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 the compound JPEG2024540163000275.jpg4839, 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 / 273,242, filed October 29, 2021, the disclosure of which is incorporated by reference in its entirety herein. [Background technology]

[0002] 2. 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 use thereof in the treatment of, for example, heart failure, fibrotic diseases and related diseases such as pulmonary diseases (e.g., idiopathic pulmonary fibrosis), renal diseases (e.g., chronic renal disease), and liver diseases (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, whose activity was first discovered in 1926 when Frederick Hisaw injected an extract from porcine corpus luteum 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 relaxin receptor in 2002 (Hsu SY., et al., Science, 2002, 295, 671-674). RXFP1 is reasonably well conserved between mouse and human, with 85% amino acid identity, and is ubiquitously expressed in humans and other species (Halls ML., et al., Br. J. Pharmacol., 2007, 150, 677-691). The relaxin and RXFP1 cell signaling pathways are cell type dependent and fairly 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, where 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 relaxin has 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 Electolyte 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 HF patients, as excessive fibrosis, impaired arterial compliance and worsening renal function are all common features in patients with heart failure (Mohammed SF., et al., Circ., 2015, 131, 550-559, Wohlfahrt P., et al., Eur. J. Heart Fail., 2015, 17, 27-34, Damman K., et al., Prog. Cardiovasc. Dis., 2011, 54, 144-153).

[0005] Heart failure (HF), hemodynamically defined as "inadequate total body perfusion to meet the metabolic demands of the body as a result of cardiac pump dysfunction," is a huge 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). By 2030, it is estimated that an additional 3 million people will have HF in the United States alone, 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, in the United States, 1 in 9 people will 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 disease progression. The major 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) leg edema resulting 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). Also, in relation to the severity of symptoms, HF patients are often described as "compensated" or "decompensated." 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 deterioration that can present as an acute event of pulmonary edema, decreased exercise tolerance and increased shortness of breath on exertion (Millane T., et al., BMJ, 2000, 320, 559-562).

[0007] Contrary to the oversimplified definition of poor cardiac performance as an inability to meet metabolic demands, the disease is extremely complex due to the large number of 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). The adverse events thought to be involved in the pathophysiology of HF range from very acute ones, such as myocardial infarction, to more chronic damage, such as lifelong hypertension. Historically, HF was initially described as "systolic HF," where reduced left ventricular (LV) systolic function limits blood ejection and therefore reduces the ejection fraction (EF is stroke volume / end-diastolic volume), or "diastolic HF," where active relaxation is reduced, passive stiffness is increased, and there is limited increase in LV filling during diastole, but global 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 realized that diastolic and systolic LV dysfunction are not uniquely specific 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 highly similar, it is currently under debate in the cardiovascular community 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 in development for the treatment of HF (Novartis, 2014). Cerulacin has been given to normal human volunteers (NHVs) and has been shown to increase RBF (Smith MC., et al., J. Am. Soc. Nephrol. 2006, 17, 3192-3197) and estimated GFR (Dahlke M., et al., J. Clin. Pharmacol., 2015, 55, 415-422). Increases in RBF were also observed in patients with stable compensated HF (Voors AA., et al., Cir. Heart Fail., 2014, 7, 994-1002). Large-scale clinical trials have observed reduced renal function deterioration, favorable changes in HF exacerbations, and reduced mortality in patients with acutely decompensated HF (ADHF) in response to in-hospital 48-hour IV Cerulaxin (Teerlink JR., et al., Lancet, 2013, 381, 29-39, Ponikowski P., et al., Eur. Heart, 2014, 35, 431-441). Suggesting that chronic administration of Cerulaxin may provide sustained benefit to HF patients, improvements in renal function based on serum creatinine levels were 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 hepatic injury (Bennett RG., Liver Int., 2014, 34, 416-426).

[0009] Taken together, there is a great deal of 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 HF patients. 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 to a number of indications in addition to HF. More specifically, chronic relaxin administration benefits patients with lung disease (e.g., idiopathic pulmonary fibrosis), kidney 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, pharma- ceutically acceptable salts or solvates, and their analogs, that 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 pharma- ceutically acceptable carrier and at least one compound of the invention or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0013] The compounds of the invention may be used for the treatment and / or prevention of heart failure, fibrotic diseases and related diseases such as 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).

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

[0015] The compounds of the present invention can be used for the preparation 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 PREFERRED EMBODIMENTS

[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 a compound of formula (I): [ka] [During the ceremony, L is -O- or -NH-; Ring A is O, S(=O) p , N and NR 16 is a 5-15 membered heterocyclyl containing 1 to 5 heteroatoms selected from; 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 Together =CR 6 R 7 where "=" is a double bond; or R 1 and R 2 together with the carbon atom to which they are attached form a dioxolanyl substituted with 0 to 1 aryl substituents; R 3 is 0 to 5 R 4 C replaced with 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 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 9 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 is H, halo, CN, 0-3 R 6a C replaced with 1-7 Alkyl, 0 to 3 R 6a C replaced with 2-7 Alkenyl, 0 to 3 R 6a C replaced with 2-7 Alkynyl, -C(=O)OR 6b , -CONR 6b R 6b, 0 to 5 R 14 Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p , N or NR 14a and 0 to 5 R 14 is a 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 0-1 aryl 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 =O,C 1-4 Alkyl or 0-5 halo, -OH, -OC 1-4 Alkyl, C 3-6 -OC substituted with cycloalkyl, aryl or 3-6 membered heterocyclyl substituents 1-6 is alkyl; R 9 is halo, CN, -C(=O)OR b , -C(=O)NR 17 R 17 , 0 to 4 R 10 and 0 to 2 R 11 C replaced with 1-8 Alkyl, 0 to 2 R 10 and 0 to 2 R 11 C replaced with 2-8 Alkenyl, 0 to 2 R 10 and 0 to 2 R 11 C replaced with 2-8 Alkynyl, 0 to 3 R 10 and 0 to 2 R 11 -(A) 0-1 -C3-6 Carbocyclyl, -(A) 0-1 -0 to 2 R 10 and 0 to 2 R 11 C replaced with 6-9 Spirocycloalkyl or O, S(=O) p , N and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 -(A) 0-1 -3 to 12 membered heterocyclyl; A is -O-, -S-, -CH2O- or -OCH2-; R 10 is halo, CN, C 1-4 Alkyl, =O, -OH or -OC 1-4 is alkyl; R 11 is 0 to 5 R 12 and 0 to 2 R 13 C replaced with 1-4 Alkyl, -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , 0 to 5 R e C replaced with 3-9 Carbocyclyl, 0 to 5 Re Aryl substituted with O, S(=O) p , N and NR 15 and 0 to 5 R e is a 3- to 12-membered heterocyclyl substituted with; R 11a is H, 0 to 4 R 11b C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, 0 to 5 R e Aryl substituted with O, S(=O) p , N and NR 15 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11b are halo, -OH, -C(=O)OH, -C(=O)OC 1-4 is alkyl or aryl; R 12 is halo, -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a OR b , C substituted with 0-3 halo 1-4 Alkyl or -OH Substituent or C 3-6 is cycloalkyl; R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -NRa S(=O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , -S(=O) p R c , 0 to 3 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p and N; and 0 to 3 R e Substituted with -(CH2) n -3 to 12 membered heterocyclyl; 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) p and N; and 0 to 3 R e Substituted with -(CH2) n -3 to 12 membered heterocyclyl; R 14a is H, C(=O)C 1-4 Alkyl, 0 to 3 Si(C 1-3 C substituted with alkyl)3 1-3 is an alkyl or aryl substituted with 0-2 halo substituents; R 15 is H, C 1-4 is alkyl or aryl; R 16 is H, -C(=O)R b, -C(=O)OR b , -C(=O)NR a R a , -S(=O) p R c , 0 to 4 R 16a C replaced with 1-4 Alkyl or 0 to 4 R 16a is an aryl substituted with; R 16a is halo, C 1-4 Alkyl, OR b , C(=O)OR b or -S(=O) p R c and; R 17 is H or 0 to 3 R 10 and 0 to 2 R 11 C replaced with 1-4 alkyl; or R 17 and R 17 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 forming a 3- to 12-membered heterocyclyl substituted with; R a -H, -OC 1-6 Alkyl, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0 to 5 R e C replaced with 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 R aare combined with the nitrogen atom to which they are both bonded to form O, S(=O) p and N, with 0 to 5 R e forming a 3- to 12-membered heterocyclyl substituted with; R b is H, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0 to 5 R e C replaced with 2-6 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or O, S(=O) p and N, with 0 to 5 R e Substituted with -(CH2) n -3 to 12 membered heterocyclyl; R c is 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0 to 5 R e C replaced with 2-6 Alkynyl, C 3-6 Carbocyclyl or O, S(=O) p and N; R d is H, C 1-4 Alkyl or C 3-6 is cycloalkyl; R e is halo, CN, NO2, =O, 0-5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0 to 5 R g C replaced with 2-6 Alkynyl, 0 to 5 R g Substituted with -(CH2) n -C3-10 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)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, 0 to 2 OH or -OC 1-4 C substituted with alkyl substituents 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; forming a 3- to 12-membered heterocyclyl containing 1-5 heteroatoms selected from; R g is halo, CN, -OH, 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 pharma- ceutically 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, Ring A is O, S(=O) p , N and NR 16 is a 5-14 membered heterocyclyl containing 1-4 heteroatoms selected from: R 4 is halo, C substituted with 0-4 halo substituents 1-4 Alkyl, substituted with 0-4 halo -OC 1-4 -S(=O) substituted with alkyl or 0-4 halo substituents p C 1-4 is alkyl; R 6 is halo, 0 to 3 R 6a C replaced with 1-7 Alkyl, 0 to 3 R 14 C replaced with 3-6 Cycloalkyl, 0 to 3 R 14 C replaced with 3-6 Cycloalkenyl, 0 to 3 R 14 C replaced with 6-10 Aryl or O, S(=O) p , N and NR 14a and 0 to 3 R 14 is a 4- to 6-membered heterocyclyl substituted with; R 6a is halo, -OH, C 3-6 is cycloalkyl or aryl; R 7 is H or C 1-3 is alkyl; R 8 =O or 0 to 5 halo, -OH, -OC 1-4 -OC substituted with alkyl or aryl substituents 1-4 is alkyl; R 9 is halo, CN, -C(=O)ORb , -C(=O)NR 17 R 17 , 0 to 3 R 10 and 0 to 2 R 11 C replaced with 1-7 Alkyl, 0 to 2 R 10 and 0 to 2 R 11 C replaced with 2-7 Alkenyl, 0 to 2 R 10 and 0 to 2 R 11 C replaced with 2-7 Alkynyl, 0 to 3 R 10 and 0 to 2 R 11 Phenyl or O, S(=O) substituted with p and 0 to 3 R 10 and 0 to 2 R 11 is a 3- to 12-membered heterocyclyl substituted with; R 10 is halo, CN, C 1-4 Alkyl, -OH or -OC 1-4 is alkyl; R 11 is 0 to 1 R 12 and 0 to 1 R 13 C replaced with 1-3 Alkyl, -OR b , -NR a R a , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, O, S(=O) p , N and NR 15 and 0 to 5 Re is a 4- to 6-membered heterocyclyl substituted with; R 12 is halo, -C(=O)OR b , -C(=O)NHR a or C substituted with 0-3 halo or OH substituents 1-4 is alkyl; R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(=O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a or -S(=O) p R c and; R 14 is halo, CN, C substituted with 0-3 halo substituents 1-4 Alkyl, substituted with 0-3 halo substituents -OC 1-4 is alkyl; R 14a is H, -C(=O)C 1-4 C substituted with 0-3 aryl substituted with alkyl or 0-2 halo substituents 1-3 is alkyl; R 16 is H, 0 to 4 R 16a C replaced with 1-3 Alkyl or 0 to 4 R 16a is an aryl substituted with; R 16a is halo, C 1-3 Alkyl, OR b , C(=O)ORb or -S(=O) p R c and; R 17 is H or C 1-3 alkyl; or R 17 and R 17 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 forming a 3- to 10-membered heterocyclyl substituted with; R a is H, 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0 to 5 R e C replaced with 2-5 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 10 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 5 R e forming a 3- to 10-membered heterocyclyl substituted with; R b is H, 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0 to 5 R e C replaced with 2-5 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 10 membered heterocyclyl; R c is 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0 to 5 R e C replaced with 2-5 Alkynyl, C 3-6 Carbocyclyl or O, S(=O) p and N; R e is halo, CN, =O, 0-5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0 to 5 R g C replaced with 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 Substituted with -(CH2) n -4 to 6 membered heterocyclyl, -(CH2) n OR f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f , -NR f C(=O)OR f , -OC(=O)NR f R f or -(CH2) n NRf R f and; R f is H, C 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 attached form a heterocyclyl; R g is halo, CN, -OH, 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 pharma- ceutically acceptable salt thereof.

[0021] In a third aspect within the second aspect, the present invention provides a compound of formula (III): [ka] [During the ceremony, [ka] teeth [ka] and; R 4 is halo or C substituted with 0 to 4 halo substituents 1-3 is alkyl; R 6 is halo, 0 to 3 R 6a C replaced with 1-4 Alkyl, C 3-6 Cycloalkyl, 0 to 3 R 14 phenyl, naphthyl or 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R 6a is halo, -OH or C 3-6 is cycloalkyl; R 7 is H; R 8 -OC is substituted with 0-5 halo or -OH substituents 1-4 is alkyl; R 9 is halo, CN, -C(=O)OR b , -C(=O)NR 17 R 17 , 0 to 3 R 10 and 0 to 2 R 11 C replaced with 1-5 Alkyl, 0 to 2 R 10 and 0 to 2 R 11 C replaced with 2-4 Alkynyl or 0 to 3 R 10 and 0 to 2 R 11 Phenyl or O, S(=O) substituted with p and 0 to 3 R 10 and 0 to 2 R 11 3-9 membered heterocyclyl substituted with; R 10 is halo, CN, C 1-4 is alkyl or -OH; R 11 -OR b and -C(=O)OR b , -C(=O)NR a R a , 0 to 1 R 12 and 0 to 1 R 13 C replaced with 1-3 Alkyl or 0 to 5 R e C replaced with 3-6 is cycloalkyl; R 12 is halo, -C(=O)OR b or C substituted with 0-3 halo or OH substituents 1-3 is alkyl; R 13 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)ORb , -NR a S(=O) p R c , -OC(=O)NR a R a , -OC(=O)NR a OR b or -S(=O) p R c and; R 17 and R 17 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 forming a 3- to 10-membered heterocyclyl substituted with; R a is H, 0 to 5 R e C replaced with 1-6 Alkyl, -(CH2) n -0 to 5 R e or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl; or R a and R a are combined with the nitrogen atom to which they are both attached and consist of 0 to 5 R e forming a heterocyclyl substituted with; R b is H, 0 to 5 R e C replaced with 1-6 Alkyl, -(CH2) 0-1 -0 to 5 R e C replaced with 3-6 Cycloalkyl, -(CH2) 0-1 -0 to 5 R e or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl; R e is halo, CN, =O, C(=O)OH, C 1-6 Alkyl, (CH2) n ORf or -S(=O) p R f and; R f is H or C 1-3 is alkyl; and n is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt thereof.

[0022] In a fourth aspect within the third aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof: R 4 is halo or C substituted with 0-4 F substituents 1-4 is alkyl; R 6 0 to 3 R 6a C replaced with 1-3 Alkyl, C 3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S, and N; R 6a is a halo; R 7 is H; R 8 -OC is substituted with 0-4 halo or OH substituents 1-3 is alkyl; R 9 teeth [ka] and; R 10 is a halo; R 11 -C(=O)OR b or 0 to 1 R 12 and 0 to 1 R 13 C replaced with 1-2 is alkyl; R 12 is halo, -C(=O)OR b or C substituted with 0-3 halo or OH substituents 1-2 is alkyl; R13 -OR b , -NR a R a , -OC(=O)NR a R a or -S(=O) p R c and; R a is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH2) n -phenyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl; or R a and R a are combined with the nitrogen atom to which they are both attached and are 0 to 4 R e forming a heterocyclyl substituted with; R b is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH2) n -phenyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 is alkyl; R e is halo, CN, =O, C 1-5 is alkyl; and n is 0, 1, or 2 Provide something.

[0023] In a fifth aspect within the fourth aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof: R 4 is F or CF3; R 6 is CF3, cyclopropyl, phenyl or [ka] and; R 8 -OC is substituted with 0-2 OH substituents 1-4 is alkyl; R 9 teeth [ka] and R 10 is F; R 11 -C(=O)OR b or [ka] and; R 12 is halo, -C(=O)OR b or CF3; R 13 is -OH or -OC(=O)NR a R a and; R a is H, C 1-4 Alkyl, C 3-6 is cycloalkyl or phenyl; and R b is H or C 1-3 Alkyl Provide something.

[0024] In a sixth aspect within the second aspect, the present invention provides a compound of formula (III): [ka] [During the ceremony, [ka] teeth [ka] and; R 4 is halo or C substituted with 0-4 halo1-4 is alkyl; R 6 0 to 3 R 6a C replaced with 1-4 Alkyl, C 3-6 Cycloalkyl, 0 to 3 R 14 or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R 6a is a halo; R 7 is H; R 8 -OC is substituted with 0-5 halo or OH substituents 1-4 is alkyl; R 9 is halo, CN, 0-3 R 10 C replaced with 1-4 Alkyl or 0 to 3 R 10 and 0 to 2 R 11 is phenyl substituted with; R 10 is halo, CN or C 1-4 is alkyl; R 11 -C(=O)OR b ;R 16 is H, 0 to 4 R 16a C replaced with 1-4 Alkyl or 0 to 4 R 16a is phenyl substituted with; R 16a is halo, -OR b , -C(=O)OR b or -S(=O) p R c and; R b is H or C 1-4 is alkyl; and R c is C 1-3 It is alkyl. or a pharma- ceutically acceptable salt thereof.

[0025] In a seventh aspect within the second aspect, the present invention provides a compound of formula (III): [ka] [During the ceremony, [ka] teeth [ka] and; R 4 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 6 0 to 3 R 6a C replaced with 1-4 Alkyl, C 3-6 Cycloalkyl, 0 to 3 R 14 or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R 7 is H; R 8 -OC is substituted with 0-5 halo or OH substituents 1-4 is alkyl; R 9 is halo, CN or 0-3 R 10 C replaced with 1-4 is alkyl; R 10 is a halo; R 16 is H, 0 to 4 R 16a C replaced with 1-4 Alkyl or 0 to 4 R 16a is an aryl substituted with; R 16a is halo, C 1-4 Alkyl or C(=O)OR b It is. or a pharma- ceutically acceptable salt thereof.

[0026] In an eighth aspect within the second aspect, the present invention provides a compound of formula (III): [ka] [During the ceremony, [ka] teeth [ka] and; R 4 is halo or C substituted with 0 to 4 halo substituents 1-4 is alkyl; R 6 0 to 3 R 6a C replaced with 1-4 Alkyl, C 3-6 Cycloalkyl, 0 to 3 R 14 or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R 7 is H; R 8 -OC is substituted with 0-5 halo or OH substituents 1-4 is alkyl; R 9 is halo or CN; R 16 is H, C 1-4 Alkyl, -S(=O) p R c or 0 to 4 R 16a C replaced with 1-4 is alkyl; and R 16a is halo, C 1-4 Alkyl, -OH, OC 1-3 Alkyl or -S(=O) p C 1-3 It is alkyl. or a pharma- ceutically acceptable salt thereof.

[0027] In a ninth aspect within the second aspect, the present invention provides a compound of formula (III): [ka] [During the ceremony, [ka] teeth [ka] and; R 4 is halo or C substituted with 0-4 halo 1-4 is alkyl; R 6 0 to 3 R 6a C replaced with 1-4 Alkyl, C 3-6 Cycloalkyl, 0 to 3 R 14 or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R 7 is H; R 8 -OC is substituted with 0-5 halo or OH substituents 1-4 is alkyl; R 9 is halo or CN; R 16 is H or 0 to 4 R 16a C replaced with 1-4 is alkyl; and R 16a is a halo. or a pharma- ceutically acceptable salt thereof.

[0028] In a tenth aspect within the third aspect, the present invention provides a compound of formula (IV): [ka] (IV) [During the ceremony, [ka] teeth [ka] and; R 4 is F or CF3; R 6 is C 3-6 is cycloalkyl; R 7 is H; R 8 Ha-OC 1-3 is alkyl; R 9 -C(=O)OR b , -C(=O)NR 17 R 17 , 0 to 1 R 11 C replaced with 1-3 Alkyl, [ka] and; R 10 is halo, CN, C 1-4 is alkyl or -OH; R 11 -OR b , -C(=O)OR b , -C(=O)NR a R a , 0 to 1 R 13 C replaced with 1-3 Alkyl or 0 to 5 R e C replaced with 3-6 is cycloalkyl; R 13 is -OH; R 17 is H or 0 to 3 R 10 and 0 to 2 R 11 C replaced with 1-2 alkyl; or R 17 and R 17 together with the nitrogen atom to which they are both attached. [ka] Forming; R ais H or C 1-3 is alkyl; R b is H, 0 to 5 R e Replaced by S with C 1-3 Alkyl or 0 to 5 R e Substituted with -(CH2) 0-1 -C 3-6 is cycloalkyl; and R e is halo, CN, =O, C(=O)OH, C 1-6 Alkyl, CH2OH or -S(=O)2C 1-3 It is alkyl. or a pharma- ceutically acceptable salt thereof.

