 0 to 3 R 14 C is replaced by 3-6 Cycloalkyl or O, S(=O) p , N, and 0 to 3 R 14 is a 5- to 6-membered heterocyclyl substituted with; R 6a Halo, -OC 1-4 Alkyl or C 3-6 is cycloalkyl; R 7 is H; R 8 -OC is substituted with 0-2 halo or -OH substituents 1-3 is alkyl; R 9 is 0 to 3 R 10 and 0 to 2 R 11 C is replaced by 1-7 is alkyl; R 10 is halo, CN or C substituted with 0-4 halo substituents 1-4 is alkyl; R 11 HA-OR b , -NR a R a , -NR a C(=O)R b , -NRa C(=O)OR b , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -OC(=O)NR a R a , 0 to 3 R e aryl substituted with 0 to 3 R e C is replaced by 3-6 Cycloalkyl or O, S(=O) p , N and NR 12 and 0 to 3 R e 4-6 membered heterocyclyl substituted with; R 12 is H, C 1-2 is alkyl or phenyl; R 14 is halo, CN, C substituted with 0-3 halo substituents 1-4 Alkyl, substituted with 0-3 halo substituents -OC 1-4 Alkyl, -(CH2) 0-2 -NR a R a , 0 to 3 R e Substituted with -(CH2) 0-2 -aryl, 0 to 3 R e -O-aryl or -(CH2) 0-2 -O, S(=O) p and N, and 0 to 3 R e is a 4- to 9-membered heterocyclyl substituted with; R a is H, 0 to 4 R e C is replaced by 1-5 Alkyl, 0 to 4 R e C is replaced by 2-5 Alkenyl, 0 to 4 R e C is replaced by 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O)p and N, and 0 to 4 R e Substituted with -(CH2) n -4 to 9-membered heterocyclyl; or R a and R a are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N, and 0 to 4 R e forming a 4- to 9-membered heterocyclyl substituted with; R b is H, 0 to 4 R e C is replaced by 1-4 Alkyl, 0 to 4 R e C is replaced by 2-4 Alkenyl, 0 to 4 R e C is replaced by 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p and N, and 0 to 4 R e Substituted with -(CH2) n -4 to 9-membered heterocyclyl; R e is halo, CN, =O, 0-5 R g C is replaced by 1-5 Alkyl, 0 to 4 R g C is replaced by 2-5 Alkenyl, 0 to 4 R g C is replaced by 2-5 Alkynyl, 0 to 4 R g Substituted with -(CH2) n -C 3-6 Cycloalkyl, 0 to 4 R g Substituted with -(CH2) n -Aryl, O, S(=O) p and N, and 0 to 4 R g Substituted with -(CH2) n -4 to 9-membered heterocyclyl, -(CH2)n OR f , -C(=O)OR f , S(=O) p R f , C(=O)NR f R f , N.R. f C(=O)R f or -(CH2) n NR f R f and; R f is H, 0 to 3 R g C is replaced by 1-5 Alkyl, C 3-6 is cycloalkyl or aryl; or R f and R f are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N to form a 4-6 membered heterocyclyl containing 1-4 heteroatoms selected from; R g Halo, CN, OH, OC 1-4 Alkyl, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2 Provide something.

[0022] In a fourth aspect within the third aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or CF3; R 6 0 to 3 halo or -OC 1-3 C substituted with alkyl substituents 1-3 Alkyl, C substituted with 0-2 halo substituents 3-6 cycloalkyl or [ka] is a heterocyclyl selected from: R 8-OC is substituted with 0 to 1 -OH substituents 1-3 is alkyl; R 9 is substituted with 0-3 halo, -OH, or CN substituents 1-7 is alkyl; and R 14 is halo, CN or C substituted with 0-3 halo substituents 1-3 is alkyl Provide something.

[0023] In a fifth aspect within the third aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or CF3; R 6 0 to 3 halo or C 3-6 Cycloalkyl-substituted C 1-3 is alkyl; R 9 is 0 to 1 R 10 and 0 to 1 R 11 C is replaced by 1-3 is alkyl; R 10 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 11 HA-OR b and; R b is 0 to 3 R e C is replaced by 1-4 Alkyl, -(CH2) 0-1 -0 to 4 R e C is replaced by 3-6 Cycloalkyl, 0 to 3 R e Substituted with -(CH2) 0-1 -phenyl or -(CH2) 0-1 -heterocyclyl, wherein the heterocyclyl is [ka] and; R eis halo, CN, 0-5 R g C is replaced by 1-5 Alkyl, -(CH2) n OR f , -C(=O)OR f or C(=O)NR f R f and; R f is H, 0 to 3 R g C is replaced by 1-4 is alkyl; R g is halo, CN, OH, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; and n is 0 or 1 Provide something.

[0024] In a sixth aspect within the third aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or CF3; R 6 is 0 to 3 halo substituents or C 3-6 Cycloalkyl-substituted C 1-3 is alkyl; R 9 is 0 to 1 R 10 and 0 to 1 R 11 C is replaced by 1-3 is alkyl; R 10 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 11 Ha-NR a R a and; R a is H or 0 to 4 R e C is replaced by 1-4 Alkyl, 0 to 4 R e C is replaced by 3-6 is cycloalkyl; or R a and R atogether with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R e is halo, CN, =O, 0-4 R g C is replaced by 1-4 Alkyl, -(CH2) n -C 3-6 Cycloalkyl, O, S(=O) p and N, containing 1 to 4 heteroatoms selected from -(CH2) n -4-6 membered heterocyclyl, -(CH2) n -aryl, -(CH2) n OR f , -C(=O)OR f , S(=O) p R f , C(=O)NR f R f or -(CH2) n NR f R f and; R f is H or C 1-4 is alkyl; and R g Halo, CN, OH, OC 1-4 Alkyl, C 1-4 Alkyl, C 3-6 cycloalkyl or aryl Provide something.

[0025] In a seventh aspect within the third aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or CF3; R 6 is 0 to 3 halo substituents or C 3-6 Cycloalkyl-substituted C 1-3 is alkyl; R 9 is 0 to 1 R 10 and 0 to 1 R 11C is replaced by 1-3 is alkyl; R 10 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 11 is -OC(=O)NR a R a and; R a is H, 0 to 4 R e C is replaced by 1-4 Alkyl, 0 to 4 R e C is replaced by 3-6 Cycloalkyl or 0 to 4 R e or R a and R a together with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R e is halo, CN, =O, 0-3 R g C is replaced by 1-4 Alkyl, -(CH2) n OR f , -C(=O)OR f , S(=O) p R f , C(=O)NR f R f , N.R. f C(=O)R f or -(CH2) n NR f R f and; R f is H or C 1-4 is alkyl; R g is halo, CN, OH, C 1-4 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0 or 1; and p is 2 Provide something.

[0026] In an eighth aspect within the third aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or CF3; R 6 is 0 to 3 halo substituents or C 3-6 Cycloalkyl-substituted C 1-3 is alkyl; R 9 is 0 to 1 R 10 and 0 to 1 R 11 C is replaced by 1-3 is alkyl; R 10 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 11 is -NHC(=O)R b or -NR a C(=O)OR b and; R a is H or C 1-3 is alkyl; R b is 0 to 3 R e C is replaced by 1-4 Alkyl, 0 to 3 R e C is replaced by 3-6 Cycloalkyl, 0 to 3 R e phenyl substituted with [ka] is a heterocyclyl selected from: R e is halo, CN, 0-4 R g C is replaced by 1-4 Alkyl, -OR f , -C(=O)OR f , C(=O)NR f R f and R f is H or C 1-4 is alkyl; and Rg is halo, CN, OH, C 1-4 Alkyl, C 3-6 cycloalkyl or aryl Provide something.

[0027] In a ninth aspect within the second aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or C substituted with 0-3 halo substituents 1-4 is alkyl; R 6 is 0 to 3 halo substituents or C 3-6 Cycloalkyl-substituted C 1-3 is alkyl; R 8 Ha-OC 1-3 is alkyl; R 9 is 0 to 2 R 10 or 0 to 2 R 11 C is replaced by 2-4 is alkenyl; R 10 C is substituted with 0-4 halo or -OH substituents 1-2 is alkyl; R 11 is -C(=O)R b , -C(=O)OR b or -C(=O)NR a R a and; R a is H, 0 to 4 R e C is replaced by 1-4 Alkyl, 0 to 4 R e C is replaced by 3-6 Cycloalkyl or 0 to 4 R e or R a and R a are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N, and 0 to 4 R e forming a 4- to 9-membered heterocyclyl substituted with; R b is H or C 1-4 is alkyl; R e is a halo, 0 to 5 R g C is replaced by 1-6 Alkyl, -(CH2) 0-1 OR f or -C(=O)OR f and; R f is H or C 1-4 is alkyl; and R g is C 1-4 is alkyl Provide something.

[0028] In a tenth aspect within the ninth aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or CF3; R 6 is CF3 or cyclopropyl; R 8 Ha-OC 1-3 is alkyl; R 9 is 0 to 1 R 11 C is replaced by 2-3 is alkenyl; R 11 is -C(=O)NR a R a and; R a is H or 0 to 4 R e C is replaced by 1-4 Alkyl, 0 to 4 R e C is replaced by 3-6 is cycloalkyl; or R a and R a together with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R eis halo, CN, 0-4 R g C is replaced by 1-4 Alkyl, -(CH2) 0-1 OR f , -C(=O)OR f and R f is H or C 1-4 is alkyl; and R g is C 1-3 is alkyl Provide something.

[0029] In an eleventh aspect within the second aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or C substituted with 0-3 halo substituents 1-4 is alkyl; R 6 is 0 to 3 halo substituents or C 3-6 Cycloalkyl-substituted C 1-3 is alkyl; R 8 -OC is substituted with 0-2 halo or OH 1-3 is alkyl; R 9 is 0 to 2 R 11 C is replaced by 2-6 is alkynyl; R 11 HA-OR b or -OC(=O)NR a R a and; R a is H, 0 to 4 R e C is replaced by 1-4 Alkyl, 0 to 4 R e C is replaced by 3-6 Cycloalkyl or 0 to 4 R e is phenyl substituted with; R b is H or C 1-4 is alkyl; and R e is halo or C1-4 is alkyl Provide something.

[0030] In a twelfth aspect within the second aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or C substituted with 0-3 halo substituents 1-4 is alkyl; R 6 is C substituted with 0 to 3 F substituents 1-2 Alkyl or C 3-6 is cycloalkyl; R 8 Ha-OC 1-3 is alkyl; R 9 is C 3-9 Cycloalkyl, -OC 3-9 Cycloalkyl or fused C 3-6 cycloalkyl, each of which is 0 to 2 R 10 and 0 to 2 R 11 is replaced by R 10 is halo, CN or C substituted with 0-4 halo or -OH substituents 1-4 is alkyl; R 11 HA-OR b , -NR a R a , -NR a C(=O)R b , -C(=O)OR b , -C(=O)NR a R a or -OC(=O)NR a R a and; R a is H, 0 to 4 R e C is replaced by 1-4 Alkyl, 0 to 4 R e C is replaced by 3-6 Cycloalkyl or 0 to 4 R e or R a and R aare combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N, and 0 to 4 R e forming a 4- to 6-membered heterocyclyl substituted with R b is H, C 1-4 Alkyl or O, S(=O) p and N; R e is halo, -(CH2) n OR f or -C(=O)OR f and R f is H or C 1-3 is alkyl Provide something.

[0031] In a thirteenth aspect within the twelfth aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is F or CF3; R 6 is CF3, cyclopropyl, cyclobutyl or cyclopentyl; R 8 Ha-OC 1-3 is alkyl; R 9 is cyclobutyl, cyclopentyl, cyclohexyl, or bicycle[2,2,2]octanyl, each of which has 0 to 2 R 10 and 0 to 2 R 11 is replaced by; R 10 is F, CN, CH2OH, C(CH3)2OH or CHC(CH3)2OH; R 11 -OH, -NHC(=O)R b , -C(=O)OR b or -OC(=O)NR a R a and; R a is H, 0 to 3 R eC is replaced by 1-4 Alkyl, 0 to 3 R e C is replaced by 3-6 Cycloalkyl or 0 to 3 R e is phenyl substituted with; and R b is H, C 1-4 Alkyl or [ka] and; R e is halo, -(CH2) 0-1 OR f or -C(=O)OR f and R f is H or C 1-3 is alkyl Provide something.

[0032] In a fourteenth aspect within the second aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: R 4 is halo or C substituted with 0-3 halo 1-4 is alkyl; R 6 is C substituted with 0 to 3 F substituents 1-2 Alkyl or C 3-6 is cycloalkyl; R 8 Ha-OC 1-3 is alkyl; R 9 is 0 to 2 R 11 C is replaced by 6-9 is a spirocycloalkyl; R 11 HA-OR b , -NR a R a or C(=O)OR b and; R a is H or C 1-4 is alkyl; and R b is H or C1-4 is alkyl Provide something.

[0033] In a fifteenth aspect within the first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: L is -NH; R 4 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 6 is substituted with 0 to 3 halo substituents 1-4 Alkyl or C 3-6 is cycloalkyl; R 7 is H; R 8 is substituted with halo or 0-5 halo substituents -OC 1-4 is alkyl; R 9 is -S(=O) p R c or -S(=O) p NR 15 R 15 and; R 15 is H, 0 to 5 R e C is replaced by 1-5 Alkyl, 0 to 5 R e C is replaced by 3-10 Carbocyclyl or O, S(=O) p , N and NR 16 and 0 to 5 R e or R 15 and R 15 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 16 and 0 to 4 R e forming a 4- to 9-membered heterocyclyl substituted with; R 16 is H, 0 to 5 R e C is replaced by1-4 Alkyl, -C(=O)R f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f or -S(=O) p NR f R f and;R c is 0 to 5 R e C is replaced by 1-5 is alkyl; R c is 0 to 3 R e C is replaced by 1-3 is alkyl; R e is halo, -(CH2) n OR f , C(=O)OR f or C 1-6 is alkyl; R f is H or C 1-3 is alkyl; and n is 0, 1, or 2 Provide something.

[0034] In a sixteenth aspect within the fifteenth aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: R 4 is F or CF3; R 6 is CF3 or C 3-6 is cycloalkyl; R 8 is F or -OC 1-2 is alkyl; R 9 is -S(=O)2NR 15 R 15 and; R 15 is H, 0 to 5 R e C is replaced by 1-5 Alkyl, 0 to 5 R e phenyl substituted with or [ka] is a heterocyclyl selected from: or R 15 and R 15 together with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R 16 is H, 0 to 5 R e C is replaced by 1-3 Alkyl, -C(=O)R f , -C(=O)OR f , -C(=O)NR f R f , -S(=O) p R f or -S(=O) p NR f R f and; R e is halo, =O, -(CH2) 0-1 OR f or C 15 is alkyl; and R f is H or C 1-3 is alkyl Provide something.

[0035] In a seventeenth aspect within the first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: L is -NH; R 3 is two R 4 is phenyl substituted with; R 4 is F or CF3; R 5 is H; R 6 is CF3 or C 3-6 is cycloalkyl; R 7 is H; R 8 Ha-OC 1-2 is alkyl; R 9 Ha-NR 17 R 17 and; R 17 is H or 0 to 4 R e Substituted with -(CH2) n -phenyl; R e is halo, -OH or C 1-6 is alkyl; and n is 0 or 1 Provide something.

[0036] In an eighteenth aspect within the first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: L is -NH; R 4 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 6 is substituted with 0 to 3 halo substituents 1-4 Alkyl or C 3-6 is cycloalkyl; R 7 is H; R 8 is substituted with halo or 0-5 halo substituents -OC 1-4 is alkyl; R 9 is -C(=O)OR 15 or -C(=O)NR 15 R 15 and; R 15 is H, 0 to 5 R e C is replaced by 1-5 Alkyl, -(CH2) n -0 to 5 R e C is replaced by 3-6 Cycloalkyl, 0 to 5 R e Phenyl or O, S(=O) substituted with p , N and NR 16and 0 to 5 R e or R 15 and R 15 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 16 and 0 to 5 R e forming a 4- to 9-membered heterocyclyl substituted with; R 16 is H, 0 to 5 R e C is replaced by 1-6 Alkyl, -C(=O)R f , -C(=O)OR f , -C(=O)NR f R f , -S(=O) p R f or -S(=O) p NR f R f and; R e C substituted with halo, =O, or 0-2 -OH substituents 1-6 Alkyl, -(CH2) n OR f , -C(=O)R f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f or -S(=O) p NR f R f and; R f is H or C 1-3 is alkyl; and n is 0, 1, or 2 Provide something.

[0037] In a nineteenth aspect within the eighteenth aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: R 4is F or CF3; R 6 is CF3 or C 3-6 is cycloalkyl; R 8 is halo or -OC 1-2 is alkyl; R 9 is -C(=O)NR 15 R 15 and; R 15 is H, 0 to 5 R e C is replaced by 1-5 Alkyl, -CH2-, 0 to 5 R e C is replaced by 3-6 Cycloalkyl, 0 to 5 R e phenyl substituted with or [ka] is a heterocyclyl selected from: or R 15 and R 15 together with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R 16 is H or 0 to 5 R e C is replaced by 1-5 is alkyl; R e C substituted with halo, =O, 0-1 OH 1-6 Alkyl, -(CH2) 0-1 OR f , -C(=O)R f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f or -S(=O) p NR f R f and R f is H or C 1-3 is alkyl Provide something.

[0038] In a twentieth aspect within the first aspect, the present invention provides a compound of formula (III): [ka] [During the ceremony, R 3 is 0 to 5 R 4 -CHR d -C 3-6 -cycloalkyl or 0 to 5 R 4 is phenyl substituted with; R 4 is halo, CN or C substituted with 0-5 halo 1-4 is alkyl; R 5 is H; R 6 is 0 to 3 R 6a C is replaced by 1-3 Alkyl, 0 to 5 R 14 C is replaced by 3-6 Cycloalkyl or O, S(=O) p , N, and 0 to 5 R 14 3- to 6-membered heterocyclyl substituted with; R 6a is a halo; R 7 is H; R 8 Ha-OC 1-3 is alkyl; R 9 is -C(=O)NR 15 R 15 , 0 to 2 R 10 and 0 to 2 R 11 -CH2-O-phenyl substituted with 0 to 2 R 10 and 0 to 2 R 11 C is replaced by 3-9 Cycloalkyl or 0 to 2 R 10and 0 to 2 R 11 -OC is substituted with 3-6 is cycloalkyl; R 10 is halo, CN or C substituted with 0-4 halo or -OH substituents 1-4 is alkyl; R 11 HA-OR b , -OC(=O)NR a R a or -C(=O)OR b and; R 14 Halo, CN or C substituted with 0-3 halo substituents 1-4 is alkyl; R 15 is H, 0 to 3 R e C is replaced by 1-5 Alkyl, 0 to 3 R e Substituted with -(CH2) n -C 3-10 carbocyclyl; or R 15 and R 15 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 16 and 0 to 3 R e forming a 4- to 9-membered heterocyclyl substituted with; R 16 is H or 0 to 5 R e C is replaced by 1-4 is alkyl; R a is H, 0 to 5 R e C is replaced by 1-4 Alkyl, C 3-6 Carbocyclyl or -(CH2) n -O, S(=O) p and N, and 0 to 5 R e is a 4- to 9-membered heterocyclyl substituted with; R b is H or C 1-4 is alkyl; R dis H or C 1-3 is alkyl; R e is halo, 0 to 3 R f C is replaced by 1-4 Alkyl, OR f or -S(=O)2C 1-4 is alkyl; R f is H or C 1-4 is alkyl; R g is halo or -OH; n is 0, 1, 2, or 3; and p is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

[0039] In certain embodiments of Formula (I), R 1 and R 2 are united =CR 6 R 7 and R 6 and R 7 are both methyl.

[0040] In another embodiment of Formula (I), R 1 and R 2 are united =CR 6 R 7 and;R 6 is CF3; R 7 is H.

[0041] In another embodiment of Formula (I), R 1 and R 2 are united =CR 6 R 7 and;R 6 is the halo; R 7 is H.

[0042] In another embodiment of Formula (I), R 1 and R 2 are united =CR 6 R 7 and;R 6 is 0 to 1 R14 is phenyl substituted with; R 7 is H;R 14 Halo, -OC 1-4 It is alkyl or phenyl.

[0043] In another embodiment of Formula (I), R 1 and R 2 are united =CR 6 R 7 and;R 6 is a 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from O and N; R 7 is H.

[0044] In another embodiment of Formula (I), R 1 and R 2 are united =CR 6 R 7 and;R 6 is C 3-6 is cycloalkyl; R 7 is H.

[0045] In another embodiment of Formula (I), R 1 and R 2 are united =CR 6 R 7 and;R 6 is substituted with halo -CH2-C 3-6 is cycloalkyl; R 7 is H.

[0046] In another embodiment of Formula (I), R 1 and R 2 are united =CR 6 R 7 and;R 6 is cyclopropyl; R 7 is H.

[0047] In another embodiment of Formula (I), R 3 is C 1-6 It is alkyl.

[0048] In another embodiment of Formula (I), R 3 teeth [ka] is.

[0049] In another embodiment of Formula (I), R 3 is 0 to 2 R 4 C is replaced by 3-6 It is cycloalkyl.

[0050] In another embodiment of Formula (I), R 3 is 0 to 2 R 4 C is replaced by 3-6 It is a cycloalkenyl.

[0051] In another embodiment of Formula (I), R 3 teeth [ka] is.

[0052] In another embodiment of Formula (I), R 3 is 0 to 2 R 4 -(CR d R d ) 1-2 -phenyl; R 4 is halo, CF3 or OCF3; R d is H or methyl.

[0053] In another embodiment of Formula (I), R 3 is 0 to 2 R 4 -(CHR d )-C 3-6 is cycloalkyl; R 4 is halo or C 1-2 alkyl; R d is H or C 1-2 It is alkyl.

[0054] In another embodiment of Formula (I), R 3 teeth [ka] and;R 4 is halo or C 1-3 It is alkyl.

[0055] In another embodiment of Formula (I), R 3 teeth [ka] and;R 4 is C 1-2 It is alkyl.

[0056] In another embodiment of Formula (I), R 3 teeth [ka] and;R 4 is halo or CN.

[0057] In another embodiment of Formula (I), R 3 contains 1 to 2 heteroatoms selected from O and N, -(CR d R d ) 1-2 -5-membered heterocyclyl; R d is H or methyl.

[0058] In another embodiment of Formula (I), R 4 is halo, CN, C substituted with 0-3 halo 1-2 It is alkyl.

[0059] In another embodiment of Formula (I), R 3 is cyclopropyl, cyclobutyl, 0 to 1 R 4 cyclopentyl or cyclohexyl substituted with R 4 is CN or C 1-2 It is alkyl.

[0060] In certain embodiments of Formula (I), R 5is H, halo or OH.

[0061] In certain embodiments of Formula (I), R 6 is CH3 or CF3.

[0062] In another embodiment of Formula (I), R 6 C substituted with 0 to 3 halo 3-6 It is cycloalkyl.

[0063] In another embodiment of Formula (I), R 6 is O, S(=O) p , N and NR 13 and 0 to 3 R 14 5-6 membered heterocyclyl substituted with R 14 C substituted with 0 to 3 halo 1-3 It is alkyl.

[0064] In certain embodiments of Formula (I), R 7 is H or CH3.

[0065] In certain embodiments of Formula (I), R 8 is halo or -OCH3.

[0066] In certain embodiments of Formula (I), R 9 is C 3-9 Cycloalkyl or fused C 3-6 cycloalkyl, each of which has 0 to 2 R 10 and 0 to 2 R 11 It has been replaced.

[0067] In another embodiment of Formula (I), R 9 is 0 to 2 R 11 C is replaced by 6-9 It is a spirocycloalkyl.

[0068] In certain embodiments of Formula (I), R 9 is 0 to 2 R 10 and 0 to 2 R11 -CH2-O-phenyl substituted with R 10 C substituted with 0 to 4 halo 1-3 alkyl; R 11 is -OC(=O)NR a R a and;R a is H or phenyl.

[0069] In another embodiment of Formula (I), R 9 is 0 to 2 R 10 and 0 to 2 R 11 -OC is substituted with 3-6 It is cycloalkyl.

[0070] In another embodiment of Formula (I), R 9 teeth [ka] is.

[0071] In another embodiment of Formula (I), R 9 teeth [ka] and;R 10 is C 1-4 alkyl; R 11 is -C(=O)OR b and;R b is H or C 1-3 It is alkyl.

[0072] For compounds of formula (I), R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , R 6 , R 6a , R 6b , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R13 , R 14 , R 15 , R 16 , R 17 , R a , R b , R c , R d , R e , R f and R g Any range of a variable substituent, including: may be used independently of any other range of a variable substituent, i.e., the present invention includes combinations of various embodiments.

[0073] Unless otherwise defined, these terms have the following meanings:

[0074] "Halo" includes fluoro, chloro, bromo and iodo.

[0075] "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 10 It is intended to include alkyl groups. Further, for example, "C1-C6 alkyl" or "C1-C6 alkyl" means an alkyl having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted, where at least one hydrogen is replaced with another chemical group. Examples of 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 mean a direct bond. "Alkyl" also includes deuteroalkyls, such as CD3.

[0076] "Alkenyl" or "alkenylene" is intended to include a hydrocarbon chain in a straight or branched configuration having one or more, preferably one to three, carbon-carbon double bonds which may be located 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.

[0077] "Alkynyl" or "alkynylene" is intended to include a hydrocarbon chain in a straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds which may be located 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.

[0078] "Fused" refers to any ring structure described herein that is fused to an existing ring structure in the compounds of the present invention.

[0079] "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, 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. It should be noted 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.

[0080] "Cycloalkyl" is intended to mean a cyclized alkyl group, including mono-, bi-, or polycyclic ring systems. 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.

[0081] "Cycloalkenyl" is intended to mean a cyclized alkenyl group, including mono- or polycyclic ring systems, containing one or more double bonds in at least one ring; if there is more than one double bond, it must not form a completely delocalized pi-electron system throughout the entire ring (otherwise the group would be an "aryl" as defined herein). Cycloalkenyls can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring.

[0082] "Spirocycloalkyl" is intended to mean a hydrocarbon bicyclic ring system in which both rings are connected through one atom. The rings may be different in size and nature or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.

[0083] "Bicyclic carbocyclyl" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system consisting of carbon atoms, including two fused rings. One of the two fused rings is benzo-fused to the second ring; the second ring is a saturated, partially unsaturated, or unsaturated 5- or 6-membered carbocyclic ring. A bicyclic carbocyclic group can be attached to its side group at any carbon atom that results in a stable structure. The bicyclic carbocyclic groups described herein can be substituted at 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.

[0084] 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, 16th Edition, John Wiley & Sons, Inc., New York (2016).

[0085] "Benzyl" is intended to mean methyl in which one of the hydrogen atoms has been replaced by a phenyl group, wherein the phenyl group is optionally substituted with 1 to 5 groups, preferably 1 to 3 groups.

[0086] "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 selected from the group consisting of N, O, and S; and includes 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., N→O and S(O)). p where p is 0, 1, or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other optional substituents). A heterocyclic ring can be attached to its side group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted at a carbon or nitrogen atom if the resulting compound is stable. A nitrogen in a heterocyclyl can optionally be quaternized. If the total number of S and O atoms in a heterocyclyl exceeds 1, then these heteroatoms are preferably not adjacent to one another. Preferably, the total number of S and O atoms in a heterocyclyl does not exceed 1. Bridged rings are also included in the definition of heterocyclyl. When the term "heterocyclyl" is used, it is intended to include heteroaryl.

[0087] Examples of heterocyclyl are 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]tetrahydrofuran ... , furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2 ,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolyl Nyl, 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, 1,3,Heterocyclyls include, but are not limited to, 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.

[0088] "Bicyclic heterocyclyl," "bicyclic heterocyclyl," or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system containing two fused rings and containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring, including a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo ring, each fused to a second ring. The second ring is saturated, partially unsaturated, or unsaturated, and is a 5- or 6-membered monocyclic ring, including a 5-membered heterocyclyl, a 6-membered heterocyclyl, or a carbocyclyl (provided that when the second ring is carbocyclyl, the first ring is not benzo).

[0089] A bicyclic heterocyclic group can be attached to its side group at any heteroatom or carbon atom that results in a stable structure. The bicyclic heterocyclic groups described herein can be substituted with carbon or nitrogen atoms if the resulting compound is stable. If the total number of S and O atoms in the heterocyclyl exceeds 1, 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 does not exceed 1.

[0090] 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.

[0091] "Heteroaryl" is intended to mean a stable monocyclic or polycyclic aromatic hydrocarbon 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, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. Nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or other optional substituents). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) p where p is 0, 1 or 2.

[0092] As used herein, the term "substituted" refers to the replacement of at least one hydrogen atom with a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. If the substituent is keto (i.e., =0), then two hydrogens on the atom are replaced. Keto substituents are not present in aromatic moieties. If a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or double bond, it is intended that the carbonyl group or double bond is part of (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).

[0093] If a compound of the invention has a nitrogen atom (e.g., an amine), it may be converted to an N-oxide by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide another compound of the invention. Thus, shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxide (N→O) derivative.

[0094] When any variable occurs more than one time in any constituent or formula for a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is indicated to be substituted with 0 to 3 R groups, then the group may optionally be substituted with up to 3 R groups, and each occurrence of R 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.

[0095] If a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. If a substituent is listed without indicating the atom to which such substituent is bonded to the remainder of the compound of a formula, then such substituent may be bonded through any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0096] The present invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ion does not significantly affect the physiological activity or toxicity of the compound, i.e., they function as pharmacological equivalents. These salts can be prepared by common organic techniques using commercially available reagents. Some anionic salt forms include acetate, acetonitrate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinafoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0097] Throughout this specification and the appended claims, a chemical formula or name encompasses all stereo and optical isomers and their racemates, if such 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 molecules 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 term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species, wherein the composition lacks optical activity.

[0098] The term "counterion" is used to refer to negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

[0099] The present invention includes all tautomeric forms, atropisomers and rotamers of the compounds.

[0100] All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

[0101] 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 describe the 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)).

[0102] The term "chiral" refers to the structural characteristic of a molecule that makes it non-superimposable on its mirror image. The term "homochiral" refers to the state of enantiomeric purity. The term "optical activity" refers to the degree to which a homochiral molecule or a non-racemic mixture of chiral molecules rotates the plane of polarization.

[0103] The present invention is intended to include all isotopes of atoms occurring in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon are 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, substituting an appropriate isotopically labeled reagent for an otherwise unlabeled reagent. Such compounds may have a variety of potential uses, for example, as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to beneficially modify biological, pharmacological, or pharmacokinetic properties.

[0104] 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% regular FBS and 300 μg / ml hygromycin (Life Technologies). Cells were dissociated and suspended in assay buffer. The assay buffer was HBSS buffer (supplemented with calcium and magnesium) containing 20 mM HEPES, 0.05% BSA, and 0.5 mM IBMX. Cells (3,000 cells / well, except for HEK293 cells stably expressing human RXFP1, 1,500 cells / well) were added to 384-well Proxiplates (Perkin-Elmer). Cells were immediately treated with a DMSO solution (2% final) of test compound at final concentrations ranging from 0.010 nM to 50 μM. Cells were incubated for 30 minutes at room temperature. Intracellular cAMP levels were determined using the HTRF HiRange cAMP Assay Reagent Kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and d2 fluorophore-labeled cAMP were prepared separately in the provided 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) with excitation at 400 nm and dual emission at 590 nm and 665 nm. A calibration curve was constructed by plotting the fluorescence intensity ratio of the intensity from 665 nm emission to the intensity from 590 nm emission versus cAMP concentration, using external cAMP standards at concentrations ranging from 2.7 μM to 0.1 pM. The potency and activity of compounds to inhibit cAMP production were then determined by fitting a four-parameter logistic equation to the plot of cAMP levels versus compound concentration.

[0105] The example compounds 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 of the hRXFP1 HEK293 cAMP assay measured with the example compounds. 50 List the values.

[0106] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0107] Pharmaceutical Compositions and Methods of Use The compounds of formula (I) are RXFP1 receptor agonists and are useful in treating heart failure (e.g., HF) RThe compounds of formula (I) may be useful in treating indications such as HF (HFrEF and HFpEF), fibrotic diseases and related diseases such as pulmonary disease (e.g., idiopathic pulmonary fibrosis or pulmonary hypertension), renal disease (e.g., chronic kidney disease) or liver disease (e.g., nonalcoholic steatohepatitis and portal hypertension). The compounds of formula (I) may also be useful in treating disorders resulting from or causing arterial stiffness, decreased arterial elasticity, decreased arterial compliance and distensibility, including hypertension, renal disease, peripheral arterial disease, carotid and cerebrovascular disease (i.e., stroke and dementia), diabetes, microvascular disease leading to end-organ damage, coronary artery disease and heart failure. The compounds described herein may also be used to treat preeclampsia.

[0108] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0109] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for the treatment of a relaxin-related disorder.

[0110] Another aspect of the present invention is a method of treating a relaxin-associated disease, comprising administering an effective amount of a compound of formula (I).

[0111] Another aspect of the invention is a method of treating cardiovascular disease, comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0112] Another aspect of the invention is a method of treating heart failure, comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0113] Another aspect of the invention is a method of treating fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0114] Another aspect of the invention is a method of treating a disease associated with fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0115] Another aspect of the 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).

