Naphthalene and quinoline analogues as RXFP1 agonists

Abstract

The present disclosure relates to compounds of formula (I) that are RXFP1 receptor agonists, compositions comprising the same, and methods of use thereof (e.g., for the treatment of heart failure, fibrosis, and related diseases, such as lung disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic kidney disease), or liver disease (e.g., nonalcoholic steatohepatitis and portal hypertension)). TIFF2024546944000073.tif59153

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 289,822, filed December 15, 2021, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] The present disclosure relates to novel compounds that are relaxin family peptide receptor 1 (RXFP1) agonists, compositions containing them, and methods of using them in the treatment of, for example, heart failure, fibrosis, and related diseases, such as lung disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic kidney disease), and liver disease (e.g., non-alcoholic steatohepatitis and portal hypertension).

[0003] Human relaxin hormone (also called relaxin or H2 relaxin) is a 6 kDa peptide consisting of 53 amino acids whose activity was first discovered in 1926 when Frederick Hisaw observed relaxation of the fibrocartilaginous symphysis pubis joints when he injected a crude extract from the porcine corpus luteum into virgin guinea pigs (Hisaw FL, Proc. Soc.Exp. Biol.Med., 1926, 23, 661-663). The relaxin receptor, formerly known as Lgr7, is now formally named relaxin family peptide receptor 1 (RXFP1) and was identified as one of the receptors for relaxin in 2002 (Hsu SY. et al., Science, 2002, 295, 671-674). RXFP1 is well conserved between mouse and human, with 85% amino acid identity, and is essentially ubiquitously expressed in humans and other species (Halls ML. et al., Br. J.Pharmacol., 2007, 150, 677-691). The relaxin and RXFP1 cell signaling pathways are cell type dependent and highly complex (Halls ML. et al., Br. J.Pharmacol., 2007, 150, 677-691; Halls ML. et al., Ann. NY Acad. Sci., 2009, 1160, 108-111; Halls ML. et al., Ann. NY Acad. Sci., 2007, 1160, 117-120). The most studied pathway is one in which relaxin functions as an RXFP1 agonist, resulting in a relaxin-dependent increase in cellular levels of cAMP, which promotes GαS coupling and activation of adenylate cyclase (Halls ML. et al., Mol. Pharmacol., 2006, 70, 214-226).

[0004] Since the initial discovery of relaxin, much experimental research has focused on clarifying the role relaxin plays in female reproductive biology and on characterizing the physiological changes that occur during mammalian pregnancy (Sherwood OD., Endocr. Rev., 2004, 25, 205-234). During human pregnancy, the female body undergoes a significant decrease in systemic vascular resistance (SVR) of approximately 30% with a concomitant increase in stroke volume of approximately 50% to meet the nutritional demands of the fetus (Jeyabalan AC., KP, Renal and Electrolyte Disorders. 2010, 462-518; Clapp JF & Capeless E., Am. J. Cardio., 1997, 80, 1469-1473). Further vascular adaptation involves an increase of approximately 30% in systemic arterial compliance, which is important for maintaining effective ventricular-arterial coupling, as well as an increase of approximately 50% in both renal blood flow (RBF) and glomerular filtration rate (GFR), which are important for the elimination of metabolic waste products (Jeyabalan AC., KP, Renal and Electrolyte Disorders. 2010, 462-518; Poppas A. et al., Circ., 1997, 95, 2407-2415). Both preclinical studies in rodents as well as clinical trials in various patient settings provide evidence that relaxin is involved, at least to some extent, in mediating these adaptive physiological changes (Conrad KP., Regul Integr. Comp. Physiol., 2011, 301, R267-275; Teichman SL. et al., Heart Fail. Rev., 2009, 14, 321-329).Importantly, many of these adaptive responses may benefit patients with HF, in that excessive fibrosis, low arterial compliance, and reduced 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), defined hemodynamically as "a condition in which the pumping function of the heart is impaired, resulting in insufficient systemic perfusion for the body's metabolic needs," is estimated to affect 5.8 million people in the United States and over 23 million people worldwide, placing a tremendous burden on today's healthcare system (Roger VL. et al., Circ. Res., 2013, 113, 646-659). It is estimated that an additional 3 million people will have HF in the United States alone by 2030, a 25% increase from 2010. The estimated direct costs associated with HF in 2010 (2008 dollars) were $25 billion, and are expected to rise to $78 billion in 2030 (Heidenreich PA. et al., Circ., 2011, 123, 933-944). Surprisingly, one in nine deaths in the United States is recorded as having HF on the death certificate (Roger VL. et al., Circ., 2012, 125, e2-220), and although survival rates after a diagnosis of HF have improved over time (Matsushita K. et al., Diabetes, 2010, 59, 2020-2026) (Roger VL. et al., JAMA, 2004, 292, 344-350), mortality remains high, with approximately 50% of HF patients dying within 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 insufficient cardiac output and can be quite debilitating depending on the stage of disease progression. The main symptoms and signs of HF include: 1) dyspnea due to pulmonary edema caused by the blockage of blood flow from the left ventricle to the system and increased pressure in the pulmonary capillary bed; 2) leg edema caused when the right ventricle cannot tolerate systemic venous return; and 3) fatigue caused by the heart's inability to maintain sufficient cardiac output (CO) for the body's metabolic needs (Kemp CD. & Conte JV., Cardiovasc. Pathol., 2011, 21, 365-371). Also, with regard 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, such as fluid retention and pulmonary edema, are absent. Decompensated heart failure is one whose deterioration can manifest as the development of acute pulmonary edema, decreased exercise tolerance, and increased shortness of breath on exertion (Millane T. et al., BMJ, 2000, 320, 559-562).

[0007] Contrary to a simple definition of a reduced cardiac function that is unable to fulfill metabolic needs, the many diseases that cause HF, the numerous risk factors, and the many pathological changes that ultimately lead to HF make this disease extremely complex (Jessup M. & Brozena S., N. Engli. J. Med., 2003, 348, 3007-2018). Adverse events thought to be involved in the pathophysiology of HF range from very acute ones, such as myocardial infarction, to chronic diseases such as lifelong hypertension. Historically, HF was initially described as "systolic HF", where reduced left ventricular (LV) contractile function limits blood ejection, resulting in a reduced ejection fraction (EF = stroke volume / end-diastolic volume), or as "diastolic HF", where active relaxation is reduced and passive stiffening is increased, limiting LV filling during diastole, but overall EF is preserved (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). More recently, it has become clear that diastolic and systolic LV dysfunction are not unique to the two groups, and so the new terms "heart failure with reduced ejection fraction" (HFrEF) and "heart failure with preserved ejection fraction" (HFpEF) have been used (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). Although these two patient populations exhibit very similar signs and symptoms, whether HFrEF and HFpEF are two distinct HF subtypes or two extremes of HF with a common pathology is currently under debate in the cardiovascular community (Borlaug BA. & Redfield MM., Circ., 2011, 123, 2006-2013), (De Keulenaer GW. & Brutsaert DL., Circ., 2011, 123, 1996-2004).

[0008] Cerulaxin is an intravenous (IV) formulation of human recombinant relaxin peptide with a relatively short phase 1 pharmacokinetic half-life of 0.09 hours, currently in development to treat HF ​​(Novartis, 2014). Administration of Cerulaxin to healthy volunteers (NHVs) demonstrated increases in 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). In large clinical trials, patients with acute decompensated HF (ADHF) were observed to experience worsening renal function, favorable changes in HF progression, and reduced mortality in response to in-hospital 48-hour intravenous infusions of 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 have a sustained effect on HF patients, improvements in renal function based on serum creatine levels were observed in patients with scleroderma who received cerulaxin 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 treating HF, continuous subcutaneous administration of relaxin has also proven 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 (Bennett RG., Liver Int., 2014, 34, 416-426) injury.

[0009] In summary, a large body of evidence has demonstrated the role of relaxin-dependent agonism of RXFP1 in mediating multiple adaptive changes that occur during mammalian pregnancy, and that these changes have favorable physiological effects and outcomes when relaxin is administered to HF patients. Further preclinical animal studies in various disease models of lung, kidney and liver damage have demonstrated that relaxin, when administered chronically, may have therapeutic effects in multiple conditions, not limited to HF. More specifically, chronic administration of relaxin may provide benefits to patients suffering from 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] The present invention provides novel substituted naphthalene and quinoline compounds, their analogs (such as stereoisomers, tautomers, pharma- ceutically acceptable salts, or solvates thereof), 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] Also provided is a pharmaceutical composition comprising a compound of the invention, 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 example, in the treatment and / or prevention of heart failure, fibrosis and related diseases such as pulmonary disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic kidney disease), or liver disease (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 may be used for the manufacture of a medicament for the treatment and / or prevention of heart failure.

[0016] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two, other drugs.

[0017] These and other features of the present invention are set forth in the broader disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The present invention includes compounds of formula (I) that are RXFP1 receptor agonists, compositions containing same, and methods of using same.

[0019] In a first aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, Q is CH, CR 1 or N; provided that at most one Q is N; R 1 is a halogen or C substituted with 0 to 5 halogens 1-4 is alkyl; R 2 is halogen, CN, -OC 1-4 Alkyl or C substituted with 0-5 halogens or OH 1-4 is alkyl; R 3 is 0 to 5 R 4 C replaced with 1-4 Alkyl, 0 to 5 R 4 Replaced with -(CR d R d ) n -C 3-10 -carbocyclyl or 0 to 5 R 4 Replaced with -(CR d R d ) n -(O, S(=O) p , N, and N da 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from; R 4 is halogen, CN, C substituted with 0-5 halogens 1-4 Alkyl, OH, -OC substituted with 0-5 halogens 1-4 Alkyl, -S(O) p R c , aryl, or O, S(=O) p , N, and N d is a 4-6 membered heterocyclyl containing 1 to 4 heteroatoms selected from; R 5 is -S(=O) p R c , -S(=O) p NR a R a , C substituted with 0 to 5 halogens or OH 2-6 Alkenyl, C substituted with 0-5 halogens or OH 2-6 Alkynyl, 0 to 3 R 6 and 0 to 2 R 7 C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N, and N 10 and 0 to 3 R 6 and 0 to 2 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, CN, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 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 aC(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 8 is halogen, -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a OR b or C substituted with 0-3 halogens or OH 1-4 is alkyl; R 9 -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 ORb , -S(=O) p NR a R a , -S(O) p R c , 0 to 3 R e Substituted with -(CH 2 ) n -C 3-6 Carbocyclyl, or O, S(=O) p and N; e Substituted with -(CH 2 ) n -heterocyclyl; R 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, or aryl; R 12 , H, C 1-3 is alkyl, or aryl; R a 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 )n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and are each 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, 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -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 heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, NO 2 , =O, 0 to 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, -(CH 2 ) n -Carbocyclyl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n ORf , -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 , 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 are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0020] In a second aspect of the first aspect, the present invention provides a compound of formula (II): [ka] [In the formula, R 1 is a halogen or C substituted with 0 to 4 halogens 1-3 is alkyl; R 2 is halogen, -OC 1-3Alkyl, or C 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-4 is alkyl; R 5 is -S(=O) p R c , C substituted with 0 to 5 halogens or OH 2-6 Alkynyl, 0 to 3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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)Rb , -S(=O) p R c , -S(=O) p NR a R a , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 8 is halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halogens or OH 1-4 is alkyl; R 9 -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 10 is H, 0 to 2 R 11 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 3-6Cycloalkyl, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, or aryl; R 12 , H, C 1-3 is alkyl, or aryl; 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and are each 0 to 5 R e forming a 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 5 R eC 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 heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, =O, 0 to 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, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -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 , 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; Rg are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0021] In a third aspect within the scope of the first and second aspects, the present invention provides a compound of formula (III): [ka] [In the formula, R 1 is Br or CF 3 and; R 2 is -OC substituted with 0 to 4 halogens 1-4 is alkyl; R 4a is a halogen; R 4b is C substituted with 0-4 F 1-3 is alkyl; R 6 is halogen, CN, C 1-3 Alkyl, -OH, or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 Alkyl, OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NRa S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , or C 3-6 is cycloalkyl; R 8 is halogen, -C(=O)OR b , -C(=O)NHR a or C substituted with 0-3 halogens or OH 1-3 is alkyl; R 9 -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 , -S(=O) p 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 C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH 2 ) n -heterocyclyl or R aand 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 C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halogen, CN, =O, 0 to 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, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f, S(=O) p R f , C(=O)NR f R f , C(=O)OR f , N.R. f C(=O)R f , S(=O) p NR f R f , N.R. f S(=O) p R f , N.R. f C(=O)OR f ,OC(=O)NR f R f , or -(CH 2 ) n NR f R f and; R f , H, C 1-6 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 are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0022] In a fourth aspect within the scope of the first to third aspects, the present invention provides a compound of formula (IV): [ka] [In the formula, R 1 is Br; R 2 -OC 1-3 is alkyl; R 4a is F; R 4bCF 3 and; R 6 is a halogen; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 Alkyl, -C(=O)OR b , -C(=O)NR a R a and; R 8 is -C(=O)OR b , -C(=O)NHR a or C substituted with 0-3 halogens or OH 1-3 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b or -OC(=O)NR a R a and; R a is H, 0 to 3 R e C replaced with 1-3 Alkyl, 0 to 3 R e Substituted with -(CH 2 ) n -C 3-6 Cycloalkyl, 0 to 3 R e is a phenyl substituted with; R b is H or 0 to 3 R e is heterocyclyl substituted with; R e is halogen, CN, =O, or C 1-6 is alkyl; and n is 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0023] In a fifth aspect of the first and second aspects, the present invention provides a compound of formula (V): [ka] [In the formula, R 1 is a halogen or C substituted with 0 to 5 halogens 1-3 is alkyl; R 2 is -OC substituted with 0 to 4 halogens 1-4 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-3 is alkyl; R 5 is O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 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)Rb , -S(=O) p R c , -S(=O) p NR a R a , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 4 R e is a 4-6 membered heterocyclyl substituted with; R 8 is -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halogens or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -S(=O) p NR a R a , or -S(O) p R c and; R 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, or aryl; R 12 , H, C 1-3 is alkyl, or aryl; R a is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH 2 ) 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 C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R eC replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halogen, CN, NO 2 , =O, C(=O)OR f , 0 to 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, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , S(=O) p R f , C(=O)NR f R f , N.R. f C(=O)R f , S(=O) p NR f R f , N.R. f S(=O) p R f , N.R. f C(=O)OR f ,OC(=O)NR f R f , or -(CH 2 ) n NR f R f and; R f , H, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl, or R f and Rf together with the nitrogen atom to which they are both attached form a heterocyclyl; R g are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0024] In a sixth aspect of the fifth aspect, the present invention provides a compound represented by formula (V): R 2 -OCH 3 and; R 4a is F; R 4b CF 3 and; R 5 teeth, [ka] and; R 6 is a halogen, -OH, or C substituted with 0 to 1 OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 is alkyl; R 8 is -C(=O)OR b , -C(=O)NHR a , or -C(=O)NHOR b and; R 9 -OR b or -NR a R a and; R 10 is H or C 1-3 is alkyl; R a is H or C 1-6is alkyl; and R b is H or C 1-6 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0025] In a seventh aspect of the fifth aspect, the present invention provides a compound represented by formula (V): R 2 -OCH 3 and; R 4a is F; R 4b CF 3 and; R 5 teeth, [ka] and; R 6 is a halogen, C 1-4 Alkyl, -OH, or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 is alkyl; R 8 is -C(=O)OR b and; R 9 is OH; R 10 is H, 0 to 2 R 11 C replaced with 1-3 Alkyl, or -C(=O)OC 1-4 is alkyl; R 11 is -OH, -C(=O)OH, or aryl; and R b is H or C 1-4 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0026] In an eighth aspect of the fifth aspect, the present invention provides a compound represented by formula (V): R 2 -OCH 3 and; R 4a is F; R 4b CF 3 and; R 5 teeth, [ka] and; R 6 is halogen, CN, C 1-4 Alkyl, =O, -OH, or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 Alkyl, -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , or -C(=O)OR b and; R 8 is -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halogens or OH 1-4 is alkyl; R 9 -NR a C(=O)R b and; R 10 is H or C 1-3 is alkyl; R a is H or C 1-4 is alkyl; and R b is H or C 1-4 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0027] In a ninth aspect of the first aspect, the present invention provides a compound represented by formula (I): R 5 is -S(=O) 2 R c and; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-3 is alkyl; R c is 0 to 2 R e C replaced with 1-3 is alkyl; R e -OR f and R f is H or C 1-2 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0028] In a tenth aspect of the first aspect, the present invention provides a compound of formula (VI): [ka] [In the formula, R 2 -OC 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-4 is alkyl; R 5 is 0 to 3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 8 is halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halogens or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NRa 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 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, or aryl; R 12 , H, C 1-3 is alkyl, or aryl; 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 -(CH 2 ) n -C 3-10Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and are each 0 to 5 R e forming a 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -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 heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, =O, 0 to 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, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 )n -aryl, -(CH 2 ) n -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 , 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 are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0029] In an eleventh aspect of the first aspect, the present invention provides a compound of formula (VII): [ka] [In the formula, R 2 -OC 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens1-4 is alkyl; R 5 is 0 to 3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 Re is a 4-6 membered heterocyclyl substituted with; R 8 is halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halogens or OH 1-4 is alkyl; R 9 -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 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, or aryl; R 12 , H, C1-3 is alkyl, or aryl; 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and are each 0 to 5 R e forming a 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -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 heterocyclyl; R d is H or C 1-4is alkyl; R e is halogen, CN, =O, 0 to 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, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -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 , 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 are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0030] In a twelfth aspect of the first aspect, the present invention provides a compound of formula (VIII): [ka] [In the formula, R 2 -OC 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-4 is alkyl; R 5 is 0 to 3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 8 is halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halogens or OH 1-4 is alkyl; R 9 -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 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a Ra , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4-6 membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, or aryl; R 12 , H, C 1-3 is alkyl, or aryl; 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and are each 0 to 5 R e forming a 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 -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH 2 ) n-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 heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, =O, 0 to 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, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -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 , H, C 1-5 Alkyl, C 3-6 cycloalkyl, or aryl, or R f and Rf together with the nitrogen atom to which they are both attached form a heterocyclyl; R g are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0031] In the compounds of formula (I), examples of optional variable substituents include R 1 , R 2 , R 3 , R 4 (R 4a , R 4b ), R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R a , R b , R c , R d , R e , R f , and R g and these ranges may be used independently of any other variable substituent ranges. Thus, the invention includes combinations of the different embodiments.

