Tetralin, phenylcyclobutane, and phenylcyclopentane analogs 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)). TIFF2024546943000118.tif59153

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 289,812, 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 tetralin, phenylcyclobutane and phenylcyclopentane compounds, and analogs thereof (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 use thereof.

[0019] In a first aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, R 1 is halogen, C substituted with 0 to 5 halogens 1-4 -OC substituted with alkyl, =O, OH, or 0-5 halogens 1-4 is alkyl; R 2 is halogen, CN, C substituted with 0-5 halogens or OH 1-4 Alkyl, -OC substituted with 0 to 5 halogens 1-4 Alkyl, OH, or -OC 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 d a 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 0 to 3 R 6 and 0 to 2 R 7 or aryl substituted with O, S(=O) p , N, and N 10 and 0 to 3 R 6 and 0 to 2 R 7 wherein said heterocyclyl is attached to the phenyl moiety through a carbon or nitrogen atom; 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)Rb , -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 OR b , -S(=O) p NR a R a , -S(O) p Rc , 0 to 3 R e Substituted with -(CH2) n -C 3-6 Carbocyclyl or O, S(=O) p and N; e Substituted with -(CH2) n -heterocyclyl; R 10 is H, 0 to 4 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, 0 to 5 R e or aryl substituted with 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, -C(=O)OC 1-4 is alkyl, or aryl; R 12 , H, C 1-4 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl or R a and R aare combined with the nitrogen atom to which they are both attached, and each is 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) 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, NO2, =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, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) n OR f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)Rf , -S(=O) p R f , -S(=O) p NR f R f , -NR f S(=O) p R f , -NR f C(=O)OR f , -OC(=O)NR f R f , or -(CH2) n NR f R f and; R f , 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 halogen, =O, OH, -OC substituted with 0-5 halogens 1-4 is alkyl; R 2 is a halogen, C 1-3 -OC substituted with alkyl or 0-4 halogens 1-3 is alkyl; R 4a is a halogen; R 4bis 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 or C6 aryl substituted with 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 dand 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 3-6 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and each is 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) 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, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) 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, or C 3-6 is cycloalkyl; 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 OH or =O; 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 -OC1-4 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 , 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 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 Rc , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , or -S(O) p R c and; R a is H, 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached to 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 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 Re 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, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) 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, or C 3-6 is cycloalkyl; 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 OH or =O; R 2 -OC 1-3 is alkyl; R4a is F; R 4b is CF3; R 6 is F; 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 0-3 halogens or OH 1-4 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 -(CH2) n -C 3-6 Cycloalkyl or 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 fourth aspect, the present invention provides a compound of formula (V): [ka] [In the formula, R 8 is -C(=O)OH or CF3; R 9 is -NHC(=O)R b or -OC(=O)NHR a and; R a -C 3-6 is cycloalkyl or phenyl; and R b is heterocyclyl] or a pharma- ceutically acceptable salt thereof.

[0024] In a sixth aspect of the first and second aspects, the present invention provides a compound of formula (VI): [ka] [In the formula, R 1 is =O; 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 9C 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 4-6 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 NRa 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 1-3 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , C 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 1-4 alkyl, or phenyl; 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached to form 0 to 4 R e forming a heterocyclyl substituted with; R b is H, 0 to 4 R e C replaced with1-5 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) 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, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) 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, or C 3-6 is cycloalkyl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0025] In a seventh aspect of the sixth aspect, the present invention provides a compound comprising: R 2 is -OCH3; R 4a But F; R 4b is CF3; R 5 but, [ka] and; R 6 is substituted with halogen, -OH, or 0-1 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, -C(=O)R b , or 0 to 1 R 11 C replaced with 1-4 is alkyl; R 11 is -OH, -C(=O)OH, or aryl; R a But H or C 1-3 is alkyl; and R b But H or C 1-3 is alkyl, There is provided a compound of formula (VI) or a pharma- ceutically acceptable salt thereof:

[0026] In an eighth aspect of the sixth aspect, the present invention provides a compound comprising: R 2 is -OCH3; R 4a But F; R 4b is CF3; R 5 but, [ka] 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 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 But H or C 1-4 is alkyl, There is provided a compound of formula (VI) or a pharma- ceutically acceptable salt thereof:

[0027] In a ninth aspect of the sixth aspect, the present invention provides a compound comprising: R 2 is -OCH3; R 4a But F; R 4bis CF3; R 5 but, [ka] 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 0-3 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, There is provided a compound of formula (VI) or a pharma- ceutically acceptable salt thereof:

[0028] In a tenth aspect of the first aspect, the present invention provides a compound of formula (VII): [ka] [In the formula, R 2 is -OC substituted with 0 to 4 halogens 1-4 Alkyl, OH, or -OC 1-4 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 or C6 aryl substituted with 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 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and each is 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl; R c is 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5Alkenyl, 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, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) 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, or C 3-6 is cycloalkyl; 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 (VIII): [ka] [In the formula, R 1 is =O or -OH; R 2 is -OC substituted with 0 to 4 halogens 1-4 Alkyl, OH, or -OC 1-4 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 or C6 aryl substituted with 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 3-6Cycloalkyl 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 3-6 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and each is 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) 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, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) 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, or C 3-6 is cycloalkyl; 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 (IX): [ka] [In the formula, R 1 is =O or -OH; R 2 is -OC substituted with 0 to 4 halogens 1-4 Alkyl, OH, or -OC 1-4 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 or C6 aryl substituted with 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 eis 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl or R a and R a are combined with the nitrogen atom to which they are both attached, and each is 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 -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) 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 eis 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, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) 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, or C 3-6 is cycloalkyl; n is 0, 1, 2, or 3; and p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0031] For compounds of formula (I), 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 Any variable substituent range, such as, can be used independently of any other variable substituent range. Thus, the invention includes combinations of different embodiments.

[0032] In certain embodiments of Formula (II), [ka] teeth, The file is TIFF2024546943000015.tif1726.

[0033] In another embodiment of Formula (II), [ka] teeth, [ka] It is.

[0034] In another embodiment of Formula (II), [ka] teeth, [ka] It is.

[0035] In another embodiment of Formula (II), R 4a is F.

[0036] In another embodiment of Formula (II), R 4b is CF3.

[0037] In another embodiment of Formula (III), [ka] teeth, TIFF2024546943000021.tif1726; R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5 teeth, [ka] and; R 6 is F; R 8 -C(=O)OH, -C(=O)NHR a or CF3; R 9 -NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl or -OC(=O)NHR a and; R a , H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl or 0 to 2 R e Substituted with -(CH2) 0-1 -phenyl; R b is H or heterocyclyl; R e is C 1-3 Alkyl or -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0038] In another embodiment of Formula (III), [ka] teeth, [ka] and; R 2 is -OCH3; R 4a is F; R 4b is CF3; R5 teeth, [ka] and; R 6 is F; R 8 -C(=O)OH, -C(=O)NHR a or CF3; R 9 -NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl or -OC(=O)NHR a and; R a , H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl or 0 to 2 R e Substituted with -(CH2) 0-1 -phenyl; R b is H or heterocyclyl; R e is C 1-3 Alkyl or -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0039] In another embodiment of Formula (III), [ka] teeth, [ka] and; R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5teeth, [ka] and; R 6 is F; R 8 -C(=O)OH, -C(=O)NHR a or CF3; R 9 -NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl or -OC(=O)NHR a and; R a , H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl or 0 to 2 R e Substituted with -(CH2) 0-1 -phenyl; R b is H or heterocyclyl; R e is C 1-3 Alkyl or -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0040] In another embodiment of Formula (III), [ka] teeth, [ka] and; R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5 teeth, [ka] and; R 7 is 0 to 1 R 9 C replaced with 1-4 is alkyl; R 9 is -OH; R 10 is -C(=O)R b and; R b is H or 0 to 4 R e C replaced with 1-3 is alkyl; R e is -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0041] In another embodiment of Formula (III), [ka] teeth, [ka] and; R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5 teeth, [ka] and; R 7 is 0 to 1 R 9 C replaced with 1-4 is alkyl; R 9 is -OH; R 10 is -C(=O)Rb and; R b is H or 0 to 4 R e C replaced with 1-3 is alkyl; R e is -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0042] In another embodiment of Formula (III), [ka] teeth, [ka] and; R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5 teeth, [ka] and; R 7 is 0 to 1 R 9 C replaced with 1-4 is alkyl; R 9 is -OH; R 10 is -C(=O)R b and; R b is H or 0 to 4 R e C replaced with 1-3 is alkyl; R e is -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0043] Unless otherwise specified, each term has the following meaning:

[0044] "Halogen" includes fluoro, chloro, bromo, and iodo.

[0045] "Alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C 10 Alkyl" or "C 1-10 "Alkyl" (or alkylene) is any of the following alkyl groups: C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 Further, for example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group can be unsubstituted or substituted, with at least one hydrogen being 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). When "C0 alkyl" or "C0 alkylene" is written, it is intended to represent a direct bond. "Alkyl" also includes deuterated alkyls (e.g., CD3).

[0046] "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) is intended to include C2, C3, C4, C5, and C6 alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, and hexenyl).

[0047] "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 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, and hexynyl).

[0048] "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.

[0049] "Cycloalkyl" is intended to mean a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems. 3-7 "Cycloalkyl" is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Examples of single-ring cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of multicyclic cycloalkyls include, but are not limited to, 1-decalinyl, norbornyl, and adamantyl.

[0050] "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.

[0051] "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.

[0052] 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).

[0053] "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.

[0054] "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)). p where p is 0, 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other 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.

[0055] 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.

[0056] 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).

[0057] 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.

[0058] 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.

[0059] "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.

[0060] 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).

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] The present invention encompasses all tautomers, atropisomers and rotamers of the compounds.

[0067] 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.

[0068] 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)).