[0029] In an eleventh aspect within the first aspect, the present invention provides a compound of formula (V): [ka] (V) [During the ceremony, R 3 0 to 3 R 4 C replaced with 1-4 Alkyl, 0 to 3 R 4 -(CHR d ) n -C 3-6 - carbocyclyl; R 4 is halo, CN or C substituted with 0-5 halo substituents 1-4 is alkyl; R 6 is halo, 0 to 3 R 6a C replaced with 1-4 Alkyl, C 3-6 Cycloalkyl or 1 to 3 heteroatoms selected from O, S and N, and 0 to 5 R 14 is a 5-6 membered heterocyclyl substituted with; R 6a is halo or OH; R 7 is H; R 8 Ha-OC 1-3is alkyl; R 9 teeth [ka] and; R 10 is halo, CN, C 1-4 is alkyl or -OH; R 11 0 to 3 R 12 and 0 to 2 R 13 , CN or OR b C replaced with 1-3 is alkyl; R 12 is a halo; R 13 -OR b or C 3-6 is a carbocyclyl; R 14 Halo, CN or C substituted with 0-3 halo substituents 1-4 is alkyl; R b is H or 0 to 5 R e C replaced with 1-3 is alkyl; R d is H or C 1-4 is alkyl; R e is halo or OH; and n is 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0030] In a twelfth aspect within the first aspect, the present invention provides a compound of formula (VI): [ka] (VI) [During the ceremony, R 3 0 to 3 R 4 C replaced with 1-4 Alkyl, 0 to 3 R 4 -(CHR d ) n-C 3-6 - carbocyclyl; R 4 is halo, CN or C substituted with 0-5 halo substituents 1-4 is alkyl; R 6 is halo, 0 to 3 R 6a C replaced with 1-4 Alkyl, C 3-6 Cycloalkyl or 1 to 3 heteroatoms selected from O, S and N, and 0 to 5 R 14 is a 5-6 membered heterocyclyl substituted with; R 6a is halo or -OH; R 7 is H; R 8 is C 1-3 is alkyl; R 9 teeth [ka] and; R 10 is halo, CN, C 1-4 is alkyl or -OH; R 11 0 to 3 R 12 and 0 to 2 R 13 C replaced with 1-3 Alkyl, CN or OR b and; R 12 is a halo; R 13 -OR b or C 3-6 is a carbocyclyl; R 14 Halo, CN or C substituted with 0-3 halo substituents 1-4 is alkyl; R b is H or 0 to 5 R e C replaced with 1-3 is alkyl; R d is H or C 1-4 is alkyl; R e is halo or OH; and n is 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0031] In a thirteenth aspect within the first aspect, the present invention provides a compound of formula (VII) [ka] (VII) [During the ceremony, [ka] teeth [ka] and; R 3 is 0 to 5 R 4 -(CHR d ) n -C 3-10 - carbocyclyl; R 4 is halo, CN, C substituted with 0-5 halo or OH substituents 1-4 Alkyl, substituted with 0-5 halo substituents -OC 1-4 Alkyl or -S(=O) p R c and; R 6 0 to 3 R 6a C replaced with 1-4 Alkyl or 0 to 5 R 14 C replaced with 3-6 is cycloalkyl; R 6a is a halo; R 7 is H; R 8 is C 1-3 Alkyl or -OC 1-3 is alkyl; R 9 is -C(=O)NR 17 R17 , 0 to 3 R 10 and 0 to 2 R 11 C replaced with 3-6 Carbocyclyl or O, S(=O) p , N and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 is a 5-12 membered heterocyclyl substituted with; R 10 is halo, CN, C 1-4 Alkyl, =O, -OH or -OC 1-4 is alkyl; R 11 is 0 to 5 R 12 and 0 to 2 R 13 C replaced with 1-4 Alkyl, -S(=O) p R c , 0 to 5 R e C replaced with 3-6 is cycloalkyl; R 11a is H, 0 to 4 R 11b C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, 0 to 5 R e Aryl substituted with O, S(=O) p , N and NR 15 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11b are halo, -OH, -C(=O)OH, -C(=O)OC 1-4 is alkyl or aryl; R 12 is halo, -C(=O)OR b , C substituted with 0-3 halo or OH substituents 1-4 Alkyl or C3-6 is cycloalkyl; R 13 -OR b , -NR a R a , -OC(=O)NR a R a and; R 14 is a halo; R 17 is H or 0 to 3 R 10 and 0 to 2 R 11 C replaced with 1-4 alkyl; or R 17 and R 17 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 11a and 0 to 3 R 10 and 0 to 2 R 11 forming a 3- to 9-membered heterocyclyl substituted with; R a is H, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 3-10 carbocyclyl; or R a and R a are combined with the nitrogen atom to which they are both attached and consist of 0 to 5 R e forming a heterocyclyl substituted with; R b is H or 0 to 5 R e C replaced with 1-4 is alkyl; R c is C 1-4 is alkyl; R d is H or C 1-3 is alkyl; R e is halo, CN, NO2, =O, 0-5 R g C replaced with 1-6 Alkyl, C 3-6 Cycloalkyl or -S(=O) p Rf and; R f is H or C 1-4 is alkyl, R g is halo, CN, -OH or C 1-4 is alkyl; n is 0 or 1; and p is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0032] In a fourteenth aspect within the twelfth aspect, the present invention provides a compound of formula (VII) or a pharma- ceutically acceptable salt thereof, R 3 is 0 to 2 R 4 -CHR d -C 3-6 Cycloalkyl or 0 to 2 R 4 is phenyl substituted with; R 4 is F, CH3 or CF3; R 6 is substituted with 0 to 3 halo substituents 1-4 C substituted with alkyl or 0-3 halo substituents 3-6 is cycloalkyl; R 7 is H; R 8 is -OCH3; R 9 is -C(=O)NR 17 R 17 , [ka] and; R 10 is a halo; R 11 0 to 3 R 12 and 0 to 2 R 13 C replaced with 1-4 Alkyl, -S(=O) p R c or 0 to 3 R eC replaced with 3-6 is cycloalkyl; R 11a is H or 0 to 3 R 11b C replaced with 1-4 is alkyl; R 11b is -OH; R 12 is substituted with 0 to 3 halo substituents 1-4 is alkyl; R 13 -OC(=O)NR a R a and; R 14 is a halo; R 17 is H or 0 to 2 R 10 and 0 to 2 R 11 C replaced with 1-4 alkyl; or R 17 and R 17 are combined with the nitrogen atom to which they are both bonded to form O, S(=O) p , N and NR 11a and 0 to 2 R 10 and 0 to 2 R 11 forming a 3- to 9-membered heterocyclyl substituted with; R a is H, 0 to 4 R e C replaced with 1-4 Alkyl, 0 to 4 R e C replaced with 3-10 carbocyclyl; or R a and R a are combined with the nitrogen atom to which they are both attached and are 0 to 4 R e forming a heterocyclyl substituted with; R b is H or C 1-3 is alkyl; R c is C 1-3 is alkyl; R d is C 1-2 is alkyl; Re is C 1-4 Alkyl, C 3-6 Cycloalkyl or -S(=O) p R f and; R f is C 1-4 is alkyl; and p is 0, 1 or 2 Provide something.

[0033] In certain embodiments of Formula (I), R 1 and R 2 Together =CR 6 R 7 and R 6 and R 7 are both methyl.

[0034] In another embodiment of formula (I), R 1 and R 2 Together =CR 6 R 7 ;R 6 is CF3; R 7 is H.

[0035] In another embodiment of formula (I), R 1 and R 2 Together =CR 6 R 7 ;R 6 is halo;R 7 is H.

[0036] In another embodiment of formula (I), R 1 and R 2 Together =CR 6 R 7 ;R 6 is 0 to 1 R 14 phenyl substituted with R 7 is H;R 14 Halo, -OC 1-4 It is alkyl or phenyl.

[0037] In another embodiment of formula (I), R1 and R 2 Together =CR 6 R 7 ;R 6 is a 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from O and N; R 7 is H.

[0038] In another embodiment of formula (I), R 1 and R 2 Together =CR 6 R 7 ;R 6 is C 3-6 Cycloalkyl; R 7 is H.

[0039] In another embodiment of formula (I), R 1 and R 2 Together =CR 6 R 7 ;R 6 is substituted with halo -CH2-C 3-6 Cycloalkyl; R 7 is H.

[0040] In another embodiment of formula (I), R 1 and R 2 Together =CR 6 R 7 ;R 6 is cyclopropyl; R 7 is H.

[0041] In another embodiment of formula (I), R 3 is C 1-6 It is an alkyl.

[0042] In another embodiment of formula (I), R 3 is methyl, ethyl, propyl or butyl or pentyl.

[0043] In another embodiment of formula (I), R 3 teeth [ka] It is.

[0044] In another embodiment of formula (I), R 3 is 0 to 2 R 4 C replaced with 3-6 It is cycloalkyl.

[0045] In another embodiment of formula (I), R 3 is 0 to 2 R 4 C replaced with 3-6 It is a cycloalkenyl.

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

[0047] 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.

[0048] In another embodiment of formula (I), R 3 is 0 to 2 R 4 -(CHR d )-C 3-6 Cycloalkyl; R 4 is halo or C 1-2 R is alkyl; d is H or C 1-2 It is an alkyl.

[0049] In another embodiment of formula (I), R 3 teeth [ka] ;R 4 is halo or C 1-3 It is an alkyl.

[0050] In another embodiment of formula (I), R 3 teeth [ka] ;R 4 is C 1-2 It is an alkyl.

[0051] In another embodiment of formula (I), R 3 teeth [ka] ;R 4 is halo or CN.

[0052] In another embodiment of formula (I), R 3 -(CR d R d ) 1-2 -5-membered heterocyclyl; R d is H or methyl.

[0053] In another embodiment of formula (I), R 4 is halo, CN, C substituted with 0-3 halo 1-2 It is an alkyl substituent.

[0054] 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 an alkyl.

[0055] In certain embodiments of Formula (I), R 5 is H, halo or OH.

[0056] In certain embodiments of Formula (I), R 6 is CH3 or CF3.

[0057] In another embodiment of formula (I), R 6 is substituted with 0 to 3 halo substituents 3-6 It is cycloalkyl.

[0058] In another embodiment of formula (I), R 6 is O, S(=O) p , N and NR 13 and 0 to 3 R 14 R is a 5- to 6-membered heterocyclyl substituted with 14 is substituted with 0 to 3 halo substituents 1-3 It is an alkyl.

[0059] In certain embodiments of Formula (I), R 7 is H or CH3.

[0060] In certain embodiments of Formula (I), R 8 is halo or -OCH. In certain embodiments of formula (V), R 3 teeth [ka] ;R 4 is halo, CF3 or -OCF3; R 6 teeth [ka] C 3-6 Cycloalkyl or 0 to 3 R 6a C replaced with 1-3 R is alkyl; 6a is halo;R 14 is substituted with 0 to 3 halo substituents 1-2 R is alkyl; 7 is H;R 8 -OC is substituted with 0-1 CF3 or -OCH3 substituents 1-3R is alkyl; 9 teeth [ka] ;R 10 is C 1-4 alkyl, CN or OH; R 11 0 to 3 R 12 and 0 to 2 R 13 C replaced with 1-3 R is alkyl; 12 is a halo; and R 13 is OH or C 3-6 It is cycloalkyl.

[0061] In certain embodiments of Formula (V), R 3 teeth [ka] ;R 4 is halo, CF3 or -OCF3; R 6 teeth [ka] C 3-6 Cycloalkyl or 0 to 3 R 6a C replaced with 1-3 R is alkyl; 6a is halo;R 14 is substituted with 0 to 3 halo substituents 1-2 R is alkyl; 7 is H;R 8 -OC is substituted with 0-1 CF3 or -OCH3 substituents 1-3 R is alkyl; 9 teeth [ka] ;R 10 is C 1-4 alkyl, CN or OH; R 11 0 to 3 R 12 and 0 to 2 R 13 C replaced with 1-3R is alkyl; 12 is a halo; and R 13 is OH or C 3-6 It is cycloalkyl.

[0062] In other embodiments of formula (V), R 3 teeth [ka] ;R 4 is halo, CN or C substituted with 0-3 halo 1-2 R is alkyl; d is C 1-2 R is alkyl; 6 teeth [ka] 0 to 3 R 6a C replaced with 3-6 Cycloalkyl or 0 to 3 R 6a C replaced with 1-3 R is alkyl; 6a is halo or OH; R 14 is substituted with 0 to 3 halo substituents 1-2 R is alkyl; 7 is H;R 8 0 to 1 C 3-6 -OC substituted with cycloalkyl substituents 1-2 R is alkyl; 9 teeth [ka] ;R 10 is C 1-4 alkyl or OH; R 11 0 to 3 R 12 and 0 to 2 R 13 C replaced with 1-3 R is alkyl; 12 is a halo; and R 13 is OH or C 3-6 It is cycloalkyl.

[0063] 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 11a , R 11b , R 12 , R 13 , R 14 , R 14a , R 15 , R 16 , R 16a , R 17 , R a , R b , R c , R d , R e , R f and R g Any range of a variable substituent, including, may be used independently of any other range of a variable substituent, i.e., the invention includes combinations of the various embodiments.

[0064] Unless otherwise defined, these terms have the following meanings:

[0065] "Halo" includes fluoro, chloro, bromo and iodo.

[0066] "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 any of the following alkyl groups: C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10It 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 may be unsubstituted or substituted in which 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.

[0067] "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 that may be 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.

[0068] "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 that may be 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.

[0069] "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 link 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.

[0070] "Cycloalkyl" is intended to mean a cyclized alkyl group, including mono-, bi-, or polycyclic ring systems. "C3-C7 cycloalkyl" or "C 3-7"Cycloalkyl" is intended to include C3, C4, C5, C6 and C7 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.

[0071] "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). "C3-C7 cycloalkenyl" or "C 3-7 "Cycloalkenyl" is intended to include C3, C4, C5, C6 and C7 cycloalkenyl groups.

[0072] "Spirocycloalkyl" is intended to mean a hydrocarbon bicyclic ring system in which both rings are connected through one atom. The rings may be of different sizes and nature or of the same size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane or spirodecane.

[0073] "Bicyclic carbocyclyl" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system consisting of carbon atoms, containing two fused rings, one of which is benzo-fused to the second ring; and the second ring is a saturated, partially unsaturated or unsaturated 5- or 6-membered carbocyclic ring. A bicyclic carbocyclic group may be attached to its side group at any carbon atom that results in a stable structure. The bicyclic carbocyclic groups described herein may be substituted at any carbon, provided that 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.

[0074] An "aryl" group refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and are described, for example, in Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997).

[0075] "Benzyl" is intended to mean methyl in which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group is optionally substituted with 1 to 5 groups, preferably 1 to 3 groups.

[0076] "Heterocycle", "heterocyclyl" or "heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6- or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14- or 15-membered polycyclic heterocyclic ring that is saturated, partially or fully unsaturated and contains carbon atoms and 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of N, O and S; and includes any polycyclic group in which any of the above heterocyclic rings are fused to a benzene ring. The nitrogen and sulfur heteroatoms may be optionally 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 be optionally quaternized. If the total number of S and O atoms in a heterocyclyl exceeds 1, then preferably these heteroatoms are 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.

[0077] Examples of heterocyclyls 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,Examples of 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.

[0078] "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 a 5- or 6-membered monocyclic ring that is saturated, partially unsaturated or unsaturated and includes a 5-membered heterocyclyl, a 6-membered heterocyclyl or a carbocyclyl (with the proviso that when the second ring is carbocyclyl, the first ring is not benzo).

[0079] Bicyclic heterocyclic groups can be attached to their side groups at any heteroatom or carbon atom that results in a stable structure. 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 a 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 a heterocyclyl does not exceed 1.

[0080] 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.

[0081] "Heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member such as sulfur, oxygen or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, 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).

[0082] As used herein, the term "substituted" refers to the replacement of at least one hydrogen atom with a non-hydrogen group, so long as normal valence is maintained and the substitution results in a stable compound. If the substituent is keto (i.e., =O), 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).

[0083] 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 intended to encompass both the shown nitrogen and its N-oxide (N→O) derivative.

[0084] When any variable occurs more than one time in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, the group may be optionally substituted with up to 3 R groups, and R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0085] If a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. If substituents are 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.

[0086] The present invention includes all pharma- ceutically 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., functions as a pharmacological equivalent. 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.

[0087] 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 racemates 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 not 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, where the composition lacks optical activity.

[0088] The present invention includes all tautomeric forms, atropisomers and rotamers of the compounds.

[0089] All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

[0090] 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 configurations 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)).

[0091] The term "chiral" refers to the structural characteristic of a molecule that makes it impossible to superimpose 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 nonracemic mixture of chiral molecules rotates the plane of polarization.

[0092] 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 include 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, using the appropriate isotopically labeled reagent in place of the unlabeled reagent that would otherwise be used. Such compounds may have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds may have the potential to beneficially modify biological, pharmacological or pharmacokinetic properties.

[0093] 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. Assay buffer was HBSS buffer (with calcium and magnesium) containing 20 mM HEPES, 0.05% BSA and 0.5 mM IBMX. Cells (3000 cells / well, except for HEK293 cells stably expressing human RXFP1, 1500 cells / well) were added to 384-well Proxiplates (Perkin-Elmer). Cells were immediately treated with DMSO solutions (2% final) of test compounds at final concentrations ranging from 0.010 nM to 50 μM. Cells were incubated at room temperature for 30 min. 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 in the lysis buffer provided separately. After reaction completion, cells were lysed with equal volumes of d2-cAMP and anti-cAMP solutions. After incubation at room temperature for 1 hour, time-resolved fluorescence intensity was measured using Envision (Perkin-Elmer) with 400 nm excitation and dual emission at 590 nm and 665 nm. Calibration curves were constructed by plotting the fluorescence intensity ratio of the intensity from 665 nm emission to 590 nm emission versus cAMP concentration with external cAMP standards at concentrations ranging from 2.7 μM to 0.1 pM. The potency and activity of compounds to inhibit cAMP production was then determined by fitting a four-parameter logistic equation from the plot of cAMP levels versus compound concentration.

[0094] 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 EC50 of the hRXFP1 HEK293 cAMP assay measured with the example compounds. 50 List the values.

[0095] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0096] 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 R The compounds of formula (I) may be useful in treating indications such as pulmonary fibrosis (HF) and HFpEF, fibrotic diseases and associated diseases such as pulmonary diseases (e.g., idiopathic pulmonary fibrosis or pulmonary hypertension), renal diseases (e.g., chronic renal disease) or liver diseases (e.g., non-alcoholic steatohepatitis and portal hypertension). The compounds of formula (I) may also be useful in treating disorders resulting from or causing arterial stiffness, reduced arterial elasticity, reduced arterial compliance and distensibility, including hypertension, renal disease, peripheral arterial disease, carotid and cerebrovascular diseases (i.e., stroke and dementia), diabetes, microvascular diseases resulting in end-organ damage, coronary artery disease and heart failure. The compounds described herein may also be used to treat pre-eclampsia.

[0097] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier.

[0098] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier for the treatment of a relaxin-related disorder.

[0099] Another aspect of the invention is a method of treating cardiovascular disease, comprising administering to a patient in need of treatment an effective amount of a compound of formula (I).

[0100] Another aspect of the invention is a method of treating heart failure, comprising administering to a patient in need of treatment an effective amount of a compound of formula (I).

[0101] Another aspect of the invention is a method of treating fibrosis comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0102] Another aspect of the invention is a method of treating a disease associated with fibrosis, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0103] Another aspect of the invention is a method of treating idiopathic pulmonary fibrosis, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0104] Another aspect of the invention is a method of treating renal disease (eg, chronic renal disease) comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0105] Another aspect of the invention is a method of treating or preventing renal failure comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0106] 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).

[0107] Another aspect of the invention is a method of treating liver disease, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0108] Another aspect of the invention is a method of treating non-alcoholic steatohepatitis and portal hypertension comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0109] Another aspect of the invention is the use of compounds of formula (I) for the prevention and / or treatment of relaxin-related disorders.

[0110] Another aspect of the invention is a compound of formula (I) for use in the prevention and / or treatment of relaxin-related disorders.

[0111] Unless otherwise stated, the following terms have the meanings indicated.

[0112] 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 humans of any age with risk factors for cardiovascular disease.Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or tobacco use, lack of exercise, arrhythmia or symptoms of insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia or polycystic ovarian syndrome (PCOS).

[0113] "Treating" or "treatment" encompasses treating a disease condition as understood by practitioners in the art, and includes: (a) arresting the disease condition, i.e., halting its progression; (b) alleviating the disease condition, i.e., inducing regression of the disease condition; and / or (c) preventing the onset of a disease condition in a mammal, particularly when such a mammal is predisposed to the disease condition but has not yet been diagnosed as having it.

