Benzothiophene RXFP1 agonists

Abstract

The present disclosure relates to compounds of formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them in the treatment of, for example, heart failure, fibrotic diseases, and related diseases such as pulmonary diseases (e.g., idiopathic pulmonary fibrosis), renal diseases (e.g., chronic kidney disease), or hepatic diseases (e.g., non-alcoholic steatohepatitis and portal hypertension). 1 , X 2 , R 1 , R 2 , and R 4 is as defined in the specification. TIFF2024546946000192.tif46145

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 289,848, 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 receptor for relaxin 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 and as a result of 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 by 2030, an additional 3 million people will have HF in the United States alone, a 25% increase from 2010. In 2010, the estimated direct costs associated with HF (in 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 benzothiophene analogs, or stereoisomers, tautomers, pharma- ceutically acceptable salts, or solvates thereof, 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: X 1 and X 2 are N or CR, respectively. 1 where X 1 and X 2 but not both N; R 1 H, halo, C 1-4 Alkyl (substituted with 0-5 halo), or C 3-6 is cycloalkyl; R 2 is phenyl (1 to 3 R 3 and one R 5 substituted with O, S(=O) p , N, and N 2a and 0 to 3 R 3 and 0 to 1 R 5 ) and R 2a is H or C 1-3 alkyl (substituted with 0-2 halo or -OH); R 3 , halo, CN, OH, C 1-4 Alkyl, or -OC 1-4 Alkyl (0-5 halo, OH, -OC 1-4 substituted with alkyl, aryl, or heterocyclyl; R4 is C 1-6 Alkyl (0-5 halo, CN, OH, or OC 1-3 substituted with alkyl), -(CR d R d ) 0-1 -C 3-10 -Cycloalkyl (0 to 2 R 4a or 0 to 2 R 4b phenyl (substituted with 0 to 2 R 4a or 0 to 2 R 4b ), -(CR d R d ) n -3 to 12 membered heterocyclyl (O, S(=O) p , N, NH, and N.C. 1-3 alkyl, 1 to 4 heteroatoms selected from 4a or 0 to 2 R 4b ) and R 4a or R 4b is halo, CN, or C 1-4 Alkyl (0-5 halo, OH, or -OC 1-4 substituted with alkyl(substituted with 0-5 halo); R 5 -NR 5a R 5a , -(CH2) 1-2 -NR 5b R 5b , -C(=O)NR 5b R 5b , -S(=O) p NR 5b R 5b , C 3-6 Alkyl (substituted with 0-2 OH), 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 3-12 Carbocyclyl (0 to 3 R 6 and 0 to 2 R 7substituted 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 ) and R 5a and R 5a together with the nitrogen atom to which they are both attached form a heterocyclyl (O,S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 (which is replaced by); R 5b is H or C 1-6 Alkyl (0 to 3 R 6 and 0 to 2 R 7 or R 5b and R 5b and together with the nitrogen atom to which they are both attached form a heterocyclyl (O, S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 (which is replaced by); R 6 are halo, CN, =O, -OH, -OC 1-4 Alkyl, or C 1-4 alkyl (substituted with 0-2 halo or OH); R 7 is C 1-6 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(=O)NR a S(=O) p R c , C 3-6 Carbocyclyl (0 to 5 R e substituted with), 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)NR a R a , -C(=O)NR a OR 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 C(=O)NR a R a , -NR a S(=O) p R c , -NR a S(=O) p NR a R a , -OC(=O)NRa R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , -S(=O) p R c , or -OP(=O)(OH)2, -(CH2) n -C 3-6 Carbocyclyl (0 to 3 R e substituted with -(CH2) n -Heterocyclyl (O, S(=O) p and N; e ) 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(=O)C(=O)OR b , -S(=O) p R c , C 3-6 Carbocyclyl (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 -OR b , -C(=O)OR b , -C(=O)NR a R a , -S(=O) p R c or aryl; R 12 , H, C 1-4 is alkyl, or aryl; R a , 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 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 1-6 Alkyl (0 to 5 R e ), C 2-6 Alkenyl (0 to 5 R e ), C 2-6 Alkynyl (0 to 5 R e ), C 3-6 carbocyclyl, or heterocyclyl; R d is H or C 1-4 is alkyl; R e Halo, CN, NO2, =O, C 1-6 Alkyl (0 to 5 R g ), C 2-6Alkenyl (0 to 5 R g ), C 2-6 Alkynyl (0 to 5 R g substituted with -(CH2) n -Carbocyclyl (0 to 5 R g substituted with -(CH2) n -heterocyclyl (0 to 5 R g substituted with -(CH2) n OR f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f , -S(=O) p NR f R f , -NR f S(=O) p R f , -NR f C(=O)OR f , -OC(=O)NR f R f , or -(CH2) n NR f R f and; R f , H, C 1-6 Alkyl (0 to 1 -OC 1-4 substituted with alkyl), C 3-6 cycloalkyl, aryl, or heterocyclyl; or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclyl; R g are halo, CN, OH, S(=O) p C 1-3 Alkyl, 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: X 1 is N or CR 1 and; R 1 is H, halo or C 1-3 alkyl(substituted with 0-4 halo); R 2 teeth [ka] and; R 2a is C 1-3 alkyl(substituted with 0-1 -OH); R 3 Halo, C 1-3 Alkyl, or -OC 1-4 alkyl(substituted with 0-4 halo); R 4a is a halo; R 4b is C 1-4 alkyl(substituted with 0-4 halo); R 5 -NR 5a R 5a , -C(=O)NR 5b R 5b , C 2-6 Alkenyl (0 to 3 R 6 and 0 to 2 R 7 ), C 2-6 Alkynyl (0 to 3 R 6 and 0 to 2 R 7 ), C 3-6 Cycloalkyl (0 to 3 R 6 and 0 to 2 R 7 phenyl (substituted with 0 to 3 R 6 and 0 to 2 R7 substituted with), or 3- to 10-membered heterocyclyl (O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 ) and R 5a and R 5a together with the nitrogen atom to which they are both attached form a heterocyclyl (O,S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 (which is replaced by); R 5b is H or C 1-5 Alkyl (0 to 1 R 6 and 0 to 1 R 7 or R 5b and R 5b together with the nitrogen atom to which they are both attached form a heterocyclyl (O,S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 (which is replaced by); R 6 are halo, CN, =O, -OH, -OC 1-3 Alkyl, or C 1-3 alkyl (substituted with 0-2 halo or OH); R 7 is C 1-5 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 Ra , -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 (0 to 5 R e substituted with), 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 , -S(=O)p R c or -OP(=O)(OH)2; 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(=O)C(=O)OR b , -S(=O)R c , 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 -OH, -C(=O)OR b , -C(=O)NR a R a , or -S(=O)2R c and; R 12 , H, C 1-3 is alkyl, or aryl; R a , H, 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 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); Rb , H, 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 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 1-3 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 -C6 aryl, -(CH2) n -heterocyclyl, -(CH2) n OR f , -C(=O)OR f , or -S(=O) p R f and; R f is H or C 1-3 Alkyl (0 to 1 -OC 1-4substituted with 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.

[0016] In a third aspect within the first and second aspects, the present invention provides a compound of formula (III): [ka] [In formula: R 1 is C 1-3 alkyl(substituted with 0-3 halo); R 3 is halo, C 1-2 Alkyl, or -OC 1-4 is alkyl; R 4a is a halo; R 4b is C 1-3 alkyl(substituted with 0-4 F); R 5 -NR 5a R 5a , -C(=O)NR 5b R 5b , C 2-6 Alkenyl (0 to 2 R 6 and 0 to 2 R 7 ), C 2-6 Alkynyl (0 to 2 R 6 and 0 to 2 R 7 ), C 3-6 Cycloalkyl (0 to 2 R 6 and 0 to 2 R 7 phenyl (substituted with 0 to 2 R 6 and 0 to 2 R 7 substituted with), or 3- to 10-membered heterocyclyl (O, S(=O) p , N and NR10 and 0 to 3 R 6 and 0 to 1 R 7 ) and R 5a and R 5a together with the nitrogen atom to which they are both attached form a heterocyclyl (O,S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 2 R 6 and 0 to 2 R 7 (which is replaced by); R 5b is H or C 1-5 Alkyl (0 to 1 R 6 and 0 to 1 R 7 or R 5b and R 5b together with the nitrogen atom to which they are both attached form a heterocyclyl (O,S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 (which is replaced by); R 6 are halo, CN, =O, -OH, -OC 1-3 Alkyl, or C 1-3 is alkyl; R 7 is C 1-5 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 (0 to 5 R e substituted with), 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 1-3 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 1-4Alkyl (0 to 2 R 11 ), -C(=O)R b , -C(=O)OR b , -C(=O)C(=O)OR b , -C(=O)NR a R a , -S(=O)2C 1-3 Alkyl, 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 -OH, -C(=O)OR b , -C(=O)NR a R a , or -S(=O)2C 1-4 is alkyl; R 12 is H or C 1-3 is alkyl; 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 1-4 Alkyl (0 to 4 R e ), C 2-4Alkenyl (0 to 4 R e ), C 2-4 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 ) or C 3-6 is a carbocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, C 1-5 Alkyl (0 to 5 R g substituted with -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -heterocyclyl, -(CH2) n -C6 aryl, -(CH2) n -heteroaryl, -(CH2) n OR f , -C(=O)OR f , or -S(=O) p R f and; R f is H or C 1-3 is alkyl; R g , halo, CN, OH, C 1-5 Alkyl, or C 3-6 is cycloalkyl] or a pharma- ceutically acceptable salt thereof.

[0017] In a fourth aspect within the third aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 1 C 1-2alkyl(substituted with 0-3 halo); R 3 Ga-OC 1-3 is alkyl; R 4a is the halo; R 4b C 1-2 alkyl(substituted with 0-4 F); R 5 but [ka] and; R 6 are halo, =O, -OH, -OC 1-2 Alkyl, or C 1-2 is alkyl; R 7 is C 1-5 Alkyl (0 to 1 R 8 and 0 to 1 R 9 substituted with -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 , -S(=O) p R c , -S(=O) p NR a R a , or C 3-6 Cycloalkyl (0 to 2 R e ) and R 8 is halo, -C(=O)OR b or C 1-3 alkyl(substituted with 0-3 halo); R 9 -ORb , -NR a R a , -NHC(=O)R b , -NHC(=O)OR b , -NHS(=O) p R c , -NHS(=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 1-3 Alkyl (0 to 2 R 11 ), -C(=O)R b , -C(=O)OR b , -C(=O)C(=O)OR b , -C(=O)NR a R a , -S(=O)2C 1-3 Alkyl, 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 4 R e ) and R 11 is -OH, -C(=O)OH, -C(=O)OC 1-4 Alkyl, or C(=O)NR a R a and; R 12 is H or C 1-2 is alkyl; R a , H, C 1-4 Alkyl (0 to 4 R e substituted with -(CH2) 0-1 -phenyl (0 to 4 R e ), C3-6 Cycloalkyl (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 1-3 Alkyl (0 to 4 R e ), C 2-3 Alkenyl (0 to 4 R e ), C 2-3 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 is alkyl; R e is halo, CN, =O, C 1-5 Alkyl (0 to 5 R g substituted with -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -heterocyclyl, -(CH2) n -C6 aryl, -(CH2) n -heteroaryl, -(CH2) n OR f , -C(=O)OR f , or -S(=O) p R f and; R f is H or C 1-2 is alkyl; R g is halo, CN, OH, or C 1-5 is alkyl, A compound, or a pharma- ceutically acceptable salt thereof, is provided.

[0018] In a fifth aspect within the fourth aspect, the present invention provides a compound of formula (IV): [ka] [In formula: R 1 is C 1-2 alkyl(substituted with 0-3 halo); R 3 Ha-OC 1-3 is alkyl; R 4a is a halo; R 4b is C 1-2 alkyl(substituted with 0-3 halo); R 6 is halo or C 1-2 is alkyl; R 7 is C 1-2 Alkyl (0 to 1 R 8 and 0 to 1 R 9 substituted with -NR a C(=O)OR b , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(=O) p R c , -S(=O) p NR a R a , or C 3-6 Cycloalkyl (0 to 2 R e ) and R 8 is halo, -C(=O)OR b , or C 1-2 alkyl(substituted with 0-3 halo); R 9 -OR b , -NR a Ra , -NHC(=O)R b , -NHC(=O)OR b , -NHS(=O) p R c , -NHS(=O) p NR a R a , -OC(=O)NR a R a , -S(=O) p NR a R a , or -S(=O) p R c and; R a , H, C 1-3 Alkyl (0 to 4 R e substituted with -(CH2) 0-1 -phenyl (0 to 4 R e ), C 3-6 Cycloalkyl (0 to 4 R e ) or heterocyclyl (substituted with 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 1-3 Alkyl (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 1-4 is alkyl; R e is halo, CN, =O, C 1-4 Alkyl (0 to 5 R g substituted with -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n-heterocyclyl, -(CH2) n -C6 aryl, -(CH2) n -heteroaryl, -(CH2) n OR f , or -C(=O)OR f and; R f is H or C 1-2 is alkyl; R g , halo, CN, OH, C 1-4 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0019] In a sixth aspect within the first aspect, the present invention provides a compound of formula (V): [ka] [In formula: R 1 is CF3; R 3 Ha-OC 1-2 is alkyl; R 4a is F; R 4b is CF3; R 6 is a halo; R 8 -C(=O)OR b or -CF3; R 9 -OR b , -NR a R a , -NHC(=O)R b , -NHS(=O) p R c , -OC(=O)NR a R a , or -S(=O)2R c and; R a , H, C 1-3 Alkyl, -(CH2) 0-1 -phenyl (0 to 2 R e ), or C 3-6cycloalkyl; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl (0-3 R e (which is replaced by); R b , H, C 1-3 Alkyl (0 to 2 R e ), C 3-6 cycloalkyl, or heterocyclyl; R c is C 1-3 is alkyl; R e -OR f And; R f is H or C 1-2 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0020] In a seventh aspect within the fourth aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 1 is CF3; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 but [ka] and; R 6 But halo, -OH, -OC 1-2 Alkyl, or C 1-2 is alkyl; R 7 But, C 1-5 Alkyl (0 to 1 R 8 and 0 to 1 R 9 substituted with -NR a R a , or -NR a C(=O)Rb 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 ), -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , or 4- to 6-membered heterocyclyl (O, S(=O) p , N and NR 12 and 0 to 4 R e ) and R 11 is -OH, -C(=O)OH, or C(=O)NR a R a and; R 12 H and C 1-2 is alkyl; R a is H or C 1-3 is alkyl; R b is H or C 1-3 Alkyl (0 to 1 R e substituted with; R e is OH, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0021] In an eighth aspect within the seventh aspect, the present invention provides a compound of formula (V) or a pharma- ceutically acceptable salt thereof, wherein: R 5 but [ka] and; R 7 C 1-4 alkyl (substituted with 0-1 OH); R 10-C(=O)R b and; R b is H or C 1-3 Alkyl (0 to 1 R e substituted with; R e is OH, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0022] In a ninth aspect within the fourth aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 1 is CF3; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 but [ka] and; R 6 is halo, -OH, or C 1-2 is alkyl; R 7 But -NR a R a , -C(=O)NR a R a , or -S(=O)2NR a R a and; R 10 But, H, C 1-4 Alkyl (0 to 1 R 11 ), or -C(=O)R b and; R 11 is -OH or -C(=O)OH; R a is H or C 1-3 alkyl; or R a and R a and together with the nitrogen atom to which they are both attached form a heterocyclyl (0 to 3 Re (which is replaced by); R b is H or C 1-3 is alkyl; R e C 1-3 Alkyl or -(CH2) 0-1 OR f And; R f is H or C 1-3 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0023] In a tenth aspect within the ninth aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 5 but [ka] and; R 6 is halo, -OH, or C 1-2 is alkyl; R 7 But -NR a R a , -C(=O)NR a R a , or -S(=O)2NR a R a and; R a is H or C 1-3 alkyl; or R a and R a and together with the nitrogen atom to which they are both attached form a heterocyclyl (0 to 2 R e (which is replaced by); R e Ga-(CH2) 0-1 OR f And; R f is H or C 1-2 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0024] In an eleventh aspect within the third aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 1 is CF3; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 -C(=O)NR 5b R 5b and; R 5b is H or C 1-5 Alkyl (0 to 1 R 6 and 0 to 1 R 7 or R 5b and R 5b and together with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R 6 is halo, -OH, or C 1-3 is alkyl; R 7 -S(=O)2C 1-3 Alkyl, or C 3-6 Cycloalkyl (0 to 2 R e ) and R a is H or C 1-3 is alkyl; R b is H or C 1-3 is alkyl; R e -S(=O)2C 1-3 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0025] In a twelfth aspect within the scope of the eleventh aspect, the present invention relates to a compound of formula (III): or a pharma- ceutical acceptable salt thereof, wherein: R 5b is H or C 1-4 Alkyl (0 to 1 R 6 and 0 to 1 R 7 ) and R 6 is halo, -OH, or C 1-4 alkyl (substituted with 0-1 OH); R 7 -S(=O)2C 1-2 Alkyl or C 3-6 Cycloalkyl (0 to 2 R e substituted with; R e -S(=O)2C 1-3 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0026] In a thirteenth aspect within the eleventh aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 5b and R 5b and together with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R 6 is halo, -OH, or C 1-3 is alkyl; R 7 -S(=O)2C 1-3 Alkyl or C 3-6 Cycloalkyl (0 to 2 R e ) and R a is H or C 1-3 is alkyl; R b is H or C 1-3 is alkyl; R e -S(=O)2C 1-3is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0027] In a fourteenth aspect within the fourth aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 1 is CF3; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 but [ka] and; R 6 But halo, =O, -OH, -OC 1-2 Alkyl, or C 1-2 is alkyl; R 7 But, C 1-2 Alkyl (0 to 1 R 8 and 0 to 1 R 9 substituted with -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , or -C(=O)OR b and; R 8 But -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b , or C 1-2 alkyl (substituted with 0-3 halo or OH); R 9 Ga-NR a C(=O)R b and; R 10 But, H, C 1-3 Alkyl (0 to 2 R 11 ), -C(=O)Rb , -C(=O)OR b , -C(=O)C(=O)OR b , -C(=O)NR a R a , -S(=O)2C 1-3 Alkyl, 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 -OH, -C(=O)OH, -C(=O)OC 1-4 Alkyl, or C(=O)NR a R a and; R 12 is H or C 1-2 is alkyl; R a is H or C 1-3 is alkyl; R b But, H, C 1-3 Alkyl (0 to 2 R e ), C 3-6 Cycloalkyl (0 to 2 R e substituted with 0 to 2 R e ) and R e But, C 1-3 Alkyl, OH, or -NR f R f And; R f is H or C 1-3 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0028] In a fifteenth aspect within the fourteenth aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 5 but [ka] and; R 10 But, H, C 1-3 Alkyl (0 to 2 R 11 ), -C(=O)R b , -C(=O)OR b , -C(=O)C(=O)OR b , 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, -C(=O)OC 1-4 Alkyl, or C(=O)NR a R a and; R 12 is H or C 1-2 is alkyl; R a is H or C 1-3 is alkyl; R b is H or C 1-3 Alkyl (0 to 1 R e ) and R e But, C 1-3 Alkyl, OH, NR f R f And; R f is H or C 1-3 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0029] In a sixteenth embodiment within the third aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 1 is CF3; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 Ga-NR 5a R 5a and; R 5a and R 5a and together with the nitrogen atom to which they are both attached, [ka] forming a heterocyclyl selected from: R 6 is halo, -OH, or C 1-3 is alkyl; R 7 -S(=O)2C 1-3 Alkyl or C 3-6 Cycloalkyl (0 to 2 R e ) and R 10 But, H, C 1-4 Alkyl (0 to 1 R 11 ), -C(=O)R b , or -S(=O)2C 1-3 is alkyl; R 11 is -OH or -C(=O)OH; R a is H or C 1-3 is alkyl; R b is H or C 1-3 is alkyl; R e -S(=O)2C 1-3 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0030] In a seventeenth aspect within the fourth aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 5 but [ka] and; R 6 But -OH, -OC 1-2 Alkyl, or C 1-2 is alkyl; R 7 But, C 1-2 Alkyl (0 to 1 R 8 and 0 to 1 R 9 substituted with -NR a R a , -C(=O)R b , -C(=O)OR b or -C(=O)NR a R a and; R 8 is the halo; R 9 -OR b and; R a But, H, C 1-3 Alkyl, C 3-6 cycloalkyl, or heterocyclyl; or R a and R a and together with the nitrogen atom to which they are both attached form a heterocyclyl (0 to 3 R e (which is replaced by); R b But, H, C 1-3 Alkyl (0 to 1 R e substituted with), or heterocyclyl; R e -OR f And; R f is H or C 1-2 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0031] In an eighteenth embodiment within the third aspect, the present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof, wherein: R 1 is CF3; R 3 Ga-OC 1-2is alkyl; R 4a is F; R 4b is CF3; R 5 -C(=O)NR 5b R 5b , [ka] and; R 5b is H or C 1-4 Alkyl (0 to 1 R 6 and 0 to 1 R 7 or R 5b and R 5b and together with the nitrogen atom to which they are both attached, [ka] Forming; R 6 is halo, -OH, or C 1-3 is alkyl; R 7 C 1-3 Alkyl (0 to 1 R 8 and 0 to 1 R 9 substituted with -C(=O)NR a R a , -C(=O)OR b , -NR a C(=O)R b , -S(=O)2NR a R a , -S(=O)2C 1-3 Alkyl, or C 3-6 Cycloalkyl (0 to 2 R e ) and R 8 But halo, -C(=O)OR b , or C 1-3 alkyl(substituted with 0-3 halo); R 9 -OH, -NR a R a , -NR a C(=O)Rb , N.R. a S(=O) p C 1-4 Alkyl, or -OC(=O)NR a R a and; R 10 But, H, C 1-4 Alkyl (0 to 2 R 11 ), -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(=O)2C 1-3 Alkyl, 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 4 R e ) and R 11 is -OH, -C(=O)OH, -C(=O)NR a R a , or -S(=O)2C 1-4 is alkyl; R 12 is H or C 1-3 is alkyl; R a But, H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl, or -(CH2) 0-1 -heterocyclyl; or R a and R a and together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclyl (0 to 2 R e (which is replaced by); R b But, H, C 1-3 Alkyl (0 to 4 R e substituted with), or heterocyclyl; R e But, C 1-3 Alkyl, -(CH2) 0-1OR f , or -S(=O)2C 1-3 is alkyl; R f is H or C 1-3 is alkyl, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0032] In one embodiment, the present invention provides a compound of formula (VI): [ka] [In formula: R 1 is halo, C 1-3 alkyl(substituted with 0-3 halo); R 3 is halo or -OC 1-4 is alkyl; R 5 -NR 5a R 5a , -C(=O)NR 5b R 5b , C 2-6 Alkenyl (0 to 2 R 6 and 0 to 2 R 7 ), C 2-6 Alkynyl (0 to 2 R 6 and 0 to 2 R 7 ), C 3-6 Cycloalkyl (0 to 2 R 6 and 0 to 2 R 7 phenyl (substituted with 0 to 2 R 6 and 0 to 2 R 7 substituted with), or 3- to 10-membered heterocyclyl (O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 ) and R 5a and R 5a means, together with the nitrogen atom to which they are both attached, a heterocyclyl (O, S(=O) p , N, and N10 and 0 to 5 additional heteroatoms selected from 0 to 2 R 6 and 0 to 2 R 7 (which is replaced by); R 5b is H or C 1-5 Alkyl (0 to 1 R 6 and 0 to 1 R 7 or R 5b and R 5b means, together with the nitrogen atom to which they are both attached, a heterocyclyl (O, S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 (which is replaced by); R 6 are halo, CN, =O, -OH, -OC 1-3 Alkyl, or C 1-3 is alkyl; R 7 is C 1-5 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 NRa 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 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 1-3 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)C(=O)OR b , -C(=O)NR a R a , -S(=O)2C 1-3 Alkyl, C 3-6 Cycloalkyl (0 to 5 Re 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 -OH, -C(=O)OR b , -C(=O)NR a R a , or -S(=O)2C 1-4 is alkyl; R 12 is H or C 1-3 is alkyl; 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 means, together with the nitrogen atom to which they are both attached, a heterocyclyl (0-4 R e (which is replaced by); R b , H, C 1-4 Alkyl (0 to 4 R e ), C 2-4 Alkenyl (0 to 4 R e ), C 2-4 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 ) or C 3-6 is a carbocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, C 1-5 Alkyl (0 to 5 R g substituted with -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -heterocyclyl, -(CH2) n -C6 aryl, -(CH2) n -heteroaryl, -(CH2) n OR f , -C(=O)OR f , or -S(=O) p R f and; R f is H or C 1-3 is alkyl; R g , halo, CN, OH, C 1-5 Alkyl, or C 3-6 is cycloalkyl] or a pharma- ceutically acceptable salt thereof.

[0033] In another embodiment, the present invention relates to a compound of formula (VII): [ka] [In formula: R 1 H, halo, C 1-3 alkyl(substituted with 0-3 halo); R 3 is halo or -OC 1-4 is alkyl; R 5 -NR 5a R 5a , -C(=O)NR 5bR 5b , C 2-6 Alkenyl (0 to 2 R 6 and 0 to 2 R 7 ), C 2-6 Alkynyl (0 to 2 R 6 and 0 to 2 R 7 ), C 3-6 Cycloalkyl (0 to 2 R 6 and 0 to 2 R 7 phenyl (substituted with 0 to 2 R 6 and 0 to 2 R 7 substituted with), or 3- to 10-membered heterocyclyl (O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 ) and R 5a and R 5a means, together with the nitrogen atom to which they are both attached, a heterocyclyl (O, S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 2 R 6 and 0 to 2 R 7 (which is replaced by); R 5b is H or C 1-5 Alkyl (0 to 1 R 6 and 0 to 1 R 7 or R 5b and R 5b means, together with the nitrogen atom to which they are both attached, a heterocyclyl (O, S(=O) p , N, and N 10 and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 (which is replaced by); R 6 are halo, CN, =O, -OH, -OC 1-3 Alkyl, or C 1-3 is alkyl; R7 is C 1-5 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 (0 to 5 R e substituted with), 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 1-3 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 , -NRa 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)C(=O)OR b , -C(=O)NR a R a , -S(=O)2C 1-3 Alkyl, 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 -OH, -C(=O)OR b , -C(=O)NR a R a , or -S(=O)2C 1-4 is alkyl; R 12 is H or C 1-3 is alkyl; 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 means, together with the nitrogen atom to which they are both attached, a heterocyclyl (0-4 R e (which is replaced by); R b , H, C 1-4 Alkyl (0 to 4 R e ), C 2-4 Alkenyl (0 to 4 R e ), C 2-4 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 ) or C 3-6 is a carbocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, C 1-5 Alkyl (0 to 5 R g substituted with -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -heterocyclyl, -(CH2) n -C6 aryl, -(CH2) n -heteroaryl, -(CH2) n OR f , -C(=O)OR f , or -S(=O) p R f and; Rf is H or C 1-3 is alkyl; R g , halo, CN, OH, C 1-5 Alkyl, or C 3-6 is cycloalkyl] or a pharma- ceutically acceptable salt thereof.