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] The examples disclosed below were tested in the human RXFP1 (hRXFP1) HEK293 cAMP assay described above and found to have agonistic activity. Tables 1-3 show the EC50 values ​​in the hRXFP1 HEK293 cAMP assay measured in the examples. 50 List the values.

[0075] Table 1. EC values ​​in the hRXFP1 HEK293 cAMP assay measured using phenylcyclohexyl examples. 50 value [ka] [Table 1] [Table 2]

[0076] Table 2. EC in hRXFP1 HEK293 cAMP assay measured with phenylcyclobutane examples 50 value [ka] [Table 3]

[0077] Table 3. EC values ​​in the hRXFP1 HEK293 cAMP assay measured using phenylcyclopentyl examples. 50 value [ka] [Table 4]

[0078] 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).

[0079] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier.

[0080] 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.

[0081] 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).

[0082] 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).

[0083] 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).

[0084] 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).

[0085] 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).

[0086] 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).

[0087] 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).

[0088] Unless otherwise stated, the following terms have the meanings indicated.

[0089] 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).

[0090] "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.

[0091] "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.

[0092] "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.

[0093] "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.

[0094] "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).

[0095] "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).

[0096] Relaxin-related diseases include, but are not limited to, cardiovascular disease and fibrosis.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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).

[0106] 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 β6 antibody, 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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).

[0114] 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.

[0115] 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.

[0116] The cyclobutane intermediates found in the present invention can be synthesized from readily available bicyclo[4.2.0]octa-1(6),2,4-triene-3-carboxylic acid. Nitration with KNO3 / cold sulfuric acid gives the nitro intermediate II, which is coupled with an amine of the present invention to give the amide intermediate I-II. Reduction of the nitro group followed by standard peptide coupling with an acid derivative of the present invention or alternative methods known to those skilled in the art gives the compounds of the present invention. [ka]

[0117] Scheme-II Alternatively, bicyclo[4.2.0]octa-1(6),2,4-triene-3-carboxylic acid can be brominated with NBS or oxidized with SeO2 to give either bromo or keto intermediates, which can be appropriately functionalized to give the substituted phenylcyclobutane intermediates of the invention. [ka] The halogen and keto intermediates can be converted to other substituted compounds of the invention. The acid moiety and the nitro group may be coupled with an amine, reduced and recoupled with an acid, respectively, to give compounds of the invention.

[0118] Scheme-III Alternatively, phenylcyclobutane can be nitrated (J. Org. Chem., Vol. 44, No. 18, 1979) and brominated with NBS to give bromo-aminophenylcyclobutane intermediate IX, which can be subjected to palladium-catalyzed carbonylation to give the desired cyclobutylbenzoate derivatives I-XI, which can then be converted to the compounds of the present invention as shown in Scheme-I. [ka]

[0119] A similar procedure may be used to synthesize phenylcyclohexyl derivatives from readily available 5,6,7,8-tetrahydronaphthalene-2-carboxylic acid as shown in Scheme-IV. [ka]

[0120] Scheme-V Alternatively, the substituted phenylcyclohexyl compounds can be obtained from commercially available 6-bromo-3,4-dihydronaphthalen-1(2H)-one. Nitration followed by palladium catalyzed carbonylation gives the desired nitro-ester derivatives, which can be further functionalized to give the compounds of the invention as outlined in Scheme-1.

[0121] [ka] The carbonyl group is reduced with NaBH4 and then alkylated or displaced with other nucleophiles via Mitsunobu reaction or tosylation compounds, or directly reduced to the methylene compounds of the invention. Alternatively, protection of the amide group and anilines allows the ketone to be alkylated with LDA and a suitable electrophile to give further compounds of the invention. The ketone intermediate is treated with Grignard and zinc reagents to give further examples of the invention.

[0122] As shown in general scheme VI, the phenylcyclopentyl analogs are also synthesized from commercially available 2,3-dihydro-1H-indene-5-carboxylic acid. The reaction sequence outlined in scheme I allows the straightforward synthesis of the phenylcyclopentyl intermediates of the present invention. [ka]

[0123] As shown in Scheme VII, a substituted benzoic acid or heterocyclic acid intermediate of the invention is synthesized. In either case, the aryl group is replaced with a heteroaryl group, and a similar reaction sequence provides the corresponding heteroaryl compound of the invention. [ka]

[0124] As shown in Scheme-VIII, commercially available aryl or heteroaryl carboxaldehydes can be used to obtain the isoxazoline intermediates of the present invention. Conversion of the aldehyde to an oxime followed by treatment with NCS can provide the desired phenyl or heteroaryl chlorooximes. The chlorooxime derivatives of the present invention can be treated with the appropriate olefin to obtain the isoxazoline intermediates shown in Scheme-VIII. [ka]

[0125] Conversely, the chlorooximes of the present invention can be treated with acetylene or bromoolefin intermediates to give the isoxazole derivatives of the present invention. Similar reactions can be carried out with heteroaryl carboxaldehydes to give the appropriate heteroaryl isoxazoline or isoxazole intermediates of the present invention. The enantiomeric mixtures are separated by chiral SFC. Other intermediates of the present invention are described below.

[0126] Chemical Methods and Abbreviations 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 5]

[0127] In the examples, the following methods were used unless otherwise noted. Purification of intermediates and final products was accomplished by either normal phase or reverse phase chromatography using pre-packed SiO2 cartridges eluted with either a hexanes and ethyl acetate gradient or a DCM and MeOH gradient unless otherwise noted. Reverse phase preparative HPLC was performed using a C18 column with detection at UV 220 nm or preparative LCMS with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA) or a gradient of solvent A (95% water, 5% ACN, 0.1% TFA) and solvent B (5% water, 95% ACN, 0.1% TFA) or a gradient of solvent A (95% water, 2% ACN, 0.1% HCOOH) and solvent B (98% ACN, 2% water, 0.1% HCOOH) or a gradient of solvent A (95% water, 5% ACN, 10 mM NH4OAc) and solvent B (98% ACN, 2% water, 10 mM The LC / MS methods used for the analysis of the examples are listed below.

[0128] 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

[0129] 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

[0130] 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

[0131] 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

[0132] 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 occur at 2.51 ppm (DMSO-d6), 3.30 ppm (CD3OD), 1.94 ppm (CD3CN), and 7.24 ppm (CDCl3). 1 The solvent peak in the 1 H NMR spectrum is used as the reference.

[0133] Preparation of intermediates Intermediate 1-1: 5'-(tert-butoxycarbonyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] To a vial was added 5-(dihydroxyboryl)-2-methoxybenzoic acid (0.50 g, 2.6 mmol), tert-butyl 3-bromo-4-fluorobenzoate (0.84 g, 3.1 mmol), K2CO3 (1.76 g, 12.8 mmol), PdCl2(dppf)·CH2Cl2 (0.31 g, 0.38 mmol), and THF (22 mL). 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 (3x25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, 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; (M+H) + =347.1; [Method A]

[0134] 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]

[0135] 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 (500MHz, CDCl3) δ 7.49(dd, J=6.6, 2.2Hz, 1H), 7.20(ddd, J=8.3, 4.6, 2.2Hz, 1H), 7.13-7.03(m, 1H), 3.49(s, 2H), 1.46(s, 9H)

[0136] Intermediate 2-3: To a reaction vial (20 mL) containing intermediate 2-2 (0.27 g, 0.92 mmol), NBS (0.20 g, 1.1 mmol), CCl4 (10 mL), and AIBN (15 mg, 0.090 mmol) were added and the solution was stirred at 77° C. for 3 h. 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 (500MHz, CDCl3) 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)

[0137] 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 (500MHz, CDCl3) δ 7.70(dd, J=6.6, 2.2Hz, 1H), 7.41(ddd, J=8.4, 4.7, 2.1Hz, 1H), 7.15(t, J=8.4Hz, 1H), 5.77(s, 1H), 2.22(s, 3H), 1.43(s, 9H)

[0138] 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. After reverse phase HPLC (conditions: column: Phenomenex Luna C18 5μ 30x100mm, gradient: 10min; solvent A: 10%ACN / 90%H2O / 0.1%TFA; solvent B: 90%ACN / 10%H2O / 0.1%TFA), half of the material was isolated as intermediate 2-7 (85mg, 0.60mmol, 34% yield). 1H NMR(500MHz, CDCl3) 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(500MHz, CDCl3) 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%CO2; Elution conditions: 45mL / min, 120Bar, 40℃; Detection wavelength: 220nm; Injection conditions: 8 injections of 0.36mL (IPA solution, ~20mg / mL) Analytical chromatographic conditions: Instrument: Waters UPC2 (analytical SFC); Column: Chiralpak ID 4.6x100mm, 3μ; Mobile phase: 25%IPA / 75%CO2; 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

[0139] 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]

[0140] 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]

[0141] 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 combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by preparative reverse-phase HPLC. 1H NMR(500MHz, CDCl3) 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%CO2; 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

[0142] 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]

[0143] Intermediate 4-2: 3-Bromo-4-fluorobenzaldehyde (4-1, 235 mg, 1.15 mmol), DMF (3.5 mL), (trifluoromethyl)trimethylsilane (0.34 mL, 2.3 mmol), and K2CO3 (8 mg, 0.06 mmol) were added to a reaction vessel 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 NH4Cl. The aqueous layer was extracted with EtOAc (2x10 mL) and the combined organic layers were dried over Na2SO4, 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(500MHz, CDCl3) 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)

[0144] Intermediate 4-3: To a reaction vessel containing 4-2 (100 mg, 0.37 mmol) was added 5-(dihydroxyboryl)-2-methoxybenzoic acid (93 mg, 0.48 mmol), PdCl2(dppf)·CH2Cl2 (50 mg, 0.06 mmol), Na2CO3 (155 mg, 1.46 mmol), and H2O (1 mL). The mixture was degassed by bubbling N2 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, dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC to give 4-3 (51 mg, 0.15 mmol, 40% yield). 1H NMR(500MHz, CDCl3) δ 8.39(d, J=1.9Hz, 1H), 7.83(dt, J=8.7, 2.1Hz, 1H), 7.59(dd, J=7.3, 2.1Hz, 1H), 7.53-7.45(m, 1H), 7.23(dd, MS(ESI):m / z=345.1(M+H) +

