Bicyclo[3.2.0]heptane bis(amide) RXFP1 agonists

Abstract

The present disclosure relates to compounds of formula (I), which are RXFP1 receptor agonists, to compositions containing them, and to methods of using them in the treatment of, for example, heart failure, fibrotic diseases, and related diseases such as pulmonary disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic kidney disease), or liver disease (e.g., nonalcoholic steatohepatitis and portal hypertension). TIFF2025503442000039.tif67136

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 289,859, filed December 15, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[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, fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), and liver disease (e.g., non-alcoholic steatohepatitis and portal hypertension). [Background technology]

[0003] Human relaxin hormone (also called relaxin or H2 relaxin) is a 6 kDa peptide composed of 53 amino acids whose activity was first discovered in 1926 when Frederick Hisaw observed relaxation of the fibrocartilaginous symphysis pubis joint when a crude extract from porcine corpora lutea was injected into virgin guinea pigs (Hisaw FL, Proc. Soc. Exp. Biol.Med., 1926, 23, 661-663). The relaxin receptor, formerly known as Lgr7, is now formally called relaxin family peptide receptor 1 (RXFP1) and was de-orphanized as a relaxin receptor in 2002 (Hsu SY. et al., Science, 2002, 295, 671-674). RXFP1 is reasonably well conserved between 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., Ann. NY Acad. Sci., 2007, 1160, 117-120). The most studied pathway is one in which relaxin functions as an RXFP1 agonist, promoting GαS coupling and activation of adenylate cyclase, resulting in a relaxin-dependent increase in cellular levels of cAMP (Halls ML. et al., Mol. Pharmacol., 2006, 70, 214-226).

[0004] Since the initial discovery of relaxin, many experimental studies have focused on clarifying the role relaxin plays in female reproductive biology and on elucidating 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% and a concomitant increase in cardiac output of approximately 50% to meet the nutritional demands imposed by the fetus (Jeyabalan AC., KP, Reanl and Electrolyte Disorders. 2010, 462-518), (Clapp JF & Capeless E., Am. J. Cardio., 1997, 80, 1469-1473). Further vascular adaptations include an approximately 30% increase in systemic arterial compliance, which is important for maintaining effective ventricular-arterial coupling, as well as an approximately 50% increase in both renal blood flow (RBF) and glomerular filtration rate (GFR), which are important for the clearance of metabolic waste products (Jeyabalan AC., KP, Reanl and Electrolyte Disorders. 2010, 462-518), (Poppas A. et al., Circ., 1997, 95, 2407-2415). Both preclinical studies in rodents as well as clinical studies conducted in various patient settings provide evidence that relaxin is involved, at least to some extent, in mediating these adaptive biological changes (Conrad KP., Regul Integr. Comp. Physiol., 2011, 301, R267-275), (Teichman SL. et al., Heart Fail. Rev., 2009, 14, 321-329).Importantly, many of these adaptive responses may benefit HF patients in that excessive fibrosis, low arterial compliance, and reduced renal function are all common characteristics 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 as a hemodynamic condition in which the cardiac pump function is impaired resulting in insufficient systemic perfusion to meet the metabolic needs of the body, is prevalent in an estimated 5.8 million people in the United States and more than 23 million people worldwide, and represents an enormous burden on today's health care systems (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, projected 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 indicated 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 signs and symptoms of HF include: 1) dyspnea (labored breathing) resulting from pulmonary edema caused by ineffective forward flow from the left ventricle and increased pressure in the pulmonary capillary bed; 2) leg edema, which occurs when the right ventricle cannot match the systemic venous return; and 3) fatigue due to the inability of heart failure to maintain sufficient cardiac output (CO) to meet the metabolic demands of the body (Kemp CD. & Conte JV., Cardiovasc. Pathol., 2011, 21, 365-371). Also, in relation to the severity of symptoms, HF patients are often described as "compensated" or "decompensated." In compensated heart failure, symptoms are stable and many of the obvious features of fluid retention and pulmonary edema are absent. Decompensated heart failure refers to an exacerbation that may be manifested as acute episodes of pulmonary edema, reduced exercise tolerance, and increased shortness of breath on exercise (Millane T. et al., BMJ, 2000, 320, 559-562).

[0007] Contrary to the simple definition that the cardiac function may be impaired leading to an inability to meet metabolic demands, the numerous causative diseases, the numerous risk factors, and the many pathological changes that ultimately lead to heart failure make this disease extremely complex (Jessup M. & Brozena S., N. Engli. J. Med., 2003, 348, 3007-2018). The adverse events thought to be involved in the pathophysiology of HF range from very acute ones such as myocardial infarction to chronic damage such as lifelong hypertension. Historically, HF has been primarily 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 reduces LV filling during diastole and passive stiffness increases it, but overall EF is preserved (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). More recently, new terms have been adopted: "heart failure with reduced ejection fraction" (HFrEF) and "heart failure with preserved ejection fraction" (HFpEF), as it has become understood that diastolic and systolic LV dysfunction are not unique and specific to these two groups (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679). Although these two patient populations show very similar signs and symptoms, it is currently under debate within the cardiovascular community whether HFrEF and HFpEF represent two distinct forms of HF or two extremes of a single spectrum sharing a common pathology (Borlaug BA. & Redfield MM., Circ., 2011, 123, 2006-2013), (De Keulenaer GW. & Brutsaert DL., Circ., 2011, 123, 1996-2004).

[0008] Serelaxin, an intravenous (IV) formulation of human recombinant relaxin peptide with a relatively short phase 1 pharmacokinetic half-life of 0.09 hours, is currently in development to treat HF ​​(Novartis, 2014). Administration of serelaxin to healthy volunteers (NHVs) has been shown to increase RBF (Smith MC. et al., J. Am. Soc. Nephrol. 2006, 17, 3192-3197) and estimated GFR (Dahlke M. et al., J. Clin. Pharmacol.,2015, 55, 415-422). 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, favorable changes in renal function deterioration, HF worsening, and less death were observed in patients with acutely decompensated HF (ADHF) in response to in-hospital 48-hour intravenous infusion of serelaxin (Teerlink JR. et al., Lancet, 2013, 381, 29-39), (Ponikowski P. et al., Eur Heart, 2014, 35, 431-441). Suggesting that chronic administration of serelaxin may provide sustained benefit to HF patients, improvements in renal function based on serum creatine levels were observed in scleroderma patients who received serelaxin continuously via subcutaneous pump for 6 months (Teichman SL. et al., Heart Fail. Rev., 2009, 14, 321-329). In addition to its therapeutic potential for treating HF, continuous subcutaneous administration of relaxin has also proven effective in various animal models of lung injury (Unemori EN. et al., J. Clin. Invet. 1996, 98, 2739-2745), kidney injury (Garber SL. et al., Kidney Int., 2001, 59, 876-882), and liver injury (Bennett RG., Liver Int., 2014, 34, 416-426).

[0009] In summary, a large body of evidence supports the role of relaxin-dependent agonism of RXFP1 in mediating adaptive changes that occur during mammalian pregnancy, and supports that these changes have favorable physiological effects and outcomes when relaxin is administered to HF patients. Further preclinical animal studies in various disease experiments of lung, kidney and liver damage provide evidence that relaxin may provide therapeutic benefits for multiple indications in addition to HF when administered chronically. More specifically, chronic administration of relaxin may benefit 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 cyclobutylcyclopentane compounds, their stereoisomers, tautomers, pharma- ceutically acceptable salts or solvates, and their analogs, that are useful as RXFP1 receptor agonists. The present invention also provides processes and intermediates for making the compounds of the present invention. The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the invention, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0011] The compounds of the invention may be used, for example, in the treatment and / or prevention of heart failure, fibrotic diseases, and pulmonary diseases (e.g., idiopathic pulmonary fibrosis), renal diseases (e.g., chronic renal disease), or liver diseases (e.g., non-alcoholic steatohepatitis and portal hypertension). The compounds of the invention may be used in therapy. The compounds of the invention may be used for the manufacture of a medicament for the treatment and / or prevention of heart failure.

[0012] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one or two, other drugs. These and other features of the invention will be described in expanded form as the disclosure proceeds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention encompasses compounds of formula (I), which are RXFP1 receptor agonists, compositions containing the compounds, and methods of using the compounds or compositions.

[0014] In a first aspect, the present invention relates to a compound of formula (I): [ka] [In formula: [ka] is an optional bond; R 1 is H or halo; or R 1 and R 1 together form a phenyl ring; R 2 Halo, C 1-4 Alkyl, OH, or -OC 1-4 Alkyl (0-4 halo, OH, or -OC 1-4 substituted with alkyl; R 4a is a halo; R 4b is C 1-4 alkyl(substituted with 0-4 halo); R 5 is C 2-8 Alkenyl (0 to 3 R 6 and 0 to 2 R 7 ), C 2-8 Alkynyl (0 to 3 R 6 and 0 to 2 R 7 ), C 6-12 Aryl (0 to 3 R 6 and 0 to 2 R 7 substituted with), or 3- to 12-membered heterocyclyl (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 halo, =O, -OH, -OC 1-4 Alkyl, or C 1-4 alkyl (substituted with 0-2 halo or OH); R 7 is C 1-3 Alkyl (0 to 1 R 8 and 0 to 1 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 , -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 4- to 6-membered heterocyclyl (O, S(=O) p , N and NR d and 0 to 5 R e ) and R 8 is halo, -C(=O)OR b , -C(=O)NHR a, -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-3 halo or OH); 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 , H, C 1-4 Alkyl (0 to 2 R 11 ), -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , C 3-6 Cycloalkyl (0 to 5 R e substituted with), or 4- to 6-membered heterocyclyl (O, S(=O) p , N and NR 12 and 0 to 5 R e ) and R 11 is -OH, -C(=O)OH, or aryl; R 12 , H, C 1-3 is alkyl, or aryl; R a , H, C 1-6 Alkyl (0 to 5 R e ), C2-5 Alkenyl (0 to 5 R e ), C 2-6 Alkynyl (0 to 5 R e substituted with -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R e substituted with -(CH2) n -heterocyclyl (0 to 5 R e or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl (0-5 R e (which is replaced by); R b , H, C 1-6 Alkyl (0 to 5 R e ), C 2-6 Alkenyl (0 to 5 R e ), C 2-6 Alkynyl (0 to 5 R e substituted with -(CH2) n -C 3-10 Carbocyclyl (0 to 5 R e substituted with -(CH2) n -heterocyclyl (0 to 5 R e ) and R c is C 1-5 Alkyl (0 to 5 R e ), C 2-5 Alkenyl (0 to 5 R e ), C 2-5 Alkynyl (0 to 5 R e ), C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-4 is alkyl; R e is halo, CN, =O, C 1-6 Alkyl (0 to 5 R g ), C 2-6 Alkenyl (0 to 5 R g), C 2-6 Alkynyl (0 to 5 R g substituted with -(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 , halo, CN, OH, C 1-6 Alkyl, C 3-6 cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2] or a pharma- ceutically acceptable salt thereof.