[0034] In the compounds of formula (I), R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 4b , R 5 , R 5a , R 5b , 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 of the exemplary ranges for a variable substituent, including, may be used independently of any other range for a variable substituent. Thus, the invention encompasses combinations of different embodiments.

[0035] In one embodiment of formula (I), X 1 and X 2 is CH;R 1 is CF3. In another embodiment of formula (I), X 1 and X 2 is CH; R 1 is H. In another embodiment of formula (I), X 1 is CR 1 ;X 2 is CH; R 1 is CF3. In another embodiment of formula (I), X 1 is N;X 2 is CH; R 1 is CH3. In another embodiment of formula (I), X 1 is N;X 2 is CH; R 1 is C 3-6 It is cycloalkyl.

[0036] In another embodiment of formula (I), X 1 is N;X 2 is CH; R 1 is a halo. In another embodiment of formula (I), X 1 is N;X 2 is CH; R 1 is CH3. In another embodiment of formula (I), X 1 is CH;X 2 is N;R 1 is H. In another embodiment of formula (I), X 1 is CH;X 2 is N;R 1 is CH3. In another embodiment of formula (I), R 4a is F. In another embodiment of formula (I), R 4b is CF3.

[0037] In another embodiment of formula (III), X 1 is CH;R 1 is CF3; R 3 is F or -OCH3; R 4a is F;R 4b is CF3; R 5 is -C(=O)NR 5b R 5b ;R 5b is H or C 1-5 Alkyl (0 to 1 R 7or R 5b and R 5b together with the nitrogen atom to which they are both attached, [ka] Forming;R 6 is -OH or C 1-3 R is alkyl; 7 is C 1-3 Alkyl (0 to 1 R 9 substituted with -S(=O)2C 1-3 Alkyl, or C 3-6 Cycloalkyl (0 to 2 R e substituted with R 9 is -OH; R e is -S(=O)2C 1-3 It is an alkyl.

[0038] In another embodiment of formula (III), X 1 is CH;R 1 is CF3; R 3 is F or -OCH3; R 4a is F;R 4b is CF3; R 5 teeth [ka] ;R 7 is C 1-5 Alkyl (0 to 1 R 9 ) or -C(=O)NHR a ;R 9 is -OH; R a is H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl, or -(CH2) 0-1 -heterocyclyl.

[0039] In another embodiment of formula (III), X 1 is CH;R 1 is CF3; R 3is F or -OCH3; R 4a is F;R 4b is CF3; R 5 teeth [ka] ;R 7 is -C(=O)NR a R a ;R a and R a together with the nitrogen atom to which they are both attached, [ka] Forming;R e is C 1-3 Alkyl (0 to 2 R g substituted with R g is -OH alkyl.

[0040] In another embodiment of formula (III), X 1 is CH;R 1 is CF3; R 3 is F or -OCH3; R 4a is F;R 4b is CF3; R 5 teeth [ka] ;R 6 is F;R 7 is -S(=O)2C 1-3 Alkyl, -S(=O)2NHR a , or C 1-3 Alkyl (0 to 1 R 8 and 0 to 1 R 9 substituted with R 8 is -C(=O)OH, or CF3; R 9 Ha-NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl or -OC(=O)NHR a ;Ra 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.

[0041] In another embodiment of formula (III), X 1 is CH;R 1 is CF3; R 3 is F or -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.

[0042] 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.

[0043] "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.

[0044] "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.

[0045] "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.

[0046] "Bicyclic carbocyclyl" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system containing two fused rings and consisting of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to another ring, which is a 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.

[0047] 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.

[0048] "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.

[0049] 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.

[0050] 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).

[0051] 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.

[0052] 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.

[0053] "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).

[0054] 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).

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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 herein to indicate the atomic configuration relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0061] 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.

[0062] 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.

[0063] 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 tautomeric forms, in so far as they exist, are included within the scope of the invention.

[0064] 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.

[0065] 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.

[0066] The examples disclosed below were tested in the human RXFP1 (hRXFP1) HEK293 cAMP assay described above and found to have agonistic activity. Table 1 shows the EC50 values ​​in the hRXFP1 HEK293 cAMP assay measured for the examples. 50 Enumerate values. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0067] 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).

[0068] 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).

[0069] 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).

[0070] 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 present invention is a method of improving, stabilizing or restoring renal function in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I).

[0071] 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).

[0072] "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.

[0073] "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.

[0074] "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.

[0075] "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).

[0076] "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.

[0077] "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.

[0078] 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.

[0079] "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.

[0080] Pharmaceutically acceptable carriers are formulated according to many factors well within the scope of a person skilled in the art. These factors include, but are not limited to, the type and nature of the active agent to be formulated; the subject to which the composition containing the drug 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 various solid and semi-solid dosage forms. Such carriers can include many different components and additives in addition to the active agent, and such additional components are incorporated into the formulation for various reasons, such as stabilization of the active agent, binders, etc., as is well known to those skilled in the art. A description of suitable pharmacologic acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as, for example, Allen, LV et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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).

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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).

[0095] Chemical Methods and Synthesis 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.

[0096] 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).

[0097] 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.

[0098] [Table 13] [Table 14] [Table 15]

[0099] In the illustrated examples, the following methods were used unless otherwise stated. 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 gradients of either hexanes and EtOAc, or DCM and MeOH, or petroleum ether and EtOAc, unless otherwise stated. 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 ...

[0100] The LC / MS methods utilized for characterization of the examples are listed below. Method A: Column: XBridge BEH XP C18 (50x2.1) mm, 2.5 μm: Mobile phase A: 5:95 ACN:H2O + 10 mM NH4OAc; Mobile phase B: 95:5 ACN:H2O + 10 mM NH4OAc; Temperature: 50°C; Gradient: 0-100% B over 3 min; Flow: 1.1 mL / min; Detection: UV (220 nm). Method B: Column: Xbridge BEH XP C18 (50x2.1) mm, 2.5 μm; Mobile phase A: 5:95 ACN:H2O + 0.1% TFA; Mobile phase B: 95:5 ACN:H2O + 0.1% TFA; Temperature: 50 °C; Gradient: 0 to 100% B over 3 min; Flow: 1.1 mL / min; Detection: UV (220 nm). Method C: Column: Kinetex XB-C18 (75x3) mm, 2.6 μm; Mobile phase A: 10 mM NH4COOH:ACN in H2O (98:2); Mobile phase B: 10 mM NH4COOH:ACN in H2O (2:98); Temperature: 50°C; Gradient: 20-100% B over 5 min; Flow rate: 1.1 mL / min; Detection: UV (220 nm). Method D: Column: Kinetix C18 (75x3) mm, 2.6 μm; Mobile phase A: 0.1% HCOOH in HO; Mobile phase B: ACN; Gradient: 20-100% B over 5 min; Detection: UV (220 nm). Method E: Acquity UPLC BEH C18 (50x3.0) mm, 1.7 μm; Buffer: 10 mM NH4OAc in HO; Mobile phase A: Buffer:ACN (95:5); Mobile phase B: Buffer:ACN (5:95); Gradient %B: 20-100% over 2.0 min, hold at 100% for 2.2 min; Flow rate: 0.7 mL / min; Detection: UV (220 nm).

[0101] Method F: Column: Aquity UPLC BEH C18 (50x3.0) mm, 1.7 μm; Mobile phase A: 5:95 ACN:H2O + 0.1% TFA; Mobile phase B: 95:5 ACN:H2O + 0.1% TFA; Gradient: 2 to 98% B over 2 min; Flow: 0.8 mL / min; Column temperature: 60 °C; Detection: UV (220 nm) Method G: Column: Luna 3.0 C18(2) 100Å LC column (20x4.0) mm, Mercury MS™; Mobile phase A: 10 mM NH4COOH:ACN in HO (98:02); Mobile phase B: 10 mM NH4COOH:ACN in HO (02:98); Flow rate: 1.5 mL / min Method H: Column: Phenomenex Luna C18(2) (30x2.0) mm, 3 μm; Buffer: 10 mM NH4OAc in HO; Mobile phase A: Buffer: MeOH (90:10); Mobile phase B: Buffer: MeOH (10:90); Gradient %B: 0-100% over 2.0 min, hold at 100% for 3.0 min; Flow rate: 1.0 mL / min; Detection: UV (220 nm).

[0102] Preparative LCMS / HPLC / SFC conditions: Fractions containing the desired product were combined and dried via centrifugal evaporation. Method 1: Column: Waters XBridge C18, (150x19) mm, 5 μm; Mobile phase A: 5:95 ACN:H2O + 10 mM NH4OAc; Mobile phase B: 95:5 ACN:H2O + 10 mM NH4OAc; Flow rate: 15 mL / min; Column temperature: 25 °C Method 2: Column: Sunfire C18, (150x19) mm, 5 μm; Mobile phase A: 5:95 ACN:H2O + 10 mM NH4OAc; Mobile phase B: 95:5 ACN:H2O + 10 mM NH4OAc; Flow: 19 mL / min Method 3: Column: Sunfire C18, (150x19) mm, 5 μm; Mobile phase A: 10 mM NH4OAc in H2O, pH 4.5; Mobile phase B: MeOH; Flow: 19 mL / min Method 4: Column: Waters Xbridge C18, (200x19) mm, 5 μm; Mobile phase A: 5:95 ACN:H2O + 0.05% TFA; Mobile phase B: 95:5 ACN:H2O + 0.05% TFA; Flow rate: 20 mL / min; Column temperature: 25 °C Method 5: Column: YMC Triart EXRS C18 (250x20) mm, 5 μm; Mobile phase A: 10 mM NH4HCO3 in H2O, pH 9.5; Mobile phase B: ACN; Flow: 19 mL / min

[0103] Method 6: Column: Sunfire C18 (150x19) mm, 5 μm; Mobile phase A: 0.1% TFA in H2O; Mobile phase B: ACN; Flow rate 19 mL / min Method 7: Column: Xbridge Phenyl (250x19) mm, 5 μm; Mobile phase A: 10 mM NH4HCO3 in H2O, pH 9.5; Mobile phase B: ACN; Flow: 19 mL / min Method 8: Column: Chiralcel OD-H (250x30) mm, 5 μm; % CO2: 50%; % co-solvent: 50% 4M NH3 in MeOH; Total flow: 80 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 240 nm Method 9: Column: ACE C18 PFP (250x21.2) mm, 5 μm; Mobile phase A: 10 mM NH4OAc in H2O, pH 4.5; Mobile phase B: ACN:IPA (70:30); Flow: 19 mL / min; UV: 254 nm Method 10: Column: Chiralpak IC (250x30) mm, 5 μm; % CO2: 75%; % co-solvent: 25% 4M NH3 in MeOH; Total flow: 95 g / min; Back pressure: 100 bar; Temperature: 40° C.; UV: 220 nm

[0104] Method 11: Column: Gemini NX C-18 (250x21.2) mm, 5 μm; Mobile phase A: 10 mM NH4HCO3 in water, pH 9.5; Mobile phase B: ACN; Flow: 19 mL / min; Gradient: 65-70%, 2 min, 70-85%, 15 min, 85%, 17 min, 85-100%, 18 min. Method 12: Column name: Luxcellulose C4 (250x21.5) mm, 5 μm; % CO2: 80%; % co-solvent: 4M NH3 in 20% MeOH; Backpressure: 100 bar; Temperature: 40°C; UV: 246 nm Method 13: Analytical SFC Conditions: Column name: Luxcellulose C4 (250x4.6) mm, 5 μm; % CO2: 65%; % co-solvent: 4M NH3 in 35% MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 246 nm Method 14: Column: Cellulose-5 (250x19) mm, 5 μm; Mobile phase: 10 mM NH4OAc in MeOH; Flow: 20 mL / min; UV: 220 nm Method 15: Column: C-5 (250x21.2mm) 5μm, DAD-1B; Mobile phase: 0.1% DEA in ACN, Flow: 19mL / min, UV: 254nm

[0105] Method 16: Column: Chiralpak IG (250x30) mm, 5 μm; % CO2: 50%; % co-solvent: 0.1% DEA in 50% IPA; Total flow: 80 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm Method 17: Analytical SFC conditions: Column: Chiralpak IG (250x4.6) mm, 5 μm; % CO2: 60%; % co-solvent: 0.2% DEA in 40% IPA; Injection volume: 10 μl; Outlet pressure: 100 bar; Temperature: 35° C.; UV: 220 nm Method 18: Column: Chiralpak IC (250x21) mm, 5 μm; % CO2: 50%; % co-solvent: 0.2% NH3 in 50% MeOH; Total flow: 90.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 265 nm Method 19: Analytical SFC conditions: Column: Chiralpak IC (250x4.6) mm, 5 μm; % CO2: 50%; % co-solvent: 0.2% NH3 in 50% MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 265 nm Method 20: Column / dimensions: Chiralpak IG (250x30mm), 5μm; %CO2: 55%; %co-solvent: 0.2% DEA in 45% MeOH:ACN (1:1); Total flow: 170.0g / min; Backpressure: 100 bar; Temperature: 35°C; UV: 220nm

[0106] Method 21: Analytical SFC conditions: Column: Chiralpak IG (250x4.6mm), 5μm; %CO2: 55%; %co-solvent: 0.2% DEA in 45% MeOH:ACN (1:1); Total flow: 4.0g / min; Back pressure: 100 bar; Temperature: 35°C; UV: 220nm Method 22: Column: Chiralpak IG (250x30) mm, 5 μm; % CO2: 70%; % co-solvent: 30% 4M NH3 in MeOH; Flow conditions: 150.0 g / min; Back pressure: 100 bar; Temperature: 30° C.; Detector wavelength: 240 nm Method 23: Analytical SFC conditions: Column: Chiralpak IG (250x4.6) mm, 5 μm; % CO2: 70%; % co-solvent: 30% 4M NH3 in MeOH; Flow conditions: 4.0 g / min; Back pressure: 100 bar; Temperature: 30° C.; Detector wavelength: 240 nm. Method 24: Column: Chiralcel OD-H (250x21) mm, 5 μm; % CO2: 80%; % co-solvent: 20% 4M NH3 in MeOH; Total flow: 95 g / min; Back pressure: 100 bar; Temperature: 40° C.; UV: 220 nm Method 25: Analytical SFC Conditions: Column: Chiralcel OD-H (250x4.6) mm, 5 μm; % CO2: 70%; % co-solvent: 30% 4M NH3 in MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm

[0107] Method 26: Column: Chiralpak AS-H (250x30) mm, 5 μm; % CO2: 80%; % co-solvent: 20% 4M NH3 in MeOH; Total flow: 140.0 g / min; Back pressure: 130 bar; Temperature: 30° C.; UV: 225 nm Method 27: Analytical SFC conditions: Column: Chiralpak AS-H (250x4.6) mm, 5 μm; % CO2: 80%; % co-solvent: 20% 4M NH3 in MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 225 nm Method 28: Column: Chiralpak IC (250x30) mm, 5 μm; % CO2: 75%; % co-solvent: 0.2% NH3 in 25% MeOH; Total flow: 100.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 264 nm Method 29: Analytical SFC conditions: Column: Chiralpak IC (250x4.6) mm, 5 μm; % CO2: 70%; % co-solvent: 0.2% NH3 in 30% MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 264 nm Method 30: Column: Lux Cellulose 4 (250x30) mm, 5 μm; % CO2: 50%; % co-solvent: 50% 4M NH3 in MeOH; Total flow: 145.0 g / min; Back pressure: 100 bar; Temperature: 40° C.; UV: 270 nm

[0108] Method 31: Analytical SFC Conditions: Column: Lux Cellulose 4 (250x4.6) mm, 5 μm; % CO2: 50%; % Co-solvent: 50% 4M NH3 in MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 270 nm Method 32: Column: Chiralcel OJ-H (250x30) mm, 5 μm; % CO2: 80%; % co-solvent: 0.2% DEA in 20% IPA; Total flow: 100.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm Method 33: Analytical SFC Conditions: Column: Chiralcel OJ-H (250x4.6) mm, 5 μm; % CO2: 80%; % co-solvent: 0.2% DEA in 20% IPA; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm Method 34: Column: Whelk (R,R) (250x21) mm, 5 μm; % CO2: 80%; % co-solvent: 0.2% NH3 in 20% MeOH; Total flow: 85.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 250 nm Method 35: Analytical SFC Conditions: Column: Welk (R,R) (250x4.6) mm, 5 μm; % CO2: 70%; % co-solvent: 0.2% NH3 in 30% MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 250 nm

[0109] Method 36: Column: Chiralpak IA (250x30) mm, 5 μm; % CO2: 80%; % co-solvent: 20% MeOH; Total flow: 90 mL / min; Back pressure: 150 bar; Temperature: 40 °C; UV: 220 nm Method 37: Analytical SFC Conditions: Column: Chiralpak IA (100x4.6) mm, 5 μm; % CO2: 75%; % co-solvent: 25% MeOH; Total flow: 2.0 mL / min; Back pressure: 150 bar; Temperature: 40° C.; UV: 220 nm Method 38: Column / dimensions: Chiralcel OD-H (250x50) mm, 5 μm; % CO2: 75%; % co-solvent: 0.2% NH3 in 25% MeOH; Total flow: 270.0 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 220 nm Method 39: Analytical SFC Conditions: Column / dimensions: Chiralcel OD-H (250x4.6) mm, 5 μm; % CO2: 80%; % co-solvent: 0.2% NH3 in 20% MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm Method 40: Column: Chiralcel OJ-H (250x21.2) mm, 5 μm; % CO2: 75%; % co-solvent: 0.2% NH3 in 25% MeOH; Total flow: 80.0 g / min; Back pressure: 100 bar; Temperature: 40° C.; UV: 265 nm

[0110] Method 41: Column: Chiralcel OJ-H (250x4.6) mm, 5 μm; % CO2: 85%; % co-solvent: 0.2% NH3 in 15% MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 40° C.; UV: 265 nm Method 42: Column: Chiralpak IC (250x50) mm, 5 μm; % CO2: 70%; % co-solvent: 0.2% NH3 in 30% MeOH; Total flow: 280 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 246 nm Method 43: Analytical SFC conditions: Column: Chiralpak IC (250x4.6) mm, 5 μm; % CO2: 70%; % co-solvent: 0.2% NH3 in 30% MeOH; Total flow: 4 g / min; Back pressure: 100 bar; Temperature: 30° C.; UV: 246 nm Method 44: Column: Gemini NX, (250x21.2) mm, 5 μm; Mobile phase A: 10 mM NH4OAc in water, pH 4.5; Mobile phase B: ACN; Flow rate: 20 mL / min; Column temperature: 25 °C Method 45: Column: Chiralcel OD-H (250x30) mm, 5 μm; % CO2: 60%; % co-solvent: 40%; 4M NH3 in MeOH; Total flow: 100 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm

[0111] Method 46: To isolate the four isomers of tert-butyl (3-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-5-yl)carbamate using the following conditions: Column: Chiralcel OJ-H (250x21) mm, 5 μm; % CO2: 80%; % co-solvent: 0.2% DEA in 20% IPA; Total flow: 80.0 g / min; Backpressure: 100 bar; Temperature: 40° C.; UV: 265 nm; (Isomer 1: Preparative SFC RT=10.6 min), (Isomer 2+3 mixture) Preparative SFC RT=13.9 min), (Isomer 4 Prep SFC RT=17.1 min); Analytical SFC conditions: (Column: Chiralcel OJ-H (250x4.6) mm, 5 μm; %CO2: 80%; %Co-solvent: 0.2% DEA in 20% IPA; Overall flow: 4.0 g / min; Backpressure: 100 bar; Temperature: 40 °C; UV: 265 nm); (Isomer 1: Prep SFC RT=5.01 min, 100% ee), (Isomer 4: Analytical SFC RT=8.35 min, 100% ee); (Mixture of isomers 2+3 was run under the following prep SFC conditions: Column: ChiralPak Further purified with AS-H (250x21) mm, 5 μm; %CO2: 80%; %co-solvent: 0.2% NH3 in 20% MeOH; total flow: 80.0 g / min; back pressure: 100 bar; temperature: 30 °C; UV: 236 nm), (isomer 2 preparative SFC RT = 5.4 min, 100% ee), (isomer 3 preparative SFC RT = 7.5 min, 98% ee); analytical SFC conditions: (Column: Chiralpak AS-H (250x4.6) mm, 5 μm; %CO2: 80%; %co-solvent: 0.2% NH3 in 20% MeOH; total flow: 3.0 g / min; back pressure: 100 bar; temperature: 30 °C; UV: 236 nm). Method 47: To isolate the four isomers of methyl 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoate using the following conditions: Column: Chiralpak AD-H (250x21) mm, 5 μm; % CO2: 85%; % co-solvent: 15% MeOH; Total flow: 45.0 mL / min; Backpressure: 150 bar; Temperature: 40 °C; UV: 210 nm, yielding isomer 1 (preparative SFC RT = 4.07 min, >99% ee), isomer 2 (preparative SFC RT = 4.55 min, >99% ee), isomer 3 (preparative SFC RT = 5.66 min, >99% ee) and isomer 4 (preparative SFC RT = 5.66 min, >99% ee). RT=9.81 min, >99% ee) was obtained. Analytical SFC conditions: (Column: Chiralpak AD-H, (4.6x100) mm, 3 micron; Mobile phase: 15% MeOH / 85% CO2; Flow conditions: 2.0 mL / min, 150 bar, 40°C; Detector wavelength: 220 nm).

[0112] Example 1 [ka] Intermediate 1-1: Methyl 3-amino-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (1.00 g, 5.29 mmol), methyl 2-mercaptoacetate (0.589 g, 5.55 mmol) and TEA (2.29 mL, 16.4 mmol) in dry DMSO (10 mL) was irradiated in a microwave reactor at 130° C. for 3 h. The reaction was cooled and poured into ice water and the solid precipitate was filtered, washed with water and dried under vacuum to give intermediate 1-1 (1.00 g, 3.63 mmol, 69% yield). LC-MS RT: 1.91 min; MS(ESI) m / z 276.1 (M+H). + ;Method E

[0113] Intermediate 1-2: 3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a solution of intermediate 1-1 (500 mg, 1.82 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (260 mg, 1.45 mmol) in THF (15 mL) was added bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (466 mg, 1.82 mmol). The resulting reaction mixture was stirred at 85° C. for 12 h. The reaction was quenched with aqueous potassium sodium tartrate (30 mL) and extracted with DCM (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 1-2 (385 mg, 0.912 mmol, 50% yield). LC-MS RT: 1.12 min; MS(ESI) m / z 421.2 (MH) - ;Method E

[0114] Intermediate 1-3: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-iodo-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a solution of intermediate 1-2 (1.20 g, 2.88 mmol) and 5-iodo-2-methoxybenzoic acid (1.00 g, 3.60 mmol) in ACN (11 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (2.02 g, 7.19 mmol) followed by 1-methylimidazole (1.48 g, 18.0 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice water (50 mL). The solid precipitate was filtered and dried under vacuum to give intermediate 1-3 (1.00 g, 1.47 mmol, 41% yield). LC-MS RT: 2.28 min; MS(ESI) m / z 683.0(M+H) + ;Method E

[0115] Example 1: Methyl 1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)azetidine-3-carboxylate To a solution of intermediate 1-3 (300 mg, 0.44 mmol) in DMSO (2 mL) was added methyl azetidine-3-carboxylate (76 mg, 0.66 mmol) and the resulting solution was degassed with N2 for 10 min. L-proline (15 mg, 0.13 mmol), copper(I) iodide (17 mg, 0.088 mmol) and cesium carbonate (430 mg, 1.3 mmol) were added to the degassed reaction mixture and stirred at 100 °C for 16 h. The reaction solution was diluted with EtOAc (100 mL) and washed with water (2x100 mL) and brine solution (50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 1 (100 mg, 0.15 mmol, 34% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.86(s,1H), 10.73(s,1H), 8.66(s,1H), 8.15(dd,J=2.7, 6.6Hz,1H), 8.05(d,J=8. 8Hz,1H), 8.02-7.93(m,1H), 7.81(dd,J=1.6, 8.7Hz,1H), 7.54(t,J=9.8Hz,1H), 7.1 2(d,J=8.8Hz,1H), 6.92(d,J=3.2Hz,1H), 6.70(dd,J=2.9, 8.8Hz,1H), 3.99(t,J=7. 7Hz,2H), 3.88(s,3H), 3.81(t,J=6.6Hz,2H), 3.67(s,3H), 3.65-3.55(m,1H);LC-MS RT:2.54min;MS(ESI) m / z 670.2(M+H) + ;Method A

[0116] Example 2 [ka]

[0117] Intermediate 2-1: 3-(5-bromo-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Intermediate 2-1 (0.48 g, 0.76 mmol, 80% yield) was prepared from intermediate 1-2 (400 mg, 0.95 mmol) and 5-bromo-2-methoxybenzoic acid (220 mg, 0.95 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.52 min; MS(ESI) m / z 635.0(M+H). + ;Method E

[0118] Intermediate 2-2: Ethyl 1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)-1H-pyrazole-4-carboxylate To a solution of intermediate 2-1 (300 mg, 0.47 mmol) in 1,4-dioxane (2 mL) was added ethyl 1H-pyrazole-4-carboxylate (99 mg, 0.71 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (27 mg, 0.094 mmol), followed by potassium carbonate (200 mg, 1.4 mmol) and copper(I) iodide (18 mg, 0.094 mmol). The resulting reaction mixture was stirred at 80° C. for 16 h. The reaction solution was diluted with EtOAc (100 mL) and washed with water (2×100 mL) and brine solution (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 2-2 (210 mg, 0.30 mmol, 64% yield). LC-MS RT: 2.18 min; MS(ESI) m / z 695.2(M+H) + ;Method E

[0119] Example 2: 1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid To a solution of intermediate 2-2 (80 mg, 0.12 mmol) in THF (5 mL), MeOH (2 mL) and water (1 mL) was added LiOH (5.5 mg, 0.23 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure, the aqueous layer was acidified to pH 4-5, and the resulting precipitate was filtered and dried under vacuum. The precipitate was purified by preparative LCMS (Method 1) to give Example 2 (41 mg, 0.060 mmol, 53% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 11.04-10.70(m,2H), 8.97(s,1H), 8.67(s,1H), 8.32(d,J=2.7Hz,2H), 8.20-8.14(m,1H), 8.13-7.96 (m,2H), 7.82(dd,J=1.8, 8.7Hz,2H), 7.53(t,J=9.8Hz,1H), 7.37(d,J=9.0Hz,1H), 3.95(s,3H);LC-MS RT:2.30min;MS(ESI) m / z 667.1(M+H) + ;Method B

[0120] Example 3: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide [ka]

[0121] A solution of intermediate 2-2 (80 mg, 0.12 mmol) in THF (10 mL) was cooled to 0° C. A solution of methylmagnesium bromide (0.19 mL, 0.58 mmol) was added and the reaction solution was stirred at room temperature for 3 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 3 (9.3 mg, 0.031 mmol, 12% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.97-10.88(m,1H), 10.82-10.70(m,1H), 8.68(s,1H), 8.28(s,1H), 8.2 4(d,J=2.9Hz,1H), 8.18(dd,J=2.7, 6.4Hz,1H), 8.10(d,J=8.6Hz,1H), 8.0 5-7.93(m,2H), 7.82(dd,J=1.6, 8.7Hz,1H), 7.65(s,1H), 7.54(t,J=9.8Hz ,1H), 7.35(d,J=9.0Hz,1H), 4.95(s,1H), 3.97(s,3H), 1.46(s,6H);LC-MS RT:2.39min;MS(ESI) m / z 681.2(M+H) + ;Method A

[0122] Examples 4 and 5 [ka]

[0123] Intermediate 4-1: Ethyl 1-(3-(tert-butoxycarbonyl)-4-methoxyphenyl)piperidine-3-carboxylate To a solution of tert-butyl 5-bromo-2-methoxybenzoate (1.20 g, 4.18 mmol) and ethyl piperidine-3-carboxylate (854 mg, 5.43 mmol) in toluene (30 mL) was added cesium carbonate (4.08 g, 12.5 mmol). The resulting solution was degassed with N2 for 10 min, Pd(OAc)2 (94.0 mg, 0.418 mmol) and BINAP (520 mg, 0.836 mmol) were added, and the solution was degassed for 5 min. The resulting reaction mixture was heated at 90° C. for 12 h. The reaction was concentrated under reduced pressure, and the residue was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 4-1 (350 mg, 0.963 mmol, 23% yield). LC-MS RT: 1.06 min; MS(ESI) m / z 364.2(M+H) + ;Method E

[0124] Intermediate 4-2: 5-(3-(ethoxycarbonyl)piperidin-1-yl)-2-methoxybenzoic acid To a solution of intermediate 4-1 (50 mg, 0.14 mmol) in DCM (2 mL) was added TFA (0.50 mL). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was concentrated in vacuo to give intermediate 4-2 (40 mg, 0.13 mmol, 95% yield). LC-MS RT: 0.35 min; MS(ESI) m / z 307.8 (M+H). + ;Method E

[0125] Intermediate 4-3: Ethyl 1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)piperidine-3-carboxylate Intermediate 4-3 (80 mg, 0.11 mmol, 48% yield) was prepared from intermediate 4-2 (150 mg, 0.47 mmol) and intermediate 1-2 (100 mg, 0.24 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.46 min; MS(ESI) m / z 712.3(M+H). + ;Method E

[0126] Examples 4 and 5: 1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)piperidine-3-carboxylic acid Intermediate 4-4 was prepared by the general procedure described for Example 2 and subsequently purified by preparative LCMS (Method 1). The isomers were separated by preparative SFC purification (column: Chiralpak IG (250x30) mm, 5 μm; %CO2: 50%; %cosolvent: 0.1% DEA in 50% IPA; total flow: 80 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm) to give Example 4 (preparative SFC RT = 9.47 min, 98% ee) and Example 5 (preparative SFC RT = 12.36 min, 98% ee).