[0145] Intermediate 4-4: Intermediate 4-3 was separated into independent enantiomers using chiral SFC (preparative chromatography conditions: Instrument: Berger MG II; Column: Kromasil 5-CelluCoat, 21x250mm, 5μ; Mobile phase: 15%IPA-ACN(0.1%DEA) / 85%CO2; Elution conditions: 45mL / min, 120Bar, 40℃; Detection wavelength: 220nm; Injection conditions: 0.4mL (ACN / IPA(1:1) solution ~15mg / 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%CO2; 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

[0146] 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]

[0147] 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 in vacuo to give a white solid. The solid was dissolved in water (200 mL) and the aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a white solid (27.1 g, 100% yield). The solid was redissolved in DMF (200 mL) and to this solution was added NCS (17.2 g, 128 mmol) and stirred at room temperature for 14 h overnight. The reaction was quenched by the addition of excess water, which precipitated a white solid. 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 (500MHz, CDCl3) 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)

[0148] 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 NCS (424 mg, 3.18 mmol) was added to the solution and the mixture was stirred at room temperature for 4 h. Water (100 mL) was added to quench the reaction and the solution was extracted with EtOAc (2x25 mL), dried (MgSO4) and concentrated in vacuo 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 in vacuo to give the diastereomeric mixture of intermediate 5-2. 1H NMR(600MHz, CDCl3) δ 8.04(d, J=2.3Hz, 1H), 7.85(dd, J=8.8, 2.3Hz, 1H), 7.03(d, J=8.8Hz, 1H), 5.30(ddd, J=9.4, 6.2, 2.9Hz, 1H), 4.50(quin, J=5.9Hz, 1H), 4.19(td, J=9.3, 4.7Hz, 1H), 3.92(s, 3H), 2.33-2.27(m, 1H), 2.18-2.06(m, 3H); LC-MS RT=0.83min; MS(ESI)m / z=278.1(M+H) + ; [Method A] The chiral intermediates of 5-2 were separated 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 CO2 / MeOH for 12min, then 45% MeOH, detection wavelength: 235nm, injection volume: 1000μL) to give 5-3 (chiral peak-1:>99%ee, analytical RT=8.80min), 5-4 (chiral peak-2:>95%ee, analytical RT=9.86min), 5-5 (chiral peak-3:>99%ee, analytical RT=13.53min), and 5-6 (chiral peak-4:>99%ee, analytical RT=16.67min). Analytical chromatographic conditions: Instrument: Agilent SFC (LVL-L4021 Lab), Column: IC 250x4.6mm ID, 5μm, Temperature: Ambient, Flow rate: 2.0mL / min, Mobile phase: Gradient 75 / 25 CO2 / MeOH for 12 min, then 45% MeOH Analytical data for peaks 1-4: 1H NMR(600MHz, CD3OD) 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)

[0149] Intermediate 6-2: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]-isoxazol-3-yl)-2-methoxybenzoic acid [ka] [ka]

[0150] 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]

[0151] Diastereomeric intermediate 6-2: Intermediate 6-1 (88 mg, 0.29 mmol) was dissolved in THF (1 mL) / MeOH (1 mL) and treated with lithium hydroxide monohydrate (36 mg, 0.86 mmol) / HO (1 mL) at room temperature. After 3 h, the reaction mixture was diluted with HO (5 mL) and the pH of the aqueous layer was adjusted to pH 7 with 1M HCl solution, extracted with EtOAc (2x25 mL), washed with brine, dried (NaSO), 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]

[0152] Homochiral intermediates 6-3 to 6-10 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%CO2; 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%CO2; Elution conditions: 2.0mL / min, 150Bar, 40℃; Detection wavelength: 220nm; Injection conditions: 5μL (MeOH solution, ~1mg / mL)

[0153] The homochiral methyl benzoate intermediate 6-3 (Peak-1, RT = 4.07 min; >99% ee) was obtained as a film (150 mg, 29% yield). 1H NMR(600MHz, CDCl3) δ 8.04(d, J=2.3Hz, 1H), 7.87(dd, J=8.7, 2.3Hz, 1H), 7.01(d, J=8.8Hz, 1H), 5.23(dd, J=8.8, 5.1Hz, 1H), 4.10(t, J=8.7Hz, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.72-3.66(m, 1H), 3.61(dt, J=10.5, 5.2Hz, 1H), 2.30-2.16(m, 2H), 2.05(dd, J=13.0, 6.1Hz, 1H), 1.76(ddd, J=12.9, 11.5, 9.4Hz, 1H), 1.68-1.62(m, 1H), 1.39(br t, J=4.8Hz, 1H)

[0154] Preparation of homochiral benzoic acid intermediate 6-4 (peak-1): 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 by a similar procedure to intermediate 6-2 with further hydrolysis of homochiral intermediate 6-3 (peak-1). LC-MS: RT=0.85 min; MS(ESI) m / z=292.3 (M+H). + ; [Method A]

[0155] The homochiral methyl benzoate intermediate 6-5 (peak-2, RT = 4.55 min; >99% ee) was obtained as a film (33.2 mg, 6.3% yield). 1H NMR(600MHz, CDCl3) 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)

[0156] Preparation of homochiral benzoic acid intermediate 6-6 (peak-2): 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 by a similar procedure to intermediate 6-2 with further hydrolysis of intermediate 6-5 (peak-2). LC-MS: RT=0.83 min; MS(ESI)m / z=292.3(M+H). + ; [Method A]

[0157] The homochiral methyl benzoate intermediate 6-7 (peak-3, RT = 5.66 min; >99% ee) was obtained as a film (161 mg, 30.6% yield). 1H NMR:(600MHz, CDCl3) 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)

[0158] Preparation of homochiral benzoic acid intermediate 6-8 (peak-3): 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 by a similar procedure to intermediate 6-2 with further hydrolysis of intermediate 6-7 (peak-3). LC-MS: RT=0.83 min; MS(ESI)m / z=292.3(M+H). + ; [Method A]

[0159] The homochiral methyl benzoate intermediate 6-9 (peak-4, RT = 9.81 min; >99% ee) was obtained as a film (47 mg, 9.0% yield). 1H NMR:(600MHz, CDCl3) 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)

[0160] Preparation of homochiral benzoic acid intermediate 6-10 (peak-4): 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 by a similar procedure to intermediate 6-2 with further hydrolysis of intermediate 6-9 (peak-4). LC-MS: RT=0.84 min; MS(ESI)m / z=292.3(M+H). + ; [Method A]

[0161] Intermediate 7-6: 3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-naphthalene-2-carboxamide The title compound was prepared according to the methods described in the following scheme. [ka] [ka] Intermediates 7-2 and 7-3: A solution of 5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (2.0 g, 11 mmol) in H2SO4 (20 mL) was treated dropwise with KNO3 (1.38 g, 13.6 mmol) in H2SO4 (10 mL) at 0 °C. After 12 h, the reaction mixture was quenched with ice and extracted with DCM (2x25 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and used in the next reaction without further purification as a mixture of regioisomers. LC-MS: RT=0.99 min; MS(ESI)m / z=221.9(M+H). + ; [Method A]

[0162] Intermediates 7-4 and 7-5: POCl3 (1.05 mL, 11.3 mmol) in DCM (10 mL) was added via syringe to a solution of 7-2 and 7-3 (2.5 g, 11 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (2.02 g, 22.6 mmol), and pyridine (7.3 mL, 90 mmol) in DCM (75 mL) at 0 °C. After 4 h, the reaction mixture was quenched with 1.0 M HCl, and the organic layer was separated, washed with 1.0 M HCl, water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by normal phase chromatography (elution: hexane / EtOAc) afforded a mixture of two regioisomers, 7-4 and 7-5 (2.88 g, 7.51 mmol, 66% yield) as an off-white solid. LC-MS: RT=1.13 min; MS(ESI)m / z=382.9(M+H) + ; [Method A]

[0163] Intermediates 7-6 and 7-7: Pd-C (wet, Degussa type, 10%, 160 mg, 1.50 mmol) was added to a solution of 7-4 and 7-5 (2.88 g, 7.52 mmol) in EtOH (75.2 mL) and placed under hydrogen atmosphere (55 psi). After 3 h, the catalyst was filtered through Celite and the filtrate was concentrated under reduced pressure. The two regioisomers were purified by SFC (Instrument: Column: Chiralpak AD-H, 21x250 mm, 5μ; Mobile phase (25% MeOH / 75% CO2); Elution conditions (45 mL / min, 150 Bar, 40 °C); Detection wavelength (220 nm); Injection conditions: ~80 mg / mL in MeOH (0.5 mL)).

