Benzothiazole, benzisoxazole and benzodioxole analogues as RXFP1 receptor agonists

Abstract

The present disclosure relates to compounds of formula (I) that are RXFP1 receptor agonists, compositions containing them, and methods of using them, for example, for the treatment of heart failure, fibrotic diseases and related diseases, such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease) or liver disease (e.g., non-alcoholic steatohepatitis and portal hypertension). TIFF2025501509000144.tif53146

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 289,830, filed December 15, 2021, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] 2. Background of the Invention The present invention relates to novel compounds that are relaxin family peptide receptor 1 (RXFP1) agonists, compositions containing same, and methods of use thereof, such as in the treatment of heart failure, fibrotic diseases and related diseases, including pulmonary diseases (e.g., idiopathic pulmonary fibrosis), renal diseases (e.g., chronic renal disease) and liver diseases (e.g., non-alcoholic steatohepatitis and portal hypertension).

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

[0004] Since the initial discovery of relaxin, many studies have focused on elucidating its role in female reproductive biology and the physiological changes that occur during mammalian pregnancy (Sherwood OD., Endocr. Rev., 2004, 25, 205-234). During human pregnancy, to meet the nutritional demands imposed by the fetus, the female body undergoes a significant decrease in systemic vascular resistance (SVR) of approximately 30% with a concomitant increase in cardiac output of approximately 50% (Jeyabalan AC., KP, Renal and Electolyte 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 efficient ventricular-arterial coupling, and 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, Renal and Electolyte Disorders. 2010, 462-518, Poppas A., et al., Circ., 1997, 95, 2407-2415). Evidence from both preclinical rodent studies and clinical trials conducted in various patient settings suggests that relaxin is involved, at least in part, in mediating these adaptive physiological changes (Conrad KP., Regul. Integr. Comp. Physiol., 2011, 301, R267-275, Teichman SL., et al., Heart Fail. Rev., 2009, 14, 321-329).Importantly, many of these adaptive responses may benefit HF patients, as excessive fibrosis, low arterial compliance and reduced renal function are all common features in heart failure patients (Mohammed SF., et al., Circ., 2015, 131, 550-559, Wohlfahrt P., et al., Eur. J. Heart Fail., 2015, 17, 27-34, Damman K., et al., Prog. Cardiovasc. Dis., 2011, 54, 144-153).

[0005] Heart failure (HF), hemodynamically defined as "insufficient total body perfusion to meet the metabolic demands of the body as a result of impaired cardiac pump function," affects an estimated 5.8 million people in the United States and over 23 million people worldwide, and represents an enormous burden on today's healthcare system (Roger VL., et al., Circ. Res., 2013, 113, 646-659). It is estimated that by 2030, an additional 3 million people in the United States alone will suffer from HF, a 25% increase from 2010. The estimated direct costs associated with HF in 2010 (2008 dollars) were $25 billion and are expected to increase to $78 billion by 2030 (Heidenreich PA., et al., Circ., 2011, 123, 933-944). Alarmingly, in the United States, 1 in 9 people will have HF listed on their death certificate (Roger VL., et al., Circ., 2012, 125, e2-220), and although survival after HF diagnosis has improved over time (Matsushita K., et al., Diabetes, 2010, 59, 2020-2026, Roger VL., et al., JAMA, 2004, 292, 344-350), mortality remains high, with approximately 50% of people dying from HF within 5 years of diagnosis (Roger VL., et al., Circ., 2012, 125, e2-220, Roger VL., et al., JAMA, 2004, 292, 344-350).

[0006] Symptoms of HF are the result of insufficient cardiac output and can be quite debilitating depending on the stage of disease progression. The major symptoms and signs of HF include: 1) dyspnea (labored breathing) due to ineffective forward blood flow from the left ventricle and pulmonary edema due to increased pressure in the pulmonary capillary bed; 2) leg edema resulting when the right ventricle cannot supply venous return; and 3) fatigue due to the inability of the heart to maintain sufficient cardiac output (CO) to meet the body's metabolic demands due to heart failure (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 a deterioration that can present as acute events of pulmonary edema, reduced exercise tolerance and increased shortness of breath on exertion (Millane T., et al., BMJ, 2000, 320, 559-562).

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

[0008] Cerulacin, an intravenous (IV) formulation of recombinant human relaxin peptide with a relatively short phase 1 pharmacokinetic half-life of 0.09 hours, is currently in development for the treatment of HF (Novartis, 2014). Cerulacin has been administered to normal human volunteers (NHVs) and has been demonstrated 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, patients with acutely decompensated HF (ADHF) were observed to respond to in-hospital 48-hour IV Cerulaxin in response to reduced renal function, favorable changes in HF exacerbations, and reduced mortality (Teerlink JR., et al., Lancet, 2013, 381, 29-39, Ponikowski P., et al., Eur. Heart, 2014, 35, 431-441). Suggesting that chronic administration of Cerulaxin may provide sustained benefit to HF patients, improved renal function based on serum creatinine levels was observed in scleroderma patients who received Cerulaxin chronically via subcutaneous pump for 6 months (Teichman SL., et al., Heart Fail. Rev., 2009, 14, 321-329). In addition to its potential as a therapeutic agent for the treatment of HF, continuous subcutaneous administration of relaxin has also been shown to be effective in various animal models of pulmonary (Unemori EN., et al., J. Clin. Invet., 1996, 98, 2739-2745), renal (Garber SL., et al., Kidney Int., 2001, 59, 876-882) and hepatic injury (Bennett RG., Liver Int., 2014, 34, 416-426).

[0009] Taken together, a large body of evidence supports a role for 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 patients with HF. Further preclinical animal studies in various disease models of lung, kidney and liver injury provide evidence that relaxin may provide therapeutic benefits for multiple indications in addition to HF when administered over a long period of time. More specifically, chronic administration of relaxin may benefit patients with lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease) or liver disease (e.g., nonalcoholic steatohepatitis and portal hypertension). Summary of the Invention

[0010] (Summary of the invention) The present invention provides novel benzothiazole analogs, such as stereoisomers, tautomers, pharma- ceutically acceptable salts or solvates thereof, that are useful as RXFP1 receptor agonists.

[0011] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0012] The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the invention or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0013] The compounds of the invention may be used for the treatment and / or prevention of heart failure, fibrotic diseases and related diseases such as pulmonary diseases (e.g., idiopathic pulmonary fibrosis), renal diseases (e.g., chronic renal disease) or liver diseases (e.g., non-alcoholic steatohepatitis and portal hypertension).

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

[0015] The compounds of the present invention can be used for the preparation of a medicament for the treatment and / or prevention of heart failure.

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

[0017] These and other features of the invention will be set forth in expanded form as the disclosure continues. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Description of the Invention The present invention encompasses compounds of formula (I) that are RXFP1 receptor agonists, compositions containing same, and methods of use thereof.