[0116] Another aspect of the invention is a method of treating renal disease (eg, chronic renal disease) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0117] Another aspect of the invention is a method of treating or preventing renal failure, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0118] Another aspect of the invention is a method of improving, stabilizing or restoring renal function in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I).

[0119] Another aspect of the invention is a method of treating liver disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0120] Another aspect of the present invention is a method of 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).

[0121] Another aspect of the present invention is the use of compounds of formula (I) for the prevention and / or treatment of relaxin-related disorders.

[0122] Another aspect of the invention is a compound of formula (I) for use in the prevention and / or treatment of a relaxin-related disorder.

[0123] Unless otherwise specified, the following terms have the meanings indicated.

[0124] The term "patient" or "subject" refers to any human or non-human organism that may benefit from treatment with RXFP1 agonist, as understood by those skilled in the art.Examples of subjects include people of all ages who have risk factors for cardiovascular disease.Common risk factors include but are not limited to age, sex, weight, family history, sleep apnea, alcohol or tobacco use, lack of exercise, arrhythmia or symptoms of insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia or polycystic ovarian syndrome (PCOS).

[0125] "Treating" or "treatment" encompasses treating a disease state as understood by practitioners in the art, and includes: (a) inhibiting the disease state, i.e., arresting its progression; (b) alleviating the disease state, i.e., inducing regression of the disease state; and / or (c) preventing the onset of a disease state in a mammal, particularly when the mammal is predisposed to the disease state but has not yet been diagnosed as having it.

[0126] "Preventing" or "prevention" refers to a prediction of the probability of occurrence of a clinical disease state as understood by practitioners in the art and encompasses prophylactic treatment (i.e., prevention and / or risk reduction) of subclinical disease states. Patients are selected for prophylactic treatment based on factors known to place them at higher risk of having a clinical disease state compared to the general population. "Prophylactic" treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment of subjects who have not yet exhibited a clinical disease state, while secondary prevention is defined as prevention of a second occurrence of the same or similar clinical disease state. "Risk reduction" or "risk reduction" encompasses treatment that reduces the incidence of development of a clinical disease state. That is, primary and secondary preventative treatments are examples of risk reduction.

[0127] 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 of the type that treat a disorder, as understood by a practitioner 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.

[0128] "Cardiovascular system disorders" or "cardiovascular disorders" include, for example, the following disorders: hypertension (high blood pressure), peripheral and cardiovascular disorders, coronary heart disease, stable and unstable angina, heart attack, myocardial failure, abnormal heart rhythm (or arrhythmia), permanent ischemic dysfunction ("hibernating myocardium"), transient post-ischemic dysfunction ("stunned myocardium"), heart failure, peripheral blood flow disorders, acute coronary syndromes, heart failure, heart muscle diseases (cardiomyopathies), myocardial infarction, and vascular diseases (vascular diseases).

[0129] "Heart failure" refers to both acute and chronic manifestations of heart failure and specific or related types of diseases, such as advanced heart failure, post-acute heart failure, cardiorenal syndrome, heart failure with renal dysfunction, chronic heart failure, chronic heart failure with preserved ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic stenosis, aortic insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary stenosis , pulmonary valve insufficiency, heart failure associated with complex heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with cardiac storage disorder, diastolic heart failure, systolic heart failure, acute phase of worsening heart failure, heart failure with preserved systolic function (HFpEF), heart failure with reduced systolic function (HFrEF), chronic heart failure with preserved systolic function (HFpEF), post-myocardial remodeling, angina pectoris, hypertension, pulmonary hypertension, and pulmonary arterial hypertension.

[0130] "Fibrotic disorders" encompass diseases and disorders characterized by fibrosis, including, inter alia, the following diseases and disorders: liver fibrosis, cirrhosis, NASH, pulmonary fibrosis or pulmonary fibrosis, cardiac fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic damage due to diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical procedures), nevi, diabetic retinopathy, proliferative vitreoretinopathy, and disorders of connective tissue (e.g., sarcoidosis).

[0131] Relaxin-related disorders include, but are not limited to, cardiovascular disorders and fibrotic disorders.

[0132] The compounds of the present invention can be administered by any suitable means, for example, orally, e.g., tablets, capsules (each including sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal mucosa, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository. While they can be administered alone, they will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0133] "Pharmaceutical composition" refers to a composition comprising a compound of the present invention and at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of a bioactive agent to an animal, particularly a mammal, i.e., depending on the method of administration and the nature of the dosage form, includes adjuvants, additives or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents.

[0134] Pharmaceutically acceptable carriers are formulated according to several factors well within the knowledge of those skilled in the art. These include, but are not limited to, the type and nature of the active agent to be formulated; the 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 and a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers may contain several different components and additives, and such additional components are included in the formulation for various reasons well known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection can be found in many readily available sources, such as Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0135] Dosage regimens for the compounds of the invention will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its method and route of administration; the species, age, sex, health, medical 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.

[0136] As a general guideline, the daily oral dose of each active ingredient, when used for the indicated effects, ranges from about 0.01 to about 5000 mg / day, preferably from about 0.1 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. Intravenously, the most preferred doses are in the range of about 0.01 to about 10 mg / kg / minute during a 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.

[0137] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriate for the intended dosage form, e.g., oral tablets, capsules, elixirs and syrups, and consistent with conventional pharmaceutical practice.

[0138] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is typically 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 sieved 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, and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to form an injectable formulation.

[0139] The compounds may be used in combination with other suitable therapeutic agents useful in the treatment of diseases or disorders, including anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenosis agents, anti-pancreatic agents, lipid-lowering agents, appetite reducing agents, memory enhancing agents, anti-dementia agents, cognition enhancing agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignancies, and anti-inflammatory agents.

[0140] 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 biased agonism towards selected cell signaling pathways, angiotensin II receptor antagonists and nephropathy inhibitors. Lysin enzyme inhibitor combinations, neprilysin enzyme inhibitors, soluble guanylate cyclase activators, myosin ATPase activators, rho-kinase 1 inhibitors, rho-kinase 2 inhibitors, apelin receptor agonists, nitroxyl-donating compounds, calcium-dependent kinase II inhibitors, antifibrotic agents, galectin-3 inhibitors, vasopressin receptor antagonists, FPR2 receptor modulators, natriuretic peptide receptor agonists, transient receptor potential vanilloid-4 channel blockers, antiarrhythmic agents, I f "Hyperpolarization-activated cation current" channel blockers, nitrates, digitalis compounds, inotropes and β-receptor agonists, cell membrane resealing agents such as poloxamer 188, antihyperlipidemic agents, plasma HDL-raising agents, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (e.g., 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, gemfibrozil, vitamin B6, vitamin B12, antioxidant vitamins, antidiabetic agents, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives, PCSK9 inhibitors, P2Y12 inhibitors such as aspirin and clopidogrel.

[0141] Additional therapeutic agents also include nintedanib, pirfenidone, LPA1 antagonist, LPA1 receptor antagonist, GLP1 analog, tralokinumab (IL-13, AstraZeneca), vismodegib (hedgehog antagonist, Roche), PRM-151 (pentraxin-2, TGF-beta-1, Promedior), SAR-156597 (bispecific Mab IL-4 & IL-13, Sanofi), simtuzumab (anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inhibitor / pentoxifylline / NAC oral suspension, Pacific Ther.), omipalisib (oral PI3K / mTOR inhibitor, GSK), IW-001 (oral solution bovine type V collagen modified, ImmuneWorks), STX-100 (integrin alpha V / beta-6 ant, Stromedix / Biogen), Actimmune (IFN gamma), PC-SOD (midismase; inhaled, LTT Bio-Pharma / CKD Pharm), lebrikizumab (anti-IL-13 SC humanized mAb, Roche), AQX-1125 (SHIP1 activator, Aquinox), CC-539 (JNK inhibitor, Celgene), FG-3019 (FibroGen), SAR-100842 (Sanofi), and obeticholic acid (OCA or INT-747, Intercept).

[0142] The therapeutic agents, when used in combination with the compounds of the present invention, may be used in amounts, for example, as set forth in the Physicians' Desk Reference, as set forth in the above-referenced patents, or as otherwise determined by one of skill in the art.

[0143] There may be chemical interactions between the combined active ingredients, especially when provided as a single dosage unit. Therefore, when the compound of the present invention and a second 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 active ingredient may be enteric-coated. Enteric coating of one active ingredient can not only minimize contact between the combined active ingredients, but can also control the release of one of these ingredients in the gastrointestinal tract so that one of these ingredients is released in the intestine rather than in the stomach. One of the active ingredients may be coated with a material that affects delayed release through the gastrointestinal tract and simultaneously acts 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 approach involves formulating a combination product in which one component is coated with a sustained and / or enteric release polymer and the other component is also coated with a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other suitable material known in the art to further separate the active ingredients. The polymer coating serves to form an additional barrier to interaction with the other component.

[0144] The compounds of the present invention are also useful as standards or control compounds, e.g., quality standards or controls, in tests or assays involving RXFP1. Such compounds can be included in commercial kits, for example, for pharmaceutical research involving RXFP1. For example, the compounds of the present invention can be used as assay controls to compare their known activity with a compound of unknown activity. This allows the experimenter to ensure 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.

[0145] The present invention also encompasses articles of manufacture. As used herein, the term "article of manufacture" is intended to include, 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 in the first container, wherein the composition comprises 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 other embodiments, the package insert stating that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) for dyslipidemia and its sequelae. The article of manufacture further comprises (d) a second container, wherein components (a) and (b) are disposed within the second container and component (c) is disposed within or outside the second container. Disposed within the first and second containers means that each container holds its items within its boundaries.

[0146] A primary container is a vessel used to hold a pharmaceutical composition. This container may be for manufacturing, storage, shipping, and / or individual / bulk sale. Primary containers are intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used in manufacturing, holding, storing, or dispensing pharmaceutical products.

[0147] The second container is used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), wooden boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert may be physically attached to the outside of the first container with tape, glue, staples, or other attachment methods, or may be placed in the second container without any physical attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert be physically attached with tape, glue, staples, or other attachment methods. Alternatively, the package insert may be adjacent to or in contact with the outside of the second container without being physically attached.

[0148] The package insert is a label, tag, marker, etc. that provides information about the pharmaceutical composition located in the first container. The information provided is usually determined by the regulatory agency that governs the region in which the product is sold (e.g., the U.S. Food and Drug Administration). Preferably, the package insert specifically describes the indications for which the pharmaceutical composition is approved. The package insert can be made of any material that allows a person to read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) onto which the desired information is formed (e.g., printed or applied).

[0149] chemical method Throughout this specification and the appended claims, a chemical formula or name includes all stereo- and optical isomers and their racemates, when such isomers exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like may also be present in the present compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the present compounds are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds may be isolated in optically active or racemic form. Optically active forms may be prepared by resolution of racemates or by synthesis from optically active starting materials. All processes used to prepare the compounds of the present invention, as well as intermediates prepared therein, are considered part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, chromatography or fractional crystallization. Depending on the process conditions, the final products of the present invention may be obtained in free (neutral) or salt form. Both the free form and salts of these final products are within the scope of the present invention. If desired, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; and an isomeric mixture of the compounds of the present invention can be separated into individual isomers. The compounds of the present invention, whether in the free form or as a salt thereof, can exist in multiple tautomeric forms in which hydrogen atoms are transferred to other parts of the molecule, resulting in a rearrangement of the chemical bonds between the atoms of the molecule. It should be understood that all tautomeric forms, to the extent that they may exist, are included within the scope of the present invention.

[0150] The compounds of the present invention can be made by a variety of methods known in the art, including those in the following schemes and specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes may differ from and may not match the structure or variable numbering in the claims or elsewhere in this specification. The variables in the schemes are only intended to illustrate how to make some of the compounds of the present invention.

[0151] The present invention is not limited to the following illustrative examples, which are to be considered in all respects as illustrative and not restrictive, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced.

[0152] It will be appreciated that another major consideration in planning any synthetic route in this field is the proper selection of protecting groups used to protect reactive functional groups present in the compounds described herein. An authoritative reference describing the many options available to the skilled artisan is Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0153] Abbreviations are defined as follows: "1x" means one time, "2x" means two times, "3x" means three times, "°C" means degrees Celsius, "aq" means aqueous, "eq" or "equiv." means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means normal, "M" means molar, "nM" means nanomolar, "pM" means picomolar, "mol" means mole, "mmol" means millimole, "min" means minute, "h" means hour, "rt" means room temperature, "RT" means retention time, "atm" means atmospheric pressure, "psi" means pounds per square inch, "conc." means concentrated, "aq" means "aqueous", "sat." means saturated, "MW" means molecular weight, "MS" or "Mass Spec" means mass spectrometry, "ESI" means electrospray ionization mass spectrometry, "LC-MS" means liquid chromatography-mass spectrometry, "HPLC" means high-performance liquid chromatography, "RP HPLC” stands for reversed-phase HPLC, NMR stands for nuclear magnetic resonance spectroscopy, SFC stands for supercritical fluid chromatography, 1 "H" is proton, "δ" is delta, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quartet, "m" is multiplet, "br" is broad, "Hz" is hertz, "MHz" is megahertz and "α", "β", "R", "S", "E" and "Z" are stereochemical designations familiar to those skilled in the art.

[0154] [Table 2]

[0155] Unless otherwise noted, the following methods were used in the exemplified examples. Purification of intermediates and final products was carried out by normal or reverse phase chromatography. Normal phase chromatography was carried out using pre-packed SiO2 cartridges eluting with a gradient of hexane and ethyl acetate or DCM and MeOH unless otherwise noted. Reverse-phase preparative HPLC was performed using a C18 column and UV 220 nm or preparative LCMS detection with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or a gradient of solvent A (95% water, 5% ACN, 0.1% TFA) and solvent B (5% water, 95% ACN, 0.1% TFA), or a gradient of solvent A (95% water, 2% ACN, 0.1% HCOOH) and solvent B (98% ACN, 2% water, 0.1% HCOOH), or a gradient of solvent A (95% water, 5% ACN, 10 mM NHOAc) and solvent B (98% ACN, 2% water, 10 mM NHOAc). NH4OAc) or solvent A (98% water, 2% ACN, 0.1% NH4OH) and solvent B (98% ACN, 2% water, 0.1% NH4OH).

[0156] The LC / MS methods used to characterize the example compounds are listed below.

[0157] Method A: Equipment: Waters Acquity coupled to a Waters MICROMASS® ZQ mass spectrometer Linear gradient from 2 to 98% B over 1 min with a 0.5 min hold time at 98% B 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

[0158] Method B: Equipment: Shimadzu Prominence HPLC coupled to a Shimadzu LCMS-2020 mass spectrometer Linear gradient from 0 to 100% B over 3 min with a 0.75 min hold time at 100% B 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

[0159] Method C: Equipment: Shimadzu Prominence HPLC coupled to a Shimadzu LCMS-2020 mass spectrometer Linear gradient from 0 to 100% B over 3 min with a 0.75 min hold time at 100% B 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

[0160] Method D: Equipment: Waters Acquity coupled to a Waters MICROMASS® ZQ mass spectrometer Linear gradient from 10% B to 98% B over 1 min with a 0.5 min hold time at 98% B UV visualization at 220 nm Column: Waters Acquity GEN C18, 2.1 x 50 mm, 1.7 μm particles Flow rate: 1mL / min Mobile phase A: 0.05% TFA, 100% water Mobile phase B: 0.05% TFA, 100% acetonitrile

[0161] NMR used to characterize example compounds. 1 H NMR spectra were obtained on a Bruker or JEOL® Fourier transform spectrometer operating at the following frequencies: 1 H NMR: 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®). Spectral data are reported in the following format: chemical shift (multiplicity, coupling constant, number of hydrogens). Chemical shifts are referenced to the solvent peak relative to a tetramethylsilane internal standard (δ units, tetramethylsilane = 0 ppm) and / or 1 In the H NMR spectrum, DMSO-d6 was identified at 2.51 ppm, CD3OD at 3.30 ppm, CD3CN at 1.94 ppm, and CDCl3 at 7.24 ppm downfield of the reference.

[0162] The synthesis of key norbornyl intermediates is outlined in Schemes I–V. Starting from I-1, norbornyl intermediates can be prepared by isopropylidene bridgehead substitution, as described in Scheme I. Diels-Alder cyclization with maleic anhydride afforded compound I-2, which was reduced and deprotected to afford I-3. Curtius reaction of the free acid with DPPA in the presence of trimethylsilylethanol afforded I-4. The trimethylsilyl carbamate was cleaved with TFA, and the amine was reprotected as trifluoroacetamide I-5. The methyl ester was converted to the amide by treatment with 4-fluoro-3-trifluoromethylaniline and trimethylaluminum to afford I-6. Deprotection of the trifluoroacetamide using K2CO3 and MeOH afforded amine I-7.

[0163] Scheme I [ka] Intermediate I-2: To a reaction vessel at 0°C was added EtO (100 mL), 5-(propan-2-ylidene)cyclopenta-1,3-diene (10 g, 94 mmol), and furan-2,5-dione (10 g, 100 mmol). The reaction mixture was stirred at 0°C for 18 hours, concentrated under reduced pressure, and purified by silica gel chromatography to give I-2 (3.74 g, 18.3 mmol, 19.0% yield). Intermediate I-2 is a known compound; see PCT International Application No. 2011163502, filed December 29, 2011.

[0164] Intermediate I-3: To a reaction vessel was added I-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 atmosphere of H (H balloon) for 60 min, filtered through Celite, and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) and heated at 50 °C for 12 h. The solution was concentrated under reduced pressure (azeotropic distillation with toluene 3 × 15 mL) to give I-3 (3.21 g, 13.5 mmol, 100% yield), which was used without further purification.

[0165] Intermediate I-4: To a reaction vessel was added I-3 (3.21 g, 13.5 mmol), EtN (3.38 mL, 24.2 mmol), toluene (75 mL), and diphenylphosphoryl azide (4.35 mL, 20.2 mmol). The reaction mixture was stirred at 23 °C for 1 h and then heated at 85 °C for 30 min. 2-(Trimethylsilyl)ethanol (4.83 mL, 33.7 mmol) was added to the reaction mixture, and after stirring at 85 °C for 66 h, the reaction mixture was cooled to 23 °C and purified by silica gel chromatography to give racemic I-4 (3.71 g, 10.5 mmol, 78% yield). LC-MS RT = 1.25 min; (M+H) = 354.1. Method A. Racemic I-4 was separated into its individual enantiomers using a Chiral SFC. Preparative chromatography conditions: Apparatus: Thar 350 SFC; Column: Whelko-RR (0.46 x 25 cm, 5 microns); Mobile phase: 5% IPA / 95% CO2; Flow conditions: 3 mL / min, 100 bar, 35 °C; Detection wavelength: 220 nm; Injection details: 4 injections of 3.5 mL of 59 g / 490 mL MeOH:DCM (4:1) 120 mg / mL IPA solution. Analytical chromatography conditions: Apparatus: Thar analytical SFC; Column: Whelko-RR (0.46 x 25 cm, 5 microns); Mobile phase: 5% IPA / 95% CO2; Flow conditions: 3 mL / min, 140 bar, 40 °C; Detection wavelength: 200-400 nm UV; RT = 3.50 peak #1, 4.42 peak #2. Intermediate I-4 product peak #1 was collected and carried forward to give chiral I-5.

[0166] Intermediate I-5: Peak #1 from Intermediate I-4 (2.87 g, 8.12 mmol) was dissolved in 10:1 DCM / TFA and stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure to give (1R,2S,3R,4R)-methyl 3-amino-7-(propan-2-ylidene)bicyclo[2.2.1]heptane-2-carboxylate (1.699 g, 8.120 mmol, 100% yield), which was used without further purification. To (1R,2S,3R,4R)-methyl 3-amino-7-(propan-2-ylidene)bicyclo[2.2.1]heptane-2-carboxylate (1.7 g, 8.1 mmol) was added DCM (41 mL), and the flask was cooled to 0 °C in an ice bath. TFAA (1.26 mL, 8.90 mmol) and DIEA (5.7 mL, 33 mmol) were added. The reaction mixture was warmed to 23 °C and stirred for 30 min. Saturated NaHCO (50 mL) was added to the reaction mixture, and the solution was extracted with EtOAc (3 × 50 mL). The combined organic portions were dried over NaSO, filtered, and concentrated under reduced pressure to give I-5 (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

[0167] Intermediate I-6: To a solution of intermediate I-5 (2.7 g, 8.8 mmol) in toluene (88 mL) was added trimethylaluminum (26.5 mmol) premixed with 4-fluoro-3(trifluoromethyl)aniline (29.2 mmol) as a toluene solution (0.275 M in amine, 0.25 M in trimethylaluminum). The reaction mixture was stirred at 60 °C for 30 min. Upon cooling to rt, the reaction mixture was diluted with EtOAc (100 mL) and saturated Rochelle's salt (100 mL) was added. The aqueous portion was extracted with EtOAc (3 × 75 mL). The combined organic portions were dried over NaSO, filtered, concentrated under reduced pressure, and subjected to silica gel chromatography, and the residue was further purified by preparative reverse-phase HPLC to afford (1R,2S,3R,4R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(propan-2-ylidene)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide I-6 (2.5 g, 5.5 mmol, 63% yield) as a yellow foam. LC-MS RT = 1.20 min; MS (ESI) m / z = 453.0 (M+H). + ; Method A

[0168] Intermediate I-7: Intermediate I-6 (133 mg, 0.290 mmol) was dissolved in water (2.9 mL) and MeOH (2.9 mL), then KCO (2.03 g, 1.47 mmol) was added. The reaction mixture was stirred at 40 °C for 4 h, then partitioned with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give I-7 (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

[0169] Scheme Ia Norbornyl intermediate IIa-8 can also be prepared from furan-2,5-dione and ferrocenium hexafluorophosphate via the general route shown in Scheme Ia. Diels-Alder condensation, followed by hydrolysis to IIa-2, Curtius rearrangement to the intermediate amine, its reduction under hydrogenation conditions, and subsequent protection afforded intermediate IIa-3. Cleavage of the benzyl ester and cross-coupling with NHR1R2 afforded intermediates with the general structure IIa-5. Conversion of the C7 hydroxy group to a ketone, followed by Wittig olefination, afforded the major isomer intermediate IIa-8. The major isomer was separated from the minor isomer by chromatography, and the racemate was isolated into enantiopure IIa-8(-).

[0170] [ka]

[0171] Scheme II illustrates the conversion of intermediate I-6 to an olefinic bromide intermediate that is now amenable to cross-coupling reactions at the C-7 methylidene. Scheme II [ka] Intermediate II-1: To a reaction vessel was added intermediate I-6 (110 mg, 0.243 mmol) and EtOAc (2 mL). The reaction mixture was cooled to -78 °C, and O was bubbled through the solution until it turned light purple / blue. N was then bubbled through the solution at -78 °C to remove excess O (the solution became colorless). Dimethyl sulfide (0.43 mL, 4.8 mmol) was then added at -78 °C, and the reaction mixture was warmed to rt and stirred at rt for 12 h. After concentration under reduced pressure, the residue was dissolved in EtOAc and filtered through silica gel. After the solvent was removed under reduced pressure, (1R,2S,3R,4S)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-oxo-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide (II-1, 101 mg, 0.237 mmol, 97.0% yield) was obtained. 1H NMR (500 MHz, CDCl3) δ 9.61 (br d, J = 6.3 Hz, 1H), 7.76 (dd, J = 5.9, 2.6 Hz, 1H), 7.71 (dt, J = 8.9, 3.4 Hz, 1H), 7.66 (s, 1H), 7.23 (t, J = 9.4 Hz, 1H), 4.70 (dt, J = 10.3, 5.3 Hz, 1H), 3.33 (dd, J = 10.5, 4.4 Hz, 1H), 2.54 (t, J = 4.3 Hz, 1H), 2.42 (t, J = 4.1 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.06 - 1.99 (m, 1H), 1.96 - 1.81 (m, 2H)

[0172] Intermediate II-2: To a reaction vessel was added bromo(methyl)triphenylphosphorane (419 mg, 1.17 mmol) (fine powder obtained by grinding the commercial product) and THF (7 mL). The reaction mixture was cooled to −78° C., and KHMDS (1.2 mL, 1.2 mmol) was added. The reaction mixture was vigorously stirred at −78° C. for 30 min, and II-1 (100 mg, 0.24 mmol) was added at −78° C. After stirring at −78° C. for an additional 10 min, the reaction mixture was warmed to 23° C. and stirred for an additional 1.5 h. The reaction mixture was cooled to −40° C. and quenched by the addition of saturated NaHCO3. The resulting solution was extracted with EtOAc. The combined organic portions were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give II-2 (71 mg, 0.17 mmol, 71% yield). LCMS RT = 1.16 min; (M+H) = 425.0; Method A

[0173] Intermediates II-3 and II-4: To a reaction vessel were added II-2 (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 using a trap with saturated NaSO to quench excess Br. The resulting dibromide was dissolved in THF (3 mL). After cooling to -78 °C, KHMDS (1.0 mL, 1.0 mmol) was added. The reaction mixture was maintained at -78 °C for 12 h and at -40 °C for 2 h, quenched by the addition of saturated NaHCO at -40 °C, and the resulting solution was extracted with EtOAc. The organic phases were collected, dried over NaSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give II-4 (27 mg, 0.050 mmol, 32% yield) (peak 2) (LCMS RT = 1.19 min; (M+H) = 504.9; Method A) and the corresponding E-isomer II-3 (28 mg, 0.06 mmol, 33% yield) (peak 1).

[0174] Racemic II-4 (4 grams) was prepared as described above and separated into its individual enantiomers using Chiral SFC. Preparative chromatographic conditions: Apparatus: Thar 350 SFC; Column: Chiralcel OD-H, 5 x 50 cm, 5 micron; Mobile phase: 20% MeOH / 80% CO2; Flow conditions: 340 mL / min, 100 bar, 35°C; Detection wavelength: 220 nm; Injection details: 3.75 mL of 30 mg / mL in MeOH. Peak #1 RT = 7.81 min, Peak #2 RT = 10.97 min. Peak #1 II-4 (1.9 grams) was collected and carried forward to give chiral II-5.

[0175] Intermediate II-5: To the reaction was added MeOH (3 mL) and AcCl (0.3 mL, 4.2 mmol). After stirring for 5 min, chiral peak #1 II-4 (75 mg, 0.15 mmol) was added and the reaction mixture was stirred at 40° C. for 48 h. The reaction mixture was concentrated under reduced pressure to yield II-5 (67 mg, 0.16 mmol, 100%), which was used without further purification. LC-MS RT = 0.78 min; (M+H) = 408.9; Method A

[0176] Scheme III [ka]

[0177] Intermediate III-1: To a reaction vessel was added diethyl benzylphosphonate (375 mg, 1.64 mmol) and THF (10 mL). The reaction mixture was cooled to -78 °C, and KHMDS (1.6 mL, 1.6 mmol) was added. The reaction mixture was stirred at -78 °C for 10 minutes, and intermediate II-1 (140 mg, 0.328 mmol) was added. After 20 minutes, the reaction mixture was warmed to rt and stirred at rt for 2 hours. The reaction mixture was quenched by the addition of saturated NaHCO3, and the solution was extracted with EtOAc. The combined organic portions were dried over NaSO, filtered, concentrated, and subjected to silica gel chromatography to afford the E-isomer by-product (111 mg, 0.222 mmol, 67.5% yield) and (1R,2S,3R,4R,Z)-7-benzylidene-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide (III-1, 49 mg, 0.098 mmol, 30% yield). RT = 1.23 min; MS(ESI) m / z = 501.1 (M+H). + ; Method A

[0178] Intermediate III-2: To a vial containing MeOH (3 mL) cooled to 0 °C (ice / water bath) was added dropwise acetyl chloride (0.3 mL, 4 mmol). The resulting solution was stirred at rt for 10 min and then added to III-1 (94 mg, 0.19 mmol). The reaction mixture was stirred at 40 °C for 48 h and concentrated under reduced pressure to give (1R,2S,3R,4R)-3-amino-7-((Z)-benzylidene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (III-2, 73 mg, 0.18 mmol, 96% yield). RT = 0.87 min; MS(ESI) m / z = 405.1 (M+H). +; Method A. It was used without further purification.

[0179] Scheme IV shows a general route to introduce C7 bridgehead functionalities such as, but not limited to, cyclopropyl, cyclobutyl, and nBu in a manner similar to Scheme II. Scheme IV [ka]

[0180] Intermediate IV-1a: A solution of II-4 (1.00 g, 1.98 mmol) in THF (9.9 mL) was treated with PdCl(dppf) (0.073 g, 0.099 mmol) under N. Cyclopropylzinc(II) bromide (15.9 mL, 7.95 mmol) was then added, and the reaction mixture was heated at 60 °C for 2 h. The cooled reaction mixture was extracted with EtOAc from brine, and the combined organic portions were concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide (IV-1a, 646 mg, 1.39 mmol, 70.0% yield). LC-MS RT = 1.07 min; MS (ESI) m / z = 492.1 (M+H) + ; Method A

[0181] Intermediate IV-2: A solution of IV-1a (646 mg, 1.39 mmol) in MeOH (9.3 mL) was treated with a solution of KCO (961 mg, 6.96 mmol) in water (4.6 mL), and the reaction mixture was stirred for 18 h. The reaction mixture was extracted with EtOAc from a phosphate buffer solution. The organic layer was concentrated to give (1R,2S,3R,4R,Z)-3-amino-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (IV-2a, 512 mg, 1.39 mmol, 100% yield), which was used without further purification. RT = 0.84 min; MS(ESI) m / z = 369.1 (M+H). + ; Method A

[0182] Intermediates IV-1b,c and IV-2b,c were prepared similarly from commercially available organozinc reagents.

[0183] Scheme V [ka]

[0184] Intermediate V-1: Intermediate V-1 was prepared from II-4. To a 250 mL round-bottom flask containing methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.5 mL, 20 mmol) in anhydrous DMF (50 mL), a suspension of II-4 and CuI (2.3 g, 12 mmol) in anhydrous DMF (100 mL) and HMPA (8.0 mL, 19 mmol) was added dropwise via a dropping funnel, and the reaction mixture was heated at 75 °C under an inert nitrogen atmosphere for 16 h. The cooled reaction mixture was filtered and purified by silica gel chromatography to give V-1 (3.0 g, 6.1 mmol, 77% yield). 1H NMR (500 MHz, CDCl3) δ 9.38 (br d, J = 6.1 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.46 (s, 1H), 7.24 (t, J = 9.1 Hz, 1H), 5.62 (q, J = 7.2 Hz, 1H), 4.50 (dt, J = 10.5, 5.3 Hz, 1H), 3.50 - 3.42 (m, 1H), 3.13 - 3.04 (m, 1H), 2.89 (t, J = 4.0 Hz, 1H), 2.02 - 1.90 (m, 2H), 1.76 - 1.60 (m, 2H)

[0185] Intermediate V-2: Intermediate V-2 was prepared from V-1. MeOH (1.5 mL) and acetyl chloride (2.1 mmol) were placed in a 2-dram vial and stirred at 23° C. for 5 minutes. V-1 was added to the reaction vial and the contents were heated at 40° C. for 24 hours. Concentration under a stream of nitrogen afforded V-2 as the HCl salt, which was used without further purification. LC-MS RT = 0.75 minutes; MS (ESI) m / z = 397.1 (M+H). + ; Method A

[0186] Scheme VI [ka] Scheme VI outlines how a norbornylamine core of general structure VI-1 can be coupled to a benzoic acid (VI-2) to form the respective amide. Amide formation can be achieved under a variety of amide coupling condensations, including but not limited to HATU and BOP-Cl.

[0187] Scheme VII [ka] Scheme VII shows an exemplary method for further functionalization of benzoic acid VI-1 for incorporation into a norbornyl scaffold according to Scheme VI. Starting from benzyl bromide VII-1, nucleophilic substitution using K2CO3 and a variety of nucleophiles VII-2 (NuH = alcohols, primary and secondary amines, etc.) leads to the formation of benzoates VII-3. Conversion of this ester to benzoic acids of general structure VII-4 was achieved using standard condensations depending on the nature of R (e.g., R = Me, Et, saponification with LiOH / water; R = tBu, TFA-mediated ester cleavage, R = -CH2CCl3, treatment with Zn / AcOH, etc.).

[0188] Scheme VIII [ka] Scheme VIII outlines another method for further functionalization of benzoic acid VI-1 for incorporation into a norbornyl scaffold according to Scheme 6. Starting from bromobenzene VIII-1, a Suzuki reaction is carried out with vinyl boronate VIII-2, a Pd catalyst, and base to form benzoate VIII-3. Alternatively, VIII-3 can be prepared by reversing the components in the Suzuki reaction by using a boronic acid of general structure VIII-4 and a vinyl halide of general structure VIII-5. The resulting benzoate VIII-3 can be cleaved to benzoic acid VIII-6. Alternatively, olefin VIII-3 can be further manipulated (e.g., reduction with Pd / C, H2; or cyclopropionic oxidation with a diazoester and Rh2(OAc)4), followed by ester hydrolysis, to afford benzoic acids (e.g., VIII-7 or VIII-8, among others).

[0189] Scheme IX [ka] Alternatively, Scheme IX depicts a strategy for the Pd-mediated coupling of intermediate VIII-1 to various alkynes IX-1. The resulting esters IX-2 can be directly cleaved to benzoic acids IX-3 or further elaborated, for example, by alkyne reduction followed by ester cleavage, to afford benzoic acids IX-4 (among other elaboration methods).