[0164] Intermediate 7-6 (peak 2, RT=5.68 min): 3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (580 mg, 22% yield) 1 H NMR (500MHz, DMSO-d6) δ 10.19(s, 1H), 8.18(dd, J=6.6, 2.4Hz, 1H), 8.01(dt, J=8.0, 3.9Hz, 1H), 7.48(t, J=9.8Hz, 1H), 7.36(s, 1H), 6.46(s, 1H), 6.07(s, 2H), 2.68-2.58(m, 4H), 1.77-1.64(m, 4H) Intermediate 7-7 (Peak 1, RT=4.27 min): 1-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (725 mg, 27% yield) 1H NMR (500MHz, DMSO-d6) δ 10.18(s, 1H), 8.19(dd, J=6.6, 2.7Hz, 1H), 8.03(ddd, J=8.9, 4.3, 2.9Hz, 1H), 7.51- 7.45(m, 2H), 6.39(d, J=8.3Hz, 1H), 6.29(s, 2H), 2.67(t, J=6.1Hz, 2H), 2.38(t, J=6.4Hz, 2H), 1.84-1.74(m, 2H), 1.72-1.63(m, 2H)

[0165] Intermediate 8-5: Preparation of 3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxamide The title compound was prepared according to the methods described in the following scheme. [ka] [ka] Intermediate 8-2: 6-Bromo-3,4-dihydronaphthalen-1(2H)-one (Intermediate 8-1, 0.5 g, 2 mmol) was dissolved in H2SO4 (5 mL) at 0 °C. After stirring for 5 min, KNO3 (0.23 g, 2.2 mmol) / H2SO4 (1 mL) was added dropwise while maintaining the temperature of the mixture below 15 °C, and then gradually warmed to room temperature. After 12 h, the reaction mixture was quenched with ice, neutralized with saturated sodium bicarbonate solution, and extracted with DCM (2x25 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by normal phase chromatography (elution: hexane / EtOAc) to give the major product 6-bromo-7-nitro-3,4-dihydronaphthalen-1(2H)-one (Intermediate 8-2, 1 70% by H NMR) and the regioisomeric by-product 6-bromo-5-nitro-3,4-dihydronaphthalen-1(2H)-one (intermediate 8-3, 1 A mixture of 30% by H NMR was obtained (540 mg, 90% yield). Intermediate 8-2 (major product): 1H NMR (600MHz, DMSO-d6) δ: 8.32(s, 1H), 8.02(s, 1H), 3.02(t, J=6.2Hz, 2H), 2.70-2.64(m, 4H), 2.13-2.04(m, 4H); Intermediate 8-3 (by-product): 1 H NMR (600MHz, DMSO-d6) δ: 7.97(d, J=8.4Hz, 1H), 7.90(d, J=8.5Hz, 1H), 2.85(t, J=6.1Hz, 2H), 2.70-2.64(m, 4H), 2.13-2.04(m, 4H)

[0166] Intermediate 8-4: A solution of 6-bromo-7-nitro-3,4-dihydronaphthalen-1(2H)-one (Intermediate 8-2, 500 mg, 1.85 mmol) in TEA (3.88 mL, 27.8 mmol), MeOH (0.90 mL, 22 mmol), and DMF (2 mL) was degassed with nitrogen and Pd(OAc)2 (10.39 mg, 0.05000 mmol) and Xantphos (53.6 mg, 0.0900 mmol) were added. The solution was degassed and CO gas was bubbled through the solution. The reaction vessel was equipped with a reflux condenser and a balloon of CO and then heated to 70 °C. After 12 h, the reaction was quenched by the addition of water and extracted with EtOAc (2x25 mL). Here, the nitro group has been reduced to aniline during carbonylation. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by normal phase chromatography (elution: hexanes / EtOAc) to give methyl 3-amino-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (8-4, 150 mg, 37% yield). 1 H NMR (500MHz, chloroform-d) δ 7.78(s, 1H), 7.32(s, 1H), 5.64(br s, 2H), 3.91(s, 3H), 2.86(t, J=6.0Hz, 2H), 2.66-2.63(m, 2H), 2.13-2.08(m, 2H); LC-MS: RT= 0.81 min; MS(ESI)m / z=220.0(M+H) + ; [Method A]

[0167] Intermediate 8-5: Me3Al (0.479 mL, 0.960 mmol) was added to 4-fluoro-3-(trifluoromethyl)aniline (0.172 g, 0.958 mmol) in toluene (2 mL) at 0° C. After 15 min, the Me3Al mixture was transferred to methyl 3-amino-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Intermediate 8-4) (0.070 g, 0.319 mmol) in toluene (3 mL) and heated to 120° C. in a microwave for 30 min. The reaction was quenched by the addition of 1.0 M HCl and extracted with EtOAc (2×25 ml). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal phase chromatography (elution: hexane / EtOAc) to give Intermediate 8-5 (41 mg, 37% yield). LC-MS: RT=0.96 min; MS(ESI) m / z=367.0(M+H) + ; [Method A]

[0168] Intermediate 9-4: 4-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[4.2.0]octa-1,3,5-triene-3-carboxamide The title compound was prepared according to the methods described in the following scheme. [ka] [ka]

[0169] Intermediate 9-2: A solution of bicyclo[4.2.0]octa-1(6),2,4-triene-3-carboxylic acid (9-1, 500 mg, 3.37 mmol) in H2SO4 (3.0 mL, 56 mmol) was treated with KNO3 (409 mg, 4.05 mmol) in H2SO4 (3.0 mL, 56 mmol) at 0 °C. After 3 h, the reaction was quenched with ice and extracted with DCM (2x25 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 9-2 (216 mg, 33% yield), which was used in the next reaction without further purification. After the next reaction step, the regioselectivity of the nitration was confirmed. LC-MS: RT=0.67 min; MS(ESI) m / z=194.1(M+H) + ; [Method A]

[0170] Intermediate 9-3: POCl3 (167 mg, 1.09 mmol) in DCM (1 mL) was added to a solution of 4-nitrobicyclo[4.2.0]octa-1(6),2,4-triene-3-carboxylic acid (Intermediate 9-2, 210 mg, 1.09 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (195 mg, 1.09 mmol) in pyridine (1 mL) in DCM (5 mL) at 0 °C. The reaction mixture was stirred cold for 1 h, then quenched with 1M HCl and extracted with EtOAc (2x50 mL). The organic layer was dried (MgSO4) and filtered. The resulting residue was partitioned between EtOAc and water, and the organic layer was washed with 1M HCl, water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by normal phase chromatography (elution: hexane / EtOAc) to give N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-nitrobicyclo[4.2.0]octa-1(6),2,4-triene-3-carboxamide (9-3, 75 mg, 20% yield). 1H NMR (600MHz, DMSO-d6) δ 10.95(s, 1H), 8.15(dd, J=6.4, 2.6Hz, 1H), 7.90(dt, J=8.4, 3.7Hz, 1H), 7.87(s, 1H), 7.53(t, J=9.5Hz, 1H), 7.52(s, 1H), 3.29(s, 4H); LC-MS: RT= 0.98 min; MS(ESI)m / z=354.9(M+H) + ; [Method A]

[0171] Intermediate 9-4: N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-nitrobicyclo[4.2.0]octa-1(6),2,4-triene-3-carboxamide (9-3, 70 mg, 0.20 mmol) was dissolved in MeOH (5 mL) followed by hydrogenation at 55 psi with the addition of Pd / C (10%, 0.1 g). After 2 h, the reaction mixture was filtered through Celite® and concentrated under reduced pressure to give 4-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[4.2.0]octa-1(6),2,4-triene-3-carboxamide (9-4, 53 mg, 82% yield) as a brown oil. Intermediate 9-4 was used without further purification. LC-MS: RT=0.91 min; MS(ESI)m / z=324.9(M+H) + ; [Method A]

[0172] Intermediate 10-4: 6-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamide It was prepared according to the method described in the following scheme. [ka] [ka]

[0173] Intermediate 10-2: A solution of 2,3-dihydro-1H-indene-5-carboxylic acid (10-1, 500 mg, 3.08 mmol) in H2SO4 (3.0 mL, 56 mmol) was cooled at 0 °C and treated with KNO3 (374 mg, 3.70 mmol) in H2SO4 (3.0 mL, 56 mmol). After 12 h, the reaction was quenched with ice and extracted with DCM. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 10-2 (552 mg, 86% yield). The resulting material was used in the next reaction without further purification. LC-MS RT = 0.93 min; MS (ESI) m / z = 207.9 (M + H). + ; [Method A]

[0174] Intermediate 10-3: POCl3 (0.25 mL, 2.66 mmol) in DCM (1 mL) was added to a solution of 6-nitro-2,3-dihydro-1H-indene-5-carboxylic acid (Intermediate 10-2, 552 mg, 2.66 mmol), 4-fluoro-3-(trifluoromethyl)aniline (477 mg, 2.66 mmol), and pyridine (1.7 mL, 21 mmol) in DCM (17.8 mL) at 0° C. After 1 h, the reaction was quenched with 1.0 M HCl and extracted with EtOAc (2×50 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by normal phase chromatography (elution: hexanes / EtOAc) to give N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-nitro-2,3-dihydro-1H-indene-5-carboxamide (10-3, 182 mg, 0.490 mmol, 19% yield). 1 H NMR: (400MHz, DMSO-d6) δ 10.93(s, 1H), 8.15(dd, J=6.5, 2.5Hz, 1H), 8.01(s, 1H), 7.93-7.88(m, 1H), 7.63(s, 1H), 7.56-7.50(m, 1H), 3.03-2.97(m, 4H), 2.16-2.09(m, 2H); LC-MS: RT=1.09min; MS(ESI)m / z=368.9(M+H) + ; [Method A]

[0175] Intermediate 10-4: Pd-C (9.82 mg, 0.0920 mmol) was added to a solution of N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-nitro-2,3-dihydro-1H-indene-5-carboxamide (Intermediate 10-3, 170 mg, 0.462 mmol) in EtOH (5 mL) and hydrogenated at 55 psi. After 3 h, the catalyst was filtered through Celite® and the filtrate was concentrated under reduced pressure to give 6-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamide (Intermediate 10-4, 136 mg, 87.0% yield). The product was pure enough to be used in the next reaction. LC-MS: RT = 1.06 min; MS (ESI) m / z = 338.9 (M+H). + ; [Method A]

[0176] Intermediate 11-3: 6-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxo-2,3-dihydro-1H-indene-5-carboxamide It was prepared according to the method described in the following scheme. [ka] [ka]

[0177] Intermediate 11-2: In a sealed vial, 6-amino-5-bromo-2,3-dihydro-1H-inden-1-one (Intermediate 11-1, 0.87 g, 3.9 mmol), TEA (0.54 mL, 3.9 mmol), PdOAc2 (0.17 g, 0.77 mmol), dppf (0.64 g, 1.2 mmol) were dissolved in a solution of DMSO (12.3 mL) and MeOH (8.2 mL), placed under a CO atmosphere (70 psi), sealed, and heated at 80° C. for 14 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2x20 mL), washed with brine (25 mL), dried (MgSO4) and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give methyl 6-amino-1-oxo-2,3-dihydro-1H-indene-5-carboxylate (Intermediate 11-2, 284 mg, 1.38 mmol, 36.0% yield) as a pale yellow solid. LC-MS: RT=0.74 min; MS(ESI)m / z=206.08(M+H). + ; [Method A]