[0015] In a second aspect within the first aspect, the present invention provides a compound of formula (II): [ka] [In formula: R 2 Ha-OC 1-4 alkyl(substituted with 0-4 halo); R 4a is a halo; R 4b is C 1-3 alkyl(substituted with 0-4 F); R 5 is C 2-6 Alkynyl (0 to 3 R 6 and 0 to 2 R 7 substituted with 0 to 3 R 6 and 0 to 2 R 7 substituted with), or 3- to 12-membered heterocyclyl (O, S(=O) p , N and NR 10and 0 to 3 R 6 and 0 to 1 R 7 ) and R 6 ,Haro,CN,C 1-3 Alkyl, -OH, or -OC 1-4 is alkyl; R 7 is C 1-2 Alkyl (0 to 1 R 8 and 0 to 1 R 9 ), 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 4- to 6-membered heterocyclyl (O, S(=O) p , N and NR d and 0 to 4 R e ) and R 8 is halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-4 alkyl (substituted with 0-3 halo or OH); 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 , H, C 1-4 Alkyl (0 to 2 R 11 ), -C(=O)R b , -C(=O)OR b or -C(=O)NR a R a and; R a , H, C 1-5 Alkyl (0 to 4 R e ), C 2-5 Alkenyl (0 to 4 R e ), C 2-5 Alkynyl (0 to 4 R e substituted with -(CH2) n -C 3-10 Carbocyclyl (0 to 4 R e substituted with -(CH2) n -heterocyclyl (0 to 4 R e or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl (0-4 R e (which is replaced by); R b , H, C 1-5 Alkyl (0 to 4 Re ), C 2-5 Alkenyl (0 to 4 R e ), C 2-5 Alkynyl (0 to 4 R e substituted with -(CH2) n -C 3-10 Carbocyclyl (0 to 4 R e substituted with -(CH2) n -heterocyclyl (0 to 4 R e ) and R c is C 1-5 Alkyl (0 to 4 R e ), C 2-5 Alkenyl (0 to 4 R e ), C 2-5 Alkynyl (0 to 4 R e ), C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, C 1-6 Alkyl (0 to 5 R g ), C 2-6 Alkenyl (0 to 5 R g ), C 2-6 Alkynyl (0 to 5 R g substituted with -(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 , halo, CN, OH, C 1-6 Alkyl, or C 3-6 is cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, or 2] or a pharma- ceutically acceptable salt thereof.

[0016] In a third aspect within the first and second aspects, the present invention provides a compound of formula (III): [ka] [In formula: R 2 Ha-OC 1-3 is alkyl; R 4a is F; R 4b is CF3; R 6 is a halo; R 7 is C 1-2 Alkyl (0 to 1 R 8 and 0 to 1 R 9 ), -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 1-4 alkyl (substituted with 0-3 halo or OH); R 9 -OR b , -NR a R a , -NR a C(=O)R b or -OC(=O)NR a R a and; R a , H, C 1-4 Alkyl (0 to 3 R e substituted with -(CH2) n -C 3-6 Cycloalkyl (0 to 3 R e ), or phenyl (substituted with 0 to 3 R e) and R b is H or heterocyclyl (0 to 3 R e ) and R e is halo, CN, =O, or C 1-6 is alkyl; n is 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0017] In a fourth aspect within the second aspect, the present invention provides a method for producing a composition comprising the steps of: R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5 but [ka] and; R 6 is halo, -OH, or C 1-4 alkyl (substituted with 0-1 OH); R 7 is C 1-2 Alkyl (0 to 1 R 8 and 0 to 1 R 9 ) and R 8 -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 C 1-4 Alkyl (0 to 1 R 11 ) and R 11 is -OH, -C(=O)OH, or aryl; R a is H or C 1-3 is alkyl; R b is H or C 1-3 is alkyl, There is provided a compound of formula (II) or a pharma- ceutically acceptable salt thereof:

[0018] In a fifth aspect within the second aspect, the present invention provides a method for producing a composition comprising the steps of: R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5 but [ka] and; R 6 But, Halo, C 1-4 Alkyl, -OH, or -OC 1-4 is alkyl; R 7 C 1-4 Alkyl (0 to 1 R 8 and 0 to 1 R 9 ) and R 8 -C(=O)OR b and; R 9 is OH; R 10 But, H, C 1-3 Alkyl (0 to 2 R 11 ) or -C(=O)OC 1-4 is alkyl; R 11 is -OH, -C(=O)OH, or aryl; R b is H or C 1-3 is alkyl, There is provided a compound of formula (II) or a pharma- ceutically acceptable salt thereof:

[0019] In a sixth aspect within the second aspect, the present invention provides a method for producing a composition comprising the steps of: R 2 is -OCH3; R 4a is F; R 4b is CF3; R 5 C 2-5 Alkynyl (0 to 1 R 7 ) and R 7 -OR b and; R b But, H, C 1-3 Alkyl, or phenyl (0 to 2 R e ) and R e But, Halo, C 1-3 Alkyl, or C(=O)OR f And; R f is H or C 1-3 is alkyl, There is provided a compound of formula (II) or a pharma- ceutically acceptable salt thereof:

[0020] In the compounds of formula (I), R 1 , R 2 , R 3 , 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 range as an example of a variable substituent, including, may be used independently of any other range as an example of a variable substituent. Thus, the present invention encompasses combinations of different embodiments.

[0021] In one embodiment of formula (II) or (III), R 4a is F. In one embodiment of formula (II) or (III), R 4b is CF3.

[0022] In one embodiment of Formula (III), R 2 is -OCH3; R 4a is F;R 4b is CF3; R 5 teeth [ka] ;R 6 is F;R 8 -C(=O)OH, -C(=O)NHR a or CF3; R 9 Ha-NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl or -OC(=O)NHR a ;R a is H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl, or -(CH2) 0-1 -phenyl (0 to 2 R e substituted with R b is H or heterocyclyl; R e is C 1-3 Alkyl, -(CH2) 0-1 OR f And;R f is H or C 1-3 It is an alkyl.

[0023] In one embodiment of Formula (II), R 2 is -OCH3; R 4a is F;R 4b is CF3; R 5 teeth [ka] ;R 7 is C 1-4 Alkyl (0 to 1 R 9 substituted with R 9 is -OH; R 10 is -C(=O)R b ;R b is H or C 1-3 Alkyl (0 to 4 R e substituted with R e Ha-(CH2) 0-1 OR f And;R f is H or C 1-3 It is an alkyl.

[0024] Unless otherwise specified, these terms have the following meanings: "Halo" includes fluoro, chloro, bromo and iodo. "Alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C 10 Alkyl" or "C 1-10 "Alkyl" (or alkylene) is any of the following alkyl groups: C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 It is intended to include alkyl groups. Additionally, for example, "C1-C6 alkyl" or "C1-C6 alkyl" refers to an alkyl having 1 to 6 carbon atoms. The alkyl group can be unsubstituted or substituted such that at least one hydrogen is replaced with another chemical group. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to indicate a direct bond. "Alkyl" also includes deuterated alkyls such as CD3.

[0025] "Alkenyl" or "alkenylene" is intended to include a hydrocarbon chain in either a straight or branched configuration having one or more, preferably one to three, carbon-carbon double bonds, which may occur at any stable point along the chain. For example, "C2-C6 alkenyl" or "C 2-6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups, such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl. "Alkynyl" or "alkynylene" is intended to include a hydrocarbon chain in either a straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds, which may occur at any stable point along the chain. For example, "C2-C6 alkynyl" or "C 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0026] "Carbocycle", "carbocyclyl", or "carbocyclic moiety" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As noted above, bridged rings are also included in the definition of carbocyclyl (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. When the term "carbocyclyl" is used, it is intended to include "aryl", "cycloalkyl", and "spirocycloalkyl". Preferred carbocyclyls, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.

[0027] "Cycloalkyl" is intended to mean a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems. "C3-C7 cycloalkyl" or "C 3-7"Cycloalkyl" is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyls include 1-decalinyl, norbornyl, and adamantyl. "Spirocycloalkyl" is intended to mean a hydrocarbon bicyclic ring system in which both rings are connected through a single atom. The rings can be of different sizes and nature or of the same size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.

[0028] "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 5- or 6-membered carbocyclic ring that is saturated, partially unsaturated, or unsaturated. A bicyclic carbocyclic group may be attached to its pendant group at any carbon atom that results in a stable structure. The bicyclic carbocyclic groups described herein may be substituted on any carbon, provided 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.

[0029] An "aryl" group refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and are described, for example, in Lewis, RJ (ed.), Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). "Benzyl" means a methyl group in which one of the hydrogen atoms is replaced by a phenyl group, where the phenyl group is optionally substituted with 1 to 5 groups, preferably 1 to 3 groups.

[0030] "Heterocycle", "heterocyclyl" or "heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered mono- or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and is intended to include any polycyclic group in which any of the above heterocyclic rings are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., [ka] and S(O) p where p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R, as defined, is H or another substituent). A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in a heterocyclyl may optionally be quaternized. It is preferred that if the total number of S and O atoms in a heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in a heterocyclyl is at most 1. Bridged rings are also included in the definition of heterocyclyl. When the term "heterocyclyl" is used, it is intended to include heteroaryl.

[0031] Examples of heterocyclyl include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetra ...4aH-carbazolyl, 4aH-carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 4aH-carbazolyl, 4aH-carbazolyl, 4aH-carbazolyl, 4aH-carbazolyl, 4aH-carbazolyl, 4aH-carbazolyl, 4aH-carbazolyl, 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 aryl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, phteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, Pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-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.

[0032] A "bicyclic heterocycle", "bicyclic heterocyclyl" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system containing two fused rings and consisting of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S. One of the two fused rings is a 5- or 6-membered monocyclic aromatic ring consisting of a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a saturated, partially unsaturated or unsaturated 5- or 6-membered polycyclic ring consisting of a 5-membered heterocyclyl, a 6-membered heterocyclyl or a carbocyclyl (with the proviso that if the second ring is a carbocyclyl then the first ring is a ring other than benzo).

[0033] 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 on carbon or nitrogen atom if the resulting compound is stable.If the total number of S and O atoms in heterocyclyl is more than 1, then it is preferred that these heteroatoms are not adjacent to each other.It is preferred that the total number of S and O atoms in heterocyclyl is at most 1.

[0034] 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.

[0035] "Heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups may be substituted or unsubstituted. Nitrogen atoms may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., [ka] and S(O) p where p is 0, 1 or 2).

[0036] As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a group other than hydrogen, provided that normal valence is maintained and the replacement results in a stable compound. If the substituent is keto (i.e., =O), then two hydrogens on the atom are replaced. Keto substituents are not present in aromatic moieties. If a ring system (e.g., a carbocyclic or heterocyclic ring system) is likely to be substituted with a carbonyl group or double bond, the carbonyl group or double bond is intended to be part of the ring (i.e., within the ring). As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0037] Where there are nitrogen atoms (e.g., amines) on the compounds of the invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to give other compounds of the invention. Thus, the depicted and claimed nitrogen atoms are the same as the depicted nitrogen and its N-oxide. [ka] It is believed that this applies to both the amide and its derivatives.