[0190] Scheme X [ka] Scheme X illustrates the generation of benzoic acid VI-1 for incorporation into the norbornyl scaffold via Scheme VI. Aldehyde X-1 underwent Horner-Wadsworth-Emmons olefination to give enoate X-2. Deprotection of the t-butyl ester (TFA / DCM) followed by amide formation (e.g., HATU, Hunig's base) afforded enamide X-3, which could be saponified to acid X-4. Alternatively, reduction of X-3 (e.g., Pd / C, H2) afforded X-5, which, upon saponification, afforded benzoic acid X-6.

[0191] Scheme XI [ka] Scheme XI shows a route for the preparation of sulfonamide-bearing benzoic acids VI-1 for incorporation into norbornyl scaffolds via Scheme VI. Treatment of benzoic acid XI-1 with chlorosulfonic acid afforded sulfonyl chloride XI-2. Treatment of XI-2 with an amine in the presence of TEA formed benzoic acid XI-3.

[0192] Scheme XII [ka] Scheme XII illustrates the method for the later functionalization at C-7. Vinyl bromides XII-1 (prepared from II-4 with benzoic acids of general structure IX-4 according to Scheme IX) were treated with various alkyl halides XII-2 according to the method described in MacMillan et al. (J. Am. Chem. Soc. 2016, 138, 8084-8087) to give example compounds of general structure XII-3.

[0193] Scheme XIII [ka] Alternatively, Scheme XIII outlines the generation of various aryl substitutions on salicylic acid. Aryl bromides XIII-1 (prepared from IV-2b or V-2 and commercially available 5-bromo-2-methoxybenzoic acid according to Scheme VI) were treated with various alkyl halides XIII-2 as described in MacMillan et al. (J. Am. Chem. Soc. 2016, 138, 8084-8087) to give example compounds of general structure XIII-3. [Example]

[0194] Example 1 [ka]

[0195] Intermediate 1-1: To a vial containing a solution of methyl 5-amino-2-methoxybenzoate (100 mg, 0.55 mmol) and (bromomethyl)benzene (94 mg, 0.55 mmol) in MeCN (1.1 mL), (bromomethyl)benzene (94 mg, 0.55 mmol) was added and the reaction mixture was heated at 50 °C for 5 h. The reaction mixture was partitioned into water (10 mL) and extracted with EtOAc. The combined organic portions were dried over NaSO, filtered, concentrated, and then purified by silica gel chromatography to give methyl 5-(dibenzylamino)-2-methoxybenzoate (1-1, 50 mg, 0.14 mmol, 25% yield). LC-MS RT: 1.05 min; MS (ESI) m / z 272 (M+H) + ; Method D

[0196] Intermediate 1-2: To a vial containing a solution of 1-1 (50 mg, 0.14 mmol) in THF (1.4 mL) was added 1N LiOH (450 μl, 0.45 mmol). After stirring for 36 h, the reaction mixture was acidified with 1N HCl (2 mL) and then partitioned into water (5 mL) and extracted with EtOAc. The combined organic portions were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase ISCO to give 5-(dibenzylamino)-2-methoxybenzoic acid (1-2, 44 mg, 0.13 mmol, 92% yield). LC-MS RT: 0.98 min; MS (ESI) m / z 348 (M+H) + ; Method D.

[0197] Example 1: To a vial containing a solution of IV-2a (16 mg, 0.043 mmol) in MeCN (430 μL) was added 1-2 (18 mg, 0.052 mmol), HATU (20 mg, 0.052 mmol), and DIEA (23 μL, 0.130 mmol). The reaction mixture was stirred for 18 hours at room temperature, then concentrated under reduced pressure, dissolved in DMSO, and purified by HPLC to give (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-3-(5-(dibenzylamino)-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (18 mg, 0.026 mmol, 60% yield). 1 H-NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.57 (d, J = 7.4 Hz, 1H), 8.00 - 7.95 (m, 1H), 7.50 (br d, J = 12.9 Hz, 1H), 7.23 (t, J = 9.7 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.09 - 7.04 (m, 5H), 7.02 - 6.94 (m, 7H), 6.72 (d, J = 9.0 Hz, 1H), 6.56 (dd, J = 8.7, 3.1 Hz, 1H), 4.39 (s, 4H), 4.17 - 4.08 (m, 1H), 3.62 (s, 3H), 2.85 (dd, J = 10.8, 4.1 Hz, 1H), 2.80 - 2.73 (m, 1H), 2.47 - 2.40 (m, 1H), 1.64 - 1.57 (m, 1H), 1.55 - 1.45 (m, 1H), 1.28 - 1.19 (m, 1H), 1.19 - 1.07 (m, 2H), 0.54 - 0.40 (m, 2H), 0.14 - 0.03 (m, 2H). LC-MS RT: 2.97 min; MS (ESI) m / z 698 (M+H) + ; Method A

[0198] Example 2 [ka] Intermediate 2-1: To a vial was added 5-borono-2-methoxybenzoic acid (158 mg, 0.810 mmol), aniline (50 mg, 0.54 mmol), copper(II) acetate (195 mg, 1.10 mmol), DCM (1.1 mL), and DIEA (281 μl, 1.6 mmol). The reaction mixture was stirred at room temperature for 3 days, then partitioned into 1N HCl and extracted with EtOAc (3 × 10 mL). The combined organic portions were dried over NaSO, filtered, concentrated, and then purified by reverse-phase ISCO to give 2-methoxy-5-(phenylamino)benzoic acid (2-1, 21 mg, 0.086 mmol, 16% yield) as a brown solid. LC-MS RT: 0.80 min; MS (ESI) m / z 244 (M+H) + ; Method D

[0199] Example 2: Prepared from Intermediate 2-1 and IV-2a according to the method of Example 1 to give (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(phenylamino)benzamido)bicyclo[2.2.1]heptane-2-carboxamide (8.5 mg, 0.014 mmol, 65% yield). 1H-NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.89 (d, J = 7.2 Hz, 1H), 8.23 ​​(dd, J = 6.1, 2.5 Hz, 1H), 8.01 (s, 1H), 7.80 - 7.75 (m, 1H), 7.75 - 7.71 (m, 1H), 7.53 - 7.44 (m, 1H), 7.25 - 7.16 (m, 3H), 7.11 (d, J = 9.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 4.68 (d, J = 9.7 Hz, δ 5.77 - 5.64 (m, 2H), 1.44 - 1.91 (m, 1H), 3.70 - 3.99 (m, 3H), 1.69 - 2.11 (m, 1H), 1.93 - 2.17 (m, 1H), 1.81 - 2.69 (m, 2H), 1.97 - 2.13 (m, 1H), 1.80 - 2.19 (m, 1H), 1.81 - 2.69 (m, 2H). LC-MS RT: 2.77 min; MS (ESI) m / z 594 (M+H)+; Method B

[0200] Example 4

change

[0201] Intermediate 4-1

change

[0202] Intermediate 4-2: [ka] Preparation of 5-((2-hydroxyethyl)sulfonyl)-2-methoxybenzoic acid: To a solution of intermediate 4-1 (28 mg, 0.10 mmol) in THF (1 mL) and water (0.33 mL) was added LiOH (0.15 mL, 0.30 mmol). The resulting solution was stirred at room temperature for 1 h, acidified by the addition of 1N HCl, and the solution was extracted with ethyl acetate. The combined organic portions were concentrated under reduced pressure to give 4-2 (22 mg, 79% yield), which was used without further purification. MS (ESI) m / z: 261.1 (M+H), RT = 0.70 min, Method A

[0203] The compound of Example 4 was prepared by the method described in Example 1 starting from V-2 and 4-2 to give (1R,2S,3R,4R,Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-((2-hydroxyethyl)sulfonyl)-2-methoxybenzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (4.4 mg; 12%). 1 H NMR (500MHz, DMSO-d6) δ 10.67 (s, 1H), 10.03 (d, J = 6.4 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 4.9 Hz, 1H), 8.04 - 7.96 (m, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.49 (t, J = 9.9 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.93 (m, 1H), 4.51 (br. s., 1H), 4.10 (s, 3H), 3.66 (d, J = 4.9 Hz, 1H), 3.51 - 3.36 (m, 1H), 3.31 - 3.21 (m, 2H), 2.99 (br. s., 1H), 1.98 - 1.82 (m, 2H), 1.49 (d, J = 5.5 Hz, 2H); LC-MS (M+H) = 639.08; HPLC RT = 2.24 minutes; Method B

[0204] Examples 5 and 6 [ka]

[0205] Intermediate 5-1 [ka] A solution of methyl 5-formyl-2-methoxybenzoate (0.500 g, 2.57 mmol), (trifluoromethyl)trimethylsilane (0.62 mL, 3.86 mmol) in THF (7.8 mL) was treated with TBAF (7 mg, 0.03 mmol) at 0 °C. The solution was warmed to rt over 18 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give methyl 2-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (5-1, 650 mg, 2.46 mmol, 96.0% yield). 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 8.8, 2.4 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 5.04 (d, J = 6.6 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 2.67 (br s, 1H)

[0206] Intermediate 5-2 [ka] Intermediate 5-2 was prepared from 5-1 by the method used for intermediate 4-2. LC-MS (M+H) = 251.0; HPLC RT = 0.64 min; Method A

[0207] The compounds of Examples 5 and 6 were prepared starting from V-2 by the method described in Example 1 to give (2S,3R,7Z)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)benzamido]-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide as a racemate. The enantiomers were separated using the following conditions: Column: Chiral AD, 30 x 250 mm, 5 microns; Flow rate: 100 mL / min; Oven temperature: 40 °C; BPR setting: 120 bar; UV wavelength: 220 nm; Mobile phase: 85% CO / 15% IPA w / 0.1% DEA (isocratic).

[0208] Example 5, ピーク1 (>95%de, 4.8mg, 48% yield), RT = 6.2 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.95 (d, J = 7.1 Hz, 1H), 8.24 (dd, J = 6.4, 2.5 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.61 (dd, J = 8.6, 2.1 Hz, 1H), 7.51 (t, J = 9.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 5.94 (q, J = 7.9 Hz, 1H), 5.24 - 5.12 (m, 1H), 4.57 - 4.50 (m, 1H), 4.02 (s, 3H), 3.58 - 3.41 (m, 1H), 3.33 - 3.20 (m, 2H), 2.99 (br s, 1H), 2.01 - 1.82 (m, 2H), 1.57 - 1.43 (m, 2H). LC-MS (M+H) = 629.31; HPLC RT = 2.48 min; Method C

[0209] Example 6, Potato 2 (>95% de, 5.2 mg, 52% yield), RT = 11.8 minutes. 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.93 (d, J = 7.0 Hz, 1H), 8.24 (dd, J = 6.3, 2.3 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.62 (dd, J = 8.7, 2.0 Hz, 1H), 7.50 (t, J = 9.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.02 - 5.88 (m, 1H), 5.25 - 5.13 (m, 1H), 4.61 - 4.50 (m, 1H), 4.02 (s, 3H), 3.24 (br s, 1H), 2.99 (br s, 1H), 2.90 (s, 1H), 2.74 (s, 1H), 1.98 (br t, J = 9.6 Hz, 1H), 1.92 - 1.83 (m, 1H), 1.50 (br d, J = 6.7 Hz, 2H). LC-MS (M+H) = 629.31; HPLC RT = 2.49 min; Method C

[0210] Example 7 [ka] A mixture of 5 and 6 (40 mg, 0.064 mmol), DCM (1 mL), pyridine (0.05 mL, 0.6 mmol), 4-nitrophenyl chloroformate (64 mg, 0.31 mmol), and DMAP (7 mg, 0.06 mmol) was added to a flask and stirred for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse-phase HPLC. The diastereomers were separated using the following conditions: Column: Chiral AD, 30 × 250 mm, 5 micron; Flow rate: 100 mL / min; Oven temperature: 40 °C; BPR setting: 120 bar; UV wavelength: 220 nm; Mobile phase: 90% CO₂ / 10% IPAw / 0.1% DEA (isocratic). Peak 1, RT = 8.4 min (2.7 mg, 5.3% yield, >95% de)

[0211] Example 7, Peak 2, RT = 11.4 min (1.2 mg, 2.4% yield, >95% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.73 - 10.62 (m, 1H), 9.97 (d, J = 7.0 Hz, 1H), 8.37 (d, J = 6.7 Hz, 1H), 8.24 (dd, J = 6.3, 2.3 Hz, 1H), 8.13 (d, J = 1.5 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.72 - 7.62 (m, 1H), 7.51 (t, J = 9.8 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.34 - 6.25 (m, 1H), 5.95 (q, J = 7.8 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.04 (s, 3H), 3.91 (s, 2H), 3.00 (br d, J = 2.7 Hz, 1H), 2.86 (td, J = 14.0, 8.2 Hz, 2H), 2.68 - 2.57 (m, 2H), 2.01 - 1.86 (m, 3H), 1.58 - 1.42 (m, 2H). LC-MS (M+H) = 762.3; HPLC RT = 2.61 min; Method C

[0212] Example 8 [ka]

[0213] Intermediate 8-1 [ka] Intermediate 8-1 was prepared in quantitative yield from the corresponding known methyl ester by the method used for 4-2 (material used without purification). LC-MS (M+H) = 279.2; HPLC RT = 0.86 min; Method A

[0214] Intermediate 8-2 [ka] Intermediate 8-2 was prepared from 8-1 and V-2 by the method of Example 1. LC-MS (M+H) = 657.36; HPLC RT = 2.88 min; Method C A solution of 8-2 (20 mg, 0.030 mmol) in DCM (0.3 mL) was treated with TFA (0.3 mL). After 30 min, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give (E)-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)acrylic acid (17 mg, 0.028 mmol, 92% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.91 (d, J = 7.0 Hz, 1H), 8.22 (dd, J = 6.1, 2.1 Hz, 1H), 8.14 (br s, 1H), 7.86 (br d, J = 8.9 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.61 - 7.46 (m, 2H), 7.24 (d, J = 8.9 Hz, 1H), 6.40 (br d, J = 16.5 Hz, 1H), 5.99 - 5.90 (m, 1H), 4.58 - 4.47 (m, 1H), 4.04 (s, 3H), 3.60 - 3.43 (m, 1H), 3.35 - 3.22 (m, 1H), 3.00 (br s, 1H), 2.02 - 1.85 (m, 2H), 1.50 (br d, J = 7.0 Hz, 2H). LC-MS (M+H) = 601.05; HPLC RT = 1.94 minutes; Method C

[0215] Example 9 [ka]

[0216] Intermediate 9-1 [ka] A solution of methyl (E)-5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-methoxybenzoate (0.108 g, 0.369 mmol) in ethanol (1.23 mL) was treated with Pd—C (10 wt%, 0.039 g, 0.37 mmol). The slurry was placed under a H atmosphere (balloon pressure) and stirred for 18 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give methyl 5-(3-(tert-butoxy)-3-oxopropyl)-2-methoxybenzoate (0.109 g, 0.369 mmol, 100% yield), which was used without further purification. LC-MS (M+H-tBu) = 233.9; HPLC RT = 0.95 min; Method A

[0217] Example 9 was prepared using the method of Example 8 with 9-1 to give 3-(3-{[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-4-methoxyphenyl)propanoic acid (39 mg, 65%). 1 H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.95 - 9.82 (m, 1H), 8.23 ​​(br d, J = 4.0 Hz, 1H), 7.79 (br s, 2H), 7.54 - 7.45 (m, 1H), 7.36 (br d, J = 7.9 Hz, 1H), 7.10 (br d, J = 8.5 Hz, 1H), 5.93 (br d, J = 7.9 Hz, 1H), 4.52 (br s, 1H), 3.97 (s, 3H), 3.39 - 3.17 (m, 1H), 2.98 (br s, 1H), 2.79 (br s, 2H), 2.51 (br s, 3H), 2.10 - 1.84 (m, 2H), 1.49 (br d, J = 6.4 Hz, 2H). LC-MS (M+H) = 603.13; HPLC RT = 1.97 min; Method C

[0218] Example 10 [ka] The compound of Example 10 was prepared using the method of Example 1 with V-2 and 5-formyl-2-methoxybenzoic acid. After the amide formation reaction was complete, the solution was diluted with MeOH and treated with excess NaBH4. After 18 hours, the reaction mixture was extracted with EtOAc from water. The organic layer was concentrated under reduced pressure, and the residue was purified by preparative reverse-phase HPLC to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(hydroxymethyl)-2-methoxybenzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (1.7 mg, 3.1%). 1 H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.90 (d, J = 6.9 Hz, 1H), 8.25 (dd, J = 6.2, 2.1 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.51 (t, J = 9.8 Hz, 1H), 7.44 (dd, J = 8.4, 2.0 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 5.95 (d, J = 7.8 Hz, 1H), 4.53 (br t, J = 4.0 Hz, 1H), 4.45 (br d, J = 4.7 Hz, 1H), 3.99 (s, 3H), 3.51 - 3.37 (m, 2H), 3.23 (br s, 1H), 3.00 (s, 2H), 2.05 - 1.82 (m, 2H), 1.49 (br d, J = 6.0 Hz, 2H). LC-MS (M+H) = 560.99; HPLC RT = 2.26 min; Method C

[0219] Example 11 [ka]

[0220] Intermediate 11-1 [ka] A slurry of methyl 4-bromo-2-(methylamino)benzoate (250 mg, 1.02 mmol), propargyl alcohol (80 μL, 1.3 mmol), palladium tetrakis (23 mg, 0.020 mmol), and copper(I) iodide (1.9 mg, 10 μmol) in TEA (3 mL) was degassed and heated at 80° C. under a N atmosphere for 18 h. The reaction mixture was quenched by the addition of water, and the solution was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 11-1 (82 mg, 0.35 mmol, 34% yield). MS (ESI) m / z: 220.2 (M+H)

[0221] Intermediate 11-2 [ka] A solution of 11-1 (80 mg, 0.36 mmol) in EtOH (1.2 mL) was treated with Pd—C (38 mg, 0.036 mmol) and hydrogenated at 55 PSI for 18 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 11-2 (81 mg, 0.36 mmol, 100% yield). MS (ESI) m / z: 220.2 (M+H).

[0222] Intermediate 11-3 [ka] To a solution of 11-2 (13 mg, 0.060 mmol) in THF (1 mL) and water (0.33 mL) was added LiOH (0.091 mL, 0.18 mmol). The solution was stirred at room temperature for 1 h, acidified using 1N HCl, and then extracted with EtOAc. The organic layer was concentrated under reduced pressure and used in the next step without further purification as 11-3 (12.6 mg, 0.06 mmol, 100% yield). MS (ESI) m / z: 210.3 (M+H)

[0223] Example 11 was prepared in a manner similar to Example 1 using Intermediate 11-3 to give (1R,2S,3R,4R,Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-hydroxypropyl)-2-(methylamino)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide, Example 11 (2.8 mg, 4.5 mmol, 4.6% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.68 (s, 1H), 9.04 (br. s., 1H), 8.12 (d, J = 3.7 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.46 (t, J = 9.8 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.89 (q, J = 7.8 Hz, 1H), 4.38 (br. s., 1H), 3.64 (br. s., 2H), 3.41 - 3.33 (m, 2H), 3.24 (dd, J = 10.8, 3.8 Hz, 1H), 3.16 (br. s., 1H), 2.97 (br. s., 1H), 2.70 (d, J = 4.3 Hz, 3H), 2.48 - 2.41 (m, 2H), 1.88 (d, J = 7.9 Hz, 2H), 1.67 - 1.58 (m, 2H), 1.48 (d, J = 7.9 Hz, 2H); LC-MS (M+H) = 588.17; HPLC RT = 2.39 min; Method B

[0224] Example 12 [ka] Intermediate 12-1: To a vial containing a solution of methyl 5-(bromomethyl)-2-methoxybenzoate (100 mg, 0.39 mmol) and tert-butyl 3-hydroxybenzoate (12-2, 90 mg, 0.46 mmol) in MeCN (0.77 mL), CsCO (377 mg, 1.20 mmol) was added, and the reaction mixture was heated at 50 °C for 5 h. The reaction mixture was partitioned with water and extracted with EtOAc. The combined organic portions were dried over NaSO, filtered, concentrated under reduced pressure, and then purified by silica gel chromatography to give methyl 5-((3-(tert-butoxycarbonyl)phenoxy)methyl)-2-methoxybenzoate (12-1, 120 mg, 0.31 mmol, 80% yield) as a clear oil. 1 H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 2.3 Hz, 1H), 7.62 - 7.59 (m, 2H), 7.56 (dd, J = 8.5, 2.4 Hz, 1H), 7.37 - 7.30 (m, 1H), 7.13 (ddd, J = LC-MS RT; Method D

[0225] Intermediate 12-3: To a vial containing a THF solution of 12-1 (55 mg, 0.15 mmol) was added 1N LiOH (480 μl, 0.16 mmol). After stirring for 36 h at room temperature, the reaction mixture was acidified by the addition of 1N HCl (2 mL), partitioned into water, and the resulting solution was extracted with EtOAc. The combined organic portions were dried over NaSO, filtered, and concentrated to give 5-((3-(tert-butoxycarbonyl)phenoxy)methyl)-2-methoxybenzoic acid (12-3, 53 mg, 0.15 mmol, 100% yield), which was used without further purification. LC-MS RT: 0.98 min; MS(ESI) m / z; Method D

[0226] Example 12: To a vial containing a solution of IV-2a (8.0 mg, 0.022 mmol) in MeCN (0.22 mL) was added 12-3 (9.3 mg, 0.026 mmol), HATU (9.9 mg, 0.026 mmol), and DIEA (11 μL, 0.065 mmol). The reaction mixture was stirred for 18 h at room temperature, concentrated under reduced pressure, and the residue was dissolved in 1:1 TFA / DCM. After stirring for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO and purified by HPLC to give 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-methoxybenzyl)oxy)benzoic acid (7.2 mg, 10 μmol, 48% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.88 (br d, J = 7.0 Hz, 1H), 8.20 (dd, J = 6.3, 1.7 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.58 (dd, J = 8.7, 1.4 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 7.9, 1.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 5.12 (s, 2H), 4.68 (d, J = 9.5 Hz, 1H), 4.47 - 4.39 (m, 1H), 3.99 (s, 2H), 3.14 (dd, J = 10.7, 4.0 Hz, 1H), 3.11 - 3.05 (m, 1H), 2.74 - 2.67 (m, 1H), 1.88 - 1.81 (m, 1H), 1.80 - 1.74 (m, 1H), 1.54 - 1.45 (m, 1H), 1.45 - 1.32 (m, 2H), 0.80 - 0.63 (m, 2H), 0.41 - 0.25 (m, 2H).LC-MS RT: 2.58 min; MS (ESI) m / z 653 (M+H) + ; Method A

[0227] The compounds of Examples 13 and 15-30 (Table 2) were prepared following the method described above for Example 12, using the appropriate nucleophile in place of 12-2 and the appropriate norbornylamine in place of IV-2a.

[0228] Example 14 [ka] Intermediate 14-1: tert-butyl 5-formyl-2-methoxybenzoate N,N-Dimethylformamide-di-tert-butyl acetate (500 mg, 2.46 mmol) was added dropwise to a solution of 5-formyl-2-methoxybenzoic acid (1.57 mL, 7.38 mmol) in toluene (7.5 mL) at 80 °C. The reaction mixture was heated at 80 °C for 16 h, then diluted with water (10 mL) and extracted with EtO (3 × 10 mL). The combined organic phase was washed with brine (30 mL), dried over MgSO, filtered, and concentrated under reduced pressure to give 14-1 (513 mg, 88%) as a pale yellow solid. This material was used in the next step without further purification. 1 H NMR (500 MHz, CDCl3) δ 9.94 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.8, 2.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.01 (s, 3H), 1.63 (s, 9H)

[0229] Intermediate 14-2: tert-butyl 5-(hydroxymethyl)-2-methoxybenzoate Intermediate 14-1 (513 mg, 2.171 mmol) was dissolved in EtOH (13 mL) and treated with NaBH (82 mg, 2.17 mmol). The reaction mixture was stirred at rt for 1 h, treated with water (10 mL), and concentrated under reduced pressure. The residue was purified by ISCO (0-100% EtOAc / Hex) to give Intermediate 14-2 (470 mg, 91%) as a clear oil. MS m / z = 239.08 (M+H). 1 H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 2.2 Hz, 1H), 7.47 (dd, J = 8.5, 2.5 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H), 3.92 (s, 3H), 1.62 (s, 9H)

[0230] Intermediate 14-3: tert-butyl 5-(bromomethyl)-2-methoxybenzoate To a solution of intermediate 14-2 (470 mg, 1.97 mmol) in DCM (10 mL) were added triphenylphosphane (776 mg, 2.96 mmol) and CBr (981 mg, 2.96 mmol). After 2 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give intermediate 14-3 (370 mg, 62%) as a white solid. MS m / z = 304.3 (M+H). 1 H NMR (500 MHz, CDCl3) δ 7.80 - 7.70 (m, 1H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.51 (s, 2H), 3.92 (s, 3H), 1.62 (s, 9H)

[0231] Intermediate 14-4: tert-butyl 2-methoxy-5-((1-(methoxycarbonyl)cyclopropoxy)methyl)benzoate To a solution of methyl 1-hydroxycyclopropane-1-carboxylate (100 mg, 0.86 mmol) and tetrabutylammonium iodide (31 mg, 0.086 mmol) in dry THF (16 mL) was added NaH (60 wt%, 37 mg, 0.94 mmol) portionwise at 0 °C. The reaction mixture was warmed to rt and stirred for an additional 15 min, then treated with Intermediate 14-3. After 3 h, the solvent was removed under reduced pressure, the residue was dissolved in 25 mL of ether, and the solution was washed with water. The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give Intermediate 14-4 (96 mg, 33%) as an oil. MS m / z = 337.08 (M+H)

[0232] Intermediate 14-5: tert-butyl 5-((1-(hydroxymethyl)cyclopropoxy)methyl)-2-methoxybenzoate A solution of intermediate 14-4 (95 mg, 0.282 mmol) in THF (2.0 mL) and water (0.667 mL) was treated with LiOH (0.282 mL, 0.282 mmol). The clear, colorless solution was stirred at rt for 24 h. The reaction mixture was acidified with HCl (1.0 M) to pH 1, and the solution was then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a clear oil, which was dissolved in THF (1.0 ml) and treated with borane (1 M in THF, 0.25 ml, 0.25 mmol). After 16 h, the reaction mixture was diluted with EtOAc, quenched by the addition of HCl (1.0 M, 10 mL), and stirred at rt for an additional 1 h. The layers were separated, and the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give a colorless oil, which was purified by silica gel chromatography to give intermediate 14-5 (38 mg, 42%) as a clear oil. MS m / z = 309.08 (M+H). 1 H NMR (500 MHz, chloroform-d) δ 7.71 - 7.62 (m, 1H), 7.41 (dd, J = 8.5, 2.2 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.57 (s, 2H), 3.90 (s, 3H), 3.74 (s, 2H), 1.61 (s, 9H), 1.02 - 0.92 (m, 2H), 0.71 - 0.61 (m, 2H)

[0233] Example 14: (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((1-(hydroxymethyl)cyclopropoxy)methyl)-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide Intermediate 14-5 (25 mg, 0.081 mmol) was combined with DCM (1 mL) and treated with TFA (0.3 mL). After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in EtOAc, and the solution was washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give a white powder, which was dissolved in DMF (1.0 mL) and treated with Intermediate IV-2a (29 mg, 0.080 mmol), HATU (36.0 mg, 0.100 mmol), and DIEA (42.5 μl, 0.240 mmol). After 18 h, the reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC to give Example 14 (13 mg, 26%) as a clear oil. LCMS RT = 2.5 min, Method B, m / z = 603.9 (M+H).

[0234] Example 31 [ka] [ka] Intermediate 31-1: To a reaction vessel containing methyl 5-bromo-2-methoxybenzoate (148 mg, 0.606 mmol), (E)-2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.51 mmol), PdCl(dppf)-CHCl adduct (82 mg, 0.10 mmol), and NaCO (1.0 mL, 2.0 mmol) were added. The reaction mixture was degassed by bubbling nitrogen through for 2 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 NaSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give 31-1 (83 mg, 0.35 mmol, 70% yield). LC-MS RT = 0.84 min; MS (ESI) m / z = 237.0 (M+H) + ; Method A

[0235] Intermediate 31-2: To a reaction vessel were added 31-1 (40 mg, 0.17 mmol), THF (1 mL), water (0.5 mL), and LiOH monohydrate (35 mg, 0.85 mmol). The reaction mixture was stirred at 23 °C for 1 h, diluted with EtOAc (10 mL), and washed with saturated NH Cl containing 1.5 mmol HCl. The organic phase was dried over Na SO , filtered, and concentrated to give 31-2 (37 mg, 0.17 mmol, 98% yield), which was used without further purification. LC-MS RT = 0.69 min; MS (ESI) m / z = 220.9 (M+H). + ; Method D

[0236] The compound of Example 31 was prepared from 31-1 and I-7 using the general method used in Example 1. (2S,3R)—N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-{2-methoxy-5-[(1E)-3-methoxyprop-1-en-1-yl]benzamido}-7-(propan-2-ylidene)bicyclo[2.2.1]heptane-2-carboxamide (9.8 mg, 62%). 1H NMR (500 MHz, CDCl3) δ 9.23 (br d, J = 7.9 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.85 (dd, J = 6.3, 2.6 Hz, 1H), 7.57 (dt, J = 8.7, 3.5 Hz, 1H), 7.47 (dd, J = 8.5, 2.4 Hz, 1H), 7.05 (t, J = 9.4 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.57 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 15.9, 6.0 Hz, 1H), 4.73 (td, J = 9.2, 4.3 Hz, 1H), 4.09 (dd, J = 6.1, 1.2 Hz, 2H), 3.97 (s, 3H), 3.39 (s, 3H), 3.08 - 2.98 (m, 3H), 2.22 - 2.12 (m, 1H), 1.81 - 1.74 (m, 1H), 1.73 (s, 3H), 1.72 (s, 3H), 1.64 - 1.53 (m, 2H). LC-MS RT = 1.23 min; MS (ESI) m / z = 651.2 (M+H) + ; Method B

[0237] Example 32 [ka] [ka] Intermediate 32-1 was prepared in the same manner as intermediate 31-1 from methyl 5-bromo-2-methoxybenzoate and (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane. (132 mg, 0.380 mmol, 98% yield). LC-MS RT = 1.28 min; MS (ESI) m / z = 351.1 (M+H). + ; Method A

[0238] Intermediate 32-2 was prepared from 32-1 in the same manner as intermediate 31-2 (56 mg, 0.17 mmol, 97% yield). LC-MS RT = 1.18 min; MS (ESI) m / z = 337.0 (M+H). + ; Method A

[0239] Intermediate 32-3: Intermediate 32-3 was prepared from 32-2 in the same manner as the compound of Example 31 (8.8 mg, 0.01 mmol, 47% yield). LC-MS RT = 1.43 min; MS (ESI) m / z = 675.1 (M+H). + ; Method A

[0240] Procedure for Example 32: To a reaction vessel was added 32-3 (8.8 mg, 0.010 mmol), AcOH (1 mL), and HO (0.1 mL). After stirring at 23 °C for 12 h, the reaction mixture was concentrated under reduced pressure and purified by preparative RP-HPLC to give Example 32 (1.9 mg, 3.25 μmol, 25% yield). 1 H NMR (500 MHz, CDCl3) δ 9.23 (br d, J = 7.6 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.12 (br s, 1H), 7.83 (dd, J = 6.1, 2.4 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.41 (dd, J = 8.5, 2.3 Hz, 1H), 7.05 (t, J = 9.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.21 - 6.08 (m, 1H), 4.77 - 4.68 (m, 1H), 3.97 (s, 3H), 3.80 - 3.69 (m, 2H), 3.09 - 2.97 (m, 3H), 2.49 (q, J = 6.6 Hz, 2H), 2.22 - 2.12 (m, 1H), 1.81 - 1.74 (m, 1H), 1.73 (s, 3H), 1.71 (s, 3H), 1.62 - 1.58 (m, 2H). LC-MS RT: 1.17 min; MS (ESI) m / z = 561.3 (M+H)+; Method B

[0241] Example 33 [ka] To a reaction vessel was added the compound from Example 32 (5 mg, 8.92 μmol), DCM (1 mL), DIEA (0.05 mL, 0.27 mmol), and methyl chloroformate (0.014 mL, 0.18 mmol). After stirring at rt for 30 minutes, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give (E)-4-(3-(((1R,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(propan-2-ylidene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenyl)but-3-en-1-yl methyl carbonate (2.4 mg, 3.6 μmol, 41% yield). 1 H NMR (500 MHz, CDCl3) δ 9.21 (br d, J = 7.6 Hz, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 7.84 (dd, J = 6.3, 2.6 Hz, 1H), 7.58 (dt, J = 8.9, 3.4 Hz, 1H), 7.41 (dd, J = 8.6, 2.3 Hz, 1H), 7.05 (t, J = 9.4 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 6.21 - 6.07 (m, 1H), 4.80 - 4.68 (m, 1H), 4.25 (t, J = 6.7 Hz, 2H), 3.97 (s, 3H), 3.78 (s, 3H), 3.11 - 2.96 (m, 3H), 2.61 - 2.55 (m, 2H), 2.22 - 2.14 (m, 1H), 1.81 - 1.74 (m, 1H), 1.73 (s, 3H), 1.72 (s, 3H), 1.64 - 1.59 (m, 2H). LC-MS RT: 1.24 min; MS (ESI) m / z = 619.3 (M+H)+; Method B

[0242] Example 34 [ka]

[0243] Intermediate 34-1 [ka] A solution of 5-borono-2-methoxybenzoic acid (1.00 g, 5.10 mmol), 3-chlorocyclohex-2-en-1-one (0.666 g, 5.10 mmol), and Pd(PhP) (0.295 g, 0.255 mmol) in dioxane (25 mL) was degassed and treated with 1 M aqueous NaCO (15.31 mL, 15.31 mmol). The reaction mixture was heated at 100 °C for 18 h, cooled, and extracted with EtOAc from water. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 4-methoxy-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxylic acid (701 mg, 2.85 mmol, 55.0% yield). LC-MS RT: 0.90 min; MS (ESI) m / z = 246.8 (M+H)+; Method A

[0244] The compound of Example 34 was prepared from V-2 and 34-1 by the general method used in Example 1. (7.2 mg, 72% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.95 (d, J = 6.8 Hz, 1H), 8.27 - 8.17 (m, 2H), 7.87 (dd, J = 8.7, 2.5 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.50 (t, J = 9.7 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.32 (s, 1H), 5.94 (d, J = 7.7 Hz, 1H), 4.58 - 4.46 (m, 1H), 4.05 (s, 3H), 3.24 (br s, 1H), 2.99 (br s, MS (ESI) m / z = 625.3 (M+H)+; Method C

[0245] Examples 35 to 38 [ka]

[0246] Intermediate 35-1 [ka] A solution of 34-1 (100 mg, 0.406 mmol) in EtOH (4 mL) was treated with PtO (9.2 mg, 0.041 mmol) at rt, and the reaction mixture was hydrogenated (50 psi) for 18 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 2-methoxy-5-(3-oxocyclohexyl)benzoic acid (35-1, 101 mg, 0.406 mmol, 100% yield). LC-MS RT: 0.99 min; MS (ESI) m / z = 250.9 (M+H)+; Method A

[0247] Example 35 was prepared from V-2 and 35-1 by the general method used in Example 1 to give (2S,3R,7Z)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[5-(3-hydroxycyclohexyl)-2-methoxybenzamido]-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide as a mixture of four isomers. The isomers were separated to give Examples 35-38 under the following conditions: Apparatus: Agilent analytical LC, Column: IG SFC 30 × 250 mm ID, 5 μm, Flow rate: 85 mL / min, Mobile phase: 85 / 15 CO2 / (IPA), Detector wavelength: 220 nm.