[0178] Intermediate 11-3: Trimethylaluminum (0.73 mL, 1.5 mmol) was added to 4-fluoro-3-(trifluoromethyl)aniline (262 mg, 1.46 mmol) in toluene (4 mL) cooled to 0° C. After 10 min, methyl 6-amino-1-oxo-2,3-dihydro-1H-indene-5-carboxylate (Intermediate 11-2, 100 mg, 0.49 mmol) in toluene (2 mL) was added and the resulting mixture was heated at 120° C. for 30 min under microwave irradiation. The reaction mixture was quenched with 1M HCl, extracted with EtOAc (2x25 mL), dried over sodium sulfate, concentrated in vacuo, purified by normal phase chromatography (eluent: hexanes / ethyl acetate) and concentrated in vacuo to give 6-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxo-2,3-dihydro-1H-indene-5-carboxamide (Intermediate 11-3, 44 mg, 0.13 mmol, 26% yield) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ 8.04-8.01(m, 1H), 7.89-7.82(m, 2H), 7.55-7.52(m, 1H), 7.20-7.17(m, 1H), 7.12-7.08(m, 1H), 5.38(br s, 2H), 3.07-3.01(m, 2H), 2.72-2.68(m, 2H); LC-MS: RT=1.21 min; MS(ESI)m / z:=353.3(M+H) + ; [Method A]

[0179] Intermediate 12-2 (diastereomeric mixture): Preparation of 5-(5-(tert-butoxycarbonyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid [ka] [ka]

[0180] Intermediate 12-1: Preparation of tert-butyl 3-(4-methoxy-3-(methoxycarbonyl)phenyl)-3a,4,6,6a-tetrahydro-5H-pyrrolo[3,4-d]isoxazole-5-carboxylate Intermediate 12-1 (500 mg, 46% yield) was prepared by the method described for Intermediate 6-1, substituting tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate for cyclopent-3-en-1-ylmethanol. 1 H NMR:(400MHz, CDCl3) δ 7.99(d, J=2.4Hz, 1H), 7.84(dd, J=8.7, 2.3Hz, 1H), 7.04(d, J=8.8Hz, 1H), 5.31(ddd, J=9.2, 5.4, 1.2Hz, 1H), 4.21(br dd, J=12.4, 9.1Hz, 1H), 3.96(s, 3H), 3.91(s, 3H), 3.72-3.61(m, 2H), 1.43(s, 9H); MS(ESI)m / z=377.4(M+H)+ ; [Method A]

[0181] Intermediate 12-2: Preparation of 5-(5-(tert-butoxycarbonyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid 12-2 (150 mg, 44% yield) was prepared from intermediate 12-1 by the method described for intermediate 6-2. MS (ESI) m / z=363.4 (M+H). + ; [Method A]

[0182] Homochiral intermediates 12-3 and 12-5 were obtained by chiral SFC of the diastereomeric mixture of intermediate 12-1 (499 mg, 1.33 mmol). Chiral SFC preparative chromatography conditions Instrument: Berger MG II (SFC); Column: Regis Whelk-01, 21x250mm, 5μ; Mobile phase: 15%MeOH / 85%CO2; Elution conditions: 45mL / min, 150Bar, 40℃; Detection wavelength: 220nm; Injection conditions: ~31mg / mL MeOH / ACN (1.0mL) Analytical chromatographic conditions Instrument: Shimadzu Nexera SFC; Column: Regis Whelk-01, 4.6x100mm, 3μ; Mobile phase: 15%MeOH / 85%CO2; Elution conditions: 2.0mL / min, 150Bar, 40℃; Detection wavelength: 220nm; Injection conditions: ~1mg / mL acetonitrile (5μL) Homochiral methyl benzoate intermediate 12-3 (peak-1, >99% ee, analytical RT = 4.02 min) was obtained as a white solid (96 mg, 19% yield). 1H NMR:(600MHz, CDCl3) δ 7.99(d, J=2.3Hz, 1H), 7.86-7.82(m, 1H), 7.04(br d, J=8.7Hz, 1H), 5.31(ddd, J=9.2, 5.4, 1.3Hz, 1H), 4.24-4.18(m, 1H), 4.01-3.93(m, 4H), 3.91(s, 3H), 3.83-3.76(m, 1H), 3.71-3.67(m, 1H), 3.63(br s, 1H), 1.43(br s, 9H)

[0183] Preparation of homochiral benzoic acid intermediate 12-4 (peak-1): 5-(5-(tert-butoxycarbonyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 12-4 (52 mg, 68% yield) was prepared following a similar procedure to intermediate 12-2 with further hydrolysis of intermediate 12-3. MS (ESI) m / z=363.1 (M+H). + ; [Method A]

[0184] Homochiral methyl benzoate intermediate 12-5 (peak-2, 99.6% ee, analytical RT = 4.56 min) was obtained as a white solid (96.7 mg, 19.4% yield). 1 H NMR (600MHz, CDCl3) δ 7.98(d, J=2.3Hz, 1H), 7.83(dd, J=8.8, 2.2Hz, 1H), 7.03(d, J=8.7Hz, 1H), 5.32-5.28(m, 1H), 4.21(td, J=8.8, 4.0Hz, 1H), 4.01-3.94(m, 1H), 3.95(s, 3H), 3.90(s, 3H), 3.83-3.73(m, 1H), 3.68(dd, J=11.4, 8.9Hz, 1H), 3.65-3.58(m, 1H), 1.43(s, 9H)

[0185] Preparation of homochiral benzoic acid intermediate 12-6 (peak-2): 5-(5-(tert-butoxycarbonyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 12-6 (48 mg, 62.3% yield) was prepared by a similar procedure to intermediate 12-2, with further hydrolysis of intermediate 12-5. MS (ESI) m / z = 363.1 (M+H). + ; [Method A]

[0186] Intermediate 13-2: tert-butyl 2-amino-2-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)-carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)acetate It was prepared according to the method described in the following scheme. [ka] [ka] Intermediate 13-1: Intermediate 7-6 (40 mg, 0.11 mmol) was added to ACN (4.54 mL), followed by DIPEA (0.46 mL, 2.1 mmol), 5'-(2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)-2-oxoethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid (Intermediate 3-6, 54.0 mg, 0.110 mmol) and HATU (51.8 mg, 0.140 mmol). After stirring for 12 h, the reaction mixture was concentrated under reduced pressure and directly purified by reverse phase HPLC chromatography (gradient: mobile phase A: 20% ACN / 80% HO / 0.1% TFA; mobile phase B: 80% ACN / 20% HO / 0.1% TFA) to give a solid. 1H NMR (400MHz, chloroform-d) δ 11.65-11.61(m, 1H), 9.25(br s, 1H), 8.58-8.54(m, 1H), 8.49-8.45(m, 1H), 8.07(s, 1H), 7.97-7.89(m, 1H), 7.72-7.68(m, 1H), 7.49(dd, J=7.3, 2.2Hz, 1H), 7.35-7.31(m, 1H), 7.18-7.11(m, 3H), 5.65(br d, J=6.6Hz, 1H), 5.25(br d, J=7.0Hz, 1H), 4.17(s, 3H), 2.44-2.33(m, 4H), 1.62-1.55(m, 4H), 1.47-1.39(m, 18H); LC-MS: RT=1.39min; MS(ESI)m / z =810.2(M+H) + ; [Method A]

[0187] Intermediate 13-2: The BOC group was removed from intermediate 13-1 by dissolving the residue in EtOAc (5 mL) followed by treatment with HCl (4.0 M in dioxane, 2 mL, 8.0 mmol). After stirring for 3 h, the reaction mixture was concentrated in vacuo to give intermediate 13-2, which was used without further purification. Analytical LCMS: RT=1.14 min; MS(ESI)m / z=710.2(M+H). + ; HPLC purity: 93%; [Method A]

[0188] Homochiral intermediate 14-1: (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethane-1-ol It was prepared according to the method described in the following scheme. [ka] A solution of (S)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole (0.163 g, 0.645 mmol) and racemic intermediate 4-2 (4.4 g, 16.12 mmol) in diisopropyl ether (54 mL) was cooled to 0°C to -20°C. The solution was treated with isobutyric anhydride (1.6 mL, 9.67 mmol) and stored in a freezer for 14 h. The reaction mixture was quenched by the addition of MeOH (~3 mL) and extracted from the phosphate buffer with EtOAc (2x25 mL). The organic layer was concentrated under reduced pressure and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol (chiral intermediate 14-1, 1.7 g, 39% yield, 99.9% ee). 1 H NMR (500 MHz, chloroform-d) δ 7.75-7.71 (m, 1H), 7.44-7.39 (m, 1H), 7.19-7.13 (m, 1H), 5.01 (q, J=6.6 Hz, 1H), 4.15-4.10 (m, 1H).