[0127] Example 4: (29 mg, 0.042 mmol, 20% yield); 1 H NMR(400MHz,DMSO-d6) δ ppm 10.87(s,2H), 8.64(s,1H), 8.20-8.12(m,1H), 8.08(d,J=9.5Hz,1H), 7.98(dd dd,J=1.2, 2.7, 5.9, 7.5Hz,1H), 7.80(d,J=8.3Hz,2H), 7.63-7.44(m,1H), 7.41 -7.32(m,2H), 7.12(s,1H), 3.87(s,3H), 3.49(brs,2H), 3.44-3.39(m,2H), 2.8 7-2.63(m,2H), 2.61-2.53(m,1H), 1.98-1.82(m,1H), 1.58-1.44(m,1H);LC-MS RT:3.38min;MS(ESI) m / z 684.2(M+H) + ;Method C

[0128] Example 5: (3.0 mg, 4.5 μmol, 2% yield); 1 H NMR(400MHz,DMSO-d6) δ ppm 10.87(s,2H), 10.74(s,1H), 8.64(s,1H), 8.16(dd,J=2.2, 6.4Hz,1H), 8.07(d,J=8.8Hz,1H) , 7.99(td,J=3.7, 8.6Hz,1H), 7.80(d,J=9.3Hz,1H), 7.52(t,J=9.7Hz,1H), 7.38(brs,1H), 7. 20-7.04(m,2H), 3.91-3.84(m,3H), 3.51(brd,J=1.2Hz,1H), 2.86-2.75(m,2H), 2.70-2.62( LC-MS RT:2.05min;MS(ESI) m / z 684.2(M+H) + ;Method A

[0129] Example 6: 1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)-N-(methylsulfonyl)piperidine-3-carboxamide [ka]

[0130] To a solution of Example 4 (10 mg, 0.015 mmol) in THF (3 mL) was added CDI (30 mg, 0.19 mmol) and the reaction mixture was heated at 60° C. for 2 h. Methanesulfonamide (50 mg, 0.53 mmol) was then added and the reaction mixture was continued to be heated for another 4 h. The reaction was diluted with EtOAc (10 mL) and washed with water (2×10 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 6 (1.2 mg, 1.6 μmol, 10% yield). 1H NMR(400MHz,DMSO-d6) δ ppm 11.79(brd,J=2.4Hz,1H), 10.87(s,1H), 10.74(s,1H), 8.66(s,1H), 8.16(dd,J=2.7, 6.6Hz,1H) , 8.06(d,J=8.3Hz,1H), 8.02-7.94(m,1H), 7.81(dd,J=1.3, 8.7Hz,1H), 7.54(t,J=9.8Hz,1H), 7. 45(d,J=3.2Hz,1H), 7.25-7.19(m,1H), 7.17-7.08(m,1H), 3.91(s,3H), 3.69-3.61(m,1H), 3.45 -3.38(m,2H), 3.22(s,3H), 2.67(brd,J=2.0Hz,2H), 1.98-1.71(m,2H), 1.61-1.43(m,2H);LC-MS RT:2.05min;MS(ESI) m / z 761.2(M+H) + ;Method A

[0131] Examples 7 and 8: 1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)-N-(2-hydroxy-2-methylpropyl)piperidine-3-carboxamide [ka]

[0132] To a solution of intermediate 4-4 (50 mg, 0.073 mmol), 1-amino-2-methylpropan-2-ol (6.5 mg, 0.073 mmol) in DMF (2 mL) was added TEA (0.031 mL, 0.22 mmol) followed by HATU (42 mg, 0.11 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (Method 2) followed by preparative SFC (Method 8) to give Example 7 (preparative SFC RT=2.9 min, 99% ee) and Example 8 (preparative SFC RT=4.4 min, 99% ee). Analytical SFC conditions: Column: Chiralcel OD-H (250x4.6) mm, 5 μm; % CO2: 60%; % co-solvent: 40% 4M NH3 in MeOH; Total flow: 3.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 240 nm

[0133] Example 7: (2.6 mg, 3.4 μmol, 5% yield); 1 H NMR(400MHz,DMSO-d6) δ ppm 10.85(s,1H), 10.73(s,1H), 8.66(s,1H), 8.17(dd,J=2.7, 6.6Hz,1H), 8.08-7.96(m,2H) , 7.83-7.73(m,2H), 7.54(t,J=9.8Hz,1H), 7.42(d,J=2.9Hz,1H), 7.22-7.12(m,2H), 4.42 (s,1H), 3.90(s,3H), 3.32(s,1H), 3.32-3.17(m,1H), 3.13-2.90(m,2H), 2.74-2.66(m,1 LC-MS RT:2.34min;MS(ESI) m / z 755.2(M+H) + ;Method B

[0134] Example 8: (2.4 mg, 3.1 μmol, 4% yield); 1H NMR(400MHz,DMSO-d6) δ ppm 10.85(s,1H), 10.73(s,1H), 8.66(s,1H), 8.16(dd,J=2.6, 6.5Hz,1H), 8.08-7.96(m,2H), 7.83- 7.73(m,2H), 7.54(t,J=9.8Hz,1H), 7.42(d,J=2.9Hz,1H), 7.22-7.12(m,2H), 4.42(s,1H), 3.90 (s,3H), 3.43(brd,J=12.2Hz,1H), 3.32(s,1H), 3.17(s,1H), 3.14-2.91(m,2H), 2.50(td,J=1.9 , 3.5Hz,2H), 2.33(brd,J=1.7Hz,1H), 1.87-1.68(m,1H), 1.65-1.43(m,2H), 1.04(s,6H);LC-MS RT:2.34min;MS(ESI) m / z 755.2(M+H) + ;Method B

[0135] Example 9 [ka]

[0136] Intermediate 9-1: Methyl 5-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-2-methoxybenzoate Intermediate 9-1 (350 mg, 0.999 mmol, 58% yield) was prepared from methyl 5-iodo-2-methoxybenzoate (500 mg, 1.71 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (319 mg, 1.71 mmol) following the general method outlined in Example 1, except using K2CO3 rather than Cs2CO3 as the base. LC-MS RT: 2.45 min; MS(ESI) m / z 351.4 (M+H). + ;Method A

[0137] Intermediate 9-2: 5-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-2-methoxybenzoic acid Intermediate 9-2 (400 mg, 1.19 mmol, 83% yield) was prepared from intermediate 9-1 (500 mg, 1.43 mmol) by the general procedure described in Example 2. LC-MS RT: 1.65 min; MS(ESI) m / z 337.2 (M+H). + ;Method C

[0138] Intermediate 9-3: tert-Butyl butyl (1-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)pyrrolidin-3-yl)carbamate Example 9-3 (250 mg, 0.337 mmol, 71% yield) was prepared from intermediate 1-2 (200 mg, 0.474 mmol) and intermediate 9-2 (159 mg, 0.474 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 3.24 min; MS(ESI) m / z 739.3 (MH). - ;Method C

[0139] Intermediates 9-4 and 9-5: 3-(5-(3-aminopyrrolidin-1-yl)-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide A solution of intermediate 9-3 (100 mg, 0.135 mmol) in 4M HCl in dioxane (5 mL) was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) followed by preparative SFC (Method 10) to give intermediate 9-4 (preparative SFC RT=7.25 min, 99% ee) and intermediate 9-5 (preparative SFC RT=9.36 min, 99% ee). Analytical SFC conditions: Column: Chiralpak IC (250x4.6) mm, 5 μm; % CO2: 75%; % co-solvent: 25% 4M NH3 in MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm.

[0140] Intermediate 9-4: (2.7 mg, 4.2 μmol, 3% yield) LC-MS RT: 1.98 min; MS(ESI) m / z 641.3(M+H) + ;Method B Intermediate 9-5: (3.7 mg, 5.5 μmol, 4% yield) 1 H NMR(400MHz,DMSO-d6) δ ppm 10.99-10.68(m,2H), 8.65(s,1H), 8.14(dd,J=2.6, 6.5Hz,1H), 8.02(d,J=7.8Hz,1H) , 8.00-7.91(m,1H), 7.80(dd,J=1.5, 8.3Hz,1H),7.53(t,J=9.9Hz,1H), 7.12(d,J=2. 9Hz,1H), 7.05(d,J=9.3Hz,1H), 6.79(dd,J=3.3, 8.9Hz,1H), 5.65-5.53(s,2H), 3.90 -3.77(m,2H), 3.87(s,3H), 3.11-3.06(m,2H), 3.01-2.97(m,1H), 1.89(s,2H);LC-MS RT:2.00min;MS(ESI) m / z 641.3(M+H) + ;Method B

[0141] Example 9: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-((2-hydroxyethyl)amino)pyrrolidin-1-yl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a solution of intermediate 9-4 (20 mg, 0.031 mmol) and 2-bromoethan-1-ol (3.9 mg, 0.031 mmol) in THF (2 mL) and DMF (1 mL) was added TEA (4.4 μl, 0.031 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with EtOAc (20 mL), washed with water (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 9 (1.0 mg, 1.4 μmol, 5% yield). 1H NMR(400MHz,DMSO-d6) δ ppm 10.85(brd,J=2.2Hz,1H), 10.73(brs,1H), 8.66(s,1H), 8.16(dd,J=2.4, 6.6Hz,1H), 8.07-7.93( m,2H), 7.81(dd,J=1.3, 8.7Hz,1H), 7.54(t,J=9.9Hz,1H), 7.10(d,J=2.7Hz,1H), 7.04(d,J=8.8Hz ,1H), 6.79(dd,J=3.1, 9.2Hz,1H), 5.66-5.54(m,1H), 4.57-4.35(m,1H), 3.95-3.75(m,5H), 3.49( brd,J=4.9Hz,3H), 2.92-2.82(m,1H), 2.68(brs,1H), 2.18-2.09(m,1H), 1.60-1.48(m,1H);LC-MS RT:1.99min;MS(ESI) m / z 685.3(M+H) + ;Method B

[0142] Example 10 [ka] Intermediate 10-1: Methyl 5-(1,1-dioxido-1,2-thiazinane-2-yl)-2-methoxybenzoate

[0143] A solution of 1,2-thiazinane 1,1-dioxide (54 mg, 0.40 mmol), methyl 5-iodo-2-methoxybenzoate (120 mg, 0.40 mmol), Xantphos (23 mg, 0.040 mmol), cesium carbonate (260 mg, 0.79 mmol) in dioxane (2.1 mL) was purged with N2 for 10 min, then Pd2(dba)3 (18 mg, 0.020 mmol) was added and the resulting reaction mixture was heated at 100 °C for 15 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The organic layers were combined, washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure to give intermediate 10-1 (120 mg, 0.40 mmol), which was used without further purification. LC-MS RT:0.98min;MS(ESI) m / z 300.2(M+H)+ ;Method F

[0144] Intermediate 10-2: 5-(1,1-dioxido-1,2-thiazinane-2-yl)-2-methoxybenzoic acid Intermediate 10-2 (61 mg, 0.21 mmol, 54% yield) was prepared from intermediate 10-1 (120 mg, 0.40 mmol) by the general procedure described for Example 2. 1 H NMR (400MHz, CDCl3) δ ppm LC-MS RT:0.67min;MS(ESI) m / z 286.3(M+H) + ;Method F

[0145] Example 10: 3-(5-(1,1-dioxido-1,2-thiazinane-2-yl)-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 10 (1.6 mg, 2.3 μmol, 9% yield) was prepared from intermediate 1-2 (10 mg, 0.025 mmol) and intermediate 10-2 (7.0 mg, 0.025 mmol) in a similar manner to intermediate 1-3. 1H NMR(500MHz,DMSO-d6) δ ppm 10.94-10.71(m,1H), 8.66(s,1H), 8.18(brd,J=3.5Hz,1H), 8.06(brd,J=8.4Hz ,1H), 8.01-7.93(m,1H), 7.83(brd,J=8.6Hz,1H), 7.73(brd,J=1.7Hz,1H), 7.6 0-7.45(m,2H), 7.26(d,J=9.0Hz,1H), 3.97(s,3H), 3.62-3.54(m,2H), 3.45-3. 35(m,2H), 3.31-3.22(m,1H), 2.21-2.07(m,2H), 1.81(brd,J=3.9Hz,2H);LC-MS RT:2.58min;MS(ESI) m / z 690.2(M+H) + ;Method A

[0146] Example 11 [ka]

[0147] Intermediate 11-1: 5-iodo-2-methoxynicotinic acid To a solution of 2-methoxynicotinic acid (2.00 g, 13.1 mmol) in a mixture of TFA (30.0 ml, 389 mmol) and TFAA (8.00 ml, 56.6 mmol) was added NIS (4.41 g, 19.6 mmol). The resulting reaction mixture was heated to reflux for 3 h. The reaction was quenched with aqueous sodium thiosulfate (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 11-1 (2.40 g, 8.60 mmol, 66% yield). LC-MS RT: 0.25 min; MS(ESI) m / z 280.0 (M+H) + ;method G

[0148] Intermediate 11-2: N-(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-5-iodo-2-methoxynicotinamide Intermediate 11-2 (900 mg, 1.32 mmol, 74% yield) was prepared from intermediate 1-2 (378 mg, 0.896 mmol) and intermediate 11-1 (500 mg, 1.79 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.68 min; MS(ESI) m / z 682.1(MH). - ;Method E

[0149] Intermediate 11-3 and Example 11: N-(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-5-(3-(hydroxymethyl)piperidin-1-yl)-2-methoxynicotinamide Intermediate 11-3 and Example 11 were prepared from Intermediate 11-2 (60 mg, 0.088 mmol) and piperidin-3-ylmethanol (10 mg, 0.088 mmol) following the general method outlined in Intermediate 9-1. A mixture of Intermediate 11-3 and Example 11 was purified by preparative HPLC (Method 1) and the isomers were separated by preparative SFC (column: Chiralpak IC (250x30) mm, 5 μm; % CO2: 85%; % co-solvent: 5 mM NH4OAc in 15% MeOH:ACN (1:1); total flow: 100.0 g / min; back pressure: 100 bar; temperature: 35° C.; UV: 250 nm) to give Intermediate 11-3 (preparative SFC RT=12.9 min) and Example 11 (preparative SFC RT=14.4 min). Analytical SFC conditions: (Column: Chiralpak IC (250x4.6) mm, 5 μm; % CO2: 85%; % co-solvent: 5 mM NH4OAc in 15% MeOH:ACN (1:1); Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 250 nm).

[0150] Intermediate 11-3: (2.6 mg, 3.8 μmol, 4% yield); LC-MS RT: 2.48 min; MS(ESI) m / z 671.2(M+H) + ;Method A

[0151] Example 11: (3.0 mg, 4.5 μmol, 5% yield); LC-MS RT: 2.48 min; MS(ESI) m / z 671.2(M+H) + ;Method A

[0152] Example 12 [ka]

[0153] Intermediate 12-1: 5-bromo-N-(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-2-methoxynicotinamide Intermediate 12-1 (0.38 g, 0.48 mmol, 37% yield) was prepared from intermediate 1-2 (0.27 g, 0.65 mmol) and 5-bromo-2-methoxynicotinic acid (0.30 g, 1.3 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.51 min; MS(ESI) m / z 634.1(MH). - ;Method E

[0154] Example 12: 5-(1,1-dioxidothiomorpholino)-N-(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-2-methoxynicotinamide To a solution of intermediate 12-1 (25 mg, 0.039 mmol) and thiomorpholine 1,1-dioxide (11 mg, 0.079 mmol) in 1,4-dioxane (2.0 mL) was added sodium tert-butoxide (15 mg, 0.16 mmol). The resulting solution was degassed with N2 for 10 min, followed by the addition of RuPhosPdG2 (6.1 mg, 7.9 μmol). The resulting mixture was heated at 110 °C for 12 h. The reaction was diluted with EtOAc (50 mL) and washed with water (2x50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 12 (6.0 mg, 8.7 μmol, 22% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.88(brs,1H), 10.76(brs,1H), 8.67(s,1H), 8.49-8.32(m,1H), 8.21-8.12(m,1H), 8.08(d,J=8.1Hz,1H), 7.97(brd,J=2.9Hz ,1H), 7.81(dd,J=1.3, 8.7Hz,1H), 7.55(t,J=9.7Hz,1H), 7.45(s,1H), 3.95(s,3H), 3.79-3.60(m,4H), 3.23-3.12(m,4H);LC-MS RT:2.38min;MS(ESI) m / z 691.2(M+H) + ;Method A

[0155] Example 13 [ka]

[0156] Intermediate 13-1: tert-Butyl 5-bromo-2-methoxybenzoate To a solution of 5-bromo-2-methoxybenzoic acid (2.00 g, 8.66 mmol) in DCM (20 mL) and DMF (2 mL) was added DMAP (212 mg, 1.73 mmol) followed by Boc2O (2.01 mL, 8.66 mmol). The resulting reaction mixture was heated at 60° C. for 12 h. The reaction was diluted with water and extracted with DCM (2×50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 13-1 (1.00 g, 3.50 mmol, 40% yield). 1 H NMR (400MHz, DMSO-d6) δ ppm 7.78-7.75(m,2H), 7.12(d,J=8.5Hz,1H), 3.81(s,3H), 1.46(s,9H)

[0157] Intermediate 13-2: tert-Butyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate To a solution of intermediate 13-1 (2.00 g, 6.96 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron (2.12 g, 8.36 mmol) and potassium acetate (2.05 g, 20.9 mmol). The resulting solution was degassed with N2 for 10 min, followed by the addition of PdCl2(dppf)-CH2Cl2 adduct (569 mg, 0.696 mmol) and further degassed for 5 min. The reaction mixture was heated at 90 °C for 12 h, cooled, diluted with EtOAc (50 mL), washed with water (2x20 mL) and brine solution (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 13-2 (1.20 g, 3.59 mmol, 52% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 7.79(s,1H), 7.78-7.75(m,1H), 7.12(d,J=8.5Hz,1H), 3.81(s,3H), 1.51(s,9H), 1.29(s,12H)

[0158] Intermediate 13-3: 3-(tert-butyl) 3'-methyl 4'-fluoro-4-methoxy-[1,1'-biphenyl]-3,3'-dicarboxylate To a solution of methyl 5-bromo-2-fluorobenzoate (400 mg, 1.72 mmol) and intermediate 13-2 (574 mg, 1.72 mmol) in dioxane (10 mL) and water (2 mL) was added potassium phosphate dibasic (299 mg, 1.72 mmol). The reaction was degassed with Ar for 10 min, then PdCl2(dppf)-CH2Cl2 adduct (1.40 g, 1.72 mmol) was added and the mixture was heated at 80 °C for 12 h. The reaction was cooled, diluted with EtOAc (50 mL) and washed with water (2x50 mL) followed by brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 13-3 (380 mg, 1.05 mmol, 61% yield). 1 H NMR (400MHz, CDCl3-d) δ ppm 8.05(dd,J=2.5, 6.5Hz,1H), 7.84(d,J=2.5Hz,1H), 7.65-7.47(m,1H), 7.21(s,1H), 7.1 5(dd,J=8.8, 10.3Hz,1H), 6.98(d,J=8.5Hz,1H), 3.92(s,3H), 3.88(s,3H), 1.57(s,9H)

[0159] Intermediate 13-4: 4'-Fluoro-4-methoxy-3'-(methoxycarbonyl)-[1,1'-biphenyl]-3-carboxylic acid Intermediate 13-4 (310 mg, 1.02 mmol, 97% yield) was prepared from intermediate 13-3 (380 mg, 1.05 mmol) in a similar manner to intermediate 4-2. LC-MS RT: 2.23 min; MS(ESI) m / z 305.2(M+H). + ;Method D

[0160] Intermediate 13-5: Methyl 4-fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylate Intermediate 13-5 (145 mg, 0.186 mmol, 45% yield) was prepared from intermediate 1-2 (175 mg, 0.414 mmol) and intermediate 13-4 (126 mg, 0.414 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.64 min; MS(ESI) m / z 707.2(M+H). + ;Method C

[0161] Example 13: 4-Fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid Example 13 (15 mg, 0.022 mmol, 10% yield) was prepared from intermediate 13-5 (150 mg, 0.21 mmol) by the general procedure described in Example 2, followed by purification by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 11.00-10.89(m,1H), 10.81(brdd,brdd,J=3.2, 5.4Hz,1H), 8.67(s,2H), 8.21-7.94(m,5H), 7.92-7.77(m,3H), 7.52(t,J= 9.8Hz,1H), 7.42-7.25(m,1H), 3.96(s,3H);LC-MS RT:2.00min;MS(ESI) m / z 695.0(M+H) + ;Method A

[0162] Example 14 [ka]

[0163] Intermediate 14-1: Methyl 3-bromo-2-fluorobenzoate To a solution of 3-bromo-2-fluorobenzoic acid (500 mg, 2.28 mmol) in acetone (10 mL) was added K2CO3 (947 mg, 6.85 mmol) followed by dimethyl sulfate (0.431 mL, 4.57 mmol). The resulting reaction mixture was heated at 60 °C for 2 h. The reaction was concentrated under reduced pressure. The residue was diluted in water (100 mL) and extracted with EtOAc (3x100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 14-1 (500 mg, 2.15 mmol, 94% yield). 1 H NMR (400MHz, CDCl3) δ ppm 7.91-7.87(m,1H), 7.77-7.74(m,1H), 7.14-7.10(m,1H), 3.98(s,3H)

[0164] Intermediate 14-2: 3'-(tert-butyl) 3-methyl-2-fluoro-4'-methoxy-[1,1'-biphenyl]-3,3'-dicarboxylate Intermediate 14-2 (320 mg, 0.888 mmol, 59% yield) was prepared from intermediate 13-2 (500 mg, 1.50 mmol) and intermediate 14-1 (383 mg, 1.65 mmol) in a similar manner to intermediate 13-3. LC-MS RT: 3.33 min; MS(ESI) m / z 305.2 (M+H-tBu). + ;Method C

[0165] Intermediate 14-3: 2'-fluoro-4-methoxy-3'-(methoxycarbonyl)-[1,1'-biphenyl]-3-carboxylic acid Intermediate 14-3 (240 mg, 0.789 mmol, 89% yield) was prepared from intermediate 14-2 (320 mg, 0.888 mmol) in a similar manner to intermediate 4-2. LC-MS RT: 0.97 min; MS(ESI) m / z 305.2(M+H). + ;Method C

[0166] Intermediate 14-4: Methyl 2-fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylate Intermediate 14-4 (12 mg, 0.017 mmol, 12% yield) was prepared from intermediate 1-2 (60 mg, 0.14 mmol) and intermediate 14-3 (86 mg, 0.28 mmol) in a similar manner to intermediate 1-3 and subsequently purified by preparative LCMS (Method 3). LC-MS RT: 1.50 min; MS(ESI) m / z 707.2 (M-H). - ;Method E

[0167] Example 14: 2-Fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid Example 14 (3.3 mg, 4.8 μmol, 34% yield) was prepared from intermediate 14-4 (10 mg, 0.014 mmol) by the general procedure described in Example 2 and subsequently purified by preparative LCMS (Method 4). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.90(brdd,J=1.0, 2.0Hz,1H), 10.78(brd,J=1.7Hz,1H), 8.67(s,1H), 8.17(dd,J=2.3, 6.7Hz,1H), 8.10(d,J=8.8Hz,1H), 8.04-7 .94(m,2H), 7.87-7.79(m,2H), 7.79-7.72(m,1H), 7.70-7.60(m,1H), 7.53(t,J=9.8Hz,1H), 7.42-7.28(m,2H), 3.99(s,3H);LC-MS RT:1.99min;MS(ESI) m / z 695.2(M+H) + ;Method A

[0168] Example 15 [ka]

[0169] Intermediate 15-1: Methyl 3-aminobenzo[b]thiophene-2-carboxylate Intermediate 15-1 (0.97 g, 4.7 mmol, 57% yield) was prepared from 2-fluorobenzonitrile (1.0 g, 8.3 mmol) and methyl 2-mercaptoacetate (0.78 mL, 8.7 mmol) in a similar manner to intermediate 1-1. LC-MS RT: 1.72 min; MS(ESI) m / z 208.2 (M+H). + ;Method E