[0032] In certain embodiments of Formula (II), R 4a is F.

[0033] In another embodiment of Formula (II), R 4b CF 3 It is.

[0034] In another embodiment of Formula (II), R 1 is absent or halogen; R 2 F or -OCH 3 R 4a is F; R4b CF 3 R 5 teeth, [ka] R 7 is -C(=O)NR a R a R a and R a are bonded together with the nitrogen atom to which they are both attached. [ka] Forming; R e is 0 to 2 R g C replaced with 1-3 alkyl; R g is -OH alkyl.

[0035] In another embodiment of Formula (II), R 1 is absent or halogen; R 2 F or -OCH 3 R 4a is F; R 4b CF 3 R 5 teeth, [ka] R 6 is F; R 7 is -S(=O) 2 C 1-3 Alkyl, -S(=O) 2 NHR a , or 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 alkyl; R 8 is -C(=O)OH, or CF 3 R 9 -NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4Alkyl or -OC(=O)NHR a R a , H, C 1-3 Alkyl, -(CH 2 ) 0-1 -C 3-6 Cycloalkyl or 0 to 2 R e Substituted with -(CH 2 ) 0-1 -phenyl; R b is H or heterocyclyl; R e is C 1-3 Alkyl, -(CH 2 ) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0036] In another embodiment of Formula (II), R 1 is absent or halogen; R 2 -OCH 3 R 4a is F; R 4b CF 3 R 5 teeth, [ka] R 6 is F; R 8 is -C(=O)OH, or CF 3 R 9 -NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl or -OC(=O)NHR a R a , H, C 1-3 Alkyl, -(CH 2 ) 0-1 -C 3-6 Cycloalkyl or 0 to 2 R e Substituted with -(CH 2 ) 0-1 -phenyl; R bis H or heterocyclyl; R e is C 1-3 Alkyl, -(CH 2 ) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0037] In another embodiment of Formula (II), R 1 is absent or halogen; R 2 F or -OCH 3 R 4a is F; R 4b CF 3 R 5 teeth, [ka] R 7 is 0 to 1 R 9 C replaced with 1-4 alkyl; R 9 is -OH; R 10 is -C(=O)R b R b is H or 0 to 4 R e C replaced with 1-3 alkyl; R e is -(CH 2 ) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0038] Unless otherwise specified, each term has the following meaning:

[0039] "Halogen" includes fluoro, chloro, bromo, and iodo.

[0040] "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, "C 1 -C 10Alkyl" or "C 1-10 "Alkyl" (or alkylene) is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 In addition, for example, "C 1 -C 6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted, where at least one hydrogen is replaced by 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). 0 Alkyl" or "C 0 When "alkylene" is written, it is intended to represent a direct bond. "Alkyl" includes deuterated alkyls (e.g., CD 3 ) is also included.

[0041] "Alkenyl" or "alkenylene" is intended to include either a straight or branched hydrocarbon chain having one or more, preferably one to three, carbon-carbon double bonds in any stable position along the chain. For example, "C 2-6 Alkenyl (or alkenylene) has C 2 , C 3 , C 4 , C 5 , and C 6 Alkenyl groups (eg, ethenyl, propenyl, butenyl, pentenyl, and hexenyl) are intended to be included.

[0042] "Alkynyl" or "alkynylene" is intended to include either a straight or branched hydrocarbon chain having one or more, preferably one to three, carbon-carbon triple bonds in any stable position along the chain. For example, "C 2-6Alkynyl" (or alkynylene) has C 2 , C 3 , C 4 , C 5 , and C 6 It is intended to include alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0043] "Carbocycle", "carbocyclyl", or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered mono- or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of such carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As noted above, bridged rings are also included in the definition of carbocyclyl (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Bridges of one or two carbon atoms are preferred. Note that a single ring always becomes a tricyclic ring. When a ring is bridged, the listed ring substituents may also be present on the bridge. When the term "carbocyclyl" is used, it is intended to include "aryl", "cycloalkyl", and "spirocycloalkyl". Preferred carbocyclyls, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.

[0044] "Cycloalkyl" is intended to mean a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems.3-7 Cycloalkyl" is C 3 , C 4 , C 5 , C 6 , and C 7 It is intended to include cycloalkyl groups. Examples of single-ring cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of multi-ring cycloalkyls include, but are not limited to, 1-decalinyl, norbornyl, and adamantyl.

[0045] "Spirocycloalkyl" is intended to mean a hydrocarbon bicyclic ring system in which both rings are connected through one atom. The size and nature of the rings can be different or the same. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.

[0046] "Bicyclic carbocyclyl" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system containing two fused rings and consisting of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to another ring, which is a saturated, partially unsaturated, or unsaturated 5- or 6-membered carbocyclic ring. A bicyclic carbocyclic group may be attached to its pendant group at any carbon atom that results in a stable structure. The bicyclic carbocyclic groups described herein may be substituted 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.

[0047] An "aryl" group refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl groups 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).

[0048] "Benzyl" refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group, where the phenyl group is optionally substituted with 1 to 5 groups, preferably 1 to 3 groups.

[0049] "Heterocycle", "heterocyclyl" or "heterocycle" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered mono- or bicyclic heterocycle, or a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocycle, which is saturated, partially unsaturated, or fully unsaturated and has carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein any of the above heterocycles also includes any polycyclic group fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). pwhere p is 0, 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent, as defined). The heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocycles described herein may be substituted at carbon or nitrogen atoms if the resulting compound is stable. Nitrogen in a heterocyclyl may be optionally quaternized. When the total number of S and O atoms in a heterocyclyl exceeds 1, it is preferred that such heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in a heterocyclyl is 1 or less. Bridged rings are also included in the definition of heterocyclyl. When the term "heterocyclyl" is used, it is intended to include heteroaryl.

[0050] Examples of heterocyclyl include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 -b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, Oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl , pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 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, 1,3,4-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.

[0051] A "bicyclic heterocyclyl" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system having two fused rings and consisting of carbon atoms and one, two, three, or four heteroatoms independently selected from the group consisting of N, O, and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring, including a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo ring, each of which is fused to another ring, which is a saturated, partially unsaturated, or unsaturated 5- or 6-membered polycyclic ring, including a 5-membered heterocyclyl, a 6-membered heterocyclyl, or a carbocyclyl (with the proviso that the first ring is not a benzo ring if the other ring is a carbocyclyl).

[0052] Bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Bicyclic heterocyclic group described herein may be substituted at carbon or nitrogen atom as long as the resulting compound is stable. If the total number of S and O atoms in heterocyclyl is more than 1, it is preferred that the heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in heterocyclyl is 1 or less.

[0053] 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.

[0054] "Heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member (e.g., sulfur, oxygen, or nitrogen). Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. Nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) p where p is 0, 1 or 2.

[0055] The term "substituted" as used herein means that at least one hydrogen atom is replaced with a group other than hydrogen, provided that the normal valence is maintained and the substitution results in a stable compound. When a substituent is keto (i.e. =O), two hydrogens on the atom are replaced. Keto substituents are not present in aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is substituted with a carbonyl group or double bond, the carbonyl group or double bond is considered to be part of the ring (i.e., within the ring). As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0056] Where there are nitrogen atoms (e.g., amines) in the compounds of the invention, they may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide additional compounds of the invention. Thus, a nitrogen atom as described and claimed is considered to include both the described nitrogen and its N-oxide (N→O) derivative.

[0057] When any variable occurs more than once in any component or formula of a compound, the definition of that variable is independent of the definitions of all other variables. That is, for example, if a group is shown to be substituted with 0-3 R groups, then that group may optionally be substituted with up to 3 R groups, where each R is selected independently of the definitions of the other R groups. Additionally, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0058] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom on the ring. When a substituent is listed without showing the atom to which it is bonded to the remainder of the compound of a formula, 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.

[0059] The present invention includes all pharma- ceutically acceptable salt forms of the compounds. A pharma-ceutically acceptable salt is one in which the counterion does not contribute significantly to the physiological activity or toxicity of the compound and acts as a pharmaceutical equivalent itself. These salts can be prepared using common organic chemistry techniques and 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, vanzatin, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine and zinc.

[0060] Throughout this specification and the appended claims, a given chemical formula or name is intended to include all isomers, such as stereoisomers and optical isomers and racemates, when such isomers exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one half of a pair of molecules that are mirror images of each other and are not superimposable. The term "diastereomer" refers to stereoisomers that are not mirror images of each other. The term "racemate" or "racemic mixture" refers to a composition in which two enantiomers are in equimolar amounts and have no optical activity.

[0061] The present invention encompasses all tautomers, atropisomers and rotamers of the compounds.

[0062] All processes used to prepare compounds of the present invention and intermediates made along the way are considered to be part of the present invention.

[0063] The symbols "R" and "S" indicate the configuration of substituents around a chiral carbon atom. The isomeric symbols "R" and "S" are used herein to indicate the configuration of atoms 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)).

[0064] The term "chiral" refers to the structural characteristic of a molecule that makes it non-superimposable on its own mirror image. The term "homochiral" refers to the state of pure enantiomers. The term "optical activity" refers to the degree to which a homochiral molecule or a chiral molecule that is not a racemic mixture rotates the plane of polarized light.

[0065] The present invention is intended to include all isotopes of atoms contained in the compounds of the present invention. 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 of skill in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent otherwise used. Such compounds may have a variety of potential uses, for example, as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have advantageously altered biological, pharmacological, or pharmacokinetic properties.

[0066] Throughout this specification and the appended claims, a given chemical formula or name is intended to include all isomers, such as stereoisomers and optical isomers and racemates, when such isomers exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers, such as C=C double bonds, C=N double bonds, rings, etc., may also exist in the present invention, and all such stable isomers are included in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described, and they may be isolated as a mixture of isomers or as separated isomers. The compounds of the present invention may be isolated in optically active or racemic form. Optically active forms may be prepared by re-separation of racemic forms or by synthesis from optically active starting materials. All processes used to prepare the compounds of the present invention, and intermediates produced along the way, are considered to be part of the present invention. When enantiomeric or diastereomeric products are produced, the products may be separated by conventional methods, such as by chromatography or fractional crystallization. Depending on the process conditions, the final products of the present invention may be obtained in either the (neutral) free form or in salt form. Both the free and salt forms of the final compounds are included within the scope of the present invention. If desired, one form of the compound may be converted to the other form. Free bases or free acids may be converted to salts, and salts may be converted to their free compounds or to other salts, and mixtures of isomeric compounds of the present invention may be separated into their respective isomers. The compounds of the present invention, their free forms and salts, may exist in multiple tautomers, where hydrogen atoms are replaced by other moiety molecules and the chemical bonds between atoms in the molecules are changed as a result. To the extent that any tautomers exist, they should be understood to be included in the present invention.

[0067] The term "stereoisomer" refers to an isomer that has the same composition but differs in the arrangement of atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one half of a pair of molecules that are mirror images of each other and are non-superimposable. The term "diastereomers" refers to stereoisomers that are not mirror images of each other. The term "racemate" or "racemic mixture" refers to a composition that contains equimolar amounts of two enantiomers and has no optical activity.

[0068] biological methods RXFP1 cyclic adenosine monophosphate (cAMP) assay Human embryonic kidney cells 293 (HEK293 cells) and HEK293 cells stably expressing human RXFP1 were cultured in MEM medium supplemented with 10% qualified FBS and 300 μg / mL hygromycin (Life Technologies). Cells were dissociated and suspended in assay buffer. Assay buffer was HBSS buffer (with calcium and magnesium) containing HEPES (20 mM), 0.05% BSA, and IBMX (0.5 mM). Cells (3000 cells / well except for HEK293 cells stably expressing human RXFP1, which were 1500 cells / well) were added to 384-well ProxiPlates (Perkin-Elmer). Cells were immediately treated with test compounds in the final concentration range of 0.010 nM to 50 μM / DMSO (2% final). Cells were incubated at room temperature for 30 min. The concentration of intracellular cAMP was determined using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and d2-fluorescently labeled cAMP were prepared in the provided lysis buffer, respectively. After completion of the reaction, cells were lysed with equal volumes of d2-cAMP and anti-cAMP solutions. After incubation at room temperature for 1 h, the time-resolved fluorescence intensity was measured using Envision (Perkin-Elmer) with excitation at 400 nm and dual emission at 590 nm and 665 nm. A calibration curve was prepared using a separate cAMP standard and obtained by plotting the fluorescence intensity at 665 nm to the fluorescence intensity at 590 nm against cAMP concentrations ranging from 2.7 μM to 0.1 pM. The potency and activity of compounds in inhibiting cAMP production were then determined by fitting a plot of cAMP concentration versus compound concentration to a four-parameter logistic equation.

[0069] The examples disclosed below were tested in the human RXFP1 (hRXFP1) HEK293 cAMP assay described above and found to have agonist activity. Table 1 shows the EC50 values ​​in the hRXFP1 HEK293 cAMP assay measured in the examples. 50 List the values.

[0070] Table 1. EC values ​​in the hRXFP1 HEK293 cAMP assay measured using naphthalene examples. 50 value [ka] [Table 1] [Table 2]

[0071] Pharmaceutical compositions and methods of use thereof The compounds of formula (I) are RXFP1 receptor agonists and may find use in the treatment of medical indications such as heart failure, fibrosis, and related diseases, such as pulmonary disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic kidney disease), or liver disease (e.g., non-alcoholic steatohepatitis and portal hypertension).

[0072] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier.

[0073] Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier for use in treating a relaxin-related disorder.

[0074] Another aspect of the present invention is a method of treating a relaxin-related disorder, comprising administering an effective amount of a compound of formula (I).

[0075] Another aspect of the invention is a method of treating cardiovascular disease, comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0076] Another aspect of the invention is a method of treating heart failure, comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0077] Another aspect of the invention is a method of treating fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0078] Another aspect of the invention is a method of treating a disease associated with fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0079] Another aspect of the invention is a method of treating or preventing renal failure, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0080] Another aspect of the invention is a method of improving, stabilizing, or restoring renal function in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I).

[0081] Unless otherwise stated, the following terms have the meanings indicated.