[0189] Intermediate 15-1: Preparation of (3-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4-methoxyphenyl)boronic acid [ka] Intermediate 7-6 (100 mg, 0.28 mmol) was added to ACN (11.4 mL), followed by DIPEA (1.14 mL, 6.53 mmol) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (79 mg, 0.28 mmol) and HATU (130 mg, 0.34 mmol). After 4 h, the reaction mixture was extracted from water with EtOAc, the organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by reverse phase chromatography (gradient: mobile phase A: 20% ACN / 80% H2O / 0.1% TFA; mobile phase B: 80% ACN / 20% H2O / 0.1% TFA) to give intermediate 15-1 (51.4 mg, 34% yield). 1 H NMR (400MHz, DMSO-d6) δ 11.51-11.49(m, 1H), 10.75(s, 1H), 8.49-8.45(m, 1H), 8.37-8.30(m, 2H), 8.09-8.02(m, 2H), 7.95(dd, Analytical LC-MS: RT=1.22 minutes; MS(ESI)m / z=530.8(M+H) + ; [Method A]

[0190] Intermediate 16-1: Preparation of 3-bromo-N-(cyclobutylmethyl)-4-fluorobenzamide [ka] To a solution of 3-bromo-4-fluorobenzoic acid (100 mg, 0.46 mmol), cyclobutylmethanamine (58.3 mg, 0.690 mmol), and DIPEA (0.16 mL, 0.91 mmol) in DMF (3 mL) was added BOP (202 mg, 0.460 mmol). After 4 h, the reaction mixture was directly purified by reverse-phase HPLC chromatography (gradient: mobile phase A: 20% ACN / 80% HO / 0.1% TFA; mobile phase B: 80% ACN / 20% HO / 0.1% TFA) to give intermediate 16-1 (32 mg, 25% yield) as a solid. Analytical LC-MS: RT=1.18 min; MS(ESI)m / z=286.1(M+H) + ; [Method A]

[0191] Intermediate 17-3: 5-(3-hydroxypropyl)-2-methoxybenzoic acid It was prepared according to the method described in the following scheme. [ka] [ka]

[0192] Intermediate 17-1: tert-Butyldimethyl(prop-2-ynyloxy)silane (2 g, 11.74 mmol) was added with THF (8 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.07 mL, 21.14 mmol) and 9-BBN / THF (0.5N, 2.35 mL, 1.17 mmol) and stirred at 75° C. for 14 h. The reaction was carefully quenched with water (gas evolution), stirred at room temperature for 1 h and diluted with EtOAc (50 mL). The organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated in vacuo and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give Intermediate 17-1 (1.9 g, 53% yield) as a clear oil. 1H NMR (400MHz, chloroform-d) δ ppm 6.68(1H, dt, J=17.9, 3.4Hz), 5.75(1H, d, J=17.9Hz), 4.22-4.27(2H, m), 1.27(12H, s), 0.92(9H, s), 0.07(6H, s)

[0193] Intermediate 17-2: A mixture of intermediate 17-1 (0.84 g, 2.8 mmol) and methyl 5-bromo-2-methoxybenzoate (0.66 g, 2.7 mmol) in DMF (6 mL) was degassed with N2, followed by the addition of XPhosPdG2 (0.106 g, 0.130 mmol). The reaction vessel was sealed and heated to 60 °C. After 1.5 h, the reaction mixture was cooled, diluted with EtOAc (50 mL), separated, washed with H2O, brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give intermediate 17-2 (752 mg, 83% yield). 1 H NMR(500MHz, CDCl3) δ 7.83(d, J=2.3Hz, 1H), 7.50(dd, J=8.7, 2.3Hz, 1H), 6.95(d, J=8.7Hz, 1H), 6.55(dt, J=15.8, 1.6Hz, 1H), 6.24(t, J=5.0Hz, 1H), 6.21(t, J=5.0Hz, 1H), 4.36(dd, J=5.0, 1.7Hz, 2H), 3.93(s, 3H), 3.92(s, 3H), 0.96(s, 9H), 0.14-0.13(m, 6H)

[0194] Intermediate 17-3: (E)-Methyl 5-(3-((tert-butyldimethyl-silyl)oxy)prop-1-en-1-yl)-2-methoxybenzoate (Intermediate 17-2, 693 mg, 2.06 mmol) was dissolved in EtOAc (15 mL) and hydrogenated at 55 psi for 3 h. The suspension was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resulting residue was added to THF (20 mL), cooled to 0° C., and TBAF (2.059 mL, 2.06 mmol) was added. After 2 h, the reaction mixture was treated with water (20 mL), extracted with ethyl acetate (2×20 mL), and the combined organic layers were washed with brine (15 mL) and concentrated under reduced pressure. The methyl benzoate was dissolved in a solution of THF / MeOH (1:1, 10 mL) and hydrolyzed by the addition of LiOH (3.09 mL, 6.18 mmol). After stirring for 14 h, the reaction was quenched with dilute hydrochloric acid (1N, 20 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to give intermediate 17-3 (0.5 g, 115% yield) as a yellow oil. 1 H NMR(500MHz, CDCl3) δ 8.05(d, J=2.3Hz, 1H), 7.44(dd, J=8.5, 2.4Hz, 1H), 7.01(d, J=8.4Hz, 1H), 5.32(s, 1H), 4.12-4.06(m, 4H), 3.69(t, J=6.3Hz, 2H), 2.81-2.71(m, 2H), 1.96-1.87(m, 2H); Analytical LC-MS: RT=0.85 min; MS(ESI)m / z= 211.2(M+H) + ; [Method A]

[0195] Intermediate 18-3: 5-(3-hydroxy-3-methylbutyl)-2-methoxybenzoic acid It was prepared according to the method described in the following scheme. [ka]

[0196] Intermediate 18-1: To a sealed vial was added methyl 5-bromo-2-methoxybenzoate (1.7 g, 6.94 mmol), 2-methylbut-3-yn-2-ol (0.584 g, 6.94 mmol), Pd(Ph3P)4 (0.401 g, 0.35 mmol), copper(I) iodide (0.013 g, 0.069 mmol), followed by TEA (15 mL). The reaction mixture was degassed, sealed, and heated at 80 °C. The reaction was diluted with water (20 mL), extracted with ethyl acetate (50 mL), and the organic layer was washed with brine (15 mL), dried (MgSO4), filtered, concentrated in vacuo, and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give Intermediate 18-1 (1.2 g, 70% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.88 (d, J=2.2 Hz, 1H), 7.52 (dd, J=8.8, 2.2 Hz, 1H), 6.89 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 1.62 (s, 6H); MS (ESI) m / z = 249 (M+H). +

[0197] Intermediate 18-2: Methyl 5-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methoxybenzoate (1.2 g, 4.8 mmol) was dissolved in EtOH (25 mL), wet 10% Pd / C (0.2 g) was added to the solution, and the reaction mixture was hydrogenated at 20 psi for 14 h. The suspension was filtered through Celite®, concentrated under reduced pressure, and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give Intermediate 18-2 (714 mg, 59.0% yield) as a pale yellow oil. 1 H NMR(400MHz, CDCl3) δ 7.67(d, J=2.4Hz, 1H), 7.33(dd, J=8.4, 2.4Hz, 1H), 6.94(d, J=8.4Hz, 1H), 3.92(s, 3H), 3.92(s, 3H), 2.88-2.59(m, 2H), 1.86-1.69(m, 2H), 1.32(s, 6H), 1.25(s, 1H); MS(ESI)m / z=253.3(M+H) +

[0198] Intermediate 18-3: To a solution of intermediate 18-2 (0.714 g, 2.83 mmol) dissolved in THF (21 mL) / water (7 mL) was added LiOH (1.4 mL, 2.83 mmol). After stirring for 12 h, the reaction mixture was diluted with 0.1 N HCl and extracted with EtOAc (2x25 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to give intermediate 18-3 (0.60 g, 89% yield) as a solid. Analytical LC-MS: RT=0.95 min; MS(ESI)m / z=239.2(M+H). + ; Method A

[0199] Intermediate 19-2: 5-(4,5-bis(2-hydroxyethyl)isoxazol-3-yl)-2-methoxybenzoic acid It was prepared according to the method described in the following scheme. [ka]

[0200] Intermediate 19-1: Intermediate 5-1 (1.0 g, 4.10 mmol) was dissolved in DCM (41 mL) and treated with hex-3-yne-1,6-diol (937 mg, 8.21 mmol) followed by TEA (1.7 mL, 12.31 mmol) at room temperature. After 12 h, the reaction mixture was concentrated under reduced pressure and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give intermediate 19-1. 1 H NMR (500MHz, DMSO-d6) δ 8.10(d, J=2.3Hz, 1H), 8.00(dd, J=8.7, 2.3Hz, 1H), 7.32-7.28(m, 1H), 4.63-4.59(m, 1H), 3.89(s, 3H), 3.82(s, 3H), 3.76(t, J=6.5Hz, 2H), 3.53-3.46(m, 4H), 3.04(t, J=6.4Hz, 2H); Analytical LC-MS: RT=1.01 min; MS(ESI)m / z=322.2(M+H) + ; [Method A]

[0201] Intermediate 19-2: The ester intermediate 19-1 was dissolved in MeOH / THF (1:1, 20 mL) and treated with lithium hydroxide monohydrate (517 mg, 12.3 mmol) in HO (3 mL). After 3 h, the reaction mixture was concentrated in vacuo and the remaining aqueous layer was acidified with 1.0 M HCl solution and extracted with EtOAc (2x25 mL). The organic layer was washed with HO, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 5-(4,5-bis(2-hydroxyethyl)isoxazol-3-yl)-2-methoxybenzoic acid (640 mg, 51% yield) as a solid. Analytical LC-MS: RT=0.91 min; MS(ESI)m / z=308.2(M+H). + ; [Method A]

[0202] Intermediate 20-2: (S)-5'-(1-((cyclobutylcarbamoyl)oxy)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid It was prepared according to the method described in the following scheme. [ka] [ka]

[0203] Intermediate 20-1: Preparation of (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl cyclobutylcarbamate A mixture of intermediate 14-1 (300 mg, 1.10 mmol), pyridine (0.44 mL, 5.49 mmol), and DMAP (13.42 mg, 0.11 mmol) was dissolved in DCM (20 mL) and 4-nitrophenylchloroformate (1.1 g, 5.49 mmol) was added. The reaction mixture was stirred for 1 h, followed by the addition of cyclobutanamine (0.78 g, 10.99 mmol). After 2 h, the reaction was concentrated and purified by normal phase chromatography (eluent: hexane / ethyl acetate) to give intermediate 20-1 (347.5 mg, 0.94 mmol, 85% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.68-7.64(m, 1H), 7.40-7.35(m, 1H), 7.18-7.13(m, 1H), 6.02-5.95(m, 1H), 4.19-4.09(m, 1H), 2.41-2.28(m, 2H), 1.97-1.84(m, 2H), 1.77-1.63(m, 2H), 1.55(s, 1H).