[0170] Intermediate 15-2: 3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzo[b]thiophene-2-carboxamide Intermediate 15-2 (0.71 g, 2.0 mmol, 94% yield) was prepared from 4-fluoro-3-(trifluoromethyl)aniline (420 mg, 2.3 mmol) and intermediate 15-1 (440 mg, 2.1 mmol) in a similar manner to intermediate 1-2. LC-MS RT: 0.90 min; MS(ESI) m / z 353.2 (MH). - ;Method E

[0171] Intermediate 15-3: 5'-(tert-butoxycarbonyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid To a solution of 5-borono-2-methoxybenzoic acid (2.00 g, 10.2 mmol), tert-butyl 3-bromo-4-fluorobenzoate (3.37 g, 12.3 mmol) and K2CO3 (7.05 g, 51.0 mmol) in water (14.3 mL) and THF (100 mL) was added PdCl2(dppf)-CH2Cl2 adduct (1.25 g, 1.53 mmol) and the solution was degassed with N2 for 5 min. The reaction was heated at 80 °C for 16 h. The reaction solution was cooled, diluted with EtOAc (300 mL), washed with a 1:1 solution of saturated brine and water (2x15 mL), dried over Na2SO4, filtered through Celite, and evaporated to dryness under vacuum to give intermediate 15-3 (2.80 g, 8.06 mmol, 79% yield). LC-MS RT:2.03min;MS(ESI) m / z 347.1(M+H) + ;method H

[0172] Intermediate 15-4: tert-Butyl 6-fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylate Intermediate 15-4 (150 mg, 0.220 mmol, 52% yield) was prepared from intermediate 15-2 (150 mg, 0.423 mmol) and intermediate 15-3 (147 mg, 0.423 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.62 min; MS(ESI) m / z 683.2(M+H). + ;Method C

[0173] Example 15: 6-Fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid Example 15 (15 mg, 0.023 mmol, 16% yield) was prepared from intermediate 15-4 (100 mg, 0.146 mmol) in a similar manner to intermediate 4-2 and subsequently purified by preparative HPLC (Method 9). 1H NMR(400MHz,DMSO-d6) δ ppm 11.9-11.8(m,1H), 10.78-10.84(m,1H), 10.61-10.66(m,1H), 8.13-8.18(m,1H), 8.10-8.12(m,1H), 8.06-8.10(m,2H), 7.96-8 .03(m,2H), 7.92-7.96(m,1H), 7.77-7.83(m,1H), 7.47-7.60(m,1H), 7.36-7.47(m,1H), 7.34-7.59(m,2H), 3.99(s,3H);LC-MS RT:2.75min;MS(ESI) m / z 627.0(M+H) + ;Method C

[0174] Examples 16 and 17 [ka]

[0175] Intermediate 16-1: Methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Intermediate 16-1 (1.2 g, 4.1 mmol, 67% yield) was prepared from methyl 5-bromo-2-methoxybenzoate (1.5 g, 6.1 mmol) in a similar manner to intermediate 13-2. LC-MS RT: 0.82 min; MS(ESI) m / z 293.2(M+H). + ;Method E

[0176] Intermediate 16-2: Methyl 5'-(((tert-butoxycarbonyl)amino)methyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylate Intermediate 16-2 (600 mg, 1.54 mmol, 90% yield) was prepared from intermediate 16-1 (500 mg, 1.71 mmol) and tert-butyl (3-bromo-4-fluorobenzyl)carbamate (573 mg, 1.88 mmol) in a similar manner to intermediate 13-3. LC-MS RT: 0.77 min; MS(ESI) m / z 334.2 (M+H-tBu). + ;Method E

[0177] Intermediate 16-3: 5'-(((tert-butoxycarbonyl)amino)methyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid Intermediate 16-3 (500 mg, 1.33 mmol, 80% yield) was prepared from intermediate 16-2 (650 mg, 1.66 mmol) by the procedure described in Example 2. LC-MS RT: 1.03 min; MS(ESI) m / z 320.2 (M+H-tBu). + ;Method E

[0178] Intermediate 16-4: tert-butyl ((6-fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)methyl)carbamate Intermediate 16-4 (310 mg, 0.398 mmol, 84% yield) was prepared from intermediate 1-2 (200 mg, 0.474 mmol) and intermediate 16-3 (178 mg, 0.474 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.55 min; MS(ESI) m / z 778.2(MH). - ;Method E

[0179] Example 16: 3-(5'-(aminomethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxamide)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 16 (180 mg, 0.252 mmol, 78% yield) was prepared from intermediate 16-4 (250 mg, 0.321 mmol) following the general conditions outlined in intermediates 9-4 and 9-5, followed by purification by preparative LCMS (Method 1). 1H NMR(400MHz,DMSO-d6) δ ppm 11.00-10.60(m,2H), 8.63(s,1H), 8.42(brs,2H), 8.17-8.09(m,2H), 8.00-7.91(m,2H), 7.83-7.69(m,2H) ), 7.58-7.45(m,2H), 7.41-7.31(m,2H), 7.25(dd,J=8.4, 10.9Hz,1H), 3.97(s,3H), 3.82(brs,2H);LC-MS RT:2.23min;MS(ESI) m / z 680.2(M+H) + ;Method A

[0180] Example 17: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2'-fluoro-4-methoxy-5'-(methylsulfonamidomethyl)-[1,1'-biphenyl]-3-carboxamide)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a cooled solution of Example 16 (40 mg, 0.056 mmol) in DCM (2 mL) was added pyridine (0.023 mL, 0.28 mmol) followed by MsCl (6.5 μl, 0.084 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc (20 mL) and washed with water (2×20 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 2) to give Example 17 (6.8 mg, 9.0 μmol, 16% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 11.00-10.60(m,2H), 8.67(s,1H), 8.16(dd,J=2.2, 6.1Hz,1H), 8.10(d,J =8.3Hz,1H), 8.05-7.93(m,2H), 7.83(dd,J=1.2, 8.8Hz,1H), 7.76(brd,J =8.6Hz,1H), 7.66-7.59(m,1H), 7.57-7.44(m,2H), 7.43-7.35(m,2H), 7. 33-7.24(m,1H), 4.21(brd,J=5.9Hz,3H),4.00(s,3H), 2.89(s,3H);LC-MS RT:2.49min;MS(ESI) m / z 756.1(MH)- ;Method A

[0181] Example 18: 3-(5'-(cyclobutanecarboxamidomethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide [ka]

[0182] Example 18 (6.4 mg, 8.4 μmol, 14% yield) was prepared from Example 16 (40 mg, 0.059 mmol) and cyclobutanecarboxylic acid (12 mg, 0.12 mmol) following the general procedures outlined in Examples 7 and 8, except using DIEA rather than TEA as the base. The residue was purified by preparative LCMS (Method 1) to give 1 H NMR(400MHz,DMSO-d6) δ ppm 10.89(s,1H), 10.76(s,1H), 8.68(s,1H), 8.22(t,J=5.7Hz,1H), 8.16(dd,J=2.4, 6.6Hz,1H), 8.09 (d,J=8.6Hz,1H), 8.03-7.92(m,2H), 7.82(dd,J=1.3, 8.7Hz,1H), 7.73(brd,J=8.8Hz,1H), 7.54(t, J=9.8Hz,1H), 7.37(d,J=8.8Hz,2H), 7.25(d,J=8.6Hz,2H), 4.28(d,J=5.9Hz,2H), 3.99(s,3H), 3. 09-3.00(m,1H), 2.20-2.08(m,2H), 2.06-1.95(m,2H), 1.92-1.82(m,1H), 1.79-1.67(m,2H);LC-MS RT:2.61min;MS(ESI) m / z 760.2(MH) - ;Method A

[0183] Example 19: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2'-fluoro-5'-((isobutylamino)methyl)-4-methoxy-[1,1'-biphenyl]-3-carboxamide)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide [ka]

[0184] To a solution of Example 16 (40 mg, 0.059 mmol) in MeOH (2 mL) was added isobutyraldehyde (8.5 mg, 0.12 mmol) followed by AcOH (0.67 μl, 0.012 mmol) dropwise at 0° C. The resulting solution was stirred at room temperature for 12 h, then sodium cyanoborohydride (7.4 mg, 0.12 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (5 mL) and then extracted with EtOAc (3×10 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 19 (5.5 mg, 7.5 μmol, 13% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 11.07-10.47(m,2H), 8.66(s,1H), 8.19-8.05(m,2H), 8.04-7.92(m,1H), 7.81(dd,J=1.6, 8.9Hz,1H), 7.75(brd,J= 8.8Hz,1H), 7.59-7.43(m,2H), 7.39-7.28(m,2H), 7.23(dd,J=8.4, 10.9Hz,2H), 4.88(brs,1H), 3.99 (brs,3H), 3.73(s,2H), 2.32(d,J=6.8Hz,2H), 1.68(td,J=6.6, 13.2Hz,1H), 0.89-0.80(m,6H);LC-MS RT:2.65min;MS(ESI) m / z 736.3(M+H) + ;Method A

[0185] Examples 20 and 21 [ka]

[0186] Intermediate 20-1: 1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethane-1-ol To 3-bromo-4-fluorobenzaldehyde (2.00 g, 9.85 mmol) and K2CO3 (0.136 g, 0.985 mmol) was added (trifluoromethyl)trimethylsilane (2.90 mL, 19.7 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was partitioned between water and EtOAc (2x50 mL), the organic layers were combined, washed with brine solution, dried over Na2SO4, concentrated under reduced pressure, and the residue was then treated with 2N HCl at 0 °C for 1 h. The reaction was then extracted with EtOAc (2x50 mL), and the organic layers were then combined, washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to give intermediate 20-1 (2.08 g, 7.62 mmol, 77% yield). LC-MS RT: 0.66 min; MS (ESI) m / z 271.0 (MH). - ;Method E

[0187] Intermediate 20-2: 1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate To a solution of intermediate 20-1 (300 mg, 1.10 mmol) in DCE (10 mL) at -10°C, 2,6-lutidine (0.384 mL, 3.30 mmol) was added dropwise followed by a solution of triflic anhydride (0.278 mL, 1.65 mmol) in DCE (1 mL). The reaction mixture was allowed to stir at 0°C for 30 min. The reaction was partitioned between water (50 mL) and Et2O (50 mL). The organic layer was separated, washed with brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 20-2 (370 mg, 0.913 mmol, 83% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 7.80-7.73(m,1H), 7.64-7.59(m,1H), 7.49-7.40(m,1H), 5.29-5.24(m,1H)

[0188] Intermediate 20-3: 1-(3-bromo-4-fluorophenyl)-N-(2,4-dimethoxybenzyl)-2,2,2-trifluoroethane-1-amine To a solution of intermediate 20-2 (500 mg, 1.23 mmol) and (2,4-dimethoxyphenyl)methanamine (0.223 mL, 1.48 mmol) in a mixture of cyclohexane (6 mL) and THF (3 mL) was added K2CO3 (512 mg, 3.70 mmol). The resulting reaction mixture was stirred at 75 °C for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (2x50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 20-3 (420 mg, 0.995 mmol, 81% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 7.82-7.85(m,1H), 7.51-7.56(m,1H), 7.37-7.43(m,1H), 7.16-7.21(m,2H), 6. 45-6.48(m,1H), 3.71(d,J=14.56Hz,2H), 3.42-3.59(m,1H), 3.25-3.38(m,6H)

[0189] Intermediate 20-4: 1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethane-1-amine To a solution of intermediate 20-3 (420 mg, 0.995 mmol) in DCM (8 mL), TFA (0.230 mL, 2.98 mmol) was added and the reaction solution was stirred at room temperature for 18 h. The reaction mixture was concentrated under high vacuum to give intermediate 20-4 (260 mg, 0.956 mmol, 96% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 7.98-8.01(m,1H), 7.54-7.70(m,1H), 6.45-6.51(m,1H), 3.74(brs,2H), 3.59(brd,J=13.55Hz,1H)

[0190] Intermediate 20-5: N-(1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-pyran-4-carboxamide Intermediate 20-5 (610 mg, 0.60 mmol, 39% yield) was prepared from intermediate 20-4 (502 mg, 1.84 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 1.54 mmol) by the general procedure described in Example 18. LC-MS RT: 0.60 min; MS(ESI) m / z 382.1(MH). - ;Method E

[0191] Intermediate 20-6: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Intermediate 20-6 (80 mg, 0.12 mmol, 50% yield) was prepared from intermediate 2-1 (150 mg, 0.236 mmol) following the general procedure described in intermediate 13-2. LC-MS RT: 1.52 min; MS(ESI) m / z 683.2(M+H). + ;Method E

[0192] Examples 20 and 21: N-(2,2,2-trifluoro-1-(6-fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide Examples 20 and 21 were prepared from intermediate 20-6 (120 mg, 0.176 mmol) and intermediate 20-5 (186 mg, 0.193 mmol) in a similar manner to intermediate 13-3, followed by purification by preparative HPLC (method 2). The isomers were separated by preparative SFC (column / dimensions: Chiralcel OD-H (250x21) mm, 5 μm; %CO2: 60%; %cosolvent: 0.2%DEA in 40% IPA; total flow: 80.0 g / min; back pressure: 100 bar; temperature: 35° C.; UV: 248 nm) to give Example 20 (preparative SFC RT=10.37 min) and Example 21 (preparative SFC RT=2.82 min). Analytical SFC conditions were obtained: (Column / dimensions: Chiralcel OD-H (250x4.6) mm, 5 μm; % CO2: 70%; % co-solvent: 0.2% DEA in 30% IPA; total flow: 4.0 g / min; back pressure: 100 bar; temperature: 35 °C; UV: 248 nm).

[0193] Example 20 (4.0 mg, 4.4 μmol, 2% yield): 1 H NMR(400MHz,DMSO-d6) δ ppm 10.62-11.01(m,2H), 9.02-9.26(m,2H), 8.48-8.80(m,1H), 8.12-81.8(m,2H), 7.9 1-8.20(m,2H), 7.61-7.89(m,2H), 7.31-7.56(m,1H), 7.23-7.25(m,2H), 5.77-6.01 (m,1H), 3.98-4.06(m,1H), 4.00(s,3H), 3.22-3.31(m,2H), 2.60(brs,1H), 2.44-2 .47(m,1H), 2.34-2.41(m,1H), 1.51-1.68(m,2H), 1.26(brd,J=19.58Hz,2H);LC-MS RT:1.21min;MS(ESI) m / z 858.2(MH) - ;Method C

[0194] Example 21 (4.0 mg, 4.4 μmol, 2% yield): 1H NMR(400MHz,DMSO-d6) δ ppm 10.67-10.98(m,2H), 8.92-9.22(m,2H), 8.54-8.78(m,1H), 8.09-8.18(m, 2H), 7.90-8.23(m,2H), 7.67-7.89(m,2H), 7.44-7.68(m,1H), 7.31-7.44( m,2H), 5.80-5.97(m,1H), 4.01(s,3H), 3.44(s,1H), 3.26-3.29(m,2H), 2. 58-2.67(m,1H), 2.39-2.45(m,2H), 1.48-1.59(m,2H), 1.18(m,2H);LC-MS RT:1.23min;MS(ESI) m / z 860.2(M+H) + ;Method C

[0195] Example 22: [ka]

[0196] Intermediate 22-1: (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl cyclobutyl carbamate To a solution of (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol (300 mg, 1.10 mmol) in THF (6 mL) at 0° C., NaH (96.0 mg, 2.20 mmol) was added and the reaction mixture was stirred at room temperature for 20 min. A solution of 4-nitrophenyl carbonochloridate (244 mg, 1.21 mmol) in THF (1 mL) was added and the reaction mixture was continued to stir for another 2 h. A solution of cyclobutanamine (156 mg, 2.20 mmol) in THF (4 mL) was added to the reaction and stirred at 65° C. for 6 h. The reaction was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 22-1 (150 mg, 0.405 mmol, 37% yield). LC-MS RT: 0.96 min; MS(ESI) m / z 368.1(MH). -;Method E

[0197] Example 22: (S)-2,2,2-trifluoro-1-(6-fluoro-3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)ethyl cyclobutyl carbamate Example 22 (25 mg, 0.027 mmol, 23% yield) was prepared from intermediate 20-6 (80 mg, 0.12 mmol) and intermediate 22-1 (43 mg, 0.12 mmol) in a similar manner to intermediate 13-3, and subsequently purified by preparative HPLC (Method 3). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.71-11.00(m,2H), 8.61-8.74(m,1H), 8.10-8.19(m,1H), 7.98-8.04(m,1H), 7.93-7.97(m,1H) ), 7.80-7.86(m,1H), 7.74-7.79(m,1H), 7.67-7.72(m,1H), 7.61-7.65(m,1H), 7.53-7.59(m,1H) , 7.46-7.48(m,1H), 7.43-7.45(m,1H), 7.38-7.40(m,1H), 6.36-6.40(m,1H), 3.92-3.94(m,1H) , 3.88-3.91(m,3H), 3.34(s,2H), 2.66-2.69(m,1H), 2.32-2.35(m,2H), 1.82-1.97(m,1H);LC-MS RT:2.02min;MS(ESI) m / z 846.0(M+H) + ;Method C

[0198] Examples 23 and 24 [ka]

[0199] Intermediate 23-1: 3-(5-bromopyrimidin-2-yl)tetrahydrothiophen-3-ol To a stirred solution of 5-bromo-2-iodopyrimidine (220 g, 772 mmol) and dihydrothiophen-3(2H)-one (165 mL, 1930 mmol) in toluene (5 L) at -78 °C, nBuLi (804 mL, 1930 mmol) was added dropwise under N2, and the reaction mixture was allowed to stir at -78 °C for 1.5 h. The reaction mixture was quenched with 150 mL of 10% aqueous NH4Cl at 0 °C, and the resulting solution was extracted with EtOAc (2x1 L). The organic layers were combined, washed with 500 mL of brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography. The resulting solid was precipitated with 200 mL of petroleum ether and 20 mL of IPA, and dried under high vacuum to give intermediate 23-1 (48.0 g, 185 mmol, 24% yield). LC-MS RT:1.36min;MS(ESI) m / z 261.0(M+H) + ;Method C

[0200] Intermediates 23-2, 23-3 and 23-4: 3-(5-bromopyrimidin-2-yl)-3-hydroxytetrahydrothiophene 1,1-dioxide To a solution of intermediate 23-1 (48.0 g, 184 mmol) in DCM (1 L) at 0° C., m-CPBA (113 g, 460 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 5 h, then diluted with 500 mL of DCM and cooled to 5° C. A solution of 1N NaOH was added thereto until the reaction mixture became clear, and the resulting solution was stirred for 10 min. The layers were separated and the aqueous layer was extracted with DCM (2×500 mL). The organic layers were combined, washed with 250 mL of brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was partitioned from 200 mL of EtOH and dried under high vacuum to give intermediate 23-2 (41.0 g, 140 mmol, 76% yield). LC-MS RT: 0.76 min; MS(ESI) m / z 293.0 (M+H) + ;Method C

[0201] Intermediate 23-2 was purified by preparative SFC (column: Chiralpak AD-H (250x50) mm, 5 μm; % CO2: 50%; % co-solvent: 0.2% NH3 in 50% MeOH:ACN (1:1); total flow: 220.0 mL / min; back pressure: 100 bar; temperature: 30 °C, UV: 220 nm) to give intermediate 23-3 (analytical SFC RT = 5.95 min, 100% ee; LC-MS RT: 0.76 min; MS (ESI) m / z 293.0 (M+H). + ; method C) and intermediate 23-4 (analytical SFC RT=9.26 min, 100%ee; LC-MS RT: 0.73 min; MS(ESI) m / z 293.0(M+H) + ; Method C) (Analytical SFC: Column: Chiralpak AD-H (250x4.6) mm, 5 μm; % CO2: 55%; % co-solvent: 0.2% NH3 in 45% MeOH:ACN (1:1); Total flow: 4.0 mL / min; Back pressure: 100 bar; Temperature: 35°C, UV: 220 nm) was obtained.

[0202] Example 23: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(2-(3-hydroxy-1,1-dioxidetetrahydrothiophen-3-yl)pyrimidin-5-yl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 23 (3.0 mg, 3.9 μmol, 8% yield) was prepared from intermediate 23-4 (13 mg, 0.044 mmol) and intermediate 20-6 (30 mg, 0.044 mmol) in a similar manner to intermediate 13-3, and subsequently purified by preparative HPLC (Method 2). 1H NMR(400MHz,DMSO-d6) δ ppm 10.87(brs,2H), 10.73(brs,1H), 9.18(s,1H), 8.68(s,1H), 8.21(s,1H), 8. 14(brd,J=8.03Hz,1H), 8.06(s,1H), 8.04(brs,1H), 7.83(brd,J=8.03Hz,1 H), 7.54(brt,J=9.54Hz,1H), 7.42(brd,J=8.53Hz,1H), 6.33(s,2H), 3.98( s,3H), 3.79(d,J=13.55Hz,1H), 3.36-3.52(m,3H), 2.49-2.55(m,2H);LC-MS RT:2.28min;MS(ESI) m / z 769.1(M+H) + ;Method B

[0203] Example 24: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(2-(3-hydroxy-1,1-dioxidetetrahydrothiophen-3-yl)pyrimidin-5-yl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 24 (4.0 mg, 5.2 μmol, 11% yield) was prepared from intermediate 23-3 (13 mg, 0.044 mmol) and intermediate 20-6 (30 mg, 0.044 mmol) in a similar manner to intermediate 13-3, and subsequently purified by preparative HPLC (Method 2). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.88(brs,1H), 10.75(brs,1H), 9.18(s,1H), 8.69(s,1H), 8.21(d,J=1.7Hz,1H), 8.14(brd,J=8.3Hz,1H), 8.09-7.97(m,1H), 7.89-7.80( LC-MS RT:2.28min;MS(ESI) m / z 769.0(M+H) + ;Method A

[0204] Examples 25 and 26 [ka]

[0205] Intermediate 25-1: Methyl 2-(3-bromophenyl)-2-(tetrahydro-2H-pyran-4-carboxamide)acetate To a solution of tetrahydro-2H-pyran-4-carboxylic acid (400 mg, 3.07 mmol) in toluene (5 mL) was added thionyl chloride (0.381 mL, 5.23 mmol). The resulting reaction mixture was heated at 80° C. for 1.5 h. The reaction was concentrated under high vacuum and dissolved in dry DCM (2 mL). The solution was added dropwise to a solution of methyl 2-amino-2-(3-bromophenyl)acetate (750 mg, 3.07 mmol) and TEA (2.14 mL, 15.4 mmol) in DCM (5 mL) that was stirred at room temperature for 5 min before addition. The reaction solution was stirred at room temperature for 12 h. The reaction was partitioned between water (50 mL) and DCM (50 mL). The organic layer was washed with water (2×50 mL) and the organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 25-1 (300 mg, 0.842 mmol, 27% yield). LC-MS RT: 1.18 min; MS(ESI) m / z 355.9(M+H). + ;Method E

[0206] Intermediate 25-2: 4-Methoxy-3'-(2-methoxy-2-oxo-1-(tetrahydro-2H-pyran-4-carboxamido)ethyl)-[1,1'-biphenyl]-3-carboxylic acid Intermediate 25-2 (110 mg, 0.257 mmol, 51% yield) was prepared from intermediate 25-1 (180 mg, 0.505 mmol) and 5-borono-2-methoxybenzoic acid (99.0 mg, 0.505 mmol) in a similar manner to intermediate 13-3, except that Na2CO3 (161 mg, 1.52 mmol) was used as the base rather than K3PO4. LC-MS RT: 0.57 min; MS(ESI) m / z 428.2 (M+H). + ;Method E

[0207] Intermediate 25-3: Methyl 2-(3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamide)acetate Intermediate 25-3 (80 mg, 0.096 mmol, 41% yield) was prepared from intermediate 1-2 (99 mg, 0.23 mmol) and intermediate 25-2 (100 mg, 0.23 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.16 min; MS(ESI) m / z 830.4 (MH). - ;Method E

[0208] Examples 25 and 26: 2-(3'-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)acetic acid Example 25 and Example 26 were prepared from Example 25-3 (80 mg, 0.096 mmol) by the procedure described in Example 2. The isomers were separated by preparative SFC (column: Chiralpak IC (250x21) mm, 5 μm; % CO2: 65%; % co-solvent: 0.2% DEA in 35% ACN:MeOH (1:1); outlet pressure: 100 bar; flow rate: 70 g / min; temperature: 30° C.; UV: 220 nm) to give Example 25 (analytical SFC RT=11.3 min, 100% ee) and Example 26 (analytical SFC RT=8.38 min, 95% ee). [Analytical SFC: Column: Chiralpak IC (250x4.6) mm, 5 μm; % CO2: 65%; % co-solvent: 0.2% DEA in 35% ACN:MeOH (1:1); Injection volume: 40 μl; Outlet pressure: 100 bar; Flow rate: 4 mL / min; Temperature: 30 °C]

[0209] Example 25: (12 mg, 0.014 mmol, 15% yield) 1 H NMR(400MHz,DMSO-d6) δ ppm 12.25-13.12(s,1H), 10.80-11.31(m,2H), 8.66(s,1H), 8.22-8.29(m,2H), 8.0 7(brd,J=6.02Hz,1H), 7.89-8.15(m,4H), 7.79(brs,2H), 7.54-7.63(m,1H), 7. 31(s,1H), 7.29(brs,1H), 6.78(s,1H), 3.91(s,4H), 3.83(brd,J=11.55Hz,1H) , 3.27(brs,2H), 2.86(q,J=7.19Hz,2H), 2.68-2.70(m,2H), 1.24(s,2H);LC-MS RT:2.57min;MS(ESI) m / z 816.0(M+H) + ;Method C

[0210] Example 26: (12 mg, 0.014 mmol, 15% yield) 1H NMR(400MHz,DMSO-d6) δ ppm 12.84-13.42(s,1H), 10.75-10.91(m,1H), 10.48-10.65(m,1H), 8.14(br d,J=4.02Hz,2H), 8.07(brd,J=6.02Hz,2H), 8.00(brs,4H), 7.77-7.92(m, 2H), 7.62-7.75(m,1H), 7.29-7.54(m,1H), 7.02-7.19(m,1H), 6.57(s,1H) , 4.01(s,5H), 3.44(brs,2H), 2.44-2.49(m,4H), 1.22-1.30(m,2H);LC-MS RT:2.57min;MS(ESI) m / z 816.0(M+H) + ;Method C

[0211] Example 27 [ka]

[0212] Intermediate 27-1: 4-Methoxy-3-(methoxycarbonyl)benzoic acid To a solution of methyl 5-formyl-2-methoxybenzoate (1.50 g, 7.72 mmol) in dioxane (35 mL), sulfamic acid (4.50 g, 46.3 mmol) in 20 mL of H2O and sodium chlorite (1.75 g, 15.5 mmol) in 10 mL of H2O were added at 0 °C, respectively, and then the reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 27-1 (1.60 g, 7.61 mmol, 99% yield). LC-MS RT: 0.35 min; MS (ESI) m / z 209.2 (MH). - ;Method E