[0248] Example 35, Peak 1, RT = 25 min (> 95%de, 23 mg, 20% yield). 1 H NMR (400 MHz, CD3OD) δ 10.22 (br d, J = 7.0 Hz, 1H), 8.17 (dd, J = 6.3, 2.3 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.77 (dt, J = 8.5, 3.4 Hz, 1H), 7.39 (dd, J = 8.5, 2.3 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 5.77 (q, J = 7.6 Hz, 1H), 4.73 - 4.60 (m, 1H), 4.06 (s, 3H), 3.75 - 3.58 (m, 1H), 3.41 (br s, 1H), 3.26 (dd, J = 10.8, 4.2 Hz, 1H), 2.95 (br s, 1H), 2.64 - 2.50 (m, 1H), 2.26 - 2.19 (m, 1H), 2.13 - 1.97 (m, 3H), 1.94 - 1.75 (m, 2H), 1.68 - 1.57 (m, 2H), 1.54 - 1.24 (m, 6H). LC-MS RT: 1.41 min; MS (ESI) m / z = 629.4 (M+H)+; Method A

[0249] Example 36, Potato 2, RT = 31 minutes (> 95% de, 19 mg, 17% yield). 1 H NMR (400 MHz, CD3OD) δ 10.31 - 10.15 (m, 1H), 8.17 (dd, J = 6.3, 2.5 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.77 (dt, J = 8.6, 3.5 Hz, 1H), 7.46 - 7.25 (m, 2H), 7.10 (d, J = 8.6 Hz, 1H), 5.78 (q, J = 7.7 Hz, 1H), 4.71 - 4.58 (m, 1H), 4.20 - 4.14 (m, 1H), 4.06 (s, 3H), 3.41 (br s, 1H), 3.26 (dd, J = 10.8, 4.2 Hz, 1H), 3.11 - 2.90 (m, 2H), 2.28 - 2.01 (m, 2H), 1.97 - 1.75 (m, 5H), 1.73 - 1.40 (m, 7H). LC-MS RT: 1.40 min; MS (ESI) m / z = 629.4 (M+H)+; Method A

[0250] Example 37, Potato 3, RT = 46.5 minutes (> 95% de, 20 mg, 18% yield). 1H NMR (400 MHz, CD3OD) δ 10.22 (br d, J = 7.3 Hz, 1H), 8.17 (dd, J = 6.3, 2.5 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.77 (dt, J = 8.5, 3.5 Hz, 1H), 7.40 (dd, J = 8.6, 2.4 Hz, 1H), 7.31 (t, J = 9.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 5.83 - 5.72 (m, 1H), 4.68 (td, J = 7.2, 3.5 Hz, 1H), 4.21 - 4.12 (m, 1H), 4.06 (s, 3H), 3.41 (br s, 1H), 3.26 (dd, J = 10.8, 4.2 Hz, 1H), 3.15 - 2.90 (m, 3H), 2.33 - 2.15 (m, 2H), 2.11 - 1.99 (m, 2H), 1.96 - 1.83 (m, 4H), 1.75 - 1.63 (m, 4H), 1.49 (br d, J = 8.6 Hz, 1H). LC-MS RT: 1.40 min; MS (ESI) m / z 629.4 (M+H)+; Method A

[0251] Example 38, Biotech 4, RT = 51 minutes (> 95% de, 20 mg, 18% yield). 1H NMR (400 MHz, CD3OD) δ 10.23 (br d, J = 7.0 Hz, 1H), 8.17 (dd, J = 6.4, 2.4 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.77 (dt, J = 8.5, 3.6 Hz, 1H), 7.39 (dd, J = 8.6, 2.4 Hz, 1H), 7.31 (t, J = 9.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 5.77 (q, J = 7.7 Hz, 1H), 4.67 (dt, J = 7.2, 3.5 Hz, 1H), 4.07 (s, 3H), 3.67 (br t, J = 4.2 Hz, 1H), 3.41 (br s, 1H), 3.25 (dd, J = 10.8, 4.2 Hz, 1H), 2.95 (br s, 1H), 2.69 - 2.54 (m, 1H), 2.28 - 2.18 (m, LC-MS RT: 1.39 min; MS (ESI) m / z = 629.4 (M+H)+; Method A

[0252] Example 39 [ka] (2S,3R,7Z)-3-(5-cyclohexyl-2-methoxybenzamido)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide, the compound of Example 39 (20 mg, 18%), was isolated as an over-reduction by-product of the synthesis of Examples 35-38. 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.84 (d, J = 7.0 Hz, 1H), 8.23 ​​(dd, J = 6.4, 2.4 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.50 (t, J = 9.6 Hz, 1H), 7.34 (dd, J = 8.5, 2.1 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.94 (q, J = 7.7 Hz, 1H), 4.52 (br d, J = 4.3 Hz, 1H), 3.96 (s, 3H), 3.22 (br s, 1H), 2.98 (br s, 1H), 2.51 - 2.39 (m, 2H), 2.06 - 1.84 (m, 2H), 1.81 - 1.65 (m, 5H), 1.49 (br d, J = 7.3 Hz, 2H), 1.40 - 1.29 (m, 4H), 1.26 - 1.16 (m, 1H). LC-MS RT: 3.00 min; MS (ESI) m / z = 613.07 (M+H)+; Method C

[0253] Examples 40 to 43 [ka] A solution of the compound of Example 35 (153 mg, 0.243 mmol) before resolution in DCM (4.8 mL) was treated with phenyl isocyanate (0.05, 0.4 mmol), and the reaction mixture was stirred for 18 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC. The resulting isomeric mixture was resolved using the following conditions: Apparatus: Waters 100 Prep SFC Column: Chiral OD 30 x 250 mm, 5 micron, Mobile phase: 80% CO2 / 20% MeOH with 0.1% DEA, Flow conditions: 100 mL / min, Detector wavelength: 220 nm

[0254] Example 40, Peak 1, RT = 15.2 min (> 95% de, 9.2 mg, 5.0% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.69 - 10.57 (m, 1H), 9.89 (br d, J = 7.0 Hz, 1H), 9.57 (br s, 1H), 8.31 - 8.19 (m, 1H), 7.92 - 7.73 (m, 2H), 7.54 - 7.45 (m, 3H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.28 (t, J = 7.9 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 5.94 (q, J = 7.9 Hz, 1H), 5.05 (br s, 1H), 4.62 - 4.46 (m, 1H), 3.98 (s, 3H), 3.32 - 3.21 (m, 1H), 3.01 (s, 1H), 3.00 - 2.87 (m, 2H), 2.07 - 1.86 (m, 4H), 1.86 - 1.69 (m, 3H), 1.65 (br dd, J = 11.1, 3.2 Hz, 1H), 1.62 - 1.36 (m, 4H). LC-MS RT: 2.88 min; MS (ESI) m / z = 748.11 (M+H)+; Method C

[0255] Example 41, Potato 2, RT = 18.1 minutes (> 95% de, 26 mg, 14% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.88 (d, J = 7.0 Hz, 1H), 9.56 (br s, 1H), 8.23 ​​(dd, J = 6.6, 2.3 Hz, 1H), 7.85 - 7.74 (m, 2H), 7.56 - 7.47 (m, 3H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 5.94 (q, J = 8.1 Hz, 1H), 5.05 (br s, 1H), 4.55 - 4.46 (m, 1H), 3.98 (s, 3H), 3.23 (br d, J = 1.2 Hz, 1H), 3.04 - 2.88 (m, 2H), 2.07 - 1.86 (m, 4H), 1.85 - 1.54 (m, 6H), 1.55 - 1.38 (m, 3H). LC-MS RT: 2.88 min; MS (ESI) m / z = 747.89 (M+H)+; Method C.

[0256] Example 42, Potato 3, RT = 24.5 minutes (> 95% de, 26 mg, 14% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.87 (d, J = 7.1 Hz, 1H), 9.62 - 9.48 (m, 1H), 8.21 (br d, J = 6.1 Hz, 1H), 7.81 (s, 2H), 7.53 - 7.39 (m, 4H), 7.26 (t, J = 7.9 Hz, 2H), 7.11 (d, J = 8.7 Hz, 1H), 6.97 (s, 1H), 5.92 (q, J = 7.8 Hz, 1H), 4.78 - 4.67 (m, 1H), 4.52 (br d, J = 3.0 Hz, 1H), 3.96 (s, 3H), 3.34 - 3.13 (m, 2H), 2.97 (br s, 1H), 2.75 - 2.63 (m, 1H), 2.16 - 2.04 (m, 2H), 2.02 - 1.95 (m, 1H), 1.91 - 1.80 (m, 2H), 1.77 - 1.69 (m, 1H), 1.54 - 1.44 (m, 4H), 1.41 - 1.27 (m, 2H). LC-MS RT: 2.87 min; MS (ESI) m / z 748.29 (M+H)+; Method C

[0257] Example 43, Potato 4, RT = 32.1 minutes (> 95% de, 24 mg, 13% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.70 - 10.61 (m, 1H), 9.87 (br d, J = 7.2 Hz, 1H), 9.55 (br s, 1H), 8.28 - 8.17 (m, 1H), 7.85 - 7.66 (m, 2H), 7.52 - 7.33 (m, 5H), 7.25 (t, J = 7.9 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 7.01 - 6.91 (m, 1H), 5.95 - 5.84 (m, 1H), 4.81 - 4.69 (m, 1H), 4.58 - 4.47 (m, 1H), 3.96 (s, 3H), 3.30 - 3.15 (m, 2H), 2.97 (br s, 1H), 2.75 - 2.63 (m, 1H), 2.13 - 2.03 (m, 2H), 1.89 - 1.82 (m, 2H), 1.77 - 1.64 (m, 1H), 1.55 - 1.44 (m, 4H), 1.41 - 1.24 (m, 2H). LC-MS RT: 2.87 min; MS (ESI) m / z = 748.10 (M+H)+; Method C

[0258] Examples 44 to 46 [ka] The compounds of Examples 44-46 were prepared as a mixture of four diastereomers in the same manner as used to produce Examples 35-38, substituting 3-chlorocyclopent-2-en-3-one as the starting material. The isomers were resolved as follows: Agilent analytical LC, IG SFC 30 x 250 mm, 5 micron, 85 mL / min, 90 / 10 CO2 / EtOH, detector wavelength: 220 nm.

[0259] Example 44, Peak 1, RT = 11.0 min (> 95% de, 5.0 mg, 5.0% yield). 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J = 6.3, 2.8 Hz, 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.77 (dt, J = 8.9, 3.5 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.31 (t, J = 9.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 5.78 (q, J = 7.5 Hz, 1H), 4.70 - 4.62 (m, 1H), 4.07 (s, 2H), 3.41 (br s, 1H), 3.29 - 3.22 (m, 6H), 2.95 (br s, 1H), 2.34 - 2.19 (m, 2H), 2.16 - 2.01 (m, 3H), 1.97 - 1.88 (m, 1H), 1.86 - 1.69 (m, 2H), 1.66 - 1.58 (m, 2H), 1.23 (td, J = 6.5, 1.2 Hz, 1H). LC-MS RT: 1.11 min; MS (ESI) m / z = 613.0 (M+H)+; Method A Peak 2, RT = 15.8 min (5.0 mg, 5.0% yield). The material was not completely resolved from a closely eluting impurity.

[0260] Example 45, peak 3, RT = 24.0 min (> 95% de, 8.0 mg, 8.0% yield). 1H NMR (400 MHz, CD3OD) δ 8.31 - 8.27 (m, 1H), 8.18 (dd, J = 6.4, 2.9 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.49 (dd, J = 8.6, 2.2 Hz, 1H), 7.32 (t, J = 9.7 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 4.72 - 4.62 (m, 1H), 4.08 (s, 2H), 3.41 (br d, J = 2.4 Hz, 2H), 3.32 δ - 3.22 (m, 2H), 2.96 (br d, J = 3.1 Hz, 1H), 2.63 (dd, J = 18.0, 7.7 Hz, 1H), 2.49 - 2.29 (m, 4H), 2.27 - 2.19 (m, 1H), 2.12 - 1.94 (m, 3H), 1.65 - 1.54 (m, 3H). LC-MS RT: 1.11 min; MS (ESI) m / z 613.0 (M+H)+; Method A

[0261] Example 46, Potato 4, RT = 27.9 minutes (> 95% de, 11.0 mg, 11.0% yield). 1H NMR (400 MHz, CD3OD) δ 8.32 - 8.27 (m, 1H), 8.18 (dd, J = 6.2, 2.9 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.16 (d, J = 8.6 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 4.72 - 4.63 (m, 1H), 4.14 (s, 1H), 4.11 - 4.06 (m, 3H), 3.52 - 3.39 (m, 2H), 3.30 - 3.23 (m, 2H), 2.96 (br d, J = 3.1 Hz, 1H), 2.63 (dd, J = 18.0, 7.7 Hz, 1H), 2.49 - 2.28 (m, 4H), 2.26 - 2.18 (m, 1H), 2.10 - 1.93 (m, 3H). LC-MS RT: 1.11 min; MS (ESI) m / z 613.0 (M+H)+; Method A

[0262] Examples 48 to 51 [ka]

[0263] Intermediate 48-1 [ka] Intermediate 48-1 was prepared according to the method for intermediate 35-1 using known methyl benzoate boronic acid as the starting material.

[0264] Intermediate 48-2 [ka] A solution of 48-1 (376 mg, 1.42 mmol) in DCM (5.7 mL) was treated with MsO (273 mg, 1.56 mmol), followed by the dropwise addition of TEA (0.30 mL, 2.1 mmol) and stirring for 18 h. The reaction mixture was extracted with 0.1 N HCl using DCM. The organic layer was concentrated under reduced pressure and used directly as methyl 2-methoxy-5-(3-((methylsulfonyl)oxy)cyclohexyl)benzoate (487 mg, 1.42 mmol, 100% yield), which was used without further purification. A solution of methyl 2-methoxy-5-(3-((methylsulfonyl)oxy)cyclohexyl)benzoate (0.487 g, 1.42 mmol) in DMF (14 mL) was treated with sodium azide (0.139 g, 2.13 mmol) and heated at 50° C. for 18 h. The reaction mixture was extracted with EtOAc from water. The organic layer was concentrated under reduced pressure, and methyl 5-(3-azidocyclohexyl)-2-methoxybenzoate (0.412 g, 1.42 mmol, 100% yield) was used without further purification. A solution of methyl 5-(3-azidocyclohexyl)-2-methoxybenzoate (412 mg, 1.42 mmol) in EtOAc (14 mL) was treated with Pd—C (152 mg, 0.142 mmol) under balloon pressure and injected H . The reaction mixture was stirred for 18 h, filtered through Celite, and concentrated under reduced pressure to give methyl 5-(3-aminocyclohexyl)-2-methoxybenzoate (48-2, 375 mg, 1.42 mmol, 100% yield). LC-MS RT: 0.57 min; MS (ESI) m / z = 264.1 (M+H)+; Method A. It was used without further purification.

[0265] Intermediate 48-3 [ka] A solution of 48-2 (120 mg, 0.456 mmol) in DCM (2.2 mL) was treated with Hunig's base (0.08 mL, 0.5 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (68 mg, 0.45 mmol), and the reaction mixture was stirred for 18 h. The reaction mixture was extracted with 0.1 N HCl using DCM. The organic layer was concentrated under reduced pressure to give methyl 2-methoxy-5-(3-(tetrahydro-2H-pyran-4-carboxamido)cyclohexyl)benzoate (174 mg, 0.463 mmol, 102% yield), which was used without further purification. A solution of methyl 2-methoxy-5-(3-(tetrahydro-2H-pyran-4-carboxamido)cyclohexyl)benzoate (171 mg, 0.455 mmol) in dioxane (1.7 mL) / water (0.35 mL) / MeOH (0.18 mL) was treated with LiOH (96 mg, 2.2 mmol) and heated at 40° C. for 18 h. The reaction mixture was adjusted to pH 1 by the addition of HCl solution and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give 2-methoxy-5-(3-(tetrahydro-2H-pyran-4-carboxamido)cyclohexyl)benzoic acid (48-3, 165 mg, 0.455 mmol, 100% yield), which was used without further purification. LC-MS RT: 0.70 min; MS (ESI) m / z = 362.1 (M+H)+; Method A

[0266] Examples 48-51: V-2 and 48-3 were combined according to the general method used in Example 1 to give four diastereomers that were separated by the following conditions: Apparatus: Waters 100 Prep SFC Column: Chiral IC 21 x 250 mm, 5 micron Mobile phase: 80% CO2 / 20% MeOH with 0.1% DEA Flow conditions: 60 mL / min Detector wavelength: 220 nm.

[0267] Example 48, Peak 1, RT = 5.75 min (> 95% de, 9.9 mg, 2.9% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.87 (br d, J = 7.0 Hz, 1H), 8.30 - 8.15 (m, 1H), 7.88 - 7.75 (m, 3H), 7.49 (t, J = 9.7 Hz, 1H), 7.35 (dd, J = 8.6, 2.1 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 5.93 (q, J = 7.9 Hz, 1H), 4.51 (br d, J = 4.4 Hz, 1H), 4.04 - 3.94 (m, 4H), 3.87 (br d, J = 11.2 Hz, 2H), 3.49 - 3.45 (m, 1H), 3.37 - 3.21 (m, 3H), 2.98 (br s, 1H), 2.93 - 2.84 (m, 1H), 2.05 - 1.83 (m, 2H), 1.79 - 1.53 (m, 11H), 1.50 - 1.34 (m, 4H). LC-MS RT: 2.47 min; MS (ESI) m / z = 739.9 (M+H)+; Method C

[0268] Example 49, Potato 2, RT = 9.3 minutes (> 95% de, 5.2 mg, 1.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.88 (br d, J = 7.2 Hz, 1H), 8.23 ​​(br d, J = 5.8 Hz, 1H), 7.79 (br d, J = 18.3 Hz, 3H), 7.50 (t, J = 9.7 Hz, 1H), 7.42 - 7.32 (m, 1H), 7.11 (d, J = 8.6 Hz, 1H), 5.94 (br d, J = 7.4 Hz, 1H), 4.64 - 4.45 (m, 1H), 3.97 (s, 4H), 3.88 (br d, J = 10.7 Hz, 2H), 3.47 - 3.41 (m, 2H), 3.36 - 3.14 (m, 3H), 2.98 (br s, 1H), 2.87 (br s, 1H), 2.05 - 1.82 (m, 2H), 1.74 - 1.52 (m, 11H), 1.49 - 1.34 (m, 3H). LC-MS RT: 2.44 min; MS (ESI) m / z = 740.3 (M+H)+; Method C

[0269] Example 50, Potato 3, RT = 11.8 minutes (> 95% de, 13.1 mg, 4.0% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.88 (br d, J = 6.5 Hz, 1H), 8.30 - 8.19 (m, 1H), 7.84 - 7.74 (m, 3H), 7.50 (br t, J = 9.6 Hz, 1H), 7.35 (br d, J = 8.3 Hz, 1H), 7.19 - 7.07 (m, 1H), 5.93 (br d, J = 7.9 Hz, 1H), 4.60 - 4.47 (m, 1H), 4.07 - 3.95 (m, 4H), 3.87 (br d, J = 11.0 Hz, 2H), 3.56 - 3.42 (m, 3H), 3.37 - 3.14 (m, 3H), 2.98 (br s, 1H), 2.02 - 1.80 (m, 3H), 1.75 - 1.37 (m, 13H). LC-MS RT: 2.44 min; MS (ESI) m / z = 740.34 (M+H)+; Method C

[0270] Example 51, Potato 2, RT = 12.6 minutes (> 95% de, 3.5 mg, 1.0% yield). 11H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.88 (br d, J = 6.9 Hz, 1H), 8.33 - 8.19 (m, 1H), 7.89 - 7.70 (m, 3H), 7.50 (br t, J = 9.7 Hz, 1H), 7.36 (dd, J = 8.5, 2.3 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.94 (q, J = 8.2 Hz, 1H), 4.59 - 4.39 (m, 1H), 4.05 - 3.93 (m, 4H), 3.87 (br d, J = 10.7 Hz, 2H), 3.56 - 3.49 (m, 1H), 3.38 - 3.15 (m, 3H), 3.05 - 2.83 (m, 2H), 2.04 - 1.84 (m, 2H), 1.78 - 1.54 (m, 10H), 1.52 - 1.32 (m, 5H). LC-MS RT: 2.58 min; MS (ESI) m / z = 740.1 (M+H)+; Method C

[0271] Examples 52 and 53

Chem.

[0272] <000316,6>Intermediate 52-1

Chem.

[0273] Intermediate 52-2 [ka] A solution of 52-1 (285 mg, 0.936 mmol) in EtOAc (9.4 mL) was treated with Pd—C (100 mg, 0.0940 mmol) and H under balloon pressure. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give methyl 2-methoxy-5-(1,4-dioxaspiro[4.5]decan-8-yl)benzoate (287 mg, 0.936 mmol, 100% yield), which was used without further purification. A solution of methyl 2-methoxy-5-(1,4-dioxaspiro[4.5]decan-8-yl)benzoate (287 mg, 0.936 mmol) in MeOH (9.4 mL) was treated with HCl (9.4 mL, 9.4 mmol) and stirred for 18 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give methyl 2-methoxy-5-(4-oxocyclohexyl)benzoate (52-2, 145 mg, 0.553 mmol, 59.1% yield), which was used without further purification. LC-MS RT: 0.76 min; MS (ESI) m / z = 285.0 (M+H+MeOH)+; Method A

[0274] Intermediate 52-3 [ka] A solution of 52-2 (145 mg, 0.553 mmol) in MeOH (5.5 mL) was treated with sodium borohydride (105 mg, 2.76 mmol) and stirred for 18 h. The reaction mixture was extracted with EtOAc from water. The organic layer was concentrated under reduced pressure to give methyl 5-(4-hydroxycyclohexyl)-2-methoxybenzoate (146 mg, 0.553 mmol, 100% yield), which was used without further purification. A solution of methyl 5-(4-hydroxycyclohexyl)-2-methoxybenzoate (0.146 g, 0.553 mmol) in THF (2.1 mL) / water (0.42 mL) / MeOH (0.21 mL) was treated with LiOH (0.116 g, 2.77 mmol) and heated at 40° C. for 18 h. The reaction mixture was adjusted to pH 1 by the addition of HCl, and the solution was then extracted with EtOAc. The organic layer was concentrated under reduced pressure to give 5-(4-hydroxycyclohexyl)-2-methoxybenzoic acid (0.138 g, 0.553 mmol, 100% yield), which was used without further purification. LC-MS RT: 0.62 min; MS (ESI) m / z = 251.1 (M+H)+; Method A

[0275] Examples 52 and 53: V-2 and 52-3 were combined by the general method used in Example 1 to give two diastereomers that were separated in the following manner: Apparatus: Waters 100 Prep SFC Column: Chiral AD 30 x 250 mm, 5 micron Mobile phase: 80% CO2 / 20% IPAw / 0.1% DEA Flow conditions: 100 mL / min Detector wavelength: 220.

[0276] Example 52, Peak 1, RT = 4.95 min (> 95% de, 20.2 mg, 11% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.85 (d, J = 7.0 Hz, 1H), 8.24 (dd, J = 6.4, 2.1 Hz, 1H), 7.78 (br d, J = 2.1 Hz, 2H), 7.51 (t, J = 9.8 Hz, 1H), 7.36 (dd, J = 8.4, 2.3 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.95 (q, J = 7.6 Hz, 1H), 4.61 - 4.48 (m, 2H), 3.97 (s, 3H), 3.45 (br dd, J = 10.2, 6.0 Hz, 1H), 3.30 - 3.20 (m, 1H), 2.99 (br s, 1H), 2.43 (td, J = 11.7, 2.7 Hz, 1H), 2.01 (br t, J = 9.3 Hz, 1H), 1.94 - 1.85 (m, 3H), 1.74 (br d, J = 12.5 Hz, 2H), 1.56 - 1.37 (m, 5H), 1.33 - 1.22 (m, 2H). LC-MS RT: 2.47 min; MS (ESI) m / z = 629.1 (M+H)+; Method C

[0277] Example 53, Peak 2, RT = 8.51 min (> 95% de, 1.1 mg, 0.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.87 (d, J = 7.0 Hz, 1H), 8.24 (dd, J = 6.1, 1.5 Hz, 1H), 7.90 - 7.75 (m, 2H), 7.51 (t, J = 9.6 Hz, 1H), 7.36 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.95 (d, J = 7.6 Hz, 2H), 4.53 (br dd, J = 10.8, 6.6 Hz, 1H), 4.04 - 3.95 (m, 3H), 3.89 (br s, LC-MS RT: 2.58 min; MS (ESI) m / z = 629.1 (M+H)+; Method C

[0278] Example 55 [ka]

[0279] Intermediate 55-1 [ka] Intermediate 55-1 was prepared by the general method used for 31-1, substituting vinylboronic acid and bromobenzoate (514 mg, 65.5% yield).

[0280] Intermediate 55-2 [ka] A solution of 55-1 (150 mg, 0.780 mmol) in THF (3.9 mL) was treated with 9-BBN (1.7 mL, 0.858 mmol) at 0 °C and warmed to rt over 18 h. The reaction mixture was treated with a solution of NaOH (31 mg, 0.78 mmol) in MeOH (1 mL), and to this solution was added hydrogen peroxide (0.03 mL, 0.8 mmol). After 1 h, the reaction mixture was extracted with EtOAc from water. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give methyl 5-(2-hydroxyethyl)-2-methoxybenzoate (60 mg, 0.28 mmol, 36% yield). A solution of methyl 5-(2-hydroxyethyl)-2-methoxybenzoate (60 mg, 0.28 mmol) in dioxane (1 mL) / water (0.22 mL) / MeOH (0.1 mL) was treated with LiOH (60.0 mg, 1.42 mmol) and heated at 40° C. for 18 h. The reaction mixture was adjusted to pH 1 by the addition of HCl, and the solution was then extracted with EtOAc. The organic layer was concentrated under reduced pressure to give 5-(2-hydroxyethyl)-2-methoxybenzoic acid (55-2, 56.0 mg, 0.285 mmol, 100% yield), which was used without further purification.

[0281] Example 55 was prepared from V-2 and 55-2 following the general method used in Example 1 (9.0 mg, 7.0% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.87 (d, J = 7.0 Hz, 1H), 8.28 - 8.17 (m, 1H), 7.87 - 7.70 (m, 2H), 7.50 (s, 1H), 7.35 (dd, J = 8.4, 1.7 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.94 (q, J = 7.9 Hz, 1H), 4.64 (s, 1H), 4.54 - 4.48 (m, 1H), 3.97 (s, 3H), 3.62 - 3.52 (m, 1H), 3.34 - 3.18 (m, 1H), 2.99 (br s, 1H), 2.69 (t, J = 6.9 Hz, 2H), 2.52 - 2.49 (m, 2H), 2.04 - 1.80 (m, 2H), 1.49 (br d, J = 6.1 Hz, 2H). LC-MS RT: 2.40 min; MS (ESI) m / z = 575.3 (M+H)+; Method C

[0282] Examples 57 and 58 (trans-isomers) [ka]

[0283] Intermediate 57-1 [ka] Intermediate 57-1 was prepared as a racemic mixture of trans-diastereomers by the method outlined for intermediate 55-2, except substituting the appropriate vinylboronic acid in the Suzuki reaction. LC-MS RT: 0.71 min; MS (ESI) m / z = 251.1 (M+H)+; Method A

[0284] The compounds of Examples 57 and 58 were prepared from V-2 and 57-1 by the method used in Example 1. The diastereomers were separated using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water and 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water and 10 mM ammonium acetate; Gradient: 50% B hold for 0 min, 50 to 95% B over 22 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C.

[0285] Example 57, Peak 1 (>95% de, 23 mg, 11% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.85 (dd, J = 6.7, 3.4 Hz, 1H), 8.22 (br d, J = 6.4 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.49 (t, J = 9.6 Hz, 1H), 7.33 (br d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 5.92 (q, J = 7.8 Hz, 1H), 4.52 (br d, J = 4.0 Hz, 1H), 4.33 (t, J = 6.6 Hz, 1H), 3.96 (s, 3H), 3.58 - 3.37 (m, 2H), 3.31 - 3.18 (m, 1H), 2.98 (br s, 1H), 2.31 (br t, J = 11.1 Hz, 1H), 2.12 - 1.84 (m, 3H), 1.79 - 1.58 (m, 3H), 1.49 (br d, J = 6.7 Hz, 2H), 1.40 - 1.16 (m, 4H). LC-MS RT: 2.59 min; MS (ESI) m / z = 629.4 (M+H)+; Method C

[0286] Example 58, Peak 2 (> 95% de, 5.6 mg, 2.5% yield), 1H NMR (500 MHz, DMSO-d6) δ 10.71 - 10.61 (m, 1H), 9.90 - 9.79 (m, 1H), 8.23 ​​(br d, J = 5.4 Hz, 1H), 8.06 (s, 1H), 7.84 - 7.74 (m, 2H), 7.59 (br d, J = 8.9 Hz, 1H), 7.50 (br t, J = 9.7 Hz, 1H), 7.11 (br d, J = 8.7 Hz, 1H), 5.97 - 5.83 (m, 1H), 4.57 - 4.46 (m, 1H), 3.99 - 3.87 (m, 3H), 3.63 - 3.46 (m, 2H), 3.31 - 3.19 (m, 1H), 2.98 (br s, 1H), 2.07 - 1.83 (m, 3H), 1.78 - 1.54 (m, 6H), 1.53 - 1.40 (m, 4H). LC-MS RT: 2.56 min; MS (ESI) m / z = 629.3 (M+H)+; Method C

[0287] Example 59 (cis-isomer) [ka] A solution of the mixture of Examples 57 and 58 (110 mg, 0.175 mmol), 4-nitrobenzoic acid (29.2 mg, 0.175 mmol), and PPh3 (55 mg, 0.21 mmol) in THF (1.7 mL) was treated with DIAD (0.04 mL, 0.2 mmol) at 0 °C and warmed to rt overnight. The reaction mixture was extracted with EtOAc from a phosphate buffer solution. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 2-(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)cyclohexyl 4-nitrobenzoate, which was used without further purification. A solution of 2-(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)cyclohexyl 4-nitrobenzoate (170 mg, 0.219 mmol) in MeOH (1.8 mL) was treated with KCO (30.2 mg, 0.219 mmol), and after 1 h, the reaction mixture was extracted with EtOAc from the phosphate buffer solution. The organic layer was concentrated, and the residue was purified by reverse-phase HPLC to give (1R,2S,3R,4R,Z)-7-(bromomethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(2-hydroxycyclohexyl)-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide as a mixture of cis-isomers (6.5 mg, 5%). 1 H NMR (500 MHz, DMSO-d6) δ 10.71 - 10.59 (m, 1H), 9.84 (br t, J = 7.3 Hz, 1H), 8.22 (br d, J = 4.0 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.49 (br t, J = 9.5 Hz, 1H), 7.37 (br d, J = 8.2 Hz, 1H), 7.06 (br d, J = 8.6 Hz, 1H), 5.92 (br d, J = 8.0 Hz, 1H), 4.57 - 4.46 (m, 1H), 4.27 - 4.13 (m, 1H), 3.95 (d, J = 2.5 Hz, 3H), 3.80 (br s, 1H), 3.31 - 3.18 (m, 2H), 3.07 - 2.94 (m, 2H), 2.03 - 1.86 (m, 3H), 1.74 (br d, J = 11.1 Hz, 2H), 1.67 - 1.59 (m, 1H), 1.57 - 1.25 (m, 6H). LC-MS RT: 2.71 min; MS (ESI) m / z = 629.0 (M+H)+; Method C

[0288] Examples 62 and 63 [ka]

[0289] Intermediate 62-1 [ka] A solution of 55-1 (150 mg, 0.780 mmol) in DCM (3.9 mL) was slowly added with rhodium(II) acetate dimer (6.9 mg, 0.016 mmol), followed by t-Bu-diazoacetate (0.11 mL, 0.78 mmol). The reaction mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give methyl 5-(2-(tert-butoxycarbonyl)cyclopropyl)-2-methoxybenzoate (61-1, 180 mg, 0.588 mmol, 75% yield). LC-MS RT: 0.85 min; MS (ESI) m / z = 250.1 (M+H-tBu)+; Method A

[0290] Intermediate 62-2 [ka] Intermediate 62-1 was treated with the general method for 35-1 to give acid 62-2 (quantitative). LC-MS RT: 0.85 min; MS (ESI) m / z = 237.1 (M+H-tBu)+; Method A

[0291] The compounds of Examples 62 and 63 were prepared from V-2 and 62-2 by the general method of Example 1, followed by treatment with TFA / DCM by the general method of Example 9. The diastereomers were separated as follows: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water and ammonium acetate; Mobile phase B: 95:5 acetonitrile:water and ammonium acetate; Gradient: 40% B hold at 0 min, 40→80% B over 20 min, then 100% B hold at 0 min; Flow rate: 20 mL / min; Column temperature: 25°C.