[0038] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, then the group may be optionally substituted with up to three R groups, where R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0039] When a bond to a substituent is shown across a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom to which such substituent is attached to the remainder of the compound of a given formula, then such substituent may be bonded through any atom of such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0040] The present invention encompasses all pharma- ceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those 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 techniques and commercially available reagents. Some forms of anionic salts include acetate, acetositolate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xynofoate. Some forms of cationic salts include ammonium, aluminum, vanzatin, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0041] Throughout the specification and the appended claims, a given chemical formula or name encompasses all such stereoisomers and optical isomers, as well as racemates, when isomers exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemates are within the scope of the present invention. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are non-superimposable. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species, where the composition lacks optical activity.

[0042] The present invention encompasses all tautomers, atropisomers and rotamers of the compounds. All processes used to prepare compounds of the present invention and intermediates made along the way are considered to be part of the present invention. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" are used as described herein to indicate the atomic configuration relative to a core molecule and are consistent with the literature (IUPAC R e The term "compounds" is intended to be used as defined in the 1996 Commendations, Pure and Applied Chemistry, 68:2193-2222 (1996).

[0043] The term "chiral" refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image. The term "homochiral" refers to the state of being enantiomerically pure. The term "optically active" refers to the angle that a homochiral molecule or a nonracemic mixture of chiral molecules rotates the plane of polarized light.

[0044] The present invention is intended to include all isotopes of atoms present in a compound. Isotopes include those atoms having the same atomic number but different mass numbers. By way of example, and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon are 13 C and 14 The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, using appropriately isotopically labeled reagents in place of unlabeled reagents used in other methods. Such compounds may have a variety of potential uses, for example, as standards or reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to advantageously modify biological, pharmacological, or pharmacokinetic properties.

[0045] Throughout the specification and the appended claims, a given chemical formula or name will encompass all stereoisomers and optical isomers as well as the racemates thereof, if 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, ring systems, etc., can also exist in the compounds, and all such stable isomers are intended to be included in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described, which may be isolated as a mixture of isomers or as separate isomers. The compounds of the present invention may be isolated in optically active or racemic forms. Optically active forms may be prepared by resolving racemic forms or by synthesis from optically active starting materials. All processes used to prepare the compounds of the present invention and intermediates prepared herein are considered to form part of the present invention. When enantiomeric or diastereomeric products are prepared, the products may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in either free (neutral) or salt form. Both free and salt forms of these end products are within the scope of the invention. If desired, one form of the compound can be converted into another form. The free base or acid can be converted into a salt; the salt can be converted into the free compound or into another salt; the mixture of isomeric compounds of the invention can be separated into the individual isomers. The compounds of the invention, both in their free form and in their salts, may exist in several tautomeric forms, in which hydrogen atoms are transferred to other parts of the molecule and the chemical bonds between the atoms of the molecule are consequently rearranged. It should be understood that all tautomeric forms, insofar as they exist, are included within the scope of the invention.

[0046] The term "stereoisomer" refers to isomers that have the same constitution but differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are non-superimposable. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The terms "racemate" or "racemic mixture" refer to a composition composed of equimolar amounts of two enantiomeric species, wherein the composition lacks optical activity.

[0047] 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 20 mM HEPES, 0.05% BSA, and 0.5 mM IBMX. Cells (3000 cells per well except for HEK293 cells stably expressing human RXFP1, which had 1500 cells per well) were added to 384-well Proxiplates (Perkin-Elmer). Cells were immediately treated with test compounds in DMSO (2% final) at final concentrations ranging from 0.010 nM to 50 μM. Cells were incubated at room temperature for 30 min. Intracellular cAMP levels were measured using the HTRF HiRange cAMP Assay Reagent Kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and d2 fluorescently labeled cAMP were prepared separately in the supplied lysis buffer. After the end of the reaction, cells were lysed with equal volumes of d2-cAMP and anti-cAMP solutions. After incubation for 1 h at room temperature, time-resolved fluorescence intensity was measured at an excitation wavelength of 400 nm and dual emission wavelengths of 590 and 665 nm using an Envision (Perkin-Elmer). A calibration curve was constructed by plotting the ratio of the fluorescence intensity at 665 nm emission to the fluorescence intensity at 590 nm emission versus cAMP concentration using external cAMP standards at concentrations ranging from 2.7 μM to 0.1 pM. The potency and activity of compounds in inhibiting cAMP production were then measured by plotting cAMP levels versus compound concentration and fitting them to a four-parametric logistic equation.

[0048] The examples disclosed below were tested in the human RXFP1 (hRXFP1) HEK293 cAMP assay described above and found to have agonist activity. Table A shows the EC50 values ​​in the hRXFP1 HEK293 cAMP assay measured for the examples. 50 Enumerate values.

[0049] [Table 1]

[0050] Pharmaceutical Compositions and Methods of Use The compounds of formula (I) are RXFP1 receptor agonists and may find use in the treatment of medical indications such as heart failure, fibrotic diseases, and associated diseases such as pulmonary disease (e.g., idiopathic pulmonary fibrosis), renal disease (e.g., chronic renal disease), or liver disease (e.g., non-alcoholic steatohepatitis, and portal hypertension).

[0051] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier. Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier for treating a relaxin-related disorder. Another aspect of the present invention is a method of treating a relaxin-associated disease, comprising administering an effective amount of a compound of formula (I).

[0052] Another aspect of the present invention is a method for treating cardiovascular disease, comprising administering to a patient in need thereof an effective amount of a compound of formula (I). Another aspect of the present invention is a method for treating heart failure, comprising administering to a patient in need thereof an effective amount of a compound of formula (I). Another aspect of the present invention is a method of treating fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0053] Another aspect of the present invention is a method for treating a disease associated with fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). Another aspect of the present invention is a method for treating or preventing renal failure, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). Another aspect of the invention is a method of improving, stabilizing or restoring renal function in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I).

[0054] Unless otherwise stated, the following terms have the meanings indicated. The term "patient" or "subject" refers to any human or non-human organism that may benefit from treatment with RXFP1 agonist, as substituted by those skilled in the art.Exemplary subjects include 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).

[0055] "Treating" or "treatment", as will be understood by those of skill in the art, extends to the treatment of a condition and includes: (a) inhibiting the condition, i.e., arresting its onset; (b) alleviating the condition, i.e., causing regression of the condition; and / or (c) preventing the onset of the disease in a mammal, particularly when such mammal is predisposed to suffering from the condition but has not yet been diagnosed as such.

[0056] "Preventing" or "prevention", as understood by those skilled in the art, covers prophylactic treatment (i.e., prevention and / or risk reduction) of subclinical conditions aimed at reducing the probability of occurrence of a clinical condition. Patients are selected for prophylactic treatment based on factors known to increase the risk of suffering from a clinical condition compared to the general population. "Preventive" therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in subjects who have not yet exhibited a clinical condition, whereas secondary prevention is defined as preventing the secondary onset of the same or similar clinical condition. "Risk reduction" or "risk reduction" covers therapy that reduces the incidence of a clinical condition. Primary and secondary prevention therapies are themselves examples of risk reduction.

[0057] "Therapeutically effective amount" is intended to include an amount of a compound of the invention that is effective when administered alone or in combination with other agents to treat a disorder, as understood by those skilled in the art. When applied to a 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.

[0058] "Cardiovascular system disorders" or "cardiovascular disorders" include, for example, the following disorders: hypertension (high blood pressure), peripheral vascular and cardiovascular disorders, coronary heart disease, stable and unstable angina, heart attack, myocardial insufficiency, abnormal heart rhythm (or arrhythmia), persistent ischemic dysfunction ("hibernating myocardium"), transient post-ischemic dysfunction ("stunned myocardium"), heart failure, impaired peripheral blood flow, acute coronary syndromes, heart failure, myocardial disease (cardiomyopathy), myocardial infarction, and vascular diseases (vascular disease).

[0059] "Heart failure" includes both acute and chronic manifestations of heart failure, as well as progressive heart failure, cardiac-renal syndrome following 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, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure secondary to congenital heart injury, valvular heart disease, heart failure secondary to valvular heart disease, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, aortic regurgitation, complex These include more specific or associated types of the disease such as heart failure associated with valvular heart disease, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with cardiac reservoir disease, 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.

[0060] "Fibrotic disorders" encompasses, inter alia, the following diseases and disorders characterized by fibrogenesis, including liver fibrosis, cirrhosis, NASH, pulmonary fibrosis, myocardial fibrosis, endocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic disorders due to diabetes, myelofibrosis and similar fibrotic disorders, scleroderma morphea, keloids, hypertrophic scars (even after surgery), nevi, diabetic retinopathy, proliferative vitreoretinopathy, and disorders of connective tissue (e.g., sarcoidosis). Relaxin-related disorders include, but are not limited to, cardiovascular and fibrotic disorders.

[0061] The compounds of the present invention can be administered by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or time release formulations), pills, powders, granules, elixirs, tinctures, suspensions (nano-suspensions, micro-suspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories.The compounds can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0062] "Pharmaceutical composition" refers to the composition comprising the compound of the present invention in combination with at least one additional pharmaceutical acceptable carrier. "Pharmaceutical acceptable carrier" refers to the medium generally accepted in the art for delivering biologically active agent to animals, particularly mammals, including adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, perfumes, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the characteristics of administration mode and dosage form.

[0063] Pharmaceutically acceptable carriers are formulated according to many factors well within the purview of one of ordinary skill in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to whom the drug-containing composition is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include many different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for a variety of reasons, such as stabilization of the active agent, binders, etc., as are well known to those of ordinary skill in the art. A description of suitable pharmacologic acceptable carriers and the factors involved in their selection can be found, for example, in Allen, LV et al., R. e These compounds are described in a variety of readily available sources, such as McMillan, Mington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0064] The administration regimen of the compounds of the invention will, of course, vary according to known factors such as the pharmacological properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; type of concurrent treatment; frequency of treatment; route of administration; the renal and hepatic function of the patient; and the desired effect.

[0065] As a general guideline, the daily oral dose of each active ingredient, when used to obtain the indicated effects, will be in the range of about 0.01 to about 5000 mg per day, preferably about 0.1 to about 1000 mg per day, and most preferably about 0.1 to about 250 mg per day. For intravenous administration, the most preferred dose will be in the range of about 0.01 to about 10 mg / kg / min at a constant rate infusion. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three or four times daily.

[0066] The compounds are typically administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (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 practice.

[0067] A dosage form (pharmaceutical composition) suitable for administration may contain about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will usually be incorporated in an amount of about 0.1% by weight-95% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and filled into a No. 1 gelatin capsule. A typical injectable formulation is produced by placing at least one compound of the present invention (250 mg) in a vial under aseptic conditions, freeze-drying it under aseptic conditions, and sealing it. At the time of use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.

[0068] 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, antilipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemia agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenosis agents, anti-pancreatic agents, lipid lowering agents, anorexic agents, memory enhancing agents, anti-dementia agents, cognition enhancing agents, appetite suppressants, heart failure therapeutic agents, peripheral arterial disease therapeutic agents, malignant tumor therapeutic agents, and anti-inflammatory agents.