[0082] The term "patient" or "subject" refers to any human or non-human organism that can benefit from treatment with RXFP1 agonist, as understood by those skilled in the art. Examples of subjects include humans of any age who have risk factors for cardiovascular disease. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arrhythmia, or symptoms of insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovarian syndrome (PCOS).

[0083] "Treatment," as will be understood by those of skill in the art, includes treating a condition, and includes: (a) inhibiting the condition, i.e., arresting the progression of the condition; (b) alleviating the condition, i.e., reducing the condition; and / or (c) preventing a mammal from acquiring a condition that is predisposed to occurring in that mammal, particularly if the mammal has not yet been diagnosed as suffering from the condition.

[0084] "Prevention", as understood by those skilled in the art, includes preventive treatment of asymptomatic conditions (i.e., prevention and / or risk reduction) with the aim of reducing the probability of occurrence of clinical disease states. Patients are selected for preventive treatment based on factors known to increase the risk of suffering from clinical disease states compared to the general population. "Preventive" therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in subjects who have not yet exhibited clinical disease states, whereas secondary prevention is defined as prevention of secondary development of the same or similar clinical disease states. "Risk reduction" includes both suppressing the progression of clinical disease states. In other words, primary prevention therapy and secondary prevention therapy are examples for risk reduction.

[0085] "Therapeutically effective amount" is intended to encompass an amount of a compound of the invention effective when administered alone, or in combination with other agents, to treat a disease as understood by one of skill in the art. When administered in combination, the term refers to the combined amount of active ingredients that results in a prophylactic or therapeutic effect, whether administered in combination, sequentially, or simultaneously.

[0086] "Cardiovascular disease" or "cardiovascular disease" includes, for example, the following diseases: hypertension, peripheral vascular disease and cardiovascular disease, coronary heart disease, stable and unstable angina, heart attack, myocardial failure, heart rhythm abnormalities (or arrhythmias), persistent ischemic heart failure ("hibernating myocardium"), transient post-ischemic heart failure ("fainting myocardium"), heart failure, impaired peripheral blood flow, acute coronary syndromes, heart failure, myocardial disease (cardiomyopathy), myocardial infarction and vascular disease.

[0087] "Heart failure" includes both acute and chronic heart failure indications, as well as more specific diseases or related diseases (e.g., advanced heart failure, cardiorenal syndrome after acute heart failure, heart failure with renal dysfunction, chronic heart failure, chronic heart failure with intermediate ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right ventricular failure, left ventricular failure, bilateral heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure secondary to congenital heart disease, valvular heart disease, heart failure secondary to valvular heart disease, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary artery disease ... These conditions include: aortic stenosis, pulmonary regurgitation, heart failure associated with mixed valvular heart disease, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with impaired cardiac volume, diastolic heart failure, systolic heart failure, acute worsening heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), chronic heart failure with reduced ejection fraction (HFrEF), chronic heart failure with preserved ejection fraction (HFpEF), stenosis after myocardial remodeling, hypertension, pulmonary hypertension and pulmonary arterial hypertension).

[0088] "Fibrosis" includes diseases and disorders characterized by fibrosis, particularly liver fibrosis, cirrhosis, NASH, pulmonary fibrosis, myocardial fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, diabetic fibrotic disorders, myelofibrosis and similar fibrotic disorders, scleroderma, localized scleroderma, keloids, hypertrophic scars (including post-surgical scars), nevi, diabetic retinopathy, proliferative vitreoretinopathy and disorders of connective tissue (e.g., sarcoidosis).

[0089] Relaxin-related diseases include, but are not limited to, cardiovascular disease and fibrosis.

[0090] The compounds of the present invention may be administered by any suitable method, for example, orally (e.g., tablets, capsules (each including sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray dried dispersions), syrups, and emulsions); sublingual administration; buccal administration; parenterally (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including administration to the nasal membranes (e.g., inhalation spray); topically (e.g., in the form of a cream or ointment); or rectally (e.g., in the form of a suppository). They may 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.

[0091] The term "pharmaceutical composition" refers to a composition comprising the compound of the present invention in combination with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the field of delivering biologically active agents to animals, particularly mammals, including adjuvants, excipients or vehicles (e.g. diluents, preservatives, bulking agents, flow regulators, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants and dispersing agents) according to the nature of administration method and administration form.

[0092] Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent to be formulated, the patient to whom the composition containing the active agent will be administered, the intended route of administration of the composition, and the therapeutic indications to be targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can include many different components and additives in addition to the active agent, and such added components are included in the formulation for various reasons (e.g., stabilization of the active agent, binders, etc., known to those skilled in the art). Descriptions of suitable pharmacologic acceptable carriers and the factors involved in selecting them can be found in a variety of readily available references, such as Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012), the contents of which are incorporated herein by reference in their entirety.

[0093] Dosing regimens for the compounds of the invention will, of course, vary depending on known factors, such as the pharmacodynamic properties 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 concomitant treatment; frequency of treatment; route of administration, the patient's renal and hepatic function, and the desired effect.

[0094] As a general guideline, the daily oral dose of each active ingredient, when used to obtain the intended effect, will range from about 0.01 to about 5000 mg / day, preferably about 0.1 to about 1000 mg / day, and most preferably between about 0.1 and about 250 mg / day. The most preferred dose for constant rate infusion intravenously is in the range of about 0.01 to about 10 mg / kg / min. The compounds of the present invention may be administered in a single daily dose or in divided doses of 2, 3, or 4 total daily doses.

[0095] The compounds will generally be administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected for the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with conventional pharmaceutical standards.

[0096] 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 of the total weight of the composition. A typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). This mixture is sieved through a 60 mesh sieve and filled into a No. 1 gelatin capsule. A typical injectable formulation is produced by adding at least one compound of the present invention (250 mg) to a vial under aseptic conditions, lyophilizing and sealing under aseptic conditions. When used, the contents of the vial are mixed with saline (2 mL) to prepare an injectable formulation.

[0097] The compounds of the present invention may be utilized in combination with other suitable therapeutic agents useful for 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-pancreatitis 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.

[0098] Additional therapeutic agents include ACE inhibitors, beta-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine A1 receptor agonists, adenosine A1 receptor partial agonists, dopamine beta-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with altered activity due to specific cell signaling pathways, angiotensin II receptor antagonists and neprilysin enzyme inhibitors. combinations of enzyme inhibitors, neprilysin enzyme inhibitors, soluble guanylate cyclase stimulators, myosin ATPase activators, Rho kinase 1 inhibitors, Rho kinase 2 inhibitors, apelin receptor agonists, nitroxyl donor compounds, calcium-dependent kinase II inhibitors, antifibrotic drugs, galectin-3 inhibitors, vasopressin receptor antagonists, FPR2 receptor modulators, natriuretic peptide receptor agonists, transient receptor potential vanilloid 4 channel blockers, antiarrhythmic drugs, If current (funny current channel inhibitors, nitrates, digitalis compounds, cardiac inotropes and beta receptor agonists, cell membrane restoring agents (e.g., poloxamer 188), antihyperlipidemic agents, plasma HDL increasing agents, antihypercholesterolemic agents, cholesterol synthesis 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, antiplatelet agents, fibrinogen receptor antagonists, aspirin and fibric acid derivatives, PCSK9 inhibitors, aspirin, and P2Y12 inhibitors (e.g., clopidogrel).

[0099] The therapeutic agents being added include nintedanib, pirfenidone, LPA1 antagonist, GLP-1 analogue, tralokinumab (IL-13, AstraZeneca), vismodegib (hedgehog inhibitor, Roche), PRM-151 (pentraxin-2, TGF β-1, Promedior), SAR-156597 (bispecific Mab against IL-4 and IL-13, Sanofi), simtuzumab (anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inhibitor / pentoxifylline / NAC oral controlled release, Pacific Ther.), omipalisib (oral PI3K / mTOR inhibitor, GSK), IW-001 (oral solution, bovine type V collagen, ImmuneWorks), STX-100 (anti-integrin α V β 6 Antibodies, Stromedix / Biogen), Actimmune (IFNγ), PC-SOD (midismase; inhalant, 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) may also be included.

[0100] The other therapeutic agents described above, when used in combination with the compounds of the present invention, may be used, for example, in amounts as set forth in the Pharmaceutical Description (PDR) or as determined by one of ordinary skill in the art.

[0101] Especially when provided as a single dosage form, chemical interactions between the combined active ingredients may occur. Therefore, when the compound of the present invention and another therapeutic agent are mixed as a single dosage form, the active ingredients are mixed to form a single dosage form, but are formulated so that the physical contact between the active ingredients is minimized (reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also to control the release of one of the ingredients in the intestine, not in the stomach, of the digestive tract. In addition, one of the active ingredients may be coated with some substance that produces a sustained release effect in the digestive tract, and also plays a role in minimizing the physical contact between the combined active ingredients. Furthermore, the sustained release ingredient may be provided with another enteric coating so that the release of the ingredient occurs only in the intestine. Yet another alternative includes formulating a combination product where one of the components is coated with a sustained release and / or enteric release polymer and the other component is further coated with a polymer (e.g., low viscosity grades of hydroxypropylmethylcellulose (HPMC) or other suitable material known to those skilled in the art) to separate the active ingredients. The polymer coating serves to further prevent interaction with the other component.

[0102] The compounds of the invention are also useful as standard or reference compounds, e.g., quality standards or control substances, in tests or assays involving RXFP1. Such compounds may be provided, for example, in commercially available kits for use in pharmaceutical research involving RXFP1. For example, the compounds of the invention may be used as control compounds in assays to compare their known activity with compounds of unknown activity. This allows the experimenter to ensure that the assay has been performed properly, and provides a basis for comparison, particularly when the test compound is a derivative of the control compound. This allows the experimenter to ensure that the assay has been performed properly, and provides a basis for comparison, particularly when the test compound is a derivative of the control compound. When developing new assays or protocols, the efficacy of compounds according to the invention may be tested. The compounds of the invention may also be used in diagnostic assays involving RXFP1.

[0103] The present invention also includes an article of manufacture. As used herein, article of manufacture is intended to include, but is not limited to, kits and packages. The article of manufacture of the present invention includes (a) a first container, (b) a pharmaceutical composition contained within the first container, wherein the composition includes a first therapeutic agent, including a compound of the present invention or a pharma- ceutically acceptable salt form thereof, and (c) a package insert that describes that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In other embodiments, the package insert describes that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat inflammatory and / or autoimmune diseases. The article of manufacture may further include (d) a second container, wherein components (a) and (b) are contained within the second container, and component (c) is located within or outside the second container. Located within the first and second containers means that each container holds the item within its area.

[0104] The first container is a container used to hold a pharmaceutical composition. This container may be for manufacturing, storage, distribution, and / or individual / bulk sales. The first container is intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., for creams), or any other containers used in manufacturing, holding, storing, or distributing pharmaceutical formulations.

[0105] The second container is for holding the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), wooden boxes, corrugated boxes, bags (e.g., paper or plastic bags), pouches, and cloth bags. The package insert can be physically attached to the first container by tape, glue, stapler, or other attachment methods, or can be present in the second container without being attached to the first container by physical means. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, the package insert is preferably physically attached by tape, glue, stapler, or other attachment methods. Alternatively, the package insert can be in close proximity to or in contact with the outside of the second container without being physically attached.

[0106] A package insert is a label, tag, marker, etc. that describes information related to the pharmaceutical composition that is placed in the first container. The information described is usually determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the geographic area in which the product is sold. Preferably, the package insert specifically describes the indications for which the pharmaceutical composition is approved. The package insert may be made of any material that allows a person to read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information is placed (e.g., printed or affixed).

[0107] Synthesis scheme The compounds of the present invention can be prepared by various methods known in the art, such as the following schemes and the methods in the specific embodiments section. The formula numbers and variable numbers shown in the synthetic schemes are distinct and should not be confused with the formula numbers or variable numbers shown in the claims or other parts of the specification. The variables in the schemes are intended only to illustrate some of the methods for preparing the compounds of the present invention.

[0108] The naphthalene compounds of the present invention can be obtained from commercially available methyl 3-amino-2-naphthoate or by the method shown in Scheme 1. [ka] Commercially available 2,3-dimethylbromobenzene was polybrominated with NBS to give intermediate II. II was condensed with succinimide in the presence of NaI / DMF to give 5-bromonaphtho[2,3-c]furan-1,3-dione. This was treated with methanol to give a mixture of bromonaphthalene derivatives I-II and I-III, which were separated by known separation methods. Curtius rearrangement of I-II followed by conversion of the isocyanate gave intermediate amine I-IV. The bromo moiety was converted (e.g., via Suzuki coupling, photoredox, alkylation, esterification, amide, sulfonamide, etc.) to other compounds of the invention. Alternatively, I-II was debrominated to give the unsubstituted naphthalene derivative. Intermediate I-III can also be converted to intermediate IV under similar conditions. Both intermediates I-IV and IV can be converted to amides I-VI and I-VII of the invention by coupling with appropriate amines or anilines.

[0109] The quinoline analogs of the present invention were also prepared by a similar procedure (Scheme 2). [ka]

[0110] Alternatively, quinolines can be obtained by the general method outlined in Scheme 3. [ka] Intermediates I-XV and / or I-XVIII were converted to the requisite quinolines (e.g., I-XVII) using photoredox conditions or conversion to the bromoquinolines by methods outlined or known to those skilled in the art, followed by standard alkylation, carbonylation, amidation and Suzuki coupling. Intermediates I-XVII were then converted to compounds of the invention as outlined in Scheme 1.

[0111] chemical method It is also recognized that another important consideration in planning any synthetic route in this field is the selection of appropriate protecting groups to be used to protect reactive functional groups contained in the compounds described in the present invention. Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) is an authoritative reference that provides those skilled in the art with many options for protecting groups.

[0112] Abbreviations are defined as follows: "1x" is one time, "2x" is two times, "3x" is three times, "℃" is Celsius, "aq" is aqueous solution, "eq" or "equiv" is equivalent, "g" is gram, "mg" is milligram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normal, "M" is molar, "nM" is nanomolar, "pM" is picomolar, "mol" is mole, "mmol" is millimole, "min" is minute, "h" is hour, "Int." is intermediate, "rt" is room temperature, "RT" is retention time, "atm" is atmospheric pressure, "psi" is pounds per square inch, "conc." is concentration, "sat." is saturation, "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 HPLC ... "HPLC" is reverse phase HPLC, "NMR" is nuclear magnetic resonance spectroscopy, "SFC" is supercritical fluid chromatography, "1H" 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 symbols well known to those of skill in the art. [Table 3]

[0113] In the examples, the following methods were used unless otherwise noted. Purification of intermediates and final products was carried out by either normal phase or reverse phase chromatography. Normal phase chromatography was carried out by pre-cleaning on SiO 2Reverse phase preparative HPLC was performed using a cartridge packed with hexane and ethyl acetate or a gradient of DCM and MeOH. 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 NH 4 OAc) and solvent B (98% ACN, 2% water, 10 mM NH 4 OAc) or solvent A (98% water, 2% ACN, 0.1% NH 4 OH) and solvent B (98% ACN, 2% water, 0.1% NH 4 The LC / MS methods used in the analysis of the examples are listed below.