[0292] Example 62, Peak 1 (3.8 mg, 5.2% yield).1 H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.91 - 9.85 (m, 1H), 8.24 - 8.18 (m, 1H), 7.83 - 7.76 (m, 1H), 7.68 (s, 1H), 7.54 - 7.45 (m, 1H), 7.31 (br d, J = 1.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.92 (q, J = 8.1 Hz, 1H), 4.57 - 4.41 (m, 1H), 3.96 (s, 3H), 3.30 - 3.21 (m, 2H), 3.00 - 2.96 (m, δ 8.7 - 9.6 (m, 1H), 2.42 - 2.33 (m, 1H), 2.02 - 1.81 (m, 2H), 1.74 - 1.67 (m, 1H), 1.53 - 1.45 (m, 2H), 1.40 (dt, J = 9.2, 4.7 Hz, 1H), 1.31 - 1.24 (m, 1H). LC-MS RT: 2.03 min; MS (ESI) m / z = 615.1 (M+H)+; Method C

[0293] Example 63, Potato 2 (2.8 mg, 3.9% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.77 - 10.65 (m, 1H), 9.88 (dd, J = 6.9, 3.8 Hz, 1H), 8.27 - 8.20 (m, 1H), 7.86 - 7.71 (m, 2H), 7.48 (t, J = 9.6 Hz, 1H), 7.35 (br d, J = 8.2 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 5.92 (q, J = 7.6 Hz, 1H), 4.55 - 4.43 (m, 1H), 3.96 (s, 3H), 3.31 - 3.20 (m, 2H), 2.98 (br s, LC-MS RT: 2.14 min; MS (ESI) m / z = 615.2 (M+H)+; Method C

[0294] Examples 64 and 65 [ka]

[0295] Intermediate 64-1 [ka] Intermediate 64-1 was prepared from 62-1 by treatment with TFA / DCM as described in the general method of Example 9 (quantitative yield). LC-MS RT: 0.68 min; MS (ESI) m / z = 251.1 (M+H-tBu)+; Method A

[0296] Intermediate 64-2 [ka] A solution of 64-1 (549 mg, 2.19 mmol) in THF (11 mL) was treated with BH3.THF (2.2 mL, 2.2 mmol), and the reaction mixture was stirred for 18 h. The reaction mixture was extracted with 1 M HCl with EtOAc, concentrated under reduced pressure, and purified by silica gel chromatography to give methyl 5-(2-(hydroxymethyl)cyclopropyl)-2-methoxybenzoate (120 mg, 0.508 mmol, 23.2% yield). A solution of methyl 5-(2-(hydroxymethyl)cyclopropyl)-2-methoxybenzoate (507 mg, 2.14 mmol) in THF (7 mL) / water (1.4 mL) was treated with LiOH (451 mg, 10.7 mmol) and heated at 40° C. for 18 h. The reaction mixture was adjusted to pH 1 by the addition of HCl, and the solution was extracted with EtOAc. The organic layer was concentrated under reduced pressure to give 5-(2-(hydroxymethyl)cyclopropyl)-2-methoxybenzoic acid (64-2, 477 mg, 2.14 mmol, 100% yield), which was used without further purification.

[0297] Examples 64 and 65 V-2 and 64-2 were combined by the general method used in Example 1 to give diastereomers that were separated using the following conditions: Waters 100 Prep SFC Chiral AS 30 x 250 mm. 5 micron, 90% CO2 / 10% MeOH w / 0.1% DEA, 100 mL / min.

[0298] Example 64, Peak 1, RT = 3.9 min (6.3 mg, 5.0% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.88 (s, 1H), 8.22 (br d, J = 6.1 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.49 (t, J = 9.6 Hz, 1H), 7.36 (td, J = 8.4, 2.1 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 5.93 (d, J = 7.9 Hz, 1H), 4.51 (br d, J = 3.7 Hz, 1H), 3.97 (d, J = 0.9 Hz, 3H), 3.31 - 3.20 (m, 2H), 3.09 - 2.91 (m, 3H), 2.15 (br d, J = 7.3 Hz, 1H), 2.04 - 1.81 (m, 3H), 1.49 (br d, J = 6.1 Hz, 2H), 1.29 (br d, J = 7.0 Hz, 1H), 0.95 (br d, J = 4.9 Hz, 1H), 0.71 (q, J = 5.4 Hz, 1H). LC-MS RT: 2.26 min; MS (ESI) m / z = 601.1 (M+H)+; Method C

[0299] Example 65, Potato 2, RT = 6.6 minutes (10.0 mg, 7.9% yield). 11H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.86 (br d, J = 6.7 Hz, 1H), 8.23 (br d, J = 4.0 Hz, 1H), 7.84 - 7.73 (m, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.50 (t, J = 9.8 Hz, 1H), 7.29 - 7.18 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.00 - 5.90 (m, 1H), 4.60 - 4.42 (m, 1H), 3.95 (s, 3H), 3.34 (br d, J = 5.5 Hz, 1H), 3.30 - 3.18 (m, 2H), 2.99 (br s, 1H), 2.04 - 1.82 (m, 3H), 1.82 - 1.73 (m, 1H), 1.49 (br d, J = 7.0 Hz, 2H), 1.19 (br d, J = 4.3 Hz, 2H), 0.89 - 0.75 (m, 2H). LC-MS RT: 2.25 min; MS (ESI) m / z = 601.4 (M+H)+; Method C

[0300] Examples 66 and 67

Chemical formula

[0301] Intermediate 66-1

Chemical formula

[0302] Intermediate 66-2 [ka] Intermediate 66-1 was converted to 66-2 (quantitative yield) using the same hydrogenation method used for 60-1 followed by the same TFA / DCM method used in Example 9. LC-MS RT: 0.87 min; Method A

[0303] Intermediate 66-3 [ka] Intermediate 66-2 was converted to 66-3 (quantitative yield) using the same reduction and saponification method used for 64-1. LC-MS RT: 0.64 min; MS (ESI) m / z = 225.1 (M+H)+; Method A

[0304] Examples 66 and 67 V-2 and 66-3 were combined using the general method used in Example 1 to give diastereomers that were separated using the following conditions: Waters 100 Prep SFC Chiral AD, 30 x 250 mm, 5 micron, 85% CO2 / 15% IPAw / 0.1% DEA, 100 mL / min.

[0305] Example 66, Potato 1, RT = 7.0 minutes (7.4 mg, 11% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.66 - 10.59 (m, 1H), 9.87 (d, J = 7.0 Hz, 1H), 8.22 (dd, J = 6.4, 2.1 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.50 (t, J = 9.6 Hz, 1H), 7.30 (dd, J = 8.5, 2.1 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.93 (d, J = 7.9 Hz, 1H), 4.57 (t, J = 5.2 Hz, 1H), 4.54 - 4.48 (m, 1H), 3.97 (s, 3H), 3.47 (br s, 1H), 3.24 (dt, J = 17.0, 5.4 Hz, 3H), 2.99 (br s, 1H), 2.68 (br dd, J = 13.4, 5.8 Hz, 1H), 2.26 (dd, J = 13.3, 8.4 Hz, 1H), 2.05 - 1.85 (m, 2H), 1.73 (br dd, J = 13.9, 6.3 Hz, 1H), 1.50 (br d, J = 6.4 Hz, 2H), 0.76 (d, J = 6.7 Hz, 3H). LC-MS RT: 2.47 min; MS (ESI) m / z = 602.9 (M+H)+; Method C

[0306] Example 67, Potato 2, RT = 14.4 minutes (7.8 mg, 12% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.88 (d, J = 6.7 Hz, 1H), 8.23 ​​(dd, J = 6.1, 2.1 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.50 (t, J = 9.8 Hz, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 5.94 (q, J = 8.0 Hz, 1H), 4.61 - 4.48 (m, 2H), 3.97 (s, 3H), 3.46 (br s, 1H), 3.31 - 3.18 (m, 3H), 2.99 (br s, 1H), 2.69 (dd, J = 13.6, 5.6 Hz, 1H), 2.26 (dd, J = 13.4, 8.2 Hz, 1H), 2.07 - 1.85 (m, 2H), 1.80 - 1.68 (m, 1H), 1.50 (br d, J = 6.7 Hz, 2H), 0.76 (d, J = 6.7 Hz, 3H). LC-MS RT: 2.47 min; MS (ESI) m / z = 603.1 (M+H)+; Method C

[0307] Example 68

change

[0308] Intermediate 68-1

change

[0309] Intermediate 68-2 [ka] Intermediate 68-2 was prepared from 68-1 by the saponification method used in 32-2 (quantitative). LC-MS RT: 0.76 min; MS (ESI) m / z = 206.8 (M+H)+; Method A

[0310] Example 68 was prepared from V-2 and 68-2 by the method used in Example 1 (27.5 mg, 48% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.93 (d, J = 7.0 Hz, 2H), 8.23 ​​(dd, J = 6.6, 2.3 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.58 - 7.48 (m, 3H), 7.21 (d, J = 8.5 Hz, 1H), 5.31 (t, J = 6.0 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.29 (d, J = 5.8 Hz, 2H), 4.03 (s, 3H), 3.24 (br s, 1H), 2.99 (br s, 1H), 2.01 - 1.87 (m, 2H), 1.59 - 1.39 (m, 2H). LC-MS RT: 2.33 min; MS (ESI) m / z = 585.2 (M+H)+; Method C

[0311] The compounds of Examples 70-81 (Table 2) were prepared by the methods outlined in Examples 68 and 69 above, substituting the appropriate acetylene, bromobenzoate, isocyanate, and / or norbornyl core as indicated by substitution.

[0312] Example 82 [ka]

[0313] Intermediate 82-1 [ka] Intermediate 82-1 was prepared following the general method for 68-1, substituting gem-dimethyl substituted propargyl alcohol for propargyl alcohol.

[0314] Intermediate 82-2 [ka] A solution of 82-1 (150 mg, 0.604 mmol) in EtOH (2 mL) was treated with Pd(OH) / C (8.5 mg, 0.060 mmol). The slurry was stirred under a balloon pressure of H for 18 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give methyl 5-(3-hydroxy-3-methylbutyl)-2-methoxybenzoate (82-2, 152 mg, 0.604 mmol, 100% yield), contaminated with some deshydroxy material. LC-MS RT: 1.12 min; MS (ESI) m / z = 253.0 (M+H); Method A

[0315] Intermediate 82-3 [ka] Intermediate 82-3 was prepared from 82-2 by the saponification method used in 32-2 (quantitative yield). LC-MS RT: 1.12 min; MS (ESI) m / z = 220.9 (M+H-HO)+; Method A

[0316] Example 82 was prepared from V-2 and 82-3 by the general method used in Example 1 (52 mg, 48% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.92 - 9.83 (m, 1H), 8.29 - 8.20 (m, 1H), 7.83 - 7.74 (m, 2H), 7.50 (t, J = 9.8 Hz, 1H), 7.32 (dd, J = 8.5, 2.3 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 5.98 - 5.90 (m, 1H), 4.58 - 4.46 (m, 1H), 4.28 (s, 1H), 3.96 (s, 3H), 3.22 (br s, 1H), 2.98 (br s, 1H), 2.62 - 2.56 (m, 3H), 2.04 - 1.86 (m, 2H), 1.64 - 1.57 (m, 2H), 1.49 (br d, J = 6.0 Hz, 2H), 1.13 (s, 6H). LC-MS RT: 2.54 min; MS (ESI) m / z = 616.89 (M+H)+; Method C

[0317] Example 83 [ka] Example 83 was isolated as a by-product of the production of Example 82 by over-reduction in the hydrogenation step (12 mg, 11% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.64 (d, J = 7.1 Hz, 1H), 8.01 (br d, J = 4.5 Hz, 1H), 7.63 - 7.48 (m, 2H), 7.27 (t, J = 9.7 Hz, 1H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.71 (q, J = 7.9 Hz, 1H), 4.33 - 4.22 (m, 1H), 3.74 (s, 3H), 3.27 - 3.15 (m, 3H), 2.99 (br s, 1H), 2.75 (br s, 1H), 1.86 - 1.58 (m, 2H), 1.33 - 1.13 (m, 5H), 0.66 (d, J = 6.6 Hz, 6H). LC-MS RT: 3.03 min; MS (ESI) m / z = 601.1 (M+H)+; Method C

[0318] The compounds of Examples 84-103 (Table 2) were prepared by the methods outlined above for Examples 82 and 83, substituting the appropriate acetylene, bromobenzoate, isocyanate and / or norbornyl cores.

[0319] Example 104 [ka]

[0320] Intermediate 104-1 [ka] To a solution of 68-1 (1.3 g, 5.9 mmol) in EtOH (60 mL) was added Pd / C (0.63 g, 5.9 mmol) and subjected to balloon pressure hydrogen. The reaction mixture was stirred for 16 h, filtered through Celite, and concentrated under reduced pressure to give methyl 5-(3-hydroxypropyl)-2-methoxybenzoate (104-1, 470 mg, 2.1 mmol, 35% yield). MS (ESI) m / z 225.3 (M+H)

[0321] Intermediate 104-2 [ka] A solution of 104-1 (60 mg, 0.26 mmol) in DMSO (1.3 μl) was treated with NaH (60%, 32 mg, 0.80 mmol) and stirred for 30 min. To this solution was added 4-chloropyridine (30 mg, 0.26 mmol), and the reaction mixture was stirred for 18 h, then treated with water and LiOH and stirred for an additional 24 h. The reaction mixture was adsorbed onto Celite and purified by reverse-phase chromatography to give 2-methoxy-5-(3-(pyridin-4-yloxy)propyl)benzoic acid 104-2 (28 mg, 0.097 mmol, 36% yield). LC-MS RT: 0.54 min; MS (ESI) m / z = 288.0 (M+H)+; Method A

[0322] Example 104 was prepared from V-2 and 104-2 following the general method used in Example 1 (33.8 mg, 40% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.88 (d, J = 6.7 Hz, 1H), 8.24 (dd, J = 6.1, 2.4 Hz, 1H), 8.14 (dd, J = 4.9, 1.2 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.74 - 7.66 (m, 1H), 7.51 (t, J = 9.8 Hz, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.96 (dd, J = 6.7, 5.5 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.95 (d, J = 7.6 Hz, 1H), 4.60 - 4.47 (m, 1H), 4.29 - 4.17 (m, 2H), 3.98 (s, 3H), 3.24 (br s, 1H), 3.00 (br s, 1H), 2.71 (br t, J = 7.6 Hz, 2H), 2.00 (quin, J = 7.2 Hz, 4H), 1.90 (br s, 1H), 1.50 (br d, J = 7.0 Hz, 2H). LC-MS RT: 2.49 min; MS (ESI) m / z = 665.9 (M+H)+; Method C

[0323] The compound of Example 105 (Table 2) was prepared by the method described in Example 104. N It was prepared by substituting the appropriate chloroarenes in the Ar process.

[0324] Example 106 [ka]

[0325] Intermediate 106-1 [ka] To a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.1 g, 5.2 mmol) in DMF (14 mL) was added K2CO3 (0.72 g, 5.2 mmol), methyl 5-bromo-2-hydroxybenzoate (1.0 g, 4.3 mmol), and sodium iodide (0.065 g, 0.43 mmol) and stirred for 72 h. The reaction was partitioned between water and EtOAc, and the organic layer was separated, dried over Na2SO4, decanted, and concentrated under reduced pressure. The residue was purified by flash chromatography to give methyl 5-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (1.0 g, 2.8 mmol, 64% yield). 1 H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 2.6 Hz, 1H), 7.55 (dd, J = 8.9, 2.6 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H), 4.76 (t, J = 3.6 Hz, 1H), 4.32 - 4.18 (m, 2H), 4.08 (dt, J = 11.4, 4.7 Hz, 1H), 3.95 - 3.82 (m, 5H), 3.60 - 3.49 (m, 1H), 1.92 - 1.79 (m, 1H), 1.78 - 1.70 (m, 1H), 1.68 - 1.49 (m, 4H). MS (ESI) m / z 382.7 (M+Na)

[0326] Intermediate 106-2 [ka] Intermediate 106-2 was prepared from 106-1 using the general method described in Example 68 utilizing propargyl alcohol for the Sonogashira cross-coupling to give (1R,2S,3R,4R,Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-hydroxyprop-1-yn-1-yl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (quantitative yield). MS (ESI) m / z 699.3 (M+H) To a solution of 106-2 (75 mg, 0.11 mmol) in THF (0.6 mL) was added water (0.2 mL) and TFA (0.3 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-(2-hydroxyethoxy)-5-(3-hydroxyprop-1-yn-1-yl)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide, 106 (11 mg, 0.019 mmol, 17% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.60 (d, J = 7.3 Hz, 1H), 8.07 (dd, J = 6.3, 2.3 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.75 (br dd, J = 8.2, 3.4 Hz, 1H), 7.53 (dd, J = 8.7, 2.3 Hz, 1H), 7.47 (t, J = 9.8 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 5.93 (q, J = 7.9 Hz, 1H), 5.36 (t, J = 6.0 Hz, 1H), 4.90 (t, J = 5.6 Hz, 1H), 4.65 - 4.53 (m, 1H), 4.02 - 3.81 (m, 2H), 3.25 (dd, J = 10.8, 4.1 Hz, 1H), 3.19 (br s, 1H), 2.99 (br s, 1H), 2.11 - 1.97 (m, 2H), 1.52 (br d, J = 8.9 Hz, 2H) Analytical LC-MS: 1.11 min; MS(ESI) m / z 615.2 (M+H); Method C

[0327] Example 109 [ka]

[0328] Intermediate 109-1 [ka] To a solution of 104-1 (1.0 g, 4.5 mmol) and DIEA (0.94 mL, 5.4 mmol) dissolved in DCM (9 mL) and cooled to 0 °C was added MsO (0.93 g, 5.4 mmol). After 30 min, the reaction mixture was diluted with EtO, and the solution was washed with 1 M HCl. The ether layer was washed with water, dried over NaSO, decanted, and concentrated under reduced pressure to give methyl 2-methoxy-5-(3-((methylsulfonyl)oxy)propyl)benzoate (109-1, 0.99 g, 3.3 mmol, 73% yield).1 H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 2.3 Hz, 1H), 7.36 - 7.31 (m, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.24 (t, J = 6.3 Hz, 2H), 3.96 - 3.87 (m, MS (ESI) m / z 303.2 (M+H)

[0329] Intermediate 109-2 [ka] To a solution of 109-1 (0.25 g, 0.66 mmol) in DMSO (2.2 mL) was added sodium azide (0.13 g, 2.0 mmol) and stirred for 16 h at 50 °C. The reaction solution was partitioned between EtOAc and water, and the organic phase was separated, washed with water, brine, and dried over Na2SO4. The liquid was decanted and concentrated under reduced pressure, and the residue was purified by flash chromatography to give methyl 5-(3-azidopropyl)-2-methoxybenzoate (109-2, 0.055 g, 0.22 mmol, 33% yield). 1 H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.5, 2.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H), 2.75 - 2.66 (m, 2H), 1.96 - 1.88 (m, 2H). MS (ESI) m / z 250.1 (M+H)

[0330] Intermediate 109-3 [ka] To a solution of 109-2 (0.30 g, 1.2 mmol) in EtOH (12 mL) was added Pd / C (0.13 g, 1.2 mmol), and the atmosphere was evacuated and replaced with balloon pressure hydrogen. The reaction solution was filtered and concentrated under reduced pressure to give methyl 5-(3-aminopropyl)-2-methoxybenzoate (109-3, 0.27 g, 1.2 mmol, quantitative yield). 1 H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.5, 2.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H), 2.75 - 2.66 (m, 2H), 1.96 - 1.88 (m, 2H). MS (ESI) m / z 250.1 (M+H)

[0331] Intermediate 109-4 [ka] To a solution of 109-3 (0.20 g, 0.90 mmol) in 1,4-dioxane (4.5 mL) was added water (4.4 mL), Boc-anhydride (0.21 mL, 0.90 mmol), and NaOH (0.072 g, 1.8 mmol) and stirred for 16 h. The reaction mixture was neutralized by the addition of 0.1 M HCl, and the solution was extracted with EtOAc. The organic phase was separated, dried over Na2SO4, decanted, and concentrated under reduced pressure to give 5-(3-((tert-butoxycarbonyl)amino)propyl)-2-methoxybenzoic acid (109-4, 0.28 g, 0.90 mmol, 100% yield) as a residue, which was used without further purification. MS (ESI) m / z 254.2 (M+H-tBu).

[0332] Example 109 was prepared from V-2 and 109-3 by the general method of Example 1 (7.3 mg, 2.4% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.85 (br d, J = 7.0 Hz, 1H), 8.20 (dd, J = 6.6, 2.3 Hz, 1H), 7.84 - 7.67 (m, 2H), 7.48 (t, J = 9.8 Hz, 1H), 7.33 (dd, J = 8.5, 2.1 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.86 - 6.74 (m, 1H), 5.91 (q, J = 7.8 Hz, 1H), 4.58 - 4.45 (m, 1H), 3.96 (s, 3H), 3.30 - 3.16 (m, 2H), 2.97 (br s, 1H), 2.94 - 2.86 (m, 2H), 2.00 (br t, J = 9.2 Hz, 1H), 1.90 - 1.84 (m, 1H), 1.70 - 1.58 (m, 2H), 1.49 (br d, J = 6.7 Hz, 2H), 1.36 (s, 9H). Analytical LC-MS: 2.74 min; MS (ESI) m / z 688.6 (M+H); Method C

[0333] Example 110 [ka] To a solution of the compound from Example 109 (0.17 g, 0.24 mmol) in methanol (2.4 mL) was added 4 N HCl in 1,4-dioxane (0.30 mL, 1.2 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give (1R,2S,3R,4R,Z)-3-(5-(3-aminopropyl)-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (0.16 g, 0.25 mmol, 100% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.89 (br d, J = 7.0 Hz, 1H), 8.33 - 8.20 (m, 1H), 7.87 - 7.72 (m, 2H), 7.51 (t, J = 9.6 Hz, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.94 (q, J = 7.6 Hz, 1H), 4.59 - 4.46 (m, 1H), 3.98 (s, 3H), 3.30 (br dd, J = 11.0, 4.3 Hz, 1H), 3.23 (br d, J = 0.6 Hz, 1H), 3.00 (br s, 1H), 2.00 (br t, J = 9.2 Hz, 1H), 1.89 (br t, J = 8.5 Hz, 1H), 1.83 (s, 3H), 1.74 - 1.61 (m, 2H), 1.57 - 1.40 (m, 2H). Analytical LC-MS: 1.98 min; MS (ESI) m / z 587.91 (M+H); Method C

[0334] Example 111 [ka] To a mixture of the compound of Example 110 (0.020 g, 0.032 mmol), DIEA (0.022 mL, 0.13 mmol) and (R)-2-hydroxypropanoic acid (3 mg, 0.03 mmol) slurried in MeCN (0.3 mL) was added HATU (0.012 g, 0.032 mmol) and the reaction mixture was stirred for 2 hours. The reaction solution was partitioned between EtOAc and pH 7.4 phosphate buffer, and the organic layer was separated, concentrated under reduced pressure, and purified by preparative HPLC to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-((R)-2-hydroxypropanamido)propyl)-2-methoxybenzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (5.0 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.87 (d, J = 7.0 Hz, 1H), 8.22 (dd, J = 6.6, 2.3 Hz, 1H), 7.85 - 7.67 (m, 3H), 7.50 (t, J = 9.8 Hz, 1H), 7.34 (dd, J = 8.5, 2.1 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.93 (q, J = 7.8 Hz, 1H), 4.59 - 4.45 (m, 1H), 3.97 (s, 3H), 3.32 - 3.26 (m, 1H), 3.22 (br s, 1H), 3.08 (q, J = 6.7 Hz, 2H), 2.98 (br s, 1H), 2.00 (br t, J = 9.2 Hz, 1H), 1.92 - 1.78 (m, 1H), 1.69 (quin, J = 7.2 Hz, 2H), 1.56 - 1.42 (m, 2H), 1.21 (d, J = 6.7 Hz, 3H). Analytical LC-MS: 2.41 min; MS (ESI) m / z 660.0 (M+H); Method C

[0335] The compounds of Examples 112-116 (Table 2) were prepared using the general method of Example 111 above, using the corresponding commercially available carboxylic acids.

[0336] Example 117 [ka] To a mixture of the compound of Example 110 (0.020 g, 0.032 mmol) and DIEA (0.017 mL, 0.096 mmol) slurried in MeCN (0.321 mL), 2,2-bis(trifluoromethyl)oxirane (4 μL, 0.03 mmol) was added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(3-((3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)amino)propyl)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (10 mg, 41% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.85 (d, J = 7.3 Hz, 1H), 8.21 (dd, J = 6.4, 2.4 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.49 (t, J = 9.8 Hz, 1H), 7.33 (dd, J = 8.5, 2.1 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.92 (q, J = 7.8 Hz, 1H), 4.58 - 4.45 (m, 1H), 3.96 (s, 3H), 3.25 (br dd, J = 10.8, 4.1 Hz, 1H), 3.21 (br s, 1H), 2.99 (s, 3H), 2.00 (br t, J = 9.5 Hz, 1H), 1.94 - 1.81 (m, 2H), 1.67 (quin, J = 7.3 Hz, 2H), 1.55 - 1.41 (m, 2H). Analytical LC-MS: 2.06 min; MS (ESI) m / z 786.2 (M+H); Method C

[0337] The compounds of Examples 118 and 119 were prepared using the general method of Example 117 above, using the corresponding commercially available epoxides.

[0338] Example 120 [ka]

[0339] Intermediate 120-1 [ka] A solution of 109-1 (0.10 g, 0.33 mmol) in DMF (1.1 mL) was added with cyclobutanamine (0.085 mL, 0.99 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction solution was partitioned between EtOAc and water, and the organic layer was separated and concentrated under reduced pressure to give methyl 5-(3-(cyclobutylamino)propyl)-2-methoxybenzoate (120-1, 0.092 g, 0.33 mmol, 100% yield), which was used directly. MS (ESI) m / z 278.2 (M+H)

[0340] Intermediate 120-2 [ka] To a solution of 120-1 (0.092 g, 0.33 mmol) dissolved in THF (2.7 mL) was added lithium hydroxide monohydrate (0.028 g, 0.66 mmol) and water (0.7 mL), and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water, neutralized to pH 6, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and 5-(3-(cyclobutylamino)propyl)-2-methoxybenzoic acid (120-2, 0.087 g, 0.33 mmol, 100% yield) was used without further purification. MS (ESI) m / z 264.2 (M+H)

[0341] Intermediate 120-3 [ka] To a solution of 120-2 (0.087 g, 0.33 mmol) dissolved in a mixture of 1,4-dioxane (1.7 mL) and water (1.7 mL), sodium hydroxide (0.026 g, 0.66 mmol) was added, followed by Boc-anhydride (0.15 mL, 0.66 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was neutralized with 1 M HCl and diluted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-(3-((tert-butoxycarbonyl)(cyclobutyl)amino)propyl)-2-methoxybenzoic acid (120-3, 60 mg, 0.17 mmol, 50% yield), which was used directly. MS (ESI) m / z 264.1 (M+H-Boc).

[0342] Example 120 was prepared from 120-3 by the general method outlined in Example 109 (17.4 mg, 16.4% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.84 (br d, J = 6.7 Hz, 1H), 8.28 - 8.16 (m, 1H), 7.85 - 7.72 (m, 2H), 7.49 (t, J = 9.6 Hz, 1H), 7.34 (dd, J = 8.5, 1.8 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 5.93 (q, J = 7.8 Hz, 1H), 4.59 - 4.45 (m, 1H), 3.26 (br dd, J = 11.0, 4.3 Hz, 1H), 3.22 (br s, 1H), 3.18 - 3.07 (m, 2H), 2.98 (br s, 1H), 2.08 - 1.95 (m, 5H), 1.93 - 1.81 (m, 1H), 1.66 (dt, J = 14.8, 7.2 Hz, 2H), 1.60 - 1.41 (m, 5H), 1.33 (br s, 9H). Analytical LC-MS: 3.07 min; MS (ESI) m / z 742.2 (M+H); Method C

[0343] The compound of Example 121 (Table 2) was prepared in accordance with the procedure of Example 120, substituting morpholine in step 120-1. The compound of Example 122 was prepared from the compound of Example 120 under conditions similar to those of Example 110.

[0344] Example 123 [ka]

[0345] Intermediate 123-1 [ka] To a solution of 109-2 (0.050 g, 0.20 mmol), ethynylbenzene (0.041 g, 0.40 mmol) in DMF (1.5 mL) and water (0.5 mL) was added copper(II) sulfate pentahydrate (0.035 g, 0.14 mmol) and sodium ascorbate (0.040 g, 0.21 mmol), and the reaction mixture was stirred for 3 h. The reaction suspension was partitioned between EtOAc and water, and the aqueous layer was washed twice with EtOAc. The combined organic layers were dried over Na2SO4. The solution was decanted and concentrated under reduced pressure, and the residue was purified by flash chromatography to give methyl 2-methoxy-5-(3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl)benzoate (52 mg, 0.15 mmol, 74% yield). MS (ESI) m / z 352.3 (M+H)

[0346] Example 123 was prepared from 123-1 by the general method used in Example 109 (27.4 mg, 41.4% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.89 (d, J = 7.0 Hz, 1H), 8.58 (s, 1H), 8.24 (dd, J = 6.3, 2.3 Hz, 1H), 7.88 - 7.73 (m, 4H), 7.50 (t, J = 9.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.40 - 7.28 (m, 2H), 7.12 (d, J = 8.5 Hz, 1H), 5.94 (q, J = 7.8 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.41 (t, J = 7.0 Hz, 2H), 3.97 (s, 3H), 3.28 (br dd, J = 11.4, 4.1 Hz, 1H), 3.24 (br s, 1H), 3.04 - 2.95 (m, 1H), 2.61 (br t, J = 7.6 Hz, 2H), 2.23 - 2.13 (m, 2H), 2.05 - 1.95 (m, 1H), 1.93 - 1.84 (m, 1H), 1.57 - 1.42 (m, 2H). Analytical LC-MS: 2.64 min; MS (ESI) m / z 716.2 (M+H); Method C

[0347] Example 124 [ka]

[0348] Intermediate 124-1 [ka] To a solution of methyl (E)-5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-methoxybenzoate (1.2 g, 4.0 mmol) in DCM (32 mL) was added TFA (8 mL), and the reaction mixture was stirred for 16 h. The reaction solution was concentrated under reduced pressure, and the residual TFA was azeotropically distilled with toluene under reduced pressure to give (E)-3-(4-methoxy-3-(methoxycarbonyl)phenyl)acrylic acid (124-1, 0.99 g, 4.0 mmol, 100% yield).1 H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 16.0 Hz, 1H), 7.68 (dd, J = 8.9, 2.3 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H). MS (ESI) m / z 237.2 (M+H)

[0349] Intermediate 124-2 [ka] To a solution of 124-1 (0.094 g, 0.40 mmol) in MeCN (4 mL) was added DIEA (0.21 mL, 1.2 mmol), piperidin-4-ol (0.041 mg, 0.40 mmol), and HATU (0.15 g, 0.40 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between EtOAc and water, and the organic phase was separated and dried over Na2SO4. The organic layer was decanted, concentrated under reduced pressure, and purified by flash chromatography to give methyl (E)-5-(3-(4-hydroxypiperidin-1-yl)-3-oxoprop-1-en-1-yl)-2-methoxybenzoate (124-2, 0.13 g, 0.40 mmol, 100% yield). MS (ESI) m / z 320.4 (M+H)

[0350] Intermediate 124-3 [ka] To a solution of 124-2 (0.060 g, 0.19 mmol) in THF (0.8 mL) was added water (0.2 mL) and lithium hydroxide monohydrate (8 mg, 0.2 mmol), and the reaction mixture was stirred for 16 h. The reaction solution was diluted with water and carefully neutralized to pH 5 by the addition of 1N HCl, followed by saturation with NaCl, and the solution was extracted with EtOAc. The organic layer was separated, dried over Na2SO4, decanted, and concentrated under reduced pressure to give (E)-5-(3-(4-hydroxypiperidin-1-yl)-3-oxoprop-1-en-1-yl)-2-methoxybenzoic acid (124-3, 35 mg, 0.12 mmol, 62% yield). MS (ESI) m / z 306.3 (M+H)

[0351] Example 124 was prepared from V-2 and 124-3 by the general method used in Example 1 (5.1 mg, 11% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.87 (br d, J = 6.7 Hz, 1H), 8.21 (br d, J = 4.0 Hz, 1H), 8.16 (s, 1H), 7.87 (br d, J = 7.3 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.54 - 7.37 (m, 2H), 7.22 (br d, J = 8.5 Hz, 1H), 7.14 (br d, J = 15.6 Hz, 1H), 4.93 (br d, J = 3.7 Hz, 1H), 4.70 (br d, J = 9.8 Hz, 1H), 4.51 - 4.36 (m, 1H), 4.10 - 3.91 (m, 4H), 3.74 (br d, J = 3.7 Hz, 1H), 3.60 (br s, 1H), 3.41 - 3.26 (m, 1H), 3.16 (br dd, J = 10.8, 3.5 Hz, 1H), 3.10 (br s, 2H), 2.72 (br s, 1H), 1.88 - 1.65 (m, 4H), 1.55 - 1.20 (m, 5H), 0.81 - 0.64 (m, 2H), 0.35 (br s, 2H). Analytical LC-MS: 2.27 min; MS (ESI) m / z 656.2 (M+H); Method C

[0352] The compounds of Examples 125-141 were prepared by the method described in Example 124, substituting the appropriate amine and norbornyl cores. For example, hydrogenation of olefins where relevant was carried out by the method of Example 9.