[0069] Additional therapeutic agents include ACE inhibitors, beta-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine A1 receptor agonists, partial adenosine A1 receptors, dopamine beta-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists biased towards agonism to select cell signaling pathways, angiotensin II receptor antagonists combinations of sedatives and neprilysin enzyme inhibitors, neprilysin enzyme inhibitors, soluble guanylate cyclase activators, myosin ATPase activators, rho-kinase 1 inhibitors, rho-kinase 2 inhibitors, apelin receptor agonists, nitroxyl-donating compounds, calcium-dependent kinase II inhibitors, antifibrogenic agents, galectin-3 inhibitors, vasopressin receptor antagonists, FPR2 receptor modulators, natriuretic peptide receptor agonists, transient receptor potential vanilloid-4 channel blockers, antiarrhythmic agents, tentative (I f ) "Funny current" channel blockers, nitrates, digitalis compounds, cardiac inotropes and β-receptor agonists, cell membrane resealing agents, e.g., poloxamer 188, antihyperlipidemic agents, plasma HDL-raising agents, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (HMG CoA reductase inhibitors), LXR agonists, FXR agonists, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, anion exchange resins, quaternary amines, cholestyramine, colestipol, low density lipoprotein receptor inducers, clofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrizol, vitamin B6, vitamin B12, antioxidant vitamins, antidiabetic agents, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives, PCSK9 inhibitors, aspirin, and P2Y12 inhibitors such as clopidogrel.

[0070] Additional therapeutic agents also include nintedanib, pirfenidone, LPA1 antagonists, LPA1 receptor antagonists, GLP1 analogs, traloquinucab (IL-13, AstraZeneca), vismodegib (hedgehog antagonist, Roche), PRM-151 (Pentraxin-2, TGF beta-1, Promedior), SAR-156597 (Bispecific Mab IL-4 & IL-13, Sanofi), simtuzumab (anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inhibitor / pentoxifylline / NAC oral controlled release, Pacific These agents may also include omipalisib (oral PI3K / mTOR inhibitor, from GSK), IW-001 (oral solution, modified bovine collagen V, from ImmuneWorks), STX-100 (integrin alpha V / beta-6 ant, from Stromedix / Biogen), Actimun (IFN gamma), PC-SOD (midismase; inhalant, from LTT Bio-Pharma / CKD Pharm), lebrikizumab (anti-IL-13 SC humanized mAb, from Roche), AQX-1125 (SHIP1 activator, from Aquinox), CC-539 (JNK inhibitor, from Celgene), FG-3019 (from FibroGen), SAR-100842 (from Sanofi), and obeticholic acid (OCA or INT-747, from Intercept).

[0071] The other therapeutic agents described above, when utilized in combination with the compounds of the present invention, may be used, for example, in those amounts set forth in the Physicians' Desk Reference, as in the patents mentioned above, or in amounts otherwise determined by one of skill in the art.

[0072] There is a possibility of chemical interaction between the combined active ingredients, especially when provided as a single dosage unit. For this reason, when the compound of the present invention and another therapeutic agent are combined in a single dosage unit, the active ingredients are combined in a single dosage unit, but are formulated so that the physical contact between the active ingredients is minimized (i.e., reduced). For example, one of the active ingredients 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 adjust the release of one of the ingredients in the digestive tract, so that one of the ingredients is not released in the stomach, but rather in the intestine. Also, one of the active ingredients may be coated with a material that affects the sustained release through the entire digestive tract and further serves to minimize the physical contact between the combined active ingredients. Furthermore, the sustained release ingredient may be further enteric coated so that the release of this ingredient occurs only in the intestine. Yet another solution would involve formulating the active ingredients into a combination product in which one component is coated with a sustained release and / or enteric polymer and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropylmethylcellulose (HPMC) or other suitable material known in the art to further separate the active ingredients. The polymer coating serves to form an additional barrier to interaction with the other component.

[0073] The compounds of the present invention are also useful as standard or control compounds, for example as quality standards or controls, 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 present invention may be used as controls in assays to compare their known activity with compounds of unknown activity. This allows the experimental researcher to ensure that the assay has been performed properly, and provides a basis for comparison, especially when the test compound is a derivative of the control compound. When developing new assays or protocols, the compounds of the present invention may be used to test their effectiveness. The compounds of the present invention may also be used in diagnostic assays involving RXFP1.

[0074] The present invention also encompasses articles of manufacture. As used herein, articles of manufacture includes, but is not limited to, kits and packages. The articles of manufacture of the present invention include (a) a first container; (b) a pharmaceutical composition contained within the first container, the composition comprising a first therapeutic agent comprising a compound of the present invention or a pharma- ceutically acceptable salt form thereof; and (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemia and its sequelae. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as described above) with a second therapeutic agent for the treatment of dyslipidemia and its sequelae. The articles of manufacture may further include (d) a second container, where components (a) and (b) are contained within the second container and component (c) is placed inside or outside the second container. Placed within the first and second containers means that each container holds items within its boundaries.

[0075] A first container is a container used to hold a pharmaceutical composition. This container can be for manufacturing, storing, and / or selling individually / in bulk. It is intended that the first container also encompasses bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

[0076] The second container is a container that is used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard boxes or plastic boxes), crates, cartons, bags (e.g., paper bags or plastic bags), pouches and sacks. The package insert can be physically attached to the outside of the first container via tape, adhesive, staples, or another attachment means, or can be fastened to the inside of the second container without being attached to the first container by any physical means. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, adhesive, staples, or another attachment means. Alternatively, the package insert can be adjacent to or in contact with the outside of the second container without being physically attached.

[0077] The package insert is a label, tag, marker, etc. that describes information about the pharmaceutical composition that is located in the first container. The information described will usually be determined by the regulatory agency (e.g., the United States Food and Drug Administration) governing the geographic area in which the product is intended to be sold. The package insert preferably 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, wheels, adhesive-backed paper or plastic, etc.) on which the desired information is formed (e.g., printed or coated).

[0078] chemical method The compounds of the invention can be made by a variety of methods known in the art, including those described in the schemes below and in the specific embodiments section. The structure and variable numbering shown in the synthetic schemes is different from, and should not be confused with, the structure or variable numbering in the claims or the remainder of the specification. The variables in the schemes are only meant to illustrate how to make some of the compounds of the invention.

[0079] It will also be appreciated that another major consideration in planning any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functionalities present in the compounds described in this invention. An authoritative text describing the many options for those skilled in the art is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0080] Abbreviations are: "1x" for 1, "2x" for 2, "3x" for 3, "°C" for Celsius, "aq" for aqueous, "eq" or "equiv" for equivalent, "g" for gram, "mg" for milligram, "L" for liter, "mL" for milliliter, "μL" for microliter, "N" for normal, "M" for mole, "nM" for nanomole, "pM" for picomole, "mol" for mole, "mmol" for millimole, "min" for minute, "h" for hour, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrated, "aq" for aqueous, "sat." for saturated, "MW" for molecular weight, and "MS" or "Mass" for mass spectrometry. Spec," for Electron Spray Ionization or Mass Spectroscopy, "ESI," for Liquid Chromatography-Mass Spectroscopy, "LC-MS," for Liquid Chromatography-Mass Spectroscopy, "HPLC," for High Pressure Liquid Chromatography, "RP HPLC," for Reverse Phase HPLC, "NMR," for Nuclear Magnetic Resonance Spectroscopy, "SFC," for Supercritical Fluid Chromatography, and " 1 "H", "δ" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for "broad", "Hz" for Hertz, "MHz" for Megahertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to those of skill in the art.

[0081] [Table 2] [Table 3]

[0082] In the illustrated examples, the following methods were used unless otherwise noted. Purification of intermediates and final products was carried out via either normal phase or reverse phase chromatography. Normal phase chromatography was carried out using pre-packed SiO2 cartridges eluting with a gradient of either hexanes and ethyl acetate or DCM and MeOH unless otherwise noted. Reverse phase preparative HPLC was performed on a C18 column with UV 220 nm or with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or with a gradient of solvent A (95% water, 5% ACN, 0.1% TFA) and solvent B (5% water, 95% ACN, 0.1% TFA), or with a gradient of solvent A (95% water, 2% ACN, 0.1% HCOOH) and solvent B (98% ACN, 2% water, 0.1% HCOOH), or with a gradient of solvent A (95% water, 5% ACN, 10 mM NH4OAc) and solvent B (98% ACN, 2% water, 10 mM Preparative LCMS detection was performed eluting with a gradient of solvent A (98% water, 2% ACN, 0.1% NH4OH) and solvent B (98% ACN, 2% water, 0.1% NH4OH) in a gradient of 1000 mL ...

[0083] The LC / MS methods utilized for characterization of the examples are listed below. Analytical HPLC Method A: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0084] Analytical HPLC Method B Conditions: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0085] Analytical HPLC Method C Conditions: Column: Sunfire C18, 3.0 x 150 mm, 3.5 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 0.05% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water + 0.05% trifluoroacetic acid; Gradient: 0% B to 100% B over 12 minutes; Flow rate: 0.5 mL / min; Detection: UV (220 nm and 254 nm).

[0086] NMR used in the characterization of the examples 1 The H NMR spectrum shows the following frequencies: 1 H NMR: Obtained using a Bruker Fourier transform spectrometer operating at 400 MHz (Bruker) or 500 MHz (Bruker). Spectral data are reported in the format: chemical shift (multiplicity, coupling constant, number of hydrogens). Chemical shifts are specified in ppm downfield of the internal tetramethylsilane standard (δ units, tetramethylsilane = 0 ppm) and / or 1 In the H NMR, the solvent peaks are referenced, which appear at 2.51 ppm for DMSO-d6, 3.30 ppm for CD3OD, 1.94 ppm for CD3CN, and 7.24 ppm for CDCl3.

[0087] Scheme I shows how the compounds of the invention can be prepared from the racemic intermediate I-1, a known compound whose synthesis is described in Org. Lett. 2012, 14, 4, 1110-1113. The benzyl ester at I-1 is subjected to hydrogenolysis to give the methyl ester / carboxylic acid I-2. The amine at I-3 is introduced as the Teoc carbamate by Curtius rearrangement. The remaining ester is subjected to hydrolysis and coupled with an amine or aniline to give I-4. The carbamate is cleaved under acidic conditions such as HCl in dioxane or TFA in CH2Cl2 to give amines suitable for coupling with various carboxylic acids (I-5) using standard amine coupling reagents such as HATU or BOP to give Example 1.

[0088] [ka]

[0089] Scheme II illustrates a general route to mandelic acid-based biaryl analogs. Commercially available II-1 was converted to t-butyl ester II-2, which was then brominated to give II-3. The bromide was subjected to displacement with acetic acid to give intermediate II-4, which was then subjected to Suzuki reaction to provide intermediate 8 (cleavage of the acetate was performed simultaneously with biaryl formation). The resulting acid was directly coupled with an amine intermediate as described in Scheme I to give II-6. The hydroxyl group in II-6 could be elaborated with either an appropriate isocyanate or a two-step carbamate formation protocol (e.g., nitrophenyl chloroformate, TEA, followed by an amine). The t-butyl ester was then cleaved (TFA / DCM) to give the compounds of the invention.