[0114] Method A: Instrument: Waters Acquity equipped with a Waters MICROMASS® ZQ mass spectrometer. Linear gradient: 2-98% B over 1 min, 98% B for 0.5 min UV visualization: 220nm Column: Waters BEH C18, 2.1x50mm Flow rate: 0.8mL / min (method A) Mobile phase A: 0.05%TFA, 100% water Mobile phase B: 0.05% TFA, 100% acetonitrile

[0115] Method B: Instrumentation: Shimadzu Prominence HPLC equipped with a Shimadzu LCMS-2020 mass spectrometer Linear gradient: 0-100% B over 3 min, elution at 100% B for 0.75 min UV visualization: 220nm Column: Waters Xbridge C18, 2.1x50mm, 1.7μm particle size 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

[0116] Method C: Instrumentation: Shimadzu Prominence HPLC equipped with a Shimadzu LCMS-2020 mass spectrometer Linear gradient: 0-100% B over 3 min, elution at 100% B for 0.75 min UV visualization: 220nm Column: Waters Xbridge C18, 2.1x50mm, 1.7μm particle size Flow rate: 1mL / min Mobile phase A: 0.1% TFA, 95:5 water:acetonitrile Mobile phase B: 0.1% TFA, 5:95 water:acetonitrile

[0117] Method D: Instrument: Waters Acquity equipped with a Waters MICROMASS® ZQ mass spectrometer. Linear gradient: 10% B to 98% B over 1 min, 98% B for 0.5 min UV visualization: 220nm Column: Waters AcquityGEN C18, 2.1x50mm, 1.7μm particle size Flow rate: 1mL / min Mobile phase A: 0.05%TFA, 100% water Mobile phase B: 0.05% TFA, 100% acetonitrile

[0118] NMR used in the analysis of the examples 1 1 H NMR spectra were obtained on a Bruker or JEOL® Fourier transform spectrometer operating at the following frequencies: 1 H NMR: 400MHz (Bruker or JEOL®) or 500MHz (Bruker or JEOL®) Spectral data are reported in the form of chemical shifts (multiplicity, coupling constants, hydrogen numbers). Chemical shifts are specified in ppm relative to the internal standard of tetramethylsilane (δ units, tetramethylsilane = 0 ppm) and / or 2.51 ppm (DMSO-d6), 3.30 ppm (CD 3 OD), 1.94 ppm (CD 3 CN), and 7.24 ppm (CDCl 3 ) 1 The solvent peak in the 1 H NMR spectrum is used as the reference.

[0119] Preparation of intermediates Intermediate 1-1: 5'-(tert-butoxycarbonyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] In a vial, add 5-(dihydroxyboryl)-2-methoxybenzoic acid (0.50 g, 2.6 mmol), tert-butyl 3-bromo-4-fluorobenzoate (0.84 g, 3.1 mmol), K 2 CO 3 (1.76 g, 12.8 mmol), PdCl 2 (dppf)·CH 2 Cl 2 (0.31 g, 0.38 mmol), and THF (22 mL) were added. The mixture was degassed with nitrogen for 2 min and then heated at 80° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with 1N HCl (25 mL) and the solution was extracted with EtOAc (3×25 mL). The organic layers were combined and washed with Na 2 SO 4The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the resulting residue was dissolved in DMF and purified by preparative reverse phase HPLC to give intermediate 1-1 (586 mg, 66.0% yield). LC-MS RT=1.02 min; MS(ESI): m / z=347.1(M+H). + ; [Method A]

[0120] Intermediate 2-6: 5'-(2-(tert-butoxy)-1-hydroxy-2-oxoethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid Intermediate 2-6 was prepared according to the methods described in the following scheme. [ka] [ka]

[0121] Intermediate 2-2: Intermediate 2-2 was prepared using known conditions for similar substrates (Ludwig, J., Lehr, M. Syn. Comm. 2004, 34, 3691-3695), except that the reaction temperature was maintained at 80° C. for 12 hours. 1 H NMR (500 MHz, CDCl 3 ) δ 7.49(dd, J=6.6, 2.2Hz, 1H), 7.20(ddd, J=8.3, 4.6, 2.2Hz, 1H), 7.13-7.03(m, 1H), 3.49(s, 2H), 1.46(s, 9H)

[0122] Intermediate 2-3: Intermediate 2-2 (0.27 g, 0.92 mmol) was added to a reaction vial (20 mL) containing NBS (0.20 g, 1.1 mmol), CCl 4 (10 mL), and AIBN (15 mg, 0.090 mmol) were added, and the solution was stirred for 3 h at 77° C. The solution was concentrated under reduced pressure and purified by normal phase silica gel chromatography to give intermediate 2-3 (310 mg, 0.84 mmol, 91% yield). 1 H NMR (500 MHz, CDCl 3) δ 7.79(dd, J=6.5, 2.3Hz, 1H), 7.55-7.46(m, 1H), 7.18-7.10(m, 1H), 5.18(s, 1H), 1.50(s, 9H)

[0123] Intermediate 2-4: To the 2-dram vial containing intermediate 2-3 was added EtOAc (2 mL), TEA (0.27 mL, 2.0 mmol), and acetic acid (0.1 mL, 2 mmol) and the mixture was stirred at 80° C. for 12 h. The reaction mixture was concentrated in vacuo and purified by normal phase silica gel chromatography to provide intermediate 2-4, which was used without further purification. 1 H NMR (500 MHz, CDCl 3 ) δ 7.70(dd, J=6.6, 2.2Hz, 1H), 7.41(ddd, J=8.4, 4.7, 2.1Hz, 1H), 7.15(t, J=8.4Hz, 1H), 5.77(s, 1H), 2.22(s, 3H), 1.43(s, 9H)

[0124] Intermediate 2-6: Intermediate 2-6 was prepared from Intermediate 2-4 using 5-(dihydroxyboryl)-2-methoxybenzoic acid (2-5) under similar conditions as described for Intermediate 1-1. Reverse phase HPLC (conditions: Column: Phenomenex Luna C18 5μ 30x100mm, Gradient: 10min; Solvent A: 10%ACN / 90%H 2 O / 0.1% TFA; Solvent B: 90% ACN / 10% H 2 After elution with 0.05% TFA (O / 0.1% TFA), half of the material was isolated as intermediate 2-7 (85 mg, 0.60 mmol, 34% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 8.43-8.36(m, 1H), 7.81(dt, J=8.7, 2.0Hz, 1H), 7.56(dd, J=7.3, 2.3Hz, 1H), 7.45(ddd, J=8.5, 4.6, 2.3Hz, 1H), 7.23-7.16(m, 2H), 5.84(s, 1H), 4.17(s, 3H), 2.23(s, 3H), 1.45(s, 9H) The other half was isolated as the alcohol intermediate 2-6 (70 mg, 0.19 mmol, 31% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 8.40(d, J=2.2Hz, 1H), 7.82(dt, J=8.6, 2.2Hz, 1H), 7.54(dd, J=7.4, 2.5Hz, 1H), 7.41(ddd, J=8.4, 4.8, 2.2Hz, 1H), 7.19-7.14(m, 2H), 5.09(s, 1H), 4.16(s, 3H), 1.47(s, 9H) Intermediates 2-6 were separated into their independent enantiomers using chiral SFC. Preparative Chromatography Conditions: Instrument: Berger MG II; Column: Chiralpak ID, 21x250mm, 5μ; Mobile phase: 25%IPA / 75%CO 2 ; Elution conditions: 45mL / min, 120Bar, 40℃; Detection wavelength: 220nm; Injection conditions: 0.36mL x 8 injections (IPA solution, ~20mg / mL) Analytical chromatographic conditions: Instrument: Waters UPC2 (analytical SFC); Column: Chiralpak ID 4.6x100mm, 3μ; Mobile phase: 25%IPA / 75%CO 2 ; Elution conditions: 2mL / min, 150Bar, 40℃; Detection wavelength: 220nm Peak 1: RT = 3.89 min, >99.5% ee; Peak 2 of intermediate 2-6: RT = 5.44 min, >99.5% ee

[0125] Intermediate 3-2: 5'-(2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)-2-oxoethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid The title compound was prepared according to the methods described in the following scheme. [ka] [ka]

[0126] Intermediate 3-1: To 2-3 (60 mg, 0.16 mmol) was added ammonia (0.5 mL, 3.5 mmol, in MeOH). After stirring at room temperature for 12 h, the mixture was concentrated in vacuo. To the amine / DCM (1 mL) was added BOC anhydride (0.11 mL, 0.49 mmol) and DIEA (57 μL, 0.33 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by silica gel chromatography to give 3-1 (42 mg, 0.1 mmol, 63% yield). LC-MS: RT=1.14 min; MS(ESI):m / z=406.0(M+H). + ; [Method A]

[0127] Intermediates 3-2 and 3-3: Intermediates 3-2 and 3-3 were prepared using Suzuki coupling conditions similar to those used for intermediate 1-1, except that the temperature was heated at 60° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with 1N HCl (25 mL) and the solution was extracted with EtOAc (3×25 mL). The organic layers were combined and washed with Na 2 SO 4 It was dried at 40° C., filtered, concentrated in vacuo, and purified by preparative reverse phase HPLC. 1 H NMR (500 MHz, CDCl 3 ) δ 8.38(d, J=1.9Hz, 1H), 7.80(dt, J=8.7, 2.0Hz, 1H), 7.46(dd, J=7.4, 2.5Hz, 1H), 7.36(dddd, J=8.8, 4.4, 2.2, 1.1Hz, 1H), 7.19-7.13(m, 2H), 5.67(br d, J=5.2Hz, 1H), 5.25(br d, J=6.3Hz, 1H), 4.16(s, 3H), 1.46(br s, 9H), 1.44(s, 9H) The resulting residue was separated into its independent enantiomers using chiral SFC. Preparative Chromatography Conditions: Instrument: Berger MG II; Column: Chiralpak ID, 21x250mm, 5μ; Mobile phase: 20%MeOH / 80%CO2 Elution conditions: 45mL / min, 120Bar, 40℃; Detection wavelength: 209nm; Injection conditions: 49 injections (MeOH solution) Analytical chromatography conditions: Instrument: Waters UPC2 (analytical SFC); Column: Chiralpak IC, 4.6x100mm, 3μ; Mobile phase: 25%MeOH / 75%CO 2 ; Elution conditions: 2mL / min, 150Bar, 40℃; Detection wavelength: 220nm Peak 1 (3-2): RT = 4.22 min, 95.7% ee; Peak 2 (3-3): RT = 5.11 min, >99% ee

[0128] Intermediate 4-4: 2'-fluoro-4-methoxy-5'-(2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-carboxylic acid The title compound was prepared according to the scheme outlined below. [ka] [ka]

[0129] Intermediate 4-2: In a reaction vessel, add 3-bromo-4-fluorobenzaldehyde (4-1, 235 mg, 1.15 mmol), DMF (3.5 mL), (trifluoromethyl)trimethylsilane (0.34 mL, 2.3 mmol), and K 2 CO 3 (8 mg, 0.06 mmol) was added and the mixture was stirred at room temperature for 60 min. The reaction mixture was cooled to room temperature and 2N HCl (3 mL) was added. After stirring at room temperature for an additional 1 h, the mixture was diluted with EtOAc (15 mL) and the solution was washed with saturated NH 4 The aqueous layer was extracted with EtOAc (2x10 mL) and the combined organic layers were washed with Na 2 SO 4The mixture was dried at rt, filtered, concentrated in vacuo, and purified by silica gel chromatography (0-35% EtOAc / hexanes) to give 4-2 (205 mg, 0.75 mmol, 65% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 7.74(dd, J=6.5, 2.1Hz, 1H), 7.43(ddd, J=8.4, 4.8, 2.2Hz, 1H), 7.19(t, J=8.4Hz, 1H), 5.11-4.98(m, 1H), 2.69(d, J=4.4Hz, 1H)

[0130] Intermediate 4-3: To a reaction vessel containing 4-2 (100 mg, 0.37 mmol), 5-(dihydroxyboryl)-2-methoxybenzoic acid (93 mg, 0.48 mmol), PdCl 2 (dppf)·CH 2 Cl 2 (50mg, 0.06mmol), Na 2 CO 3 (155 mg, 1.46 mmol), and H 2 O (1 mL) was added. The mixture was then cooled to 50° C. 2 The mixture was degassed by bubbling for 10 min, sealed, and stirred at 65° C. for 3 h. After cooling to room temperature, the reaction was quenched by the addition of 1N HCl, and the solution was extracted with EtOAc and Na 2 SO 4 The mixture was dried at rt, filtered, concentrated in vacuo, and purified by HPLC to give 4-3 (51 mg, 0.15 mmol, 40% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 8.39(d, J=1.9Hz, 1H), 7.83(dt, J=8.7, 2.1Hz, 1H), 7.59(dd, J=7.3, 2.1Hz, 1H), 7.53-7.45(m, 1H), 7.23(dd, J=10.2, 8.8Hz, 1H), 7.18(d, J=8.5Hz, 1H), 5.11(q, J=6.6Hz, 1H), 4.17(s, 3H); MS(ESI):m / z=345.1(M+H) +

[0131] Intermediate 4-4: Chiral SFC (Preparative Chromatography Conditions: Instrument: Berger MG II; Column: Kromasil 5-CelluCoat, 21x250mm, 5μ; Mobile phase: 15%IPA-ACN (0.1%DEA) / 85%CO 2 Intermediate 4-3 was separated into independent enantiomers using 0.4 mL (ACN / IPA (1:1) solution ∼15 mg / mL)) under the following conditions: elution conditions; 45 mL / min, 120 Bar, 40°C; detection wavelength: 220 nm; injection conditions: 0.4 mL (ACN / IPA (1:1) solution ∼15 mg / mL). Peak 2 was collected to give intermediate 4-4. Analytical chromatographic conditions: Instrument: Aurora Infinity (analytical SFC); Column: Kromasil 5-CelluCoat, 4.6x250mm, 5μ; Mobile phase: 20%IPA-ACN(0.1%DEA) / 80%CO 2 ; Elution conditions: 2mL / min, 150Bar, 40℃; Detection wavelength: 220nm Peak 1: RT=9.12 min, 99%ee; Peak 2: RT=10.19 min, 98%ee

[0132] Intermediate 5-2: 5-(5-hydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid The title compound was prepared according to the scheme outlined below. [ka] [ka]

[0133] Intermediate 5-1: Methyl 5-formyl-2-methoxybenzoate (24.9 g, 128 mmol) was dissolved in DCM (500 mL). To this solution was added triethylamine (17.9 mL, 128 mmol), followed by hydroxylamine hydrochloride (8.91 g, 128 mmol). The mixture was stirred at room temperature for 14 h and concentrated under reduced pressure to give a white solid. This solid was dissolved in water (200 mL) and the aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were dried (MgSO 4 ), filtered, and concentrated under reduced pressure to give a white solid (27.1 g, 100% yield). The solid was redissolved in DMF (200 mL) and NCS (17.2 g, 128 mmol) was added to the solution and stirred at room temperature for 14 h. Excess water was added to quench the reaction, causing a white solid to precipitate. The solid was isolated by filtration, washed with excess water, and dried under vacuum to give intermediate 5-1 as a white solid (28.7 g, 89% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 8.32-8.30(m, 1H), 7.99-7.96(m, 1H), 7.80-7.78(m, 1H), 7.05-7.02(d, 1H), 3.98(s, 3H), 3.94(s, 3H)

[0134] Intermediate 5-2 (diastereomeric mixture): Alternatively, (E)-5-((hydroxyimino)methyl)-2-methoxybenzoic acid (620 mg, 3.18 mmol) was dissolved in DMF (5 mL), and to this solution was added NCS (424 mg, 3.18 mmol), and the mixture was stirred at room temperature for 4 h. The reaction was quenched by the addition of water (100 mL), and the solution was extracted with EtOAc (2x25 mL) and dried (MgSO 4 ) and concentrated under reduced pressure to an oil. The resulting oil was redissolved in DCM (10 mL) and cyclopent-3-en-1-ol (2.67 g, 31.8 mmol) was added, followed by TEA (0.44 mL) and stirred at room temperature for 14 h. The resulting solution was filtered through silica gel and concentrated under reduced pressure to give a diastereomeric mixture of intermediate 5-2 (227 mg, 26% yield). 1 H NMR (600 MHz, CDCl 3) δ 8.04(d, J=2.3Hz, 1H), 7.85(dd, J=8.8, 2.3Hz, 1H), 7.03(d, J=8.8Hz, 1H), 5.30(ddd, J=9.4, 6.2, 2.9Hz, 1H), 4.50(quin, J=5.9Hz, 1H), 4.19(td, J=9.3, 4.7Hz, 1H), 3.92(s, 3H), 2.33-2.27(m, 1H), 2.18-2.06(m, 3H); LC-MS RT=0.83min; MS(ESI)m / z=278.1(M+H) + ; [Method A] The chiral intermediate of 5-2 was isolated by preparative chromatography using chiral SFC (instrument: Berger SFC; column: IC 25x3cm ID, 5μm, temperature: 40°C, flow rate: 85mL / min, mobile phase: gradient 75 / 25 CO 2 / MeOH for 12 min, then 45% MeOH, detection wavelength: 235 nm, injection volume: 1000 μL) to obtain 5-3 (chiral peak-1: >99% ee, analytical RT = 8.80 min), 5-4 (chiral peak-2: >95% ee, analytical RT = 9.86 min), 5-5 (chiral peak-3: >99% ee, analytical RT = 13.53 min), and 5-6 (chiral peak-4: >99% ee, analytical RT = 16.67 min). Analytical chromatographic conditions: Instrument: Agilent SFC (LVL-L4021 Lab), Column: IC 250x4.6mm ID, 5μm, Temperature: Ambient, Flow rate: 2.0mL / min, Mobile phase: Gradient 75 / 25 CO 2 / MeOH for 12 min, then 45% MeOH Analytical data for peaks 1-4: 1 H NMR (600 MHz, CD 3OD) δ 8.07(d, J=2.2Hz, 1H), 7.82(dd, J=8.7, 2.1Hz, 1H), 7.18(d, J=8.8Hz, 1H), 5.21(ddd, J=9.2, 6.2, 2.5Hz, 1H), 4.27(m, 1H), 4.24(td, J=9.4, 4.0Hz, 1H), 3.94(s, 3H), 2.16(m, 1H), 2.05(m, 1H), 2.00(m, 1H), 1.99(m, 1H); 13 C NMR (151 MHz, CD 3 OD) δ 169.5, 161.6, 160.0, 133.2, 131.4, 122.6(2C), 113.9, 87.3, 72.7, 56.8, 51.5, 44.1, 40.3