[0114] "Prevent" or "prevention" refers to the prediction of the probability of occurrence of a clinical disease state as understood by practitioners in the art and includes prophylactic treatment (i.e., prevention and / or risk reduction) of subclinical disease states. Patients are selected for prophylactic treatment based on factors known to be 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 the treatment of subjects who have not yet exhibited a clinical disease state, while secondary prevention is defined as the prevention of a second occurrence of the same or similar clinical disease state. "Risk reduction" or "risk reduction" includes treatment that reduces the incidence of development of a clinical disease state. That is, primary and secondary prevention treatments are examples of risk reduction.

[0115] "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 treating a disorder, as understood by practitioners in the art. When applied to a combination, the term refers to the combined amounts of active ingredients that result in a prophylactic or therapeutic effect, whether administered in combination, serially or simultaneously.

[0116] "Disorders of the cardiovascular system" 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 insufficiency, abnormal heart rhythm (or arrhythmia), permanent ischemic dysfunction ("hibernating myocardium"), transient post-ischemic dysfunction ("fainting myocardium"), heart failure, peripheral blood flow disorders, acute coronary syndromes, heart failure, heart muscle diseases (cardiomyopathy), myocardial infarction and vascular diseases (vascular diseases).

[0117] "Heart failure" refers to both acute and chronic manifestations of heart failure as well as 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 ventricular failure, left ventricular 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 failure, 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 reduced systolic function (HFrEF), chronic heart failure with preserved systolic function (HFpEF), post myocardial remodeling, angina pectoris, hypertension, pulmonary hypertension and pulmonary arterial hypertension.

[0118] "Fibrotic disorders" encompass diseases and disorders characterized by fibrosis, including, inter alia, the following diseases and disorders: liver fibrosis, liver 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, localized scleroderma, keloids, hypertrophic scarring (also following surgical procedures), nevi, diabetic retinopathy, proliferative vitreoretinopathy and disorders of connective tissue (e.g., sarcoidosis).

[0119] Relaxin-related disorders include, but are not limited to, cardiovascular disorders and fibrotic disorders.

[0120] The compounds of the present invention can be administered by any suitable means, for example, orally, such as 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, such as 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. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0121] "Pharmaceutical composition" refers to a composition containing the compound of the present invention and at least one additional pharma- ceutically 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 nature of the method of administration and the dosage form, includes adjuvants, additives or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents.

[0122] 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 subject to which the drug-containing composition is administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media as well as a variety of solid and semi-solid dosage forms. Such carriers may contain several different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for various reasons well known to those skilled in the art, for example, for stabilization of the active agent, binding agents, etc. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in many readily available sources, such as, for example, Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0123] 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 the condition; type of concurrent treatment; frequency of treatment; route of administration, renal and hepatic function of the patient and the desired effect.

[0124] As a general guideline, the daily oral dosage of each active ingredient, when used for the indicated effects, will range 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 at a constant rate infusion. The compounds of the present invention may be administered in a single daily dose or the total daily dosage may be administered in divided doses two, three or four times daily.

[0125] 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.

[0126] A dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is usually 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 (250 mg) of the compound of the present invention, 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 (250 mg) of the compound of the present invention into a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL physiological saline to produce an injectable formulation.

[0127] 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-hyperinsulinemia agents, anti-thrombotic agents, anti-retinopathy agents, anti-neuropathy 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 malignant tumors, and anti-inflammatory agents.

[0128] Additional therapeutic agents include ACE inhibitors, β-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine A1 receptor agonists, partial adenosine A1 receptors, dopamine β-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with biased agonism towards selected cell signaling pathways, angiotensin II receptor antagonists and nephrectomycin. 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.

[0129] Additional therapeutic agents also include nintedanib, pirfenidone, LPA1 antagonist, LPA1 receptor antagonist, GLP1 analogue, 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 collagen type V 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).

[0130] The above 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-listed patents, or as otherwise determined by one of skill in the art.

[0131] 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 the second therapeutic agent are combined in a single dosage unit, the active ingredients are combined in a single dosage unit, but are formulated so that the physical contact between the active ingredients is minimized (i.e., reduced). For example, one active ingredient may be enteric coated. Enteric coating of one active ingredient can not only minimize the contact of the combined active ingredients, but also control the release of one of these ingredients in the digestive tract, so that one of these ingredients is not released in the stomach, but rather in the intestine. One of the active ingredients may be coated with a material that affects delayed release through the digestive tract and at the same time acts to minimize the physical contact between the combined active ingredients. In addition, the sustained release ingredient may be further enteric coated so that the release of this ingredient 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 low viscosity grades of hydroxypropyl methylcellulose (HPMC) or other suitable materials 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.

[0132] The compounds of the present invention are also useful as standard or control compounds, e.g., quality standards or controls, in tests or assays involving RXFP1. Such compounds can be included in commercial kits, e.g., for pharmaceutical research involving RXFP1. For example, the compounds of the present invention can be used as controls in assays 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 for efficacy. The compounds of the present invention can also be used in diagnostic assays involving RXFP1.

[0133] The present invention also encompasses articles of manufacture. As used herein, articles of manufacture is intended to include, but is not limited to, kits and packages. The articles of manufacture of the present invention include (a) a first container; (b) a pharmaceutical composition contained in the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharma- ceutically acceptable salt form thereof; and (c) a package insert describing that the pharmaceutical composition can be used for dyslipidemia and its sequelae. In another embodiment, the package insert describes that the pharmaceutical composition can be used in combination (as defined above) with a second therapeutic agent for dyslipidemia and its sequelae. The articles of manufacture further include (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.

[0134] A first container is a vessel used to hold a pharmaceutical composition. This container may be for manufacturing, storage, shipping, and / or individual / bulk sale. A first container is 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.

[0135] 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), crates, 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 by tape, glue, staples, or other attachment methods, or may be placed in the second container without any physical attachment means 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 preferred that the package insert is physically attached by tape, glue, staples, or other attachment means. Alternatively, it may be adjacent to or in contact with the outside of the second container without being physically attached.

[0136] The package insert is a label, tag, marker, etc. that describes information about the pharmaceutical composition located in the first container. The information described is usually determined by the regulatory agency governing the region in which the product is sold (e.g., the U.S. Food and Drug Administration). Preferably, the package insert describes, among other things, the indications for which the pharmaceutical composition is approved. The package insert can be any material that allows a person to read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive backed paper or plastic, etc.) on which the desired information is formed (e.g., printed or applied).

[0137] chemical method The compounds of the invention can be made by a variety of methods known in the art, including those in the following schemes and specific embodiments sections. The structure numbering and variable numbering shown in the synthetic schemes differs from and does 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 invention.

[0138] It will be appreciated that another major consideration in the planning of 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 for the skilled artisan is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0139] The following abbreviations are defined: "1x" is one time, "2x" is two times, "3x" is three times, "°C" is degrees Celsius, "aq" is aqueous, "eq" or "equiv." is equivalent, "g" is gram, "mg" is milligram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normalized, "M" is molar concentration, "nM" is nanomolar concentration, "pM" is picomolar concentration, "mol" is mole, "mmol" is millimole, "min" is minute, "h" is hour, "rt" is room temperature, "RT" is retention time, "atm" is atmospheric pressure, "psi" is pounds per square inch, "conc." is concentrated, "aq" is "aqueous", "sat." is saturated, "MW" is molecular weight, "MS" or "Mass Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "LC-MS" is liquid chromatography mass spectrometry, "HPLC" is high performance liquid chromatography, "RPMS" is liquid chromatography mass spectrometry ... "HPLC" stands for reverse 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 well known to those skilled in the art.

[0140] [Table 6]

[0141] The following general methods were used in the illustrated examples unless otherwise stated. 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 eluted with a gradient of hexane and ethyl acetate or DCM and MeOH unless otherwise stated. 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 NH4OAc) and solvent B (98% ACN, 2% water, 10 mM NH4OAc) or solvent A (98% water, 2% ACN, 0.1% NH4OH) and solvent B (98% ACN, 2% water, 0.1% NH4OH). Stereoisomers separation was achieved with >95% ee or de.

[0142] The LC / MS methods used to characterize the example compounds are listed below.

[0143] 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 220nm 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

[0144] Method B: Instrumentation: 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 220nm 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

[0145] Method C: Instrumentation: 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 220nm 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

[0146] 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 220nm 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

[0147] 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 tetramethylsilane internal standard (δ units, tetramethylsilane = 0 ppm) relative to the solvent peak 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.

[0148] The synthesis of the key norbornyl intermediates is outlined in Schemes I-XI. The norbornyl intermediates can be prepared by isopropylidene bridgehead substitution starting from I-1 as described in Scheme 1. Diels-Alder cyclization with maleic anhydride gave compound I-2, which was reduced and the anhydride was ring-opened with methanol to give I-3. Curtius reaction with DPPA on the free acid in the presence of trimethylsilylethanol gave I-4. The enantiomers of I-4 were separated, 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 give I-6. Deprotection of the trifluoroacetamide using K2CO3 and MeOH gave amine I-7.

[0149] Scheme I [ka] Intermediate I-2: At 0° C., a reaction vessel was charged with Et2O (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 h, 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 Dec. 29, 2011.

[0150] 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 atm H2 (H2 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.

[0151] Intermediate I-4: To a reaction vessel was added I-3 (3.21 g, 13.5 mmol), Et3N (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 individual enantiomers using Chiral SFC. Preparative Chromatography Conditions: Apparatus: Thar 350 SFC; Column: Whelko-RR, 5 x 50 cm, 10 micron; Mobile phase: 13% IPA / 87% CO2; Flow conditions: 300 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 micron; 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.

[0152] Intermediate I-5: Peak #1 of intermediate I-4 (2.87 g, 8.12 mmol) was dissolved in 10:1 DCM / TFA and stirred at rt 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 NaHCO3 (50 mL) was added to the reaction mixture and the solution was extracted with EtOAc (3 x 50 mL). The combined organic portions were dried over Na2SO4, 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

[0153] 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 Na2SO4, filtered, concentrated under reduced pressure, subjected to silica gel chromatography, and the residue was further purified by preparative reverse-phase HPLC to give (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

[0154] Intermediate I-7: Intermediate I-6 (133 mg, 0.290 mmol) was dissolved in water (2.9 mL) and MeOH (2.9 mL) and then K2CO3 (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 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-7 (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

[0155] Scheme Ia Norbornyl intermediate IIa-8 can also be prepared from furan-2,5-dione and ferrocenium hexafluorophosphate by 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, followed by 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 separated into enantiopure IIa-8(-). [ka]

[0156] Scheme II utilizes bridgehead-substituted olefinic bromides that allow for elaboration via ozonolysis and Horner-Wadsworth-Emmons (although functionalization proceeds with a variety of reagents including, but not limited to, alkyllithium, alkylmagnesium, and Wittig reactions) and Suzuki cross-coupling reactions of more advanced intermediates. 3 This procedure is illustrated with a more advanced intermediate containing a substituted heteroaryl functionality at position 1. Scheme II [ka]

[0157] 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 O3 was bubbled through the solution until the solution turned light purple / blue. N2 was then bubbled through the solution at -78 °C to remove excess O3 (the solution became colorless). Dimethylsulfide (0.43 mL, 4.8 mmol) was then added at -78 °C and the reaction mixture was allowed to warm 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 removing the solvent 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. 1 H 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)

[0158] Intermediate II-2: To a reaction vessel was added bromo(methyl)triphenylphosphorane (419 mg, 1.17 mmol) (fine powder from grinding of 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 stirred vigorously 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

[0159] Intermediates II-3 and II-4: To a reaction vessel was added II-2 (71 mg, 0.17 mmol), DCM (3 mL) and Br2 (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 Na2S2O3 to quench excess Br2. 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 kept at −78° C. for 12 h and −40° C. for 2 h, quenched by the addition of saturated NaHCO3 at −40° C., and the resulting solution was extracted with EtOAc. The organic phase was collected, dried over Na2SO4, 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).

[0160] Racemic II-4 (4 grams) was prepared as 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.

[0161] 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

[0162] Scheme III illustrates the versatility possible with a variety of reagents, such as but not limited to alkyllithium, alkylmagnesium, Wittig, and Horner-Wadsworth-Emmons. Scheme III [ka]

[0163] 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 min and intermediate II-1 (140 mg, 0.328 mmol) was added. After 20 min, the reaction mixture was warmed to rt and stirred at rt for 2 h. 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 Na2SO4, filtered, concentrated, and subjected to silica gel chromatography purification to give 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

[0164] Intermediate III-2: To a vial containing MeOH (3 mL) cooled to 0° C. (ice / water bath) was added acetyl chloride (0.3 mL, 4 mmol) dropwise. The resulting solution was stirred at rt for 10 min 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.

[0165] Scheme IV illustrates the introduction of cycloalkyl and heterocyclic bridgehead functionalities in a manner similar to Scheme II, in this example including but not limited to isoxazole and cyclopropyl groups. Scheme IV [ka] Intermediate IV-1: To a reaction vessel containing II-4 (125 mg, 0.250 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (125 mg, 0.610 mmol), PdCl2(dppf)-CH2Cl2 adduct (50.7 mg, 0.0620 mmol) and Na2CO3 (1.5 mL, 3.00 mmol) were added. The reaction mixture was degassed with a stream of nitrogen for 3 min, sealed and stirred at 60 °C for 2 h. After cooling to 23 °C, the reaction mixture was extracted with EtOAc, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography to give IV-1 (100 mg, 0.21 mmol, 83% yield). LC-MS RT = 1.07 min; MS(ESI) m / z = 492.1 (M+H) + ; Method A

[0166] Intermediate IV-2: Intermediate IV-2 was prepared from IV-1 in the same manner as intermediate III-2 in Scheme III (67 mg, 0.16 mmol, 100% yield). RT = 0.76 min; MS (ESI) m / z = 396.0 (M+H). + ; Method A

[0167] Intermediate IV-3: Intermediate IV-3 was prepared from II-4 in the same manner as intermediate IV-1 of Scheme IV (5.1 mg, 0.01 mmol, 23% yield). RT = 1.21 min; MS (ESI) m / z = 465.1 (M+H). + ; Method A

[0168] Intermediate IV-4: Intermediate IV-4 was prepared from IV-3 in the same manner as intermediate I-7 in Scheme I (4.0 mg, 0.01 mmol, 100% yield). RT = 0.84 min; MS (ESI) m / z = 369.1 (M+H). + ; Method A

[0169] Scheme V shows the functionalization of the C7 position with a trifluoromethyl group. Scheme V [ka]

[0170] 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 an addition 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). 1 H 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)

[0171] 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 min. V-1 was added to the reaction vial and the contents were heated at 40° C. for 24 h. Concentration with a stream of nitrogen afforded V-2 as the HCl salt, which was used without further purification. LC-MS RT = 0.75 min; MS(ESI) m / z = 397.1 (M+H). + ; Method A

[0172] Scheme VI shows a general method for the preparation of intermediates, such as heterocyclic carboxylic acids to amides for coupling with V-2, utilizing a coupling agent such as (but not limited to) HATU. Further carboxylic acids can be assembled in different orders or using different protection strategies. Scheme VI [ka] Intermediate VI-1: A 20 mL vial was charged with methyl 5-bromo-2-methoxynicotinate (0.150 g, 0.610 mmol), 3-borono-4-fluorobenzoic acid (0.168 g, 0.910 mmol), Pd(OAc)2 (0.013 g, 0.061 mmol), K2CO3 (0.253 g, 1.80 mmol), followed by water (0.120 mL) and DMF (6 mL). The reaction mixture was stirred for 18 h at 23 °C. The reaction mixture was quenched by addition of HCl (20 mL, 1.0 M) and extracted with ethyl acetate (3 x 20 mL), after which the combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give intermediate VI-1 (120 mg, 0.41 mmol, 67% yield). LC-MS RT = 0.82 min; MS(ESI) m / z = 306.1 (M+H) + ; Method A

[0173] Intermediate VI-2: To a 20 mL vial containing a solution of VI-1 (0.120 mg, 0.41 mmol) in toluene (4 mL), 1,1-di-tert-butoxy-N,N-dimethylmethanamine (0.49 mL, 2.0 mmol) was added. The reaction mixture was heated at 40° C. for 2 days. The reaction mixture was concentrated under reduced pressure onto silica gel and purified by normal phase column chromatography to give VI-2 (110 mg, 0.31 mmol, 76%). LC-MS RT = 1.15 min; MS(ESI) m / z = 362.1 (M+H). + ; Method A

[0174] Intermediate VI-3: To a vial containing a solution of VI-2 (56 mg, 0.16 mmol) in THF (0.89 mL) / water (0.44 mL) / MeOH (0.22 mL) was added 1N aqueous lithium hydroxide (1N, 0.78 mL, 0.78 mmol) and the reaction mixture was stirred at rt for 18 h, then diluted with 1N HCl (5 mL) and the solution was extracted with EtOAc (3×5 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-(5-(tert-butoxycarbonyl)-2-fluorophenyl)-2-methoxynicotinic acid (54 mg, 0.16 mmol, 100% yield). LC-MS RT = 1.02 min; MS(ESI) m / z = 348.1 (M+H). + ; Method A

[0175] Alternatively, various heteroaryl halides and aryl boronic acids or esters can be cross-coupled via the general route shown in Scheme VI to provide, for example, but not limited to, aryl-pyrimidines and isomeric pyridines. Additionally, cross-coupling can be achieved with aliphatic groups via treatment with Sonogashira conditions using the appropriate alkyne, Pd(PPh3)4, CuI and triethylamine, followed by subsequent reduction with Pd / C and hydrogen and hydrolysis with lithium hydroxide, as shown in Scheme VII. Scheme VII [ka]

[0176] Intermediate VII-1: To a slurry of methyl 5-bromo-2-methoxynicotinate (0.50 g, 2.0 mmol) in TEA (20 mL) was added propargyl alcohol (0.15 mL, 2.5 mmol), Pd(PPh3)4 (0.047 g, 0.041 mmol) and CuI (3.9 mg, 0.020 mmol). The reaction mixture was degassed and heated at 80 °C under N2 for 16 h. The reaction solution was partitioned between EtOAc and water, the organic layer was separated and dried over Na2SO4. The liquid was decanted and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give methyl 5-(3-hydroxyprop-1-yn-1-yl)-2-methoxynicotinate (300 mg, 1.4 mmol, 68% yield). 1 H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 4.52 (d, J = 6.3 Hz, 2H), 4.08 (s, 3H), 3.93 (s, 3H), 1.69 (t, J = 6.2 Hz, 1H). MS (ESI) m / z 222.2 (M+H)

[0177] Intermediate VII-2: To a solution of VII-1 (0.16 g, 0.72 mmol) in ethanol (7 mL) was added Pd-C 10 wt% (0.077 g, 0.072 mmol) and hydrogen was introduced via a balloon at atmospheric pressure for 16 h. The reaction solution was filtered and concentrated under reduced pressure to give methyl 5-(4-hydroxypropyl)-2-methoxynicotinate, contaminated with the over-reduction product methyl 2-methoxy-5-propylnicotinate, which was used without further purification (0.65 g, 2.7 mmol, 65% yield). MS (ESI) m / z 226.1 (M+H)

[0178] Intermediate VII-3: To a solution of methyl VII-2 (0.022 g, 0.099 mmol) in THF (0.8 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (4 mg, 0.1 mmol) and stirred for 16 h. The reaction was then neutralized by the addition of 1 M HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, decanted, and concentrated under reduced pressure. The residue was used without further purification: 5-(3-hydroxypropyl)-2-methoxynicotinic acid (0.02 g, 0.1 mmol, 100% yield). MS (ESI) m / z 222.2 (M+H)

[0179] Scheme VIII [ka] Scheme VIII shows a general route to amides from the general aniline amide VIII-1. Analogs are prepared by activation of amine VIII-1 with Boc2O in the presence of DMAP, followed by displacement of the activated amide, VIII-2, with an amine. Further derivatives are prepared by treatment of VIII-3 with acid, followed by formation of an amide between amine VIII-4 and a carboxylic acid with a cross-coupling agent, such as but not limited to HATU. EXAMPLES

[0180] Example 1 [ka] 5-Bromo-N-[(2R,3S)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(propan-2-ylidene)bicyclo[2.2.1]heptan-2-yl]-2-methoxypyridine-3-carboxamide: To a reaction vessel was added intermediate I-7 (12 mg, 0.077 mmol), 5-bromo-2-methoxynicotinic acid (18 mg, 0.077 mmol), MeCN (2.3 mL), DIEA (0.04 mL, 0.3 mmol) and HATU (53 mg, 0.14 mmol). The reaction mixture was stirred at RT for 3 h, concentrated under reduced pressure and subjected to HPLC purification to give 1 (24 mg, 0.042 mmol, 60% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.57 (br s, 1H), 10.01 (br d, J = 6.7 Hz, 1H), 8.44 (br d, J = 2.4 Hz, 1H), 8.32 (br d, J = 2.1 Hz, 1H), 8.23 ​​- 8.17 (m, 1H), 7.83 - 7.76 (m, 1H), 7.48 (br t, J = 9.6 Hz, 1H), 4.34 - 4.25 (m, 1H), 4.05 (s, 3H), 3.12 - 3.06 (m, 1H), 3.06 - 3.00 (m, 1H), 2.95 - 2.89 (m, 1H), 1.80 - 1.63 (m, 8H), 1.40 - 1.28 (m, 2H). LC-MS RT: 2.89 min; MS (ESI) m / z = 570.2 (M+H)+; Method B