[0090] [ka]

[0091] Scheme III illustrates a route to generate substituted isoxazoline analogs. III-1 was treated with NaOCl followed by a substituted olefin, followed by saponification of the ester to give intermediates III-2. These intermediates were coupled with amines according to the methods outlined in Scheme I to give compounds of the invention.

[0092] [ka]

[0093] Scheme IV illustrates the photochemical [2+2] reaction for making the core structures of benzo-fused embodiments of the invention. Indene IV-1 reacts with monobenzyl maleate IV-2 in the presence of a suitable photocatalyst such as (Ir[dF(CF3)ppy]2(dtbpy))PF6 upon exposure to blue or violet LED light to give [2+2] adducts IV-3 and IV-4 (benzo-fused regioisomers resulting from an endo-cycloaddition reaction), IV-5 and IV-6 (benzo-fused regioisomers resulting from an exo-cycloaddition reaction), and IV-7, IV-8, IV-9, and IV-10 (trans isomers of IV-3 through IV-6).

[0094] [ka]

[0095] Scheme V illustrates the synthesis of benzo-fused analogs using an intermediate in Scheme IV, IV-3 as an example, but not limited to, IV-3. IV-3 can be subjected to Curtius rearrangement to give V-1. The remaining benzyl ester is subjected to hydrogenolysis and standard amine coupling conditions with the appropriate amine V-2 to give V-3. The carbamate in V-3 is cleaved under acidic conditions such as HCl in dioxane or TFA in CH2Cl2 to give amines suitable for coupling with various carboxylic acids (V-4) using standard amine coupling reagents such as HATU or BOP to give compounds of general structure V-5.

[0096] [ka]

[0097] Intermediate 1- cis-6-benzyl 7-methyl-bicyclo[3.2.0]heptane-6,7-dicarboxylate [ka]

[0098] Intermediate 1 was prepared as a racemate using the method described in Org. Lett. 2012, 14, 4, 1110-1113.

[0099] Intermediate 2- 5-(3-hydroxyprop-1-yn-1-yl)-2-methoxybenzoic acid [ka]

[0100] Preparation of Intermediate 2A- Methyl 5-(3-hydroxyprop-1-yn-1-yl)-2-methoxybenzoate To methyl 5-bromo-2-methoxybenzoate (3.0 g, 12 mmol) and propargyl alcohol (1.5 mL, 25 mmol) slurried in TEA (31 mL) was added Pd(PPh3)4 (0.28 g, 0.25 mmol) and CuI (0.023 g, 0.12 mmol). The vessel was agitated with N2 and heated at 80 °C for 16 h. The reaction mixture was partitioned between water and EtOAc, the organic layer was separated and dried over Na2SO4. The organic layer was decanted and concentrated under vacuum, and the residue was loaded onto an 80 g ISCO column and eluted with a linear gradient of 0% to 100% EtOAc in hexane to give methyl 5-(3-hydroxyprop-1-yn-1-yl)-2-methoxybenzoate (1.3 g, 6.1 mmol, 50% yield). 1H NMR(500MHz, CDCl3)δ 7.92(d,J=2.1Hz,1H), 7.56(dd,J=8.7,2.3Hz,1H), 6.95(d,J=8.7Hz,1H), 4.50(d,J=6.1Hz, 2H), 3.94(s,3H), 3.91(s,3H), 1.64(t,J=6.1Hz,1H);MS(ESI)m / z 221.1(M+H) +

[0101] Intermediate 2: To a reaction vial of 2 dram was added intermediate 2A (50 mg, 0.23 mmol), THF (1 mL), water (0.5 mL), and LiOH monohydrate (35 mg, 0.85 mmol). The reaction mixture was stirred at 23° C. for 1 h, diluted with EtOAc (10 mL), and washed with saturated NH4Cl containing 1.5 mmol HCl. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 2, which was used without further purification (47 mg, 0.23 mmol). LC-MS RT: 0.76 min; MS(ESI) m / z=206.8 (M+H). +

[0102] Intermediate 3 (Chiral Peak-1), Intermediate 4 (Chiral Peak-2): 2-Methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoic acid: [ka]

[0103] Preparation of Intermediate 3A: Methyl (E)-5-((hydroxyimino)methyl)-2-methoxybenzoate: Commercially available methyl 5-formyl-2-methoxybenzoate (1.16 g, 6.00 mmol) was dissolved in DCM (5 mL) and HONH2·HCl (415 mg, 6.00 mmol) was added to the solution followed by TEA (1 mL) and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x25 mL). The organic layers were combined, dried over MgSO4 and concentrated to dryness in vacuo to give Intermediate 3A (1.2 g, 95%) as a white solid.1 H NMR (400MHz, CDCl3)δ 8.13(s,1H), 8.03(d,J=2.4Hz,1H), 7.78-7.67(m,1H), 7.03(d,J=8.8Hz,1H), 3.97(s,3H), 3.93(s,3H);LCMS(ESI)m / z=210.1(M+H) +

[0104] Preparation of Intermediate 3B: Methyl (Z)-5-(chloro(hydroxyimino)methyl)-2-methoxybenzoate: Intermediate 3A (23 g, 0.10 mol) was dissolved in DMF (100 mL) and to this solution was added NCS (15 g, 0.10 mol) and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with water (300 mL) at which point a solid formed which was collected by filtration. The filtered solid was then dried under vacuum to give Intermediate 3B (23 g, 86% yield) as a pale yellow solid. LCMS (ESI) m / z: = 244.1 (M+H). +

[0105] Preparation of Intermediate 3C: Methyl 2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoate: To a mixture of Intermediate 3B (0.4 g, 2 mmol) and 2,5-dihydrofuran (1.2 g, 17 mmol) in DCM (10 mL), TEA (0.7 mL, 5.2 mmol) was added and the reaction mixture was stirred for 24 h. The solvent was removed under reduced pressure and the residue was loaded onto a 40 g ISCO column and eluted with a linear gradient of 0% to 10% MeOH in CHCl to give Intermediate 3C (0.40 g, 83% yield). 1 H NMR (500MHz, CDCl3)δ 7.98(d,J=2.3Hz,1H), 7.86(dd,J=8.8, 2.4Hz,1H), 7.04(d,J=8.7Hz,1H), 5.38(dd,J=9.2, 3.9Hz,1H), 4.34-4.26(m ,2H), 4.20-4.09(m,1H), 3.96(s,3H), 3.91(s,3H), 3.83-3.76(m,1H), 2.92-2.70(m,1H);LCMS(ESI)m / z=278.3(M+H) +

[0106] Chiral intermediates 3D and 3E: The following chiral intermediates were prepared from intermediate 3C by the following preparative chromatographic method (apparatus: Berger MG II Separation was performed using chiral SFC with column: Chiralpak IA, 21x250mm, 5 micron, mobile phase: 20% MeOH / 80% CO2, flow conditions: 45mL / min, 150 bar, 40°C, detector wavelength: 220nm) and analytical method (Apparatus: Shimadzu Nexera SFC, column: Chiralpak IA, 4.6x100mm, 3 micron, mobile phase: 20% MeOH / 80% CO2, flow conditions: 2mL / min, 150 bar, 40°C, detector wavelength: 220nm) to give chiral intermediate 3D (Peak-1, RT=3.80min, >99%ee) and chiral intermediate 3E (Peak-2, RT=7.43min, >98%ee).

[0107] Preparation of intermediate 3: 2-Methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoic acid: To a solution of intermediate 3D (75 mg, 0.30 mmol) in THF (3 mL) was added MeOH (0.6 mL) followed by LiOH (2M, 0.4 mL, 0.8 mmol). After 4 h, the reaction mixture was diluted with water (20 mL) and the solution was brought to pH=4-5 with HCl (1N). The reaction mixture was extracted with EtOAc (2x25 mL) and the organic layers were combined, dried (MgSO4) and concentrated to dryness under reduced pressure to give intermediate 3 (71 mg, 100% yield). 1 H NMR(400MHz, CD3OD)δ 7.78(d,J=2.3Hz,1H), 7.71(dd,J=8.7, 2.3Hz,1H), 7.09(d,J=8.8Hz,1H), 5.33(dd,J=9.2, 3.6Hz,1H), 4.44(ddd,J=8.9, 7.2, 1.3Hz,1H), 4.18(d,J= 10.6Hz,1H), 4.08(dd,J=9.4, 1.0Hz,1H), 3.91-3.88(m,3H), 3.86(dd,J=9.4, 6.9Hz,1H), 3.73(dd,J=10.7, 3.7Hz,1H);LCMS(ESI)m / z:=264.1(M+H) +

[0108] Preparation of Intermediate 4: 2-Methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoic acid: Intermediate 3E (52 mg, 0.2 mmol, 100% yield) was prepared in a similar manner to Intermediate 3, except that Intermediate 3E was used instead of Intermediate 3D. 1 H NMR (500MHz, CD3OD) δ 8.10(d,J=2.4Hz,1H), 7.87(dd,J=8.8, 2.4Hz,1H), 7.23(d,J=8.7Hz,1H), 5.3 8(dd,J=9.2, 3.7Hz,1H), 4.47(ddd,J=8.9, 7.2, 1.2Hz,1H), 4.22(d,J=10.7Hz, 1H), 4.12(q,J=7.1Hz,1H), 4.07(dd,J=9.5, 0.9Hz,1H), 3.97(s,3H), 3.88(dd ,J=9.5, 6.9Hz,1H), 3.76(dd,J=10.8, 3.6Hz,1H);LCMS(ESI)m / z:=264.1(M+H) +

[0109] Intermediate 5C: 5-(5-hydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid [ka]

[0110] Intermediate 5 was prepared as a mixture of four isomers in a similar manner to Intermediate 3C by substituting cyclopent-3-en-1-ol instead of cyclopent-3-en-1-ylmethanol, followed by ester hydrolysis as described for Intermediate 3, to give a diastereomeric mixture of Intermediate 5. 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);MS(ESI)m / z=292.0(M+H) +

[0111] The isomers of intermediate 5 were separated by chiral SFC using the following preparative chromatography method: Apparatus: Berger SFC (LVL-L4021 Lab) Column: IC 25x3cm ID, 5μm, Temperature: 40°C, Flow rate: 85mL / min, Mobile phase: 75 / 25 CO2 / MeOH to 45% MeOH gradient over 12 min; Detector wavelength: 235nm, Injection volume: 1000μL to give intermediate 5A (Peak 1, >99%ee, Analytical RT=8.80min), intermediate 5B (Peak 2, >95%ee, Analytical RT=9.86min), intermediate 5C (Peak 3, >99%ee, Analytical RT=13.53min), intermediate 5D (Peak 4, >99%ee, Analytical RT=16.67min). Analytical chromatographic conditions: Instrument: Agilent SFC (LVL-L4021 Lab), Column: IC 250x4.6mmID, 5μm, Temperature: Ambient, Flow rate: 2.0mL / min, Mobile phase: 75 / 25 CO2 / MeOH to 45% MeOH gradient in 12 minutes. Analytical data for peaks 1-4: 1 H 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); 13C NMR (151MHz, CD3OD)δ 169.5, 161.6, 160.0, 133.2, 131.4, 122.6(2C), 113.9, 87.3, 72.7, 56.8, 51.5, 44.1, 40.3