[0019] In a first aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, Ring A is O, S(=O) p , N and NR 1a and 0 to 4 R 1 is a 5-membered heterocyclyl substituted with; R 1 is halo or C substituted with 0-5 halo or -OH 1-4 is alkyl; R 1a teeth 、 H or C 1-3 is alkyl; R 2 is 0 to 3 R 3 and one R 5 Phenyl substituted with 0-3 R 3 and 0 to 1 R 5 Bicyclic carbocyclyl substituted with, or O, S(=O) p , N and NR 2a and 0 to 3 R 3 and 0 to 1 R 5 is a 5-12 membered heterocyclyl substituted with; R 2a teeth 、 H, C 1-3 Alkyl or C(=O)R b and; R 3 , halo, CN, OH, C 1-4 -OC substituted with alkyl or 0 to 5 halo 1-4 Alkyl, OH, -OC 1-4 is alkyl, aryl, or heterocyclyl; R 4 is halo, CN, C substituted with 0-5 halo 1-4 -OC substituted with alkyl, OH or 0-5 halo 1-4 is alkyl; R 5 is -C(=O)NR 13 R 13 , -S(=O) p NR 13 R 13 , 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-8 Alkenyl, 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-8 Alkynyl, 0 to 3 R 6 and 0 to 2 R 7 C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 3-12 membered heterocyclyl substituted with R 2 is phenyl and R 5 is heterocyclyl, said heterocyclyl is attached to the phenyl ring via a carbon or nitrogen atom; R 6 are halo, CN, =O, -OH, -OC 1-4 C substituted with alkyl or 0-2 halo and OH 1-4 is alkyl; R 7is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-5 Alkyl, -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , -C(=O)NR a S(=O) p R c , 0 to 5 R e C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is halo, -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a OR b or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR aC(=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 , -OP(=O)(OH)2, 0 to 3 R e Substituted with -(CH2) n -C 3-6 Carbocyclyl, or O, S(=O) p , N and NR d and 0 to 5 R c Substituted with -(CH2) n -heterocyclyl; R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(O) p R c , 0 to 5 R e C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, -C(=O)NR a R aor aryl; R 12 , H, C 1-3 is alkyl or aryl; R 13 is H or 0 to 2 R 6 and 0 to 2 R 7 C replaced with 1-3 alkyl; or R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which is O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 2 R 7 is replaced by; R a is H, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0 to 5 R e C replaced with 2-6 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl; or R a and R a are, together with the nitrogen atom to which they are both attached, 0 to 5 R e forming a heterocyclyl substituted with; R b is H, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0 to 5 R e C replaced with 2-6 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl; R c is 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0 to 5 R e C replaced with 2-6 Alkynyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-4 is alkyl; R e is halo, CN, NO2, =O, 0-5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0 to 5 R g C replaced with 2-6 Alkynyl, 0 to 5 R g Substituted with -(CH2) n -Carbocyclyl, 0 to 5 R g Substituted with -(CH2) n -heterocyclyl, -(CH2) n OR f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f , -S(=O) p NR f R f , -NR f S(=O) p R f , -NR f C(=O)OR f , -OC(=O)NR f R f or -(CH2) n NR f R f and; R f H, 0 to 1 -OC 1-4 Alkyl-substituted C 1-6 Alkyl, C 3-6 cycloalkyl, aryl, or heterocyclyl; or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclyl; R g are halo, CN, OH, S(=O)2C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0, 1, 2 or 3; and p is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0020] In a second aspect within the first aspect, the present invention provides a compound of formula (II): [ka] [In the formula, [ka] teeth, [ka] and; R 1 is halo or C 1-3 is alkyl; R 3 Halo, C 1-3 -OC substituted with alkyl or 0 to 4 halo 1-4 is alkyl; R 4a is a halo; R 4b is C substituted with 0 to 4 halo 1-4 is alkyl; R 5 is -C(=O)NR 13 R 13, -S(=O) p NR 13 R 13 , 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-7 Alkenyl, 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-7 Alkynyl, 0 to 3 R 6 and 0 to 2 R 7 Phenyl substituted with, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 10-membered heterocyclyl substituted with; R 6 are halo, =O, -OH, -OC 1-4 C substituted with alkyl or 0-2 halo and OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NRa R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , or -S(O) p R c and; R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR 12and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH or aryl; R 12 , H, C 1-3 is alkyl or aryl; R 13 is H or 0 to 1 R 6 and 0 to 1 R 7 C replaced with 1-3 alkyl; or R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which is O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 2 R 7 has been replaced with; R a is H, 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0 to 5 R e C replaced with 2-5 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl; or R a and R a are, together with the nitrogen atom to which they are both attached, 0 to 5 R e forming a heterocyclyl substituted with; R b is H, 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0 to 5 Re C replaced with 2-5 Alkynyl, 0 to 5 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 5 R e Substituted with -(CH2) n -heterocyclyl; R c is 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0 to 5 R e C replaced with 2-5 Alkynyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-3 is alkyl; R e is halo, CN, =O, 0-5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0 to 5 R g C replaced with 2-6 Alkynyl, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) n OR f , -C(=O)OR f or -S(=O) p R f and; R f is H or 0 to 1 -OC 1-4 Alkyl-substituted C 1-3 is alkyl; R g , halo, CN, OH, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0, 1, 2 or 3; and p is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0021] In a third aspect within the first and second aspects, the present invention provides a compound of formula (III): [ka] [In the formula, R 1 is C 1-2 is alkyl; R 3 -OC 1-4 is alkyl; R 4a is a halo; R 4b is C substituted with 0-4 F 1-3 is alkyl; R 5 is -S(=O) p NR 13 R 13 , 0 to 3 R 6 and 0 to 2 R 7 Phenyl substituted with, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 10-membered heterocyclyl substituted with; R 6 ,Haro,CN,C 1-3 Alkyl, -OH or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)NR a R a , -NRa S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 4 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is halo, -C(=O)OR b , -C(=O)NHR a or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b or -S(=O) p NR a R a and; R 10 is H, 0 to 2 R 11C replaced with 1-4 Alkyl, or -C(=O)R b and; R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which is O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 2 R 7 is replaced by; R a is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl; or R a and R a are, together with the nitrogen atom to which they are both attached, 0 to 4 R e forming a heterocyclyl substituted with; R b is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, 0-5 R g C replaced with 1-6Alkyl, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) n OR f OR -C(=O)OR f and; R f is H or 0 to 1 -OC 1-4 Alkyl-substituted C 1-3 is alkyl; R g , halo, CN, OH, C 1-6 Alkyl or C 3-6 is cycloalkyl; n is 0, 1, 2 or 3; and p is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0022] In a fourth aspect within the third aspect, the present invention provides a compound of formula (III): [In the formula, R 1 is -CH3; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 is -S(=O)2NR 13 R 13 , [ka] and; R 6 Halo, C 1-4 Alkyl, -OH or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, -C(=O)NRa R a or 0 to 2 R e C replaced with 3-6 is cycloalkyl; R 8 is halo, -C(=O)OC 1-4 Alkyl or C 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b or -OC(=O)NR a R a and; R 10 is H, 0 to 2 R 11 C replaced with 1-3 Alkyl or -C(=O)R b and; R 11 is -OH; R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which is O, S(=O) p and N, and 0 to 5 additional heteroatoms selected from 0 to 3 R 6 and 0 to 2 R 7 has been replaced with; R a , H, C 1-3 Alkyl or C 3-6 is cycloalkyl; R b is H, 0 to 1 R e C replaced with 1-4 alkyl or heterocyclyl; R e -OR f and R f is H or -OC 1-3 Alkyl-substituted C 1-3 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0023] In a fifth aspect within the fourth aspect, the present invention provides a compound of formula (III): [In the formula, R 5 teeth, [ka] and; R 7 is 0 to 1 R 9 C replaced with 1-4 is alkyl; R 9 -OR b and; R 10 is H or -C(=O)R b and; R b is H or 0 to 1 R e C replaced with 1-4 is alkyl; R e -OR f and; R f is H or C 1-2 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0024] In a sixth aspect within the second aspect, the present invention provides a compound of formula (IV): [ka] [In the formula, R 1 is C 1-2 is alkyl; R 3 -OC 1-4 is alkyl; R 4a is a halo; R 4b is C substituted with 0-4 F 1-3 is alkyl; R 5 is C substituted with OH 2-4 Alkynyl or 0 to 3 R 6and 0 to 2 R 7 is a phenyl substituted with; R 6 ,Haro,CN,C 1-3 Alkyl, -OH or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 is alkyl; R 8 is halo or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -OC(=O)NR a R a or -OC(=O)NR a OR b and; R a , H, C 1-3 Alkyl or C 3-6 is cycloalkyl; and R b is H or C 1-3 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0025] In a seventh aspect within the first aspect, the present invention provides a compound of formula (V): [ka] [In the formula, R 1 is a halo; R 3 Halo, C 1-3 Alkyl or -OC 1-3 is alkyl; R 4a is a halo; R 4b is C substituted with 0 to 3 halo 1-3 is alkyl; R 5 is -C(=O)NR 13 R13 , 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-6 Alkenyl, 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-6 Alkynyl, 0 to 3 R 6 and 0 to 2 R 7 Phenyl substituted with, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 10-membered heterocyclyl substituted with; R 6 are halo, =O, -OH, -OC 1-4 C substituted with alkyl or 0-2 halo and OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , -C(=O)NRa S(=O) p R c , 0 to 4 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 4 R e is a 4- to 6-membered heterocyclyl substituted with; R 8 is halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -S(=O) p NR a R a or -S(O) p R c and; R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(O) p R c , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH, -C(=O)NR a R a or aryl; R 12 , H, C 1-3 is alkyl or aryl; R 13 is H or 0 to 3 R 6 and 0 to 2 R 7 C replaced with 1-4 alkyl; or R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which includes O, S(=O), N, and NR 10 and 0 to 3 R 6 and 0 to 2 R 7 is replaced by; R a is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) n -heterocyclyl; or R a and R a are, together with the nitrogen atom to which they are both attached, 0 to 4 R e forming a heterocyclyl substituted with; R b is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH2) n -C 3-10 Carbocyclyl or 0 to 4 R e Substituted with -(CH2) n-heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, 0-5 R g C replaced with 1-6 Alkyl, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n -aryl, -(CH2) n -heterocyclyl, -(CH2) n OR f OR -C(=O)OR f and; R f is H or 0 to 1 -OC 1-4 Alkyl-substituted C 1-3 is alkyl; R g , halo, CN, OH, C 1-6 Alkyl or C 3-6 is cycloalkyl; n is 0, 1, 2 or 3; and p is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0026] In an eighth aspect within the seventh aspect, the present invention provides a compound of formula (VI): [ka] [In the formula, R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 6is a halo; R 7 is -C(=O)OR b , -C(=O)NR a R a , -S(=O) p NR a R a or -C(=O)NR a S(=O) p C 1-4 is alkyl; R a is H, 0 to 5 R e C replaced with 1-3 Alkyl or 0 to 4 R e is heterocyclyl substituted with; R b is H or 0 to 5 R e C replaced with 1-3 is alkyl; and R e is halo, CN, =O or C 1-6 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0027] In a ninth aspect within the seventh aspect, the present invention provides a compound of formula (V): [In the formula, R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 teeth, [ka] and; R 6 is halo, -OH or C substituted with 0-1 OH 1-4 is alkyl; R 7 -NR a R a or -S(=O)NR a Ra and; R 10 is H, -C(=O)R b or 0 to 1 R 11 C replaced with 1-4 is alkyl; R 11 is -OH, -C(=O)OH or aryl; R a is H or C 1-3 alkyl; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl; and R b is H or C 1-3 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0028] In a tenth aspect within the seventh aspect, the present invention provides a compound of formula (V): [In the formula, R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 teeth, [ka] and; R 6 are halo, =O, -OH, -OC 1-4 Alkyl or C 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 Alkyl, -NR a R a or -NR a C(=O)R b and; R 8 is -C(=O)OR b and; R 9 is OH; R 10 is H, 0 to 2 R 11 C replaced with 1-3 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , or O, S(=O) p , N and NR 12 and 0 to 4 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH or C(=O)NR a R a and; R 12 H and C 1-3 is alkyl; R a is H or C 1-3 is alkyl; R b is H or 0 to 1 R e C replaced with 1-3 is alkyl; and R e is OH] or a pharma- ceutically acceptable salt thereof.