[0213] Intermediate 27-2: 1-(tert-butyl) 3-methyl 4-methoxyisophthalate To a solution of intermediate 27-1 (1.47 g, 7.01 mmol) in toluene (70 mL), N,N-dimethylformamide di-tert-butyl acetal (6.72 mL, 28.0 mmol) was added at 80 °C, and the reaction solution was stirred at the same temperature for 16 h. The reaction was concentrated under reduced pressure, extracted with EtOAc, washed with 10% NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via column chromatography to give intermediate 27-2 (1.62 g, 6.08 mmol, 87% yield). LC-MS RT: 1.68 min; MS(ESI) m / z 267.2(M+H) + ;Method E

[0214] Intermediate 27-3: 5-(tert-butoxycarbonyl)-2-methoxybenzoic acid To a solution of intermediate 27-2 (500 mg, 1.88 mmol) in dioxane (10 mL) was added 1M NaOH solution (4.69 mL, 4.69 mmol) and the resulting reaction mixture was stirred at 60° C. for 2 h. The reaction was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in water (2 mL) and acidified with 0.5 N HCl cooled at 0° C., the solid precipitate was filtered, washed with water and dried under vacuum to give intermediate 27-3 (320 mg, 1.27 mmol, 68% yield). LC-MS RT: 0.74 min; MS(ESI) m / z 251.1 (MH). - ;Method E

[0215] Intermediate 27-4: tert-Butyl 3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxybenzoate Intermediate 27-4 (10 mg, 0.015 mmol, 21% yield) was prepared from intermediate 1-2 (30 mg, 0.071 mmol) and intermediate 27-3 (27 mg, 0.11 mmol) by the method described for preparing intermediate 1-3, and subsequently purified by preparative LCMS (Method 1).1 H NMR(400MHz,DMSO-d6) δ ppm 10.96-10.67(m,2H), 8.66(s,1H), 8.27(brd,J=1.2Hz,1H), 8.17-8.02(m,3H), 8.02-7.91(m,1H), 7.82 LC-MS RT:2.77min;MS(ESI) m / z 655.1(MH) - ;Method A

[0216] Intermediate 27-5: 3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxybenzoic acid Intermediate 27-5 (180 mg, 0.30 mmol, 98% yield) was prepared from intermediate 27-4 (200 mg, 0.31 mmol) in a similar manner to intermediate 4-2 and subsequently purified by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.85(brd,J=3.9Hz,2H), 10.77(brs,1H), 8.67(d,J=0.7Hz,1H), 8.37(d,J=2.4Hz,1H), 8.20-8.05(m,2H), 8.0(t LC-MS RT:1.83min;MS(ESI) m / z 601.0(M+H) + ;Method A

[0217] Example 27: 3-(5-(3,3-dimethylazetidine-1-carbonyl)-2-methoxybenzamide)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 27 (4.8 mg, 7.2 μmol, 29% yield) was prepared from intermediate 27-5 (15 mg, 0.025 mmol) and 3,3-dimethylazetidine·TFA (25 mg, 0.13 mmol) by the procedures described in Examples 7 and 8, and subsequently purified by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.81(s,1H), 10.74(s,1H), 8.67(s,1H), 8.14(dd,J=2.2, 6.4Hz,1H), 8.08(d,J=8.3Hz,1H), 8.04(d,J=2.2Hz,1H), 8.02-7.91(m,1) LC-MS RT:2.48min;MS(ESI) m / z 668.2(M+H) + ;Method B

[0218] Example 28 [ka]

[0219] Intermediate 28-1: Methyl 4-fluoro-5-iodo-2-methoxybenzoate To a solution of methyl 4-fluoro-2-methoxybenzoate (1.00 g, 5.43 mmol) in MeOH (20 mL) was added silver trifluoromethanesulfonate (2.79 g, 10.9 mmol) followed by iodine (2.76 g, 10.9 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to give intermediate 28-1 (850 mg, 2.74 mmol, 51% yield). LC-MS RT: 2.08 min; MS(ESI) m / z 311.2 (M+H). + ;Method C

[0220] Intermediate 28-2: 4-Fluoro-5-iodo-2-methoxybenzoic acid Intermediate 28-2 (120 mg, 0.405 mmol, 63% yield) was prepared from intermediate 28-1 (200 mg, 0.645 mmol) by the procedure described in Example 2. LC-MS RT: 0.59 min; MS(ESI) m / z 295.0(MH). - ;Method C

[0221] Intermediate 28-3: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-fluoro-4-iodo-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Intermediate 28-3 (165 mg, 0.236 mmol, 42% yield) was prepared from intermediate 1-2 (235 mg, 0.557 mmol) and intermediate 28-2 (165 mg, 0.557 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.53 min; MS(ESI) m / z 701.2(M+H). + ;Method E

[0222] Intermediate 28-4: 2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxybenzoic acid To a solution of intermediate 28-3 (500 mg, 0.71 mmol) in ACN (30 mL) and water (10 mL) was added 1,3-bis(diphenylphosphino)propane (29 mg, 0.071 mmol) and palladium(II) acetate (16 mg, 0.071 mmol). The solution was degassed with N2 for 5 min, and then TEA (3.0 mL, 22 mmol) was added. The resulting reaction mixture was heated in an autoclave at 80° C. under CO gas at 5 kg / cm 3 . 2The mixture was heated under reduced pressure for 3 h. The reaction was diluted with EtOAc (100 mL) and filtered. The filtrate was washed with water (2x50 mL). The aqueous layers were combined, acidified to pH 1 with 12M HCl, and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 4) to give intermediate 28-4 (380 mg, 0.34 mmol, 48% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 13.31-13.02(m,1H), 10.77(d,J=2.7Hz,2H), 8.67(s,1H), 8.38(d,J=8.8Hz,1H), 8.15(dd,J=2.2, 6.1Hz,1H), 8.06(d,J LC-MS RT:2.42min;MS(ESI) m / z 619.0(M+H) + ;Method C

[0223] Example 28: 3-(4-fluoro-2-methoxy-5-(3-(methylsulfonyl)azetidine-1-carbonyl)benzamide)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 28 (2.2 mg, 2.9 μmol, 12% yield) was prepared in a manner similar to Example 18 from intermediate 28-4 (15 mg, 0.024 mmol) and 3-(methylsulfonyl)azetidine hydrochloride (4.2 mg, 0.024 mmol) and subsequently purified by preparative LCMS (Method 1). 1H NMR(400MHz,DMSO-d6) δ ppm 10.88-10.66(m,2H), 8.66(s,1H), 8.18(dd,J=4.0, 2.1Hz,1H), 8.11-7.89(m,3H), 7.81(d,J=8.6Hz,1H), 7.54(t,J=9 .7Hz,1H), 7.28(d,J=12.2Hz,1H), 4.46-4.27(m,2H), 4.27-4.15(m,2H), 3.98(s,3H), 3.90(s,1H), 3.04(s,3H);LC-MS RT:2.21min;MS(ESI) m / z 736.0(M+H) + ;Method A

[0224] Example 29 [ka]

[0225] Intermediate 29-1: Methyl 3-amino-6-chlorothieno[3,2-c]pyridine-2-carboxylate To a solution of 4,6-dichloronicotinonitrile (5.00 g, 28.9 mmol) in DMF (90 mL) was added methyl 2-mercaptoacetate (3.35 mL, 34.7 mmol) followed by potassium tert-butoxide (34.0 mL, 57.8 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with saturated NH4Cl solution (50 mL) at 5° C. and stirred at room temperature for 20 min. The solid precipitate was filtered and dried under vacuum to give intermediate 29-1 (5.00 g, 20.6 mmol, 71% yield). LC-MS RT: 0.57 min; MS(ESI) m / z 243.0 (M+H). + ;Method E

[0226] Intermediate 29-2: 3-Amino-6-chlorothieno[3,2-c]pyridine-2-carboxylic acid. Intermediate 29-2 (175 mg, 0.765 mmol, 74% yield) was prepared from intermediate 29-1 (250 mg, 1.03 mmol) by the general procedure described for Example 2. LC-MS RT: 0.31 min; MS(ESI) m / z 229.0(M+H). + ;Method E

[0227] Intermediate 29-3: 3-Amino-6-chloro-N-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine-2-carboxamide. To a solution of intermediate 29-2 (250 mg, 1.09 mmol) in DCM (15 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (294 mg, 1.64 mmol), followed by EDC (419 mg, 2.19 mmol) and DMAP (134 mg, 1.09 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2x50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified via column chromatography to give intermediate 29-3 (250 mg, 0.641 mmol, 59% yield). LC-MS RT: 0.85 min; MS(ESI) m / z 388.0(MH) - Method E

[0228] Intermediate 29-4: tert-butyl 3-((6-chloro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)thieno[3,2-c]pyridin-3-yl)carbamoyl)-4-methoxybenzoate Intermediate 29-4 (200 mg, 0.179 mmol, 39% yield) was prepared from intermediate 29-3 (180 mg, 0.462 mmol) and intermediate 27-3 (233 mg, 0.924 mmol) in a similar manner to intermediate 1-3. 1H NMR(400MHz,DMSO-d6) δ ppm 11.09(brd,J=2.7Hz,1H), 10.79(brd,J=1.5Hz,1H), 9.00(s,1H), 8.39(d,J=0.7Hz,1H), 8.34(d,J=2.2Hz,1H), 8.15(dd,J=2.2, 6.4H z,1H), 8.07(dd,J=2.3, 8.7Hz,1H), 8.02-7.93(m,1H), 7.54(t,J=9.8Hz,1H), 7.33(d,J=8.8Hz,1H), 3.99(s,3H), 1.53(s,9H);LC-MS RT:2.61min;MS(ESI) m / z 625.2(M+H) + ;Method B

[0229] Intermediate 29-5: tert-Butyl 3-((6-cyclopropyl-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)thieno[3,2-c]pyridin-3-yl)carbamoyl)-4-methoxybenzoate Intermediate 29-5 (56 mg, 0.089 mmol, 79% yield) was prepared from intermediate 29-4 (70 mg, 0.11 mmol) and cyclopropylboronic acid (70 mg, 0.82 mmol) in a similar manner to intermediate 13-3, except that K2CO3 (47 mg, 0.34 mmol) was used as the base instead of K3PO4. LC-MS RT: 1.34 min; MS(ESI) m / z 630.3 (M+H). + ;Method E

[0230] Intermediate 29-6: 3-((6-cyclopropyl-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)thieno[3,2-c]pyridin-3-yl)carbamoyl)-4-methoxybenzoic acid Intermediate 29-6 (60 mg, 0.11 mmol, 82% yield) was prepared from intermediate 29-5 (80 mg, 0.13 mmol) in a similar manner to intermediate 13-4. LC-MS RT: 0.43 min; MS(ESI) m / z 574.2(M+H). + ;Method E

[0231] Example 29: 6-Cyclopropyl-3-(5-(2,2-dioxide-2-thia-6-azaspiro[3.3]heptane-6-carbonyl)-2-methoxybenzamide)-N-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine-2-carboxamide Example 29 (2.0 mg, 2.9 μmol, 11% yield) was prepared from intermediate 29-6 (15 mg, 0.026 mmol) and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (5.8 mg, 0.039 mmol) by the general procedure described in Example 18, followed by purification by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ 11.14(s,1H), 10.66(s,1H), 9.00(s,1H), 8.22-8.16(m,1H), 8.06-8.03 (m,1H), 8.03-7.98(m,1H), 7.89-7.83(m,1H), 7.59-7.53(m,1H), 7.33( LC-MS RT:2.04min;MS(ESI) m / z 703.2(M+H) + ;Method A

[0232] Examples 30 and 31 [ka]

[0233] Intermediate 30-1: 5-(chlorosulfonyl)-2-methoxybenzoic acid To an ice-cold solution of chlorosulfonic acid (1.10 mL, 16.4 mmol) in DCM (5.0 mL) was added 2-methoxybenzoic acid (500 mg, 3.29 mmol) over 15 min. Thionyl chloride (0.240 mL, 3.29 mmol) was added to the reaction mixture, which was then stirred at room temperature for 12 h. The reaction mixture was poured into crushed ice to give a white precipitate, which was filtered, washed with petroleum ether, and dried under vacuum to give intermediate 30-1 (800 mg, 3.20 mmol, 97% yield). LC-MS RT: 0.46 min; MS(ESI) m / z 251.0(M+H) + ;Method E

[0234] Intermediate 30-2: 5-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)-2-methoxybenzoic acid A mixture of intermediate 30-1 (500 mg, 2.00 mmol) and tert-butyl (R)-piperidin-3-ylcarbamate (400 mg, 2.00 mmol) in DCM (10 mL) was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 30-2 (290 mg, 0.700 mmol, 35% yield). LC-MS RT: 1.66 min; MS(ESI) m / z 315.1 (M+H-Boc). + ;Method E

[0235] Intermediate 30-3: tert-butyl (R)-(1-((3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)sulfonyl)piperidin-3-yl)carbamate Intermediate 30-3 (250 mg, 0.305 mmol, 65% yield) was prepared from intermediate 1-2 (200 mg, 0.474 mmol) and intermediate 30-2 (294 mg, 0.710 mmol) by a similar method to intermediate 1-3. LC-MS RT: 2.60 min; MS(ESI) m / z 819.2(M+H). + ;Method E

[0236] Example 30: (R)-3-(5-((3-aminopiperidin-1-yl)sulfonyl)-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a mixture of intermediate 30-3 (200 mg, 0.244 mmol) in DCM (15 mL) at 0° C. was added TFA (56.0 μL, 0.733 mmol). The resulting reaction mixture was stirred at room temperature for 5 h. The reaction was concentrated in vacuo and the residue was purified by preparative LCMS (Method 1) to give Example 30 (150 mg, 0.209 mmol, 85% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.88-10.83(m,1H), 10.78(brd,J=1.2Hz,1H), 8.63(s,1H), 8.17(dd,J=2.2, 6.4Hz,1H), 8.11(d,J=8. 6Hz,1H), 8.03(d,J=2.2Hz,1H), 7.96-7.89(m,1H), 7.86(dd,J=2.3, 8.9Hz,1H), 7.80(d,J=8.8Hz,1H), 7.53(t,J=9.7Hz,1H), 7.45(d,J=8.8Hz,1H), 3.99(s,3H), 3.47-3.44(m,1H), 2.82-2.72(m,1H), 2.29- 2.18(m,1H), 2.01(brt,J=10.0Hz,1H), 1.76-1.61(m,2H), 1.52-1.39(m,1H), 1.02-0.87(m,2H);LC-MS RT:2.17min;MS(ESI) m / z 719.2(M+H) + ;Method A

[0237] Example 31: (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-((3-(3-hydroxypropanamido)piperidin-1-yl)sulfonyl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 31 (6.0 mg, 7.8 μmol, 55% yield) was prepared from Example 30 (10 mg, 0.014 mmol) and 2-bromoacetamide (2.3 mg, 0.017 mmol) in a similar manner to Example 9, except using DCM as the solvent, and subsequently purified by preparative HPLC (Method 2). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.94-10.86(m,1H), 10.80(brd,J=2.0Hz,1H), 8.67(s,1H), 8.23-8.18(m,1H), 8.11(d,J=8.8Hz,1H), 8.07(d ,J=2.7Hz,1H), 8.00-7.94(m,1H), 7.90(dd,J=2.2, 8.8Hz,1H), 7.85-7.78(m,1H), 7.60-7.50(m,1H), 7.46(d, J=9.3Hz,1H), 7.26(dd,J=1.7, 2.4Hz,1H), 7.07-6.98(m,2H), 4.01(s,4H), 3.48(brd,J=2.0Hz,1H), 3.07(s,2 LC-MS RT:2.17min;MS(ESI) m / z 776.1(M+H) + ;Method A

[0238] Examples 32 and 33 [ka]

[0239] Intermediate 32-1: Methyl 2-methoxy-5-(3-oxocyclohexyl)benzoate To a solution of chloro(1,5-cyclooctadiene)rhodium(I) dimer (16 mg, 0.033 mmol) in 1,4-dioxane (15 mL) was added a previously degassed solution of KOH (370 mg, 6.5 mmol) in HO (1 mL) and the reaction mixture was stirred at room temperature for 15 min. Intermediate 16-1 (3.8 g, 13 mmol) and 2-cyclohexen-1-one (1.3 mL, 13 mmol) were added successively to the reaction solution and stirred at room temperature for 30 min. The reaction was diluted with water and extracted with DCM (2x50 mL). The organic layer was separated, dried over NaSO, filtered and concentrated under reduced pressure to give intermediate 32-1 (1.2 g, 4.6 mmol, 35% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 7.47-7.42(m,1H), 7.46-7.40(m,1H), 7.07-7.05(m,1H), 3.93(m,6H), 2.99(m,1H), 2.45-2.40(m,2H), 2.01-1.99(m,2H), 1.07(m,4H)

[0240] Intermediate 32-2: 2-Methoxy-5-(3-oxocyclohexyl)benzoic acid Intermediate 32-2 (4.0 g, 16 mmol, 85% yield) was prepared from intermediate 32-1 (5.0 g, 19 mmol) by the procedure described in Example 2. LC-MS RT: 0.28 min; MS(ESI) m / z 249.2(M+H). + ;Method E

[0241] Intermediate 32-3: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(3-oxocyclohexyl)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Intermediate 32-3 (2.0 g, 3.1 mmol, 32% yield) was prepared from intermediate 1-2 (4.0 g, 9.5 mmol) and intermediate 32-2 (2.4 g, 9.5 mmol) according to the conditions described in intermediate 1-3. LC-MS RT: 1.24 min; MS(ESI) m / z 651.2 (MH). - ;Method E

[0242] Examples 32 and 33: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-hydroxycyclohexyl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a solution of intermediate 32-3 (120 mg, 0.184 mmol) in THF (2 mL) was added sodium borohydride (6.96 mg, 0.184 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with crushed ice and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 32 (Preparative LCMS RT=2.50 min) and Example 33 (Preparative LCMS RT=2.49 min).

[0243] Example 32: (11.4 mg, 17.0 μmol, 10% yield) 1 H NMR(400MHz,DMSO-d6) δ ppm 10.86-10.66(m,2H), 8.66(s,1H), 8.18-8.11(m,1H), 8.07(d,J=8.6Hz,1H), 8.02-7.92 (m,1H), 7.82(d,J=8.8Hz,1H), 7.63(s,1H), 7.54(t,J=10.0Hz,1H), 7.46-7.36(m,1H), 7.16(d,J=8.3Hz,1H), 4.62(d,J=4.4Hz,1H), 3.93(s,3H), 3.55-3.43(m,1H), 2.54(brs ,1H), 1.97-1.82(m,2H), 1.80-1.71(m,1H), 1.68-1.59(m,1H), 1.43-1.06(m,4H);LC-MS RT:2.50min;MS(ESI) m / z 655.2(M+H) + ;Method B

[0244] Example 33: (12.8 mg, 19.0 μmol, 11% yield) 1H NMR(400MHz,DMSO-d6) δ ppm 10.86-10.65(m,2H), 8.66(s,1H), 8.15(dd,J=2.6, 6.2Hz,1H), 8.07(d,J=8.3Hz,1H), 8.0 3-7.93(m,1H), 7.82(d,J=8.6Hz,1H), 7.63(s,1H), 7.55(t,J=10.0Hz,1H), 7.45-7.37(m, 1H), 7.16(d,J=8.8Hz,1H), 4.62(d,J=4.2Hz,1H), 3.93(s,3H), 3.55-3.46(m,1H), 2.54(b rs,1H), 1.98-1.82(m,2H), 1.79-1.71(m,1H), 1.69-1.59(m,1H), 1.41-1.01(m,4H);LC-MS RT:2.49min;MS(ESI) m / z 655.2(M+H) + ;Method A

[0245] Intermediate 34-1, Examples 34, 35, and 36: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-hydroxy-3-methylcyclohexyl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide [ka]

[0246] To a solution of intermediate 32-3 (160 mg, 0.245 mmol) in THF (2 mL) was added methylmagnesium bromide (0.123 mL, 0.245 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The diastereomers were separated by preparative HPLC (column: YMC EXRS C18 (250×21.2) mm, 5 μm; mobile phase A: 10 mM NH4OAc in H2O; mobile phase B: ACN; flow: 20 mL / min, gradient: 80% in 2 min, 80-93% in 14 min; diastereomer 1: RT=11.906 min, diastereomer 2: RT=13.650 min). The first eluting diastereomer from the preparative HPLC was purified by preparative SFC (column: Welk (R,R) (250x21) mm, 5 μm; %CO2: 75%; %cosolvent: 0.2% TFA in 25% MeOH; total flow: 90.0 g / min; back pressure: 100 bar; temperature: 40°C; UV: 220 nm) to give Example 35 (preparative SFC RT = 4.08 min) and Example 36 (preparative SFC RT = 3.03 min, 99% de). Analytical SFC conditions: (column: Welk (R,R) (250x4.6) mm, 5 μm; %CO2: 60%; %cosolvent: 0.2% TFA in 40% MeOH; total flow: 4.0 g / min; back pressure: 100 bar; temperature: 30°C; UV: 220 nm). The second eluting diastereomer from the preparative HPLC was purified by preparative SFC (column: Chiralpak AD-H (250x21) mm, 5 μm; %CO2: 50%; %cosolvent: 0.2% TFA in 50% MeOH; total flow: 90.0 g / min; back pressure: 100 bar; temperature: 40° C., UV: 248 nm) to give Example 34 (preparative SFC RT=11.2 min) and intermediate 34-1 (preparative SFC RT=6.3 min, 95% de). Analytical SFC conditions: (column: Chiralpak AD-H (250x4.6) mm, 5 μm; %CO2: 50%; %cosolvent: 0.2% TFA in 50% MeOH; total flow: 4.0 g / min; back pressure: 100 bar; temperature: 40° C., UV: 248 nm).

[0247] Intermediate 34-1: (4.3 mg, 6.4 マイクロモル, yield 2%) 1 H NMR (400MHz, DMSO-d6) δ ppm 10.80-10.85(m,1H), 10.72-10.79(m,1H), 8.68-8.73(m,1H), 8.15-8.22(m,1H), 8.07-8.14( m,1H), 7.97-8.06(m,1H), 7.81-7.89(m,1H), 7.63-7.68(m,1H), 7.54-7.62(m,1H), 7.40-7.4 6(m,1H), 7.10-7.25(m,1H), 4.12-4.17(m,1H), 3.95-4.00(m,3H), 3.46-3.49(m,1H), 3.27-3 .42(m,3H), 2.52-2.59(m,2H), 1.69-1.79(m,2H), 1.53-1.66(m,1H), 1.26-1.29(m,3H); LC-MS RT:1.51 points;MS(ESI) m / z 669.2(M+H) + ;Method C

[0248] Example 34: (15 mg, 22 マイクロモル, yield 9%); 1 H NMR (400MHz, DMSO-d6) δ ppm 10.80(s,1H), 10.74(s,1H), 8.67(s,1H), 8.12-8.19(m,1H), 8.07(d,J= 8.53Hz,2H), 7.83(d,J=8.30Hz,1H), 7.61(d,J=2.01Hz,1H), 7.55(t,J= 9.78Hz,1H), 7.39(d,J=7.86Hz,1H), 7.08-7.18(m,1H), 4.12(m,2H), 3.94(s,3H), 3.45(s,3H), 1.54(brs,3H), 1.33(s,2H), 1.24(s,3H); LC-MS RT:1.51 points;MS(ESI) m / z 669.2(M+H) + ;Method C

[0249] Example 35: (3.4 mg, 5.1 マイクロモル, yield 2%); 11H NMR (400 MHz, DMSO-d6) δ ppm 10.78 - 10.85 (m, 1H), 10.69 - 10.75 (m, 1H), 8.63 - 8.70 (m, 1H), 8.13 - 8.18 (m, 1H), 8.05 - 8.10 (m, 2H), 8.06 (s, 1H), 7.79 - 7.85 (m, 1H), 7.69 - 7.75 (m, 1H), 7.55 (s, 1H), 7.46 - 7.60 (m, 1H), 7.16 - 7.24 (m, 1H), 4.52 - 4.12 (m, 1H), 3.94 (s, 3H), 3.36 - 3.45 (m, 1H), 3.08 - 3.29 (m, 1H), 1.77 - 1.89 (m, 1H), 1.61 - 1.77 (m, 1H), 1.39 - 1.43 (m, 3H), 1.24 (brs, 3H), 1.12 (m, 2H); LC-MS RT: 3.56 min; MS(ESI) m / z 651.2 (M - OH) + ; Method C

[0250] Example 36: (4.6 mg, 6.9 μmol, yield 3%); 1 1H NMR (400 MHz, DMSO-d6) δ ppm 10.65 - 10.92 (m, 2H), 8.63 - 8.69 (m, 1H), 8.14 - 8.19 (m, 1H), 8.05 - 8.11 (m, 1H), 7.94 - 8.03 (m, 1H), 7.80 - 7.85 (m, 1H), 7.64 - 7.66 (m, 1H), 7.52 - 7.59 (m, 1H), 7.38 - 7.45 (m, 1H), 7.13 - 7.20 (m, 1H), 4.38 - 4.41 (m, 1H), 3.91 - 3.96 (m, 3H), 3.27 - 3.37 (m, 2H), 1.57 - 1.74 (m, 2H), 1.54 - 1.79 (m, 1H), 1.43 - 1.53 (m, 3H), 1.31 - 1.42 (m, 1H), 1.16 - 1.26 (m, 3H); LC-MS RT: 3.96 min; MS(ESI) m / z 667.3 (M - H) - ; Method C

[0251] Examples 37 and 38

Chemical Structure

[0252] Intermediate 37-1: Methyl 2-methoxy-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoate Intermediate 37-1 (4.80 g, 15.7 mmol, 66% yield) was prepared in a similar manner to intermediate 13-3 from (4-methoxy-3-(methoxycarbonyl)phenyl)boronic acid (5.00 g, 23.8 mmol) and 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (6.86 g, 23.8 mmol). LC-MS RT: 2.10 min; MS(ESI) m / z 305.2(M+H). + ;Method C

[0253] Intermediate 37-2: Methyl 2-methoxy-5-(1,4-dioxaspiro[4.5]decan-8-yl)benzoate A solution of intermediate 37-1 (5.00 g, 16.4 mmol) in MeOH (50 mL) was purged with N2 gas, then Pd-C (1.75 g, 16.4 mmol) was added, the reaction was evacuated and purged with H2 gas through a balloon connected to the mixture. The reaction mixture was stirred at room temperature for 8 h. The suspension was filtered through a bed of Celite, and the filtrate was collected and concentrated under reduced pressure to give intermediate 37-2 (4.00 g, 13.1 mmol, 79% yield). LC-MS RT: 0.87 min; MS(ESI) m / z 307.1 (M+H). + ;Method F

[0254] Intermediate 37-3: 2-Methoxy-4-(1,4-dioxaspiro[4.5]decan-8-yl)benzoic acid Intermediate 37-3 (320 mg, 1.10 mmol, 75% yield) was prepared from intermediate 37-2 (500 mg, 1.63 mmol) by the procedure described in Example 2. 1H NMR(400MHz,DMSO-d6) δ ppm 12.46-12.72(m,1H), 7.30-7.54(m,2H), 7.10(dd,J=10.29, 8.78Hz,1H), 5.81(s,1H), 3.81-3.96(m,3 H), 3.40(brs,2H), 2.53-2.67(m,6H), 2.31(brd,J=14.06Hz,1H), 1.76-1.96(m,2H), 1.58-1.76(m,1H)