[0112] Intermediate 6: (S)-5'-(1-((cyclobutylcarbamoyl)oxy)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0113] Preparation of Intermediate 6A: 1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol 3-Bromo-4-fluorobenzaldehyde (0.2 g, 1.2 mmol) was dissolved in DMF (3.5 mL), and (trifluoromethyl)trimethylsilane (0.30 mL, 2.3 mmol) and K2CO3 (8.0 mg, 58 μmol) were added to the solution. The reaction mixture was stirred at room temperature for 60 min, and HCl (2N, 3 mL) was added. After stirring at room temperature for an additional 1 h, the reaction mixture was diluted with EtOAc (15 mL), and the solution was washed with saturated NH4Cl (25 mL). The aqueous phase was extracted with EtOAc (2x10 mL), dried (Na2SO4), concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give intermediate 6A (0.2 g, 0.8 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)

[0114] Preparation of Intermediate 6B: (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol (S)-2-Phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole (0.4 g, 1.6 mmol) and intermediate 6A (11 g, 40 mmol) were dissolved in diisopropyl ether (134 mL) and cooled to between 0° C. and −20° C. The solution was then treated with isobutyl anhydride (4 mL, 24 mmol) and transferred to a freezer (−20° C. for 18 h). The reaction was quenched with phosphate buffer using MeOH (1 mL), the resulting solution was extracted with EtOAc (2×25 mL), and the organic extracts were dried (MgSO4) and concentrated under reduced pressure to a residue which was purified by normal phase chromatography using hexane / EtOAc as eluent to give intermediate 6B (5.0 g, 18 mmol, 44% yield, >99% ee). 1 H NMR(500MHz, CDCl3)δ 7.74(dd,J=6.3, 1.9Hz,1H), 7.50-7.39(m,1H), 7.18(t,J=8.4Hz,1H), 6.71-5.53(m,1H), 5.03(q,J=6.5Hz,1H)

[0115] Preparation of Intermediate 6C: (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl cyclobutylcarbamate Intermediate 6B (0.30 g, 1.1 mmol), pyridine (0.40 mL, 5.5 mmol), and DMAP (13 mg, 0.10 mmol) were dissolved in DCM (20 mL) and 4-nitrophenyl carbonochloridate (1.0 g, 5.5 mmol) was added. The reaction mixture was stirred for 1 h, followed by the addition of cyclobutanamine (0.78 g, 11 mmol). After 2 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by normal phase chromatography using hexanes / EtOAc as eluent to give Intermediate 6C (0.35 g, 0.90 mmol, 85% yield) as a white solid. LCMS (ESI) m / z 369.7-371.7 (M+H). +

[0116] Intermediate 6: Preparation of (S)-5'-(1-((cyclobutylcarbamoyl)oxy)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid In a sealed vial, intermediate 6C (0.3 g, 0.8 mmol), 5-borono-2-methoxybenzoic acid (0.2 g, 1 mmol), PdCl2(dppf)-DCM (98 mg, 0.12 mmol), Na2CO3 (0.3 g, 3.2 mmol), THF (12 mL) and H2O (2.9 mL) were added. 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 HCl (1N) and extracted with EtOAc (2x25 mL). The organic extracts were combined, dried (Na2SO4), concentrated under reduced pressure and purified by reverse phase chromatography to give intermediate 6 (72 mg, 0.16 mmol, 20% yield). LCMS (ESI) m / z 442.0 (M+H) +

[0117] Intermediate 8: 5'-(2-(tert-butoxy)-1-hydroxy-2-oxoethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0118] Intermediate 8A: Intermediate 8A was prepared using known conditions (Ludwig, J.; Lehr, M. Syn. Comm. 2004, 34, 3691-3695) for similar substrates, except 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)

[0119] Intermediate 8B: To a 20 mL reaction vial charged with intermediate 8A (266 mg, 0.920 mmol), NBS (196 mg, 1.10 mmol), carbon tetrachloride (10 mL), and AIBN (15 mg, 0.090 mmol) were added. The solution was stirred at 77° C. for 3 hours, cooled to room temperature, concentrated under reduced pressure, and purified by normal phase silica gel chromatography to give intermediate 8B (308 mg, 0.840 mmol, 91.0% yield).

[0120] Intermediate 8C: To a 2-dram vial charged with Intermediate 8B was added ethyl acetate (2 mL), triethylamine (0.27 mL, 2.0 mmol), and acetic acid (0.1 mL, 2 mmol). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by normal phase silica gel chromatography to give Intermediate 8C. 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)

[0121] Intermediate 8: To a reaction vessel containing Intermediate 8C (51 mg, 0.15 mmol), 5-borono-2-methoxybenzoic acid (37 mg, 0.19 mmol), PdCl2(dppf)-CH2Cl2 adduct (24 mg, 0.030 mmol), and Na2CO3 (93 mg, 0.88 mmol) were added. The reaction mixture was purged with nitrogen for 3 min, sealed, and stirred at 65 °C for 2 h. After cooling to 23 °C, the reaction mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to produce Intermediate 8. Half of the material was isolated as the O-acetate (85 mg, 0.60 mmol, 34%); 1H NMR (500 MHz, CDCl3) δ 8.43-8.36 (m, 1H), 7.81 (dt, J = 8.7, 2.0 Hz, 1H), 7.56 (dd, J = 7.3, 2.3 Hz, 1H), 7.45 (ddd, J = 8.5, 4.6, 2.3 Hz, 1H), 7.23-7.16 (m, 2H), 5.84 (s, 1H), 4.17 (s, 3H), 2.23 (s, 3H), 1.45 (s, 9H); while the other half was isolated as the free alcohol (70 mg, 0.19 mmol, 31%); 1 H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 2.2 Hz, 1H), 7.82 (dt, J = 8.6, 2.2 Hz, 1H), 7.54 (dd, J = 7.4, 2.5 Hz, 1H), 7.41 (ddd, J = 8.4, 4.8, 2.2 Hz, 1H), 7.19-7.14 (m, 2H), 5.09 (s, 1H), 4.16 (s, 3H), 1.47 (s, 9H). Racemic intermediate 8 was separated into its individual enantiomers using chiral SFC. Preparative Chromatography Conditions: Instrument: Berger MG II; Column: ChiralPak ID, 21x250mm, 5 micron; Mobile phase: 25%IPA / 75%CO2; Flow conditions: 45mL / min, 120 bar, 40°C; Detector wavelength: 220nm; Injection details: 8 injections of 0.36mL at approximately 20mg / mL in IPA; Analytical Chromatography Conditions: Instrument: Waters UPC2 Analytical SFC; Column: ChiralPak ID 4.6x100mm, 3 micron; Mobile phase: 25%IPA / 75%CO2; Flow conditions: 2mL / min, 150 bar, 40°C; Detector wavelength: 220nm; Peak 1, RT=3.89min, >99.5%ee; Peak 2, RT=5.44min, >99.5%ee; Intermediate 8-2 was collected in peak #2 (31% yield).

[0122] Intermediate 9: 5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoic acid [ka]

[0123] Preparation of Intermediate 9A: Methyl (E)-5-((hydroxyimino)methyl)-2-methoxybenzoate Commercially available methyl 5-formyl-2-methoxybenzoate (1.16 g, 5.97 mmol) was dissolved in CHCl (5 mL) and to this solution was added hydroxylamine·HCl (415 mg, 5.97 mmol) followed by EtN (1 mL) and the reaction mixture was stirred at room temperature for 18 h. Water (100 mL) was added and the solution was extracted with EtOAc (2×25 mL) and the combined organic portions were dried (MgSO), filtered and evaporated under reduced pressure to yield intermediate 9A (1.2 g, 95% yield). 1 H NMR (400MHz, CDCl3)δ 8.13(s,1H), 8.03(d,J=2.4Hz,1H), 7.78-7.67(m,1H), 7.03(d,J=8.8Hz,1H), 3.97(s,3H), 3.93(s,3H);MS(ESI)m / z=210.1(M+H) +

[0124] Intermediate 9B: Preparation of methyl 5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoate Intermediate 9A (55 mg, 0.26 mmol) was dissolved in DMF (2 mL), NCS (35 mg, 0.26 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 4 h. Water (10 mL) was added, the solution was extracted with EtOAc (2x25 mL), the organic portions were combined, dried (MgSO4), filtered, concentrated under reduced pressure, and the residue was immediately redissolved in DCM (5 mL). Allyl alcohol (61 mg, 1.1 mmol) was added to the solution, followed by TEA (0.5 mL), and the resulting reaction mixture was stirred at room temperature for 18 h. Water (20 mL) was added, the solution was extracted with EtOAc (2x20 mL), the organic portions were combined, dried (MgSO4), filtered, and purified by normal phase chromatography eluting with hexane / EtOAc to give Intermediate 9B (58 mg, 85% yield). 1H NMR (500MHz, CDCl3)δ 8.05(d,J=2.4Hz,1H), 7.89(dd,J=8.8, 2.4Hz,1H), 7.05(d,J=8.9Hz,1H), 4.90(dddd,J=10.8, 7.7, 4.6, 3.2Hz,1H), 4. 08-3.85(ss,6H), 3.81-3.68(m,1H), 3.46-3.36(m,1H), 1.89(brt,J=6.2Hz,1H), 1.57(s,2H);MS(ESI)m / z=266.1(M+H) +

[0125] Intermediate 9C: Intermediate 9B (58 mg, 0.22 mmol) was dissolved in THF (2 mL) and LiOH (6.3 g, 0.26 mmol) was added followed by water (2 mL) and methanol (1 mL) and stirred at room temperature for 4 h. HCl (1N) was added to the reaction mixture to reach a pH of 7 and the resulting solution was extracted with EtOAc (2x25 mL). The organic portions were combined, dried (MgSO4), filtered and concentrated under reduced pressure to give Intermediate 9C (640 mg, 84% yield). 1 H NMR (500MHz, CDCl3)δ 8.28(d,J=2.3Hz,1H), 8.14(dd,J=8.8, 2.4Hz,1H), 7.28-7.14(m,1H), 4.92(dddd,J=10.8, 7.7, 4.6, 3.1Hz,1H), 4.16(s,3H), 4.09-3.89 (m,1H), 3.72(dd,J=12.4, 4.6Hz,1H), 3.48-3.39(m,1H), 3.38-3.29(m,1H), 1.94-1.72(m,1H), 1.60(brs,1H);MS(ESI)m / z=252.3(M+H) +

[0126] Intermediate 9D and 9: Intermediate 9C (640 mg) was separated using the following separation method: Apparatus: Berger MG II, Column: ChiralPak IC, 21x250mm, 5 microns; mobile phase: 20% methanol / 80% CO2; flow conditions: 2mL / min, 150 bar, 40°C; detector wavelength: 220nm; injection details: inject 0.7mL of approximately 35mg / mL in MeOH to give intermediate 9C (peak 1, >99%de, analytical RT=5.6min) and intermediate 9 (peak 2, 99%de, analytical RT=6.6min), analytical chromatographic conditions: apparatus: Shimadzu Nexiera SFC (CTR-L410-SFC3), column: ChiralPak IC, 4.6x100mm, 3 microns, mobile phase: 20% methanol / 80% CO2; flow conditions: 2.0mL / min, 150 bar, 40°C, detector wavelength: 220nm; injection details: inject 5μL of approximately 1mg / mL in MeOH