[0029] In an eleventh aspect within the tenth aspect, the present invention provides a compound of formula (V): [In the formula, R 5 teeth, [ka] and; R 7 is 0 to 1 R 9 C replaced with 1-3 is alkyl; R 9 is -OH; R 10 is H, 0 to 2 R 11 C replaced with 1-3 Alkyl or -C(=O)R b and; R 11 is -OH; R b is H or 0 to 1 R e C replaced with 1-3 is alkyl; and R e is OH] or a pharma- ceutically acceptable salt thereof.

[0030] In a twelfth aspect within the seventh aspect, the present invention provides a compound of formula (V): [In the formula, R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 teeth, [ka] and; R 6 are halo, =O, -OH, -OC 1-4 Alkyl or C 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 Alkyl, -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b OR -C(=O)OR b and; R 8 is -C(=O)OR b , -C(=O)NHRa , -C(=O)NHOR b or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -NR a C(=O)R b and; R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(=O)2C 1-3 Alkyl, 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with; R 11 is -OH, -C(=O)OH or C(=O)NR a R a and; R 12 , H, C 1-3 is alkyl or aryl; R a is H or C 1-3 is alkyl; R b is H or 0 to 1 R e C replaced with 1-3 is alkyl; and R e is OH] or a pharma- ceutically acceptable salt thereof.