[0255] Intermediate 37-4: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(1,4-dioxaspiro[4.5]decan-8-yl)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Intermediate 37-4 (1.50 g, 2.15 mmol, 61% yield) was prepared from intermediate 1-2 (1.50 g, 3.55 mmol) and intermediate 37-3 (1.25 g, 4.26 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.39 min; MS(ESI) m / z 695.3(MH). - ;Method C

[0256] Intermediate 37-5: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(4-oxocyclohexyl)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a solution of intermediate 37-4 (1.20 g, 1.72 mmol) in ACN (20 mL) and H2O (1 mL) was added TFA (1.33 mL, 17.2 mmol). The reaction mixture was heated at 70 °C for 30 min. The reaction mixture was cooled, diluted with EtOAc (100 mL) and washed with NaHCO3 saturated solution (50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 37-5 (1.00 g, 1.53 mmol, 89% yield). LC-MS RT: 1.26 min; MS (ESI) m / z 653.2 (M+H) + ;Method E

[0257] Examples 37 and 38: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(4-hydroxy-4-methylcyclohexyl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide

[0258] Examples 37 and 38 were prepared from intermediate 37-5 (120 mg, 0.184 mmol) in the same general manner as described for Examples 34, 35, and 36, and subsequently purified by preparative HPLC (column: Gemini NX C-18 (250x21.2) mm, 5 μm; mobile phase A: 10 mM NH4HCO3 in water, pH 9.5; mobile phase B: ACN; flow: 19 mL / min; gradient: 65-80% in 15 min, 80% in 20 min, 80-100% in 21 min) to give Example 37 (preparative HPLC RT=15.49 min, analytical HPLC RT=6.84 min) and Example 38 (preparative HPLC RT=18.96 min, analytical HPLC RT=7.54 min). [Analytical HPLC: Column: Kinetex BIPHENYL (4.6x100) mm, 2.6 μm; Buffer: 0.05% TFA in water; Mobile phase A: Buffer:ACN (95:5); Mobile phase B: ACN:Buffer (95:5)] Example 37: (17 mg, 25 μmol, 13% yield) 1 H NMR(400MHz,DMSO-d6) δ ppm 10.66-10.95(m,2H), 8.53-8.77(m,1H), 8.06-8.14(m,1H), 7.94-8.02(m,1H), 7.79-7. 86(m,1H), 7.60-7.64(m,1H), 7.50-7.57(m,2H), 7.41-7.46(m,1H), 7.12-7.17(m,1H), 4 .32-4.36(m,1H), 3.90-3.95(m,3H), 3.36-3.39(m,1H), 3.31-3.37(m,2H), 1.66-1.72(m ,1H), 1.59-1.64(m,1H), 1.41-1.56(m,1H), 1.22-1.26(m,1H), 1.14-1.19(m,1H);LC-MS RT:4.07min;MS(ESI) m / z 667.3(MH)- ;Method C

[0259] Example 38: (4.9 mg, 7.3 μmol, 4% yield) 1 H NMR(400MHz,DMSO-d6) δ ppm 10.64-10.93(m,2H), 8.63-8.68(m,1H), 8.08-8.16(m,1H), 7.92-8.02(m,1H) , 7.79-7.85(m,1H), 7.60-7.65(m,1H), 7.48-7.56(m,2H), 7.40-7.47(m,1H), 7 .11-7.17(m,1H), 4.31-4.36(m,1H), 3.90-3.95(m,3H), 3.31-3.37(m,2H), 1.5 9-1.73(m,3H), 1.42-1.56(m,2H), 1.22-1.27(m,3H), 1.13-1.20(m,2H);LC-MS RT:3.86min;MS(ESI) m / z 667.2(MH) - ;Method C

[0260] Example 39 [ka]

[0261] Intermediate 39-1: tert-Butyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate To a solution of tert-butyl 4-oxoazepane-1-carboxylate (5.00 g, 23.4 mmol) in THF (50 mL) was added LDA (29.3 mL, 58.6 mmol) dropwise at -78 °C and the reaction was allowed to continue stirring for 1 h. N-phenyl-bis(trifluoromethanesulfonimide) (10.1 g, 28.1 mmol) was dissolved in THF (50 mL) and added at -78 °C and the reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (3x100 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 39-1 (2.50 g, 7.24 mmol, 31% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 5.31(m,1H), 3.90(brs,1H), 3.38-3.56(m,2H), 3.33(brs,2H), 2.47-2.54(m,2H), 1.81-1.91(m,1H), 1.35-1.43(m,9H)

[0262] Intermediate 39-2: tert-Butyl 4-(4-methoxy-3-(methoxycarbonyl)phenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate Intermediate 39-2 (400 mg, 1.11 mmol, 47% yield) was prepared from (4-methoxy-3-(methoxycarbonyl)phenyl)boronic acid (500 mg, 2.38 mmol) and intermediate 39-1 (987 mg, 2.86 mmol) in a similar manner to intermediate 13-3. 1 H NMR (400MHz, CDCl3-d) δ ppm 7.97-8.02(m,1H), 7.36(s,1H), 6.97-7.09(m,1H), 4.02-4.22(m,1H), 3.85- 3.98(m,6H), 2.04(s,4H), 1.60(s,2H), 1.47-1.56(m,9H), 1.21-1.31(m,2H)

[0263] Intermediate 39-3: tert-Butyl 4-(4-methoxy-3-(methoxycarbonyl)phenyl)azepane-1-carboxylate Intermediate 39-3 (350 mg, 0.963 mmol, 77% yield) was prepared from intermediate 39-2 (450 mg, 1.25 mmol) in a similar manner to intermediate 37-2. 1 H NMR (400MHz, CDCl3-d) δ ppm 7.22-7.28(m,2H), 7.02(dd,J=8.53, 2.51Hz,1H), 3.87(m,3H), 3.66-3.78(m,3H), 3.56-3.74(m,1H), 3.42-3.55 (m,1H), 3.17-3.40(m,2H), 2.60(s,1H), 1.84-2.06(m,2H), 1.80(brs,2H), 1.57-1.76(m,2H), 1.44-1.49(m,9H)

[0264] Intermediate 39-4: 5-(1-(tert-butoxycarbonyl)azepan-4-yl)-2-methoxybenzoic acid Intermediate 39-4 (280 mg, 0.801 mmol, 83% yield) was prepared from intermediate 39-3 (350 mg, 0.963 mmol) by the same hydrolysis conditions used in Example 2. 1 H NMR(400MHz,DMSO-d6) δ ppm 12.54(brs,1H), 7.39-7.48(m,1H), 7.25-7.34(m,1H), 7.03(dd,J=8.53, 2.51Hz,1H), 3.78(s,3H), 3.48-3.64(m,1H), 3.3 8-3.47(m,2H), 3.07-3.29(m,1H), 2.61(brt,J=9.29Hz,1H), 1.79-1.89(m,2H), 1.57-1.77(m,4H), 1.42(d,J=3.01Hz,9H)

[0265] Intermediate 39-5 and 39-6: tert-butyl 4-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)azepane-1-carboxylate Intermediates 39-5 and 39-6 were prepared from intermediate 1-2 (800 mg, 1.89 mmol) and intermediate 39-4 (993 mg, 2.84 mmol) in a similar manner to intermediate 1-3. The isomers were separated by preparative SFC purification (Method: Column / dimensions: Welk (R,R) (250x30) mm, 5 μm; %CO2: 75%; %cosolvent: 0.2% DEA in 25% IPA; Total flow: 140.0 g / min; Backpressure: 100 bar; Temperature: 30° C.; UV: 220 nm) to give intermediate 39-5 (preparative SFC RT=12.76 min, 99% ee) and intermediate 39-6, (preparative SFC RT=14.62 min, 99% ee). Analytical SFC conditions: (Method: Column / dimensions: Welk(R,R) (250x4.6) mm, 5 μm; % CO2: 75%; % co-solvent: 0.2% DEA in 25% IPA; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 220 nm)

[0266] Intermediate 39-5: (400 mg, 0.531 mmol, 28% yield); 1 H NMR (300MHz, CDCl3-d) δ ppm 10.94(s,1H), 9.72(brd,J=6.8Hz,1H), 8.15(s,1H), 7.96-7.74(m,4H), 7.39(dd,J=2 .3, 8.7Hz,1H), 7.28(brd,J=8.7Hz,1H), 7.10-7.00(m,2H), 4.07(s,3H), 3.70(brd,J= 14.0Hz,1H), 3.56-3.44(m,1H), 3.41(s,1H), 3.36-3.17(m,1H), 2.68(brd,J=8.7Hz,1 LC-MS RT:2.71min;MS(ESI) m / z 752.2(MH) - ;Method C

[0267] Intermediate 39-6: (400 mg, 0.531 mmol, 28% yield); 1H NMR (300MHz, CDCl3-d) δ ppm 10.75(brs,1H), 9.81(brd,J=10.2Hz,1H), 8.14(s,1H), 7.98(s,1H), 7.90-7 .77(m,2H), 7.47-7.36(m,2H), 7.19(s,1H), 7.12-7.00(m,2H), 4.07(s,3H), 3.83-3.54(m,1H), 3.48(brs,1H), 3.40-3.16(m,1H), 2.77-2.65(m,2H), 2.5 4(s,1H), 2.01-1.82(m,4H), 1.80-1.62(m,1H), 1.43(d,J=3.0Hz,9H);LC-MS RT:2.04min;MS(ESI) m / z 712.2(M+H) + ;Method A

[0268] Example 39 and Intermediate 39-7: 3-(5-(azepan-4-yl)-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Intermediate 39-7 (3.7 mg, 5.6 μmol, 4% yield) was prepared from intermediate 39-6 (100 mg, 0.13 mmol) in a similar manner to intermediates 9-4 and 9-5, and subsequently purified by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.86-10.65(m,2H), 8.61(s,1H), 8.13-8.04(m,2H), 7.97-7.88(m,1H), 7.78(dd,J=1.8, 8.7Hz,1H), 7.62(d,J=2.4Hz,1H), 7.50(t,J LC-MS RT:2.14min;MS(ESI) m / z 654.2(M+H) + ;Method A

[0269] Example 39 (3.6 mg, 5.5 μmol, 4% yield) was prepared from intermediate 39-5 (100 mg, 0.13 mmol) in a similar manner to intermediates 9-4 and 9-5, and subsequently purified by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6)δ=10.82-10.63(m,2H), 8.61(s,1H), 8.14-8.04(m,2H) , 7.97-7.88(m,1H), 7.78(dd,J=1.5, 8.3Hz,1H), 7.63(d,J=2.4Hz,1H), 7.50(t ,J=9.4Hz,1H), 7.38(dd,J=2.3, 8.4Hz,1H), 7.13(d,J=8.6Hz,1H), 3.90(s,3H) ), 3.02-2.94(m,2H), 2.90-2.76(m,2H), 1.88(s,3H), 1.83-1.50(m,4H);LC-MS RT:2.15min;MS(ESI) m / z 654.2(M+H) + ;Method A

[0270] Example 40 [ka]

[0271] Intermediate 40-1: 2-(4-(4-methoxyphenyl)bicyclo[2.2.2]octan-1-yl)propan-2-ol Intermediate 40-1 (70 mg, 0.26 mmol, 70% yield) was prepared in a similar manner to Example 3 from methyl 4-(4-methoxyphenyl)bicyclo[2.2.2]octane-1-carboxylate (100 mg, 0.36 mmol). 1 H NMR(400MHz,DMSO-d6) δ ppm 7.21(d,J=9.04Hz,2H), 6.82(d,J=8.53Hz,2H), 3.85(s,1H), 3.70(s,3H), 1.61-1.74(m,6H), 1.47-1.61(m,6H), 1.01(s,6H)

[0272] Intermediate 40-2: 2-(4-(3-bromo-4-methoxyphenyl)bicyclo[2.2.2]octan-1-yl)propan-2-ol To a solution of intermediate 40-1 (60 mg, 0.22 mmol) in ACN (3 mL) at 0° C. was added a solution of NBS (39 mg, 0.22 mmol) in ACN (1 mL). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure and 3 mL of water was added to the residue. The solid precipitate was filtered and dried under vacuum to give intermediate 40-2 (65 mg, 0.18 mmol, 84% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 7.43-7.29(s,1H), 7.27-7.20(d,J=8.53Hz,1H), 7.02-6.99(d,J=9.04Hz,1H) , 3.85(s,1H), 3.70(s,3H), 1.61-1.74(m,6H), 1.47-1.61(m,6H), 1.01(s,6H)

[0273] Intermediate 40-3: Methyl 5-(4-(2-hydroxypropan-2-yl)bicyclo[2.2.2]octan-1-yl)-2-methoxybenzoate To a solution of intermediate 40-2 (250 mg, 0.71 mmol) in a mixture of DMF (6 mL) and MeOH (6 mL), dppf (59 mg, 0.11 mmol), Pd(OAc) (16 mg, 0.071 mmol) and TEA (0.49 mL, 3.5 mmol) were added under N atmosphere. The reaction mixture was pressurized at 10 kg / cm 2 The mixture was heated at 100° C. under a pressure of CO gas for 12 h. The reaction mixture was filtered through a bed of celite and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 40-3 (130 mg, 0.39 mmol, 55% yield). LC-MS RT: 0.74 min; MS(ESI) m / z 333.2 (M+H). + ;Method E

[0274] Intermediate 40-4: 5-(4-(2-hydroxypropan-2-yl)bicyclo[2.2.2]octan-1-yl)-2-methoxybenzoic acid Intermediate 40-4 (85 mg, 0.27 mmol, 68% yield) was prepared from intermediate 40-3 (130 mg, 0.39 mmol) by the procedure described in Example 2. LC-MS RT: 0.83 min; MS(ESI) m / z 319.2(M+H). + ;Method E

[0275] Example 40: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(4-(2-hydroxypropan-2-yl)bicyclo[2.2.2]octan-1-yl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 40 (22 mg, 0.028 mmol, 22% yield) was prepared from intermediate 1-2 (27 mg, 0.063 mmol) and intermediate 40-4 (40 mg, 0.13 mmol) in a similar manner to intermediate 1-3, followed by preparative LCMS purification (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.74(brd,J=12.2Hz,2H), 8.66(s,1H), 8.13(dd,J=2.9, 6.6Hz,1H), 8.08(d,J=8.6Hz,1H), 8.01-7.94(m,1H), 7.83(dd,J=1.2, 8.3Hz,1H), 7.6 4(d,J=2.4Hz,1H), 7.58-7.44(m,2H), 7.13(d,J=8.6Hz,1H), 3.92(s,3H) ), 3.88(s,1H), 1.70-1.62(m,6H), 1.57-1.51(m,6H), 1.01(s,6H);LC-MS RT:2.79min;MS(ESI) m / z 723.2(M+H) + ;Method A

[0276] Example 42 [ka]

[0277] Example 42: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(3-hydroxyprop-1-yn-1-yl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide To a solution of intermediate 2-1 (50 mg, 0.079 mmol) in toluene (2 mL) and diisopropylamine (0.056 mL, 0.39 mmol), copper(I) iodide (3.0 mg, 0.016 mmol) and bis(triphenylphosphine)palladium(II) dichloride (5.5 mg, 7.9 μmol) were added, and the resulting solution was degassed with N2 for 10 min, after which prop-2-yn-1-ol (22 mg, 0.39 mmol) was added. The reaction mixture was heated at 85° C. for 5 h. The reaction was diluted with EtOAc (25 mL) and washed with water (2×20 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 2) to give Example 42 (12 mg, 0.019 mmol, 24% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.66-10.95(m,2H), 8.49-8.77(m,1H), 8.14-8.19(m,1H), 8.07-8.11(m,1H), 7.97-8.03(m,1H), 7.79-7.84 (m,2H),7.53-7.64(m,1H),7.23-7.27(m,2H),5.28-5.33(m,1H),3.92-3.96(s,3H),3.37-3.39(m,2H);LC-MS RT:3.61min;MS(ESI) m / z 611.2(M+H) + ;Method C

[0278] Example 44 [ka]

[0279] Intermediate 44-1: 3-Amino-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid Intermediate 44-1 (184 mg, 0.704 mmol, 65% yield) was prepared from intermediate 1-1 (300) by the general procedure described for Example 2. LC-MS RT: 0.83 min; MS(ESI) m / z 260.2 (MH). - ;Method E

[0280] Intermediate 44-2: 3-amino-6-(trifluoromethyl)-N-(3-(trifluoromethyl)cyclohexyl)benzo[b]thiophene-2-carboxamide Intermediate 44-2 (50 mg, 0.11 mmol, 41% yield) was prepared from intermediate 44-1 (70 mg, 0.27 mmol) and 3-(trifluoromethyl)cyclohexane-1-amine (90 mg, 0.54 mmol) in a similar manner to intermediate 29-3. LC-MS RT: 1.34 min; MS(ESI) m / z 410.0(MH). - ;Method E

[0281] Intermediate 44-3: 5-(3-hydroxypropyl)-2-methoxybenzoic acid To a solution of 3-(4-methoxyphenyl)propan-1-ol (1.00 g, 6.02 mmol) in THF (20 mL) at -78 °C, n-butyllithium (8.27 mL, 13.2 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and slowly added to a suspension of carbon dioxide (dry ice) (6.62 g, 150 mmol) in Et2O (10 mL) and the reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched with water and concentrated under reduced pressure. The residue was diluted with ice water (20 mL) and extracted with ether (1x). The organic layer was discarded. The aqueous layer was then acidified to pH 6 with concentrated HCl and stirred for 10 min. The resulting precipitate was collected by filtration, washed with petroleum ether and dried under vacuum to give intermediate 44-3 (700 mg, 3.33 mmol, 55% yield). LC-MS RT:0.34min;MS(ESI) m / z 209.2(MH) - ;Method C

[0282] Example 44: 3-(5-(3-hydroxypropyl)-2-methoxybenzamido)-6-(trifluoromethyl)-N-(3-(trifluoromethyl)cyclohexyl)benzo[b]thiophene-2-carboxamide Example 44 was prepared from intermediate 44-2 (180 mg, 0.439 mmol) and intermediate 44-3 (184 mg, 0.877 mmol) in a similar manner to intermediate 1-3, and obtained by filtration of the precipitate. The individual isomers were subjected to preparative SFC purification (column: Chiralpak IG (250x30) mm, 5 μm; % CO2: 65%; % co-solvent: 0.2% NH3 in 35% MeOH; total flow: 100.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 242 nm) to give Example 44 (preparative SFC RT = 3.54 min, 100% ee), Intermediate 44-4 (preparative SFC RT = 4.12 min, 99% ee), Intermediate 44-5 (preparative SFC RT = 3.56 min, 100% ee), Intermediate 44-6 (preparative SFC RT = 2.84 min, 100% ee). Analytical SFC conditions: (Column: Chiralpak IG (250x4.6) mm, 5 μm; % CO2: 55%; % co-solvent: 0.2% NH3 in 45% MeOH; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 35° C.; UV: 242 nm).

[0283] Example 44: (7.0 mg, 11 μmol, 3% yield); LC-MS RT: 3.28 min; MS(ESI) m / z 603.3(M+H) + ;Method C Intermediate 44-4: (6.0 mg, 9.0 μmol, 2% yield); LC-MS RT: 3.27 min; MS(ESI) m / z 603.3(M+H) + ;Method C Intermediate 44-5: (34 mg, 0.056 mmol, 13% yield); 1H NMR (400MHz, DMSO-d6) δ ppm 8.54(brs,1H), 7.98(d,J=8.0Hz,1H), 7.74(brd,J=8.5Hz,1H), 7.62(brs,1H), 7.36(brs,1H), 7.14(brd,J=7.0Hz,1H), 4.49(brs,1H), 3 .97(s,3H), 3.88(brs,2H), 2.66-2.58(m,2H), 2.05(brd,J=13.1Hz,1H), 1.93-1.67(m,7H), 1.49-1.33(m,2H), 1.30-1.06(m,4H); LC-MS RT:3.33 points;MS(ESI) m / z 603.2(M+H) + ;Method C Intermediate 44-6: (34 mg, 0.056 ミリモル, yield 13%); 1 H NMR (400MHz, DMSO-d6) δ ppm 8.54(brs,1H), 7.98(d,J=8.5Hz,1H), 7.74(brd,J=8.0Hz,1H), 7.69-7.53(m,1 H), 7.42-7.32(m,1H), 7.14(brd,J=8.5Hz,1H), 4.49(brs,1H), 3.97(s,3H), 3.8 8(brs,2H), 2.65-2.57(m,2H), 2.56-2.52(m,2H), 2.46-2.34(m,1H), 2.05(brd ,J=13.1Hz,1H), 1.93-1.67(m,7H), 1.45-1.34(m,2H), 1.30-1.07(m,4H); LC-MS RT:3.33 points;MS(ESI) m / z 603.2(M+H) + ;Method C

[0284] Example 45

change

[0285] Intermediate 45-1: メチル(Z)-5-(3-(tert-ブトキシ)-3-オキソプロパ-1-エン-1-イル)-2-メトキシベンゾエート To a solution of tert-butyl diethylphosphonoacetate (2.04 mL, 8.65 mmol) in THF (10 mL) was added sodium tert-butoxide (831 mg, 8.65 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. Methyl 5-formyl-2-methoxybenzoate (1.40 g, 7.21 mmol) in THF (10 mL) was added to the reaction mixture, and stirring was continued at room temperature for 10 h. The reaction was diluted with EtOAc (25 mL), washed with water (2×20 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 45-1 (1.40 g, 4.79 mmol, 70% yield). LC-MS RT:2.96min;MS(ESI) m / z 293.2(M+H) + ;Method C

[0286] Intermediate 45-2: Methyl 5-(2-(tert-butoxycarbonyl)cyclopropyl)-2-methoxybenzoate To a cooled (0° C.) solution of intermediate 45-1 (500 mg, 1.71 mmol) in dioxane (10 mL) was added NaOH (68.4 mg, 1.71 mmol) and the reaction was heated at 90° C. for 2 h. The reaction was concentrated and acidified to pH 4 with 1.5 N HCl, and the aqueous layer was extracted with DCM (15 mL), then washed with water (2×10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 45-2 (150 mg, 0.539 mmol, 32% yield). 1 H NMR(400MHz,DMSO-d) δ ppm 7.97(m,2H), 7.65(d,J=2.5Hz,1H), 7.26(d,8.4 0Hz,1H), 6.34(d,J=16.1Hz,1H), 3.84(s,3H), 1.47(s,9H)

[0287] Intermediate 45-3: tert-butyl (Z)-3-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)acrylate Intermediate 45-3 (210 mg, 0.308 mmol, 52% yield) was prepared from intermediate 1-2 (250 mg, 0.592 mmol) and intermediate 45-2 (198 mg, 0.710 mmol) in a similar manner to intermediate 1-3. 1 H NMR (300MHz, CDCl3-d) δ ppm 10.81(s,1H), 9.41(s,1H), 8.47(d,J=2.3Hz,1H), 8.01-7.91(m,2H), 7.85-7.65(m,3H), 7.56(d,J=15.9 Hz,1H), 7.41(d,J=8.7Hz,2H), 7.23-7.07(m,1H), 6.36(d,J=16.2Hz,1H), 4.13(s,3H), 1.66-1.40(m,9H)

[0288] Example 45: (Z)-3-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)acrylic acid Example 45 (2.6 mg, 4.0 μmol, 13% yield) was prepared from intermediate 45-3 (20 mg, 0.029 mmol) in a similar manner to intermediate 4-2 and subsequently purified by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.93-10.72(m,1H), 8.66(s,1H), 8.21-8.08(m,2H), 8.06(brs,1H), 8.04-7.96(m,1H), 7.88(brd,J=8.3Hz,1H) ,7.82(d,J=8.6Hz,1H),7.64-7.44(m,2H),7.26(brd,J=9.0Hz,1H),6.44(brd,J=15.9Hz,2H),3.92(s,3H);LC-MS RT:1.92min;MS(ESI) m / z 625.1(MH) - ;Method A

[0289] Examples 46, 47 and 48 [ka]

[0290] Intermediate 46-1: tert-butyl (Z)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-methoxybenzoate Intermediate 46-1 (140 mg, 0.457 mmol, 54% yield) was prepared in a similar manner to intermediate 45-1 from triethyl phosphonoacetate (228 mg, 1.02 mmol) and tert-butyl 5-formyl-2-methoxybenzoate (200 mg, 0.846 mmol). 1 H NMR (400MHz, CDCl3-d) δ ppm 7.90(d,J=2.01Hz,1H), 7.58-7.67(m,1H), 7.27(s,1H), 6.97(d,J=8.53Hz,1H), 6.35(d,J=1 5.56Hz,1H), 4.27(q,J=7.36Hz,2H), 3.94(s,3H), 1.45-1.56(m,9H), 1.35(t,J=7.03Hz,3H)

[0291] Intermediate 46-2: tert-Butyl 5-(2-(ethoxycarbonyl)cyclopropyl)-2-methoxybenzoate To a solution of intermediate 46-1 (100 mg, 0.326 mmol) in DMSO (5 mL) was added trimethylsulfoxonium iodide (144 mg, 0.653 mmol) followed by NaOH (19.6 mg, 0.490 mmol) at 0° C. The resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction was diluted with EtOAc (50 mL) and washed with water (2×25 mL) and then with brine (25 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 46-2 (75.0 mg, 0.234 mmol, 71% yield). 1H NMR (400MHz, CDCl3-d) δ ppm 7.48(d,J=2.4Hz,1H), 7.29(s,1H), 7.18(dd,J=2.4, 8.6Hz,1H), 6.89(d,J=8.6Hz,1H), 4.19(q,J=7.1Hz,2 H), 3.89(s,3H), 2.54-2.45(m,2H), 1.86(ddd,J=4.3, 5.2, 8.4Hz,1H), 1.62-1.56(m,9H), 1.36-1.24(m,3H)

[0292] Intermediate 46-3: 5-(2-(ethoxycarbonyl)cyclopropyl)-2-methoxybenzoic acid Intermediate 46-3 (70.0 mg, 0.265 mmol, 85% yield) was prepared from intermediate 46-2 (100 mg, 0.312 mmol) in a similar manner to intermediate 4-2. 1 H NMR(300MHz, CDCl3-d)d ppm 8.06(brs,1H), 7.80(d,J=2.3Hz,1H), 7.31(dd,J=2.5, 8.5Hz,1H), 6.93(d,J=8.7Hz,1H), 4.11(q,J= 7.2Hz,2H), 4.00(s,3H), 2.50-2.41(m,1H), 1.85-1.77(m,1H), 1.59-1.43(m,1H), 1.30-1.14(m,5H)

[0293] Intermediate 46-4: Ethyl 2-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)cyclopropane-1-carboxylate Intermediate 46-4 (50 mg, 0.074 mmol, 63% yield) was prepared from intermediate 1-2 (50 mg, 0.12 mmol) and intermediate 46-3 (47 mg, 0.18 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.64 min; MS(ESI) m / z 667.2(MH). - ;Method E

[0294] Examples 46, 47 and 48: 2-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)cyclopropane-1-carboxylic acid Example 46 (3.0 mg, 4.7 μmol, 6% yield) was prepared from intermediate 46-4 (50 mg, 0.074 mmol) by the general procedure described in Example 2 and subsequently purified using preparative LCMS conditions (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.87-10.62(m,2H), 8.65(s,1H), 8.14(dd,J=2.3, 6.5Hz,1H), 8.08(d,J=8.6H z,1H), 8.03-7.93(m,1H), 7.81(dd,J=1.5, 8.6Hz,1H), 7.63-7.46(m,2H), 7.37( dd,J=2.3, 8.4Hz,1H), 7.14(d,J=8.6Hz,1H), 3.90(s,3H), 2.44-2.36(m,1H), 1. 74(td,J=4.8, 7.7Hz,1H), 1.40(td,J=4.8, 9.0Hz,1H), 1.32-1.24(m,1H);LC-MS RT:1.99min;MS(ESI) m / z 641.1(M+H) + ;Method A

[0295] Example 46 (287 mg, 0.449 mmol) was purified by preparative SFC (Column: Chiralpak IG (250x30) mm, 5 μm; % CO2: 50%; % co-solvent: 0.2% NH3 in 50% MeOH; flow conditions: 140.0 g / min; back pressure: 100 bar; temperature: 40°C; detector wavelength: 220 nm) to give Example 47 (Peak 1, Prep SFC RT=4.8 min) and Example 48 (Peak 2, Prep SFC RT=8.3 min). Analytical SFC conditions: (Column: Chiralpak IG (250x4.6) mm, 5 μm; % CO2: 50%; % co-solvent: 0.2% NH3 in 50% MeOH; Flow conditions: 4.0 g / min; Back pressure: 100 bar; Temperature: 40° C.; Detector wavelength: 220 nm).