[0127] Example 1: 6-Fluoro-3'-(((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0128] Example 1: Preparation of methyl (1R,5S,6R,7S)-7-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)bicyclo[3.2.0]heptane-6-carboxylate

[0129] Intermediate 1 (450 mg, 1.56 mmol) was dissolved in EtOAc (30 mL) in a 250 mL round bottom pressure flask and the solution was degassed by injecting nitrogen and stirring for 5 min. Pd-C (166 mg, 0.156 mmol) was then added under a gentle stream of nitrogen. The flask was then degassed by vacuum / backfilling with nitrogen three times and vacuum / backfilling with hydrogen twice. The flask was pressurized with 40 psi of hydrogen and stirred at room temperature for 3 h. After vacuum and backfilling with nitrogen, the reaction mixture was filtered through a plug of Celite® and the filtrate was concentrated under vacuum to give (1S,5R,6S,7R)-7-(methoxycarbonyl)bicyclo[3.2.0]heptane-6-carboxylic acid (300 mg, 1.5 mmol, 97% yield) as a clear, colorless oil, which was used without further purification. MS(ESI)m / z 199.1[M+H] + The resulting (1S,5R,6S,7R)-7-(methoxycarbonyl)bicyclo[3.2.0]heptane-6-carboxylic acid was dissolved in toluene (3 mL) in a 20 mL vial equipped with a Teflon septum cap, and Et3N (420 μl, 3.03 mmol) and DPPA (391 μl, 1.81 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, during which vigorous evolution of nitrogen began. Stirring was continued at 60° C. until gas evolution ceased. 2-(trimethylsilyl)ethan-1-ol (870 μl, 6.05 mmol) was then added and the mixture was heated at 80° C. for 26 h. The mixture was allowed to cool to room temperature and concentrated to dryness under vacuum. The residue was loaded onto a 40 g ISCO column and eluted with a linear gradient of 0% to 100% EtOAc in hexanes over 18 min with detection by ELSD. Methyl (1R,5S,6R,7S)-7-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)bicyclo[3.2.0]heptane-6-carboxylate (400 mg, 1.3 mmol, 84% yield) was isolated in racemic form as a clear, colorless oil. MS(ESI) m / z 314.2[M+H] + ; 1H NMR (500MHz, CDCl3)δ 5.68-5.39(m,1H), 4.13(brs,2H), 4.06-3.94(m,1H), 3.69(s,3H), 3.00-2.90(m,1H), 2.89-2.78( m,1H), 2.77-2.63(m,1H), 1.78(brd,J=9.0Hz,3H), 1.69-1.40(m,3H), 0.97(brs,2H), 0.04(s,9H)

[0130] Example 1-2: Preparation of 2-(trimethylsilyl)ethyl ((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamate

[0131] Example 1-1 was dissolved in a mixture of acetonitrile (3.8 mL), water (0.12 mL), and Et3N (0.53 mL, 3.8 mmol) in a 20 mL vial. LiBr (1.10 g, 12.8 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with EtOAc (50 mL) and water (50 mL), and the aqueous layer was then separated, acidified with 1N HCl, and back-extracted with EtOAc. The organic layer was separated and concentrated in vacuo to a tan powder, and 2-(trimethylsilyl)ethyl ((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamate was used in the next step without further purification. MS(ESI) m / z 300.0[M+H] +2-(Trimethylsilyl)ethyl ((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamate (240 mg, 0.80 mmol), 4-fluoro-3-(trifluoromethyl)aniline (144 mg, 0.800 mmol), and Et3N (0.22 mL, 1.60 mmol) were dissolved in DMF (2 mL). BOP (390 mg, 0.88 mmol) was added and the reaction mixture was stirred at 65° C. for 2 h. The reaction mixture was allowed to cool to room temperature and diluted with water (25 mL). A precipitate formed which was filtered and dried under vacuum to give Example 1-2, 2-(trimethylsilyl)ethyl ((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamate (460 mg, 65% yield) as a tan solid. 1 H NMR (500 MHz, CDCl3) δ 7.86-7.78(m,1H), 7.75-7.65(m,2H), 7.15(t,J=9.3Hz,1H), 5.26-5.1 5(m,1H), 4.13-4.05(m,1H), 4.02-3.91(m,2H), 3.26-3.17(m,1H), 2.97 -2.89(m,1H), 2.65-2.56(m,1H), 1.98-1.87(m,1H), 1.83-1.72(m,2H) , 1.68-1.63(m,3H), 1.59-1.49(m,1H), 0.87-0.71(m,2H), -0.02(s,9H)

[0132] Example 1-3: Preparation of (1R,5S,6R,7S)-7-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[3.2.0]heptane-6-carboxamide hydrochloride

[0133] Example 1-2 (57 mg, 0.12 mmol) was dissolved in dioxane (6 mL) and HCl (0.25 mL, 1.0 mmol) was added as a 4 M solution in dioxane. The clear solution was stirred for 1 h and then concentrated to dryness under reduced pressure. Racemic Example 1C, (1R,5S,6R,7S)-7-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[3.2.0]heptane-6-carboxamide hydrochloride (44 mg, 100%) was isolated as a brown solid. MS (ESI) m / z 317.1 [M+H] + ; 1 H NMR(500MHz, CD3OD)δ 8.13(dd,J=6.4, 2.6Hz,1H), 7.86-7.79(m,1H), 7.32(t,J=9.6Hz,1H), 3.52(dd,J=7.8, 4.4Hz,1H ), 3.11-3.00(m,2H), 2.98-2.89(m,1H), 2.04-1.93(m,1H), 1.92-1.79(m,3H), 1.76-1.58(m,2H)

[0134] Example 1-4: (1R,5S,6R,7S)-7-(5-bromo-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[3.2.0]heptane-6-carboxamide

[0135] Example 1-3 (100 mg, 0.232 mmol), 5-bromo-2-methoxybenzoic acid (54 mg, 0.23 mmol), EtN (0.032 mL, 0.23 mmol) and then HATU (88 mg, 0.23 mmol) were dissolved in DMF (2 mL) in a 20 mL vial and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200mm x 19mm, 5μm particles; Mobile phase A: 5:95 acetonitrile:water + 10mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10mM ammonium acetate; Gradient: 44% B hold for 0 min, 44-84% B over 20 min, then 100% B hold for 10 min; Flow rate: 20mL / min; Column temperature: 25°C. Fractions were started to be collected by MS and UV signal. Fractions containing the desired product were combined and dried via centrifugal evaporation. Example 1-1, (1R,5S,6R,7S)-7-(5-bromo-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[3.2.0]heptane-6-carboxamide, racemic (118 mg, 96%), was isolated as a white powder. MS(ESI) m / z 529.0[M+H] + ;MS(ESI)m / z 531.1[M+3] + ; 1 H NMR (500MHz, DMSO-d6)δ 10.26(s,1H), 8.88(brd,J=8.2Hz,1H), 8.25-8.13(m,1H), 7.79-7.66(m,1H), 7. 62-7.49(m,2H), 7.44(t,J=9.7Hz,1H), 7.06(d,J=8.8Hz,1H), 4.29(td,J=8.5,5 .1Hz,1H), 3.85-3.69(m,3H), 3.07(brdd,J=8.7, 4.1Hz,1H), 3.01-2.92(m,1H), 2.73(brd,J=5.1Hz,1H), 1.94-1.76(m,2H), 1.75-1.62(m,2H), 1.60-1.38(m,2H)

[0136] Example 1: 6-Fluoro-3'-(((1S,5R,6S,7R)-7-((4-fluoro-3-trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid

[0137] Example 1-4 (54 mg, 0.10 mmol) and 3-borono-4-fluorobenzoic acid (19 mg, 0.10 mmol) were dissolved in DMF (2 mL) in a 20 mL vial with a septum seal cap. A 3 M aqueous solution of K3PO4 (0.10 mL, 0.30 mmol) was added to the solution, and the reaction mixture was degassed via vacuum and backfilling with nitrogen three times. XPhos Pd G2 (8 mg, 10.2 μmol) was added under a gentle stream of nitrogen, and the reaction mixture was stirred at 75° C. for 30 minutes. The reaction mixture was then concentrated to dryness under reduced pressure and the residue was purified by preparative HPLC using the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 42% B hold for 0 min, 42-82% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS signal and 6-fluoro-3'-(((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (4.3 mg, 7%) was isolated in 97.1% purity (Method A, retention time: 1.78 min). MS(ESI) m / z 589.3[M;H] + ; 1H NMR (500MHz, DMSO-d6)δ 10.25(s,1H), 8.90(brd,J=8.3Hz,1H), 8.12(brd,J=3.2Hz,1H), 8.02-7.90(m,2H), 7.73(brs,2H), 7.64(brd,J=8.6Hz,1H), 7.39(brt,J=9.3Hz,1H), 7.34(brt,J=9.7Hz,1H), 7.21(d,J=8.5Hz,1H),4. 39-4.26(m,1H), 3.86(s,3H), 3.08(brdd,J=8.9, 4.2Hz,1H), 3.02-2.93(m,1H), 2.79-2.71(m,1H), 1 .95-1.76(m,2H), 1.73(brdd,J=12.2, 5.5Hz,1H), 1.66(brdd,J=12.5, 5.7Hz,1H), 1.60-1.42(m,2H)

[0138] Example 2: (1R,5S,6R,7S)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(5-(3-hydroxyprop-1-yn-1-yl)-2-methoxybenzamido)bicyclo[3.2.0]heptane-6-carboxamide [ka]

[0139] Example 2: Example 2 was prepared by coupling Example 1-3 (100 mg, 0.32 mmol) with 5-(3-hydroxyprop-1-yn-1-yl)-2-methoxybenzoic acid (65 mg, 0.32 mmol) using the general procedure described for Examples 1-4. Example 2 (153 mg, 96%) was isolated in 95% purity.

[0140] Example 7: Preparation of 2-(6-fluoro-3'-(((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-((phenylcarbamoyl)oxy)acetic acid [ka]

[0141] Example 7-1: Preparation of tert-butyl 2-(6-fluoro-3'-(((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-hydroxyacetate

[0142] Example 7-1 was prepared using the general coupling procedure described for preparing Example 1-4, substituting Intermediate 8-2 (43 mg, 0.11 mmol) for 5-bromo-2-methoxybenzoic acid to give tert-butyl 2-(6-fluoro-3'-(((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-hydroxyacetate (61 mg, 80% yield). MS (ESI) m / z 589.3 [M+H] +

[0143] Example 7-2: tert-Butyl 2-(6-fluoro-3'-(((1S,5R,6S,7R)-7-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[3.2.0]heptan-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-hydroxyacetate (60 mg, 0.089 mmol) and pyridine (0.072 mL, 0.89 mmol) were dissolved in CHCl (4 mL) in a 2-dram vial, followed by the addition of phenyl isocyanate (0.10 mL, 0.89 mmol). The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was loaded onto a 40 g ISCO column and eluted with a linear gradient of 0% to 100% EtOAc in hexanes. MS(ESI)m / z 794.3(M+H) +

[0144] Example 7: Example 7-2 was dissolved in CH2Cl2 (4 mL) and TFA (1 mL). The resulting solution was stirred at room temperature for 2 hours. After concentrating to dryness under reduced pressure, the residue was purified by preparative HPLC under the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 45% B hold for 0 minutes, 45-85% B over 20 minutes, then 100% B hold for 4 minutes; Flow rate: 20 mL / min; Column temperature: 25°C. Fractions were started to be collected by MS and UV signals.