[0031] In a thirteenth aspect within the seventh aspect, the present invention provides a compound of formula (V): [In the formula, R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 is -C(=O)NR 13 R 13 and; R 6 is halo, -OH or C substituted with 0-1 OH 1-4 is alkyl; R 7 is -S(=O)2C 1-3 Alkyl or 0 to 2 R e C replaced with 3-6 is cycloalkyl; R 10 is H, -C(=O)R b or 0 to 1 R 11 C replaced with 1-4 is alkyl; R 11 is -OH, -C(=O)OH or aryl; R 13 is H or 0 to 1 R 6 and 0 to 1 R 7 C replaced with 1-3 alkyl; or R 13 and R 13 together with the nitrogen atom to which they are both attached form: [ka] forming a heterocyclyl selected from R b is H or C 1-6 is alkyl; and R e is -S(=O)2C 1-3 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0032] In a fourteenth aspect within the thirteenth aspect, the present invention relates to a compound of formula (?) [In the formula, R 5is -C(=O)NHR 13 and; R 13 is 0 to 1 R 7 C replaced with 1-3 is alkyl; R 7 is 0 to 2 R e C replaced with 3-6 is cycloalkyl; and R e is -S(=O)2C 1-3 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0033] In a fifteenth embodiment within the second aspect, the present invention provides a compound of formula (II): [In the formula, [ka] teeth, [ka] and; R 3 -OC 1-3 is alkyl; R 4a is F; R 4b is CF3; R 5 is -C(=O)NHR 13 , [ka] and; R 7 is 0 to 1 R 9 C replaced with 1-3 Alkyl or 0 to 5 R e C replaced with 3-6 is cycloalkyl; R 8 is halo, -C(=O)OR b or C substituted with 0 to 3 halo 1-4 is alkyl; R 9-OH, -NR a C(=O)R b or -OC(=O)NR a R a and; R 10 is H, 0 to 2 R 11 C replaced with 1-3 Alkyl or -C(=O)R b and; R 11 is -OH; R 13 is H or 0 to 1 R 7 C replaced with 1-3 is alkyl; R b is H, 0 to 5 R e C replaced with 1-3 alkyl or heterocyclyl; R e -OR f or -S(=O)2C 1-3 is alkyl; and R f is H or C 1-3 is alkyl] or a pharma- ceutically acceptable salt thereof.

[0034] In a sixteenth aspect within the twelfth aspect, the present invention provides a compound of formula (V): [In the formula, R 1 is F; R 3 is -OCH3; R 4a is F; R 4b is CF3; R 5 is 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-6 Alkenyl, 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-6 is alkynyl; R 6is halo, -OH or C substituted with 0-1 OH 1-4 is alkyl; R 7 -OR b or -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; and R b , H, C 1-3 alkyl or heterocyclyl] or a pharma- ceutically acceptable salt thereof.

[0035] In the compounds of formula (I), variable substituents such as R 1 , R 2 , R 3 , R 4 (R 4a , R 4b ), R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R a , R b , R c , R d , R e , R f and R g can be used independently of any other exemplary ranges for the variable substituents. Thus, the present invention includes combinations of different embodiments.

[0036] In one embodiment of Formula (II), [ka] teeth, [ka] It is.

[0037] In another embodiment of Formula (II), [ka] teeth, [ka] It is.

[0038] In another embodiment of Formula (II), [ka] teeth, [ka] It is.

[0039] In another embodiment of Formula (II), R 4a is F.

[0040] In another embodiment of Formula (II), R 4b is CF3.

[0041] In another embodiment of Formula (II), [ka] teeth, [ka] ;R 3 is F or -OCH3; R 4a is F;R 4b is CF3; R 5 is -C(=O)NR 13 R 13 ;R 13 is H or 0 to 1 R 7 C replaced with 1-5 alkyl; or R 13 and R 13together with the nitrogen atom to which they are both attached, [ka] R 6 is -OH or C 1-3 R is alkyl; 7 is 0 to 1 R 9 C replaced with 1-3 Alkyl, -S(=O)2C 1-3 Alkyl or 0 to 2 R e C replaced with 3-6 Cycloalkyl; R 9 is -OH; and R e is -S(=O)2C 1-3 It is an alkyl.

[0042] In another embodiment of Formula (II), [ka] teeth, [ka] ;R 3 is F or -OCH3; R 4a is F;R 4b is CF3; R 5 teeth, [ka] ;R 7 is 0 to 1 R 9 C replaced with 1-5 Alkyl or -C(=O)NHR a ;R 9 is -OH; R a , H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl or -(CH2) 0-1 -heterocyclyl.

[0043] In another embodiment of Formula (II), [ka] teeth, [ka] ;R 3 is 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 0 to 2 R g C replaced with 1-3 R is alkyl; g is -OH alkyl.

[0044] In another embodiment of Formula (II), [ka] teeth, [ka] ;R 3 is F or -OCH3; R 4a is F;R 4b is CF3; R 5 teeth, [ka] ;R 6is F;R 7 is -S(=O)2C 1-3 Alkyl, -S(=O)2NHR a , or 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 R is alkyl; 8 is -C(=O)OH or CF3; R 9 -NHR a , -NHC(=O)R b , -NHS(=O) p C 1-4 Alkyl or -OC(=O)NHR a ;R a , H, C 1-3 Alkyl, -(CH2) 0-1 -C 3-6 Cycloalkyl or 0 to 2 R e Substituted with -(CH2) 0-1 -phenyl; R b is H or heterocyclyl; R e is C 1-3 Alkyl, -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0045] In another embodiment of Formula (II), [ka] teeth, [ka] ;R 3 is F or -OCH3; R 4a is F;R 4b is CF3; R 5 teeth, [ka] ;R 7 is 0 to 1 R 9 C replaced with1-4 R is alkyl; 9 is -OH; R 10 is -C(=O)R b ;R b is H or 0 to 4 R e C replaced with 1-3 R is alkyl; e is -(CH2) 0-1 OR f and R f is H or C 1-3 It is an alkyl.

[0046] Unless otherwise stated, these terms have the following meanings.

[0047] "Halo" includes fluoro, chloro, bromo and iodo.

[0048] "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: C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 It is intended to include alkyl groups. Further, for example, "C1-C6 alkyl" or "C1-C6 alkyl" means an alkyl having 1 to 6 carbon atoms. An alkyl group may be unsubstituted or substituted in which at least one hydrogen is replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to mean a direct bond. "Alkyl" also includes deuteroalkyls such as CD3.

[0049] "Alkenyl" or "alkenylene" is intended to include a hydrocarbon chain in a straight or branched configuration having one or more, preferably one to three, carbon-carbon double bonds, 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.

[0050] "Alkynyl" or "alkynylene" is intended to include a hydrocarbon chain in a straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds, 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; for example, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0051] "Carbocycle", "carbocyclyl" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12- or 13-membered bicyclic or tricyclic hydrocarbon ring, 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 described 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.

[0052] "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.

[0053] "Spirocycloalkyl" is intended to mean a hydrocarbon bicyclic ring system in which both rings are linked through one atom. The rings may be of different sizes and nature or of the same size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane or spirodecane.