[0353] Example 142 [ka]

[0354] Intermediate 142-1 [ka] A solution of 5-borono-2-methoxybenzoic acid (1.0 g, 5.10 mmol) in DMF (20 mL) was treated with benzyl bromide (0.61 mL, 5.1 mmol) and K2CO3 (0.705 g, 5.10 mmol) and stirred at rt for 18 h. The reaction mixture was extracted with EtOAc from water. The organic layer was washed with water and brine, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM / MeOH). The product-containing fractions were concentrated under reduced pressure, dissolved in EtOAc, and the solution was washed with 1N HCl. The organic layer was concentrated under reduced pressure to give (3-((benzyloxy)carbonyl)-4-methoxyphenyl)boronic acid (142-1, 1104 mg, 3.86 mmol, 76% yield). Analytical LC-MS: 0.94 min; MS(ESI) m / z 243.2 (M+HB(OH)2); Method A

[0355] Intermediate 142-2 [ka] A slurry of 4-methoxybenzenesulfonohydrazide (594 mg, 2.94 mmol) and ethyl 3-oxocyclohexane-1-carboxylate (500 mg, 2.94 mmol) in dioxane (14 mL) was heated to 80 °C and stirred for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give ethyl (Z)-3-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)cyclohexane-1-carboxylate (142-2, 704 mg, 1.98 mmol, 67.6% yield). Analytical LC-MS: 0.89 min; MS(ESI) m / z 355.1 (M+H); Method A

[0356] Intermediate 142-3 [ka] A slurry of 142-1 (0.424 g, 1.481 mmol), 142-2 (0.350 g, 0.988 mmol), and CsCO (0.804 g, 2.469 mmol) in dioxane (4.9 mL) was heated at 110 °C for 18 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give benzyl 5-(3-(ethoxycarbonyl)cyclohexyl)-2-methoxybenzoate (142-3, 298 mg, 0.752 mmol, 76% yield). Analytical LC-MS: 1.32 min; MS(ESI) m / z 397.3 (M+H); Method A

[0357] Intermediate 142-4 [ka] A solution of 142-3 (200 mg, 0.504 mmol) in EtOAc (5 mL) was treated with Pd—C (53 mg, 0.050 mmol) and H under balloon pressure for 18 h. The reaction mixture was filtered and concentrated under reduced pressure to give 5-(3-(ethoxycarbonyl)cyclohexyl)-2-methoxybenzoic acid (142-4, 155 mg, 0.504 mmol, 100% yield). Analytical LC-MS: 1.15 min; MS(ESI) m / z 307.2 (M+H); Method A

[0358] Example 142 was prepared from V-2 and 142-4 by the general method used in Example 1 as a mixture of 4 diastereomers (12.9 mg, 36% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.83 (br d, J = 7.6 Hz, 1H), 8.21 (br d, J = 6.1 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.49 (br t, J = 9.3 Hz, 1H), 7.39 - 7.30 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.96 - 5.89 (m, 1H), 4.55 - 4.48 (m, 1H), 4.16 - 4.04 (m, 2H), 3.95 (s, 3H), 3.29 - 3.17 (m, 2H), 2.98 (br s, 1H), 2.71 - 2.63 (m, 1H), 2.38 - 2.30 (m, 1H), 2.12 - 1.94 (m, 3H), 1.88 - 1.76 (m, 2H), 1.68 - 1.57 (m, 1H), 1.55 - 1.37 (m, 6H), 1.20 (q, J = 7.1 Hz, 3H). Analytical LC-MS: 2.81 min; MS (ESI) m / z 685.2 (M+H); Method C

[0359] The compound of Example 143 (Table 2) was prepared by the method outlined in Example 142, substituting the appropriate cyclohexanone. The compound of Example 144 was prepared from the compound of Example 142 by the saponification used in the synthesis of 12-3. Examples 145-148 were prepared by the method outlined in Example 142, starting from the appropriate norbornylamine and 3-benzyloxy-cyclobutanone; the benzyl ether was cleaved during ester hydrogenation, and the diastereomers were separable by reverse-phase HPLC.

[0360] Examples 149 and 150 [ka]

[0361] Intermediate 149-1 [ka] A solution of 6-oxospiro[3.3]heptane-2-carboxylic acid (500 mg, 3.24 mmol) in THF (6.5 mL) was treated with (4-methoxyphenyl)magnesium bromide (7.8 mL, 3.89 mmol) at −78° C. and warmed to rt over 18 h. The reaction mixture was extracted with 1N HCl using EtOAc. The organic layer was concentrated under reduced pressure to give 6-hydroxy-6-(4-methoxyphenyl)spiro[3.3]heptane-2-carboxylic acid (851 mg, 3.24 mmol, 100% yield), which was used without further purification. A solution of 6-hydroxy-6-(4-methoxyphenyl)spiro[3.3]heptane-2-carboxylic acid (0.851 g, 3.24 mmol) in EtOAc (39 mL) was treated with Pd—C (10 wt%, 0.414 g, 3.89 mmol) and H (50 psi). The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 6-(4-methoxyphenyl)spiro[3.3]heptane-2-carboxylic acid (0.848 g, 3.24 mmol, 100% yield), which was used without further purification. A solution of 6-(4-methoxyphenyl)spiro[3.3]heptane-2-carboxylic acid (848 mg, 3.24 mmol) in MeOH (19 mL) was treated with Ts-OH (37 mg, 0.19 mmol) and heated at 60 °C for 18 h. The reaction mixture was partitioned between EtOAc and phosphate buffer. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give methyl 6-(4-methoxyphenyl)spiro[3.3]heptane-2-carboxylate (149-1, 406 mg, 1.56 mmol, 40.1% yield). Analytical LC-MS: 1.06 min; MS(ESI) m / z 261.1 (M+H); Method A

[0362] Intermediate 149-2 [ka] A solution of 149-1 (574 mg, 2.20 mmol) in acetone (22 mL) was treated with NBS (412 mg, 2.31 mmol) followed by one drop of HCl, and the reaction mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give methyl 6-(3-bromo-4-methoxyphenyl)spiro[3.3]heptane-2-carboxylate (149-2, 406 mg, 1.19 mmol, 54.3% yield). Analytical LC-MS: 1.10 min; no mol. ion detected. (M+H); Method A

[0363] Intermediate 149-3 [ka] To a slurry of 149-2 (100 mg, 0.295 mmol), Pd(OAc) (6.6 mg, 0.029 mmol), 1,3-bis(diphenylphosphino)propane (12 mg, 0.029 mmol), and TEA (0.13 mL, 0.88 mmol) in DMF (2.6 mL) / water (0.3 mL), a CO atmosphere was introduced under 100 psi pressure, and the reaction mixture was heated at 100 °C for 18 h. The reaction mixture was extracted with 1N HCl using EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography to give 2-methoxy-5-(6-(methoxycarbonyl)spiro[3.3]heptan-2-yl)benzoic acid (149-3, 41 mg, 0.15 mmol, 45% yield). Analytical LC-MS: 0.87 min; MS(ESI) m / z 305.1 (M+H); Method A

[0364] Examples 149 and 150 V-2 and 149-3 were combined according to the general method of Example 1 to give a mixture of two diastereomers. The diastereomers were separated using the following conditions: Apparatus: Waters 100 Prep SFC Column: Chiral IC, 21 x 250 mm, 5 micron Mobile phase: 90% CO2 / 10% IPA / 0.1% DEA Flow conditions: 60 mL / min.

[0365] Example 149, ピーク1, RT = 10.5 minutes (8.1mg, 21% yield, > 95%de). 1 H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.86 (d, J = 7.3 Hz, 1H), 8.23 ​​(dd, J = 6.4, 2.1 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.50 (t, J = 9.8 Hz, 1H), 7.32 (dd, J = 8.5, 2.1 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.94 (q, J = 7.8 Hz, 1H), 4.52 (br dd, J = 6.9, 3.2 Hz, 1H), 3.96 (s, 3H), 3.60 (s, 3H), 3.33 - δ 3.20 (m, 3H), 3.10 - 2.92 (m, 2H), 2.48 - 2.35 (m, 2H), 2.31 - 2.23 (m, 2H), 2.13 (d, J = 8.2 Hz, 2H), 2.07 - 1.92 (m, 3H), 1.90 - 1.83 (m, 1H), 1.49 (br d, J = 6.7 Hz, 2H). Analytical LC-MS: 2.82 min; MS (ESI) m / z 683.2 (M+H); Method C

[0366] Example 150, ピーク2, RT = 13.5 minutes (8.4mg, 22% yield, > 95%de). 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.86 (d, J = 7.0 Hz, 1H), 8.22 (dd, J = 6.3, 2.3 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.50 (t, J = 9.8 Hz, 1H), 7.32 (dd, J = 8.5, 2.1 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.93 (d, J = 7.9 Hz, 1H), 4.57 - 4.46 (m, 1H), 3.96 (s, 3H), 3.60 (s, 3H), 3.36 - 3.20 (m, 2H), 3.13 - 2.93 (m, 2H), 2.56 (s, 1H), 2.38 (br d, J = 9.2 Hz, 2H), 2.33 - 2.24 (m, 2H), 2.13 (d, J = 8.5 Hz, 2H), 2.07 - 1.81 (m, 4H), 1.58 - 1.42 (m, 2H). Analytical LC-MS: 2.82 min; MS (ESI) m / z 683.1 (M+H); Method C

[0367] Examples 151 and 152 [ka]

[0368] The compounds of Examples 151 and 152 were prepared from the epimeric mixture of Examples 149 and 150 by saponification using the general method outlined in the preparation of 12-3. The diastereomers were separated using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; Gradient: 49% B hold at 0 min, 49 to 89% B over 30 min, then 100% B hold at 0 min; Flow Rate: 20 mL / min; Column Temperature: 25°C.

[0369] Example 151, Peak 1 (5.5 mg, 14% yield, >95% de). 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.40 (br d, J = 6.4 Hz, 1H), 8.12 (dd, J = 6.1, 2.1 Hz, 1H), 7.89 - 7.76 (m, 1H), 7.47 (t, J = 9.6 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.29 (dd, J = 8.5, 1.8 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 5.74 (q, J = 8.1 Hz, 1H), 4.63 - 4.55 (m, 1H), 3.86 (s, 3H), 3.32 (br d, J = 3.7 Hz, 1H), 2.46 - 2.40 (m, 1H), 2.36 (br t, J = 9.8 Hz, 1H), 2.29 - 2.21 (m, 2H), 2.15 - 2.07 (m, 2H), 2.05 - 1.89 (m, 4H), 1.80 - 1.65 (m, 2H), 1.62 - 1.50 (m, 1H). Analytical LC-MS: 2.82 min; MS (ESI) m / z 683.2 (M+H); Method C

[0370] Example 152, ピーク2 (7.8 mg, 38% yield, >95% de). 1H NMR (500 MHz, DMSO-d6) 10.64 (s, 1H), 9.86 (br d, J = 6.9 Hz, 1H), 8.29 - 8.17 (m, 1H), 7.83 - 7.70 (m, 2H), 7.49 (br t, J = 9.8 Hz, 1H), 7.31 (br d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 5.92 (q, J = 7.5 Hz, 1H), 4.51 (br d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.69 - 3.54 (m, 2H), 3.36 - 3.16 (m, 2H), 3.02 - 2.91 (m, 2H), 2.46 - 2.32 (m, 2H), 2.26 (q, J = 9.2 Hz, 2H), 2.09 (br d, J = 8.4 Hz, 2H), 2.04 - 1.79 (m, 4H), 1.57 - 1.41 (m, 2H). Analytical LC-MS: 2.82 min; MS (ESI) m / z 683.1 (M+H); Method C

[0371] The compound of Example 153 (Table 2) was prepared as a mixture of diastereomers using the known N-Boc spiroheptanone as the starting material by the method outlined in Example 149. The compound of Example 154 was prepared from Example 153 by deprotection by the method used in Example 110.

[0372] Example 155 [ka]

[0373] Intermediate 155-1 [ka] 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 for 18 hours. The reaction mixture was concentrated under reduced pressure, and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid was used without further purification (0.284 g, 1.02 mmol, 100% yield). Coupling with intermediate V-2 in the same manner as in Example 1 gave intermediate 155-1 (424 mg, 58% yield). Analytical LC-MS: 1.23 min; MS(ESI) m / z 657.1 (M+H); Method A 155-1 (50 mg, 0.076 mmol), 1-(bromomethyl)-4-fluorobenzene (14 mg, 0.076 mmol), Pd(PhP) (17 mg, 0.015 mmol), and KPO (48 mg, 0.22 mmol) were combined, and the reaction mixture was heated to 110 °C. The reaction mixture was cooled to rt and partitioned between water and EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(4-fluorobenzyl)-2-methoxybenzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (24 mg, 0.039 mmol, 51% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.70 - 10.59 (m, 1H), 9.95 - 9.86 (m, 1H), 8.33 - 8.23 ​​(m, 1H), 7.87 - 7.75 (m, 2H), 7.60 - 7.45 (m, 1H), 7.43 - 7.33 (m, 1H), 7.31 - 7.22 (m, 2H), 7.18 - 7.05 (m, 3H), 6.02 - 5.88 (m, 1H), 4.57 - 4.46 (m, 1H), 4.04 - 3.94 (m, 3H), 3.94 - 3.88 (m, 2H), 3.45 - 3.36 (m, 1H), 3.22 (br s, 1H), 2.99 (br d, J = 0.8 Hz, 1H), 2.07 - 1.77 (m, 2H), 1.58 - 1.43 (m, 2H). Analytical LC-MS: 2.80 min; MS (ESI) m / z 638.9 (M+H); Method C

[0374] Example 157 [ka]

[0375] Intermediate 157-1 [ka] Intermediate 157-1 was prepared from 104-1 by saponification according to the conditions described in 12-3 (quantitative yield).

[0376] Intermediate 157-2 [ka] Intermediate 157-2 was prepared from II-5 and 157-1 by the method outlined in Example 1 (202 mg, 63.6% yield). Analytical LC-MS: 1.07 min; MS(ESI) m / z 601.1 (M+H); Method A 157-2 (30 mg, 0.050 mmol), Na2CO3 (16 mg, 0.15 mmol), (4,4'-di-t-Bu-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-κ]] in DME (2.0 mL) N ) Phenyl-κ C A slurry of ]Ir(III)PF6 (0.51 mg, 0.50 μmol), NiCl2-DME (0.55 mg, 2.5 μmol), 4,4'-di-t-Bu-2,2'-bipyridine (0.67 mg, 2.5 μmol), (TMS)3SiH (0.05 mL, 0.2 mmol), and 2-bromopropane (18 mg, 0.15 mmol) was degassed and irradiated with a blue LED under N2 for 96 h. The reaction mixture was diluted with EtOAc, filtered through silica gel, concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give (1R,2S,3R,4R,Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-hydroxypropyl)-2-methoxybenzamido)-7-(2-methylpropylidene)bicyclo[2.2.1]heptane-2-carboxamide (9.4 mg, 0.017 mmol, 33% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.78 (d, J = 7.3 Hz, 1H), 8.22 (dd, J = 6.5, 2.4 Hz, 1H), 7.82 - 7.71 (m, 2H), 7.47 (t, J = 9.8 Hz, 1H), 7.31 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 5.10 (d, J = 9.0 Hz, 1H), 4.45 - 4.36 (m, 1H), 3.95 (s, 3H), 3.44 (br d, J = 1.7 Hz, 2H), 3.13 δ (dd, J = 10.6, 4.3 Hz, 1H), 2.96 (br s, 1H), 2.68 (br s, 1H), 2.61 - 2.54 (m, 3H), 2.49 - 2.44 (m, 1H), 1.96 - 1.86 (m, 1H), 1.81 - 1.73 (m, 1H), 1.70 - 1.61 (m, 2H), 1.38 (br d, J = 7.7 Hz, 2H), 1.07 - 1.01 (m, 3H), 0.98 (d, J = 6.6 Hz, 3H). Analytical LC-MS: 2.58 min; MS (ESI) m / z 563.1 (M+H); Method C

[0377] Example 176

change

[0378] Intermediate 176-1

change

[0379] Example 197 [ka]

[0380] Intermediate XI-2 [ka] 2-Methoxybenzoic acid (XI-1, 1.00 g, 6.57 mmol) was dissolved in chlorosulfonic acid (2.201 ml, 32.90 mmol) at 0° C. The resulting mixture was heated at 50° C. for 1 h and then poured into ice-cold water. The precipitate was filtered and used without further purification (quantitative yield). 1 H NMR (500MHz, CDCl3) δ 8.82 (d, J = 2.6 Hz, 1H), 8.25 (dd, J = 8.9, 2.7 Hz, 1H), 7.31 - 7.28 (m, 1H), 4.20 (s, 3H)

[0381] Intermediate 197-1 [ka] To a solution of XI-2 (50 mg, 0.199 mmol) in DCM (2.5 mL) was added (S)-1-aminopropan-2-ol (16.48 mg, 0.219 mmol) followed by TEA (0.11 mL, 0.79 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h and then extracted with EtOAc from water. The aqueous portion was acidified and then extracted with EtOAc. The combined organic portions were concentrated under reduced pressure, and the residue was used without further purification (quantitative yield). MS (ESI) m / z: 290.4 (M+H) (1R,2S,3R,4R,Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(N-((S)-2-hydroxypropyl)sulfamoyl)-2-methoxybenzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide, the compound of Example 197, was prepared using Intermediate 197-1 according to the general table described in Example 1 (8.4 mg, 26% yield). 1 H NMR (500MHz, DMSO-d6) δ 10.68 (s, 1H), 10.02 (d, J = 6.8 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 6.0 Hz, 1H), 7.90 (dd, J = 8.7, 2.4 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.59 - 7.45 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 7.9 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.55 - 4.44 (m, 1H), 4.07 (s, 3H), 3.23 (br. s., 2H), 2.98 (br. s., 1H), 2.67 - 2.57 (m, 3H), 1.97 - 1.81 (m, 2H), 1.49 (d, J = 5.7 Hz, 2H), 0.97 (d, J = 6.1 Hz, 3H); LC-MS (M+H) = 668.28; HPLC RT = 2.24 min; Method B

[0382] In Table 2, when multiple diastereomers are listed, the compounds were separated by preparative reverse-phase HPLC using the general conditions before listing, unless otherwise noted. The isomers are listed in order of elution by the method (i.e., the first eluting compound is listed as Isomer 1, the second as Isomer 2, etc.). When a compound is prepared as a diastereomeric mixture, the variable stereocenter is indicated by a wavy line. [Table 3-1] [Table 3-2]

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

[0383] The compounds of Examples 209 to 226 were prepared as described in the general table shown in Example 197.

[0384] Example 227 [ka]

[0385] Intermediate 227-1 [ka] Intermediate 227-1 was prepared from methyl 5-formyl-2-methoxybenzoate as described in US Pat. No. 5,665,719 (320 mg, 68%). LC-MS RT: 2.5 min, m / z = 251.1 (MH); Method B

[0386] Example 227: Prepared from intermediates 227-1 and IV-2a by the general method of Example 1 to give (1R,2S,3R,4R,Z)-3-amino-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (310 mg, 94% yield). 1 H-NMR (500 MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ = 10.53 (s, 1H), 9.90 (d, J = 7.1 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.22 (dd, J = 2.7, 6.6 Hz, 1H), 8.01 (dd, J = 2.3, 8.7 Hz, 1H), 7.77 (br s, 1H), 7.48 (t, J = 9.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 4.68 (d, J = 9.8 Hz, 1H), 4.47 - 4.36 (m, 1H), 4.06 (s, 3H), 3.20 - 3.06 (m, 2H), 2.72 (t, J = 3.7 Hz, 1H), 1.85 - 1.72 (m, 2H), 1.58 - 1.32 (m, 14H), 0.82 - 0.67 (m, 2H), 0.35 (dd, J = 2.0, 4.6 Hz, 2H). LC-MS RT: 2.83 min; MS (ESI) m / z 603.3 (MH) + ; Method B

[0387] Example 228 [ka]

[0388] Intermediate 238-1 [ka]

[0389] The compound of Example 227 (150 mg, 0.25 mmol) was dissolved in DCM (3.0 mL) at 0° C. and treated with TFA (0.3 mL, 4 mmol). The cooling bath was removed, and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to give intermediate 236-1 (130 mg, 96% yield) as an off-white solid, which was used without further purification. LC-MS RT: 0.56 min, m / z = 547.3 (M+H). + ; Method B

[0390] Example 228: Prepared from intermediates 238-1 and IV-2a by the general method of Example 1 to give (1R,2S,3R,4R,Z)-3-amino-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (310 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.88 (d, J = 7.0 Hz, 1H), 8.51 - 8.39 (m, 2H), 8.23 ​​(dd, J = 2.5, 6.5 Hz, 1H), 7.98 (dd, J = 2.5, 9.0 Hz, 1H), 7.85 - 7.74 (m, 1H), 7.49 (t, J = 9.8 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 4.70 (d, J = 9.5 Hz, 1H), 4.51 - 4.41 (m, 2H), 4.05 (s, 3H), 3.46 (q, J = 6.0 Hz, 2H), 3.17 (br dd, J = 4.3, 10.8 Hz, 1H), 3.13 - 3.09 (m, 1H), 2.73 (br s, 1H), 1.88 - 1.77 (m, 2H), 1.67 (quin, J = 6.7 Hz, 2H), 1.51 (br d, J = 5.0 Hz, 1H), 1.45 - 1.33 (m, 2H), 1.24 (s, 1H), 0.80 - 0.67 (m, 2H), 0.36 (dd, J = 2.3, 4.8 Hz, 2H). LC-MS RT: 2.12 min; MS (ESI) m / z 646.3 (M+H) + ; Method B

[0391] The compounds of Examples 229 to 259 were prepared as described in the general table shown in Example 228.

[0392] The compounds of Examples 260 to 279 were prepared as described in the general table shown in Example 157.

[0393] Examples 280 and 281 [ka]

[0394] The compounds of Examples 280 and 281 were prepared by the general method described in Example 149 to give a mixture of two diastereomers. The diastereomers were separated by the following conditions: Preparative Chromatography Conditions: Apparatus: Berger SFC Column: AS 25 x 3 cm ID, 5 micron Temperature: 40°C Flow Rate: 85 mL / min Mobile Phase: 88 CO2 / 12% MeOH Analytical Conditions: Analytical Chromatography Conditions: Apparatus: Agilent SFC (LVL-L4021 Lab) Column: AS 250 x 4.6 mm ID, 5 micron Flow Rate: 2.0 mL / min Mobile Phase: 85 CO2 / 15% MeOH.

[0395] Example 280, Peak 1, RT = 15.8 min (5.1 mg, 7%). 1 H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.84 (d, J = 7.1 Hz, 1H), 8.28 - 8.16 (m, 1H), 7.84 - 7.73 (m, 2H), 7.48 (t, J = 9.8 Hz, 1H), 7.30 (dd, J = 8.5, 2.2 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 5.92 (q, J = 7.8 Hz, 1H), 4.57 - 4.44 (m, 1H), 3.94 (s, 3H), 3.52 (br d, J = 3.0 Hz, 2H), 3.35 - 3.14 (m, 4H), 2.97 (br s, 1H), 2.38 (ddd, J = 10.4, 7.7, 4.9 Hz, 1H), 2.29 - 2.21 (m, 2H), 2.17 - 2.08 (m, 1H), 2.02 - 1.79 (m, 6H), 1.65 (dd, J = 11.4, 7.7 Hz, 1H), 1.48 (br d, J = 7.2 Hz, 2H). LC-MS: 2.67 min; MS (ESI) m / z 655.3 (M+H) + ; Method C

[0396] Example 281, peak 2, RT = 18.1 min (854 mg, 6% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.84 (d, J = 7.0 Hz, 1H), 8.26 - 8.16 (m, 1H), 7.81 - 7.71 (m, 2H), 7.48 (t, J = 9.6 Hz, 1H), 7.30 (dd, J = 8.5, 2.2 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 5.92 (q, J = 7.8 Hz, 1H), 4.54 - 4.45 (m, 1H), 3.94 (s, 3H), 3.54 - 3.50 (m, 2H), 3.38 - 3.15 (m, 4H), 2.97 (br s, 1H), 2.39 (ddd, J = 10.5, 7.8, 4.6 Hz, 1H), 2.29 - 2.20 (m, 2H), 2.18 - 2.10 (m, 1H), 2.02 - 1.77 (m, 6H), 1.65 (dd, J = 11.4, 7.5 Hz, 1H), 1.47 (br d, J = 7.9 Hz, 2H). LC-MS: 2.67 min; MS (ESI) m / z 655.3 (M+H) + Method C

[0397] Example 282

change

[0398] Intermediate 282-1

change

[0399] Example 282: A solution of 282-1 (0.039 g, 0.11 mmol) in DCM (10 mL) was treated with DIBAL-H (0.24 mL, 0.24 mmol) at 0 °C, and the solution was allowed to warm to RT over 14 h. The reaction mixture was quenched with 1 N HCl, diluted with EtOAc, and the layers were separated. The organic layer was concentrated under reduced pressure. The residue was combined with a solution of Pd(OAc) (2.5 mg, 11 μmol), 1,3-bis(diphenylphosphino)propane (4.5 mg, 11 μmol), and TEA (0.46 mL, 0.33 mmol) in 1 mL DMF / 0.11 mL water, covered with CO (100 psi) at 100 °C, and stirred for 14 h. 1 N HCl (5 mL) was added to the reaction mixture, and the resulting aqueous solution was extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue, which was combined with IV-2a by the general method described in Example 1 to give the compound of Example 282, (1R,2S,3R,4R,Z)-7-(cyclopropylmethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-((Z)-1,1,1-trifluoro-4-hydroxybut-2-en-2-yl)benzamide)bicyclo[2.2.1]heptane-2-carboxamide (5.8 mg, 9.3 μmol, 10% yield). 1H NMR (500 MHz, CD3OD) δ 8.18 (dd, J = 6.3, 2.7 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.41 (dd, J = 8.5, 2.3 Hz, 1H), 7.34 - 7.24 (m, 2H), 6.66 - 6.58 (m, 1H), 4.74 (d, J = 9.5 Hz, 1H), 4.58 (ddd, J = 10.6, 4.0, 1.4 Hz, 1H), 4.13 (s, 3H), 4.08 (d, J = 11.4 Hz, 1H), 3.24 (t, J = 4.0 Hz, 1H), 3.17 (ddd, J = 10.7, 4.4, 1.1 Hz, 1H), 2.73 (t, J = 3.9 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.98 - 1.90 (m, 1H), 1.68 (dq, J = 7.1, 2.5 Hz, 3H), 1.62 - 1.47 (m, 4H). LC-MS (M-OH) = 611.5; HPLC RT = 1.53 min; Method A

[0400] The compounds of Examples 283 to 296 were prepared as described in the general table shown in Example 14.

[0401] Example 297 [ka] A solution of the compound from Example 285 (30 mg, 0.05 mmol) in acetone (2.0 mL) was treated with NMO (12 mg, 0.10 mmol) and a solution of osmium tetroxide in t-BuOH (0.039 mL, 5.0 μmol). The reaction mixture was stirred at RT. After 6 h, the reaction mixture was diluted with ethyl acetate and washed with sodium thiosulfate (2×) and brine (2×). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give (1R,2S,3R,4R,7Z)-7-(cyclopropylmethylidene)-3-[5-({[(3R,4S)-3,4-dihydroxycyclopentyl]oxy}methyl)-2-methoxybenzamido]-N-[4-fluoro-3-(trifluoromethyl)phenyl]bicyclo[2.2.1]heptane-2-carboxamide (2.9 mg, 9.0%). 1 H NMR (400 MHz, methanol-d4) δ 8.21 - 8.08 (m, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.84 - 7.70 (m, 1H), 7.60 - 7.42 (m, 1H), 7.35 - 7.12 (m, 2H), 5.14 - 5.05 (m, 1H), 4.94 - 4.81 (m, 10H), 4.22 - 4.11 (m, 1H), 4.08 (s, 2H), 3.65 (dd, J = 10.5, 3.2 Hz, 1H), 2.48 (dt, J = 18.0, 3.8Hz, 2H), 2.37 - 2.14 (m, 1H), 2.08 - 1.76 (m, 5H), 1.73 - 1.44 (m, 2H), 1.38 - 1.24 (m, 1H), 0.65 - 0.54 (m, 2H), 0.46 - 0.31 (m, 2H). LC-MS RT: 2.32 min; MS (ESI) m / z 633.2 (M+H) + ; Method B

[0402] Example 298 [ka] [ka]

[0403] Intermediate 298-1 [ka] To a solution of hydroxycarbonimidic acid dibromide (300 mg, 1.5 mmol) in DMF (10 mL) at −15° C., 2,5-dihydrofuran (0.12 mL, 1.8 mmol) was added, followed by saturated aqueous sodium bicarbonate (3.0 mL, 3.0 mmol) over 1 hour 45 minutes (internal temperature rose to 0° C.). After stirring for 75 minutes at 0° C., the reaction mixture was diluted with EtOAc, and the resulting solution was extracted with water. The layers were separated, and the aqueous layer was further extracted with EtOAc (2×). The combined organic layers were washed successively with brine and water (10 mL each), dried, and concentrated under reduced pressure. The residue was purified by ISCO (0-100% Hex / EtOAc) to afford 3-bromo-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (90 mg, 32%) as a clear oil. 1 H NMR (500 MHz, chloroform-d) δ 5.39 - 5.19 (m, 1H), 4.38 - 4.22 (m, 2H), 4.02 - 3.94 (m, 1H), 3.75 - 3.64 (m, 2H)

[0404] Intermediate 298-2 [ka] A solution of intermediate 298-1 (90 mg, 0.47 mmol) in dioxane (10 mL) was treated with sodium hydroxide (1 N, 1.9 mL, 1.9 mmol) and heated at 80 °C for 16 h. After cooling to RT, the reaction mixture was acidified with 1 N HCl and extracted with ethyl acetate (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by ISCO (0-100% EtOAc / Hex) to give 3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-ol (30 mg, 50%). 1H NMR (500 MHz, chloroform-d) δ 5.33–5.15 (m, 1H), 4.13 (d, J = 7.2 Hz, 1H), 3.94 (br d, J = 8.5 Hz, 2H), 3.61–3.37 (m, 2H)

[0405] Intermediates 298-3 and 298-4 [ka] A solution of intermediate 298-2 (30 mg, 0.23 mmol), methyl 5-(bromomethyl)-2-methoxybenzoate, and potassium carbonate in acetonitrile (2 mL) was combined in a pressure vial, capped, and heated by microwave irradiation at 120 °C for 30 min. After cooling to RT, the reaction mixture was filtered, concentrated under reduced pressure, and purified by ISCO (0-100% EtOAc / Hex) to give methyl 2-methoxy-5-(((3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)oxy)methyl)benzoate, intermediate 298-3 (8.0 mg, 13%). 1 H NMR (400 MHz, chloroform-d) δ 7.90 - 7.84 (m, 1H), 7.53 (dd, J = 8.6, 2.4 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 5.28 (dd, J = 8.8, 4.2 Hz, 1H), 5.10 (d, J = 4.4 Hz, 2H), 4.32 - 4.26 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.85 - 3.78 (m, 1H), 3.70 - 3.63 (m, 2H) LC-MS RT: 0.71 min; MS (ESI) m / z 330.0 (M+Na) + Method D) and methyl 2-methoxy-5-((3-oxotetrahydrofuro[3,4-d]isoxazol-2(3H)-yl)methyl)benzoate, intermediate 298-4 (15 mg, 22%) was obtained. 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.6, 2.4 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 8.2, 4.1 Hz, 1H), 4.65 (s, 2H), 4.44 (dd, J = 9.4, 1.0 Hz, 1H), 4.13 (d, J = 11.0 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.76 (dd, J = 9.4, 6.7 Hz, 1H), 3.67 (dd, J = 11.1, 4.2 Hz, 1H), 3.56 - 3.49 (m, 1H). LC-MS RT: 0.64 min; MS (ESI) m / z 308.0 (M+H) + ; Method D)

[0406] Intermediate 298-5 [ka] To a suspension of 298-3 (8 mg, 0.03 mmol) in THF (1.0 mL) and water (0.3 mL) was added LiOH (1.0 M, 78 μl, 0.078 mmol). After stirring for 12 h at room temperature, the reaction mixture was diluted with water and acidified to pH 1.0 with 1 N HCl. The reaction mixture was extracted with EtOAc (3×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methoxy-5-(((3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)oxy)methyl)benzoic acid (7.0 mg, 86%), which was used without further purification.