[0181] Example 20 [ka] Method for 4-(5-{[(2R,3S)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(propan-2-ylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-6-methoxypyridin-3-yl)benzoic acid: To a vial was added the compound of Example 1 (4.4 mg, 0.026 mmol), 4-boronobenzoic acid (4.4 mg, 0.026 mmol), 0.5 M aqueous K3PO4 (0.07 mL, 0.04 mmol), THF (0.3 mL) and Xphos Pd G2 (1.4 mg, 1.8 μmol). The reaction mixture was heated under microwave irradiation at 100° C. for 30 min, then cooled to RT, partitioned into water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic portions were dried over Na2SO4, filtered, concentrated, and purified by HPLC to give 20 (7.8 mg, 0.013 mmol, 71% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.58 (br s, 1H), 10.04 (br d, J = 6.9 Hz, 1H), 8.72 (br s, 1H), 8.57 (br s, 1H), 8.24 (br d, J = 3.9 Hz, 1H), 8.03 (br d, J = 8.1 Hz, 2H), 7.82 (br d, J = 7.7 Hz, 3H), 7.49 (br t, J = 9.7 Hz, 1H), 4.36 (br s, 1H), 4.13 (s, 3H), 3.12 (br d, J = 10.9 Hz, 1H), 3.08 - 3.03 (m, 1H), 2.98 - 2.93 (m, 1H), 1.85 - 1.78 (m, 1H), 1.77 - 1.70 (m, 7H), 1.41 - 1.31 (m, 2H). LC-MS RT: 2.11 min; MS (ESI) m / z = 612.2 (M+H)+; Method C

[0182] Example 21 [ka] 4-Fluoro-3-(5-{[(2R,3S)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(propan-2-ylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-6-methoxypyridin-3-yl)benzoic acid was prepared by a method similar to that of Example 20, substituting 3-borono-4-fluorobenzoic acid for 4-boronobenzoic acid. 21 (4.1 mg, 5.80 μmol, 30.1% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.59 (br s, 1H), 10.06 (br d, J = 6.6 Hz, 1H), 8.56 (br s, 1H), 8.45 (br s, 1H), 8.23 ​​(br d, J = 4.5 Hz, 1H), 8.13 - 8.04 (m, 1H), 8.03 - 7.98 (m, 1H), 7.87 - 7.79 (m, J = 2.9 Hz, 1H), 7.53 - 7.43 (m, 2H), 4.41 - 4.29 (m, 1H), 4.14 (s, 3H), 3.21 - 3.09 (m, 1H), 3.08 - 3.03 (m, 1H), 2.98 - 2.92 (m, 1H), 1.85 - 1.78 (m, 1H), 1.77 - 1.68 (m, 7H), 1.41 - 1.32 (m, 2H). LC-MS RT: 2.11 min; MS (ESI) m / z = 630.5 (M+H)+; Method B

[0183] Example 26 [ka]

[0184] Intermediate 26-1 [ka] To a vial was added methyl 6-bromo-3-methoxypyrazine-2-carboxylate (0.10 g, 0.41 mmol), 3-borono-4-fluorobenzoic acid (0.10 g, 0.61 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), K2CO3 (0.170 g, 1.2 mmol), followed by H2O (0.080 mL, 4.5 mmol) and DMF (4 mL). The reaction was degassed with nitrogen for 2 min and then stirred at rt for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, and the resulting residue was purified by HPLC to give 4-fluoro-3-(5-methoxy-6-(methoxycarbonyl)pyrazin-2-yl)benzoic acid (37 mg, 0.12 mmol, 30% yield). MS (ESI) m / z 307.0 (M+H) +

[0185] Intermediate 26-2 [ka] To a vial containing 26-1 (0.038 g, 0.12 mmol) suspended in toluene (1.3 mL) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (0.15 mL, 0.62 mmol). The reaction mixture was heated at 40° C. for 5 h. The reaction was concentrated onto silica gel and then purified by silica gel chromatography to give methyl 6-(5-(tert-butoxycarbonyl)-2-fluorophenyl)-3-methoxypyrazine-2-carboxylate (29 mg, 0.080 mmol, 65% yield). MS (ESI) m / z 363.1 (M+H) +

[0186] Intermediate 26-3 [ka] To a vial containing 26-2 (0.0296 g, 0.080 mmol) dissolved in THF (0.45 mL) / water (0.2 mL) / MeOH (0.1 mL) was added lithium hydroxide (0.4 mL, 1 M, 0.4 mmol) and the reaction mixture was stirred at rt for 18 h, then partitioned into 1N HCl (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-(5-(tert-butoxycarbonyl)-2-fluorophenyl)-3-methoxypyrazine-2-carboxylic acid (28 mg, 0.080 mmol, 100% yield). MS (ESI) m / z 349.1 (M+H) +

[0187] Example 26: To a solution of IV-2 (10 mg, 0.025 mmol), 26-3 (11 mg, 0.030 mmol), MeCN (0.25 mL) and DIEA (0.02 mL, 0.09 mmol) was added HATU (11 mg, 0.028 mmol). The reaction mixture was stirred at rt for 3 h, concentrated under reduced pressure and redissolved in 20% TFA in DCM (1 mL). The reaction was stirred at rt for 5 h then concentrated under reduced pressure and purified by HPLC to give 4-fluoro-3-(6-(((1R,2R,3S,4R,Z)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(isoxazol-4-ylmethylene)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-5-methoxypyrazin-2-yl)benzoic acid (2.8 mg, 4.0 μmol, 16% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.80 (br d, J = 7.3 Hz, 1H), 8.96 (s, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.70 (s, 1H), 8.53 (dd, J = 7.6, 1.8 Hz, 1H), 8.07 - 8.01 (m, 1H), 8.00 - 7.96 (m, 1H), 7.86 - 7.79 (m, 1H), 7.45 - 7.33 (m, 2H), 6.13 (s, 1H), 4.53 - 4.45 (m, 1H), 4.01 (s, 3H), 3.49 (br s, 1H), 3.30 - 3.24 (m, 1H), 2.92 (br s, 1H), 1.99 - 1.87 (m, 2H), 1.61 - 1.47 (m, 2H) LC-MS RT: 2.27 min; MS (ESI) m / z = 670.3 (M+H)+; Method C

[0188] Example 33 [ka]

[0189] Intermediate 33-1 [ka] Tert-butyl 3-formylbenzoate (0.10 g, 0.49 mmol) was dissolved in DCM (5 mL). To this solution was added hydroxylamine hydrochloride (34 mg, 0.49 mmol) followed by TEA (1 mL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with water and the DCM layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give tert-butyl (E)-3-((hydroxyimino)methyl)benzoate as an oil (126 mg, quantitative). 1H NMR (500 MHz, chloroform-d) δ 8.17 (m, 2H), 8.03 (d, J = 7.7 Hz, 1H), 7.80 (dt, J = 7.7, 1.4 Hz, 1H), 7.57 - 7.42 (m, 2H), 1.70 - 1.48 (m, 9H). LCMS m / z 222.08 (M+H). The oil was dissolved in DCM (5 mL) and to this solution was added NCS (0.066 g, 0.49 mmol) and the reaction mixture was stirred at rt for 18 h. To this solution was added excess methyl acrylate (2 mL) followed by saturated NaHCO3 solution (5 mL) and stirred at rt for 18 h. The reaction mixture was diluted with water (50 mL) and the solution was extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSO4), filtered, and concentrated under reduced pressure to give an oil which was purified by 12 g silica gel chromatography to give methyl 3-(3-(tert-butoxycarbonyl)phenyl)-4,5-dihydroisoxazole-5-carboxylate (140 mg, 0.46 mmol, 94%). 1 H NMR (500 MHz, chloroform-d) δ 8.20 (s, 1H), 8.06 (dt, J = 7.8, 1.4 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 5.24 (dd, J = LCMS m / z = 306.1 (M+H)

[0190] Intermediate 33-2 [ka] To a solution of 33-1 (0.085 g, 0.28 mmol) dissolved in MeOH (3 mL) was added LiOH (14 mg, 0.56 mmol) followed by water (3 mL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with water (50 mL), acidified (HCl, 1N) and the solution was extracted with EtOAc (2×25 mL). The combined organic portions were dried (MgSO4), filtered and evaporated under reduced pressure to give 3-(3-(tert-butoxycarbonyl)phenyl)-4,5-dihydroisoxazole-5-carboxylic acid, which was used without further purification (79 mg, 0.27 mmol, 97%). 1 H NMR (500 MHz, chloroform-d) δ 8.20 (t, J = 1.6 Hz, 1H), 8.07 (dt, J = 7.8, 1.4 Hz, 1H), 7.93 (dt, J = 8.0, 1.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 5.37 - 5.23 (m, 1H), 3.84 - 3.67 (m, 2H), 1.68 - 1.47 (m, 9H). LCMS m / z = 292.3 (M+H)

[0191] Example 33: 3-(5-{[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-4,5-dihydro-1,2-oxazol-3-yl)benzoic acid was prepared by the coupling method described in Example 1 using trifluoromethylnorbornyl intermediates V-2 and 33-2, followed by deprotection with TFA as in the preparation of Example 26 (4.7 mg, 7.7 mmol, 20% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.19 (br d, J = 7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.05 (br d, J = 6.4 Hz, 1H), 8.03 (br d, J = 7.9 Hz, 1H), 7.88 (br d, J = 7.3 Hz, 2H), 7.58 (br t, J = 7.8 Hz, 1H), 7.51 (br t, J = 9.6 Hz, 1H), 5.90 (q, J = 7.6 Hz, 1H), 5.23 (dd, J = 11.7, 5.6 Hz, 1H), 4.30 (br s, 1H), 3.78 (br dd, J = 17.2, 11.7 Hz, 1H), 3.22 (br d, J = 10.4 Hz, 1H), 3.05 (br s, 1H), 2.96 (br s, 1H), 2.74 (s, 1H), 1.92 - 1.83 (m, 1H), 1.74 - 1.68 (m, 1H), 1.52 - 1.35 (m, 1H). MS (ESI) m / z = 614.0 (M+H). HPLC purity: 100.0%; RT = 2.13 min. Method C

[0192] Example 34

change

[0193] Intermediate 34-1

change

[0194] Intermediate 34-2 [Chemical formula] A solution of (S)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole (0.41 g, 1.6 mmol) and 34-1 (11 g, 40 mmol) in diisopropyl ether (130 mL) was cooled to -20 °C. The resulting solution was treated with isobutyric anhydride (4.0 mL, 24 mmol) and transferred to the freezer (-20 °C < t < 0 °C) for 16 hours. The reaction mixture was diluted with MeOH (ca. 1 mL), and the solution was extracted from the phosphate buffer using EtOAc, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol (4.9 g, 18 mmol, 44% yield).

[0195] Intermediate 34-3 [ka] To a solution of 34-2 (0.50 g, 1.8 mmol) in 1,4-dioxane (4.6 ml) was added bis(pinacolato)diboron (0.93 g, 3.7 mmol), potassium acetate (0.54 g, 5.5 mmol), and PdCl2(dppf)-DCM adduct (0.15 g, 0.18 mmol). The reaction mixture was heated at 110 °C for 2 h, cooled, and partitioned between EtOAc and water. The organic phase was separated, concentrated under reduced pressure, and purified by silica gel chromatography to give (S)-2,2,2-trifluoro-1-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol (0.41 g, 1.3 mmol, 70% yield). 1 H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 5.4, 2.4 Hz, 1H), 7.67 - 7.56 (m, 1H), 7.11 (t, J = 8.7 Hz, 1H), 5.05 (q, J = 6.6 Hz, 1H), 1.39 (s, 12H). MS (ESI) m / z 251.0 (M+H-Pinacol)

[0196] Intermediate 34-4 [ka] To a flask containing methyl 6-bromo-3-methoxypyrazine-2-carboxylate (40 mg, 0.16 mmol), 34-3 (57 mg, 0.18 mmol), 0.5 M aqueous KPO (0.65 mL, 0.32 mmol) and THF (0.32 mL) was added a solution of XPhos-Pd-G (2.7 mg, 3.2 μmol). The reaction mixture was stirred at rt for 16 h and then partitioned between EtOAc and water. The organic layer was separated, dried over NaSO, decanted and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl (S)-6-(2-fluoro-5-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-3-methoxypyrazine-2-carboxylate (11 mg, 0.031 mmol, 19% yield). MS (ESI) m / z 360.9 (M+H)

[0197] Intermediate 34-5 [ka] To a solution of 34-4 (11 mg, 0.031 mmol) in THF (0.120 mL) was added water (0.030 mL) and lithium hydroxide monohydrate (1.3 mg, 0.031 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water and EtOAc and neutralized by the addition of about 0.2 mL of 1N HCl. The organic layer was separated and concentrated under reduced pressure to give (S)-6-(2-fluoro-5-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-3-methoxypyrazine-2-carboxylic acid (12 mg, quantitative), which was used without further purification. MS (ESI) m / z 346.8 (M+H)

[0198] The compound of Example 34 was prepared by coupling of 34-5 and V-2 under HATU conditions similar to Example 1 to give N-[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]-6-{2-fluoro-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}-3-methoxypyrazine-2-carboxamide (17 mg, 0.023 mmol, 68% yield). 1 H NMR (500 MHz, DMSO-d6) δ 9.85 - 9.73 (m, 1H), 8.84 - 8.71 (m, 1H), 8.09 (br d, J = 7.2 Hz, 1H), 8.02 (br d, J = 5.6 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.69 - 7.59 (m, 1H), 7.53 - 7.39 (m, 1H), 7.32 - 7.21 (m, 1H), 6.95 (br t, J = 7.3 Hz, 1H), 6.03 - 5.91 (m, 1H), 5.30 - 5.16 (m, 1H), 4.60 - 4.47 (m, 1H), 4.10 - 3.94 (m, 3H), 3.30 - 3.21 (m, 1H), 3.07 - 2.96 (m, 1H), 2.04 - 1.91 (m, 2H), 1.58 - 1.44 (m, 2H). in 1 aliphatic proton solvent. LC-MS RT: 2.59 min; MS (ESI) m / z = 724.94 (M+H)+; Method C

[0199] Example 35 [ka] (1S)-2,2,2-trifluoro-1-[4-fluoro-3-(6-{[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-5-methoxypyrazin-2-yl)phenyl]ethyl N-phenylcarbamate was prepared by carbamate formation with phenyl isocyanate: to a solution of the compound of Example 35 (0.017 g, 0.023 mmol) dissolved in DCM (2.3 mL) was added pyridine (0.038 mL, 0.47 mmol) and phenyl isocyanate (0.013 mL, 0.117 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give (S)-2,2,2-trifluoro-1-(4-fluoro-3-(6-(((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)-5-methoxypyrazin-2-yl)phenyl)ethyl phenylcarbamate (6.4 mg, 7.6 μmol, 32% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 10.25 (br s, 1H), 9.77 (br d, J = 7.3 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.23 ​​- 8.14 (m, 1H), 7.99 (dd, J = 6.3, 2.3 Hz, 1H), 7.74 (br t, J = 9.2 Hz, 2H), 7.52 (dd, J = 10.8, 8.7 Hz, 1H), 7.42 (br d, J = 7.6 Hz, 2H), 7.37 (br t, J = 9.8 Hz, 1H), 7.28 (br t, J = 7.9 Hz, 2H), 7.03 (br t, J = 7.3 Hz, 1H), 6.42 (q, J = 7.1 Hz, 1H), 5.93 (q, J = 7.6 Hz, 1H), 4.61 - 4.46 (m, 1H), 4.00 (s, 3H), 3.29 (br dd, J = 11.0, 4.0 Hz, 1H), 3.24 (br s, 1H), 2.99 (br s, 1H), 2.05 - 1.87 (m, 2H), 1.48 (br d, J = 8.2 Hz, 2H). LC-MS: 2.83 min; MS (ESI) m / z 844.28 (M+H); Method C

[0200] Example 40

change

[0201] Intermediate 40-1

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[0202] Intermediate 40-2 [ka] To a solution of 40-1 (1.0 g, 3.6 mmol) in 1,4-dioxane (9.1 mL) was added bis(pinacolato)diboron (1.8 g, 7.3 mmol), potassium acetate (1.1 g, 11 mmol) and PdCl2(dppf)-DCM adduct (0.30 g, 0.36 mmol) and the reaction was heated at 110 °C for 2 h. The reaction mixture was partitioned between EtOAc and water and the organic phase was separated, concentrated under reduced pressure and purified by silica gel chromatography to give tert-butyl 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, 3.2 mmol, 88% yield). 1 H NMR (500 MHz, CDCl3) δ 8.40 (dd, J = 5.7, 2.4 Hz, 1H), 8.08 (ddd, J = 8.6, 5.3, 2.4 Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 1.62 (s, 9H), 1.39 (s, 12H)

[0203] Intermediate 40-3 [ka] To 40-1 (0.053 g, 0.15 mmol), 40-2 (0.05 g, 0.2 mmol), 0.5 M aqueous K3PO4 (0.59 mL, 0.30 mmol) and THF (0.3 mL) in a flask was added XPhos-Pd-G2 (3 mg, 3 μmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water, the organic layer was separated, dried over Na2SO4, decanted and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl 5-(5-(tert-butoxycarbonyl)-2-fluorophenyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (47 mg, 0.099 mmol, 67% yield). MS (ESI) m / z 498.0 (M+Na)

[0204] Intermediate 40-4 [ka] To a solution of 40-3 (0.047 g, 0.099 mmol) dissolved in THF (0.4 mL) was added water (0.1 mL) and lithium hydroxide monohydrate (4.2 mg, 0.10 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water and EtOAc and neutralized by the addition of about 0.2 mL of 1N HCl. The organic layer was separated and concentrated under reduced pressure to give 5-(5-(tert-butoxycarbonyl)-2-fluorophenyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid (46 mg, 0.10 mmol, 100% yield), which was used without further purification. MS (ESI) m / z 462.1 (M+H) To a mixture of V-2 (0.043 g, 0.100 mmol), DIEA (0.052 mL, 0.299 mmol) and 40-4 (0.046 g, 0.10 mmol) slurried in MeCN (1 mL) was added HATU (0.038 g, 0.100 mmol) and the reaction mixture was stirred for 16 h. Water (0.1 mL) and TFA (0.23 mL) were added to the reaction mixture and the resulting solution was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 4-fluoro-3-(5-(((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)-6-(2-hydroxyethoxy)pyridin-3-yl)benzoic acid (5 mg, 7 μmol, 7% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.82 (br d, J = 7.3 Hz, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.12 (br d, J = 4.3 Hz, 1H), 8.09 - 8.04 (m, 1H), 8.04 - 7.98 (m, 1H), 7.82 - 7.72 (m, 1H), 7.52 - 7.39 (m, 2H), 5.94 (q, J = 7.6 Hz, 1H), 4.75 - 4.64 (m, 1H), 4.65 - 4.53 (m, 2H), 4.03 - 3.83 (m, 2H), 3.29 (br dd, J = 10.7, 4.3 Hz, 1H), 3.22 (br s, 1H), 3.01 (br s, 1H), 2.05 (br d, J = 8.5 Hz, 2H), 1.53 (br d, J = 7.9 Hz, 2H). LC-MS: 2.27 min; MS (ESI) m / z 699.97 (M+H); Method C

[0205] Example 42 [ka]

[0206] Intermediate 42-1 [ka] To a mixture of 40-1 (0.051 g, 0.14 mmol), 34-3 (0.050 g, 0.16 mmol), 0.5 M aqueous KPO solution (0.57 mL, 0.284 mmol) and THF (0.28 mL) in a flask, XPhos-Pd-G2 (2.4 mg, 2.8 μmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water, the organic layer was separated, dried over NaSO4, decanted and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl 5-(2-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (0.031 g, 0.065 mmol, 46% yield). MS (ESI) m / z 360.8 (M+H)

[0207] Intermediate 42-1 was hydrolyzed with aqueous LiOH in THF and coupled with an amine as described in the general method of Example 1, which was then dissolved in DCM (1.6 mL). To this solution, pyridine (0.025 mL, 0.31 mmol) and phenyl isocyanate (9 μL, 0.08 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in 0.8 mL MeCN and a mixture of 0.2 mL water and 0.1 mL TFA. After 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC fractionation to obtain (S)-2,2,2-trifluoro-1-(4-fluoro-3-(5-(((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)-6-(2-hydroxyethoxy)pyridin-3-yl)phenyl)ethyl phenylcarbamate (3.2 mg, 3.7 μmol, 23% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.29 (br s, 1H), 9.85 (br d, J = 7.3 Hz, 1H), 8.54 (br s, 1H), 8.46 (s, 1H), 8.13 (br d, J = 4.0 Hz, 1H), 7.85 (br d, J = 7.0 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.69 (br d, J = 4.9 Hz, 1H), 7.57 - 7.42 (m, 4H), 7.31 (br t, J = 7.8 Hz, 2H), 7.05 (br t, J = 7.3 Hz, 3H), 7.77 (m, 1H), 5.11 (m, 1H), 4.72 (t, J = 5.6 Hz, 1H), 4.81 (t, J = 5.6 Hz, 1H), 4.74 (m, 1H), 4.61 (dt, J = 10.8, 5.3 Hz, 2H), 4.05 (m, 2H), 3.84 (br s, 1H), 3.22 (br s, 1H), 3.02 (br s, 1H), 2.04 (br d, J = 11.3 Hz, 2H), 1.53 (br d, J = 7.9 Hz, 2H). Analytical LC-MS: 2.95 min; MS (ESI) m / z 873.3 (M+H); Method C