[0054] "Bicyclic carbocyclyl" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system consisting of carbon atoms, containing two fused rings. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a saturated, partially unsaturated, or unsaturated 5- or 6-membered carbocyclic ring. A bicyclic carbocyclic group may be attached to its 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.

[0055] 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).

[0056] "Benzyl" means methyl in which one of the hydrogen atoms is replaced by a phenyl group, which phenyl group may optionally be substituted with 1 to 5, preferably 1 to 3, groups.

[0057] "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 or fully unsaturated and contains carbon atoms and 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of N, O and S; and 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., N→O and S(O)). p , where p is 0, 1, or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other optional substituents). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted at a carbon or nitrogen atom if the resulting compound is stable. A nitrogen in a heterocyclyl can optionally be quaternized. When the total number of S and O atoms in a heterocyclyl exceeds 1, it is preferred that these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in a heterocyclyl does not exceed 1. Bridged rings are also included in the definition of heterocyclyl. When the term "heterocyclyl" is used, it is intended to include heteroaryl.

[0058] Examples of heterocyclyl include acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran ... Ran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolopyridinyl, Oxazolidinylperimidinyl, Oxindolyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Piperidonyl, 4-Piperidonyl, Piperonyl, Pteridinyl, Purinyl, Pyranyl, Pyranyl, Pyrazinyl, Pyrazolidinyl, Pyrazoly nyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,Examples of heterocyclyls include, but are not limited to, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing the above heterocyclyls.

[0059] "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 containing carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring, including a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring that is saturated, partially unsaturated or unsaturated and includes a 5-membered heterocyclyl, a 6-membered heterocyclyl or a carbocyclyl (with the proviso that if the second ring is a carbocyclyl then the first ring is not benzo).

[0060] Bicyclic heterocyclic groups can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. Bicyclic heterocyclic groups described herein can be substituted with carbon or nitrogen atoms if the resulting compound is stable. If the total number of S and O atoms in a heterocyclyl exceeds 1, it is preferred that these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in a heterocyclyl does not exceed 1.

[0061] 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.

[0062] "Heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member such as sulfur, oxygen or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl and benzodioxane. Heteroaryl groups are substituted or unsubstituted. Nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or other optional substituents). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) p , where p is 0, 1 or 2).

[0063] As used herein, the term "substituted" means that at least one hydrogen atom is replaced with a group other than hydrogen, so long as the normal valence is maintained and the replacement results in a stable compound. When a substituent is keto (i.e., =O), two hydrogens on the atom are replaced. Keto substituents are not present in aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or double bond, it is intended that the carbonyl group or double bond is part of (i.e., within) the ring. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0064] Where nitrogen atoms (e.g., amines) are present in the compounds of the invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide additional compounds of the invention. Thus, the indicated and claimed nitrogen atoms are considered to cover both the indicated nitrogen and its N-oxide (N→O) derivative.

[0065] When any variable occurs more than one time in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, the group may also be optionally substituted with up to 3 R groups, and each occurrence of R 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.

[0066] When a bond to a substituent is depicted as crossing a bond connecting two atoms in a ring, such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom to which such substituent is attached to the remainder of the compound in a given formula, then the 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.

[0067] The present invention includes all pharma- ceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ion does not significantly affect the physiological activity or toxicity of the compound and acts as a pharmaceutical equivalent itself. These salts can be prepared by common organic techniques using commercially available reagents. Some anionic salt forms include acetate, acetonitrate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate and xinafoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine and zinc.

[0068] Throughout this specification and the appended claims, a given chemical formula or name includes all such stereoisomers and optical isomers and racemates, where 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 half 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.

[0069] The invention includes all tautomeric forms, atropisomers and rotamers of the compounds.

[0070] All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

[0071] 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 atomic configurations relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)).

[0072] The term "chiral" refers to the structural characteristic of a molecule that makes it impossible for one molecule to be superimposed on its mirror image. The term "homochiral" refers to the state of being enantiomerically pure. The term "optical activity" refers to the angle through which a homochiral molecule or a non-racemic mixture of chiral molecules rotates the plane of polarization.

[0073] The present invention is intended to include all isotopes of atoms occurring in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 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 suitable isotopically labeled reagents instead of unlabeled reagents that would otherwise be used. Such compounds may have a variety of potential uses, for example, as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological or pharmacokinetic properties.

[0074] Throughout this specification and the appended claims, a given chemical formula or compound name is intended to encompass all 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. Many geometric isomers, such as C=C double bonds, C=N double bonds, ring systems, and the like, may also exist in the compounds of the present invention, and all such stable isomers are included in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomers. The compounds of the present invention can be isolated in optically active or racemic form. Optically active forms can be prepared by resolution of racemic forms or synthesis from optically active starting materials. All processes used to prepare the compounds and intermediates of the present invention are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions, the end products of the present invention are obtained in free (neutral) or salt form. Both the free and salt forms of these end products are within the scope of the present invention. If desired, one form of the compound may be converted into another form. Free bases or acids may be converted into salts; salts may be converted into free compounds or into other salts; mixtures of isomers of the compounds of the present invention may be separated into individual isomers. The compounds of the present invention, their free forms and salts, may exist in multiple tautomeric forms in which hydrogen atoms are transferred to different sites of the molecule with a consequent rearrangement of the chemical bonds between the atoms of the molecule. It will be apparent that all tautomeric forms are encompassed by the present invention, insofar as they exist.

[0075] "Stereoisomer" refers to an isomer of identical structure that differs in the arrangement of atoms in space. Enantiomers and diastereomers are examples of stereoisomers. "Enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are non-superimposable. "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, the composition lacking optical activity.

[0076] biological methods RXFP1 cyclic adenosine monophosphate (cAMP) assay. Human embryonic kidney 293 (HEK293) cells and HEK293 cells stably expressing human RXFP1 were cultured in MEM medium supplemented with 10% regular FBS and 300 μg / ml hygromycin (Life Technologies). Cells were detached and suspended in assay buffer. Assay buffer was HBSS buffer (with calcium and magnesium) containing 20 mM HEPES, 0.05% BSA and 0.5 mM IBMX. Cells (3000 cells / well, except for HEK293 cells stably expressing human RXFP1, 1500 cells / well) were added to 384-well Proxiplates (Perkin-Elmer). Cells were immediately treated with DMSO solutions (2% final) of test compounds at final concentrations ranging from 0.010 nM to 50 μM. Cells were incubated at room temperature for 30 min. Intracellular cAMP levels were determined using the HTRF HiRange cAMP Assay Reagent Kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and d2 fluorophore-labeled cAMP were prepared in the lysis buffer provided separately. After reaction completion, cells were lysed with equal volumes of d2-cAMP and anti-cAMP solutions. After incubation at room temperature for 1 h, time-resolved fluorescence intensity was measured at 400 nm excitation wavelength and dual emission wavelengths of 590 nm and 665 nm using Envision (Perkin-Elmer). Calibration curves were constructed by plotting the fluorescence intensity ratio of the intensity of 665 nm emission to 590 nm emission versus cAMP concentration with cAMP external standards at concentrations ranging from 2.7 μM to 0.1 pM. The potency and activity of compounds to inhibit cAMP production was then determined by fitting a four-parameter logistic equation from the plot of cAMP levels versus compound concentration.