[0135] Intermediate 6-2: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]-isoxazol-3-yl)-2-methoxybenzoic acid [ka] [ka]

[0136] Intermediate 6-1: Intermediate 5-1 (3.0 g, 12.3 mmol) was dissolved in DCM (123.13 mL) and cyclopent-3-en-1-ylmethanol (4.8 g, 49.3 mmol) was added thereto, followed by TEA (5.15 mL, 36.9 mmol) and stirred at room temperature. After stirring for 14 h, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by normal phase chromatography (elution: hexane / EtOAc) to give 6-1 (2.8 g, 9.2 mmol, 75% yield) as an oil. LC-MS: RT=0.95 min; MS(ESI)m / z=306.3(M+H). + ;[Method A]

[0137] Diastereomeric intermediate 6-2: Intermediate 6-1 (88 mg, 0.29 mmol) was dissolved in THF (1 mL) / MeOH (1 mL) and added to lithium hydroxide monohydrate (36 mg, 0.86 mmol) / H 2 After 3 h, the reaction mixture was treated with H 2 The mixture was diluted with 2×O (5 mL), the pH of the aqueous layer was adjusted to pH 7 with 1 M HCl solution, extracted with EtOAc (2×25 mL), washed with brine and dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give 6-2 (62 mg, 74% yield). The carboxylic acid (6-2) was used in the next reaction without further purification. LC-MS: RT=0.85 min; MS(ESI)m / z=292.3(M+H). + ;[Method A]

[0138] Intermediates 6-3 to 6-10 (homochiral) Each of the chiral diastereomeric ester intermediates 6-3, 6-5, 6-7, and 6-9 was obtained by chiral SFC separation of the diastereomeric mixture intermediate 6-1 (525 mg, 1.72 mmol). Chiral SFC preparative chromatography conditions: Instrument: Berger MG II (SFC); Column: Chiralpak AD-H, 21x250mm, 5μ; Mobile phase: 15%MeOH / 85%CO 2 ; Elution conditions: 45mL / min, 150Bar, 40℃; Detection wavelength: 210nm; Injection conditions: 0.5mL (MeOH solution, ~35mg / mL) Analytical chromatographic conditions: Instrument: Shimadzu Nexera SFC; Column: Chiralpak AD-H, 4.6x100mm, 3μ; Mobile phase: 15%MeOH / 85%CO 2 ; Elution conditions: 2.0mL / min, 150Bar, 40℃; Detection wavelength: 220nm; Injection conditions: 5μL (MeOH solution, ~1mg / mL)

[0139] The methyl benzoate intermediate 6-3 (peak-1, RT = 4.07 min; >99% ee) was obtained as a film (150 mg, 29% yield). 1 H NMR (600 MHz, CDCl 3 ) δ 8.04(d, J=2.3Hz, 1H), 7.87(dd, J=8.7, 2.3Hz, 1H), 7.01(d, J=8.8Hz, 1H), 5.23(dd, J=8.8, 5.1Hz, 1H), 4.10(t, J=8.7Hz, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.72-3.66(m, 1H), 3.61(dt, J=10.5, 5.2Hz, 1H), 2.30-2.16(m, 2H), 2.05(dd, J=13.0, 6.1Hz, 1H), 1.76(ddd, J=12.9, 11.5, 9.4Hz, 1H), 1.68-1.62(m, 1H), 1.39(br t, J=4.8Hz, 1H)

[0140] Benzoic acid intermediate 6-4: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 6-4 (100 mg, 78% yield) was prepared following a similar procedure to intermediate 6-2 with further hydrolysis of intermediate 6-3. LC-MS: RT=0.85 min; (ESI) m / z=292.3 (M+H). + ;[Method A]

[0141] The methyl benzoate intermediate 6-5 (peak-2, RT = 4.55 min; >99% ee) was obtained as a film (33.2 mg, 6.3% yield). 1 H NMR (600 MHz, CDCl 3) δ 8.05(d, J=2.3Hz, 1H), 7.87(dd, J=8.8, 2.3Hz, 1H), 7.02(d, J=8.8Hz, 1H), 5.25(ddd, J=10.1, 6.2, 4.2Hz, 1H), 4.04-3.98(m, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.63-3.57(m, 1H), 3.56-3.50(m, 1H), 2.38-2.26(m, 3H), 1.92-1.85(m, 1H), 1.73-1.66(m, 1H), 1.51(t, J=5.3Hz, 1H)

[0142] Benzoic acid intermediate 6-6: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 6-6 (20.2 mg, 92% yield) was prepared following a similar procedure to intermediate 6-2 with further hydrolysis of intermediate 6-5. LC-MS: RT=0.83 min; MS(ESI)m / z=292.3(M+H). + ;[Method A]

[0143] The methyl benzoate intermediate 6-7 (peak-3, RT = 5.66 min; >99% ee) was obtained as a film (161 mg, 30.6% yield). 1 H NMR: (600MHz, CDCl 3 ) δ 8.05-8.03(m, 1H), 7.86(dd, J=8.7, 2.3Hz, 1H), 7.01(d, J=8.8Hz, 1H), 5.23(dd, J=8.7, 5.2Hz, 1H), 4.10(t, J=8.7Hz, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.69(br dd, J=10.6, 5.2Hz, 1H), 3.63-3.58(m, 1H), 2.28-2.17(m, 2H), 2.05(br dd, J=12.9, 6.2Hz, 1H), 1.76(ddd, J=13.0, 11.5, 9.4Hz, 1H), 1.64-1.60(m, 1H), 1.49(br s, 1H)

[0144] Benzoic acid intermediate 6-8: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 6-8 (120 mg, 85% yield) was prepared following a similar procedure to intermediate 6-2 with further hydrolysis of intermediate 6-7. LC-MS: RT=0.83 min; MS(ESI)m / z=292.3(M+H). + ;[Method A]

[0145] The methyl benzoate intermediate 6-9 (peak-4, RT = 9.81 min; >99% ee) was obtained as a film (47 mg, 9.0% yield). 1 H NMR: (600MHz, CDCl 3 ) δ 8.04(d, J=2.3Hz, 1H), 7.87(dd, J=8.7, 2.3Hz, 1H), 7.02(d, J=8.8Hz, 1H), 5.24(ddd, J=10.1, 6.2, 4.2Hz, 1H), 4.03-3.98(m, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.63-3.57(m, 1H), 3.56-3.49(m, 1H), 2.38-2.25(m, 3H), 1.91-1.85(m, 1H), 1.72-1.66(m, 1H), 1.55(br s, 1H)

[0146] Benzoic Acid Intermediate 6-10: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 6-10 (18.2 mg, 52% yield) was prepared following a similar procedure to intermediate 6-2 with further hydrolysis of intermediate 6-9. LC-MS: RT=0.84 min; MS(ESI)m / z=292.3(M+H). + ; [Method A]

[0147] Intermediate 7-1: The preparation of 3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-naphthamide is depicted in the following scheme. [ka] To a solution of 3-amino-2-naphthoic acid (0.5 g, 3 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.96 g, 5.3 mmol), and pyridine (0.65 mL, 8.0 mmol) in DCM (26.7 mL) was added POCl 3 (0.25 mL, 2.7 mmol) was added at 0° C. After 12 h, the reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), brine (2×25 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (eluent: hexanes / EtOAc) to give intermediate 7-1 (284 mg, 31% yield) as a solid. LC-MS: RT=1.09 min; MS(ESI)m / z=348.9(M+H). + ;[Method A]

[0148] Intermediate 8-6: The preparation of 3-amino-5-bromo-2-naphthoic acid is shown in the following scheme. [ka]

[0149] Intermediate 8-1: Preparation of 1-bromo-2,3-bis(dibromomethyl)benzene 1-Bromo-2,3-dimethylbenzene (5 g, 30 mmol) / CCl 4 To the 25 mL solution was added NBS (10 g, 57 mmol), benzoyl peroxide (65 mg, 0.27 mmol) and the mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and additional NBS (10 g, 57 mmol) and benzoyl peroxide (65 mg, 0.27 mmol) were added and heated again for 24 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with water (3x20 mL), saturated sodium thiosulfite (20 mL), brine (20 mL), dried (Na 2 SO 4 ), 8-1 (13 g, 96%) was obtained. 1 H NMR (400 MHz, CDCl 3) δ 7.99(d, J=7.9Hz, 1H), 7.61(dd, J=8.0, 1.2Hz, 1H), 7.35-7.28(m, 2H), 7.09(s, 1H)

[0150] Intermediate 8-2: Preparation of 8-bromo-3-(methoxycarbonyl)-2-naphthoic acid diethylammonium salt To intermediate 8-1 (2 g, 4 mmol) and furan-2,5-dione (0.4 g, 4 mmol) in DMF (8 mL) was added NaI (1.8 g, 12 mmol) and heated at 50° C. for 24 hours. The reaction mixture was cooled to room temperature, MeOH (10 mL) was added, and the mixture was stirred for 24 hours. The solvent was concentrated under reduced pressure, and the resulting residue was washed with saturated sodium bisulfite and then purified by reverse phase chromatography (elution: gradient H 2 O:AcN / 0.05%TFA (90:10 to 10:90)), and SFC (Instrument: Berger MG II Column: Chiralpak AD-H, 21x250mm, 5μ, Mobile phase: 15%IPA-ACN (1:1, 0.1%DEA) / 85%CO 2 , Elution conditions: 45mL / min, 150Bar, 40℃, Detection wavelength: 240nm; Analysis method: Instrument: Shimadzu analytical SFC, Column: Chiralpak AD-H, 4.6x100mm, 3μ, Mobile phase: 20%IPA-ACN(1:1, 0.1%DEA) / 80%CO 2 (elution conditions: 2 mL / min, 150 Bar, 40°C, detection wavelength: 220 nm) to obtain peak-1 (RT = 3.82 min) and chiral peak-2 (RT = 5.26 min). The resulting residue was separated to obtain intermediate 8-2 (peak-1, RT = 3.82 min, 0.3 g, 0.8 mmol, 30% yield) and intermediate 8-3 (peak-2, RT = 5.26 min; 0.3 g, 0.8 mmol, 32% yield). Intermediate 8-2: 1H NMR (400MHz, DMSO-d6) δ 9.71-9.33(m, 1H), 8.48(s, 1H), 8.06(d, J=8.4Hz, 1H), 8.04(s, 1H), 7.96(dd, J=7.4, 1.0Hz, 1H), 7.62-7.39(m, 1H), 3.78(s, 3H) Intermediate 8-3: 1 H NMR (400MHz, DMSO-d6) δ 9.26-8.90(m, 1H), 8.31(s, 1H), 8.13-8.07(m, 2H), 7.97-7.93(m, 1H), 7.52(t, J=7.8Hz, 1H), 3.80(s, 3H)

[0151] Intermediate 8-4: Preparation of methyl 5-bromo-3-(3,3-diethylureido)-2-naphthoate To intermediate 8-2 (0.3 g, 1 mmol) in toluene (10 mL) and TEA (1 mL, 7 mmol) was added diphenylphosphoryl azide (0.2 mL, 1 mmol), and the mixture was stirred at room temperature for 3 h, and then added with acetone (80 mL) / H2O via a dropping funnel. 2 The mixture was added dropwise to 2H2O (10 mL) at 80 °C. After 1 h, the mixture was allowed to warm to room temperature and stirred for 24 h. The solvent was concentrated under reduced pressure and the resulting residue was partitioned between brine (20 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with EtOAc (2x20 mL) and the combined organic layers were washed with brine (15 mL) and dried (MgSO 4 The resulting residue was purified by silica gel chromatography (elution: hexane / EtOAc) to give intermediate 8-4 (0.17 g, 0.50 mmol, 43% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3) δ 10.58(s, 1H), 9.51(s, 1H), 8.63(s, 1H), 7.84(dd, J=7.4, 1.0Hz, 1H), 7.77(d, J=8.4Hz, 1H), 7.21(dd, J=8.1, 7.5Hz, 1H), 4.03(s, 3H), 3.53(q, J=7.3Hz, 4H), 1.41-1.12(m, 6H); MS(ESI)m / z=275~277(M+H) +

[0152] Intermediate 8-5: Preparation of 3-amino-5-bromo-2-naphthoic acid Intermediate 8-4 (0.17 g, 0.5 mmol) in water (10 mL) and MeOH (0.5 mL) was heated in a microwave oven at 150 °C for 2.3 h. After concentrating the solvent in vacuo and acidifying with 1M HCl, the solid was filtered and dried in vacuo to give intermediate 8-5 as a yellow solid (0.1 g, 0.4 mmol, 97% yield), which was used without further purification. MS (ESI) m / z = 266-268.0 (M+H). +

[0153] Intermediate 8-6: Preparation of methyl 3-amino-5-bromo-2-naphthoate Intermediate 8-5 (0.1 g, 0.4 mmol) in MeOH (5 mL) was dissolved in 10% H 2 SO 4 / MeOH and the mixture was heated at 60° C. After 24 h, the reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to give a residue with saturated NaHCO 3 (10 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (15 mL) and dried (Na 2 SO 4 ) and concentrated in vacuo to give intermediate 8-6 (0.1 g, 0.4 mmol, 90% yield) as a brown oil, which was used without further purification. MS (ESI) m / z = 280-282.1 (M+H). +

[0154] Intermediate 9-1: The preparation of 3-amino-5-bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-naphthamide is depicted in the following scheme. [ka] 4-Fluoro-3-(trifluoromethyl)aniline (0.2 g, 1.0 mmol) in toluene (4 mL) was added to Me 3 A solution of Al (2M, 0.5 mL, 1 mmol) was added. After 10 min, this solution was added to intermediate 8-6 (0.1 g, 0.3 mmol) in toluene (6 mL) and the resulting solution was heated in a microwave at 120 °C for 30 min. 1N HCl (10 mL) was added to quench the reaction and then extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO 4 The resulting residue was purified by silica gel chromatography (elution: hexane / EtOAc) to give intermediate 9-1 (54 mg, 0.13 mmol, 35% yield) as a bright yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 10.94-10.59(m, 1H), 8.34-8.21(m, 2H), 8.14-8.03(m, 1H), 7.84(d, J=8.4Hz, 1H), 7.77(dd, J=7.5, 1.1Hz, MS(ESI)m / z=427~429.0(M+H) +

[0155] Intermediate 11-2: Preparation of 2-methoxy-5-(6-oxopyridazin-1(6H)-yl)benzoic acid according to the method described in the following scheme [ka] Intermediate 11-1: Preparation of methyl 2-methoxy-5-(6-oxopyridazin-1(6H)-yl)benzoate In a pressure-resistant vial, methyl 5-iodo-2-methoxybenzoate (100 mg, 0.34 mmol), pyridazin-3(2H)-one (29.9 mg, 0.310 mmol), quinolin-8-ol (18 mg, 0.13 mmol), copper(I) iodide (24 mg, 0.13 mmol), and K 2 CO 3 (86 mg, 0.62 mmol) in DMSO (1.6 mL) was added. The vessel was sealed and stirred at 140° C. for 14 h. The reaction mixture was cooled, filtered through Celite®, and the filtrate was purified by reverse phase chromatography (elution: gradient H 2 Purification with 0:AcN / 0.05% TFA (90:10 to 10:90) gave intermediate 11-1. LC-MS: RT=0.89 min; MS(ESI)m / z=261.2(M+H) + ;[Method A]