[0208] Example 49

change

[0209] Intermediate 49-1

change

[0210] Example 50 [ka] N-[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]-5-(3-hydroxypropyl)-2-methoxypyridine-3-carboxamide was prepared by HATU coupling of V-2 and VII-3 as described in the general method of Example 1 (21 mg, 0.035 mmol, 31% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.98 (d, J = 7.0 Hz, 1H), 8.21 (dd, J = 6.3, 2.3 Hz, 1H), 8.14 (dd, J = 13.6, 2.3 Hz, 2H), 7.86 - 7.73 (m, 1H), 7.49 (t, J = 9.6 Hz, 1H), 5.92 (q, J = 7.6 Hz, 1H), 4.56 - 4.43 (m, 1H), 4.04 (s, 3H), 3.39 (t, J = 6.3 Hz, 1H), 3.26 (dd, J = 11.0, 4.3 Hz, 1H), 3.22 (br s, 1H), 2.99 (br s, 1H), 2.61 (t, J = 7.6 Hz, 2H), 2.03 - 1.93 (m, 1H), 1.90 - 1.79 (m, 1H), 1.73 - 1.63 (m, 2H), 1.49 (br d, J = 7.9 Hz, 2H). Analytical LC-MS: 2.36 min; MS (ESI) m / z 590.25 (M+H); Method C

[0211] Example 51 [ka] N-[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]-2-methoxy-5-propylpyridine-3-carboxamide was isolated from Example 50 as a by-product that was an over-reduction product from hydrogenation in the preparation of intermediate 50-1 (2.1 mg, 0.0032 mmol, 2.8% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.98 (br d, J = 7.0 Hz, 1H), 8.23 ​​(br dd, J = 6.3, 2.6 Hz, 1H), 8.18 - 8.06 (m, 2H), 7.84 - 7.72 (m, 1H), 7.50 (br t, J = 9.9 Hz, 1H), 5.93 (q, J = 7.8 Hz, 1H), 4.58 - 4.41 (m, 1H), 4.05 (s, 3H), 3.33 - 3.17 (m, 2H), 3.00 (s, 2H), 2.05 - 1.76 (m, 2H), 1.64 - 1.40 (m, 4H), 0.86 (t, J = 7.3 Hz, 3H). Analytical LC-MS: 2.87 min; MS (ESI) m / z 574.12 (M+H); Method C

[0212] Example 53 [ka]

[0213] Intermediate 53-1 [ka] To a solution of tert-butyl 3-iodobenzoate (0.21 g, 0.71 mmol) in DMSO (4.7 mL) was added proline (11 mg, 0.094 mmol), ethyl 3-methoxy-1H-pyrazole-4-carboxylate (0.08 g, 0.5 mmol), K2CO3 (0.13 g, 0.94 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was partitioned between water and EtOAc, the organic layer was separated and dried over Na2SO4. The liquid was decanted and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give ethyl 1-(3-(tert-butoxycarbonyl)phenyl)-3-methoxy-1H-pyrazole-4-carboxylate (92 mg, 0.27 mmol, 57% yield). MS (ESI) m / z 347.3 (M+H) 3-(4-{[(2R,3S,7Z)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]carbamoyl}-3-methoxy-1H-pyrazol-1-yl)benzoic acid was prepared by hydrolysis of the methyl ester 53-1 with LiOH, followed by amide formation and deprotection with V-2 under HATU conditions as outlined in Example 26 to give the compound of Example 53 (8.8 mg, 0.14 mmol, 50% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.99 (br d, J = 7.0 Hz, 1H), 8.77 (br s, 1H), 8.46 - 8.16 (m, 2H), 8.04 (br d, J = 7.3 Hz, 1H), 7.95 - 7.75 (m, 2H), 7.74 - 7.58 (m, 1H), 7.51 (br t, J = 9.6 Hz, 1H), 5.93 (q, J = 7.6 Hz, 1H), 4.57 - 4.43 (m, 1H), 4.10 (s, 3H), 3.26 (br dd, J = 11.1, 3.5 Hz, 1H), 3.18 (br s, 1H), 3.04 - 2.93 (m, 1H), 1.97 (br d, J = 9.5 Hz, 1H), 1.92 - 1.83 (m, 1H), 1.57 - 1.42 (m, 2H). Analytical LC-MS: 2.44 min; MS (ESI) m / z 641.23 (M+H); Method C

[0214] Example 55

change

[0215] Intermediate 55-1

change

[0216] Intermediate 55-1. To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.47 g, 2.8 mM) dissolved in THF (5 mL) was added LHMDS (4.1 mL, 4.1 mM) and diethyl oxalate (0.40 g, 2.8 mM). The reaction mixture was stirred at rt for 16 h, followed by the addition of AcOH (10 mL) and hydrazine (66 mg, 2.1 mmol). The reaction mixture was heated at 85 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 7-cyano-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid, which was redissolved in a toluene / THF (8:3, 15 mL) mixture and NaH (60 wt % dispersion in oil) (83 mg, 2.07 mmol) was added. The reaction mixture was stirred at rt for 1 h followed by the addition of difluoroethyl triflate (440 mg, 2.1 mmol). The reaction mixture was heated at 70° C. for 18 h and cooled. Water (25 mL) was added to the reaction mixture and the solution was extracted with EtOAc (2×25 mL) and the combined organic portions were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give ethyl 2-(6-cyano-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-oxoacetate (520 mg, 1.6 mmol, 76%). 1 H NMR (400 MHz, CDCl3) δ 7.76 - 7.69 (m, 1H), 7.68 - 7.62 (m, 2H), 6.38 - 6.14 (tt, J = 55.3, 4.6 Hz, 1H), 4.92 - 4.79 (m, 2H), 4.69 - 4.41 (m, 2H), 3.11 - 2.87 (m, 4H), 1.75 - 1.23 (m, 3H). MS (ESI) m / z = 332.08 (M+H)

[0217] Intermediate 55-2. Intermediate 55-1 (520 mg, 1.6 mmol) was dissolved in MeOH / THF (5:1, 25 mL and water 5 mL). To this solution was added LiOH (75 mg, 3.2 mmol) and stirred at rt for 16 h. The reaction was diluted with HCl and extracted with EtOAc (2×100 mL) and the combined organic portions were dried over MgSO4, filtered and concentrated under reduced pressure to give 55-2 (420 mg, 88%). 1 H NMR (400 MHz, CD3OD) δ 7.90 (d, J = 8.1 Hz, 1H), 7.80 - 7.71 (m, 2H), 6.40 (tt, J = 54.9, 4.0 Hz, 1H), 5.08 - 4.90 (m, 2H), 3.11 - 2.94 (m, 4H). MS (ESI) m / z = 304.08 (M+H)

[0218] Example 55. 7-Cyano-1-(2,2-difluoroethyl)-N-((1R,2R,3S,4R,Z)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide was prepared by the general coupling method described in Example 1 using trifluoromethylnorbornyl intermediate V-2 and intermediate 55-2. (2.1 mg, 3.1 mmol, 48% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.74 - 10.65 (m, 1H), 9.33 (br d, J = 7.2 Hz, 1H), 8.16 (br s, 1H), 7.86 (br s, 2H), 7.81 (br s, 1H), 7.76 (br s, 1H), 7.57 - 7.45 (m, 1H), 6.49 (br s, 1H), 5.95 (br d, J = 6.5 Hz, 1H), 5.05 (br t, J = 14.5 Hz, 2H), 4.47 (br s, 1H), 3.27 (br d, J = 9.8 Hz, 1H), 3.02 - 2.92 (m, 2H), 2.89 (br s, 2H), 1.99 - 1.80 (m, 2H), 1.52 (br d, J = 7.7 Hz, 2H). MS (ESI) m / z = 682.3 (M+H). HPLC purity: 99.2%; retention time: 2.54 min. Method B

[0219] Example 56

change

[0220] Intermediate 56-1:

change

[0221] Example 59

Chemical Structure

[0222] Intermediate IX-1

Chemical Structure

[0223] Intermediate 59-1 [ka] To a solution of IX-1 (0.11 g, 0.19 mmol) in DCM (1.3 mL) was added 2,2-dimethylpropan-1-amine (0.14 g, 1.5 mmol). The reaction mixture was stirred overnight, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give tert-butyl ((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate (69 mg, 0.18 mmol, 95% yield). LC-MS RT: 1.21 min; MS(ESI) m / z = 377.3 (M+H). + ; Method A

[0224] Intermediate 59-2 [ka] To a flask containing 59-1 (69 mg, 0.18 mmol), HCl solution (4 M in dioxane) (1.5 mL, 6.0 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure and azeotroped with hexanes under reduced pressure to give (1R,2S,3R,4R,Z)-3-amino-7-(cyclopropylmethylene)-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide (67 mg, 0.18 mmol, 100% yield) as the hydrochloride salt, which was used without further manipulation. LC-MS RT: 0.87 min; MS(ESI) m / z = 277.1 (M+H). + ; Method A

[0225] Intermediate 59-3 [ka] To a solution of methyl 5-bromo-2-methoxynicotinate (1.2 g, 4.9 mmol) dissolved in DMF (24 mL) was added 2-isocyano-2-methylpropane (0.66 mL, 5.9 mmol), triethylsilane (0.78 mL, 4.9 mmol), 2-(dicyclohexylphosphino)biphenyl (68 mg, 0.20 mmol) and Na2CO3 (520 mg, 4.9 mmol). The reaction mixture was degassed with nitrogen for 5 min, after which Pd(OAc)2 (33 mg, 0.15 mmol) was added and the reaction mixture was heated at 65 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with 10% aqueous LiCl and ethyl acetate, and then extracted with ethyl acetate. The organic portion was dried over sodium sulfate, filtered and partially concentrated under reduced pressure (approximately 5 mL solvent remaining). To this solution was added 1M HCl (50 mL) and the resulting solution was stirred for 2 h and then quenched with 1M sodium carbonate to pH 9. The reaction mixture was extracted with ethyl acetate (3×30 mL) and the organic portion was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl 5-formyl-2-methoxynicotinate (390 mg, 2.0 mmol, 41% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 10.04 (s, 1H), 8.81 (d, J = 2.5 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 4.18 (s, 3H), 3.96 (s, 3H). LC-MS RT: 0.73 min; MS (ESI) m / z = 196.1 (M+H) + ; Method A

[0226] Intermediate 59-4 [ka] 59-3 (390 mg, 2.0 mmol) was dissolved in THF (8 mL) and water (2 mL), lithium hydroxide monohydrate (110 mg, 2.6 mmol) was added, and the reaction mixture was stirred for 30 h. The reaction mixture was neutralized with 1N HCl, ethyl acetate was added, and the resulting solution was extracted three times with ethyl acetate. The combined organic portions were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 5-formyl-2-methoxynicotinic acid (340 mg, 1.9 mmol, 96% yield), which was used without further purification. LC-MS RT: 0.57 min; MS(ESI) m / z = 182.1 (M+H) + ; Method A

[0227] Intermediate 59-5 [ka] N,N-Dimethylformamide di-tert-butyl acetal (2.5 mL, 11 mmol) was added dropwise to a solution of 59-4 (340 mg, 1.9 mmol) dissolved in toluene (0.5 mL). The solution was heated at 80° C. for 30 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and then concentrated under reduced pressure. The residue was then purified by silica gel chromatography to give tert-butyl 5-formyl-2-methoxynicotinate (200 mg, 0.85 mmol, 45% yield). 1H NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 2.2 Hz, 1H), 4.17 (s, 3H), 1.63 (s, 9H). LC-MS RT: 0.89 min; MS (ESI) m / z = 238.1 (M+H) + ; Method A

[0228] Intermediate 59-6 [ka] To a solution of 59-5 (200 mg, 0.85 mmol) in ethanol (8.5 mL) was added NaBH4 (34 mg, 0.89 mmol) and the reaction mixture was stirred at rt for 4 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give tert-butyl tert-butyl 5-(hydroxymethyl)-2-methoxynicotinate (170 mg, 0.72 mmol, 85% yield), which was used without further purification. 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.07 (s, 3H), 1.69 (t, J = 5.6 Hz, 1H), 1.62 (s, 9H). LC-MS RT: 0.81 min; MS (ESI) m / z = 240.3 (M+H) + ; Method A

[0229] Intermediate 59-7 [ka] To a solution of 59-6 (170 mg, 0.72 mmol) dissolved in DCM (3.6 mL) was added triphenylphosphine (280 mg, 1.1 mmol) and CBr4 (36 mg, 1.1 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography to give tert-butyl 5-(hydroxymethyl)-2-methoxynicotinate (180 mg, 0.60 mmol, 82% yield). 1 H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H), 4.50 (s, 2H), 4.06 (s, 3H), 1.62 (s, 9H). LC-MS RT: 1.06 min; MS (ESI) m / z = 302.1 (M+H) + ; Method A

[0230] Intermediate 59-8 [ka] To a solution of methyl 1-hydroxycyclopropane-1-carboxylate (52 mg, 0.45 mmol) in THF (1.3 mL) cooled to 0 °C was added tetrabutylammonium iodide (10 mg, 0.03 mmol) and NaH (18 mg, 0.45 mmol). The reaction mixture was warmed to rt and stirred for an additional 15 min, after which a solution of 59-7 (80 mg, 0.27 mmol) in THF (1.3 mL) was added dropwise. The reaction was stirred at rt for 3 days. The reaction was diluted with water and the aqueous solution was extracted three times with ethyl acetate. The organic portion was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give tert-butyl 2-methoxy-5-((1-(methoxycarbonyl)cyclopropoxy)methyl)nicotinate (87 mg, 0.26 mmol, 98% yield), which was used without further purification. LC-MS RT: 1.03 min; MS(ESI) m / z = 338.3 (M+H) + ; Method A

[0231] Intermediate 59-9 [ka] To a solution of 59-8 (87 mg, 0.26 mmol) dissolved in a mixture of THF (2 mL) and water (0.67 mL) was added lithium hydroxide monohydrate (16 mg, 0.36 mmol) and the reaction mixture was stirred at rt for 24 h. The reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate (3×). The organic portion was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 1-((5-(tert-butoxycarbonyl)-6-methoxypyridin-3-yl)methoxy)cyclopropane-1-carboxylic acid (76 mg, 0.24 mmol, 92% yield), which was used without further purification. LC-MS RT: 0.91 min; MS(ESI) m / z = 324.2 (M+H) + ; Method A

[0232] Intermediate 59-10 [ka] To a solution of 59-9 (76 mg, 0.24 mmol) dissolved in THF (2.0 ml) and cooled to 0° C., borane (0.47 mL, 0.47 mmol, 1 M in THF) was added and stirred at rt for 18 h. The reaction mixture was quenched with 1N HCl (0.5 mL) and then extracted with ethyl acetate (3×). The organic portion was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give tert-butyl 5-((1-(hydroxymethyl)cyclopropoxy)methyl)-2-methoxynicotinate (72 mg, 0.23 mmol, 99% yield), which was used without purification. LC-MS RT: 0.89 min; MS(ESI) m / z = 310.3 (M+H) + ; Method A

[0233] Intermediate 59-11 [ka] To a solution of 59-10 in DCM (1.7 mL) was added TFA (0.6 mL) and stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed with 1 M potassium phosphate solution (pH 7.4), followed by brine and drying over Na2SO4. The aqueous portion was then brought to pH 1 with 1N HCl and extracted three times with ethyl acetate, the organic portion was washed with brine, dried over Na2SO4, combined with the other organic portion and concentrated to give 5-((1-(hydroxymethyl)cyclopropoxy)methyl)-2-methoxynicotinic acid (57 mg, 0.22 mmol, 97% yield), which was used without further purification. LC-MS RT: 0.62 min; MS(ESI) m / z = 254.1 (M+H) + ; Method A

[0234] Example 59: To a solution of 59-11 (13 mg, 0.051 mmol) and 59-2 hydrochloride (9.7 mg, 0.031 mmol) dissolved in DMF (0.4 mL) was added BOP (16 mg, 0.037 mmol) and DIEA (0.027 mL, 0.15 mmol) and stirred for 1.5 h. The reaction mixture was diluted with MeOH, filtered through a syringe filter, and purified by HPLC to give N-[(1R,2R,3S,4R,7Z)-7-(cyclopropylmethylidene)-3-[(2,2-dimethylpropyl)carbamoyl]bicyclo[2.2.1]heptan-2-yl]-5-{[(1-hydroxycyclopropyl)methoxy]methyl}-2-methoxypyridine-3-carboxamide (6.9 mg, 0.013 mmol, 43%). 1H NMR (500 MHz, DMSO-d6) δ 10.03 (br d, J = 7.0 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.00 - 7.92 (m, 1H), 4.77 (t, J = 5.8 Hz, 1H), 4.63 (d, J = 9.8 Hz, 1H), 4.57 (s, 2H), 4.33 - 4.23 (m, 1H), 4.02 (s, 3H), 3.58 (d, J = 5.8 Hz, 1H), 3.07 - 2.95 (m, 2H), 2.81 (br dd, J = 13.0, 5.6 Hz, 1H), 1.90 - 1.81 (m, 1H), 1.76 - 1.67 (m, 1H), 1.51 - 1.42 (m, 1H), 1.33 (br t, J = 9.8 Hz, 2H), 0.81 (s, 9H), 0.75 - 0.66 (m, 4H), 0.60 - 0.52 (m, 2H), 0.32 (br d, J = 2.7 Hz, 2H). LC-MS RT: 2.20 min; MS (ESI) m / z = 512.5 (M+H) + ; Method B

[0235] Example 61

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[0236] Intermediate 61-1

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[0237] Intermediate 61-2 [ka] To a solution of 61-1 (0.59 g, 3.0 mmol) dissolved in DCM (15 mL) was added hydroxylamine hydrochloride (0.25 g, 3.6 mmol) followed by TEA (1.3 mL, 9.0 mmol) and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and water (50 mL) was added. The resulting solid was collected by filtration and dried to give methyl (E)-5-((hydroxyimino)methyl)-2-methoxynicotinate (0.43 g, 2.0 mmol, 68%) which was used without further purification. 1 H NMR (500 MHz, CDCl3) δ 8.45 (s, 2H), 8.14 (s, 1H), 4.10 (s, 3H), 3.94 (s, 3H). LCMS (ESI) m / z: 211.1 (M+H)+

[0238] Intermediate 61-3 [ka] To a solution of 61-2 (0.24 g, 1.1 mmol) in DMF (3 mL) was added NCS (0.18 mg, 1.4 mmol) and the mixture was stirred overnight. The reaction mixture was diluted with water and the resulting solid was collected by filtration to give methyl (Z)-5-(chloro(hydroxyimino)methyl)-2-methoxynicotinate (0.24 g, 1.0 mmol, 86%), which was used without purification. 1 H NMR (500 MHz, CDCl3) δ 8.80 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 2.6 Hz, 1H), 7.88 (s, 1H), 4.12 (s, 3H), 3.95 (s, 3H). LCMS(ESI) m / z: 245.1 (M+H) +

[0239] Intermediate 61-4 [ka] To a solution of 61-3 (200 mg, 0.82 mmol) in DCM (5 mL) was added 2,5-dihydrofuran (0.57 g, 8.2 mmol) and TEA (0.34 mL, 2.5 mmol). After 24 h, the solvent was removed under reduced pressure and the residue was purified by normal phase silica gel chromatography using hexanes / EtOAc as eluent to give methyl 2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)nicotinate (160 mg, 0.56 mmol, 69% yield). LCMS (ESI) m / z: 279.1 (M+H) +

[0240] Intermediates 61-5 (isomer 1) and 61-6 (isomer 2): [ka] 61-4 was subjected to chiral separation SFC using the following conditions (column: Chiralpak IA, 21×250 mm, 5 micron, mobile phase: 40%-60% MeOH / 60%-40% CO2, flow conditions: 90 mL / min, 150 bar, 40° C.; analytical method: column Chiralpak IA, 4.6×250 mm, 3 micron, mobile phase: 25% MeOH / 75% CO2, flow conditions: 2 mL / min, 150 bar, 40° C.) to give chiral peak-1, (RT=1.91 min, >99% ee), 61-5 (30 mg, 0.11 mmol, 13% yield). 1 H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 5.55 - 5.29 (m, 1H), 4.36 (d, J = 10.8 Hz, 1H), 4.31 (s, 1H), 4.16 (dd, J = 9.5, 1.1 Hz, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 3.90 (dd, J = 9.5, 6.7 Hz, 1H), 3.81 (dd, J = 11.0, 3.8 Hz, 1H) and chiral peak-2, (RT = 7.51 min, >99%ee), 61-6 (38 mg, 0.14mmol, 17% yield). 1 H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.6 Hz, 1H), 5.46 - 5.41 (m, 1H), 4.36 (d, J = 10.8 Hz, 1H), 4.31 (s, 1H), 4.16 (dd, J = 9.5, 1.2 Hz, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 3.91 (d, J = 6.7 Hz, 1H), 3.81 (dd, J = 10.8, 4.0 Hz, 1H)