[0077] The example compounds disclosed below were tested in the human RXFP1 (hRXFP1) HEK293 cAMP assay described above and found to have agonist activity. Tables 1-3 show the EC50 of the hRXFP1 HEK293 cAMP assay measured with the example compounds.50 Indicates the value.

[0078] Table A [Table 1] [Table 2] [Table 3]

[0079] Pharmaceutical Compositions and Methods of Use The compounds of formula (I) are RXFP1 receptor agonists and may be useful in the treatment of indications such as heart failure, fibrotic diseases and related 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).

[0080] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier.

[0081] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier for the treatment of a relaxin-related disorder.

[0082] Another aspect of the invention is a method of treating a relaxin-related disorder, comprising administering an effective amount of a compound of formula (I).

[0083] Another aspect of the invention is a method of treating cardiovascular disease, comprising administering to a patient in need of treatment an effective amount of a compound of formula (I).

[0084] Another aspect of the invention is a method of treating heart failure, comprising administering to a patient in need of treatment an effective amount of a compound of formula (I).

[0085] Another aspect of the invention is a method of treating fibrosis, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0086] Another aspect of the invention is a method of treating a disease associated with fibrosis, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0087] Another aspect of the invention is a method of treating or preventing renal failure comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0088] Another aspect of the invention is a method of improving, stabilizing or restoring renal function in a patient in need of treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (I).

[0089] Unless otherwise stated, the following terms have the meanings stated.

[0090] The term "patient" or "subject" refers to any human or non-human organism that may benefit from treatment with RXFP1 agonist, as understood by those skilled in the art. Examples of subjects include humans of any age with risk factors for cardiovascular disease. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arrhythmia or symptoms of insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia or polycystic ovarian syndrome (PCOS).

[0091] "Treating" or "treatment", as will be understood by those of skill in the art, extends to the treatment of a disease state and includes: (a) inhibiting the disease state, i.e., arresting its progression; (b) alleviating the disease state, i.e., causing regression of the disease state; and / or (c) preventing the onset of disease in a mammal, particularly where the mammal is predisposed to suffering from a disease state but has not yet been diagnosed as suffering from the disease state.

[0092] "Prevent" or "prevention", as understood by those skilled in the art, covers prophylactic treatment (i.e., prevention and / or risk reduction) of subclinical disease states aimed at reducing the probability of occurrence of a clinical disease state. Patients are selected for prophylactic treatment based on factors known to increase the risk of suffering from a clinical disease state compared to the general population. "Prophylactic" treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment for subjects who have not yet exhibited a clinical disease state, whereas secondary prevention is defined as preventing the secondary onset of the same or similar clinical disease state. "Risk reduction" or "risk reduction" covers therapies that reduce the incidence of clinical disease states. That is, primary and secondary prevention treatments are examples of risk reduction.

[0093] "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 will be understood by those of skill in the art. When applied to a combination, the term refers to the combined amounts of active ingredients that result in a prophylactic or therapeutic effect, whether administered in combination, serially or simultaneously.

[0094] "Disorders of the cardiovascular system" or "cardiovascular disorders" include, for example, the following disorders: hypertension (high blood pressure), peripheral and cardiovascular disorders, coronary heart disease, stable and unstable angina, heart attack, myocardial insufficiency, abnormal heart rhythm (or arrhythmias), permanent ischemic dysfunction ("hibernating myocardium"), transient post-ischemic dysfunction ("fainting myocardium"), heart failure, peripheral blood flow disorders, acute coronary syndromes, heart failure, heart muscle diseases (cardiomyopathy), myocardial infarction and vascular diseases (vascular diseases).

[0095] "Heart failure" includes both acute and chronic symptoms of heart failure, as well as specific types or related types of diseases, such as advanced heart failure, cardiac-renal syndrome after acute heart failure, heart failure with renal dysfunction, chronic heart failure, chronic heart failure with intermediate ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right ventricular failure, left ventricular failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic stenosis, aortic insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, These include: total, pulmonary stenosis, pulmonary valve insufficiency, heart failure associated with complex heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with cardiac storage disorder, diastolic heart failure, systolic heart failure, acute 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.

[0096] "Fibrotic disorders" specifically encompasses the following diseases and disorders characterized by fibrogenesis, including liver fibrosis, liver cirrhosis, NASH, pulmonary fibrosis or pulmonary fibrosis, cardiac fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic damage due to diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, localized scleroderma, keloids, hypertrophic scarring (even after surgery), nevi, diabetic retinopathy, proliferative vitreoretinopathy, and disorders of connective tissue (e.g., sarcoidosis).

[0097] Relaxin-related disorders include, but are not limited to, cardiovascular disorders and fibrotic disorders.

[0098] The compounds of the present invention may be administered in any suitable manner, including oral means such as tablets, capsules (each including sustained release or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray dried dispersions), syrups and emulsions; sublingual means; buccal means; parenteral means, such as subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasal means, including administration to the nasal mucosa, such as by inhalation spray; topical means, such as in the form of a cream or ointment; or rectal means, such as in the form of a suppository. The compounds of the present invention can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0099] "Pharmaceutical composition" refers to a composition comprising the compound of the present invention and at least one additional pharma- ceutical acceptable carrier. "Pharmaceutical acceptable carrier" refers to a medium generally accepted in the art for the delivery of a bioactive agent to an animal, particularly a mammal, i.e., depending on the nature of the administration method and administration form, for example, adjuvants, additives or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants and dispersants.

[0100] Pharmaceutically acceptable carriers are formulated according to many factors well within the knowledge of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent to be formulated; the subject to which the drug-containing composition is administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media as well as various solid and semi-solid dosage forms. Such carriers can contain several different ingredients and additives in addition to the active agent, and the additional ingredients are incorporated into the formulation for various reasons well known to those skilled in the art, such as stabilization of the active agent, binders, etc. 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, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0101] The administration regimen of the compounds of the invention will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its method and route of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and extent of the condition; type of concurrent treatment; frequency of treatment; route of administration; renal and hepatic function of the patient; and the desired effect.

[0102] As a general guideline, the daily oral dose of each active ingredient, when used for a given effect, ranges from about 0.01 to about 5000 mg / day, preferably from about 0.1 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. Intravenously, the most preferred doses are in the range of about 0.01 to about 10 mg / kg / 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.

[0103] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriate for the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practice.

[0104] A dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.1 to 95% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is sieved through a 60 mesh sieve and filled into a No. 1 gelatin capsule. A typical injectable formulation is produced by placing at least one compound of the present invention (250 mg) in a vial, lyophilizing and sealing under aseptic conditions. At the time of use, the contents of the vial are mixed with 2 mL physiological saline to produce an injectable formulation.