[0296] Example 47: (80.0 mg, 0.125 mmol, 28% yield) 1 H NMR(400MHz,DMSO-d6)δ 12.38-12.23(m,1H), 10.80(brd,J=4.2Hz,1H), 10.73(brd,J=1.2Hz,1H), 8.66(s,1H), 8.1 5(dd,J=6.5, 2.3Hz,1H), 8.08(d,J=8.3Hz,1H), 8.00(dt,J=5.0, 3.6Hz,1H), 7.81(d,J=8.1H z,1H), 7.62-7.50(m,2H), 7.38(dd,J=8.6, 2.0Hz,1H), 7.14(d,J=8.8Hz,1H), 3.89(s,3H), 2.44-2.36(m,1H), 1.80-1.70(m,1H), 1.41(dt,J=9.0, 4.7Hz,1H), 1.33-1.19(m,2H);LC-MS RT:2.16min;MS(ESI) m / z 639.1(MH) - ;Method A

[0297] Example 48: (80.0 mg, 0.125 mmol, 28% yield) 1 H NMR (400MHz, DMSO-d6) δ 10.80(brd,J=10.0Hz,1H), 8.65(s,1H), 8.15(dd,J=6.6, 2.4Hz,1H), 8.08(d,J=8.6Hz,1H), 8.03-7.94(m,1H), 7.83-7.75(m,1H), 7.60-7.46(m ,2H), 7.42-7.31(m,1H), 7.14(d,J=8.8Hz,1H), 3.89(s,3H), 2.43-2.35 (m,1H), 1.77-1.67(m,1H), 1.44-1.36(m,1H), 1.29-1.18(m,2H);LC-MS RT:2.02min;MS(ESI) m / z 639.1(MH) - ;Method A

[0298] Example 49: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(2-(hydroxymethyl)cyclopropyl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide [ka]

[0299] To a solution of intermediate 46-4 (60 mg, 0.090 mmol) in THF (2 mL) was added LAH (0.045 mL, 0.090 mmol) at -78 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction solution was diluted with EtOAc (20 mL) and washed with water (2x20 mL) and then with brine (10 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LCMS (Method 1) to give Example 49 (13 mg, 0.020 mmol, 23% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.85-10.75(m,1H), 10.75-10.63(m,1H), 8.66(s,1H), 8.15(dd,J=2.2, 6.4Hz,1H), 8.06(d, J=8.6Hz,1H), 8.02-7.94(m,1H), 7.81(dd,J=1.1, 8.7Hz,1H), 7.60-7.46(m,2H), 7.27(dd,J= 2.0, 8.3Hz,1H), 7.12(d,J=8.3Hz,1H), 4.60(t,J=5.6Hz,1H), 3.91(s,3H), 3.46(td,J=5.8, 1 LC-MS RT:2.39min;MS(ESI) m / z 627.2(M+H) + ;Method A

[0300] Example 50 [ka]

[0301] Intermediate 50-1: Methyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-1H-pyrazole-3-carboxylate To a solution of methyl 4-methoxy-1H-pyrazole-5-carboxylate (320 mg, 2.05 mmol) in DMF (12 mL) was added K2CO3 (850 mg, 6.15 mmol) followed by (3-bromopropoxy)(tert-butyl)dimethylsilane (779 mg, 3.07 mmol). The resulting reaction mixture was stirred at 70 °C for 5 h. The reaction was filtered through Celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the residue was then purified by column chromatography to give intermediate 50-1 (180 mg, 0.548 mmol, 27% yield). LC-MS RT: 2.07 min; MS(ESI) m / z 329.2 (M+H). + ;Method E

[0302] Intermediate 50-2: 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-1H-pyrazole-5-carboxylic acid Intermediate 50-2 (85 mg, 0.27 mmol, 49% yield) was prepared from intermediate 50-1 (180 mg, 0.55 mmol) in a similar manner to Example 2. LC-MS RT: 0.46 min; MS(ESI) m / z 315.1(M+H). + ;Method E

[0303] Example 50: N-(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-1-(3-hydroxypropyl)-4-methoxy-1H-pyrazole-3-carboxamide Example 50 (10 mg, 0.017 mmol, 12% yield) was prepared from intermediate 1-2 (30 mg, 0.071 mmol) and intermediate 50-2 (45 mg, 0.14 mmol) in a similar manner to intermediate 1-3, and subsequently purified by preparative LCMS (Method 1). 1H NMR(400MHz,DMSO-d6) δ ppm 10.76(s,1H), 10.11(s,1H), 8.68(s,1H), 8.14(dd,J=2.4, 6.4Hz,1H), 8.03(d,J=8.6Hz,1H), 8.01-7.92(m,1H), 7.81(dd,J=1. 3, 8.7Hz,1H), 7.59(s,1H), 7.54(t,J=9.9Hz,1H), 4.50-4.41(m,3H), 3.95(s,3H), 3.31-3.28(m,2H), 1.84-1.72(m,2H);LC-MS RT:2.21min;MS(ESI) m / z 603.1(MH) - ;Method A

[0304] Example 51 [ka]

[0305] Intermediate 51-1: Ethyl 4-fluoro-1H-pyrazole-5-carboxylate To a solution of ethyl 1H-pyrazole-5-carboxylate (1.00 g, 7.14 mmol) in ACN (10 mL) was added Selectfluor (2.78 g, 7.85 mmol) and the reaction mixture was stirred at 80° C. for 48 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography to give intermediate 51-1 (910 mg, 2.24 mmol, 32% yield). LC-MS RT: 0.84 min; MS(ESI) m / z 157.1 (MH). - ;Method E

[0306] Intermediate 51-2: Ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-fluoro-1H-pyrazole-5-carboxylate Intermediate 51-2 (500 mg, 1.51 mmol, 44% yield) was prepared from intermediate 51-1 (550 mg, 3.48 mmol) in a similar manner to intermediate 50-1. LC-MS RT: 1.54 min; MS(ESI) m / z 331.1(M+H). + ;Method E

[0307] Intermediate 51-3: 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-fluoro-1H-pyrazole-5-carboxylic acid Intermediate 51-3 (240 mg, 0.794 mmol, 53% yield) was prepared from intermediate 51-2 (500 mg, 1.51 mmol) in a similar manner to Example 2. LC-MS RT: 0.96 min; MS(ESI) m / z 303.2(M+H). + ;Method E

[0308] Example 51: 4-Fluoro-N-(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-1-(3-hydroxypropyl)-1H-pyrazole-3-carboxamide Example 51 (17 mg, 0.029 mmol, 24% yield) was prepared from intermediate 51-3 (36 mg, 0.12 mmol) and intermediate 1-2 (50 mg, 0.12 mmol) in a similar manner to intermediate 1-3, and subsequently purified by preparative HPLC (Method 5). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.79(brs,1H), 10.66(s,1H), 8.71-8.66(m,1H), 8.18-8.08(m,1H), 8.18-8.08(m,1H), 8.02-7.94(m,1H), 7.86-7.80(m,1H), 7.73-7.68(m,1H), 7.59-7.51(m,1H), 4.59-4.49(m,1H), 4.41-4.32(m,2H), 4.37(brt,J=7.0Hz,2H), 1.89-1.80(m,2H);LC-MS RT:2.71min;MS(ESI) m / z 593.2(M+H) + ;Method C

[0309] Example 52 [ka]

[0310] Intermediate 52-1: Methyl (E)-5-((hydroxyimino)methyl)-2-methoxybenzoate To a solution of methyl 5-formyl-2-methoxybenzoate (1.45 g, 7.47 mmol) in MeOH (30 mL) was added TEA (4.16 mL, 29.9 mmol) followed by hydroxylamine hydrochloride (0.778 g, 11.2 mmol). The reaction mixture was stirred at 75° C. for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in EtOAc (50 mL) and washed with water (2×50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give intermediate 52-1 (1.41 g, 6.74 mmol, 90% yield). LC-MS RT: 1.11 min; MS(ESI) m / z 210.2 (M+H) + ;Method E

[0311] Intermediate 52-2: Methyl (Z)-5-(chloro(hydroxyimino)methyl)-2-methoxybenzoate To a solution of intermediate 52-1 (170 mg, 0.813 mmol) in DMF (6 mL) at 0° C., NCS (163 mg, 1.22 mmol) was added. The reaction solution was stirred at room temperature for 1 h, then 10 mL of ice-cold water was added to the reaction and stirred for an additional 5 min. The solid precipitate was filtered and dried under vacuum to give intermediate 52-2 (120 mg, 0.493 mmol, 61% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 12.29-12.33(m,1H), 8.05-8.08(m,1H), 7.92-7.97(m,1H), 7.24-7.29(m,1H), 3.88(s,3H), 3.81(s,3H)

[0312] Intermediate 52-3: Methyl 5-(5,5-dioxido-3a,4,6,6a-tetrahydrothieno[3,4-d]isoxazol-3-yl)-2-methoxybenzoate To a solution of intermediate 52-2 (60.0 mg, 0.246 mmol) and 2,5-dihydrothiophene 1,1-dioxide (145 mg, 1.23 mmol) in DCM (5 mL) was added TEA (0.172 mL, 1.23 mmol). The resulting reaction mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give intermediate 52-3 (60.0 mg, 0.184 mmol, 75% yield). LC-MS RT: 1.15 min; MS(ESI) m / z 326.2 (M+H). + ;Method E

[0313] Intermediate 52-4: 5-(5,5-dioxido-3a,4,6,6a-tetrahydrothieno[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 52-4 (25 mg, 0.080 mmol, 87% yield) was prepared from intermediate 52-3 (30 mg, 0.092 mmol) by the procedure described in Example 2. LC-MS RT: 0.40 min; MS(ESI) m / z 310.2 (MH). - ;Method E

[0314] Example 52: 3-(5-(5,5-dioxido-3a,4,6,6a-tetrahydrothieno[3,4-d]isoxazol-3-yl)-2-methoxybenzamide)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 52 was prepared from intermediate 1-2 (25 mg, 0.059 mmol) and intermediate 52-4 (18 mg, 0.059 mmol) in a similar manner to intermediate 1-3, and subsequently purified by preparative HPLC (Method 44) ​​and then preparative SFC (Method 45) to give Example 52 (Prep SFC RT=6.0 min) and intermediate 52-5 (Prep SFC RT=8.1 min).

[0315] Example 52: (4.8 mg, 6.7 μmol, 11% yield); 1H NMR(400MHz,DMSO-d6) δ ppm 10.97-10.73(m,2H), 8.44(d,J=0.7Hz,1H), 8.18(d,J=8.6Hz,1H), 8.13-8.06 (m,1H), 8.00(d,J=2.2Hz,1H), 7.80-7.72(m,1H), 7.72-7.61(m,2H), 7.43(t, J=9.8Hz,1H), 7.22(d,J=8.6Hz,1H), 5.42(ddd,J=10.9, 6.7, 2.2Hz,1H), 4.76 (td,J=10.2, 4.5Hz,1H), 3.85(s,3H), 3.74-3.66(m,2H), 3.52(brs,2H);LC-MS RT:2.29min;MS(ESI) m / z 714.0(MH) - ;Method A

[0316] Intermediate 52-5: (5.9 mg, 8.2 μmol, 14% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.86-10.66(m,2H), 8.49(s,1H), 8.16(d,J=8.3Hz,1H), 8.14-8.08(m ,1H), 8.02(d,J=2.2Hz,1H), 7.85-7.76(m,1H), 7.75-7.64(m,2H), 7.45 LC-MS RT:2.29min;MS(ESI) m / z 714.1(MH) - ;Method A

[0317] The following intermediates (Table 2) were prepared by following the general method outlined in intermediate 52-3, but substituting the appropriate alkene or alkyne followed by hydrolysis. [Table 16] [Table 17] [Table 18] [Table 19]

[0318] Examples 53 and 54 [ka]

[0319] Examples 53 and 54: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(2-hydroxy-2-methylpropyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzamide)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide A solution of intermediate 53-1 (100 mg, 0.15 mmol) and 2,2-dimethyloxirane (54 mg, 0.75 mmol) in EtOH (5 mL) was heated at 70° C. for 3 h. The reaction was concentrated under reduced pressure and purified by preparative HPLC (Method 2) followed by preparative SFC purification (Column: Chiralpak IC (250×21.2) mm, 5 μm; % CO2: 65%; % co-solvent: 35% ACN: 0.2% DEA in IPA; Total flow: 80.0 g / min; Back pressure: 100 bar; Temperature: 40° C.; UV: 265 nm) to give Example 53 (Prep SFC RT=1.7 min) and Example 54 (Prep SFC RT=2.4 min, 99.3% ee). Analytical SFC conditions: (Column: Chiralpak IC (250x4.6) mm, 5 μm; % CO2: 65%; % co-solvent: 35% ACN: 0.2% DEA in IPA; Total flow: 4.0 g / min; Back pressure: 100 bar; Temperature: 40° C.; UV: 265 nm)

[0320] Example 53: (16 mg, 0.021 mmol, 14% yield) 11H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.39 (s, 2H), 8.17 (d, J = 6.4 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.93 (brs, 1H), 7.83 - 7.77 (m, 2H), 7.51 (t, J = 9.8 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 5.11 (dd, J = 4.3, 9.3 Hz, 1H), 4.26 (brt, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.07 (brd, J = 9.5 Hz, 1H), 2.90 - 2.66 (m, 2H), 2.47 - 2.39 (m, 2H), 2.39 - 2.13 (m, 2H), 1.24 (s, 3H), 1.09 (t, J = 7.3 Hz, 3H); LC-MS RT: 2.76 min; MS (ESI) m / z 739.2 (M + H) + ; Method C

[0321] Example 54: (22 mg, 0.029 mmol, 20% yield) 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.39 (s, 2H), 8.17 (d, J = 6.4 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.93 (brs, 1H), 7.83 - 7.77 (m, 2H), 7.51 (t, J = 9.8 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 5.11 (dd, J = 4.3, 9.3 Hz, 1H), 4.26 (brt, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.07 (brd, J = 9.5 Hz, 1H), 2.90 - 2.66 (m, 2H), 2.47 - 2.39 (m, 2H), 2.39 - 2.13 (m, 2H), 1.24 (s, 3H), 1.09 (t, J = 7.3 Hz, 3H); LC-MS RT: 2.76 min; MS (ESI) m / z 739.2 (M + H) + ; Method C

[0322] Examples 55 and 56 [Chemical formula]

[0323] Intermediate 55-1: tert-Butyl 5-formyl-2-methoxybenzoate Intermediate 55-1 (4.20 g, 17.8 mmol, 64% yield) was prepared from 5-formyl-2-methoxybenzoic acid (5.00 g, 27.8 mmol) in a similar manner to intermediate 27-2. LC-MS RT: 2.36 min; MS(ESI) m / z 181.1 (M-tBu+H). + ;Method C

[0324] Intermediate 55-2: tert-Butyl (E)-5-((hydroxyimino)methyl)-2-methoxybenzoate To a solution of intermediate 55-1 (5.00 g, 21.2 mmol), hydroxylamine hydrochloride (4.41 g, 63.5 mmol) in EtOH (70 mL) and H2O (70 mL) was added NaOAc (5.21 g, 63.5 mmol). The reaction solution was heated at 50 °C for 3 h. The reaction mixture was cooled and concentrated under reduced pressure, and the resulting mixture was diluted with ice-cold water (150 mL) and extracted with EtOAc (2x100 mL). The organic layers were combined, washed with water, followed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 55-2 (5.20 g, 20.7 mmol, 98% yield). LC-MS RT: 2.10 min; MS (ESI) m / z 250.0 (MH). - ;Method C

[0325] Intermediate 55-3: tert-Butyl (Z)-5-(chloro(hydroxyimino)methyl)-2-methoxybenzoate Intermediate 55-3 (5.50 g, 19.2 mmol, 97% yield) was prepared from intermediate 55-2 (5.00 g, 19.9 mmol) in a similar manner to intermediate 52-2. 1 H NMR(400MHz,DMSO-d6) δ ppm 12.30(s,1H), 7.99-7.87(m,1H), 7.97-7.87(m,1H), 7.25-7.20(m,1H), 3.93-3.85(m,3H), 1.57-1.51(m,9H)

[0326] Intermediate 55-4: Methyl 3-(3-(tert-butoxycarbonyl)-4-methoxyphenyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazole-5-carboxylate Intermediate 55-4 (1.40 g, 3.73 mmol, 21% yield) was prepared from intermediate 55-3 (5.00 g, 17.5 mmol) and methyl cyclopent-3-ene-1-carboxylate (11.0 g, 87.0 mmol) in a similar manner to intermediate 52-3. LC-MS RT: 2.67 min; MS(ESI) m / z 376.2(M+H). + ;Method C

[0327] Intermediate 55-5: 2-Methoxy-5-(5-(methoxycarbonyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)benzoic acid Intermediate 55-5 (280 mg, 0.877 mmol, 94% yield) was prepared from intermediate 55-4 (350 mg, 0.932 mmol) in a similar manner to intermediate 4-2. LC-MS RT: 1.90 min; MS(ESI) m / z 320.0 (M+H). + ;Method C

[0328] Intermediate 55-6: Methyl 3-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazole-5-carboxylate Intermediate 55-6 (160 mg, 0.221 mmol, 42% yield) was prepared from intermediate 55-4 (216 mg, 0.677 mmol) and intermediate 1-2 (220 mg, 0.521 mmol) in a similar manner to intermediate 1-3. LC-MS RT: 1.24 min; MS(ESI) m / z 722.3(MH). - ;Method E

[0329] Examples 55 and 56: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(2-hydroxypropan-2-yl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamide)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Examples 55 and 56 were prepared from intermediate 55-6 (100 mg, 0.138 mmol) in a similar manner to Example 3. The residue was purified by preparative LCMS (Method 2) followed by preparative SFC purification (Column: Luxcellulose-4 (250x30) mm, 5 μm; % CO2: 65%; % co-solvent: 35% of 0.2% 4M NH3 in MeOH; Total flow: 80.0 g / min; Back pressure: 100 bar; Temperature: 30°C; UV: 265 nm) to give Example 55 (Preparative SFC RT=4.2 min, 100% ee) and Example 56 (Preparative SFC RT=5.7 min, 99.5% ee). Analytical SFC conditions: (Column name: Luxcellulose-4 (250x4.6) mm, 5 μm; % CO2: 65%; % co-solvent: 35% of 4 M NH3 in 0.2% MeOH; total flow: 4.0 g / min; back pressure: 100 bar; temperature: 30 °C; UV: 265 nm) were obtained.

[0330] Example 55: (17.0 mg, 23.5 μmol, 17% yield); 1 H NMR(400MHz,DMSO-d6) δ ppm 10.97-10.73(m,1H), 8.69-8.61(m,1H), 8.19-8.06(m,3H), 8.01-7.93(m,1H), 7.86-7.78(m,2H), 7.57-7.48(m,1H), 7.3 4-7.27(m,1H), 5.14-5.08(m,1H), 4.21-4.13(m,2H), 4.01-3.93(m,3H), 2.10-1.58(m,6H), 1.03(d,J=13.6Hz,7H);LC-MS RT:0.76min;MS(ESI) m / z 724.2(M+H) + ;Method C

[0331] Example 56: (16.0 mg, 22.1 μmol, 16% yield); 1 H NMR(400MHz,DMSO-d6) δ ppm 10.97-10.75(m,1H), 8.69-8.62(m,1H), 8.19-8.06(m,3H), 8.01-7.93(m,1H), 7.86-7.76(m,2H), 7.58-7.49(m,1H), 7.3 5-7.28(m,1H), 5.14-5.07(m,1H), 4.22-4.13(m,2H), 4.01-3.92(m,3H), 1.97-1.62(m,6H), 1.03(d,J=13.1Hz,7H);LC-MS RT:0.73min;MS(ESI) m / z 724.3(M+H) + ;Method C

[0332] Example 57 [ka]

[0333] Intermediate 57-1: Methyl 3-(3-(tert-butoxycarbonyl)-4-methoxyphenyl)-4,5-dihydroisoxazole-5-carboxylate To a stirred solution of intermediate 55-1 (500 mg, 2.12 mmol) in DCM (10 mL) was added hydroxylamine hydrochloride (221 mg, 3.17 mmol) and K2CO3 (219 mg, 1.59 mmol). The reaction mixture was stirred at room temperature for 18 h, then DMF (0.2 mL) and NCS (424 mg, 3.17 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, then Et3N (0.442 mL, 3.17 mmol) and methyl acrylate (182 mg, 2.12 mmol) were added. The reaction mixture was stirred at room temperature for 2 h, then the reaction was quenched with aqueous NaHCO3. The reaction solution was extracted with DCM (2x), the organic layers were combined, dried over Na2SO4, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate 57-1 (400 mg, 1.19 mmol, 56% yield). LC-MS RT: 1.52 min; MS(ESI) m / z 336.2(M+H).+ ;Method E

[0334] Intermediate 57-2: 2-Methoxy-5-(5-(methoxycarbonyl)-4,5-dihydroisoxazol-3-yl)benzoic acid Intermediate 57-2 (280 mg, 1.00 mmol, 96% yield) was prepared from intermediate 57-1 (350 mg, 1.04 mmol) in a similar manner to intermediate 4-2. LC-MS RT: 0.45 min; MS(ESI) m / z 280.2(M+H). + ;Method E

[0335] Example 57: Methyl 3-(3-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)carbamoyl)-4-methoxyphenyl)-4,5-dihydroisoxazole-5-carboxylate Example 57 (1.0 mg, 1.5 μmol, 0.4% yield) was prepared from intermediate 57-2 (100 mg, 0.36 mmol) and intermediate 1-2 (91 mg, 0.22 mmol) in a similar manner to intermediate 1-3, and subsequently purified by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 11.04-10.67(m,1H), 8.65(brs,1H), 8.16(brd,J=4.0Hz,1H), 8.13-8.04(m ,2H), 7.97(brd,J=8.0Hz,1H),7.86(brd,J=8.0Hz,1H),7.81(brd,J=9.0Hz, 1H), 7.53(t,J=9.8Hz,1H), 7.32(brd,J=8.5Hz,1H), 5.29(dd,J=11.5, 6.5Hz ,1H), 3.96(s,3H), 3.82-3.70(m,4H), 3.67-3.61(m,1H), 1.23(s,2H);LC-MS RT:2.57min;MS(ESI) m / z 682.1(MH) - ;Method A

[0336] Example 58 [ka]

[0337] Intermediate 58-1: Methyl 5-(((1-hydroxycyclohexyl)methyl)carbamoyl)-2-methoxybenzoate Intermediate 58-1 (220 mg, 0.685 mmol, 72% yield) was prepared from intermediate 27-1 (200 mg, 0.952 mmol) and 1-(aminomethyl)cyclohexan-1-ol (148 mg, 1.14 mmol) in a similar manner to Examples 7 and 8. LC-MS RT: 1.00 min; MS(ESI) m / z 322.3 (M+H). + ;Method E

[0338] Intermediate 58-2: Methyl 2-methoxy-5-(1-oxa-3-azaspiro[4.5]dec-2-en-2-yl)benzoate To a stirred solution of intermediate 58-1 (300 mg, 0.933 mmol) in DCM (10 mL) cooled to -78 °C was added DAST (0.493 mL, 3.73 mmol) dropwise. The reaction solution was allowed to warm gradually to room temperature and stirred at room temperature for 2 h. The reaction was diluted with water and extracted with DCM (2x). The organic layers were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography gave intermediate 58-2 (220 mg, 0.725 mmol, 78% yield). LC-MS RT: 1.62 min; MS(ESI) m / z 304.3 (M+H) + ;Method E

[0339] Intermediate 58-3: 2-Methoxy-5-(1-oxa-3-azaspiro[4.5]dec-2-en-2-yl)benzoic acid Intermediate 58-3 (180 mg, 0.622 mmol, 70% yield) was prepared from intermediate 58-2 (270 mg, 0.890 mmol) by the procedure described in Example 2. LC-MS RT: 0.74 min; MS(ESI) m / z 290.2(M+H). + ;Method E

[0340] Example 58: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-methoxy-5-(1-oxa-3-azaspiro[4.5]dec-2-en-2-yl)benzamide)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 58 (8.6 mg, 12 μmol, 7% yield) was prepared from intermediate 1-2 (44 mg, 0.10 mmol) and intermediate 58-3 (50 mg, 0.17 mmol) in a similar manner to intermediate 1-3, and subsequently purified by preparative LCMS (Method 1). 1 H NMR(400MHz,DMSO-d6) δ ppm 10.86(brdd,J=4.5, 2.8Hz,1H), 10.76(brd,J=6.6Hz,1H), 8.73-8.66(m,1H), 8.66-8.54(m,1H), 8.39 (brd,J=3.9Hz,1H), 8.22-8.14(m,1H), 8.14-8.04(m,2H), 8.04-7.92(m,1H), 7.82(d,J=9.3Hz,1H), 7 .54(t,J=9.7Hz,1H), 7.31(d,J=8.8Hz,1H),5.51(brd,J=1.2Hz,1H), 3.99(s,3H), 3.81-3.73(m,1H), 3.53-3.41(m,1H), 2.01-1.88(m,2H), 1.76-1.63(m,1H), 1.61-1.40(m,6H), 1.31-1.19(m,1H);LC-MS RT:2.73min;MS(ESI) m / z 694.2(M+H) + ;Method A