[0407] Example 298: Prepared from intermediate 298-5 and IV-2a by the general method of Example 1 to give (1R,2S,3R,4R,7Z)-3-(5-{[(3aR,6aR)-3-oxo-hexahydrofuro[3,4-d][1,2]oxazol-2-yl]methyl}-2-methoxybenzamido)-7-(cyclopropylmethylidene)-N-[4-fluoro-3-(trifluoromethyl)phenyl]bicyclo[2.2.1]heptane-2-carboxamide (1.0 mg, 14% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.60 - 10.47 (m, 1H), 9.86 (t, J = 6.6 Hz, 1H), 8.22 (br d, J = 6.3 Hz, 1H), 7.87 (s, 1H), 7.82 - 7.73 (m, 1H), 7.48 (br t, J = 9.9 Hz, 1H), 7.38 (dd, J = 8.6, 2.4 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 5.16 (dd, J = 7.3, 4.4 Hz, 1H), 4.69 (d, J = 9.5 Hz, 1H), 4.61 (s, 2H), 4.51 - 4.37 (m, 1H), 4.12 (br d, J = 8.0 Hz, 1H), 4.05 - 3.91 (m, 4H), 3.72 - 3.56 (m, 2H), 3.21 - 3.02 (m, 2H), 2.72 (br s, 1H), 1.95 - 1.72 (m, 2H), 1.57 - 1.33 (m, 3H), 0.83 - 0.66 (m, 2H), 0.35 (br s, 2H). LC-MS RT: 2.36 min; MS (ESI) m / z 644.05 (M+H) + ; Method B

[0408] Example 299: Prepared from intermediate 298-4 by the general method of example 298 to give (1R,2S,3R,4R,7Z)-3-(5-{[(3aR,6aR)-3-oxo-hexahydrofuro[3,4-d][1,2]oxazol-2-yl]methyl}-2-methoxybenzamido)-7-(cyclopropylmethylidene)-N-[4-fluoro-3-(trifluoromethyl)phenyl]bicyclo[2.2.1]heptane-2-carboxamide (20 mg, 47% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.29 (br s, 1H), 9.63 (br s, 1H), 7.97 (br s, 1H), 7.62 (br s, 1H), 7.53 (br d, J = 1.2 Hz, 1H), 7.30 - 7.11 (m, 2H), 6.93 (br d, J = 8.2 Hz, 1H), 4.92 (br d, J = 3.7 Hz, 1H), 4.45 (br d, J = 9.5 Hz, 1H), 4.37 (br s, 2H), 4.19 (br d, J = 5.2 Hz, 1H), 3.88 (br d, J = 7.9 Hz, 1H), 3.80 - 3.68 (m, 3H), 3.47 - 3.24 (m, 4H), 2.97 - 2.80 (m, 2H), 2.48 (br s, 1H), 1.65 - 1.47 (m, 2H), 1.33 - 1.07 (m, 3H), 0.58 - 0.43 (m, 2H), 0.11 (br s, 2H). LC-MS RT: 2.37 min; MS (ESI) m / z 644.05 (M+H) + ; Method B

[0409] The compounds of Examples 300 and 301 were prepared as described in the general table shown in Example 298.

[0410] The compounds of Examples 302 to 320 were prepared as described in the general table shown in Example 124.

[0411] The compounds of Examples 321 to 326 were prepared as described in the general table shown in Example 62.

[0412] The compounds of Examples 327 to 333 were prepared as described in the general table shown in Example 48.

[0413] Example 340 [ka]

[0414] Intermediate 340-1 [ka] A solution of hepta-1,6-dien-4-ol (4.9 g, 44 mmol) in acetonitrile (53 mL) was treated with methyl 5-bromo-2-methoxybenzoate (2.2 g, 8.8 mmol), EtN (2.4 mL, 18 mmol), tri-o-tolylphosphine (0.27 g, 0.88 mmol), and Pd(OAc) (0.1 g, 0.4 mmol). The reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to rt, and the reaction mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography to give methyl (E)-5-(4-hydroxyhepta-1,6-dien-1-yl)-2-methoxybenzoate (2.3 g, 8.3 mmol, 95% yield). MS (ESI) m / z 277.0 (M+H) +

[0415] Intermediates 340-2a, 340-2b, 340-2c and 340-2d [ka] To a solution of intermediate 340-1 (2.3 g, 8.3 mmol) in acetonitrile (179 mL) was added (Ir[dF(CF3)ppy]2(dtbpy))-PF6 (93 mg, 83 μmol), and the solution was irradiated with a violet LED for 24 hours. The reaction mixture was concentrated under reduced pressure, and the isomers were separated by silica gel chromatography to give the following: Isomeric mixture peak 1 as methyl 5-(3-hydroxybicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (425 mg, 1.5 mmol, 18% yield). 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.5, 2.3 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.62 (tt, J = 5.3, 2.5 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.59 - 3.49 (m, 1H), 2.90 - 2.76 (m, 2H), 2.43 - 2.34 (m, 1H), 2.33 - 2.23 (m, 1H), 2.12 - 2.04 (m, 1H), 2.03 - 1.97 (m, 1H), 1.95 - 1.83 (m, 2H) and isomeric mixture peak 2 as methyl 5-(3-hydroxybicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (264 mg, 0.96 mmol, 11% yield): 1 H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 2.4 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.82 (tt, J = 8.4, 6.0 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.03 (ddd, J = 9.2, 7.2, 5.3 Hz, 1H), 2.94 - 2.80 (m, 2H), 2.35 - 2.24 (m, 1H), 2.11 - 1.98 (m, 3H), 1.76 - 1.65 (m, 2H) The isomeric mixture peak 1 was further purified on an SFC Chiralpak IA (4.6 × 100 mm), 3 micron, mobile phase: 20% IPA-ACN / 80% CO, flow conditions: 2.0 mL / min, 150 bar, 40 °C to give 340-2a (peak 1), RT: 3.7 min; and 340-2b (peak 2, 264 mg, 11%)), RT: 7.0 min. The isomeric mixture peak 2 was further purified on an SFC Chiralpak IA (4.6 × 100 mm), 3 micron, mobile phase: 20% IPA-ACN / 80% CO, flow conditions: 2.0 mL / min, 150 bar, 40 °C to give 340-2c (peak 1), RT: 3.2 min; and 340-2d (peak 2), RT: 5.5 min.

[0416] Example 340 was prepared from Intermediate 340-2a following the general method of Example 298 to give (1R,2S,3R,4R,7Z)-7-(cyclopropylmethylidene)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(5-{3-hydroxybicyclo[3.2.0]heptan-6-yl}-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxamide (35 mg, 89% yield). 1H NMR (500 MHz, CD3CN) δ 9.81 - 9.70 (m, 1H), 8.73 (s, 1H), 8.11 (dd, J = 6.6, 2.9 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.39 (dd, J = 8.5, 2.1 Hz, 1H), 7.28 (t, J = 9.7 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H), 4.61 - 4.53 (m, 1H), 4.46 (tt, J = 5.6, 2.7 Hz, 1H), 4.01 (s, 3H), 3.58 - 3.50 (m, 1H), 3.15 (t, J = 4.0 Hz, 1H), 3.11 (dd, J = 10.7, 4.3 Hz, 1H), 2.80 (d, J = 3.1 Hz, 2H), 2.74 - 2.67 (m, 2H), 2.38 - 2.28 (m, 1H), 2.25 - 2.19 (m, 1H), 2.13 - 2.12 (m, 1H), 1.85 (tdd, J = 2.4, 1.2, 0.6 Hz, 1H), 1.84 - 1.82 (m, 1H), 1.81 - 1.76 (m, 1H), 1.61 - 1.53 (m, 1H), 1.52 - 1.43 (m, 2H), 0.83 - 0.69 (m, 2H), 0.47 - 0.33 (m, 2H). LC-MS RT: 2.66 min; MS (ESI) m / z 613.4 (M+H) + Method A

[0417] The compounds of Example 341 to Example 343, the intermediates 340-2b to 340-2d, and the method of Example 340 were produced.

[0418] Example 348

change

[0419] Intermediate 348-1 [ka] 2-Allylpent-4-en-1-ol (0.98 g, 7.8 mmol) was combined with a solution of methyl 5-bromo-2-methoxybenzoate (0.50 g, 2.0 mmol), EtN (0.57 mL, 4.1 mmol), tri-o-tolylphosphine (0.062 g, 0.20 mmol), and Pd(OAc) (0.023 g, 0.10 mmol) in acetonitrile (12 mL), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to rt. The reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography to give the regioisomeric mixture methyl (E)-5-(4-(hydroxymethyl)hepta-1,6-dien-1-yl)-2-methoxybenzoate and methyl 5-(4-(hydroxymethyl)hepta-1,6-dien-2-yl)-2-methoxybenzoate (180 mg, 0.63 mmol, 31% yield). MS (ESI) m / z 291.1 (M+H) 1 H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.6, 2.4 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.38 (d, J = 15.9 Hz, 1H), 6.15 (dt, J = 15.7, 7.3 Hz, 1H), 5.97 - 5.64 (m, 1H), 5.19 - 4.96 (m, 2H), 3.96 - 3.88 (m, 6H), 3.64 (d, J = 5.5 Hz, 2H), 2.32 - 2.25 (m, 2H), 2.22 - 2.12 (m, 2H), 1.81 (dt, J = 12.7, 6.1 Hz, 1H)

[0420] Intermediates 348-2a1 to 348-2a7 and 348-2b1 to 348-2b2 [ka] Intermediates 348-2a1 to 348-2a7 and 348-2b1 to 348-2b2 were prepared from 350-1 and methyl 5-(4-(hydroxymethyl)hepta-1,6-dien-2-yl)-2-methoxybenzoate by the general method used for intermediate 340-2. The stereoisomers were separated on an SFC IG 250 x 4.6 mm ID, 5 mm, 85 / 15 CO2 / MeOH, 2 mL / min to give the following: 348-2a1 (Peak 1): Methyl 5-(3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (2.0 mg, 0.0069 mmol, 1.1% yield) RT: 16.1 min. 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.3, 2.0 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 3.90 (s, 6H), 3.73 (q, J = 9.5 Hz, 1H), 3.58 - 3.45 (m, 2H), 3.12 (q, J = 8.5 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.49 - 2.38 (m, 1H), 2.29 - 2.16 (m, 1H), 1.94 (ddd, J = 12.2, 9.7, 6.7Hz, 1H), 1.70 (dd, J = 12.6, 6.0 Hz, 1H), 1.44 (dd, J = 13.6, 6.7 Hz, 1H), 1.25 - 1.22 (m, 1H), 1.17 - 1.10 (m, 1H)

[0421] 348-2a2 (Peak 2): Regioisomeric mixture of methyl 5-(3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate and methyl 5-((1R,3S,5R)-3-(hydroxymethyl)bicyclo[3.2.0]heptan-1-yl)-2-methoxybenzoate (5.5 mg mixture). RT: 17.6 min. LC-MS RT: 0.65 min; MS(ESI) m / z = 291.0 (M+H). + ; Method A

[0422] 348-2a3 (Peak 3): Methyl 5-(3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (3.1 mg, 0.010 mmol, 1.7% yield) RT = 18.8 min. 1 H NMR (500 MHz, CDCl3) δ 7.49 (dd, J = 2.4, 0.9 Hz, 1H), 7.18 (ddd, J = 8.5, 2.4, 0.9 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.67 - 3.54 (m, 3H), 3.10 - 2.99 (m, 1H), 2.77 - 2.63 (m, 2H), 2.18 - 2.03 (m, 2H), 1.94 (td, J = 10.4, 7.4 Hz, 1H), 1.80 - 1.72 (m, 1H), 1.25 (br s, 1H), 1.16 - 1.04 (m, 2H)

[0423] 348-2a4 (Peak 6): Methyl 5-(3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (4.6 mg, 0.016 mmol, 2.5% yield) RT = 31.8 min. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 2.3 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.73 (d, J = 6.3 Hz, 2H), 3.02 - 2.94 (m, 1H), 2.88 - 2.83 (m, 1H), 2.83 - 2.79 (m, 1H), 2.67 (tt, J = 11.8, 6.0 Hz, 1H), 2.31 - 2.23 (m, 1H), 2.05 - 1.98 (m, 1H), 1.84 (dd, J = 12.7, 5.9 Hz, 1H), 1.77 (dd, J = 12.8, 6.3 Hz, 1H), 1.41 - 1.32 (m, 2H)

[0424] 348-2a5 (Peak 7): Methyl 5-(3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (23 mg, 0.079 mmol, 12% yield) RT = 32.8 min. 1 H NMR (500 MHz, CDCl3) δ 7.75 - 7.57 (m, 1H), 7.33 (dd, J = 8.5, 2.0 Hz, 1H), 6.99 - 6.88 (m, 1H), 3.90 (d, J = 6.1 Hz, 6H), 3.76 (d, J = 6.4 Hz, 2H), 3.23 - 3.08 (m, 1H), 2.83 - 2.63 (m, 2H), 2.34 - 2.06 (m, 5H), 1.52 - 1.40 (m, 2H)

[0425] 348-2a6 (Peak 8): Methyl 5-(3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (6.4 mg, 0.022 mmol, 3.5% yield) RT = 44.7 min. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 2.3 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.73 (d, J = 6.3 Hz, 2H), 3.02 - 2.94 (m, 1H), 2.88 - 2.83 (m, 1H), 2.83 - 2.79 (m, 1H), 2.67 (tt, J = 11.8, 6.0 Hz, 1H), 2.31 - 2.23 (m, 1H), 2.05 - 1.98 (m, 1H), 1.84 (dd, J = 12.7, 5.9 Hz, 1H), 1.77 (dd, J = 12.8, 6.3 Hz, 1H), 1.41 - 1.32 (m, 2H)

[0426] 348-2a7 (Peak 9): Methyl 5-(3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl)-2-methoxybenzoate (36 mg, 0.12 mmol, 19% yield) RT = 46.4 min. 1 H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 8.5, 2.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 3.91 (d, J = 6.0 Hz, 6H), 3.77 (br d, J = 6.4 Hz, 2H), 3.27 - 3.13 (m, 1H), 2.82 - 2.65 (m, 2H), 2.34 - 2.08 (m, 5H), 1.52 - 1.38 (m, 3H)

[0427] 348-2b1 (peak 4): Methyl 5-((1R,3S,5R)-3-(hydroxymethyl)bicyclo[3.2.0]heptan-1-yl)-2-methoxybenzoate (5.6 mg, 0.019 mmol, 3.0% yield) RT = 20.5 min. 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 8.0, 2.5 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.72 (br s, 2H), 3.00 - 2.89 (m, 1H), 2.40 - 2.31 (m, 1H), 2.31 - 2.17 (m, 4H), 2.06 - 2.01 (m, 1H), 2.00 - 1.93 (m, 1H), 1.74 - 1.66 (m, 1H), 1.46 (ddd, J = 13.2, 9.2, 4.0 Hz, 1H), 1.33 (br s, 1H)

[0428] 348-2b2(ピーク5):メチル5-((1R,3S,5R)-3-(ヒドロキシメチル)ビシクロ[3.2 .0]ヘプタン-1-イル)-2-メトキシベンゾエート (1.6mg, 0.0055mmol, 1.0% yield) RT = 22.1 points. 1 H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.6, 2.4 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.73 (br t, J = 5.1 Hz, 2H), 3.02 - 2.94 (m, 1H), 2.83 - 2.73 (m, 1H), 2.31 (dd, J = 11.7, 6.1 Hz, 1H), 2.25 - 2.20 (m, 1H), 2.11 (td, J = 10.9, 6.5 Hz, 1H), 2.04 - 2.01 (m, 1H), 1.81 (dd, J = 12.3, 5.7 Hz, 1H), 1.60 - 1.57 (m, 2H), 1.35 - 1.32 (m, 1H)

[0429] Example 348 compound was prepared from intermediate 348-2a1 following the general method of example 340 to give (1R,2S,3R,4R,7Z)-7-(cyclopropylmethylidene)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-{5-[3-(hydroxymethyl)bicyclo[3.2.0]heptan-6-yl]-2-methoxybenzamido}bicyclo[2.2.1]heptane-2-carboxamide (26 mg, 57% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.56 (d, J = 7.1 Hz, 1H), 7.98 (dd, J = 6.4, 2.3 Hz, 1H), 7.61 - 7.48 (m, 2H), 7.23 (t, J = 9.7 Hz, 1H), 7.10 (dd, J = 8.5, 2.3 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.44 (d, J = 9.6 Hz, 1H), 4.37 - 4.26 (m, 1H), 4.24 - 4.15 (m, 1H), 3.72 (s, 3H), 3.27 (br t, J = 5.8 Hz, 1H), 3.16 (s, 1H), 2.98 - 2.87 (m, 1H), 2.84 (br t, J = 3.6 Hz, 1H), 2.46 (br s, 1H), 2.39 - 2.32 (m, 3H), 1.98 - 1.68 (m, 6H), 1.63 (br t, J = 8.7 Hz, 1H), 1.58 - 1.49 (m, 1H), 1.31 - 1.06 (m, 5H), 0.61 - 0.42 (m, 2H), 0.11 (br dd, J = 4.3, 1.9 Hz, 2H) LC-MS RT: 2.79 min; MS (ESI) m / z 627.1 (M+H) + ; Method A

[0430] The compounds of Examples 349-352 were prepared by the general method of Example 348.

[0431] Example 353 was prepared from intermediate 348-2b2 by the method of Example 348.

[0432] Example 354 [ka]

[0433] Intermediate 354-1 [ka] Methyl 5-bromo-2-methoxybenzoate (10 g, 41 mmol), bis(pinacolato)diboron (12 g, 47 mmol), potassium acetate (12 g, 12 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.7 g, 3.3 mmol) were combined in 1,4-dioxane (100 mL) and heated at reflux for 2 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (8.0 g, 27 mmol, 67% yield). MS (ESI) m / z 293.1 (M+H) +

[0434] Intermediate 354-2 [ka] Potassium hydroxide (0.15 g, 2.7 mmol) was combined with HO (2.5 mL), and the solution was degassed with nitrogen for 5 minutes. The solution was added to a solution of chloro(1,5-cyclooctadiene)rhodium(I) dimer (6.6 mg, 0.013 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was stirred at room temperature. After 10 minutes, the reaction mixture was treated successively with Intermediate 354-1 (1.8 g, 5.4 mmol) and cyclohex-2-en-1-one (0.52 mL, 5.4 mmol) and stirred at room temperature. After 10 hours, the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous sodium hydroxide (2x). The layers were separated, and the organic layer was washed with brine (2x), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-methoxy-5-(3-oxocyclohexyl)benzoate (1.0 g, 3.3 mmol, 61% yield). To a stirring solution of methyl 2-methoxy-5-(3-oxocyclohexyl)benzoate (2 g, 8 mmol) and ethylene glycol (4.3 mL, 76 mmol) in toluene (15 mL) was added p-toluenesulfonic acid (0.15 g, 0.76 mmol), and the reaction mixture was heated at reflux with a Dean-Stark trap for 4 h. Upon cooling to RT, the reaction mixture was diluted with EtOAc and washed with sodium bicarbonate (2x). The layers were separated, and the combined organic portion was concentrated under reduced pressure and purified by silica gel chromatography to give methyl 2-methoxy-5-(1,4-dioxaspiro[4.5]decan-7-yl)benzoate (1.3 g, 4.2 mmol, 56% yield). 1H NMR (400MHz, DMSO-d6) δ = 7.47 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 2.4, 8.8 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 3.93 - 3.84 (m, 4H), 3.78 (s, 3H), 3.77 (s, 3H), 2.72 (tt, J = 3.3, 12.6 Hz, 1H), 1.80 - 1.66 (m, 4H), 1.60 (t, J = 12.7 Hz, 1H), 1.57 - 1.41 (m, 2H), 1.39 - 1.27 (m, 1H)

[0435] Intermediate 354-4 [ka] To a solution of intermediate 354-2 (1.5 g, 4.9 mmol) in THF (15 mL) and water (3.0 mL) was added LiOH (0.59 g, 24 mmol). The resulting solution was stirred at room temperature for 1 hour, 1N HCl was added to acidify the solution, and the solution was extracted with ethyl acetate. The combined organic portions were concentrated under reduced pressure to give 2-methoxy-5-(1,4-dioxaspiro[4.5]decan-7-yl)benzoic acid, which was used without further purification (1.3 g, 91% yield). MS (ESI) m / z: 293.1 (M+H) + , RT = 0.59 min, Method B

[0436] Intermediate 354-5 [ka] Intermediate 354-5 was prepared from intermediate 354-4 and V-2 by the general method of Example 1 to give (1R,2S,3R,4R,Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(1,4-dioxaspiro[4.5]decan-7-yl)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (10 mg, 49%). MS (ESI) m / z: 671.4 (M+H)+ , RT = 1.40 minutes, Method B

[0437] Intermediate 354-6 [ka] To a stirring solution of 354-5 (130 mg, 0.19 mmol) in DCM (5 mL) was added TFA (75 μL, 0.97 mmol), and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate solution (2×), and the layers were separated. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give (1R,2S,3R,4R,Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(3-oxocyclohexyl)benzamido)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (110 mg, 0.18 mmol, 91% yield). MS (ESI) m / z: 627.3 (M+H) + , RT = 1.21 min, Method B

[0438] Intermediate 354-7 [ka] To a stirred solution of 354-6 (100 mg, 0.16 mmol) and glycine ethyl ester hydrochloride (67 mg, 0.48 mmol) in a mixture of DMF (2 mL) and THF (2 mL) was added triethylamine (67 μL, 0.48 mmol). The reaction mixture was stirred at RT for 14 h. Sodium cyanoborohydride (30.1 mg, 0.479 mmol) was added, and the solution was stirred for an additional 1 h at RT. The reaction mixture was diluted with ethyl acetate, washed with brine, concentrated under reduced pressure, and purified by silica gel column chromatography to give ethyl (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)cyclohexyl)glycinate (100 mg, 0.14 mmol, 88% yield). MS (ESI) m / z: 714.4 (M+H) + , RT = 1.29 minutes, Method B

[0439] Example 354 [ka]

[0440] Example 354: To a solution of intermediate 354-7 (100 mg, 0.14 mmol) in THF (3.0 mL) and water (2.0 mL) was added LiOH (3.4 mg, 0.14 mmol). The resulting solution was stirred at room temperature for 16 hours, acidified by the addition of 1N HCl, and the solution was extracted with ethyl acetate. The combined organic portions were concentrated under reduced pressure and purified by HPLC to give (1R,2S,3R,4R,7Z)-3-{5-[3-(3,3-difluoroazetidin-1-yl)cyclohexyl]-2-methoxybenzamido}-N-[4-fluoro-3-(trifluoromethyl)phenyl]-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptane-2-carboxamide (1.0 mg, 1%). 1H NMR (400 MHz, DMSO-d6) δ = 10.64 (br s, 1H), 9.88 (d, J = 7.0 Hz, 1H), 9.00 - 8.59 (m, 7H), 8.23 ​​(dd, J = 2.8, 6.3 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.67 - 7.45 (m, 2H), 7.38 (dd, J = 2.3, 8.3 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.94 (q, J = 8.2 Hz, 1H), 4.53 (br s, 1H), 3.97 (s, 3H), 2.98 (br d, J = 4.0 MS (ESI) m / z: 686.3 (M+H) + , RT = 2.0 minutes, Method A

[0441] Example 355 was prepared from 354-6 and 3,3-difluoroazetidine by the method of Example 354.

[0442] Example 356 [ka]

[0443] Intermediate 356-1 [ka] To an oven-dried 2-dram vial purged with N2 was added zinc (100 mg, 1.5 mmol), tert-butyl 2-bromoacetate (170 μL, 1.1 mmol), and THF (2.0 mL). To a separate oven-dried 1-dram vial purged with N2 was added methyl 5-bromo-2-methoxybenzoate (250 mg, 1.0 mmol), bis(dibenzylideneacetone)palladium(0) (29 mg, 0.051 mmol), and tri-tertbutylphosphine (1 M in THF, 51 μL, 0.051 mmol) and THF (2.0 mL). Both solutions were stirred at room temperature for 15 minutes, at which point the contents of the 1-dram were transferred via syringe to the 2-dram vial. The resulting suspension was stirred at room temperature for 16 hours. The reaction mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (0-100% EtOAc / Hex) to afford methyl 5-(2-(tert-butoxy)-2-oxoethyl)-2-methoxybenzoate (255 mg, 0.91 mmol, 89% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.79 (d, J = 7.7 Hz, 1H), 6.97 - 6.88 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.57 (s, 2H), 1.46 (s, 9H). LC-MS RT: 0.98 min; MS (ESI) m / z 281.3 (M+H) + ; Method A

[0444] Intermediate 356-2 [ka] A solution of intermediate 356-1 (255 mg, 0.91 mmol) in THF (3.6 mL), water (0.91 mL), and MeOH (0.10 mL) was treated with lithium hydroxide monohydrate (57 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and 1 N HCl (5 mL). The layers were separated, and the aqueous solution was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc / Hex) to give 5-(2-(tert-butoxy)-2-oxoethyl)-2-methoxybenzoic acid (114 mg, 0.43 mmol, 47% yield). 1 H NMR (500 MHz, chloroform-d) δ 8.16 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 4.11 (s, 3H), 3.61 (s, 2H), 1.48 (s, 9H). LC-MS RT: 0.88 min; MS (ESI) m / z 267.2 (M+H) + ; Method A

[0445] Intermediate 356-3 [ka] Intermediate 356-3 was prepared from intermediate 356-2 and VI-2a by the general method of Example 1 to give tert-butyl 2-(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)acetate (257 mg, 0.42 mmol, 88% yield). 1H NMR (500 MHz, クロロホルム-d) δ 9.26 (br d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.05 (br s, 1H), 7.88 (dd, J = 6.2, 2.3 Hz, 1H), 7.58 (dt, J = 8.3, 3.5 Hz, 1H), 7.07 (t, J = 9.5 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 4.91 - 4.81 (m, 1H), 4.65 (d, J = 9.6 Hz, 1H), 4.01 (s, 3H), 3.56 (s, 2H), 3.18 (t, J = 3.7 Hz, 1H), 3.11 (dd, J = 10.7, 3.0 Hz, 1H), 2.79 - 2.69 (m, 1H), 2.27 - 2.16 (m, 1H), 1.91 - 1.82 (m, 1H), 1.77 - 1.62 (m, 2H), 1.53 - 1.46 (m, 2H), 1.45 (s, 9H), 0.79 - 0.70 (m, 2H), 0.36 (br d, J = 2.8 Hz, 2H). LC-MS RT: 2.82 min; MS (ESI) m / z 617.33 (M+H) + Method B

[0446] Intermediate 356-4

change

[0447] Example 356 [ka] To a solution of 356-4 (20 mg, 0.036 mmol) and methyl (R)-pyrrolidine-3-carboxylate.HCl (5.9 mg, 0.036 mmol) in DMF (0.5 mL) was added DIEA (0.019 mL, 0.11 mmol) and BOP (17 mg, 0.039 mmol). The reaction mixture was stirred at rt for 18 h, concentrated under reduced pressure, and purified by preparative HPLC to give methyl (R)-1-(2-(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)acetyl)pyrrolidine-3-carboxylate (8.5 mg, 0.013 mmol, 35% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.80 (d, J = 7.2 Hz, 1H), 8.22 (dd, J = 6.5, 2.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.48 (t, J = 9.7 Hz, 1H), 7.04 (d, J = 5.9 Hz, 1H), 6.90 (br d, J = 8.0 Hz, 1H), 4.69 (d, J = 9.5 Hz, 1H), 4.49 - 4.38 (m, 1H), 3.98 (s, 3H), 3.75 (dd, J = 10.3, 8.0 Hz, 1H), 3.69 (br d, J = 5.8 Hz, 2H), 3.66 - 3.60 (m, 3H), 3.60 - 3.33 (m, 2H), 3.29 - 3.11 (m, 2H), 3.10 - 3.02 (m, 1H), 2.75 - 2.66 (m, 1H), 2.23 - 2.14 (m, 1H), 2.14 - 2.03 (m, 1H), 2.03 - 1.93 (m, 1H), 1.91 - 1.82 (m, 1H), 1.83 - 1.73 (m, 1H), 1.51 (ddd, J = 12.6, 8.1, 4.6 Hz, 1H), 1.46 - 1.31 (m, 2H), 0.84 - 0.67 (m, 2H), 0.35 (dd, J = 4.1, 2.6 Hz, 2H). LC-MS RT: 2.39 min; MS (ESI) m / z 672.32 (M+H) + ; Method A

[0448] Example 357 was prepared from 356-4 and 3-methylpyrrolidin-3-ol by the general method of Example 356.

[0449] The compounds of Examples 358 to 361 were prepared as described in the general table shown in Example 197. [Table 4-1] [Table 4-2]

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

Table 4-31

Table 4-32

Table 4-33

Table 4-34

Table 4-35

Table 4-36

Table 4-37

Table 4-38

Table 4-39

Table 4-40

Table 4-41

Table 4-42

Table 4-43

Table 4-44

Table 4-45

Table 4-46

Table 4-47

Table 4-48

Table 4-49

Table 4-50

Table 4-51

Table 4-52

Table 4-53

[0450] [Table 5] All LC retention times are based on Method C unless otherwise noted. (b) Protons 1–3 were not considered in these samples due to overlap with solvent residues and / or water suppression artifacts.

[0451] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] All LC retention times are based on Method C unless otherwise noted. (b) Protons 1–3 were not considered in these samples due to overlap with solvent residues and / or water suppression artifacts.