[0105] The compounds may be used 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-hyperinsulinaemic 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, appetite reducing 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.

[0106] Additional therapeutic agents include ACE inhibitors, β-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine A1 receptor agonists, partial adenosine A1 receptors, dopamine β-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with agonistic bias to select cell signaling pathways, angiotensin II receptor antagonists and Neprilysin enzyme inhibitor combinations, neprilysin enzyme inhibitors, soluble guanylate cyclase activators, myosin ATPase activators, rho-kinase 1 inhibitors, rho-kinase 2 inhibitors, apelin receptor agonists, nitroxyl donating compounds, calcium-dependent kinase II inhibitors, antifibrogenic agents, galectin-3 inhibitors, vasopressin receptor antagonists, FPR2 receptor modulators, natriuretic peptide receptor agonists, transient receptor potential vanilloid-4 channel blockers, antiarrhythmic agents, (I f ) "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 (e.g., HMG CoA reductase inhibitors), LXR agonists, FXR agonists, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, anion exchange resins, quaternary amines, cholestyramine, colestipol, low density lipoprotein receptor inducers, clofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrozil, vitamin B6, vitamin B12, antioxidant vitamins, antidiabetic agents, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives, PCSK9 inhibitors, P2Y12 inhibitors such as aspirin and clopidogrel.

[0107] Additional therapeutic agents include nintedanib, pirfenidone, LPA1 antagonist, LPA1 receptor antagonist, GLP1 analog, tralokinumab (IL-13, AstraZeneca), vismodegib (hedgehog antagonist, Roche), PRM-151 (pentraxin-2, TGF beta-1, Promedior), SAR-156597 (bispecific Mab IL-4 & IL-13, Sanofi), simtuzumab (anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inhibitor / pentoxifylline / NAC oral depletion therapy, Pacific Ther.), omipalisib (oral PI3K / mTOR inhibitor, GSK), and IW-001 (oral solution bovine type V collagen modification, ImmuneWorks), STX-100 (integrin alpha V / beta-6 ant, Stromedix / Biogen), Actimmune (IFN gamma), PC-SOD (midismase; inhaled, LTT Bio-Pharma / CKD Pharm), lebrikizumab (anti-IL-13 SC humanized mAb, Roche), AQX-1125 (SHIP1 activator, Aquinox), CC-539 (JNK inhibitor, Celgene), FG-3019 (FibroGen), SAR-100842 (Sanofi) and obeticholic acid (OCA or INT-747, Intercept).

[0108] The above therapeutic agents, when used 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 set forth in the above patents, or as otherwise determined by one of skill in the art.

[0109] In particular, when provided as a single dosage unit, there may be chemical interactions between the combined active ingredients. Therefore, when the compound of the present invention and the second therapeutic agent are combined in a single dosage unit, the active ingredients are combined in a single dosage unit, but are formulated so that the physical contact between the active ingredients is minimized (i.e., reduced). For example, one 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 of the combined active ingredients, but also to control 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. One of the active ingredients may be coated with a material that affects the delayed release through the digestive tract and at the same time acts to minimize the physical contact between the combined active ingredients. In addition, the sustained release component may be further enteric coated so that the release of this component occurs only in the intestine. Yet another approach involves formulating a combination product in which one component is coated with a sustained and / or enteric release polymer and the other component is coated with a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or another 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 ingredient.

[0110] The compounds of the present invention are also useful as standard or control compounds, e.g., quality standards or controls, in tests or assays involving RXFP1. Such compounds can be included in commercial kits, e.g., for pharmaceutical research involving RXFP1. For example, the compounds of the present invention can be used as controls in assays to compare their known activity with a compound of unknown activity. This allows researchers to ensure that the assay was performed properly and provides a basis for comparison, especially when the test compound is a derivative of the control compound. When developing new assays or protocols, the compounds of the present invention can be used to test for efficacy. The compounds of the present invention can also be used in diagnostic assays involving RXFP1.

[0111] The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but is not limited to, kits and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition contained in the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharma- ceutical acceptable salt form thereof; and (c) a package insert describing that the pharmaceutical composition can be used for dyslipidemia and its sequelae. In another embodiment, the package insert describes that the pharmaceutical composition can be used in combination (as defined above) with a second therapeutic agent for dyslipidemia and its sequelae. The article of manufacture further comprises (d) a second container, wherein components (a) and (b) are disposed within the second container, and component (c) is disposed within or outside the second container. Each of the first and second containers is meant to hold the item within its boundaries.

[0112] A first container is a container used to hold a pharmaceutical composition. This container can be used for manufacturing, storing, shipping, and / or individual / bulk sales. A first container is intended to include 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.

[0113] The second container is used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches and sacks. The package insert may be physically attached to the outside of the first container by tape, glue, staples or other attachment methods, or may be placed in the second container without any physical attachment means to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, the package insert is preferably physically attached by tape, glue, staples or other attachment means. Alternatively, the package insert may be adjacent to or in contact with the outside of the second container without being physically attached.

[0114] The package insert is a label, tag, marker, etc. that describes information about the pharmaceutical composition located in the first container. The information is usually determined by the regulatory agency governing the region in which the product is sold (e.g., the U.S. Food and Drug Administration). The package insert preferably describes, among other things, the indications for which the pharmaceutical composition is approved. The package insert may be made of any material on which the information contained therein or present thereon can be read. It may be made of any material. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive backed paper or plastic, etc.) on which the desired information is formed (e.g., printed or applied).

[0115] General synthesis method The compounds of the invention can be made by a variety of methods known in the art, including those in the Schemes and Specific Embodiments sections below. The numbering of structures and numbering of variables shown in the synthetic schemes are different and should not be confused with the numbering of structures or variables in the claims or elsewhere in this specification. The variables in the schemes are only intended to illustrate how to make some compounds of the invention.

[0116] It will also be appreciated that another major consideration in planning any synthetic route in this field is the proper selection of protecting groups used to protect reactive functional groups present in the compounds described herein. An authoritative text that describes many options for the skilled artisan is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0117] The benzothiazole compounds of the present invention can be synthesized by the general methods outlined in Schemes I-IV. Scheme I illustrates how appropriately substituted benzothiazole compounds of the present invention can be prepared from commercially available intermediate II. [ka] Starting from amine II, intermediate I-II can be obtained by chlorination (NCS). Subsequent bromination (NBS) can provide intermediate I-III. Intermediate I-IV can be palladium catalyzed in the presence of CO / MeOH to provide methyl ester intermediate I-IV, which can be converted to various amides of the invention by treatment with appropriate amines in the presence of amide AlMe3 or by successive hydrolysis (LiOH, THF / MeOH / water), followed by standard peptide coupling methods known in the art to provide intermediate IV. The chloro moiety of IV can be further converted to various functional groups or dechlorinated under dehalogenation conditions (e.g., Pd(OAc)2, JohnPhos) to provide intermediate I-VI. Alternatively, chlorine can be removed from I-IV followed by formation of amides using appropriate amines and AlMe3, or carboxylic acids (derived from hydrolysis of esters) can be coupled to appropriate amines of the invention by standard coupling methods known in the art to form amides. Intermediates I-VI can be coupled with an appropriate carboxylic acid of the invention using a variety of amide bond forming conditions (e.g., TCFH, 1-methyl-1H-imidazole or BOP, DIEA or other conditions known in the art) to provide the claimed compounds. [ka]