[0156] Intermediate 11-2: Preparation of 2-methoxy-5-(6-oxopyridazin-1(6H)-yl)benzoic acid Intermediate 11-1 was dissolved in MeOH / THF (1:1; 2 mL) and the solution was treated with lithium hydroxide monohydrate (0.93 mL, 0.93 mmol) and heated in a microwave at 120 °C for 15 min. The reaction mixture was diluted with water, extracted with EtOAc, and the organic layer was discarded. The remaining aqueous layer was acidified with 1.0 M HCl, and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give intermediate 11-2 (44 mg, 57% yield for two steps). LC-MS: RT=0.78 min; MS(ESI)m / z=247.2(M+H). + ;[Method A]

[0157] Intermediate 12-3: Preparation of (S)-5'-(1-((cyclobutylcarbamoyl)oxy)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] Intermediate 12-1: Preparation of (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol A solution of (S)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole (0.13 g, 0.50 mmol) and intermediate 4-2 (racemic) (3.43 g, 12.6 mmol) in diisopropyl ether (41.9 mL) was cooled to 0 to -20 °C. The solution was treated with isobutyric anhydride (0.42 mL, 2.5 mmol) and transferred to a freezer for 14 h. MeOH (~1 mL) was added to quench the reaction, and the solution was extracted with phosphate buffer and EtOAc (2x25 mL). The combined organic layers were concentrated under reduced pressure and purified by silica gel chromatography (eluent: hexane / ethyl acetate) to give intermediate 12-1 (chiral, 2.59 g, 9.48 mmol, 75% yield, 99% ee). 1 H NMR (500 MHz, CDCl 3 ) δ 7.72(dd, J=6.3, 1.9Hz, 1H), 7.44-7.39(m, 1H), 7.20-7.13(m, 1H), 5.01(q, J=6.6Hz, 1H), 4.15-4.10(m, 1H)

[0158] Intermediate 12-2: Preparation of (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl cyclobutylcarbamate Intermediate 12-1 (300 mg, 1.10 mmol), pyridine (0.44 mL, 5.5 mmol), and DMAP (13.42 mg, 0.11 mmol) were dissolved in DCM (20 mL) and 4-nitrophenyl chloroformate (1.1 g, 5.5 mmol) was added. After 1 h, cyclobutanamine (782 mg, 11.0 mmol) was added and stirring was continued for 2 h. The reaction was quenched by addition of MeOH (3 mL), concentrated in vacuo, and purified by normal phase chromatography to give intermediate 12-2 (350 mg, 0.94 mmol, 85% yield) as a white solid. LC-MS: RT=1.27 min; MS(ESI)m / z=371.7(M+H). + ;[Method A]

[0159] Intermediate 12-3: Preparation of (S)-5'-(1-((cyclobutylcarbamoyl)oxy)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid A reaction vessel containing intermediate 12-2 (350 mg, 0.80 mmol) was charged with 5-(dihydroxyboryl)-2-methoxybenzoic acid (203 mg, 1.04 mmol), PdCl 2 (dppf)·CH 2 Cl 2 (98mg, 0.12mmol), Na 2 CO 3 (338 mg, 3.19 mmol), THF (11.5 mL) and H 2 O (2.88 mL) was added. The reaction mixture was cooled to 5°C and cooled to 10°C. 2 The mixture was degassed by bubbling for 10 min, sealed and stirred at 65° C. for 3 h. It was cooled to room temperature, quenched by addition of 1N HCl and extracted with EtOAc. 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by reverse phase HPLC (Conditions: Column: Phenomenex Luna AXIA C18 5u 30x100mm; Gradient (10 min): Solvent A: 20%ACN / 80%H 2 O / 0.1% TFA; Solvent B: 80% ACN / 20% H 2 O / 0.1% TFA) and lyophilization gave intermediate 12-3 (72 mg, 0.16 mmol, 21% yield) as a solid. LC-MS: RT=0.94 min; MS(ESI)m / z=442.0(M+H). + ;[Method A]

[0160] Intermediate 13-5: Preparation of 3-amino-7-bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-naphthamide as shown in the following scheme: [ka] Intermediate 13-1: Preparation of 4-bromo-1,2-bis(dibromomethyl)benzene 4-Bromo-1,2-dimethylbenzene (1.9 g, 10 mmol) / CCl4 (20 mL) was added 1-bromopyrrolidine-2,5-dione (3.84 g, 21.6 mmol) and benzoyl peroxide (0.025 g, 0.10 mmol) and heated to reflux for 14 h. After cooling to room temperature, the solid was collected by filtration, washed with DCM (2x25 mL) and discarded. The filtrate was washed with water (3x20 mL), sodium thiosulfite solution (20 mL), brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give intermediate 13-1 (4-bromo-1,2-bis(dibromomethyl)benzene, 4.9 g, 9.8 mmol, 95% yield) as a yellow solid, which was used without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 7.90-7.80(m, 1H), 7.65-7.57(m, 1H), 7.56-7.49(m, 1H), 7.15-6.98(m, 2H)

[0161] Intermediates 13-2 and 13-3: Preparation of 7-bromo-3-(methoxycarbonyl)-2-naphthoic acid and 6-bromo-3-(methoxycarbonyl)-2-naphthoic acid To a solution of intermediate 13-1 (2.2 g, 4.4 mmol) and furan-2,5-dione (0.47 g, 4.8 mmol) in DMF (8 mL) was added sodium iodide (1.98 g, 13.2 mmol) and heated at 50° C. After stirring for 14 h, the reaction mixture was cooled to room temperature, MeOH (10 mL) was added and stirred for 24 h. The solvent was removed by concentration under reduced pressure, and the resulting residue was washed with saturated sodium bisulfite and purified by reverse phase chromatography (elution gradient: H 2 The mixture was purified by SFC (instrument: Berger MG II, column: Chiralpak AD-H, 21x250mm, 5μ; mobile phase: 15% IPA-ACN (1:1, 0.1% DEA) / 85% CO 2; Elution conditions: 45mL / min, 150Bar, 40℃; Detection wavelength: 233nm; Injection conditions: 0.5mL (MeOH-IPA (1:1, 0.1%DEA) solution, 10mg / mL); Analytical SFC: Instrument: Shimadzu; Column: Chiralpak AD-H, 4.6x100mm, 3μ; Mobile phase: 20%IPA-ACN(1:1, 0.1%DEA) / 80%CO 2 ; elution conditions: 2.0 mL / min, 150 Bar, 40°C, detection wavelength: 220 nm; injection conditions: 10 μL (MeOH solution, ~1 mg / mL)) to give intermediate 13-2 (peak-1, RT = 4.32 min, 350 mg, 21% yield) and intermediate 13-3 (peak-2; RT = 5.89 min, 370 mg, 22% yield). 13-2: 1 H NMR (400 MHz, DMSO-d 6 ) δ 110.04-9.54(m, 1H), 8.31(d, J=1.8Hz, 1H), 8.22(s, 1H), 8.00(s, 1H), 7.97(d, J=9.0Hz, 1H), 7.69(dd, J=8.8, 2.0Hz, 1H), 3.77(s, 3H); MS(ESI)m / z=308.8~310.8(M+H) + 13-3: 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.62-9.31(m, 1H), 8.31-8.17(m, 2H), 7.99(d, J=8.8Hz, 1H), 7.94(s, 1H), 7.70(dd, J=8.7, 2.1Hz, 1H), 3.77(s, 3H); MS(ESI)m / z=309~311.0(M+H) +

[0162] Intermediate 13-4: Preparation of methyl 7-bromo-3-(((2-(trimethylsilyl)ethoxy)carbonyl)-amino)-2-naphthoate To a three-necked round bottom flask containing 6-bromo-3-(methoxycarbonyl)-2-naphthoic acid (13-3, 180 mg, 0.57 mmol) in toluene (8 mL), TEA (0.18 mL, 1.3 mmol) and diphenylphosphoryl azide (0.10 mL, 0.48 mmol) were added and stirred at room temperature for 2.5 h. 2-(trimethylsilyl)ethan-1-ol (0.32 mL, 2.3 mmol) was then added and the mixture was heated at 80° C. for 1 h. The reaction mixture was cooled, concentrated in vacuo, and purified by normal phase chromatography to give intermediate 13-4 (175 mg, 0.412 mmol, 72.4% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 10.50-10.21(m, 1H), 8.84(s, 1H), 8.56(s, 1H), 8.19-7.88(m, 1H), 7.82-7.55(m, 2H), 4.44-4.26(m, 2H), 4.03(s, 3H), 1.18-1.06(m, 2H), 0.12(s, 9H)

[0163] Intermediate 13-5: Preparation of methyl 3-amino-7-bromo-2-naphthoate Intermediate 13-4 (167 mg, 0.394 mmol) was deprotected by treatment with 20% TFA / DCM (4 mL). After 14 h, the reaction mixture was concentrated in vacuo and further dried under high vacuum to give intermediate 13-5 (110 mg, 0.393 mmol, 100% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.45(s, 1H), 8.08(d, J=1.3Hz, 1H), 7.56-7.50(m, 1H), 7.50-7.45(m, 1H), 7.07(s, 1H), 6.55(s, 2H), 3.90(s, 3H); LC-MS: RT= 1.29 min; MS(ESI)m / z=280~282(M+H) + ;[Method A]

[0164] Intermediate 13-6: Preparation of 3-amino-7-bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-naphthamide 4-Fluoro-3-(trifluoromethyl)aniline (211 mg, 1.18 mmol) in toluene (1 mL) 3 Al (589 μL, 1.18 mmol) was added and stirred for 10 min, then intermediate 13-5 (110 mg, 0.393 mmol) in toluene (9 mL) was added. The solution was heated at 120° C. for 30 min under microwave irradiation and the reaction was quenched by the addition of dilute HCl (10 mL). It was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (15 mL) and dried (Na 2 SO 4 ), filtered, concentrated in vacuo, and purified by normal phase chromatography to give intermediate 13-6 (140 mg, 0.33 mmol, 85% yield). 1 H NMR (400MHz, DMSO-d6) δ 10.78(s, 1H), 8.27(dd, J=6.6, 2.6Hz, 1H), 8.16(s, 1H), 8.06(ddd, J=8.7, 4.1, 2.9Hz, 1H), 8.02(d, J=2.0Hz, 1H), 7.61-7.54(m, 2H), 7.51-7.47(m, 1H), 7.06(s, 1H), 6.08(s, 2H); LC-MS: RT= 1.37 min; MS(ESI)m / z=427.9~429.9(M+H) + ;[Method A]

[0165] Intermediate 14-3: Preparation of 5-((3-hydroxypropyl)sulfonyl)-2-methoxybenzoic acid as shown in the following scheme [ka] Intermediate 14-1: Preparation of 4-methoxy-3-(methoxycarbonyl)benzenesulfinate Methyl 5-iodo-2-methoxybenzoate (200 mg, 0.69 mmol), potassium pyrosulfite (304 mg, 1.37 mmol), sodium formate (102 mg, 1.51 mmol), tetrabutylammonium bromide (243 mg, 0.750 mmol), 1,10-phenanthroline (37 mg, 0.21 mmol), triphenylphosphine (54 mg, 0.21 mmol), and Pd(OAc). 2 (15.4 mg, 0.068 mmol) in DMSO (5 mL) and N 2 The mixture was degassed at rt and heated at 70° C. After 3 h, the reaction mixture was cooled to room temperature and used in the next step without further purification.

[0166] Intermediate 14-2: Preparation of methyl 5-((3-hydroxypropyl)sulfonyl)-2-methoxybenzoate Intermediate 14-1 was treated with 3-bromopropan-1-ol (310 μL, 3.42 mmol) and after stirring for 14 h, the reaction mixture was washed with brine (10 mL) and purified by normal phase chromatography (elution: hexane / EtOAc) to give intermediate 14-2 (150 mg, 76% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 8.34(d, J=2.4Hz, 1H), 8.02(dd, J=8.9, 2.4Hz, 1H), 7.14(d, J=8.9Hz, 1H), 3.99(s, 3H), 3.91(s, 3H), 3.79-3.72(m, 2H), 3.32-3.19(m, 2H), 2.05-1.96(m, 2H), 1.92-1.75(m, 1H); LC-MS: RT=0.86 min; MS(ESI)m / z=289.1(M+H) + ;[Method A]

[0167] Intermediate 14-3: Preparation of 5-((3-hydroxypropyl)sulfonyl)-2-methoxybenzoic acid Methyl 5-((3-hydroxypropyl)sulfonyl)-2-methoxybenzoate (150 mg, 0.520 mmol) obtained in the above step was dissolved in THF (5 mL) and diluted with LiOH (2 M, 0.78 mL, 1.56 mmol) in H2 After 1 h, the reaction mixture was acidified with 1M HCl, extracted with EtOAc (2x10 mL) and washed with H 2 O, washed with brine, dried over sodium sulfate, filtered and concentrated to give intermediate 14-3 (28 mg, 19% yield). 1 H NMR (500 MHz, CD 3 OD) δ 8.30(d, J=2.4Hz, 1H), 8.06(dd, J=8.9, 2.4Hz, 1H), 7.39(d, J=8.9Hz, 1H), 3.91(s, 3H), 3.61(t, J=6.1Hz, 2H), 3.31-3.22(m, 2H), 1.95-1.79(m, 2H); LC-MS: RT= 0.74 min; MS(ESI)m / z=275.1(M+H) + ;[Method A]

[0168] Intermediate 15-2: Preparation of (S)-5-(3-hydroxybut-1-yn-1-yl)-2-methoxybenzoic acid as shown in the following scheme: [ka] Intermediate 15-1: Preparation of (S)-5-(3-hydroxybut-1-yn-1-yl)-2-methoxybenzoate Methyl 5-bromo-2-methoxybenzoate (500 mg, 2.04 mmol), propargyl alcohol (0.15 mL, 2.6 mmol), Pd(Ph 3 P) 4 A slurry of (47 mg, 0.041 mmol) and copper(I) iodide (3.9 mg, 0.020 mmol) in TEA (5 mL) was degassed and flushed with N 2 and heated at 80° C. for 14 h. The reaction mixture was cooled, water was added, and the aqueous layer was extracted with EtOAc. The organic layer was then washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by normal phase chromatography (elution: hexane / EtOAc) to give intermediate 15-1 (390 mg, 1.6 mmol, 81% yield). LC-MS: RT= 0.72 min; MS(ESI)m / z= 235.1(M+H).+ [Method A]

[0169] Intermediate 15-2: Preparation of (S)-5-(3-hydroxybut-1-yn-1-yl)-2-methoxybenzoic acid A solution of intermediate 15-1 (190 mg, 0.81 mmol) in THF (6 mL) was treated with LiOH (34 mg, 0.81 mmol) in water (2 mL). The reaction mixture was acidified with 0.1 N HCl, extracted with EtOAc (20 mL), concentrated in vacuo, and the resulting residue (15-2, 179 mg, 0.811 mmol, 100% yield) was used without further purification. LC-MS: RT = 0.61 min; MS (ESI) m / z = 221.1 (M+H). + ;[Method A]

[0170] Intermediate 16-2: Preparation of 5-(1,1-dioxidoisothiazolidine-2-yl)-2-methoxybenzoic acid [ka] Isothiazolidine 1,1-dioxide (41 mg, 0.30 mmol), methyl 5-iodo-2-methoxybenzoate (0.1 g, 0.3 mmol), Xantphos (20 mg, 0.034 mmol), Cs 2 CO 3 A solution containing (0.2 g, 0.7 mmol) in dioxane (1.8 mL) was purged with nitrogen for 10 min, followed by Pd 2 (dba) 3 (16 mg, 1.7 μmol) was added and heated at 100 °C for 15 h. After cooling, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (30 mL) and the aqueous layer was extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure to give intermediate 16-1, which was immediately added to THF (2 mL) / MeOH (0.5 mL) / water (0.5 mL), cooled to 0° C., and LiOH (2M, 0.17 mL, 0.34 mmol) was added. After 3 h, the reaction mixture was diluted with water (10 mL) and Et 2The mixture was partitioned between 200 and 250 ml of ethyl acetate (50 mL), and the aqueous layer was acidified and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO 4 ), filtered and concentrated in vacuo to give intermediate 16-2 (70 mg, 0.26 mmol, 75% yield) as a brown oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 7.89-7.87(m, 1H), 7.20-7.17(m, 1H), 6.87(d, J=8.8Hz, 1H), 4.13-4.09(m, 3H), 3.51-3.40(m, 2H), 3.14-3.03(m, 2H), 2.53-2.43(m, 2H); LCMS:(ESI)m / z: 272.1(M+H) +