[0204] Intermediate 20-2: To a reaction vessel containing intermediate 20-1 (347 mg, 0.800 mmol) was added 5-(dihydroxyboryl)-2-methoxybenzoic acid (203 mg, 1.04 mmol), PdCl2(dppf)·CH2Cl2 adduct (98 mg, 0.12 mmol), Na2CO3 (338 mg, 3.19 mmol), THF (11.5 mL) and H2O (3 mL). The reaction mixture was degassed by bubbling N2 for 10 min, sealed and stirred at 65 °C for 3 h. After cooling to room temperature, the reaction was quenched with 1N HCl, extracted with EtOAc (2x25 mL) and the organic layer was dried over Na2SO4, concentrated in vacuo, purified by reverse phase chromatography and lyophilized to give intermediate 20-2 (72 mg, 21% yield). Analytical LC-MS: RT=0.94 min; MS(ESI)m / z=442.0(M+H) + ; [Method A]

[0205] Intermediate 21-2: 2-(4-bromo-1H-pyrazol-1-yl)acetic acid It was prepared according to the method described in the following scheme. [ka]

[0206] Intermediate 21-1: K2CO3 (2.82 g, 20.4 mmol) was added to a solution of 4-bromo-1H-pyrazole (1 g, 7 mmol) in DMF (27.2 mL) at 80 °C. After 5 min, tert-butyl 2-bromoacetate (1.99 g, 10.2 mmol) was added and the mixture was stirred for 14 h before being quenched with water and extracted with DCM (2x25 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by normal phase chromatography gave Intermediate 21-1 (1.78 g, 6.81 mmol, 100% yield) as a clear, colorless oil. 1 H NMR (500 MHz, chloroform-d) δ 7.51-7.49(m, 2H), 4.78(s, 2H), 1.48(s, 9H)

[0207] Intermediate 21-2: To a solution of intermediate 21-1 (500 mg, 1.91 mmol) in DCM (7.66 mL) was added TFA (2.2 mL, 28.7 mmol). After 2 h, the reaction mixture was concentrated in vacuo to dryness. The resulting residue was dissolved in EtOAc (20 mL), neutralized with NaHCO3 solution, reacidified with 1.0 M HCl solution, and extracted with EtOAc (2x25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give intermediate 21-2 (323 mg, 82%), which was used without further purification. 1 H NMR (500MHz, chloroform-d) δ 7.51-7.49(m, 2H), 4.78(s, 2H), 1.48(s, 9H); Analytical LC-MS: RT=0.81 min; MS(ESI)m / z=205.0(M+H) + ; [Method A]

[0208] Intermediate 22-2: 5-(1,1-dioxidoisothiazolidine-2-yl)-2-methoxybenzoic acid [ka] [ka]

[0209] Intermediate 22-1: To a solution of isothiazolidine 1,1-dioxide (41.5 mg, 0.340 mmol) in dioxane (1.8 mL) was added methyl 5-iodo-2-methoxybenzoate (100 mg, 0.342 mmol), Xantphos (20 mg, 0.034 mmol), cesium carbonate (223 mg, 0.685 mmol), and the reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd2(dba)3 (16 mg, 0.017 mmol). The reaction vessel was sealed and heated at 100° C. for 15 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (30 mL), and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo. Analytical LC-MS: RT=0.93 min; MS(ESI)m / z=286.1(M+H) + ; [Method A]

[0210] Intermediate 22-2: The methyl benzoate intermediate 22-1 was dissolved in THF / MeOH / water (20 mL), cooled to 0° C., and LiOH solution (0.171 mL, 0.342 mmol) was added. After 3 h, the reaction mixture was partitioned between water (10 mL) and Et2O (50 mL). The aqueous layer was acidified with 1N HCl solution, extracted with EtOAc (3×20 mL), and the organic layer was washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 5-(1,1-dioxidoisothiazolidin-2-yl)-2-methoxybenzoic acid (70 mg, 75% yield) as a brown oil. Analytical LC-MS: RT=0.83 min; MS(ESI)m / z=272.1(M+H). + ; [Method A]

[0211] Intermediate 23-1: Preparation of 2-(3-bromo-4-fluorophenyl)-N-(cyclobutylmethyl)acetamide [ka] Intermediate 23-1 (44 mg, 34%) was prepared in a similar manner to intermediate 16-1, replacing 3-bromo-4-fluorobenzoic acid with 2-(3-bromo-4-fluorophenyl)acetic acid (100 mg, 0.429 mmol).

[0212] Example 1 6-Fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] Example 1 was prepared by adding DIEA (0.342 mL, 1.96 mmol) and HATU (38.9 mg, 0.102 mmol) to a solution of 3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Intermediate 7-6, 30 mg, 0.085 mmol) and 5'-(tert-butoxycarbonyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid (Intermediate 1-1, 35.4 mg, 0.10 mmol) in ACN (3.4 mL), respectively. After 12 h, the reaction mixture was extracted with EtOAc (2x25 mL), washed with H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was treated with 50% TFA / DCM (1 mL). After 3 h, the reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC (gradient: mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid)) to give Example 1 (3.3 mg, 6%). 1H NMR (500MHz, DMSO-d6) δ 11.62-11.58(m, 1H), 10.81-10.75(m, 1H), 8.36-8.29(m, 2H), 8.21-8.18(m, 1H), 8.05(br d, J=6.2Hz, 2H), 8.00-7.95(m, 1H), 7.82-7.78(m, 1H), 7.57-7.50(m, 2H), 7.45(br t, J=9.4Hz, 1H), 7.38-7.33(m, 1H), 4.05(s, 3H), 2.82-2.72(m, 4H), 1.83-1.71(m, 4H); Analytical LC-MS: RT=2.11 min; MS(ESI)m / z=623.1(M+H) + ; HPLC purity: 88%; [Method B]

[0213] Example 2 2-(6-Fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydro-naphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)acetic acid (homochiral) [ka] Example 2 was prepared by adding 2-amino-2-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)tert-butyl acetate (Intermediate 13-2, 55.4 mg, 0.074 mmol) to DCM (1.5 mL) and treating with DIPEA (0.130 mL, 0.74 mmol) followed by the addition of tetrahydro-2H-pyran-4-carbonyl chloride (11.03 mg, 0.074 mmol). After stirring for 1 h, the solution was concentrated under reduced pressure and purified by reverse phase chromatography (gradient: mobile phase A: 10% ACN / 90% HO / 0.1% TFA; mobile phase B: 90% ACN / 10% HO / 0.1% TFA) to give 2-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)tert-butyl acetate. Analytical LC-MS: RT=1.30 min; MS(ESI)m / z=822.1(M+H). + ; [Method A]

[0214] 2-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamide) tert-butyl acetate was redissolved in DCM (1 mL) and treated with TFA (1 mL) to remove the t-butyl group. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (gradient: mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid)) to give Example 2 (6.0 mg, 11% yield). 1H NMR (500MHz, DMSO-d6) δ 11.65(s, 1H), 10.80(s, 1H), 8.66(d, J=7.7Hz, 1H), 8.39-8.32(m, 2H), 8.21(s, 1H), 8.09-8.03(m, 1H), 7.78-7.72(m, 1H), 7.59-7.52(m, 3H), 7.46-7.41(m, 1H), 7.38-7.30(m, 2H), 7.25-7.03(m, 1H), 5.44-5.40(m, 1H), 4.05(s, 3H), 3.89-3.82(m, 2H), 3.34-3.25(m, 1H), 2.82-2.75(m, 4H), 1.81-1.75(m, 4H), 1.66-1.53(m, 4H); Analytical LC-MS: RT=2.04 min; MS(ESI)m / z=766.2(M+H) + ; HPLC purity: 93%; [Method B]

[0215] Example 3 2-Amino-2-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)acetic acid, TFA salt (homochiral) [ka] When Example 2 was purified by reverse phase chromatography (gradient: mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid)), Example 3 (1.2 mg, 2% yield) was isolated as the more polar peak. 1H NMR (500MHz, DMSO-d6) δ 11.64(s, 1H), 10.79(s, 1H), 8.38-8.32(m, 2H), 8.24(s, 1H), 8.08-8.04(m, 1H), 7.78-7.73(m, 1H), 7.68-7.63(m, 1H), 7.57-7.52(m, 2H), 7.46(br d, J=3.1Hz, 1H), 7.39-7.32(m, 2H), 4.74-4.63(m, 1H), 4.07-4.02(m, 3H), 2.83-2.75(m, 4H), 1.82-1.68(m, 5H); Analytical LC-MS: RT=2.025 min; MS(ESI)m / z=654.1(M+H) + ; HPLC purity: 99%; [Method B]

[0216] Example 4 (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2'-fluoro-4-methoxy-5'-(2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-carboxamide)-5,6,7,8-tetrahydronaphthalene-2-carboxamide [ka] Example 4: Tetrakis(triphenylphosphine)palladium(0) (10.9 mg, 9.43 μmol) was added to a solution of (3-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4-methoxyphenyl)boronic acid (Intermediate 15-1, 50 mg, 0.094 mmol), (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol (Intermediate 14-1, 25.7 mg, 0.0940 mmol), potassium phosphate (60.0 mg, 0.280 mmol), and toluene (0.943 mL), which was sealed and stirred at 80° C. for 14 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc (2×25 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by normal phase chromatography (eluent: hexanes / EtOAc) to give Example 4 (45.3 mg, 71% yield) as a solid. Further purification by reverse phase chromatography (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)) afforded an analytical sample. 1 H NMR (500MHz, DMSO-d6) δ 11.62(s, 1H), 10.78(s, 1H), 8.36-8.32(m, 2H), 8.21-8.19(m, 1H), 8.08-8.04(m, 1H), 7.75(br d, J=8.8Hz, 1H), 7.66(br d, J=7.5Hz, 1H), 7.57-7.51(m, 3H), 7.40-7.34(m, 2H), 6.99(br d, J=5.2Hz, 1H), 5.31-5.25(m, 1H), 4.05(s, 3H), 2.82-2.74(m, 4H), 1.82-1.74(m, 4H); Analytical LC-MS: RT=2.75 min; MS(ESI)m / z=679.14(M+H) + ; HPLC purity: 100%; [Method B]