[0241] Intermediate 61-7 [ka] To a solution of 61-6 (38 mg, 0.14 mmol) in THF (1 mL) and MeOH (0.5 mL) cooled to 0 °C, 1 M aqueous LiOH (0.41 mL, 0.41 mmol) was added and the reaction mixture was stirred for 14 h. The reaction mixture was neutralized with 1 N HCl and the solvent volume was reduced under reduced pressure. The residue was lyophilized to give 2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)nicotinic acid (36 mg, 0.14 mmol, quantitative), which was used without purification. 1 H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.84 - 7.68 (m, 1H), 5.32 (dd, J = 9.2, 3.5 Hz, 1H), 4.61 - 4.37 (m, 1H), 4.09 (d, J = 10.7 Hz, 1H), 3.91 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.77 (dd, J = 9.4, 6.9 Hz, 1H), 3.65 (dd, J = 10.5, 3.7 Hz, 1H). LCMS(ESI) m / z: 265.1 (M+H) +

[0242] Example 61. To a solution of IV-4 (9.8 mg, 26 μmol), 61-7 (7 mg, 26 μmol), and BOP (13 mg, 29 μmol) dissolved in DMF (1 mL) was added DIEA (14 μL, 79 μmol). After 24 hours, the reaction mixture was purified by reverse phase HPLC to give Example 5-{3aH,4H,6H,6aH-furo[3,4-d][1,2]oxazol-3-yl}-N-[(1R,2R,3S,4R,7Z)-7-(cyclopropylmethylidene)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}bicyclo[2.2.1]heptan-2-yl]-2-methoxypyridine-3-carboxamide (12 mg, 17 μmol, 64% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.66 - 10.49 (m, 1H), 10.04 (d, J = 7.0 Hz, 1H), 8.68 - 8.46 (m, 2H), 8.23 ​​(dd, J = 6.5, 2.5 Hz, 1H), 7.80 (br dd, J = 7.8, 3.8 Hz, 1H), 7.49 (t, J = 9.8 Hz, 1H), 5.39 (dd, J = 9.2, 3.6 Hz, 1H), 4.70 (d, J = 9.5 Hz, 1H), 4.55 (br t, J = 7.8 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.14 (s, 3H), 4.11 (d, J = 10.7 Hz, 1H), 3.96 (br d, J = 9.2 Hz, 1H), 3.77 (dd, J = 9.5, 6.8 Hz, 1H), 3.67 (dd, J = 10.9, 3.7 Hz, 1H), 3.17 (br dd, J = 11.1, 3.9 Hz, 1H), 3.12 (br s, 1H), 2.74 (br s, 1H), 1.86 - 1.67 (m, 2H), 1.59 - 1.47 (m, 1H), 1.44 - 1.29 (m, 2H), 0.89 - 0.66 (m, 2H), 0.45 - 0.21 (m, 2H). LCMS(ESI) m / z: 615.3 (M+H) + RT = 2.54 points., Method B

[0243] Example 65:

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[0244] Intermediates 65-1, 65-2 and 65-3:

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[0245] Intermediate 65-2 (peak 1; >95% ee; chiral analysis RT = 1.70 min) was obtained as a film (25 mg, 0.080 mmol, 29%). 1H NMR (500 MHz, DMSO-d6) δ 13.28 (br s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 7.33 (br s, 1H), 6.80 (br s, 1H), 5.16 (dd, J = 8.7, 5.0 Hz, 1H), 4.31 (t, J = 8.8 Hz, 1H), 3.94 (s, 3H), 2.08 (dd, J = 13.8, 6.0 Hz, 1H), 2.04 - 1.86 (m, 4H)

[0246] Intermediate 65-3 (peak 2; >95% ee; chiral analysis RT = 2.80 min) was obtained as a film (25 mg, 0.080 mmol, 29%). 1 H NMR (500 MHz, DMSO-d6) δ 8.50 (br s, 1H), 8.21 (br s, 1H), 7.36 (br s, 1H), 6.82 (br s, 1H), 5.18 (dd, J = 8.5, 5.0 Hz, 1H), 4.32 (t, J = 8.9 Hz, 1H), 3.94 (s, 3H), 2.60 - 2.53 (m, 1H), 2.10 (dd, J = 13.8, 6.0 Hz, 1H), 2.06 - 1.89 (m, 4H)

[0247] The compound of Example 65 was prepared as described in Example 59 using 65-2 (23 mg, 0.075 mmol) and IV-4 to give 3-(5-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoro-methyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxypyridin-3-yl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazole-5-carboxamide (isomer-1) (26 mg, 0.038 mmol, 50% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 10.05 (d, J = 7.0 Hz, 1H), 8.61 - 8.57 (m, 2H), 8.23 ​​(dd, J = 6.6, 2.6 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.50 (t, J = 9.8 Hz, 1H), 7.34 (s, 1H), 6.82 (s, 1H), 5.19 (dd, J = 8.7, 5.0 Hz, 1H), 4.70 (d, J = 9.6 Hz, 1H), 4.43 (ddd, J = 10.2, 6.3, 4.0 Hz, 1H), 4.33 (t, J = 8.9 Hz, 1H), 4.14 (s, 3H), 3.17 (dd, J = 10.6, 4.3 Hz, 1H), 3.12 (t, J = 3.5 Hz, 1H), 2.74 (t, J = 3.4 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.13 - 1.88 (m, 4H), 1.84 - 1.75 (m, 2H), 1.54 - 1.47 (m, 1H), 1.44 - 1.40 (m, 1H), 0.79 - 0.70 (m, 2H), 0.38 - 0.32 (m, 2H). LC-MS (M+H) = 656.3; HPLC RT = 1.34 points; Method A

[0248] Example 71:

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[0249] Intermediate 71-1

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[0250] Intermediate 71-2 [ka] Intermediate 71-2 was prepared from 71-1 by the general method described in 61-1 to give methyl 2-formyl-5-methoxyisonicotinate (24 mg, 0.13 mmol, 27% yield). LC-MS RT: 0.65 min; MS(ESI) m / z = 196.1 (M+H)+; Method A

[0251] Intermediate 71-3 [ka] Intermediate 71-3 was prepared from 71-2 by the general method described in 61-7 to give 5-methoxy-2-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)isonicotinic acid (18 mg, 0.068 mmol, 54% yield over 4 steps). LC-MS RT: 0.58 min; MS(ESI) m / z = 265.1 (M+H). + ; Method A

[0252] Intermediate 71-4 [ka] Intermediate 71-4 was prepared from 71-3 and IV-4 by the general method described in Example 59 to give the diastereomeric mixture N-((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-5-methoxy-2-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)isonicotinamide (30 mg, 0.048 mmol, 70% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.01 (dd, J = 6.8, 3.7 Hz, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 8.23 ​​(br d, J = 6.1 Hz, 1H), 7.78 (br dd, J = 8.3, 4.1 Hz, 1H), 7.49 (t, J = 9.8 Hz, 1H), 5.38 (dt, J = 9.2, 2.9 Hz, 1H), 4.70 (d, J = 9.5 Hz, 1H), 4.51 - 4.39 (m, 2H), 4.17 (s, 3H), 4.14 - 4.06 (m, 2H), 3.83 - 3.74 (m, 1H), 3.66 (dd, J = 10.8, 3.5 Hz, 1H), 3.17 (br dd, J = 11.0, 4.3 Hz, 1H), 3.13 (br s, 1H), 2.74 (br s, 1H), 1.86 - 1.73 (m, 2H), 1.58 - 1.48 (m, 1H), 1.47 - 1.33 (m, 2H), 0.81 - 0.66 (m, 2H), 0.35 (br d, J = 4.0 Hz, 2H). LC-MS RT: 2.53 min; MS (ESI) m / z = 615.05 (M+H) + ; Method B

[0253] Examples 71 (Isomer 1) and 72 (Isomer 2) 71-4 was subjected to SFC-chiral chromatography under the following conditions: Column: Chiral AS 30×250 mm. 5 micron; Mobile phase: 65% CO2 / 35% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Analytical chromatography conditions: Column: Chiral AS, 4.6×100 mm, 5 micron; Mobile phase: 65% CO2 / 35% MeOH w / 0.1% DEA; Flow conditions: 2 mL / min; Peak 1 (71), RT=1.2 min, >95% ee, 1 H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 10.01 (br d, J = 6.7 Hz, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.27 - 8.19 (m, 1H), 7.85 - 7.74 (m, 1H), 7.49 (br t, J = 9.5 Hz, 1H), 5.39 (br dd, J = 9.3, 3.2 Hz, 1H), 4.71 (br d, J = 9.8 Hz, 1H), 4.52 - 4.37 (m, 2H), 4.17 (s, 3H), 4.15 - 4.03 (m, 2H), 3.79 (br dd, J = 9.0, 7.2 Hz, 1H), 3.67 (br dd, J = 10.4, 3.1 Hz, 1H), 3.18 (br dd, J = 10.7, 3.4 Hz, 1H), 3.13 (br s, 1H), 2.74 (br s, 1H), 1.87 - 1.71 (m, 2H), 1.59 - 1.48 (m, 1H), 1.46 - 1.32 (m, 2H), 0.84 - 0.61 (m, 2H), 0.36 (br s, 2H), LC-MS RT: 2.44 min; MS (ESI) m / z = 614.9 (M+H) + ; Method B.; Peak 2 (72), RT = 3.0 min, > 95%ee, 1H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.02 (br d, J = 6.7 Hz, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.23 ​​(br d, J = 3.7 Hz, 1H), 7.79 (br d, J = 7.9 Hz, 1H), 7.50 (br t, J = 9.6 Hz, 1H), 5.39 (br dd, J = 9.0, 2.9 Hz, 1H), 4.71 (br d, J = 10.1 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.17 (s, 3H), 4.16 - 4.05 (m, 2H), 3.85 - 3.74 (m, 1H), 3.71 - 3.63 (m, 1H), 3.18 (br dd, J = 10.2, 2.9 Hz, 1H), 3.13 (br s, 1H), 2.75 (br s, 1H), 1.80 (br dd, J = 10.4, 9.2 Hz, 2H), 1.53 (br d, J = 5.8 Hz, 1H), 1.43 (br s, 2H), 0.84 - 0.64 (m, 2H), 0.36 (br s, 2H), LC-MS RT: 2.43 min; MS (ESI) m / z = 614.9 (M+H) + ; Method B

[0254] Example 74:

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[0255] Intermediate 74-1:

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[0256] Example 74 compound was prepared by the general method described in Example 1 using 74-1 (20 mg, 0.037 mmol) and (1-(methylsulfonyl)cyclopropyl)methanamine hydrochloride (10 mg, 0.055 mmol) to give N3-((1R,2R,3R,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-2-methoxy-N5-((1-(methylsulfonyl)cyclopropyl)methyl)pyridine-3,5-dicarboxamide (6.5 mg, 9.2 μmol, 25% yield). LC-MS RT: 2.3 min, Method A. MS(ESI) m / z = 679.2 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 10.03 (d, J = 7.1 Hz, 1H), 8.87 (t, J = 6.1 Hz, 1H), 8.81 - 8.76 (m, 1H), 8.76 - 8.66 (m, 1H), 8.23 (dd,J = 6.7, 2.6 Hz, 1H), 7.84 - 7.74 (m, 1H), 7.49 (t, J = 10.0 Hz, 1H), 4.70 (d, J = 9.5 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.14 (s, 3H), 3.83 (d, J = 6.1 Hz, 2H),3.20 - 3.13 (m, 1H), 3.13 - 3.09 (m, 1H), 3.06 (s, 3H), 2.78 - 2.71 (m, 1H), 1.85 - 1.72 (m, 2H), 1.56 - 1.44 (m, 1H), 1.44 - 1.34 (m, 2H), 1.29 - 1.21(m, 3H), 1.17 - 1.11 (m, 2H), 0.79 - 0.68 (m, 2H), 0.36 (dd, J = 4.4, 2.0 Hz, 2H)

[0257] Example 77:

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[0258] Intermediate 77-1:

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[0259] Intermediate 77-2: [ka] To a solution of 77-1 (0.2 g, 0.763 mmol) cooled to 0° C. was added 2N aqueous LiOH (0.037 g, 1.5 mmol). The reaction mixture was allowed to warm to rt over 3 h, then concentrated under reduced pressure and the residue was dissolved in water (5 mL). The aqueous portion was acidified with 1.5 N HCl and the resulting precipitate was filtered and dried under reduced pressure to give the regioisomeric mixture (0.12 g, 0.37 mmol, 48% yield). The mixture was used without further purification. LC-MS RT: 0.31 min; Method E; MS(ESI) m / z = 249.2 (M+H) +

[0260] The compound of Example 77 was prepared by the general method described in Example 1 using 77-2 and IV-4 to give N-[(1R,2R,3S,4R,7Z)-7-(cyclopropylmethylidene)-3-{[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}bicyclo[2.2.1]heptan-2-yl]-1-(2-methanesulfonylethyl)-4-methoxy-1H-pyrazole-3-carboxamide (5 mg, 8 μmol, 6% yield). LC-MS RT: 3.47 min; Method C; MS(ESI) m / z = 599.2 (M+H). + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.51 (s, 1 H) 9.24 (d, J = 7.53 Hz, 1 H) 8.22 (dd, J = 6.53, 2.51 Hz, 1 H) 7.75 - 7.81 (m, 1 H) 7.58 (s, 1 H) 7.49 (t, J = 9.79 Hz, 1 H) 4.76 - 4.95 (m, 1 H) 4.42 (br s, 1 H) 3.92 (s, 3 H) 3.57 (t, J = 7.03 Hz, 1 H) 3.36 - 3.39 (m, 1 H) 3.22 - 3.29 (m, 1 H) 3.14 (dd, J = 10.79, 4.27 Hz, 2 H) 3.06 (br s, 1 H) 2.96 (s, 2 H) 2.68 - 2.73 (m, 1 H) 2.52 - 2.56 (m, 2 H) 2.34 - 2.47 (m, 2 H) 1.63 - 1.89 (m, 1 H) 1.46 - 1.58 (m, 2 H) 1.42 (br s, 2 H) 1.24 (s, 1 H)

[0261] Example 78:

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[0262] Intermediate 78-1:

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[0263] Intermediate 78-2: [ka] A solution of 78-1 (400 mg, 1.5 mmol) in THF (25 mL) was cooled to 0° C. and 1N aqueous NaOH (3.0 mL, 3.0 mmol) was added. The reaction mixture was allowed to warm to rt over 3 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (2 ml) and the aqueous phase was washed with diethyl ether (10 ml). The aqueous portion was acidified to pH 4 with 1.5 N HCl and the resulting precipitate was filtered and dried under reduced pressure to give 5-(tert-butoxycarbonyl)-2-methoxynicotinic acid (210 mg, 0.83 mmol, 55% yield) which was used without further purification. LCMS RT = 0.80 min, Method E. LCMS (ESI) m / z = 254.2 (M+H) +

[0264] Example 78 was prepared by the general coupling described in Example 1 using IV-4 (10 mg, 0.027 mmol) and 78-2 (6.87 mg, 0.027 mmol) to give tert-butyl 5-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxynicotinate (9.2 mg, 0.014 mmol, 53% yield). LC-MS RT: 2.92 min; [A] MS(ESI) m / z = 604.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ = 10.54 (s, 1H), 10.02 (d, J = 6.8 Hz, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.22 (dd, J = 2.7, 6.6 Hz, 1H), 7.84 -7.75 (m, 1H), 7.49 (t, J = 9.7 Hz, 1H), 4.70 (d, J = 9.5 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.15 (s, 3H), 3.20 - 3.14 (m, 1H), 3.13 - 3.09 (m, 1H), 2.76 - 2.71 (m, 1H),1.83 - 1.73 (m, 2H), 1.60 - 1.45 (m, 13H), 1.44 - 1.37 (m, 2H)

[0265] Example 81: [ka]

[0266] Intermediate 81-1 [ka] A solution of 2-bromoprop-2-en-1-ol (1.4 g, 10 mmol) in DMF (15 mL) was treated with (2-fluoro-5-(methoxycarbonyl)phenyl)boronic acid (2.0 g, 10 mmol), potassium phosphate (3.4 mL, 10 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.08 g, 0.10 mmol) and the reaction mixture was purged with nitrogen for 10 min, sealed and stirred at 65 °C for 3 h. The reaction mixture was neutralized with 1N HCl, extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure, and then purified by reverse phase purification to give methyl 4-fluoro-3-(3-hydroxyprop-1-en-2-yl)benzoate (1.0 g, 4.7 mmol, 47% yield). MS (ESI) m / z: 211.1 (M+H).

[0267] Intermediate 81-2 [ka] To a round bottom flask containing 81-1 (0.50 g, 2.4 mmol) and rhodium(II) acetate dimer (48 mg, 0.11 mmol) was added toluene (10 mL) and the reaction mixture was heated to reflux. To the reaction mixture was added a solution of 1-(tert-butyl) 3-methyl 2-diazomalonate (0.43 g, 2.2 mmol) dissolved in toluene (2 mL) dropwise over 5 min and the resulting solution was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography to give 1-(tert-butyl) 3-methyl 2-((2-(2-fluoro-5-(methoxycarbonyl)phenyl)allyl)oxy)malonate (610 mg, 1.6 mmol, 71% yield). MS (ESI) m / z: 211.1 (M+H) +

[0268] Intermediate 81-3 [ka] To a solution of 81-2 (612 mg, 1.6 mmol) in DCM (10 mL) was added dimethylmethylideneammonium iodide (440 mg, 2.4 mmol) followed by TEA (0.34 mL, 2.4 mmol) and the reaction mixture was stirred for 14 h. The reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography to give 1-(tert-butyl) 3-methyl 2-((dimethylamino)methyl)-2-((2-(2-fluoro-5-(methoxycarbonyl)phenyl)allyl)oxy)malonate (420 mg, 0.96 mmol, 57% yield). MS (ESI) m / z: 440.2 (M+H) +

[0269] Intermediate 81-4 [ka] To a solution of 81-3 (420 mg, 0.94 mmol) in acetone (10 mL) was added methyl iodide (0.089 mL, 1.4 mmol) and the reaction mixture was stirred for 14 h. The reaction mixture was concentrated under reduced pressure to give 3-(tert-butoxy)-2-((2-(2-fluoro-5-(methoxycarbonyl)phenyl)allyl)oxy)-2-(methoxycarbonyl)-N,N,N-trimethyl-3-oxopropan-1-aminium (430 mg, 0.94 mmol, quantitative), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.02 - 7.94 (m, 2H), 7.45 - 7.36 (m, 1H), 5.70 (s, 1H), 5.54 (s, 1H), 4.63 (s, 2H), 4.14 - 4.01 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.05 (s, 9H), 1.46 (s, 9H)

[0270] Intermediate 81-5 [ka] To a solution of 81-4 (430 mg, 0.94 mmol) in DMSO (6 mL) was added 1 M sodium hydroxide solution (1.1 mL, 1.1 mmol) and the reaction mixture was stirred for 3 h at rt. The reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography to give methyl 3-(3-((3-(tert-butoxy)-3-oxoprop-1-en-2-yl)oxy)prop-1-en-2-yl)-4-fluorobenzoate (210 mg, 0.62 mmol, 66% yield). MS (ESI) m / z: 337.3 (M+H) +

[0271] Intermediate 81-6 [ka] To a solution of 81-5 (200 mg, 0.6 mmol) dissolved in DMSO (30 mL) was added (Ir[dF(CF3)ppy]2(dtbpy))-PF6 (7 mg, 6 μmol) and the reaction mixture was degassed using vacuum and backfilling with N2 three times. The reaction mixture was irradiated with a blue LED for 60 h. The reaction mixture was diluted with brine, extracted with ethyl acetate, and the organic portion was concentrated under reduced pressure and then purified by silica gel chromatography to give tert-butyl 4-(2-fluoro-5-(methoxycarbonyl)phenyl)-2-oxabicyclo[2.1.1]hexane-1-carboxylate (120 mg, 0.36 mmol 57% yield). MS (ESI) m / z: 337.0 (M+H)

[0272] Intermediate 81-7 [ka] To a solution of 81-6 (120 mg, 0.36 mmol) dissolved in DCM (2.4 mL) was added TFA (0.6 mL, 8 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to give 4-(2-fluoro-5-(methoxycarbonyl)phenyl)-2-oxabicyclo[2.1.1]hexane-1-carboxylic acid (100 mg, 0.36 mmol, quantitative), which was used without further purification. MS (ESI) m / z: 280.0 (M+H) +

[0273] Intermediate 81-8: [ka] 81-8 was prepared from intermediate V-2 and intermediate 81-7 by the general method outlined in Example 1 to give methyl 4-fluoro-3-(1-(((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)-2-oxabicyclo[2.1.1]hexan-4-yl)benzoate (16 mg, 0.020 mmol, 38% yield). MS (ESI) m / z: 659.3 (M+H) +