[0145] The resulting mixture of diastereomers was separated by chiral SFC using the following conditions: Column: Chiral OD, 30x250mm, 5 micron particles; Mobile phase: 75% CO2 / 25% MeOHw / 0.1% DEA; Flow conditions: 100mL / min; Detector wavelength: 220nm; Injection details: 4.4mg dissolved in 3mL MeOH and inject 1,500μL.

[0146] Peak 1 elutes at 25.7 minutes. Peak 2 (Example 7) eluted at 31.4 minutes.

[0147] The peak was purified and then analyzed for enantiomeric purity using the following analytical conditions: Column: Chiral OD, 4.6x100mm, 5 micron, Mobile phase 75%CO2 / 25%MeOHw / 0.1%DEA, Flow conditions: 2.0mL / min, 150 bar, 40°C, Detector wavelength: 220nm, Injection details: 10μL injection of approximately 1mg / mL in MeOH.

[0148] Peak 1 (>95% ee) is the diastereomer of Example 7. 11H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.87 (brs, 1H), 8.97 (d, J = 8.5 Hz, 1H), 8.17 (dd, J = 6.6, 2.3 Hz, 1H), 7.89 (s, 1H), 7.80 - 7.71 (m, 1H), 7.61 (brt, J = 9.9 Hz, 2H), 7.53 (brdd, J = 5.0, 2.6 Hz, 1H), 7.48 (brd, J = 7.9 Hz, 2H), 7.39 (t, J = 9.8 Hz, 1H), 7.35 - 7.26 (m, 3H), 7.23 (d, J = 8.9 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 5.85 (s, 1H), 4.41 - 4.34 (m, 1H), 3.87 (s, 2H), 3.14 - 3.07 (m, 1H), 3.03 - 2.93 (m, 1H), 2.78 - 2.71 (m, 1H), 1.92 - 1.79 (m, 2H), 1.75 (brdd, J = 12.4, 5.3 Hz, 1H), 1.69 (brdd, J = 12.7, 6.0 Hz, 1H), 1.61 - 1.53 (m, 1H), 1.53 - 1.45 (m, 1H)

[0149] Peak 2 (>95% ee) is Example 7. MS (ESI) m / z 738.1 [M + H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.94 - 9.78 (m, 1H), 8.96 (d, J = 8.5 Hz, 1H), 8.17 (dd, J = 6.4, 2.4 Hz, 1H), 7.88 (s, 1H), 7.79 - 7.71 (m, 1H), 7.66 - 7.57 (m, 2H), 7.56 - 7.51 (m, 1H), 7.48 (brd, J = 7.6 Hz, 2H), 7.42 - 7.35 (m, 1H), 7.34 - 7.26 (m, 3H), 7.26 - 7.20 (m, 1H), 7.06 - 6.97 (m, 1H), 5.85 (s, 1H), 4.41 - 4.32 (m, 1H), 3.87 (s, 2H), 3.14 - 3.06 (m, 1H), 3.01 - 2.92 (m, 1H), 2.79 - 2.70 (m, 1H), 1.93 - 1.78 (m, 2H), 1.79 - 1.71 (m, 1H), 1.72 - 1.64 (m, 1H), 1.62 - 1.53 (m, 1H), 1.53 - 1.44 (m, 1H), 1.28 - 1.20 (m, 1H)

[0150] Examples 2, 3, and 5 in Table 1 below were prepared by the general procedures described in Examples 1 & 7. [Table 4] [Table 5]

[0151] It will be apparent to those skilled in the art that the present disclosure is not limited to the illustrative embodiments described above, and that the disclosure may be embodied in other specific forms without departing from its essential attributes. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, and reference should be made to the appended claims rather than to the embodiments described above, and all changes that come within the meaning and range of equivalence of the claims are intended to be embraced therein.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: 【Chemistry 2】 is an optional bond; R １ is H or halo; or R １ and R １ together form a phenyl ring; R ２ Ha, Haro, C １－４ Alkyl, OH, or -OC １－４ Alkyl (0-4 halo, OH, or -OC １－４ substituted with alkyl; R ４ａ is a halo; R ４ｂ is C １－４ alkyl (substituted with 0-4 halo); R ５ is C ２－８ Alkenyl (0 to 3 R ６ and 0 to 2 R ７ substituted with), C ２－８ Alkynyl (0 to 3 R ６ and 0 to 2 R ７ substituted with), C ６－１２ Aryl (0 to 3 R ６ and 0 to 2 R ７ substituted with), or 3- to 12-membered heterocyclyl (O, S(=O) ｐ , N and N 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 is halo, =O, -OH, -OC １－４ Alkyl, or C １－４ alkyl (substituted with 0-2 halo or OH); R ７ is C １－３ Alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ C(=O)NR ａ R ａ , -NR ａ S (=O) ｐ R ｃ , -C(=O)R ｂ , -C(=O)OR ｂ , -C(=O)NR ａ R ａ , -C(=O)NR ａ S (=O) ｐ R ｃ , -OC(=O)R ｂ , -S(=O) ｐ R ｃ , -S(=O) ｐ N.R. ａ R ａ , C ３－６ Cycloalkyl, or 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N and N ｄ and 0 to 5 R ｅ substituted with; R ８ is halo, -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－４ alkyl (substituted with 0-3 halo or OH); R ９ is -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ S (=O) ｐ R ｃ , -NR ａ S (O) ｐ N.R. ａ R ａ , -OC(=O)NR ａ R ａ , -OC(=O)NR ａ OR ｂ , -S(=O) ｐ N.R. ａ R ａ or -S(O) ｐ R ｃ and R １０ is H, C １－４ Alkyl (0 to 2 R １１ substituted with —C(═O)R ｂ , -C(=O)OR ｂ , -C(=O)NR ａ R ａ , C ３－６ Cycloalkyl (0 to 5 R ｅ substituted with), or 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N and N １２ and 0 to 5 R ｅ 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, C １－６ Alkyl (0 to 5 R ｅ substituted with), C ２－５ alkenyl (0 to 5 R ｅ substituted with), C ２－６ Alkynyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -heterocyclyl (0 to 5 R ｅ or R ａ and R ａ together with the nitrogen atom to which they are both attached, form heterocyclyl (0-5 R ｅ substituted with; R ｂ is H, C １－６ Alkyl (0 to 5 R ｅ substituted with), C ２－６ Alkenyl (0 to 5 R ｅ substituted with), C ２－６ Alkynyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with -(CH ２ ) ｎ -heterocyclyl (0 to 5 R ｅ substituted with; R ｃ is C １－５ Alkyl (0 to 5 R ｅ substituted with), C ２－５ alkenyl (0 to 5 R ｅ substituted with), C ２－５ Alkynyl (0 to 5 R ｅ substituted with), C ３－６ carbocyclyl, or heterocyclyl; R ｄ is H or C １－４ is alkyl; R ｅ is halo, CN, =O, C １－６ Alkyl (0 to 5 R ｇ substituted with), C ２－６ alkenyl (0 to 5 R ｇ substituted with), C ２－６ Alkynyl (0 to 5 R ｇ substituted with -(CH ２ ) ｎ -C ３－６ Cycloalkyl, -(CH ２ ) ｎ -aryl, -(CH ２ ) ｎ -heterocyclyl, -(CH ２ ) ｎ OR ｆ or -C(=O)OR ｆ and R ｆ is H or C １－３ is alkyl; R ｇ is halo, CN, OH, C １－６ Alkyl, C ３－６ cycloalkyl, or aryl; n is 0, 1, 2, or 3; p is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

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

2. The compound of claim 1, wherein:

3. Formula (III): 【Chemistry 4】 [In the formula: R ２ Ha-OC １－３ is alkyl; R ４ａ is F; R ４ｂ is CF ３ and R ６ is a halo; R ７ is C １－２ Alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with -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 １－４ alkyl (substituted with 0-3 halo or OH); R ９ is -OR ｂ , -NR ａ R ａ , -NR ａ C(=O)R ｂ or -OC(=O)NR ａ R ａ and R ａ is H, C １－４ Alkyl (0 to 3 R ｅ substituted with -(CH ２ ) ｎ -C ３－６ Cycloalkyl (0 to 3 R ｅ phenyl (substituted with 0 to 3 R ｅ substituted with; R ｂ is H or heterocyclyl (0 to 3 R ｅ substituted with; R ｅ is halo, CN, =O, or C １－６ is alkyl; n is 0 or 1. or a pharma- ceutically acceptable salt thereof.

4. R ２ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ but 【Chemistry 5】 and R ６ is halo, -OH, or C １－４ alkyl (substituted with 0-1 OH); R ７ is C １－２ Alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with; R ８ is -C(=O)OR ｂ , -C(=O)NHR ａ or -C(=O)NHOR ｂ and R ９ Yes - OR ｂ Or -NR ａ R ａ and R １０ is H, -C(=O)R ｂ , or C １－４ Alkyl (0 to 1 R １１ substituted with; R １１ is -OH, -C(=O)OH, or aryl; R ａ is H or C １－３ is alkyl; R ｂ is H or C １－３ is alkyl, 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

5. R ２ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ but 【Chemistry 6】 and R ６ But, Halo, C １－４ Alkyl, -OH, or -OC １－４ is alkyl; R ７ C １－４ Alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with; R ８ -C(=O)OR ｂ and R ９ is OH; R １０ But, H, C １－３ Alkyl (0 to 2 R １１ substituted with -C(=O)OC １－４ is alkyl; R １１ is -OH, -C(=O)OH, or aryl; R ｂ is H or C １－３ is alkyl, 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

6. R ２ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ C ２－５ Alkynyl (0 to 1 R ７ substituted with; R ７ Ga-OR ｂ and R ｂ But, H, C １－３ alkyl, or phenyl (0 to 2 R ｅ substituted with; R ｅ But, Halo, C １－３ Alkyl, or C(=O)OR ｆ Wherein; R ｆ is H or C １－３ is alkyl, 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

7. 13. A pharmaceutical composition comprising a compound of claim 1 and a pharma- ceutically acceptable carrier.

8. A method for treating a relaxin-related disease, comprising administering a therapeutically effective amount of the composition of claim 7 to a patient in need of treatment.

9. 9. The method of claim 8, wherein the disease is selected from the group consisting of angina, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and cardiac ectopic damage.

10. 10. The method of claim 9, wherein the disease is heart failure.

11. The method of claim 8, wherein the disease is fibrosis.

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