[0217] Example 5 (S)-2,2,2-trifluoro-1-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)ethyl phenylcarbamate [ka] Example 5: Phenyl isocyanate (35.1 mg, 0.300 mmol) was added to (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2'-fluoro-4-methoxy-5'-(2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-carboxamide)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Example 4, 20 mg, 0.029 mmol) and pyridine (0.048 mL, 0.59 mmol) in DCM (2.0 mL) and stirred for 14 hours. The reaction mixture was quenched with MeOH, concentrated in vacuo, and purified by reverse phase chromatography (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 5 (14 mg, 58% yield) as a solid. 1H NMR (500MHz, DMSO-d6) δ 11.59-11.57(m, 1H), 10.73-10.71(m, 1H), 10.24(br s, 1H), 8.32-8.27(m, 2H), 8.19-8.15(m, 1H), 8.01(br dd, J=8.1, 3.8Hz, 1H), 7.78-7.70(m, 2H), 7.62-7.58(m, 1H), 7.52-7.46(m, 2H), 7.45-7.39(m, 3H), 7.32(d, J=8.9Hz, 1H), 7.25(t, J=7.8Hz, 2H), 7.02-6.96(m, 1H), 6.52(q, J=7.0Hz, 1H), 4.01(s, 3H), 2.78-2.69(m, 4H), 1.78-1.68(m, 4H); Analytical LC-MS: RT=3.05min; MS(ESI)m / z=798.3(M+H) + ; HPLC purity: 99%; [Method B]

[0218] Example 6 (S)-2,2,2-trifluoro-1-(6-fluoro-3'-((3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)ethyl cyclobutylcarbamate [ka] Example 6: A solution of (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2'-fluoro-4-methoxy-5'-(2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-carboxamide)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Example 4, 20 mg, 0.029 mmol) and pyridine (0.024 mL, 0.30 mmol) in DCM (2.0 mL) was treated with 4-nitrophenylchloroformate (29.7 mg, 0.150 mmol) followed by DMAP (3.6 mg, 0.029 mmol) and stirred for 14 h. Cyclobutanamine (0.025 mL, 0.30 mmol) was added to the above solution and the mixture was stirred for 1 h before being concentrated under reduced pressure and purified by reverse phase chromatography (gradient: mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid)) to give Example 6 (14 mg, 60% yield) as a solid. 1 H NMR (500MHz, DMSO-d6) δ 11.63-11.61(m, 1H), 10.78-10.75(m, 1H), 8.37-8.31(m, 2H), 8.21-8.18(m, 1H), 8.17-8.13(m, 1H), 8.08-8.03(m, 1H), 7.76-7.69(m, 2H), 7.57-7.51(m, 3H), 7.46-7.42(m, 1H), 7.38-7.33(m, 1H), 6.41-6.34(m, 1H), 4.06(s, 3H), 3.94(dq, J=16.4, 8.4Hz, 1H), 2.83-2.74(m, 4H), 2.18-2.07(m, 2H), 2.01-1.85(m, 2H), 1.78(br s, 4H), 1.60-1.53(m, 2H); Analytical LC-MS: 2.99 min; MS(ESI)m / z=888.15(M+H); HPLC purity: 99%; [Method B]

[0219] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0220] Example 29 6-Fluoro-3'-((6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-3-hydroxy-2,3-dihydro-1H-inden-5-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (racemic) [ka] Example 29: 6-Fluoro-3'-((6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-3-oxo-2,3-dihydro-1H-inden-5-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (Example 26, 9 mg, 0.013 mmol) was dissolved in THF / MeOH (1:1, 2 mL) and treated with NaBH4 (2 mg) at room temperature. After 1 h, the reaction mixture was concentrated under reduced pressure, quenched with 1N HCl, and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure, and the resulting residue was treated with 50% TFA / DCM (0.25 mL). After 2 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (gradient: mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid)) to give 6-fluoro-3'-((6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-3-hydroxy-2,3-dihydro-1H-inden-5-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (Example 29, 1 mg, 11% yield). 1 H NMR (500MHz, DMSO-d6) δ 11.49(s, 1H), 11.22-10.99(m, 1H), 8.84-8.67(m, 1H), 8.35(br d, J=4.2Hz, 1H), 8.22(s, 1H), 8.05(br d, J=5.7Hz, 1H), 8.02-7.96(m, 1H), 7.81(br d, J=8.4Hz, 1H), 7.56(br t, J=9.7Hz, 1H), 7.45(br t, J=9.6Hz, 1H), 7.36(d, J=8.7Hz, 1H), 4.04(s, 3H), 3.17(br d, Analytical LC-MS: RT=1.76 min; MS(ESI)m / z=627.18(M+H) + ; HPLC purity: 98%; [Method B]

[0221] 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 to the above-described examples, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 is a halogen, C substituted with 0 to 5 halogens 1-4 -OC substituted with alkyl, ═O, OH, or 0-5 halogens 1-4 is alkyl; R 2 is halogen, CN, C substituted with 0 to 5 halogens or OH 1-4 Alkyl, or 0-5 halogens, OH, or -OC 1-4 Alkyl-substituted -OC 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 0 to 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 1 R 7 wherein said heterocyclyl is attached to the phenyl moiety through a carbon or nitrogen atom; 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 0 to 3 R e substituted with -(CH 2 ) n -(O, S(=O) p and N), heterocyclyl containing 1 to 4 heteroatoms selected from; 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 are combined with the nitrogen atom to which they are both attached to 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 -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 , -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 2】 [In the formula, R 1 is halogen, =O, OH, -OC substituted with 0 to 5 halogens 1-4 is alkyl; R 2 is a halogen, C 1-3 -OC substituted with alkyl or 0 to 4 halogens 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 are combined with the nitrogen atom to which they are both attached to 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): 【Transformation 3】 [In the formula, R 1 is OH or =O; 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 , 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 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 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 are combined with the nitrogen atom to which they are both attached to 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 , 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, or C 3-6 is cycloalkyl; 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): 【Chemistry 4】 [In the formula, R 1 is OH or =O; R 2 -OC 1-3 is alkyl; R 4a is F; R 4b CF 3 and; R 6 is F; 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 1-4 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, or 0 to 3 R e is phenyl substituted with; R b is H or 0 to 5 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): 【Transformation 5】 [In the formula, R 8 is -C(=O)OH or CF 3 and; R 9 is -NHC(=O)R b or -OC(=O)NHR a and; R a -C 3-6 is cycloalkyl or phenyl; and R b is heterocyclyl] 5. The compound of claim 4, having the formula: or a pharmaceutically acceptable salt thereof.

6. Formula (VI): 【Transformation 6】 [In the formula, R 1 is =O; 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 are combined with the nitrogen atom to which they are both attached to 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 -heteroaryl, -(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, or C 3-6 is cycloalkyl; 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.

7. During the ceremony, R 2 -OCH 3 and; R 4a is F; R 4b CF 3 and; R 5 teeth, 【Transformation 7】 and; R 6 is a C substituted with halogen, -OH, or 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, -C(=O)R b , or 0 to 1 R 11 C replaced with 1-4 is alkyl; R 11 is —OH, —C(═O)OH, or aryl; R a is H or C 1-3 is alkyl; and R b is H or C 1-3 is alkyl, 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof.

8. During the ceremony, R 2 -OCH 3 and; R 4a is F; R 4b CF 3 and; R 5 teeth, 【Transformation 8】 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, 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof.

9. During the ceremony, R 2 -OCH 3 and; R 4a is F; R 4b CF 3 and; R 5 teeth, 【Chemistry 9】 and; R 6 are halogens, 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 to 3 halogens or OH 1-4 is alkyl; R 9 is -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, 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof.

10. Formula (VII): 【Chemistry 10】 [In the formula, R 2 is halogen, CN, -C(=O)OR b , -NR a R a , C substituted with 0 to 5 halogens or OH 1-4 Alkyl, or 0-4 halogens, OH, or -OC 1-4 Alkyl-substituted -OC 1-4 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 are combined with the nitrogen atom to which they are both attached to 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 1-5 Alkyl, 0 to 5 R g C replaced with 2-5 Alkenyl, 0-5 R g C replaced with 2-5 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 1-5 Alkyl, or C 3-6 is cycloalkyl; 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 (VIII): 【Chemistry 11】 [In the formula, R 1 is =O or -OH; R 2 is halogen, CN, -C(=O)OR b , -NR a R a , C substituted with 0 to 5 halogens or OH 1-4 Alkyl, or 0-4 halogens, OH, or -OC 1-4 Alkyl-substituted -OC 1-4 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 are combined with the nitrogen atom to which they are both attached to 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 1-5 Alkyl, 0 to 5 R g C replaced with 2-5 Alkenyl, 0-5 R g C replaced with 2-5 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, or C 3-6 is cycloalkyl; 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 (IX): 【Chemistry 12】 [In the formula, R 1 is =O or -OH; R 2 is halogen, CN, -C(=O)OR b , -NR a R a , C substituted with 0 to 5 halogens or OH 1-4 Alkyl, or 0-4 halogens, OH, or -OC 1-4 Alkyl-substituted -OC 1-4 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 are combined with the nitrogen atom to which they are both attached to 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 1-5 Alkyl, 0 to 5 R g C replaced with 2-5 Alkenyl, 0-5 R g C replaced with 2-5 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(4- to 6-membered heterocyclyl), -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -(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, or C 3-6 is cycloalkyl; 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.

Images