[0274] The compound of Example 81 was prepared from Intermediate 81-8 as outlined in Example 26 and then purified by HPLC to give 4-fluoro-3-(1-(((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)-2-oxabicyclo[2.1.1]hexan-4-yl)benzoic acid (6.9 mg, 0.01 mmol, 59% yield). 1H NMR (500MHz, DMSO-d6) δ 10.65 (s, 1H), 9.05 (d, J = 7.2 Hz, 1H), 8.04 - 7.97 (m, 1H), 7.95 - 7.88 (m, 1H), 7.87 - 7.79 (m, 2H), 7.51 (t, J = 9.7 Hz, 1H), 7.35 - 7.28 (m, 1H), 5.93 (q, J = 7.8 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.03 (d, J = 5.5 Hz, 1H), 3.98 (d, J = 5.4 Hz, 1H), 3.23 (dd, J = 10.7, 4.2 Hz, 1H), 3.14 (br. s., 1H), 2.97 (br. s., 1H), 2.37 (dd, J = 14.9, 7.0 Hz, 2H), 2.19 - 2.12 (m, 1H), 2.11 - 2.03 (m, 1H), 1.88 - 1.77 (m, 2H), 1.49 (d, J = 7.8 Hz, 2H); LC-MS (M+H) = 645.2; RT = 2.03 min; Method B

[0275] Example 82:

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[0276] Intermediate 82-1:

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[0277] Intermediate 82-2: [ka] Pd2(dba)3 (1.5 g, 1.6 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.0 g, 2.4 mmol) were added to 82-2 (5.0 g, 16 mmol), methanol (6.5 mL, 160 mmol) and Cs2CO3 (26 g, 80 mmol) dissolved in dioxane (80 mL) at rt, degassed with nitrogen for 5 min, and then stirred at 85 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and then purified by silica gel chromatography to give tert-butyl 6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (4.0 g, 15 mmol, 95% yield). LCMS: MS (ES): m / z = 164.1 [M+H-Boc]

[0278] Intermediate 82-3: [ka] NBS (4.1 g, 23 mmol) was added to a solution of 82-2 (6.0 g, 23 mmol) in acetonitrile (100 mL) at rt and the reaction mixture was stirred for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was extracted with EtOAc. The organic portion was washed with water, dried over Na2SO4, concentrated, and then purified by silica gel chromatography eluting with 25-45% EtOAc in petroleum ether to give tert-butyl 7-bromo-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, 15 mmol, 64% yield). LCMS: MS (ES): m / z = 288.0 [M+2H-tBu]

[0279] Intermediate 82-4: [ka] To a solution of 82-3 dissolved in methanol (70 mL) and DMF (70 mL) and degassed by nitrogen bubbling was added TEA (4.5 mL, 32 mmol), Pd(OAc)2 (0.14 g, 0.64 mmol) and dppf (0.54 g, 0.96 mmol) at rt. The reaction mixture was stirred in an autoclave at 100 °C under 10 kg pressure of CO(g) for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc, filtered through Celite, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and then purified by silica chromatography eluting with 30-35% EtOAc in petroleum ether to give 2-(tert-butyl) 7-methyl 6-methoxy-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (520 mg, 1.6 mmol, 25% yield). LCMS: MS (ES): m / z = 322.2 [M+H]

[0280] Intermediate 82-5: [ka] To a solution of 82-4 (350 mg, 1.1 mmol) dissolved in MeOH (5.0 mL) and THF (5.0 mL) was added a solution of LiOH (260 mg, 11 mmol) dissolved in water (3.0 mL) and the reaction mixture was stirred at rt for 5 h. The solution was concentrated under reduced pressure and the residue was diluted with water (10 mL) and washed with 20% EtOAc in petroleum ether (20 mL). The aqueous layer was acidified with 0.1 N HCl and the resulting precipitate was filtered, washed with water and dried under reduced pressure to give 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (260 mg, 0.85 mmol, 78% yield), which was used without further purification. LCMS: MS (ES): m / z = 306.1 [MH]

[0281] Example 82 Prepared from intermediates 82-5 and IV-4 by the general method described in Example 1 to give tert-butyl 7-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (180 mg, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.49 (s, 1H), 9.78 (d, J = 7.1 Hz, 1H), 8.21 (dd, J = 2.7, 6.6 Hz, 1H), 7.83 - 7.74 (m, 1H), 7.69 (s, 1H), 7.47 (t, J = 9.8 Hz, 1H), 6.97 (s, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.50 - 4.33 (m, 3H), 3.96 (s, 3H), 3.53 (br t, J = 5.7 Hz, 2H), 3.14 (dd, J = 4.4, 10.8 Hz, 1H), 3.07 (t, J = 3.4 Hz, 1H), 2.80 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 3.9 Hz, 1H), 1.85 (br d, J = 9.8 Hz, 1H), 1.80 - 1.72 (m, 1H), 1.49 (br dd, J = 4.6, 9.5 Hz, 1H), 1.46 - 1.31 (m, 12H), 0.81 - 0.64 (m, 2H), 0.34 (dd, J = 2.1, 4.5 Hz, 2H); LCMS: RT = 2.788 min, MS (ES): m / z = 658.4 [M+H + Method B

[0282] Example 83:

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[0283] Example 83: To a solution of the compound of Example 82 (200 mg, 0.30 mmol) dissolved in DCM (5.0 mL) was added TFA (0.11 mL, 1.5 mmol) at 0° C., then the reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to give N-((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (160 mg, 0.29 mmol, 97% yield) as an off-white solid. LCMS: MS (ES): m / z = 558.3 ​​[M+H]. 1 H NMR (400 MHz, DMSO-d6) δ = 10.48 (s, 1H), 9.75 (d, J = 7.1 Hz, 1H), 8.22 (dd, J = 2.4, 6.6 Hz, 1H), 7.82 - 7.71 (m, 1H), 7.58 (s, 1H), 7.47 (t, J = 9.8Hz, 1H), 6.86 (s, 1H), 4.67 (d, J = 9.8 Hz, 1H), 4.47 - 4.34 (m, 1H), 3.94 (s, 3H), 3.80 (s, 2H), 3.13 (dd, J = 4.2, 10.8 Hz, 1H), 3.09 - 3.04 (m, 1H), 2.99 - 2.89(m, 2H), 2.76 - 2.66 (m, 3H), 1.89 - 1.81 (m, 1H), 1.79 - 1.70 (m, 1H), 1.55 - 1.44 (m, 1H), 1.44 - 1.30 (m, 2H), 0.82 - 0.66 (m, 2H), 0.34 (dd, J = 2.0, 4.6 Hz,2H)

[0284] Example 84: [ka] To a solution of the compound of Example 83 (20.0 mg, 0.036 mmol) and 1-chloro-2-(methylsulfonyl)ethane (5.1 mg, 0.036 mmol) in DMF (1.0 mL) and THF (1.0 mL) solvent mixture, TEA (0.015 mL, 0.11 mmol) was added at rt, and the reaction mixture was stirred for 14 hours. The reaction mixture was purified by preparative HPLC to give N-((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (6.7 mg, 27%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.47 (s, 1H), 9.76 (d, J = 7.3 Hz, 1H), 8.21 (dd, J = 2.6, 6.5 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.63 (s, 1H), 7.47 (t, J = 9.8 Hz, 1H), 6.90 (s, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.09 (q, J = 5.4 Hz, 1H), 3.94 (s, 3H), 3.57 (s, 2H), 3.38 (s, 3H), 3.20 - 3.10 (m, 2H), 3.06 (br t, J = 3.8 Hz, 1H), 2.99 (s, 3H), 2.90 - 2.79 (m, 4H), 2.74 - 2.66 (m, 3H), 1.91 - 1.83 (m, 1H), 1.81 - 1.74 (m, 1H), 1.55 - 1.33 (m, 3H), 0.80 - 0.65 (m, 2H), 0.34 (dd, J = 2.1, 4.8 Hz, 2H). LCMS: RT = 2.491 min, MS (ES): m / z = 664.3 [M+H] Method B

[0285] Example 85: [ka] To a solution of Example 83 and 1-chloro-2-methylpropan-2-ol (3.9 mg, 0.036 mmol) in DMF (1.0 mL) and THF (1.0 mL) was added TEA (0.015 mL, 0.11 mmol) at rt, then the mixture was heated at 80° C. for 14 h. The reaction mixture was cooled, concentrated under reduced pressure, and purified by preparative HPLC to give N-((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-2-(2-hydroxy-2-methylpropyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (1 mg, 5% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 9.75 (d, J = 7.6 Hz, 1H), 8.22 (dd, J = 2.3, 6.5 Hz, 1H), 7.83 - 7.72 (m, 1H), 7.57 (s, 1H), 7.48 (t, J = 9.9 Hz, 1H), 6.88 (s, 1H), 4.67 (d, J = 9.8 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.15 (s, 1H), 3.94 (s, 3H), 3.63 (s, 2H), 3.19 - 3.09 (m, 1H), 3.08 - 3.02 (m, 1H), 2.87 - 2.74 (m, 4H), 2.68 (br d, J = 8.6 Hz, 1H), 2.35 (s, 2H), 1.90 - 1.82 (m, 1H), 1.79 - 1.72 (m, 1H), 1.54 - 1.45 (m, 1H), 1.44 - 1.34 (m, 2H), 1.10 (s, 6H), 0.79 - 0.70 (m, 2H), 0.41 - 0.27 (m, 2H). LCMS: RT = 2.573 min, MS (ES): m / z = 630.4 [M+H] Method B

[0286] Example 88: [ka] To a solution of the compound of Example 83 (20 mg, 0.036 mmol) and 2-methylpropane-1-sulfonyl chloride (11 mg, 0.072 mmol) in DCM (2.0 mL) was added TEA (0.015 mL, 0.11 mmol) at 0° C., and the reaction mixture was then stirred at rt for 14 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give N-((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-2-(isobutylsulfonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (6.2 mg, 27% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.50 (s, 1H), 9.80 (d, J = 7.1 Hz, 1H), 8.22 (dd, J = 2.8, 6.7 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.71 (s, 1H), 7.48 (t, J = 9.8 Hz, 1H), 6.99 (s, 1H), 4.68 (d, J = 9.8 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.34 (s, 2H), 3.96 (s, 3H), 3.51 - 3.40 (m, 2H), 3.14 (dd, J = 4.5, 10.9 Hz, 1H), 3.07 (t, J = 3.9 Hz, 1H), 2.98 (d, J = 6.6 Hz, 2H), 2.92 (br t, J = 6.0 Hz, 2H), 2.70 (t, J = 3.7 Hz, 1H), 2.12 (td, J = 6.6, 13.4 Hz, 1H), 1.89 - 1.66 (m, 2H), 1.56 - 1.45 (m, 1H), 1.45 - 1.29 (m, 2H), 1.03 (d, J = 6.8 Hz, 6H), 0.81 - 0.68 (m, 2H), 0.34 (dd, J = 2.0, 4.6 Hz, 2H). LCMS: RT = 2.465 min, MS (ES): m / z = 658.3 [M+H + Method B

[0287] Example 90:

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[0288] Intermediate 90-1:

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[0289] Intermediate 90-2: [ka] NBS (2.2 g, 12 mmol) was added to a solution of 90-1 (3.2 g, 12 mmol) in acetonitrile (60 mL) at rt and the reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with water, dried over Na2SO4, concentrated under reduced pressure and then purified by silica gel chromatography eluting with 25-35% EtOAc in petroleum ether to give tert-butyl 6-bromo-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.0 g, 8.8 mmol, 72% yield). LCMS: MS (ES): m / z = 244.0 [M+2H-Boc]

[0290] Intermediate 90-3: [ka] To a solution of 90-2 (2.0 g, 5.8 mmol) dissolved in methanol (70 mL) and DMF (70 mL) and degassed with nitrogen, TEA (4.1 mL, 29 mmol), Pd(OAc)2 (0.13 g, 0.58 mmol) and dppf (0.49 g, 0.88 mmol) were added at rt. The reaction mixture was stirred in an autoclave at 100 °C under 10 kg pressure of CO(g) for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and the solid was filtered through Celite. The filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure and then purified by silica gel chromatography eluting with 30-40% EtOAc in petroleum ether to give 2-(tert-butyl) 6-methyl 7-methoxy-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate (1.2 g, 3.7 mmol, 64% yield). LCMS: MS (ES): m / z = 322.2 [M+H]

[0291] Intermediate 90-4: [ka] LiOH (0.75 g, 31 mmol) dissolved in water (5.0 mL) was added to 90-3 (1.0 g, 3.1 mmol) dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). The reaction mixture was stirred for 14 h and then concentrated under reduced pressure. The residue was diluted with water (10 mL), washed with 20% EtOAc in petroleum ether (20 mL), the aqueous layer was acidified with 0.1 N HCl, and the resulting precipitate was filtered, washed with water, and dried under reduced pressure to give 2-(tert-butoxycarbonyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (760 mg, 2.5 mmol, 79% yield), which was used without further purification. LCMS: MS (ES): m / z = 306.2 [MH]

[0292] Intermediate 90-5: [ka] Intermediate 34-5 was prepared from intermediate 90-4 and IV-4 by the general method described in Example 1 to give tert-butyl 6-(((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 56% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 9.77 (d, J = 7.3 Hz, 1H), 8.21 (dd, J = 2.6, 6.5 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.70 (s, 1H), 7.48 (t, J = 9.7 Hz, 1H), 7.01 (s, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.53 (br s, 2H), 4.43 (br s, 1H), 3.95 (s, 3H), 3.53 (br t, J = 6.0 Hz, 2H), 3.17 - 3.10 (m, 1H), 3.06 (br s, 1H), 2.76 - 2.67 (m, 3H), 1.90 - 1.82 (m, 1H), 1.79 - 1.71 (m, 1H), 1.53 - 1.46 (m, 1H), 1.45 - 1.29 (m, 11H), 0.79 - 0.64 (m, 2H), 0.34 (dd, J = 2.0, 4.6 Hz, 2H). LCMS: RT = 2.788 min, MS (ES): m / z = 658.3 [M+H] Method B

[0293] Intermediate 90-6: [ka] Intermediate 34-6 was prepared from 90-5 by the general method described in Example 82. N-((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (150 mg, 0.27 mmol, 98% yield). LCMS: MS (ES): m / z = 558.3 ​​[M+H]

[0294] Example 90: [ka] To intermediate 90-6 (20 mg, 0.036 mmol) and 3-bromopropan-1-ol (5.0 mg, 0.036 mmol) dissolved in THF (1.0 mL) and DMF (1.0 mL) was added TEA (0.015 mL, 0.11 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred at rt for 14 h. The reaction mixture was purified by preparative HPLC to give N-((1R,2R,3S,4R,Z)-7-(cyclopropylmethylene)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-2-(3-hydroxypropyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (10 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 9.76 (d, J = 7.3 Hz, 1H), 8.22 (dd, J = 2.7, 6.6 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.66 (s, 1H), 7.48 (t, J = 9.8 Hz, 1H), 6.87 (s, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.53 - 4.32 (m, 2H), 3.93 (s, 3H), 3.57 (br s, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.18 - 3.11 (m, 1H), 3.08 - 3.02 (m, 1H), 2.77 - 2.59 (m, 5H), 1.85 (br d, J = 9.8 Hz, 1H), 1.81 - 1.58 (m, 3H), 1.53 - 1.28 (m, 3H), 0.82 - 0.65 (m, 2H), 0.41 - 0.30 (m, 2H). LCMS: RT = 1.86 min, MS (ES): m / z = 616.4 [M+H] Method B

[0295] Compounds 2-32, 57 and 58 in Table 2 were prepared by the general methods described in Examples 1, 20, 21, 26 and / or 33.

[0296] Compounds 36-39 in Table 2 were prepared by the general methods described in Examples 34-35. Compounds 41-48 in Table 2 were prepared by the general methods described in Examples 40 or 42.

[0297] Compound 52 in Table 2 was prepared by the general method described in Example 51.

[0298] Compound 54 in Table 2 was prepared by the general method described in Example 53.

[0299] Compounds 60-70 in Table 3 were prepared by the general methods described in Examples 61 and 65.

[0300] Compound 73 in Table 2 was prepared by the general method described in Example 59.

[0301] Compounds 75-76 in Table 3 were prepared by the general method described in Example 74.

[0302] Compounds 79-80 in Table 3 were prepared by the general method described in Example 77.

[0303] Compounds 86-95 in Table 3 were prepared by the general methods described in Examples 84, 85 and 88.

[0304] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] 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.

[0305] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34]

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

[0306]

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

Table 67

[0307] [Table 68] [Table 69] [Table 70] [Table 71] [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77] [Table 78] [Table 79] [Table 80] [Table 81] [Table 82] [Table 83] [Table 84] [Table 85] [Table 86] [Table 87] [Table 88] [Table 89] [Table 90] 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.