[0341] Example 59 [ka]

[0342] Intermediate 59-1: Methyl 5-cyano-2-methoxybenzoate To a solution of methyl 5-bromo-2-methoxybenzoate (1.00 g, 4.08 mmol) in DMF (3 mL) that had been degassed with N2 for 10 min, zinc cyanide (963 mg, 8.16 mmol), dichloro(9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene)palladium(II) (308 mg, 0.408 mmol), and zinc (400 mg, 6.12 mmol) were added. The resulting solution was degassed for an additional 5 min and then heated at 100 °C for 3 h. The reaction was filtered through a bed of Celite and the filtrate was diluted with EtOAc (100 mL) and then washed with water (2x150 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 59-1 (650 mg, 3.40 mmol, 83% yield). LC-MS RT: 1.08 min; MS(ESI) m / z 192.2(M+H). + ;Method E

[0343] Intermediate 59-2: Methyl (E)-5-(N'-hydroxycarbamimidoyl)-2-methoxybenzoate To a solution of intermediate 59-1 (50 mg, 0.26 mmol) in EtOH (10 mL) was added hydroxylamine solution (43 mg, 0.65 mmol) and the reaction solution was heated at 80° C. for 1 h. The reaction was concentrated under reduced pressure to give intermediate 59-2 (40 mg, 0.18 mmol, 68% yield). LC-MS RT: 0.92 min; MS(ESI) m / z 225.2 (M+H). + ;Method E

[0344] Intermediate 59-3: Methyl 5-(5-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-yl)-2-methoxybenzoate To a solution of intermediate 59-2 (50 mg, 0.22 mmol) in DMF (2 mL) was added 2-hydroxy-2-methylpropanoic acid (28 mg, 0.27 mmol), BOP (200 mg, 0.45 mmol) and Et3N (0.093 mL, 0.67 mmol). The resulting mixture was heated at 85° C. for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (2×50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give intermediate 59-3 (40 mg, 0.14 mmol, 61% yield). LC-MS RT: 1.13 min; MS(ESI) m / z 293.2 (M+H) + ;Method E

[0345] Intermediate 59-4: 5-(5-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-yl)-2-methoxybenzoic acid Intermediate 59-4 (40 mg, 0.14 mmol, 84% yield) was prepared from intermediate 59-3 (50 mg, 0.171 mmol) by the procedure described in Example 2. LC-MS RT: 0.42 min; MS(ESI) m / z 279.2(M+H). + ;Method E

[0346] Example 59: N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(5-(5-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-yl)-2-methoxybenzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxamide Example 59 (25 mg, 0.036 mmol, 20% yield) was prepared from intermediate 1-2 (49 mg, 0.11 mmol) and intermediate 59-4 (50 mg, 0.18 mmol) in a similar manner to intermediate 1-3. 1H NMR (400MHz, DMSO-d6) δ ppm 10.90(brs,1H), 10.80-10.69(m,1H), 8.67(s,1H), 8.45(d,J=2.4Hz,1H), 8.24-8.13(m,2H), 8.09(d,J=8.3Hz,1H), 8.04-7.96( LC-MS RT:2.47 points;MS(ESI) m / z 683.2(M+H) + Method A

[0347]

Table 20

Table 21

Table 22

Table 23

Table 24

[0348]

Table 25

Table 26

Table 27

Table 28

Table 29

[0349]

Table 30

Table 31

Table 32

Table 33

Table 34

[0350]

Table 35

Table 36

Table 37

Table 38

Table 39

[0351]

Table 40

Table 41

Table 42

Table 43

Table 44

[0352]

Table 45

Table 46

Table 47

Table 48

Table 49

[0353]

Table 50

Table 51

Table 52

Table 53

Table 54

[0354]

Table 55

Table 56

Table 57

Table 58

Table 59

[0355]

Table 60

Table 61

Table 62

Table 63

Table 64

[0356]

Table 65

Table 66

Table 67

Table 68

Table 69

[0357]

Table 70

Table 71

Table 72

Table 73

Table 74

[0358]

Table 75

Table 76

Table 77

Table 78

Table 79

[0359]

Table 80

Table 81

Table 82

Table 83

Table 84

[0360]

Table 85

Table 86

Table 87

Table 88

Table 89

[0361]

Table 90

Table 91

Table 92

Table 93

Table 94

[0362]

Table 95

Table 96

Table 97

Table 98

Table 99

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: X １ and X ２ are N or CR, respectively. １ where X １ and X ２ are not both N; R １ is H, halo, C １－４ alkyl (substituted with 0-5 halo), or C ３－６ is cycloalkyl; R ２ is phenyl (1 to 3 R ３ and one R ５ substituted with), or 5- to 6-membered heteroaryl (O, S(=O) ｐ , N, and NR ２ａ and 0 to 3 R ３ and 0 to 1 R ５ substituted with R ２ａ is H or C １－３ alkyl (substituted with 0-2 halo or —OH); R ３ Halo, CN, OH, C １－４ Alkyl, or —OC １－４ Alkyl (0-5 halo, OH, —OC １－４ substituted with alkyl, aryl, or heterocyclyl; R ４ is C １－６ Alkyl (0-5 halo, CN, OH, or OC １－３ alkyl-substituted), -(CR ｄ R ｄ ) ０－１ -C ３－１０ -cycloalkyl (0 to 2 R ４ａ or 0 to 2 R ４ｂ phenyl (substituted with 0 to 2 R ４ａ or 0 to 2 R ４ｂ substituted with), -(CR ｄ R ｄ ) ｎ -3 to 12-membered heterocyclyl (O, S(=O) ｐ , N, NH, and NC １－３ alkyl, and 0 to 2 R ４ａ or 0 to 2 R ４ｂ substituted with R ４ａ or R ４ｂ is halo, CN, or C １－４ alkyl (0-5 halo, OH, or —OC １－４ substituted with alkyl (substituted with 0-5 halo); R ５ is -NR ５ａ R ５ａ , -(CH ２ ) １－２ -NR ５ｂ R ５ｂ , —C(═O)NR ５ｂ R ５ｂ , -S(=O) ｐ NR ５ｂ R ５ｂ , C ３－６ Alkyl (substituted with 0-2 OH), 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 ３－１２ Carbocyclyl (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 substituted with R ５ａ and R ５ａ together with the nitrogen atom to which they are both attached form a heterocyclyl (O, S(=O) ｐ , N, and NR １０ and 0 to 5 additional heteroatoms selected from 0 to 3 R ６ and 0 to 2 R ７ substituted with; R ５ｂ is H or C １－６ Alkyl (0 to 3 R ６ and 0 to 2 R ７ or R ５ｂ and R ５ｂ and together with the nitrogen atom to which they are both attached form a heterocyclyl (O, S(=O) ｐ , N, and NR １０ and 0 to 5 additional heteroatoms selected from 0 to 3 R ６ and 0 to 2 R ７ substituted with; R ６ is halo, CN, =O, -OH, -OC １－４ Alkyl, or C １－４ alkyl (substituted with 0-2 halo or OH); R ７ is C １－６ 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 NR ａ R ａ , —C(═O)NR ａ S (= O) ｐ R ｃ , C ３－６ Carbocyclyl (0 to 5 R ｅ substituted with), or 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N and NR ｄ and 0 to 5 R ｅ substituted with R ８ is halo, -C(=O)OR ｂ , —C(═O)NR ａ R ａ , —C(═O)NR ａ OR 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 C(=O)NR ａ R ａ , -NR ａ S (= O) ｐ R ｃ , -NR ａ S (= O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ , -OC(=O)NR ａ OR ｂ , -S(=O) ｐ NR ａ R ａ , -S(=O) ｐ R ｃ , or -OP(=O)(OH) ２ , -(CH ２ ) ｎ -C ３－６ Carbocyclyl (0 to 3 R ｅ substituted with), or -(CH ２ ) ｎ -heterocyclyl (O, S(=O) ｐ and N, and 0 to 3 R ｅ substituted with 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(=O)C(=O)OR ｂ , -S(=O) ｐ R ｃ , C ３－６ Carbocyclyl (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 substituted with R １１ is -OR ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , -S(=O) ｐ R ｃ or aryl; R １２ is H, C １－４ alkyl, or aryl; R ａ 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), or -(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 a 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), or -(CH ２ ) ｎ -heterocyclyl (0 to 5 R ｅ substituted with R ｃ is 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), C ３－６ carbocyclyl, or heterocyclyl; R ｄ is H or C １－４ is alkyl; R ｅ Ha, Halo, CN, NO ２ , =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 -carbocyclyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -heterocyclyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , —C(═O)NR ｆ R ｆ , -NR ｆ C(=O)R ｆ , -S(=O) ｐ R ｆ , -S(=O) ｐ NR ｆ R ｆ , -NR ｆ S (= O) ｐ R ｆ , -NR ｆ C(=O)OR ｆ , -OC(=O)NR ｆ R ｆ , or -(CH ２ ) ｎ NR ｆ R ｆ and R ｆ is H, C １－６ Alkyl (0 to 1 -OC １－４ substituted with alkyl), C ３－６ cycloalkyl, aryl, or heterocyclyl; or R ｆ and R ｆ together with the nitrogen atom to which they are both attached form a heterocyclyl; R ｇ is halo, CN, OH, S(=O) ２ C １－３ Alkyl, 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 pharmaceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 2】 [In the formula: X １ is N or CR １ and R １ is H, halo or C １－３ alkyl (substituted with 0-4 halo); R ２ teeth 【Transformation 3】 and R ２ａ is C １－３ alkyl (substituted with 0-1 -OH); R ３ Ha, Halo, C １－４ Alkyl, or —OC １－４ alkyl (substituted with 0-4 halo); R ４ａ is a halo; R ４ｂ is C １－４ alkyl (substituted with 0-4 halo); R ５ is -NR ５ａ R ５ａ , —C(═O)NR ５ｂ R ５ｂ , C ２－６ alkenyl (0 to 3 R ６ and 0 to 2 R ７ substituted with), C ２－６ Alkynyl (0 to 3 R ６ and 0 to 2 R ７ substituted with), C ３－６ Cycloalkyl (0 to 3 R ６ and 0 to 2 R ７ phenyl (substituted with 0 to 3 R ６ and 0 to 2 R ７ substituted with), or 3- to 10-membered heterocyclyl (O, S(=O) ｐ , N and NR １０ and 0 to 3 R ６ and 0 to 1 R ７ substituted with R ５ａ and R ５ａ together with the nitrogen atom to which they are both attached form a heterocyclyl (O, S(=O) ｐ , N, and NR １０ and 0 to 5 additional heteroatoms selected from 0 to 3 R ６ and 0 to 2 R ７ substituted with; R ５ｂ is H or C １－５ alkyl (0 to 1 R ６ and 0 to 1 R ７ or R ５ｂ and R ５ｂ together with the nitrogen atom to which they are both attached form a heterocyclyl (O, S(=O) ｐ , N, and NR １０ and 0 to 5 additional heteroatoms selected from 0 to 3 R ６ and 0 to 2 R ７ substituted with; R ６ is halo, CN, =O, -OH, -OC １－３ Alkyl, or C １－３ alkyl (substituted with 0-2 halo or OH); R ７ is C １－５ 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 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 ｄ and 0 to 4 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 NR ａ R ａ , -OC(=O)NR ａ R ａ , -OC(=O)NR ａ OR ｂ , -S(=O) ｐ NR ａ R ａ , -S(=O) ｐ R ｃ , or -OP(=O)(OH) ２ 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(=O)C(=O)OR ｂ , -S(=O)R ｃ , 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 substituted with R １１ is -OH, -C(=O)OR ｂ , —C(═O)NR ａ R ａ , or -S(=O) ２ R ｃ and R １２ is H, C １－３ alkyl, or aryl; R ａ is H, 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), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with), or -(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 a heterocyclyl (0-5 R ｅ substituted with; R ｂ is H, 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), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 5 R ｅ substituted with), or -(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 １－３ is alkyl; R ｅ 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 -C ６ Aryl, -(CH ２ ) ｎ -heterocyclyl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , or -S(=O) ｐ R ｆ and R ｆ is H or C １－３ Alkyl (0 to 1 -OC １－４ substituted with 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.

2. The compound of claim 1, wherein:

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

3. The compound of claim 2, wherein: or a pharmaceutically acceptable salt thereof.

4. R １ is C １－２ alkyl (substituted with 0-3 halo); R ３ Ga-OC １－３ is alkyl; R ４ａ is a halo; R ４ｂ is C １－２ alkyl (substituted with 0-4 F); R ５ but 【Transformation 5】 and R ６ Halo, =O, -OH, -OC １－２ Alkyl, or C １－２ is alkyl; R ７ But C １－５ alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with —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 , -S(=O) ｐ R ｃ , -S(=O) ｐ NR ａ R ａ , or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with R ８ Halo, -C(=O)OR ｂ , or C １－３ alkyl (substituted with 0-3 halo); R ９ But, -OR ｂ , -NR ａ R ａ , -NHC(=O)R ｂ , -NHC(=O)OR ｂ , -NHS(=O) ｐ R ｃ , -NHS(=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 But H, C １－３ Alkyl (0 to 2 R １１ substituted with), —C(═O)R ｂ , -C(=O)OR ｂ , -C(=O)C(=O)OR ｂ , —C(═O)NR ａ R ａ , -S(=O) ２ C １－３ Alkyl, 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 4 R ｅ substituted with R １１ is -OH, -C(=O)OH, -C(=O)OC １－４ Alkyl, or —C(═O)NR ａ R ａ and R １２ is H or C １－２ is alkyl; R ａ But H, C １－４ Alkyl (0 to 4 R ｅ substituted with), -(CH ２ ) ０－１ -phenyl (0 to 4 R ｅ substituted with), C ３－６ Cycloalkyl (0 to 4 R ｅ substituted with), or -(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 But H, C １－３ Alkyl (0 to 4 R ｅ substituted with), C ２－３ alkenyl (0 to 4 R ｅ substituted with), C ２－３ Alkynyl (0 to 4 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 4 R ｅ substituted with), or -(CH ２ ) ｎ -heterocyclyl (0 to 4 R ｅ substituted with R ｃ is C １－４ is alkyl; R ｅ Halo, CN, =O, C １－５ Alkyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -C ３－６ Cycloalkyl, -(CH ２ ) ｎ -heterocyclyl, -(CH ２ ) ｎ -C ６ Aryl, -(CH ２ ) ｎ -heteroaryl, -(CH ２ ) ｎ OR ｆ , -C(=O)OR ｆ , or -S(=O) ｐ R ｆ and R ｆ is H or C １－２ alkyl; R ｇ is halo, CN, OH, or C １－５ is alkyl, 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof.

5. Formula (IV): 【Transformation 6】 [In the formula: R １ is C １－２ alkyl (substituted with 0-3 halo); R ３ Ha-OC １－３ is alkyl; R ４ａ is a halo; R ４ｂ is C １－２ alkyl (substituted with 0-3 halo); R ６ is halo or C １－２ is alkyl; R ７ is C １－２ alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with —NR ａ C(=O)OR ｂ , -NR ａ S (= O) ｐ R ｃ , -C(=O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , -S(=O) ｐ R ｃ , -S(=O) ｐ NR ａ R ａ , or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with R ８ is halo, -C(=O)OR ｂ , or C １－２ alkyl (substituted with 0-3 halo); R ９ is -OR ｂ , -NR ａ R ａ , -NHC(=O)R ｂ , -NHC(=O)OR ｂ , -NHS(=O) ｐ R ｃ , -NHS(=O) ｐ NR ａ R ａ , -OC(=O)NR ａ R ａ , -S(=O) ｐ NR ａ R ａ , or -S(=O) ｐ R ｃ and R ａ is H, C １－３ Alkyl (0 to 3 R ｅ substituted with), -(CH ２ ) ０－１ -phenyl (0 to 3 R ｅ substituted with), C ３－６ Cycloalkyl (0 to 3 R ｅ ) or heterocyclyl (substituted with 0 to 3 R ｅ or R ａ and R ａ together with the nitrogen atom to which they are both attached form a heterocyclyl (0-3 R ｅ substituted with; R ｂ is H, C １－３ Alkyl (0 to 3 R ｅ substituted with), -(CH ２ ) ｎ -C ３－１０ Carbocyclyl (0 to 4 R ｅ substituted with), or -(CH ２ ) ｎ -heterocyclyl (0 to 4 R ｅ substituted with R ｃ is C １－３ is alkyl; R ｅ Halo, CN, =O, C １－４ Alkyl (0 to 5 R ｇ substituted with), -(CH ２ ) ｎ -C ３－６ Cycloalkyl, -(CH ２ ) ｎ -heterocyclyl, -(CH ２ ) ｎ -C ６ Aryl, -(CH ２ ) ｎ -heteroaryl, -(CH ２ ) ｎ OR ｆ or -C(=O)OR ｆ and R ｆ is H or C １－２ alkyl; R ｇ Halo, CN, OH, C １－４ alkyl] 5. The compound of claim 4, wherein: or a pharmaceutically acceptable salt thereof.

6. Formula (V): 【Transformation 7】 [In the formula: R １ is CF ３ and R ３ Ha-OC １－２ is alkyl; R ４ａ is F; R ４ｂ is CF ３ and R ６ is a halo; R ８ is -C(=O)OR ｂ or -CF ３ and R ９ is -OR ｂ , -NR ａ R ａ , -NHC(=O)R ｂ , -NHS(=O) ｐ R ｃ , -OC(=O)NR ａ R ａ , or -S(=O) ２ R ｃ and R ａ is H, C １－３ Alkyl, -(CH ２ ) ０－１ -phenyl (0 to 2 R ｅ substituted with), or C ３－６ cycloalkyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached form a heterocyclyl (0-3 R ｅ substituted with; R ｂ is H, C １－３ Alkyl (0 to 2 R ｅ substituted with), C ３－６ cycloalkyl, or heterocyclyl; R ｃ is C １－３ is alkyl; R ｅ Ha-OR ｆ and R ｆ is H or C １－２ alkyl] 6. The compound of claim 5, wherein: or a pharmaceutically acceptable salt thereof.

7. R １ is CF ３ and R ３ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ but 【Transformation 8】 and R ６ Halo, -OH, -OC １－２ Alkyl, or C １－２ is alkyl; R ７ But C １－５ alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with —NR ａ R ａ , or -NR ａ C(=O)R ｂ 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 substituted with), —C(═O)R ｂ , -C(=O)OR ｂ , —C(═O)NR ａ R ａ , or 4- to 6-membered heterocyclyl (O, S(=O) ｐ , N and NR １２ and 0 to 4 R ｅ substituted with R １１ is —OH, —C(═O)OH, or —C(═O)NR ａ R ａ and R １２ is H and C １－２ is alkyl; R ａ is H or C １－３ is alkyl; R ｂ is H or C １－３ alkyl (0 to 1 R ｅ substituted with; R ｅ is OH, 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof.

8. R ５ but 【Chemistry 9】 and R ７ is C １－４ alkyl (substituted with 0-1 OH); R １０ is -C(=O)R ｂ and R ｂ is H or C １－３ alkyl (0 to 1 R ｅ substituted with; R ｅ is OH, 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof.

9. R １ is CF ３ and R ３ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ but 【Chemistry 10】 and R ６ is halo, —OH, or C １－２ is alkyl; R ７ But, -NR ａ R ａ , —C(═O)NR ａ R ａ , or -S(=O) ２ NR ａ R ａ and R １０ But H, C １－４ alkyl (0 to 1 R １１ substituted with -C(=O)R ｂ and R １１ is —OH or —C(═O)OH; R ａ is H or C １－３ alkyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached form a heterocyclyl; R ｂ is H or C １－３ is alkyl; R ｅ is C １－３ Alkyl or -(CH ２ ) ０－１ OR ｆ and R ｆ is H or C １－２ is alkyl, 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof.

10. R ５ but 【Chemistry 11】 and R ６ is halo, —OH, or C １－２ is alkyl; R ７ But, -NR ａ R ａ , —C(═O)NR ａ R ａ , or -S(=O) ２ NR ａ R ａ and R ａ is H or C １－３ alkyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached form a heterocyclyl (0 to 2 R ｅ substituted with; R ｅ Ga-CH ２ OR ｆ and R ｆ is H or C １－２ is alkyl, 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof.

11. R １ is CF ３ and R ３ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ -C(=O)NR ５ｂ R ５ｂ and R ５ｂ is H or C １－５ alkyl (0 to 1 R ６ and 0 to 1 R ７ or R ５ｂ and R ５ｂ together with the nitrogen atom to which they are both attached, 【Chemistry 12】 forming a heterocyclyl selected from: R ６ is halo, —OH, or C １－３ is alkyl; R ７ is -S (=O) ２ C １－３ Alkyl or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with R ａ is H or C １－３ is alkyl; R ｂ is H or C １－３ alkyl; R ｅ is -S (=O) ２ C １－３ is alkyl, 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof.

12. R ５ｂ is H or C １－４ alkyl (0 to 1 R ６ and 0 to 1 R ７ substituted with R ６ is halo, —OH, or C １－４ alkyl (substituted with 0-1 OH); R ７ is -S (=O) ２ C １－２ Alkyl, or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with; R ｅ is -S (=O) ２ C １－３ is alkyl, 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof.

13. R ５ａ and R ５ａ together with the nitrogen atom to which they are both attached, 【Chemistry 13】 forming a heterocyclyl selected from: R ６ is halo, —OH, or C １－３ is alkyl; R ７ is -S (=O) ２ C １－３ Alkyl, or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with R ａ is H or C １－３ is alkyl; R ｂ is H or C １－３ alkyl; R ｅ is -S (=O) ２ C １－３ is alkyl, 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof.

14. R １ is CF ３ and R ３ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ but 【Chemistry 14】 and R ６ Halo, =O, -OH, -OC １－２ Alkyl, or C １－２ is alkyl; R ７ But C １－２ alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with —NR ａ R ａ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ or -C(=O)OR ｂ and R ８ is -C(=O)OR ｂ , -C(=O)NHR ａ , -C(=O)NHOR ｂ , or C １－２ alkyl (substituted with 0-3 halo or OH); R ９ Ga-NR ａ C(=O)R ｂ and R １０ But H, C １－３ Alkyl (0 to 2 R １１ substituted with), —C(═O)R ｂ , -C(=O)OR ｂ , -C(=O)C(=O)OR ｂ , —C(═O)NR ａ R ａ , -S(=O) ２ C １－３ Alkyl, 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 substituted with R １１ is -OH, -C(=O)OH, -C(=O)OC １－４ alkyl, or C(=O)NR ａ R ａ and R １２ is H or C １－２ is alkyl; R ａ is H or C １－３ is alkyl; R ｂ But H, C １－３ Alkyl (0 to 2 R ｅ substituted with), C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with 0 to 2 R ｅ substituted with R ｅ But C １－３ Alkyl, OH, or —NR ｆ R ｆ and R ｆ is H or C １－３ is alkyl, 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof.

15. R ５ but 【Chemistry 15】 and R １０ But H, C １－３ Alkyl (0 to 2 R １１ substituted with), —C(═O)R ｂ , -C(=O)OR ｂ , -C(=O)C(=O)OR ｂ , 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 substituted with R １１ is -OH, -C(=O)OH, -C(=O)OC １－４ alkyl, or C(=O)NR ａ R ａ and R １２ is H or C １－２ is alkyl; R ａ is H or C １－３ is alkyl; R ｂ is H or C １－３ alkyl (0 to 1 R ｅ substituted with R ｅ But C １－３ Alkyl, OH, NR ｆ R ｆ and R ｆ is H or C １－３ is alkyl, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

16. R １ is CF ３ and R ３ Ga-OCH ３ and R ４ａ is F; R ４ｂ is CF ３ and R ５ Ga-NR ５ａ R ５ａ and R ５ａ and R ５ａ together with the nitrogen atom to which they are both attached, 【Chemistry 16】 forming a heterocyclyl selected from: R ６ is halo, —OH, or C １－３ is alkyl; R ７ is -S (=O) ２ C １－３ Alkyl, or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with R １０ But H, C １－４ alkyl (0 to 1 R １１ substituted with -C(=O)R ｂ and R １１ is —OH or —C(═O)OH; R ａ is H or C １－３ is alkyl; R ｂ is H or C １－３ alkyl; R ｅ is -S (=O) ２ C １－３ is alkyl, 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof.

17. R ５ but 【Chemistry 17】 and R ６ But -OH, -OC １－２ Alkyl, or C １－２ is alkyl; R ７ But C １－２ alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with —NR ａ R ａ , -C(=O)R ｂ , -C(=O)OR ｂ or —C(═O)NR ａ R ａ and R ８ is a halo; R ９ Ga-OR ｂ and R ａ But H, C １－３ Alkyl, C ３－６ cycloalkyl, or heterocyclyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached form a heterocyclyl (0-3 R ｅ substituted with; R ｂ But H, C １－３ alkyl (0 to 1 R ｅ substituted with), or heterocyclyl; R ｅ Ga-OR ｆ and R ｆ is H or C １－２ is alkyl, 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof.

18. R １ is CF ３ and R ３ Ga-OC １－２ is alkyl; R ４ａ is F; R ４ｂ is CF ３ and R ５ is -C(=O)NR ５ｂ R ５ｂ , [Chemistry 18] and R ５ｂ is H or C １－４ alkyl (0 to 1 R ６ and 0 to 1 R ７ or R ５ｂ and R ５ｂ together with the nitrogen atom to which they are both attached, 【Chemistry 19】 Forming; R ６ is halo, —OH, or C １－３ is alkyl; R ７ But C １－３ alkyl (0 to 1 R ８ and 0 to 1 R ９ substituted with —C(═O)NR ａ R ａ , -C(=O)OR ｂ , -NR ａ C(=O)R ｂ , -S(=O) ２ NR ａ R ａ , -S(=O) ２ C １－３ Alkyl, or C ３－６ Cycloalkyl (0 to 2 R ｅ substituted with R ８ Halo, -C(=O)OR ｂ , or C １－３ alkyl (substituted with 0-3 halo); R ９ But -OH, -NR ａ R ａ , -NR ａ C(=O)R ｂ , N.R. ａ S (= O) ｐ C １－４ Alkyl, or —OC(═O)NR ａ R ａ and R １０ But 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 , -S(=O) ２ C １－３ Alkyl, 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 4 R ｅ substituted with R １１ is -OH, -C(=O)OH, -C(=O)NR ａ R ａ , or -S(=O) ２ C １－４ is alkyl; R １２ is H or C １－３ is alkyl; R ａ But H, C １－３ Alkyl, -(CH ２ ) ０－１ -C ３－６ cycloalkyl, or -(CH ２ ) ０－１ -heterocyclyl; or R ａ and R ａ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclyl (0-2 R ｅ substituted with; R ｂ But H, C １－３ Alkyl (0 to 4 R ｅ substituted with), or heterocyclyl; R ｅ But C １－３ Alkyl, -(CH ２ ) ０－１ OR ｆ , or -S(=O) ２ C １－３ alkyl; R ｆ is H or C １－３ is alkyl, 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof.

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

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

21. 21. The pharmaceutical composition of claim 20, 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.

22. 22. The pharmaceutical composition of claim 21, wherein the disease is heart failure.

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