[0171] Intermediate 17-4: Preparation of 3-amino-6,7-dibromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-naphthamide as shown in the following scheme: [ka] Intermediates 17-1 and 17-2: Preparation of 3-amino-6,7-dibromo-2-naphthoic acid and methyl 3-amino-7-bromo-2-naphthoate Intermediate 17-1 (0.39 g, 1.39 mmol, 43% yield) and intermediate 17-2 (0.33 g, 0.92 mmol, 28% yield) were prepared as described in Torikai, K, et al. Bioorg. Med. Chem. 2017, 25(20), 5216-37. 17-1: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58(s, 1H), 8.25(d, J=2.0Hz, 1H), 7.85-7.80(m, 1H), 7.76-7.69(m, 1H), 6.76(br s, 2H), 3.94(s, 3H); LCMS:(ESI)m / z: 357~359.6(M+H) + 17-2:1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65-8.53(m, 1H), 7.95(d, J=8.1Hz, 1H), 7.89(dd, J=8.6, 0.7Hz, 1H), 7.65(ddd, J=8.5, 7.0, 1.2Hz, 1H), 7.32(ddd, J=8.1, 7.0, 1.0Hz, 1H), 6.90-6.43(m, 2H), 4.16-3.83(m, 3H); LCMS:(ESI)m / z: 280~281.8(M+H) +

[0172] Intermediate 17-3: Preparation of 3-amino-6,7-dibromo-2-naphthoic acid Intermediate 17-3 (0.2 g, 0.6 mmol, 100% yield) was prepared as described in Intermediate 6-2. LCMS: (ESI) m / z: 265-267.8 (M+H) +

[0173] Intermediate 17-4: Intermediate 17-4 (0.17 g, 0.34 mmol, 85% yield) was prepared in a similar procedure to intermediate 7-1 using intermediate 17-3 instead of 3-amino-2-naphthoic acid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.94(s, 1H), 8.32-8.23(m, 2H), 8.16(d, J=2.0Hz, 1H), 8.06(dt, J=8.0, 4.0Hz, 1H), 7.86(d, J=9.2Hz, 1H), 7.73(dd, J=9.0, 2.0Hz, 1H), 7.59(t, J=9.8Hz, 1H), 6.25(s, 2H); LCMS:(ESI)m / z: 504.8~508.9(M+H) +

[0174] Intermediate 18-1: Preparation of tert-butyl 2-((tert-butoxycarbonyl)amino)-2-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)naphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)acetate [ka] Intermediate 18-1: Intermediate 7-1 (25 mg, 0.072 mmol), Intermediate 3-6 (34 mg, 0.072 mmol), DIPEA (9.3 mg, 0.072 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (27 mg, 0.072 mmol) were added to THF / DMF (1:1, 2 mL) and heated at 50° C. for 14 h. The reaction mixture was purified by reverse phase chromatography (gradient: Solvent A (80% water / 20% ACN / 0.1% TFA) and Solvent B (5% water / 95% ACN / 0.1% TFA)) to give Intermediate 18-1 (13 mg, 22% yield) as a solid. 1 H NMR (500 MHz, CDCl 3 ) δ 11.29(br s, 1H), 10.26-10.13(m, 1H), 8.75(s, 1H), 8.68(s, 1H), 8.50(br d, J=4.1Hz, 1H), 8.11(d, J=8.2Hz, 1H), 7.83(s, 1H), 7.80-7.70(m, 1H), 7.59(br d, J=5.5Hz, 1H), 7.41-7.19(m, 2H), 7.15-7.08(m, 1H), 7.08-6.99(m, 3H), 5.80(br s, 1H), 5.31(br s, 1H), 4.12(br s, 2H), 3.85(s, 3H), 1.49-1.43(m, 18H)

[0175] Example 1 6-Fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)naphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] Intermediate 7-1 (50 mg, 0.14 mmol) was added to ACN (5.7 mL) followed by DIPEA (0.58 mL, 3.3 mmol) and intermediate 1-1 (50 mg, 0.14 mmol) and HATU (66 mg, 0.17 mmol) to produce Example 1. After 14 h, the reaction mixture was partitioned between water and EtOAc (25 mL). The organic layer was washed with water, 1M HCl, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (5 mL) and treated with TFA (1 mL). After 3 h, the reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (conditions: gradient mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate) to give Example 1 (2.7 mg, 3% yield) as a solid. 1 H NMR (500MHz, DMSO-d6) δ 11.61-11.57(m, 1H), 11.18-11.14(m, 1H), 9.07(s, 1H), 8.44(s, 1H), 8.39(br d, J=5.0Hz, 1H), 8.27(s, 1H), 8.14-8.06(m, 2H), 8.04-7.94(m, 3H), 7.82(br d, J=8.8Hz, 1H), 7.66-7.53(m, 3H), 7.46(t, J=9.5Hz, 1H), 7.38(d, J=8.8Hz, 1H), 4.07(s, 3H);Analytical LC-MS: RT=2.49min; MS(ESI)m / z=621.1(M+H) + ;HPLC purity: 97%; [Method C]

[0176] Example 2 2-(6-Fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)naphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)acetic acid [ka] Intermediate 18-1 (13 mg, 0.016 mmol) was dissolved in EtOAc (2 mL) and treated with HCl / dioxane (4N, 3 mL) to prepare Example 2. After 2 h, the reaction mixture was concentrated under reduced pressure to give the amine hydrochloride intermediate. The solid was redissolved in DCM (1 mL) and to this solution was added tetrahydro-2H-pyran-4-carbonyl chloride (2.4 mg, 0.016 mmol) followed by DIEA (0.05 ml). After 1 h, the solution was concentrated under reduced pressure, redissolved in DCM (1 mL) and TFA (1 mL) was added. After 2 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (gradient mobile phase A: 5:95 ACN:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 ACN:water (containing 10 mM ammonium acetate)) to give Example 2 (2.9 mg, 24% yield). 1 H NMR (500MHz, DMSO-d6) δ 11.59(s, 1H), 9.07(s, 1H), 8.43(s, 2H), 8.38(br d, J=6.6Hz, 1H), 8.25(s, 1H), 8.10(br d, J=9.2Hz, 1H), 8.02(d, J=8.2Hz, 1H), 7.95(d, J=8.2Hz, 1H), 7.76(br d, J=8.5Hz, 1H), 7.66-7.52(m, 4H), 7.43-7.35(m, 2H), 7.28(t, J=9.5Hz, 1H), 5.26(brd, J=7.0Hz, 1H), 4.06(s, 3H), 3.85(br s, 2H), 3.62(br s, 1H), 3.35-3.27(m, 2H), 1.65-1.51(m, 4H); Analytical LC-MS: RT=1.93 min; MS(ESI)m / z=762.1(M+H) +;HPLC purity: 100%; [Method B]

[0177] Example 3 2-(3'-((6,7-dibromo-3-((4-fluoro-3-(trifluoromethyl)phenyl)-carbamoyl)naphthalen-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)acetic acid [ka] Intermediate 17-4 (22 mg, 0.043 mmol) and intermediate 3-6 (21 mg, 0.043 mmol) were coupled with 1-methyl-1H-imidazole (4 mg, 0.043 mmol) in ACN (1 mL), TCFH (12 mg, 0.043 mmol) to produce the title compound (1.5 mg, 1.6 μmol, 3.7% yield). After 24 h, the solvent was removed in vacuo and the resulting residue was treated with 4N HCl (0.5 mL) in EtOAc (2 mL) for 1 h, and the solvent was removed in vacuo. To the resulting residue was added tetrahydro-2H-pyran-4-carbonyl chloride (7 mg, 0.043 mmol) in DCM (1 mL), followed by DIEA (38 μL, 0.22 mmol). The reaction mixture was stirred for 0.5 h and then concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to give Example 3 (1.5 mg, 1.6 μmol, 3.7% yield). 1 H NMR (500 MHz, DMSO-d 6) δ 10.96-10.73(m, 1H), 10.44(s, 1H), 8.54(br d, J=7.3Hz, 1H), 8.49(d, J=1.5Hz, 1H), 8.36(s, 1H), 8.24(d, J=9.2Hz, 1H), 8.17-8.10(m, 1H), 8.02-7.90(m, 3H), 7.73(br d, J=8.2Hz, 1H), 7.52(br s, 1H), 7.49-7.44(m, 1H), 7.43-7.35(m, 2H), 7.27(br dd, J=10.7, 8.5Hz, 1H), 5.36(br d, J=7.6Hz, 1H), 4.05(s, 3H), 3.91-3.77(m, 2H), 3.44-3.17(m, 1H), 1.97-1.19(m, 5H); Analysis LC-MS: RT=2.02min; MS(ESI)m / z=918(M+H) + ;HPLC purity: 98%; [Method B]

[0178] Example 4 2-(6-Fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)naphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-hydroxyacetic acid (homochiral) [ka] Example 4 (5.7 mg, 0.0090 mmol, 11% yield) was prepared following a procedure similar to that of Example 1, using Intermediate 2-6 (30 mg, 0.080 mmol) instead of Intermediate 1-1. 1H NMR (500MHz, DMSO-d6) δ 11.61-11.56(m, 1H), 11.15(s, 1H), 9.05(s, 1H), 8.43-8.40(m, 1H), 8.37(br d, J=6.0Hz, 1H), 8.24(s, 1H), 8.08(br s, 1H), 8.02(br d, J=8.1Hz, 1H), 7.95(d, J=8.2Hz, 1H), 7.76(br d, J=8.6Hz, 1H), 7.64(t, J=7.5Hz, 1H), 7.60-7.51(m, 2H), 7.50-7.42(m, 1H), 7.41-7.26(m, 1H), 4.05(s, 1H), 3.75(br s, 3H); Analytical LC-MS: RT=2.28 min; MS(ESI)m / z= 650.9(M+H) + ;HPLC purity: 98%; [Method B]

[0179] Example 5 (S)-2,2,2-trifluoro-1-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-naphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)ethyl cyclobutylcarbamate [ka] Example 5 (0.6 mg, 0.7 μmol, 2% yield) was prepared from intermediate 7-1 (10 mg, 0.029 mmol), intermediate 12-3 (12.67 mg, 0.029 mmol), and 1-methyl-1H-imidazole (2.36 mg, 0.029 mmol) in ACN (1 mL) followed by TCFH (8.06 mg, 0.029 mmol). After 12 h, the reaction mixture was purified by reverse phase HPLC (gradient: mobile phase A: 5:95 ACN:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 ACN:water (containing 10 mM ammonium acetate)) to give a solid. 1H NMR (500MHz, DMSO-d6) δ 9.11(s, 1H), 8.90-8.53(m, 1H), 8.48(s, 1H), 8.40(br d, J=4.3Hz, 1H), 8.26(br s, 1H), 8.17(br d, J=7.9Hz, 1H), 8.14-8.09(m, 1H), 8.04(br d, J=8.2Hz, 1H), 7.97(br d, J=7.9Hz, 1H), 7.79(br d, J=8.5Hz, 1H), 7.74(br d, J=7.0Hz, 1H), 7.69-7.63(m, 1H), 7.61-7.53(m, 2H), 7.47(br d, J=10.7Hz, 1H), 7.41(d, J=8.5Hz, 1H), 7.33-6.91(m, 1H), 6.39(q, J=6.8Hz, 1H), 4.08(s, 3H), 3.98-3.88(m, 1H), Analytical LC-MS: RT=2.96 min; MS(ESI)m / z=772.3(M+H) + ;HPLC purity: 90%; [Method B]

[0180] Example 6 3'-((8-bromo-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)naphthalen-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] Following a procedure similar to that of Example 1, but using Intermediate 9-1 (8 mg, 1.9 μmol) instead of Intermediate 1-1, Example 6 was prepared (3 mg, 5 μmol, 24% yield). 1 H NMR (500 MHz, DMSO-d 6) δ 11.72(s, 1H), 11.24(br s, 1H), 9.53(s, 1H), 8.54(s, 1H), 8.45-8.36(m, 1H), 8.31(d, J=0.6Hz, 1H), 8.18-8.05(m, 3H), 8.04-7.94(m, 2H), 7.90-7.78(m, 1H), 7.60(t, J=9.9Hz, 1H), 7.52-7.42(m, 2H), 7.40(d, J=8.9Hz, 1H), 4.09(s, 3H); Analysis LC-MS: RT=2.2 min; MS(ESI)m / z= 699(M+H) + ;HPLC purity: 100%; [Method B]

[0181] Example 8 3'-((6-bromo-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)naphthalen-2-yl)carbamoyl)-6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] Following a similar procedure to Example 5, using intermediate 13-5 instead of intermediate 12-3, and hydrolyzing the t-butyl ester with TFA / DCM, Example 8 was prepared (10 mg, 1.4 μmol, 27% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.53(s, 1H), 11.17(s, 1H), 9.05(br s, 1H), 8.47-8.33(m, 2H), 8.26(br s, 2H), 8.12-8.03(m, 2H), 8.02-7.95(m, 1H), 7.91(br d, J=8.8Hz, 1H), 7.80(br d, J=8.1Hz, 1H), 7.72(br d, J=8.8Hz, 1H), 7.57(br t, J=9.7Hz, 1H), 7.45(br t, J=8.5Hz, 1H), 7.36(br d, J=8.5Hz, 1H), 4.05(s, 3H), 3.63-3.49(m, 1H); Analytical LC-MS: RT=2.29min; MS(ESI)m / z= 699.3(M+H)+ ;HPLC purity: 100%; [Method B]

[0182] Example 9 N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-((3-hydroxypropyl)sulfonyl)-2-methoxybenzamido)-2-naphthamide [ka] Example 9 (2.8 mg, 0.004 mmol, 32% yield) was prepared following a procedure similar to that of Example 5, using Intermediate 14-3 instead of Intermediate 12-3. 1 H NMR (500MHz, DMSO-d6) δ 11.62(s, 1H), 11.15(s, 1H), 9.08-9.04(m, 1H), 8.72-8.67(m, 1H), 8.54-8.46(m, 2H), 8.40-8.35(m, 1H), 8.14-7.96(m, 4H), 7.65(t, J=7.5Hz, 1H), 7.62-7.56(m, 2H), 7.51(d, J=8.9Hz, 1H), 4.68-4.63(m, 1H), 4.13(s, 3H), 2.54(s, 2H), 1.72-1.65(m, 2H); Analytical LC-MS: RT=2.14 min; MS(ESI)m / z=605.1(M+H) + ;HPLC purity: 99%; [Method C]

[0183] Example 10 (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-hydroxybut-1-yn-1-yl)-2-methoxybenzamido)-2-naphthamide [ka] Following a similar procedure to Example 5, using Intermediate 15-2 instead of Intermediate 12-3, Example 10 (2.4 mg, 0.004 mmol, 30% yield) was prepared. 1H NMR (500MHz, DMSO-d6) δ 11.52(s, 1H), 11.15-11.11(m, 1H), 9.04(s, 1H), 8.43(s, 1H), 8.38-8.35(m, 1H), 8.10(br dd, J=7.2, 2.3Hz, 1H), 8.07-8.00(m, 2H), 7.96(d, J=7.9Hz, 1H), 7.67-7.54(m, 4H), 7.24(d, J=8.9Hz, 1H), 4.59(quin, J=6.2Hz, 1H), 4.02(s, 3H), 1.39(d, J=6.4Hz, 3H); Analytical LC-MS: RT=2.39min; MS(ESI)m / z= 551.1(M+H) + ;HPLC purity: 100%; [Method C]