[0308] 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 it is desired to place reliance on the appended claims rather than on 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—; Ring A is O, S(=O) ｐ , N and NR １６ a 5- to 15-membered heterocyclyl containing 1 to 5 heteroatoms selected from: 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 R ４ C substituted with 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 alkyl, substituted with 0 to 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 is a 4- to 9-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 ３－１０ Carbocyclyl or O, S(=O) ｐ , N or NR １４ａ 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 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 Ha = O, C １－４ Alkyl or 0 to 5 halo, —OH, —OC １－４ Alkyl, C ３－６ -OC substituted with a cycloalkyl, aryl, or 3- to 6-membered heterocyclyl substituent １－６ is alkyl; R ９ is halo, CN, -C(=O)OR ｂ , —C(═O)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 3 R １０ and 0 to 2 R １１ -(A) ０－１ -C ３－６ Carbocyclyl, -(A) ０－１ -0 to 2 R １０ and 0 to 2 R １１ C substituted with ６－９ Spirocycloalkyl or O, S(=O) ｐ , N and NR １１ａ and 0 to 3 R １０ and 0 to 2 R １１ -(A) ０－１ - 3 to 12 membered heterocyclyl; A is -O-, -S-, -CH ２ O- or -OCH ２ - and; R １０ Halo, CN, C １－４ Alkyl, ═O, —OH or —OC １－４ is alkyl; R １１ is 0 to 5 R １２ and 0 to 2 R １３ C substituted with １－４ Alkyl, -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ C(=O)NR ａ R ａ , -NR ａ S (= O) ｐ R ｃ , -C(=O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , —C(═O)NR ａ S (= O) ｐ R ｃ , -OC(=O)R ｂ , -S(=O) ｐ R ｃ , -S(=O) ｐ NR ａ R ａ , 0 to 5 R ｅ C substituted with ３－９ carbocyclyl, 0 to 5 R ｅ aryl substituted with O, S(=O) ｐ , N and NR １５ and 0 to 5 R ｅ 3-12 membered heterocyclyl substituted with R １１ａ is H, 0 to 4 R １１ｂ C substituted with １－４ Alkyl, —C(═O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , 0 to 5 R ｅ C substituted with ３－６ cycloalkyl, 0 to 5 R ｅ aryl substituted with O, S(=O) ｐ , N and NR １５ and 0 to 5 R ｅ 4-6 membered heterocyclyl substituted with R １１ｂ is halo, -OH, -C(=O)OH, -C(=O)OC １－４ is alkyl or aryl; R １２ is halo, -C(=O)OR ｂ , —C(═O)NR ａ R ａ , —C(═O)NR ａ OR ｂ , C substituted with 0 to 3 halo １－４ Alkyl or —OH substituent or C ３－６ is cycloalkyl; R １３ 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 , —OC(═O)NR ａ R ａ , —OC(═O)NR ａ OR ｂ , -S(=O) ｐ NR ａ R ａ , -S(=O) ｐ R ｃ , 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 - 3 to 12 membered heterocyclyl; 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 １４ａ 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 １５ is H, C １－４ is alkyl or aryl; R １６ is H, -C(=O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , -S(=O) ｐ R ｃ , 0 to 4 R １６ａ C substituted with １－４ alkyl or 0 to 4 R １６ａ is an aryl substituted with R １６ａ Halo, C １－４ Alkyl, OR ｂ , -C(=O)OR ｂ or -S(=O) ｐ R ｃ and R １７ is H or 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－４ alkyl; or R １７ and R １７ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ , N and NR １１ａ and 0 to 3 R １０ and 0 to 2 R １１ forming a 3- to 12-membered heterocyclyl substituted with R ａ 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; 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, C ３－６ Carbocyclyl or O, S(=O) ｐ and N; 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 ３－１０ 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)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 heterocyclyl; or R ｆ and R ｆ together with the nitrogen atom to which they are both attached form a heterocyclyl; R ｇ is halo, CN, -OH, 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, Ring A is O, S(=O) ｐ , N and NR １６ a 5- to 12-membered heterocyclyl containing 1 to 4 heteroatoms selected from: R ４ is halo, C substituted with 0 to 4 halo substituents １－４ alkyl, substituted with 0 to 4 halo substituents, —OC １－４ -S(=O) substituted with alkyl or 0-4 halo substituents ｐ C １－４ is alkyl; R ６ is halo, 0 to 3 R ６ａ C substituted with １－７ alkyl, 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 C substituted with ６－１０ Aryl or O, S(=O) ｐ , N and NR １４ａ and 0 to 3 R １４ 4-6 membered heterocyclyl substituted with R ６ａ is halo, -OH, C ３－６ is cycloalkyl or aryl; R ７ is H or C １－３ is alkyl; R ８ is ═O or 0 to 5 halo, —OH, —OC １－４ -OC substituted with alkyl or aryl substituents １－４ is alkyl; R ９ is halo, CN, -C(=O)OR ｂ , —C(═O)NR １７ R １７ , 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－７ alkyl, 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 3 R １０ and 0 to 2 R １１ Phenyl or O, S(=O) substituted with ｐ and 0 to 3 R １０ and 0 to 2 R １１ 3-12 membered heterocyclyl substituted with R １０ Halo, CN, C １－４ Alkyl, —OH or —OC １－４ is alkyl; R １１ is 0 to 1 R １２ and 0 to 1 R １３ C substituted with １－３ Alkyl, -OR ｂ , -NR ａ R ａ , -C(=O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , —C(═O)NR ａ S (= O) ｐ R ｃ , -OC(=O)R ｂ , -S(=O) ｐ R ｃ , -S(=O) ｐ NR ａ R ａ , 0 to 5 R ｅ C substituted with ３－６ Cycloalkyl, O, S(=O) ｐ , N and NR １５ and 0 to 5 R ｅ 4-6 membered heterocyclyl substituted with R １２ is halo, -C(=O)OR ｂ , —C(═O)NHR ａ or C substituted with 0-3 halo or OH substituents １－４ is alkyl; R １３ Ha-OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , -NR ａ S (= O) ｐ NR ａ R ａ , —OC(═O)NR ａ R ａ , —OC(═O)NR ａ OR ｂ , -S(=O) ｐ NR ａ R ａ or -S(=O) ｐ R ｃ and R １４ is halo, CN, C substituted with 0-3 halo substituents １－４ alkyl, substituted with 0 to 3 halo substituents, —OC １－４ is alkyl; R １４ａ is H, C(=O)C １－４ C substituted with alkyl or 0-3 aryl substituted with 0-2 halo substituents １－３ is alkyl; R １６ is H, 0 to 4 R １６ａ C substituted with １－３ alkyl or 0 to 4 R １６ａ is an aryl substituted with R １６ａ Halo, C １－３ Alkyl, OR ｂ , C(=O)OR ｂ or -S(=O) ｐ R ｃ and R １７ is H or 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－３ alkyl; or R １７ and R １７ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ , N and NR １１ａ and 0 to 3 R １０ and 0 to 2 R １１ forming a 3- to 10-membered heterocyclyl substituted with R ａ is H, 0 to 5 R ｅ C substituted with １－５ alkyl, 0 to 5 R ｅ C substituted with ２－５ alkenyl, 0 to 5 R ｅ C substituted with ２－５ 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 10-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 10-membered heterocyclyl substituted with R ｂ is H, 0 to 5 R ｅ C substituted with １－５ alkyl, 0 to 5 R ｅ C substituted with ２－５ alkenyl, 0 to 5 R ｅ C substituted with ２－５ 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 10 membered heterocyclyl; R ｃ is 0 to 5 R ｅ C substituted with １－５ alkyl, 0 to 5 R ｅ C substituted with ２－５ alkenyl, 0 to 5 R ｅ C substituted with ２－５ Alkynyl, C ３－６ Carbocyclyl or O, S(=O) ｐ and N; 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 -substituted with -(CH ２ ) ｎ -4 to 6-membered heterocyclyl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -NR ｆ C(=O)R ｆ , -S(=O) ｐ R ｆ , -NR ｆ C(=O)OR ｆ , —OC(═O)NR ｆ R ｆ or -(CH ２ ) ｎ NR ｆ R ｆ and R ｆ is H, C １－５ Alkyl, C ３－６ cycloalkyl or aryl; or R ｆ and R ｆ together with the nitrogen atom to which they are both attached form a heterocyclyl; R ｇ is halo, CN, -OH, C １－６ Alkyl, C ３－６ 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. Formula (III): 【Transformation 3】 [During the ceremony, 【Chemistry 4】 teeth 【Transformation 5】 and R ４ is halo or C substituted with 0 to 4 halo １－３ is alkyl; R ６ is halo, 0 to 3 R ６ａ C substituted with １－４ Alkyl, C ３－６ cycloalkyl, 0 to 3 R １４ phenyl, naphthyl or 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R ６ａ is halo, —OH or C ３－６ is cycloalkyl; R ７ is H; R ８ is substituted with 0 to 5 halo or OH substituents １－４ is alkyl; R ９ is halo, CN, -C(=O)OR ｂ , —C(═O)NR １７ R １７ , 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－５ alkyl, 0 to 2 R １０ and 0 to 2 R １１ C substituted with ２－４ alkynyl, 0 to 3 R １０ and 0 to 2 R １１ Phenyl or O, S(=O) substituted with ｐ and 0 to 3 R １０ and 0 to 2 R １１ 3-9 membered heterocyclyl substituted with R １０ Halo, CN, C １－４ alkyl or —OH; R １１ Ha-OR ｂ and -C(=O)OR ｂ , —C(═O)NR ａ R ａ , 0 to 1 R １２ and 0 to 1 R １３ C substituted with １－３ alkyl or 0 to 5 R ｅ C substituted with ３－６ is cycloalkyl; R １２ is halo, -C(=O)OR ｂ or C substituted with 0-3 halo or OH substituents １－３ is alkyl; R １３ Ha-OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , —OC(═O)NR ａ R ａ , —OC(═O)NR ａ OR ｂ or -S(=O) ｐ R ｃ and R １６ is H or C １－３ is alkyl; R １７ is H or 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－２ alkyl or R １７ and R １７ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ , N and NR １１ａ and 0 to 3 R １０ and 0 to 2 R １１ forming a 3- to 10-membered heterocycle substituted with R ａ is H, 0 to 5 R ｅ C substituted with １－６ Alkyl, -(CH ２ ) ｎ -0 to 5 R ｅ or phenyl substituted with 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -heterocyclyl; or R ａ and R ａ are, together with the nitrogen atom to which they are both attached, 0 to 5 R ｅ forming a heterocyclyl substituted with R ｂ is H, 0 to 5 R ｅ C substituted with １－６ Alkyl, -(CH ２ ) ０－１ -0 to 5 R ｅ C substituted with ３－６ Cycloalkyl, -(CH ２ ) ０－１ -0 to 5 R ｅ or phenyl substituted with 0 to 5 R ｅ -substituted with -(CH ２ ) ｎ -heterocyclyl; R ｅ is halo, CN, =O, C(=O)OH, C １－６ Alkyl, (CH ２ ) ｎ OR ｆ or -S(=O) ｐ R ｆ and R ｆ is H or C １－５ is alkyl; and n is 0, 1, 2 or 3.

3. The compound of claim 2, wherein:

4. R ４ is substituted with halo or 0-4 F １－４ is alkyl; R ６ 0 to 3 R ６ａ C substituted with １－３ Alkyl, C ３－６ cycloalkyl, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S, and N; R ６ａ is a halo; R ７ is H; R ８ is substituted with 0 to 4 halo or OH substituents １－３ is alkyl; R ９ but 【Transformation 6】 and R １０ is a halo; R １１ -C(=O)OR ｂ or 0 to 1 R １２ and 0 to 1 R １３ C substituted with １－２ is alkyl; R １２ is halo, -C(=O)OR ｂ or C substituted with 0-3 halo or OH substituents １－２ is alkyl; R １３ Ga-OR ｂ , -NR ａ R ａ , —OC(═O)NR ａ R ａ or -S(=O) ｐ R ｃ and R ａ is H, 0 to 4 R ｅ C substituted with １－５ alkyl, 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -phenyl or 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -heterocyclyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached, form 0 to 4 R ｅ forming a heterocyclyl substituted with R ｂ is H, 0 to 4 R ｅ C substituted with １－５ alkyl, 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -phenyl or 0 to 4 R ｅ -substituted with -(CH ２ ) ｎ -heterocyclyl; R ｃ 0 to 4 R ｅ C substituted with １－５ is alkyl; R ｅ Halo, CN, =O, C １－５ is alkyl; and n is 0, 1 or 2; 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

5. R ４ is F or CF ３ and R ６ is CF ３ , cyclopropyl, phenyl or 【Transformation 7】 and R ８ is substituted with 0 to 2 OH substituents １－４ is alkyl; R ９ but 【Transformation 8】 and R １０ is F; R １１ -C(=O)OR ｂ or 【Chemistry 9】 and R １２ is halo, -C(=O)OR ｂ or CF ３ and R １３ is —OH or —OC(═O)NR ａ R ａ and R ａ H, C １－４ Alkyl, C ３－６ is cycloalkyl or phenyl; and R ｂ is H or C １－３ is alkyl, 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof. 【Request Item 6】 【Chemistry 10】 but 【Chemistry 11】 and R ４ is substituted with halo or 0 to 4 halo １－４ is alkyl; R ６ 0 to 3 R ６ａ C substituted with １－４ Alkyl, C ３－６ cycloalkyl, 0 to 3 R １４ or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R ６ａ is a halo; R ７ is H; R ８ is substituted with 0 to 5 halo or OH substituents １－４ is alkyl; R ９ Halo, CN, 0-3 R １０ C substituted with １－４ alkyl or 0 to 3 R １０ and 0 to 2 R １１ is phenyl substituted with; R １０ is halo, CN or C １－４ is alkyl; R １１ -C(=O)OR ｂ and R １６ is H, 0 to 4 R １６ａ C substituted with １－４ alkyl or 0 to 4 R １６ａ is phenyl substituted with; R １６ａ is halo, -OR ｂ , -C(=O)OR ｂ or -S(=O) ｐ R ｃ and R ｂ is H or C １－４ is alkyl; and R ｃ is C １－３ is alkyl, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof. 【Request Item 7】 【Chemistry 12】 but 【Chemistry 13】 and R ４ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R ６ 0 to 3 R ６ａ C substituted with １－４ Alkyl, C ３－６ cycloalkyl, 0 to 3 R １４ or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R ７ is H; R ８ is substituted with 0 to 5 halo or OH substituents １－４ is alkyl; R ９ is halo, CN or 0-3 R １０ C substituted with １－４ is alkyl substituted; R １０ is a halo; R １６ is H, 0 to 4 R １６ａ C substituted with １－４ alkyl or 0 to 4 R １６ａ aryl substituted with R １６ａ Halo, C １－４ Alkyl or C(=O)OR ｂ That is, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof. 【Request Item 8】 【Chemistry 14】 but 【Chemistry 15】 and R ４ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R ６ 0 to 3 R ６ａ C substituted with １－４ Alkyl, C ３－６ cycloalkyl, 0 to 3 R １４ or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R ７ is H; R ８ is substituted with 0 to 5 halo or OH substituents １－４ is alkyl; R ９ is halo or CN; R １６ H, C １－４ Alkyl, -S(=O) ｐ R ｃ or 0 to 4 R １６ａ C substituted with １－４ is alkyl; and R １６ａ Halo, C １－４ Alkyl, —OH, OC １－３ Alkyl or -S(=O) ｐ C １－３ is alkyl, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof. 【Request Item 9】 【Chemistry 16】 but 【Chemistry 17】 and R ４ is substituted with halo or 0 to 4 halo substituents １－４ is alkyl; R ６ 0 to 3 R ６ａ C substituted with １－４ Alkyl, C ３－６ cycloalkyl, 0 to 3 R １４ or a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N, substituted with R ７ is H; R ８ is substituted with 0 to 5 halo or OH substituents １－４ is alkyl; R ９ is halo or CN; R １６ is H or 0 to 4 R １６ａ C substituted with １－４ is alkyl; and R １６ａ is the halo, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

10. Formula (IV): [Chemistry 18] (IV) [During the ceremony, 【Chemistry 19】 teeth 【Chemistry 20】 and R ４ is F or CF ３ and R ６ is C ３－６ is cycloalkyl; R ７ is H; R ８ Ha-OC １－３ is alkyl; R ９ is -C(=O)OR ｂ , —C(═O)NR １７ R １７ , 0 to 1 R １１ C substituted with １－３ Alkyl, 【Chemistry 21】 and R １０ Halo, CN, C １－４ alkyl or —OH; R １１ Ha-OR ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , 0 to 1 R １３ C substituted with １－３ alkyl or 0 to 5 R ｅ C substituted with ３－６ is cycloalkyl; R １３ is —OH; R １７ is H or 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－２ alkyl; or R １７ and R １７ together with the nitrogen atom to which they are both attached. 【Chemistry 22】 Forming; R ａ is H or C １－３ is alkyl; R ｂ is H, 0 to 5 R ｅ C substituted with １－３ Alkyl or -(CH ２ ) ０－１ -0 to 5 R ｅ C substituted with ３－６ is cycloalkyl; and R ｅ is halo, CN, =O, C(=O)OH, C １－６ Alkyl, CH ２ OH or -S(=O) ２ C １－３ It is alkyl.

4. The compound of claim 3, wherein:

11. Formula (V): 【Chemistry 23】 (V) [During the ceremony, R ３ is 0 to 3 R ４ C substituted with １－４ alkyl, 0 to 3 R ４ -(CHR ｄ ) ｎ -C ３－６ -carbocyclyl; R ４ is halo, CN or C substituted with 0 to 5 halo substituents １－４ is alkyl substituted; R ６ is halo, 0 to 3 R ６ａ C substituted with １－４ Alkyl, C ３－６ cycloalkyl or containing 1 to 3 heteroatoms selected from O, S and N, and 0 to 5 R １４ 5-6 membered heterocyclyl substituted with R ６ａ is a halo; R ７ is H; R ８ Ha-OC １－３ is alkyl; R ９ teeth 【Chemistry 24】 and R １０ Halo, CN, C １－４ alkyl or —OH; R １１ is 0 to 3 R １２ and 0 to 2 R １３ C substituted with １－３ Alkyl, CN or OR ｂ ; R １２ is a halo; R １３ Ha-OR ｂ or C ３－６ is carbocyclyl; R １４ is halo, CN or C substituted with 0-3 halo １－４ is alkyl; R ｂ is H or 0 to 5 R ｅ C substituted with １－３ is alkyl; R ｄ is H or C １－４ is alkyl; R ｅ is halo or OH; and n is 0 or 1.

2. The compound of claim 1, wherein:

12. Formula (VI): 【Chemistry 25】 (VI) [During the ceremony, R ３ is 0 to 3 R ４ C substituted with １－４ alkyl, 0 to 3 R ４ -(CHR ｄ ) ｎ -C ３－６ -carbocyclyl; R ４ is halo, CN or C substituted with 0-5 halo substituents １－４ is alkyl substituted; R ６ is halo, 0 to 3 R ６ａ C substituted with １－４ Alkyl, C ３－６ cycloalkyl or containing 1 to 3 heteroatoms selected from O, S and N, and 0 to 5 R １４ 5-6 membered heterocyclyl substituted with R ６ａ is halo or —OH; R ７ is H; R ８ Ha-OC １－３ is alkyl; R ９ teeth 【Chemistry 26】 and R １０ Halo, CN, C １－４ alkyl or —OH; R １１ is 0 to 3 R １２ and 0 to 2 R １３ C substituted with １－３ Alkyl, CN or OR ｂ and R １２ is a halo; R １３ Ha-OR ｂ or C ３－６ is carbocyclyl; R １４ Halo, CN or C substituted with 0-3 halo substituents １－４ is alkyl; R ｂ is H or 0 to 5 R ｅ C substituted with １－３ is alkyl; R ｄ is H or C １－４ is alkyl; R ｅ is halo or OH; and n is 0 or 1.

2. The compound of claim 1, wherein:

13. Formula (VII): 【Chemistry 27】 (VII) [During the ceremony, 【Chemistry 28】 teeth 【Chemistry 29】 and R ３ is 0 to 5 R ４ -(CHR ｄ ) ｎ -C ３－１０ -carbocyclyl; R ４ is halo, CN, C substituted with 0 to 5 halo or —OH １－４ alkyl, substituted with 0 to 5 halo substituents, —OC １－４ Alkyl or -S(=O) ｐ R ｃ and R ６ is 0 to 3 R ６ａ C substituted with １－４ alkyl or 0 to 5 R １４ C substituted with ３－６ is cycloalkyl; R ６ａ is a halo; R ７ is H; R ８ is C １－３ Alkyl or —OC １－３ is alkyl; R ９ is -C(=O)NR １７ R １７ , 0 to 3 R １０ and 0 to 2 R １１ C substituted with ３－６ Carbocyclyl or O, S(=O) ｐ , N and NR １１ａ and 0 to 3 R １０ and 0 to 2 R １１ 5-12 membered heterocyclyl substituted with R １０ Halo, CN, C １－４ Alkyl, ═O, —OH or —OC １－４ is alkyl; R １１ is 0 to 5 R １２ and 0 to 2 R １３ C substituted with １－４ Alkyl, -S(=O) ｐ R ｃ , 0 to 5 R ｅ C substituted with ３－６ is cycloalkyl; R １１ａ is H, 0 to 4 R １１ｂ C substituted with １－４ Alkyl, —C(═O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , 0 to 5 R ｅ C substituted with ３－６ cycloalkyl, 0 to 5 R ｅ aryl substituted with O, S(=O) ｐ , N and NR １５ and 0 to 5 R ｅ 4-6 membered heterocyclyl substituted with R １１ｂ is halo, -OH, -C(=O)OH, -C(=O)OC １－４ is alkyl or aryl; R １２ is halo, -C(=O)OR ｂ , C substituted with 0 to 3 halo １－４ Alkyl or —OH or C ３－６ is cycloalkyl; R １３ Ha-OR ｂ , -NR ａ R ａ , —OC(═O)NR ａ R ａ and R １４ is a halo; R １７ is H or 0 to 3 R １０ and 0 to 2 R １１ C substituted with １－４ alkyl; or R １７ and R １７ are combined with the nitrogen atom to which they are bonded to form O, S(=O) ｐ , N and NR １１ａ and 0 to 3 R １０ and 0 to 2 R １１ forming a 3- to 9-membered heterocyclyl substituted with R ａ is H, 0 to 5 R ｅ C substituted with １－６ alkyl, 0 to 5 R ｅ C substituted with ３－１０ carbocyclyl; or R ａ and R ａ are, together with the nitrogen atom to which they are both attached, 0 to 5 R ｅ forming a heterocyclyl substituted with R ｂ is H or 0 to 5 R ｅ C substituted with １－４ is alkyl; R ｃ is C １－４ is alkyl; R ｄ is H or C １－３ is alkyl; R ｅ Halo, CN, NO ２ , = O, 0 to 5 R ｇ C substituted with １－６ Alkyl, C ３－６ Cycloalkyl or -S(=O) ｐ R ｆ and R ｆ is H, C １－６ is alkyl, R ｇ is halo, CN, —OH or C １－６ is alkyl; n is 0 or 1; and p is 0, 1 or 2.

2. The compound of claim 1, wherein:

14. R ３ 0 to 2 R ４ -CHR substituted with ｄ -C ３－６ cycloalkyl or 0 to 2 R ４ is phenyl substituted with; R ４ F, CH ３ or CF ３ and R ６ is substituted with 0 to 3 halo １－４ C substituted with alkyl or 0-3 halo substituents ３－６ is cycloalkyl; R ７ is H; R ８ Ga-OCH ３ and R ９ -C(=O)NR １７ R １７ , 【Transformation 30】 and R １０ is a halo; R １１ 0 to 3 R １２ and 0 to 2 R １３ C substituted with １－４ Alkyl, -S(=O) ｐ R ｃ or 0 to 3 R ｅ C substituted with ３－６ is cycloalkyl; R １１ａ is H or 0 to 3 R １１ｂ C substituted with １－４ is alkyl; R １１ｂ is —OH; R １２ is substituted with 0 to 3 halo substituents １－４ is alkyl; R １３ -OC(=O)NR ａ R ａ and R １４ is a halo; R １７ is H or 0 to 2 R １０ and 0 to 2 R １１ C substituted with １－４ alkyl; or R １７ and R １７ Together with the nitrogen atom to which they are both bonded, they form O, S(=O) ｐ , N and NR １１ａ and 0 to 2 R １０ and 0 to 2 R １１ forming a 3- to 9-membered heterocyclyl substituted with R ａ is H, 0 to 4 R ｅ C substituted with １－４ Alkyl-substituted, 0 to 1 R ｅ C substituted with ３－１０ carbocyclyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached, form 0 to 4 R ｅ forming a heterocyclyl substituted with R ｂ is H or C １－３ is alkyl; R ｃ is C １－３ is alkyl; R ｄ is H or C １－３ is alkyl; R ｅ is C １－４ Alkyl, C ３－６ Cycloalkyl or -S(=O) ｐ R ｆ and R ｆ is C １－４ is alkyl; n is 0 or 1; and p is 0, 1 or 2; 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof.

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

16. 16. The pharmaceutical composition of claim 15 for treating a disease associated with relaxin.

17. 17. The pharmaceutical composition of claim 16, 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.

18. 18. The pharmaceutical composition of claim 17, wherein the disease is heart failure.

19. 17. The pharmaceutical composition of claim 16, wherein the disease is fibrosis.

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