[0452] It will be apparent to those skilled in the art that the present invention is not limited to the following illustrative examples, but may be embodied in other specific forms without departing from its essential characteristics. The examples are therefore to be considered in all respects as illustrative and not restrictive, and reference should be made to the appended claims rather than to said examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, L is —O— or —NH—; R １ is one aryl or C ３－６ C substituted with a cycloalkyl substituent １－３ is alkyl; R ２ is H; or R １ and R ２ Together = CR ６ R ７ where "=" is a double bond; or R １ and R ２ together with the carbon atoms to which they are attached form a dioxolanyl substituted with 0 to 1 aryl substituents; R ３ is 0 to 5 halo, CN, —OH or —OC １－３ C substituted with alkyl substituents １－８ alkyl, 0 to 5 R ４ -(CR ｄ R ｄ ) ｎ -C ３－１０ -carbocyclyl or O, S(=O) ｐ , N, N.R. ４ａ and 0 to 5 R ４ -(CR ｄ R ｄ ) ｎ - 3 to 12 membered heterocyclyl; R ４ is halo, CN, -OH, -SF ５ , -S(=O) ｐ R ｃ , 0 to 5 halo, —OH or —OC １－４ C substituted with alkyl substituents １－４ -OC substituted with alkyl or 0 to 5 halo substituents １－４ Alkyl, -, 0 to 5 R ｅ -(CR ｄ R ｄ ) ｎ -C ３－１０ Carbocyclyl or O, S(=O) ｐ , N and NR ４ａ -(CR ｄ R ｄ ) ｎ - 4- to 6-membered heterocyclyl; R ４ａ is H, C １－４ Alkyl or -S(=O) ２ CF ３ and R ５ is H, halo, OH, C substituted with 0 to 5 halo substituents １－４ -OC substituted with alkyl or 0 to 5 halo substituents １－４ is alkyl; R ６ is H, halo, CN, 0-3 R ６ａ C substituted with １－７ alkyl, 0 to 3 R ６ａ C substituted with ２－７ alkenyl, 0 to 3 R ６ａ C substituted with ２－７ Alkynyl, —C(═O)OR ６ｂ , -CONR ６ｂ R ６ｂ , 0 to 5 R １４ -substituted with -(CH ２ ) ｎ -C ３－６ Carbocyclyl or O, S(=O) ｐ , N or NR １３ and 0 to 5 R １４ 3- to 12-membered heterocyclyl substituted with R ６ａ is halo, -OH, -OC １－４ Alkyl, C １－４ C substituted with alkyl, aryl or 0-4 halo substituents ３－６ is cycloalkyl; R ６ｂ is H, C substituted with 0 to 1 aryl １－４ C substituted with alkyl or 0 to 4 halo substituents ３－６ is cycloalkyl; R ７ is H or C １－４ is alkyl; R ８ is H, halo, CN, -NR ７ R ７ or 0 to 5 halo, OH, —OC １－４ Alkyl, C ３－６ Cycloalkyl, aryl or O, S(=O) ｐ and N, and substituted with a 4- to 9-membered heterocyclyl substituent containing 1 to 4 heteroatoms selected from １－４ is alkyl; R ９ is -C(=O)OR １５ , —C(═O)NR １５ R １５ , -S(=O) ｐ NR １５ R １５ , -S(=O) ｐ R ｃ , -NR １７ R １７ , 0 to 4 R １０ and 0 to 2 R １１ C substituted with １－８ alkyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ２－８ alkenyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ２－８ alkynyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ３－９ cycloalkyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ３－９ cycloalkenyl, 0 to 2 R １０ and 0 to 2 R １１ A fused C substituted with ３－６ cycloalkyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ６－９ spirocycloalkyl, 0 to 2 R １０ and 0 to 2 R １１ A-C substituted with ３－６ Carbocyclyl or O, S(=O) ｐ , N and NR １８ and 0 to 2 R １０ and 0 to 2 R １１ A-4 to 9 membered heterocyclyl substituted with; A is -O-, -S-, -CH ２ O- or -OCH ２ - and; R １０ is halo, CN or 0-4 R １１ C substituted with １－６ is alkyl; R １１ is halo, -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 , -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 , -OC(=O)OR ｂ , —OC(═O)NR ａ R ａ , —OC(═O)NR ａ OR ｂ , -S(=O) ｐ R ｃ , -S(=O) ｐ NR ａ R ａ , 0 to 5 R ｅ C substituted with ３－９ Carbocyclyl, O, S(=O) ｐ , N and NR １２ and 0 to 5 R ｅ 3-12 membered heterocyclyl substituted with R １２ is H, 0 to 4 halo, or OR ｂ C substituted with a substituent １－４ is alkyl or aryl; R １３ is H, C(=O)C １－４ Alkyl, 0 to 3 Si(C １－３ alkyl) ３ C substituted with １－３ is an alkyl or aryl substituted with 0-2 halo substituents; R １４ is halo, CN, C substituted with 0-3 halo substituents １－４ alkyl, substituted with 0 to 3 halo substituents, —OC １－４ Alkyl, -(CH ２ ) ｎ -NR ａ R ａ , 0 to 3 R ｅ -substituted with -(CH ２ ) ｎ -aryl, 0 to 3 R ｅ -O-aryl or O, S(=O) ｐ and N, and 0 to 3 R ｅ -substituted with -(CH ２ ) ｎ - 3 to 12 membered heterocyclyl; R １５ is H, 0 to 5 R ｅ C substituted with １－６ alkyl, 0 to 5 R ｅ C substituted with ２－６ alkenyl, 0 to 5 R ｅ C substituted with ２－６ alkynyl, 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or O, S(=O) ｐ , N and NR １６ and 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl; or R １５ and R １５ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ , N and NR １６ and 0 to 5 R ｅ forming a 3- to 12-membered heterocyclyl substituted with R １６ is H, 0 to 5 R ｅ C substituted with １－６ Alkyl, —C(═O)R ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -S(=O) ｐ R ｆ or -S(=O) ｐ NR ｆ R ｆ and R １７ is H, 0 to 5 R ｅ C substituted with １－６ alkyl, 0 to 5 R ｅ C substituted with ２－６ alkenyl, 0 to 5 R ｅ C substituted with ２－６ alkynyl, 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or O, S(=O) ｐ , N and NR １８ and 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ - 4 to 12 membered heterocyclyl; R １８ is H, C substituted with 0-4 halo or —OH substituents １－４ Alkyl, —C(═O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , -S(=O) ｐ R ｃ , -S(=O) ｐ NR ａ R ａ , 0 to 5 R ｅ aryl substituted with 0 to 5 R ｅ C substituted with ３－６ Cycloalkyl or O, S(=O) ｐ and N, and 0 to 5 R ｅ 4-6 membered heterocyclyl substituted with R ａ is H, 0 to 8 R ｅ C substituted with １－６ alkyl, 0 to 5 R ｅ C substituted with ２－６ alkenyl, 0 to 5 R ｅ C substituted with ２－６ alkynyl, 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or O, S(=O) ｐ and N, and 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl; or R ａ and R ａ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ and N, and 0 to 5 R ｅ forming a 3- to 12-membered heterocyclyl substituted with R ｂ is H, 0 to 5 R ｅ C substituted with １－６ alkyl, 0 to 5 R ｅ C substituted with ２－６ alkenyl, 0 to 5 R ｅ C substituted with ２－６ alkynyl, 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or O, S(=O) ｐ and N, and 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ - 3 to 12 membered heterocyclyl; R ｃ is 0 to 5 R ｅ C substituted with １－６ alkyl, 0 to 5 R ｅ C substituted with ２－６ alkenyl, 0 to 5 R ｅ C substituted with ２－６ alkynyl, 0 to 5 R ｅ C substituted with ３－６ Carbocyclyl or O, S(=O) ｐ and N, and 0 to 5 R ｅ 3-12 membered heterocyclyl substituted with R ｄ is H, C １－４ Alkyl or C ３－６ is cycloalkyl; R ｅ Halo, CN, NO ２ , =O, 0 to 5 R ｇ C substituted with １－６ alkyl, 0 to 5 R ｇ C substituted with ２－６ alkenyl, 0 to 5 R ｇ C substituted with ２－６ alkynyl, 0 to 5 R ｇ -substituted with -(CH ２ ) ｎ -C ３－６ Carbocyclyl, O, S(=O) ｐ and N, and 0 to 5 R ｇ -substituted with -(CH ２ ) ｎ -3 to 12-membered heterocyclyl, -(CH ２ ) ｎ OR ｆ , -C(=O)R 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, C ３－６ Cycloalkyl, aryl or O, S(=O) ｐ and N; or R ｆ and R ｆ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ and N, forming a 3- to 12-membered heterocyclyl containing 1 to 4 heteroatoms selected from; R ｇ Halo, CN, OH, OC １－６ Alkyl, C １－６ Alkyl, C ３－６ is cycloalkyl or aryl; n is 0, 1, 2, or 3; and p is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 2】 [During the ceremony, R ４ is halo, C substituted with 0 to 3 halo substituents １－４ -OC substituted with alkyl or 0-3 halo substituents １－４ is alkyl; R ６ is halo, CN, 0-3 R ６ａ C substituted with １－６ alkyl, 0 to 3 R ６ａ C substituted with ２－６ alkenyl, 0 to 3 R ６ａ C substituted with ２－６ alkynyl, 0 to 3 R １４ C substituted with ３－６ cycloalkyl, 0 to 3 R １４ C substituted with ３－６ cycloalkenyl, 0 to 3 R １４ Phenyl or O, S(=O) substituted with ｐ , N and NR １３ and 0 to 3 R １４ 5-6 membered heterocyclyl substituted with R ７ is H or C １－２ is alkyl; R ６ａ Halo, -OC １－４ Alkyl, C ３－６ is cycloalkyl or phenyl; R ８ is H, halo, CN or 0 to 4 halo, OH or —OC １－４ Alkyl-substituted —OC １－４ is alkyl; R ９ is 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－７ alkyl, and 0 to 2 R １０ and 0 to 2 R １１ C substituted with ２－７ alkenyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ２－７ alkynyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ３－９ cycloalkyl or 0 to 2 R １０ and 0 to 2 R １１ C substituted with ６－９ spirocycloalkyl, 0 to 2 R １０ and 0 to 2 R １１ -CH substituted with ２ -O-C ６ Carbocyclyl or 0 to 2 R １０ and 0 to 2 R １１ -O-C substituted with ３－６ is cycloalkyl; R １０ is halo, CN or C substituted with 0-4 halo or —OH substituents １－５ is alkyl; R １１ Ha-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 , -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 , —OC(═O)NR ａ R ａ , -S(=O) ｐ R ｃ , -S(=O) ｐ NR ａ R ａ , 0 to 4 R ｅ aryl substituted with 0 to 4 R ｅ C substituted with ３－６ Cycloalkyl or O, S(=O) ｐ , N and NR １２ and 0 to 4 R ｅ 4-6 membered heterocyclyl substituted with R １２ is H, C １－２ alkyl or phenyl; R １３ is H, C(=O)C １－３ C substituted with 0-2 aryl substituted with alkyl or 0-2 halo substituents １－３ is alkyl; R １４ is halo, CN substituted with 0 to 3 halo, C １－４ alkyl, substituted with 0 to 3 halo, —OC １－４ Alkyl, -(CH ２ ) ０－２ -NR ａ R ａ , 0 to 3 R ｅ -substituted with -(CH ２ ) ０－２ -aryl, 0 to 3 R ｅ -O-aryl or -(CH ２ ) ０－２ -O, S(=O) ｐ and N, and 0 to 3 R ｅ 4-9 membered heterocyclyl substituted with R ａ is H, 0 to 4 R ｅ C substituted with １－５ alkyl, 0 to 4 R ｅ C substituted with ２－５ alkenyl, 0 to 4 R ｅ C substituted with ２－５ alkynyl, 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or -(CH ２ ) ｎ -O, S(=O) ｐ and N, and 0 to 4 R ｅ or R ａ and R ａ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ and N, and 0 to 4 R ｅ forming a 4- to 9-membered heterocyclyl substituted with R ｂ is H, 0 to 4 R ｅ C substituted with １－５ alkyl, 0 to 4 R ｅ C substituted with ２－５ alkenyl, 0 to 4 R ｅ C substituted with ２－５ alkynyl, 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or -(CH ２ ) ｎ -O, S(=O) ｐ and N, and 0 to 4 R ｅ 4-9 membered heterocyclyl substituted with R ｃ is 0 to 4 R ｅ C substituted with １－５ alkyl, 0 to 4 R ｅ C substituted with ２－５ alkenyl, 0 to 4 R ｅ C substituted with ２－５ alkynyl, 0 to 4 R ｅ C substituted with ３－６ Carbocyclyl or O, S(=O) ｐ and N, and 0 to 4 R ｅ 4-9 membered heterocyclyl substituted with R ｅ is halo, CN, =O, 0 to 5 R ｇ C substituted with １－６ alkyl, 0 to 5 R ｇ C substituted with ２－６ alkenyl, 0 to 5 R ｇ C substituted with ２－６ alkynyl, 0 to 5 R ｇ -substituted with -(CH ２ ) ｎ -C ３－６ Carbocyclyl, O, S(=O) ｐ and N, and 0 to 5 R ｇ , -(CH ２ ) ｎ OR ｆ -substituted with -(CH ２ ) ｎ -4 to 9-membered heterocyclyl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , S(=O) ｐ R ｆ , C(═O)NR ｆ R 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 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 are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ and N, forming a 4- to 9-membered heterocyclyl containing 1 to 4 heteroatoms selected from; R ｇ Halo, CN, OH, C １－４ Alkyl, C ３－６ is cycloalkyl or aryl; n is 0, 1, 2, or 3; and p is 0, 1 or 2.

2. The compound of claim 1, wherein:

3. R ４ is substituted with halo or 0 to 3 halo substituents １－３ is alkyl; R ６ 0 to 3 R ６ａ C substituted with １－５ alkyl, 0 to 3 R １４ C substituted with ３－６ Cycloalkyl or O, S(=O) ｐ , N and NR １３ and 0 to 3 R １４ 5-6 membered heterocyclyl substituted with R ６ａ Halo, -OC １－４ Alkyl or C ３－６ It is a cycloalkyl R ７ is H; R ８ is substituted with 0 to 2 halo or OH １－３ alkyl and the substituent; R ９ 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－７ is alkyl; R １０ is substituted with halo, CN or 0-4 halo substituents １－４ is alkyl; R １１ Ga-OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -C(=O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , —OC(═O)NR ａ R ａ , 0 to 3 R ｅ aryl substituted with 0 to 3 R ｅ C substituted with ３－６ Cycloalkyl or O, S(=O) ｐ , N and NR １２ and 0 to 3 R ｅ 4-6 membered heterocyclyl substituted with R １２ H, C １－２ alkyl or phenyl; R １４ is substituted with halo, CN, 0-3 halo substituents １－４ alkyl, substituted with 0 to 3 halo substituents, —OC １－４ Alkyl, -(CH ２ ) ０－２ -NR ａ R ａ , 0 to 3 R ｅ -substituted with -(CH ２ ) ０－２ -aryl, 0 to 3 R ｅ -O-aryl or -(CH ２ ) ０－２ -O, S(=O) ｐ and N, and 0 to 3 R ｅ 4-9 membered heterocyclyl substituted with R ａ is H, 0 to 4 R ｅ C substituted with １－５ alkyl, 0 to 4 R ｅ C substituted with ２－５ alkenyl, 0 to 4 R ｅ C substituted with ２－５ alkynyl, 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or O, S(=O) ｐ and N, and 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -4 to 9-membered heterocyclyl; or R ａ and R ａ Together with the nitrogen atom to which they are both bonded, they form O, S(=O) ｐ and N, and 0 to 4 R ｅ forming a 4- to 9-membered heterocyclyl substituted with R ｂ is H, 0 to 4 R ｅ C substituted with １－４ alkyl, 0 to 4 R ｅ C substituted with ２－４ Alkenyl-substituted, 0 to 4 R ｅ C substituted with ２－５ alkynyl, 0 to 3 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl or O, S(=O) ｐ and N, and 0 to 3 R ｅ -substituted with -(CH ２ ) ｎ - 4- to 9-membered heterocyclyl; R ｅ is halo, CN, =O, 0 to 5 R ｇ C substituted with １－５ alkyl, 0 to 4 R ｇ C substituted with ２－５ alkenyl, 0 to 4 R ｇ C substituted with ２－５ alkynyl, 0 to 4 R ｇ -substituted with -(CH ２ ) ｎ -C ３－６ Cycloalkyl, O, S(=O) ｐ and N, and 0 to 4 R ｆ -substituted with -(CH ２ ) ｎ -4 to 9-membered heterocyclyl, 0 to 4 R ｇ -substituted with -(CH ２ ) ｎ -aryl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , S(=O) ｐ R ｆ , C(═O)NR ｆ R ｆ , N.R. ｆ C(=O)R ｆ or -(CH ２ ) ｎ NR ｆ R ｆ and R ｆ is H, 0 to 3 R ｇ C substituted with １－５ Alkyl, C ３－６ cycloalkyl or aryl; or R ｆ and R ｆ Together with the nitrogen atom to which they are both bonded, they form O, S(=O) ｐ and N, forming a 4- to 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from; R ｇ Halo, CN, OH, OC １－４ Alkyl, C １－６ Alkyl, C ３－６ is cycloalkyl or aryl; n is 0, 1, 2 or 3; and p is 0, 1 or 2; 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

4. R ４ is halo or CF ３ and R ６ 0 to 3 halo or OCC １－３ C substituted with alkyl substituents １－３ alkyl, C substituted with 0-2 halo ３－６ cycloalkyl or 【Transformation 3】 is a heterocyclyl selected from: R ８ is substituted with 0 to 1 —OH substituents １－３ is alkyl; R ９ is substituted with 0-3 halo, —OH or CN substituents １－７ is alkyl; and R １４ is substituted with halo, CN or 0-3 halo substituents １－３ is alkyl, 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

5. R ４ is halo or CF ３ and R ６ is substituted with 0 to 3 halo substituents １－３ Alkyl or C ３－６ is cycloalkyl; R ９ 0 to 1 R １０ and 0 to 1 R １１ C substituted with １－３ is alkyl; R １０ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R １１ Ga-OR ｂ and R ｂ 0 to 4 R ｅ C substituted with １－４ Alkyl, -(CH ２ ) ０－１ -0 to 4 R ｅ C substituted with ３－６ Cycloalkyl, -(CH ２ ) ０－１ -0 to 4 R ｅ phenyl substituted with -(CH ２ ) ０－１ -heterocyclyl, where heterocyclyl is 【Chemistry 4】 and R ｅ is halo, CN, 0 to 5 R ｇ C substituted with １－５ Alkyl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ or C(=O)NR ｆ R ｆ and R ｆ is H, 0 to 3 R ｇ C substituted with １－４ is alkyl; R ｇ Halo, CN, OH, C １－６ Alkyl, C ３－６ is cycloalkyl or aryl; and n is 0 or 1; 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

6. R ４ is halo or CF ３ and R ６ is substituted with 0 to 3 halo substituents １－３ Alkyl or C ３－６ is cycloalkyl; R ９ 0 to 1 R １０ and 0 to 1 R １１ C substituted with １－３ is alkyl; R １０ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R １１ Ga-NR ａ R ａ and R ａ is H or 0 to 4 R ｅ C substituted with １－４ alkyl, 0 to 4 R ｅ C substituted with ３－６ cycloalkyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached, 【Transformation 5】 forming a heterocyclyl selected from: R ｅ is halo, CN, =O, 0 to 5 R ｇ C substituted with １－４ Alkyl, -(CH ２ ) ｎ -C ３－６ Cycloalkyl, O, S(=O) ｐ and N, containing 1 to 4 heteroatoms selected from -(CH ２ ) ｎ -4 to 6-membered heterocyclyl, -(CH ２ ) ｎ -aryl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , S(=O) ｐ R ｆ , C(═O)NR ｆ R ｆ or -(CH ２ ) ｎ NR ｆ R ｆ ; R ｆ is H or C １－４ is alkyl; and R ｇ Halo, CN, OH, OC １－４ Alkyl, C １－４ Alkyl, C ３－６ is cycloalkyl or aryl; 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

7. R ４ is halo or CF ３ and R ６ is 0 to 3 halo substituents or C ３－６ C substituted with cycloalkyl １－３ is alkyl; R ９ 0 to 1 R １０ and 0 to 1 R １１ C substituted with １－３ is alkyl; R １０ is substituted with halo or 0 to 4 halo １－４ is alkyl; R １１ -OC(=O)NR ａ R ａ and R ａ is H, 0 to 4 R ｅ C substituted with １－４ alkyl, 0 to 4 R ｅ C substituted with ３－６ cycloalkyl or 0 to 4 R ｅ or R ａ and R ａ together with the nitrogen atom to which they are both attached, 【Transformation 6】 forming a heterocyclyl selected from: R ｅ is halo, CN, =O, 0-3 R ｇ C substituted with １－４ Alkyl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , S(=O) ｐ R ｆ , C(═O)NR ｆ R ｆ , N.R. ｆ C(=O)R ｆ or -(CH ２ ) ｎ NR ｆ R ｆ and R ｆ is H or C １－４ is alkyl; R ｇ Halo, CN, OH, C １－４ Alkyl, C ３－６ is cycloalkyl or aryl; n is 0 or 1; and p is 2; 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

8. R ４ is halo or CF ３ and R ６ is 0 to 3 halo substituents or C ３－６ C substituted with cycloalkyl １－３ is alkyl; R ９ 0 to 1 R １０ and 0 to 1 R １１ C substituted with １－３ is alkyl; R １０ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R １１ -NHC(=O)R ｂ or -NR ａ C(=O)OR ｂ and R ａ is H or C １－３ is alkyl; R ｂ 0 to 3 R ｅ C substituted with １－４ alkyl, 0 to 3 R ｅ C substituted with ３－６ cycloalkyl, 0 to 3 R ｅ phenyl substituted with 【Transformation 7】 is a heterocyclyl selected from: R ｅ is halo, CN, 0 to 4 R ｇ C substituted with １－４ Alkyl, -OR ｆ , -C(=O)OR ｆ , C(═O)NR ｆ R ｆ and R ｆ is H or C １－４ is alkyl; and R ｇ Halo, CN, OH, C １－４ Alkyl, C ３－６ is cycloalkyl or aryl; 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

9. R ４ is substituted with halo or 0 to 3 halo substituents １－４ is alkyl; R ６ is substituted with 0 to 3 halo substituents １－３ Alkyl or C ３－６ is cycloalkyl; R ８ Ga-OC １－３ is alkyl; R ９ 0 to 2 R １０ or 0 to 2 R １１ C substituted with ２－４ alkenyl; R １０ is substituted with 0 to 4 halo or OH substituents １－２ is alkyl; R １１ -C(=O)R ｂ , -C(=O)OR ｂ or -C(=O)NR ａ R ａ and R ａ is H, 0 to 4 R ｅ C substituted with １－４ alkyl, 0 to 4 R ｅ C substituted with ３－６ cycloalkyl or 0 to 4 R ｅ or R ａ and R ａ Together with the nitrogen atom to which they are both bonded, they form O, S(=O) ｐ and N, and 0 to 4 R ｅ forming a 4- to 9-membered heterocyclyl substituted with R ｂ is H or C １－４ is alkyl; R ｅ is halo, 0 to 5 R ｇ C substituted with １－６ Alkyl, -(CH ２ ) ０－１ OR ｆ or -C(=O)OR ｆ and R ｆ is H or C １－４ is alkyl; and R ｇ is C １－４ is alkyl, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

10. R ４ is halo or CF ３ and R ６ is CF ３ or cyclopropyl; R ８ Ga-OC １－３ is alkyl; R ９ 0 to 1 R １１ C substituted with ２－３ alkenyl; R １１ -C(=O)NR ａ R ａ and R ａ is H or 0 to 4 R ｅ C substituted with １－４ alkyl, 0 to 4 R ｅ C substituted with ３－６ cycloalkyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached, 【Transformation 8】 forming a heterocyclyl selected from: R ｅ is halo, CN, 0 to 4 R ｇ C substituted with １－４ Alkyl, -(CH ２ ) ０－１ OR ｆ , -C(=O)OR ｆ and R ｆ is H or C １－４ is alkyl; and R ｇ is C １－３ is alkyl, 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof.

11. R ４ is substituted with halo or 0 to 3 halo substituents １－４ is alkyl; R ６ 0 to 3 halo or C ３－６ C substituted with cycloalkyl １－３ is alkyl; R ８ is substituted with 0 to 2 halo or OH １－３ alkyl and the substituent; R ９ 0 to 2 R １１ C substituted with ２－６ is alkynyl; R １１ Ga-OR ｂ or —OC(═O)NR ａ R ａ ; R ａ is H, 0 to 4 R ｅ C substituted with １－４ alkyl, 0 to 4 R ｅ C substituted with ３－６ cycloalkyl or 0 to 4 R ｅ is phenyl substituted with; R ｂ is H or C １－４ is alkyl; and R ｅ is halo or C １－４ is alkyl, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

12. R ４ is substituted with halo or 0 to 3 halo substituents １－４ is alkyl; R ６ is substituted with 0 to 3 F substituents １－２ Alkyl or C ３－６ is cycloalkyl; R ８ Ga-OC １－３ is alkyl; R ９ is C ３－９ Cycloalkyl, —O—C ３－９ Cycloalkyl or fused C ３－６ cycloalkyl, each of which is 0 to 2 R １０ and 0 to 2 R １１ is replaced by R １０ is substituted with halo, CN or 0-4 halo or —OH substituents １－４ is alkyl; R １１ Ga-OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ or -OC(=O)NR ａ R ａ and R ａ is H, 0 to 4 R ｅ C substituted with １－４ alkyl, 0 to 4 R ｅ C substituted with ３－６ cycloalkyl or 0 to 4 R ｅ or R ａ and R ａ Together with the nitrogen atom to which they are both bonded, they form O, S(=O) ｐ and N, and 0 to 4 R ｅ forming a 4- to 6-membered heterocyclyl substituted with R ｂ H, C １－４ Alkyl or O, S(=O) ｐ and N; R ｅ Halo, -(CH ２ ) ｎ OR ｆ or -C(=O)OR ｆ and R ｆ is H or C １－３ is alkyl, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

13. R ４ is F or CF ３ and R ６ is CF ３ , cyclopropyl, cyclobutyl or cyclopentyl; R ８ Ga-OC １－３ is alkyl; R ９ is cyclobutyl, cyclopentyl, cyclohexyl, bicycle[2,2,2]octanyl, each of which has 0 to 2 R １０ and 0 to 2 R １１ is substituted with; R １０ F, CN, CH ２ OH, C(CH ３ ) ２ OH or CHC(CH ３ ) ２ OH; R １１ -OH, -NHC(=O)R ｂ , -C(=O)OR ｂ or -OC(=O)NR ａ R ａ and R ａ is H, 0 to 3 R ｅ C substituted with １－４ alkyl, 0 to 3 R ｅ C substituted with ３－６ cycloalkyl or 0 to 3 R ｅ is phenyl substituted with; R ｂ H, C １－４ Alkyl or 【Chemistry 9】 and R ｅ Halo, -(CH ２ ) ０－１ OR ｆ or -C(=O)OR ｆ and R ｆ is H or C １－３ is alkyl, 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof.

14. R ４ is substituted with halo or 0 to 3 halo １－４ is alkyl; R ６ is substituted with 0 to 3 F substituents １－２ Alkyl or C ３－６ is cycloalkyl; R ８ Ga-OC １－３ is alkyl; R ９ 0 to 2 R １１ C substituted with ６－９ is a spirocycloalkyl; R １１ Ga-OR ｂ , -NR ａ R ａ or C(=O)OR ｂ and R ａ is H or C １－４ is alkyl; and R ｂ is H or C １－４ is alkyl, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

15. L is —NH; R ４ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R ６ is substituted with 0 to 3 halo １－４ Alkyl or C ３－６ is cycloalkyl; R ７ is H; R ８ is substituted with halo or 0 to 5 halo substituents １－４ is alkyl; R ９ is -S(=O) ｐ R ｃ or -S(=O) ｐ NR １５ R １５ and R １５ is H, 0 to 5 R ｅ C substituted with １－５ alkyl, 0 to 5 R ｅ C substituted with ３－１０ Carbocyclyl or O, S(=O) ｐ , N and NR １６ and 0 to 5 R ｅ or R １５ and R １５ Together with the nitrogen atom to which they are both bonded, they form O, S(=O) ｐ , N and NR １６ and 0 to 4 R ｅ forming a 4- to 9-membered heterocyclyl substituted with R １６ is H, 0 to 5 R ｅ C substituted with １－４ Alkyl, —C(═O)R ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -S(=O) ｐ R ｆ or -S(=O) ｐ NR ｆ R ｆ ; R ｃ 0 to 3 R ｅ C substituted with １－３ is alkyl; R ｅ Halo, -(CH ２ ) ｎ OR ｆ , C(=O)OR ｆ or C １－６ is alkyl; R ｆ is H or C １－３ is alkyl; and n is 0, 1 or 2; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. R ４ is F or CF ３ and R ６ is CF ３ or C ３－６ is cycloalkyl; R ８ is F or -OC １－２ is alkyl; R ９ is -S(=O) ２ NR １５ R １５ and R １５ is H, 0 to 5 R ｅ C substituted with １－５ alkyl, 0 to 5 R ｅ phenyl substituted with or 【Chemistry 10】 is a heterocyclyl selected from: or R １５ and R １５ together with the nitrogen atom to which they are both attached, 【Chemistry 11】 forming a heterocyclyl selected from: R １６ is H, 0 to 5 R ｅ C substituted with １－３ Alkyl, —C(═O)R ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -S(=O) ｐ R ｆ or -S(=O) ｐ NR ｆ R ｆ and R ｅ is halo, =O, -(CH ２ ) ０－１ OR ｆ or C １－５ is alkyl; and R ｆ is H or C １－３ is alkyl, 16. The compound of claim 15 or a pharmaceutically acceptable salt thereof.

17. L is —NH; R ３ There are two R ４ is phenyl substituted with; R ４ is F or CF ３ and R ５ is H; R ６ is CF ３ or C ３－６ is cycloalkyl; R ７ is H; R ８ Ga-OC １－２ is alkyl; R ９ Ga-NR １７ R １７ and R １７ is H or 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -phenyl; R ｅ is halo, —OH or C １－６ is alkyl; and n is 0 or 1; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. L is —NH; R ３ There are two R ４ is phenyl substituted with; R ４ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R ５ is H; R ６ is substituted with 0 to 3 halo substituents １－４ Alkyl or C ３－６ is cycloalkyl; R ７ is H; R ８ is substituted with halo or 0 to 5 halo substituents １－４ is alkyl; R ９ -C(=O)OR １５ or -C(=O)NR １５ R １５ and R １５ is H, 0 to 5 R ｅ C substituted with １－５ Alkyl, -(CH ２ ) ｎ -0 to 5 R ｅ C substituted with ３－６ cycloalkyl, 0 to 5 R ｅ Phenyl or O, S(=O) substituted with ｐ , N and NR １６ and 0 to 5 R ｅ or R １５ and R １５ Together with the nitrogen atom to which they are both bonded, they form O, S(=O) ｐ , N and NR １６ and 0 to 5 R ｅ forming a 4- to 9-membered heterocyclyl substituted with R １６ is H, 0 to 5 R ｅ C substituted with １－６ Alkyl, —C(═O)R ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -S(=O) ｐ R ｆ or -S(=O) ｐ NR ｆ R ｆ and R ｃ 0 to 5 R ｅ C substituted with １－５ Alkyl; R ｅ is substituted with halo, ═O, 0-2 OH substituents １－６ Alkyl, -(CH ２ ) ｎ OR ｆ , -C(=O)R ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -NR ｆ C(=O)R ｆ , -S(=O) ｐ R ｆ or -S(=O) ｐ NR ｆ R ｆ and R ｆ is H or C １－３ is alkyl; and n is 0, 1 or 2; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. R ４ is F or CF ３ and R ６ is CF ３ or C ３－６ is cycloalkyl; R ８ is halo or -OC １－２ is alkyl; R ９ -C(=O)NR １５ R １５ and R １５ is H, 0 to 5 R ｅ C substituted with １－５ Alkyl, —CH ２ -0 to 5 R ｅ C substituted with ３－６ cycloalkyl, 0 to 5 R ｅ phenyl substituted with or 【Chemistry 12】 is a heterocyclyl selected from: or R １５ and R １５ together with the nitrogen atom to which they are both attached, 【Chemistry 13】 forming a heterocyclyl selected from: R １６ is H or 0 to 5 R ｅ C substituted with １－５ is alkyl; R ｅ C substituted with halo, ═O, 0-1 OH １－６ Alkyl, -(CH ２ ) ０－１ OR ｆ , -C(=O)R ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -NR ｆ C(=O)R ｆ , -S(=O) ｐ R ｆ or -S(=O) ｐ NR ｆ R ｆ and R ｆ is H or C １－３ is alkyl, 20. The compound of claim 18 or a pharmaceutically acceptable salt thereof.

20. Formula (III); 【Chemistry 14】 [During the ceremony, R ３ is 0 to 5 R ４ -CHR substituted with ｄ -C ３－６ -cycloalkyl or 0 to 5 R ４ is phenyl substituted with; R ４ is halo, CN or C substituted with 0 to 5 halo substituents １－４ is alkyl; R ５ is H; R ６ is 0 to 3 R ６ａ C substituted with １－３ alkyl, 0 to 5 R １４ C substituted with ３－６ Cycloalkyl or O, S(=O) ｐ , N; and 0 to 5 R １４ 3-6 membered heterocyclyl substituted with R ７ is H; R ６ａ is a halo; R ８ Ha-OC １－３ is alkyl; R ９ is -C(=O)NR １５ R １５ , 0 to 2 R １０ and 0 to 2 R １１ -CH substituted with ２ -O-phenyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ３－９ cycloalkyl or 0 to 2 R １０ and 0 to 2 R １１ -O-C substituted with ３－６ is cycloalkyl; R １０ is halo, CN or C substituted with 0-4 halo or —OH substituents １－４ is alkyl; R １１ Ha-OR ｂ , —OC(═O)NR ａ R ａ or -C(=O)OR ｂ and R １４ Halo, CN or C substituted with 0-3 halo substituents １－４ is alkyl; R １５ is H, 0 to 3 R ｅ C substituted with １－５ alkyl, 0 to 3 R ｅ -substituted with -(CH ２ ) ｎ -C ３－１０ carbocyclyl; or R １５ and R １５ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ , N and NR １６ and 0 to 3 R ｅ forming a 4- to 9-membered heterocyclyl substituted with R １６ is H or 0 to 5 R ｅ C substituted with １－４ is alkyl; R ａ is H, 0 to 5 R ｅ C substituted with １－４ Alkyl, C ３－６ Carbocyclyl or -(CH ２ ) ｎ -O, S(=O) ｐ and N, and 0 to 5 R ｅ 4-9 membered heterocyclyl substituted with R ｂ is H or C １－４ is alkyl; R ｄ is H or C １－３ is alkyl; R ｅ is halo, 0 to 3 R ｆ C substituted with １－４ Alkyl, OR ｆ or -S(=O) ２ C １－４ is alkyl; R ｆ is H or C １－４ is alkyl; R ｇ is halo or —OH; n is 0 or 1, 2 or 3; and p is 0, 1 or 2.

2. The compound of claim 1, wherein:

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

22. 22. The pharmaceutical composition of claim 21 for treating a disease associated with relaxin.

23. 23. The pharmaceutical composition of claim 22, wherein the disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary vascular disease, acute heart failure, chronic heart failure, and iatrogenic cardiac injury.

24. 24. The pharmaceutical composition of claim 23, wherein the disease is heart failure.

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