[0184] Example 11 3-(5-(1,1-dioxidoisothiazolidine-2-yl)-2-methoxybenzamide)-N-(4-fluoro-3-(trifluoromethyl)-phenyl)-2-naphthamide [ka] Example 11 (4 mg, 6 μmol, 10% yield) was prepared from intermediate 16-2 using a procedure similar to that of Example 5. 1 H NMR (500 MHz, DMSO-d 6) δ 11.59(s, 1H), 11.24-10.91(m, 1H), 9.10(s, 1H), 8.62-8.33(m, 2H), 8.18-8.08(m, 1H), 8.04(d, J=8.2Hz, 1H), 8.00(d, J=3.1Hz, 1H), 7.97(d, J=8.5Hz, 1H), 7.66(t, J=7.2Hz, 1H), 7.62-7.55(m, 2H), 7.44(dd, J=8.9, 3.1Hz, 1H), 7.30(d, J=9.2Hz, 1H), 4.02(s, 3H), 3.76(t, J=6.6Hz, 2H), 3.58-3.40(m, 1H), 2.43(quin, J=6.9Hz, 2H); Analytical LC-MS: RT=2.44min; MS(ESI)m / z= 602.3(M+H) + ;HPLC purity: 92%; [Method B]

[0185] Example 12 N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(6-oxopyridazin-1(6H)-yl)benzamido)-2-naphthamide [ka] Example 12 (5.6 mg, 10 μmol, 68% yield) was prepared from intermediate 11-2 using a procedure similar to that of Example 5. 1H NMR (500MHz, DMSO-d6) δ 11.60(s, 1H), 11.14(s, 1H), 9.05(s, 1H), 8.46-8.43(m, 1H), 8.40-8.37(m, 1H), 8.23(d, J=2.7Hz, 1H), 8.14-8.06(m, 2H), 8.06-8.00(m, 1H), 7.95(d, J=8.2Hz, 1H), 7.81-7.75(m, 1H), 7.67-7.54(m, 3H), 7.50(dd, J=9.5, 3.7Hz, 1H), 7.39-7.33(m, 1H), 7.09(dd, J=9.5, 1.2Hz, 1H), 4.07(s, 3H); Analytical LC-MS: RT=2.24min; MS(ESI)m / z= 577.1(M+H) + ;HPLC purity: 99%; [Method C]

[0186] Example 13 N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)-2-naphthamide (homochiral, peak 4) [ka] Example 13 (6.2 mg, 0.009 mmol, 32% yield) was prepared from intermediate 6-10 using a procedure similar to that of example 5. 1H NMR (500MHz, DMSO-d6) δ 11.57(s, 1H), 11.14(s, 1H), 9.09(s, 1H), 8.45(s, 1H), 8.40-8.35(m, 2H), 8.13-8.09(m, 1H), 8.03(br d, J=7.9Hz, 1H), 7.96(br d, J=8.2Hz, 1H), 7.87(dd, J=8.5, 2.1Hz, 1H), 7.66-7.55(m, 3H), 7.33(d, J=8.5Hz, 1H), 5.19-5.14(m, 1H), 4.17-4.11(m, 1H), 4.06(s, Analytical LC-MS: RT=2.35 min; MS(ESI)m / z= 622.3(M+H) + ;HPLC purity: 100%; [Method C]

[0187] Example 14 N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)-2-naphthamide (homochiral, peak 3) [ka] Example 14 (6.6 mg, 0.01 mmol, 25% yield) was prepared from intermediate 6-8 using a procedure similar to that of example 5. 1H NMR (500MHz, DMSO-d6) δ 11.57(s, 1H), 11.14(s, 1H), 9.09(s, 1H), 8.47-8.44(m, 1H), 8.41-8.34(m, 2H), 8.14-8.10(m, 1H), 8.03(br d, J=7.9Hz, 1H), 7.96(br d, J=8.2Hz, 1H), 7.87(dd, J=8.5, 1.8Hz, 1H), 7.94(br s, 1H), 7.66-7.53(m, 3H), 7.33(d, J=8.9Hz, 1H), 5.14(br dd, J=8.7, 5.0Hz, 1H), 4.53-4.47(m, 1H), 4.23(br t, J=8.7Hz, 1H), 4.06(s, 3H), 2.02-1.79(m, 3H), 1.73-1.65(m, 1H), 1.61-1.53(m, 1H); Analytical LC-MS: RT=2.35 min; MS(ESI)m / z= 622.3(M+H) + ;HPLC purity: 95%; [Method C]

[0188] Example 15 N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-hydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamide)-2-naphthamide (homochiral, peak 1) [ka] Example 15 (5.5 mg, 9.05 μmol, 21% yield) was prepared from intermediate 5-3 using a procedure similar to that of Example 5. 1H NMR (400MHz, DMSO-d6) δ 11.57(s, 1H), 11.14(s, 1H), 9.09(s, 1H), 8.45(s, 1H), 8.38(dd, J=6.6, 2.4Hz, 1H), 8.36-8.34(m, 1H), 8.15-8.09(m, 1H), 8.03(d, J=8.1Hz, 1H), 7.97(d, J=8.1Hz, 1H), 7.86(dd, J=8.7, 2.3Hz, 1H), 7.67-7.54(m, 3H), 7.33(d, J=8.8Hz, 1H), 5.16(ddd, J=9.4, 6.1, 2.9Hz, 1H), 4.25(td, J=9.4, 4.2Hz, 1H), 4.11(quin, J=6.2Hz, 1H), 4.06(s, 3H), 2.03-1.88(m, 3H), 1.83(dt, J=12.7, 4.8Hz, 1H); Analytical LC-MS: 1.02 min; MS(ESI)m / z=608.1(M+H) + ;HPLC purity: 100%; [Method A]

[0189] Example 16 N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-hydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamide)-2-naphthamide (homochiral, peak 4) [ka] Example 16 (8.4 mg, 0.013 mmol, 32% yield) was prepared from intermediate 5-6 using a procedure similar to that of example 5. 1H NMR (500MHz, DMSO-d6) δ 11.57(s, 1H), 11.16-11.12(m, 1H), 9.08(s, 1H), 8.44(s, 1H), 8.40-8.33(m, 2H), 8.14-8.09(m, 1H), 8.02(br d, J=7.6Hz, 1H), 7.96(br d, J=7.9Hz, 1H), 7.87-7.82(m, 1H), 7.64(br t, J=7.6Hz, 1H), 7.61-7.53(m, 2H), 7.32(d, J=8.9Hz, 1H), 5.15-5.09(m, 1H), 4.18-4.10(m, 2H), 4.05(s, 3H), 2.15-2.06(m, 2H), 1.93-1.88(m, 1H), 1.80-1.74(m, 1H); Analytical LC-MS: RT=2.27 min; MS(ESI)m / z= 607.96(M+H) + ;HPLC purity: 100%; [Method B]

[0190] It will be apparent to those skilled in the art that the present disclosure is not limited to the above-described examples, and that it may be embodied in other specific forms without departing from the essential characteristics of the present disclosure. The examples are therefore to be considered in all respects as illustrative and not restrictive, with reference to the claims rather than the above-described examples, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced herein.

Claims

1. Formula (I): [In the formula, Q is CH, CR 1 or N; provided that no more than one Q is N; R 1 is a C substituted with halogen or 0 to 5 halogens 1-4 is alkyl; R 2 is halogen, CN, -NR a R a , or -OC 1-4 Alkyl R b , C substituted with 0 to 5 halogens or OH 1-4 is alkyl; R 3 is 0 to 5 R 4 C replaced with 1-4 Alkyl, 0 to 5 R 4 -(CR d R d ) n -C 3-10 -carbocyclyl or 0 to 5 R 4 -(CR d R d ) n -(O, S(=O) p , N, and NR d a 3- to 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from: R 4 is halogen, CN, C substituted with 0 to 5 halogens 1-4 Alkyl, OH, -OC substituted with 0-5 halogens 1-4 Alkyl, -S(O) p R c , aryl, or O, S(=O) p , N, and NR d is a 4- to 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from: R 5 is -S(=O) p R c , C substituted with 0 to 5 halogens or OH 2-6 Alkenyl, C substituted with 0-5 halogen or OH 2-6 Alkynyl, 0-3 R 6 and 0 to 2 R 7 C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N, and NR 10 and 0 to 3 R 6 and 0 to 2 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, CN, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is a halogen, -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a OR b or C substituted with 0 to 3 halogens or OH 1-4 is alkyl; R 9 -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 3-6 Carbocyclyl, or O, S(=O) p and N, and 0 to 3 R e substituted with -(CH 2 ) n -heterocyclyl; R 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is —OH, —C(═O)OH, or aryl; R 12 is H, C 1-3 alkyl, or aryl; R a is H, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0-5 R e C replaced with 2-6 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 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 5 R e forming a 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, 0-5 R e C replaced with 2-6 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e substituted with -(CH 2 ) n -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, 0-5 R e C replaced with 2-6 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-4 is alkyl; R e are halogens, CN, NO 2 , =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -carbocyclyl, -(CH 2 ) n -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 are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 1】 [In the formula, R 1 is a C substituted with halogen or 0 to 4 halogens 1-3 is alkyl; R 2 is a halogen, C 1-3 Alkyl, or -OC 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-4 is alkyl; R 5 is -S(=O) p R c , C substituted with 0 to 5 halogens or OH 2-6 Alkynyl, 0-3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is a halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0 to 3 halogens or OH 1-4 is alkyl; R 9 -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 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is —OH, —C(═O)OH, or aryl; R 12 is H, C 1-3 alkyl, or aryl; 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 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 5 R e forming a 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e substituted with -(CH 2 ) n -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, 0-5 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , or -C(=O)OR f and; R f is H or C 1-3 is alkyl; R g are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

3. Formula (III): 【Chemistry 2】 [In the formula, R 1 is Br or CF 3 and; R 2 is -OC substituted with 0 to 4 halogens 1-4 is alkyl; R 4a is a halogen; R 4b is C substituted with 0-4 F 1-3 is alkyl; R 6 are halogens, CN, C 1-3 Alkyl, -OH, or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 Alkyl, OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , or C 3-6 is cycloalkyl; R 8 is a halogen, -C(=O)OR b , -C(=O)NHR a or C substituted with 0 to 3 halogens or OH 1-3 is alkyl; R 9 -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 , -S(=O) p 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 C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0-4 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl 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 replaced with 1-5 Alkyl, 0 to 4 R e C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0-4 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 4 R e substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halogen, CN, =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , S(=O) p R f , C(=O)NR f R f , C(=O)OR f , N.R. f C(=O)R f , S(=O) p NR f R f , N.R. f S(=O) p R f , N.R. f C(=O)OR f , OC(=O)NR f R f , or -(CH 2 ) n NR f R f and; R f is H, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclyl; R g are halogens, CN, -OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

3. The compound of claim 2, having the formula: or a pharmaceutically acceptable salt thereof.

4. Formula (IV): 【Transformation 3】 [In the formula, R 1 is Br; R 2 -OC 1-3 is alkyl; R 4a is F; R 4b CF 3 and; R 6 is a halogen; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 Alkyl, -C(=O)OR b , or -C(=O)NR a R a and; R 8 is -C(=O)OR b , -C(=O)NHR a or C substituted with 0 to 3 halogens or OH 1-3 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , or -OC(=O)NR a R a and; R a is H, 0 to 3 R e C replaced with 1-4 Alkyl, 0 to 3 R e substituted with -(CH 2 ) n -C 3-6 cycloalkyl, 0 to 3 R e is phenyl substituted with; R b is H or 0 to 3 R e is heterocyclyl substituted with; R e is a halogen, CN, =O, or C 1-6 is alkyl; and n is 0 or 1.

4. The compound of claim 3, wherein:

5. Formula (V): 【Chemistry 4】 [In the formula, R 1 is a C substituted with halogen or 0 to 5 halogens 1-3 is alkyl; R 2 is -OC substituted with 0 to 4 halogens 1-4 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-3 is alkyl; R 5 is O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 4 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0 to 3 halogens or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -S(=O) p NR a R a , or -S(O) p R c and; R 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is —OH, —C(═O)OH, or aryl; R 12 is H, C 1-3 alkyl, or aryl; R a is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0-4 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl 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 replaced with 1-5 Alkyl, 0 to 4 R e C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, 0-4 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 4 R e substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e C replaced with 2-5 Alkenyl, 0 to 4 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-3 is alkyl; R e is halogen, CN, =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , or -C(=O)OR f and; R f is H or C 1-3 is alkyl; R g are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

3. The compound of claim 2, having the formula: or a pharmaceutically acceptable salt thereof.

6. During the ceremony, R 2 But, -OCH 3 and; R 4a But F; R 4b But CF 3 and; R 5 but, 【Transformation 5】 and; R 6 is substituted with halogen, -OH, or 0 to 1 OH 1-4 is alkyl; R 7 But 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 is alkyl; R 8 But -C(=O)OR b , -C(=O)NHR a , or -C(=O)NHOR b and; R 9 But, -OR b or -NR a R a and; R 10 But H or C 1-3 is alkyl; R a But H or C 1-6 is alkyl; and R b But H or C 1-6 is alkyl, 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof.

7. During the ceremony, R 2 But, -OCH 3 and; R 4a But F; R 4b But CF 3 and; R 5 but, 【Transformation 6】 and; R 6 But halogen, C 1-4 Alkyl, -OH, or -OC 1-4 is alkyl; R 7 But 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 is alkyl; R 8 But -C(=O)OR b and; R 9 is OH; R 10 But H or C 1-3 is alkyl; and R b But H or C 1-4 is alkyl, 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof.

8. During the ceremony, R 2 But, -OCH 3 and; R 4a But F; R 4b But CF 3 and; R 5 but, 【Transformation 7】 and; R 6 But halogen, CN, C 1-4 Alkyl, =O, -OH, or -OC 1-4 is alkyl; R 7 But 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 Alkyl, -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , or -C(=O)OR b and; R 8 But -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0 to 3 halogens or OH 1-4 is alkyl; R 9 But, -NR a C(=O)R b and; R 10 But H or C 1-3 is alkyl; R a But H or C 1-4 is alkyl; and R b But H or C 1-4 is alkyl, 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof.

9. During the ceremony, R 5 But -S(=O) 2 R c and; R 4a is a halogen; R 4b C substituted with 0 to 4 halogens 1-3 is alkyl; R c However, 0 to 5 R e C replaced with 1-3 is alkyl; R e But, -OR f and R f But H or C 1-3 is alkyl, 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. Formula (VI): 【Transformation 8】 [In the formula, R 2 -OC 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-4 is alkyl; R 5 is 0 to 3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is a halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0 to 3 halogens or OH 1-4 is alkyl; R 9 -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 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is —OH, —C(═O)OH, or aryl; R 12 is H, C 1-3 alkyl, or aryl; 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 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 5 R e forming a 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e substituted with -(CH 2 ) n -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, 0-5 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , or -C(=O)OR f and; R f is H or C 1-3 is alkyl; R g are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

11. Formula (VII): 【Chemistry 9】 [In the formula, R 2 -OC 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-4 is alkyl; R 5 is 0 to 3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is a halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0 to 3 halogens or OH 1-4 is alkyl; R 9 -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 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is —OH, —C(═O)OH, or aryl; R 12 is H, C 1-3 alkyl, or aryl; 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 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 5 R e forming a 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e substituted with -(CH 2 ) n -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, 0-5 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , or -C(=O)OR f and; R f is H or C 1-3 is alkyl; R g are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

12. Formula (VIII): 【Chemistry 10】 [In the formula, R 2 -OC 1-3 is alkyl; R 4a is a halogen; R 4b is C substituted with 0 to 4 halogens 1-4 is alkyl; R 5 is 0 to 3 R 6 and 0 to 2 R 7 C replaced with 6 Aryl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 12-membered heterocyclyl substituted with; R 6 are halogens, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halogens or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 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 , C 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is a halogen, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0 to 3 halogens or OH 1-4 is alkyl; R 9 -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 10 is H, 0 to 2 R 11 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, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is —OH, —C(═O)OH, or aryl; R 12 is H, C 1-3 alkyl, or aryl; 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 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 5 R e forming a 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, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0 to 5 R e substituted with -(CH 2 ) n -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, 0-5 R e C replaced with 2-5 Alkynyl, C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-4 is alkyl; R e is halogen, CN, =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , or -C(=O)OR f and; R f is H or C 1-3 is alkyl; R g are halogens, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; and p is 0, 1, or 2.

2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

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

14. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof for treating a relaxin-related disorder.

15. 15. The pharmaceutical composition of claim 14, wherein the disease is selected from the group consisting of angina, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic cardiac injury.

16. 16. The pharmaceutical composition of claim 15, wherein the disease is heart failure.

17. 15. The pharmaceutical composition of claim 14, wherein the disease is fibrosis.

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