[0118] Alternatively, Scheme II describes how benzothiazole examples of the invention can be prepared from commercially available intermediates I-VII. Starting from methyl 2-methylbenzo[d]thiazole-5-carboxylate intermediate I-VII, nitration (HNO3, H2SO4) provides nitro intermediates I-VIIIa and I-VIIIb. Intermediate I-VIIIa can be hydrolyzed (e.g., LiOH, HO) to carboxylic acid derivative I-IX, which can be coupled with various amines of the invention (e.g., POCl3 or BOP, DIEA or HATU, DIEA and / or other methods known in the art) to provide intermediate IX. Reduction of the nitro group of IX (e.g., H2, Pd / C or Zn, NH4Cl) provides intermediate I-XI, which can be coupled with the appropriate carboxylic acid intermediate of the invention under various amide bond forming conditions (e.g., TCFH, 1-methyl-1H-imidazole or BOP, DIEA) to provide compounds of the invention.

[0119] Alternatively, the benzothiazoles of the invention (Scheme III) can be synthesized via the general methods described in Schemes I and II. The aniline intermediates I-XV can then be coupled with appropriately substituted benzoic acids under conditions previously described or known in the art to provide the benzothiazole compounds of the invention. [ka]

[0120] Trifluoromethylbenzothiazole intermediates I-XVI can be obtained following the general route shown in Scheme IV (Du, G. et.al. Het. 2015, 9, 1723). Intermediates I-XIII can then be converted to trifluorobenzothiazole intermediates I-XVI as shown in Scheme II above. [ka]

[0121] Substituted benzoic or heterocyclic acid intermediates used in the preparation of the examples of this invention can be synthesized by the general route shown in Scheme V. This scheme is general for aryl and heteroaryl groups where X=C or N, and provides compounds of general formulae I-XIX which can be further hydrolyzed or hydrogenated to give compounds of the invention. [ka]

[0122] The aryl isoxazoline intermediates of the present invention can be obtained from commercially available aryl or heteroaryl carboxaldehydes as shown in the general route of Scheme VI. The aldehyde I-XX is converted to the oxime I-XXI, which is then treated with NCS to give the chlorooxime I-XXII. Treatment of IXII with an appropriate olefin gives the aryl isoxazoline intermediates as general formula I-XXIII or IXXIV. Conversely, treatment of I-XXII with an acetylenic intermediate gives the aryl isoxazole derivative I-XXV of the present invention. Heteroaryl carboxaldehydes can also be subjected to similar conditions to give the heteroaryl isoxazoline or isoxazole intermediates of the present invention. The diastereomeric mixtures produced by the condensation can be separated by chiral SFC. [ka]

[0123] The difluorodioxolone intermediates of the invention can be obtained from commercially available 2,2-difluorobenzo[d][1,3]dioxol-5-amine as shown in Scheme VII. Bromination (NBS) gives intermediate I-XXVI. Palladium catalysis of intermediate I-XXVI in the presence of CO / MeOH gives methyl ester intermediate I-XXVII, which can be converted to various amides of the invention by treatment with XNH2 in the presence of AlMe3 or successive hydrolysis (LiOH, THF / MeOH / water), followed by peptide coupling methods known in the art to give intermediate I-XXVIII. Intermediate I-XXVII was coupled with an aryl carboxylic acid to give I-XXIX. Deprotection of I-XXXIX with TFA / DCM gave the corresponding carboxylic acid intermediate I_XXX, which could be coupled with amines NHR1R2 using peptide coupling methods to give compounds of the invention. [ka]

[0124] Intermediates I-XXVIII can also be coupled with heterocyclic carboxylic acids as shown in Scheme VIII. Conversion of the carboxylic acid to the corresponding aldehyde I-XXIX, followed by reductive amination, afforded the benzylamine examples of the invention. [ka]

[0125] The following abbreviations are defined: "1x" is one time, "2x" is two times, "3x" is three times, "°C" is degrees Celsius, "aq" is aqueous, "eq" or "equiv." is equivalent, "g" is gram, "mg" is milligram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normalized, "M" is molar concentration, "nM" is nanomolar concentration, "pM" is picomolar concentration, "mol" is mole, "mmol" is millimole, "min" is minute, "h" is hour, "rt" is room temperature, "RT" is retention time, "atm" is atmospheric pressure, "psi" is pounds per square inch, "conc." is concentrated, "aq" is "aqueous", "sat." is saturated, "MW" is molecular weight, "MS" or "Mass Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "LC-MS" is liquid chromatography mass spectrometry, "HPLC" is high performance liquid chromatography, "RPMS" is liquid chromatography mass spectrometry ... "HPLC" stands for reverse phase HPLC, "NMR" stands for nuclear magnetic resonance spectroscopy, "SFC" stands for supercritical fluid chromatography, 1 "H" is proton, "δ" is delta, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quartet, "m" is multiplet, "br" is broad, "Hz" is hertz, "MHz" is megahertz and "α", "β", "R", "S", "E" and "Z" are stereochemical designations well known to those skilled in the art.

[0126] [Table 4-1] [Table 4-2]

[0127] In the illustrated examples, the following methods were used unless otherwise noted. Purification of intermediates and final products was accomplished using normal or reverse phase chromatography. Normal phase chromatography was performed using pre-packed SiO2 cartridges eluted with either a hexanes and EtOAc gradient or a DCM and MeOH gradient unless otherwise indicated. Reverse phase preparative HPLC was performed using a C18 column with UV 220 nm or prep LCMS detection, with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or solvent A (95% water, 5% ACN, 0.1% TFA) and solvent B (5% water, 95% ACN, 0.1% TFA), or solvent A (95% water, 2% ACN, 0.1% HCOOH) and solvent B (98% ACN, 2% water, 0.1% HCOOH), or solvent A (95% water, 5% ACN, 10 mM NH4OAc) and solvent B (98% ACN, 2% water, 10 mM NH4OAc), or solvent A (98% water, 2% ACN, 0.1% NH4OH) and solvent B (98% ACN, 2% A gradient of 0.1% NH4OH (water, 0.1% NH4OH) was used. The LC / MS method used for characterization of the examples is given below.

[0128] Method A: Equipment: Waters Acquity coupled to a Waters MICROMASS™ ZQ mass spectrometer. Linear gradient from 2 to 98% B over 1 min, hold at 98% B for 0.5 min UV visualization at 220 nm Column: Waters BEH C18, 2.1 x 50 mm Flow rate: 0.8 mL / min (method A) Mobile phase A: 0.05% TFA, 100% water Mobile phase B: 0.05% TFA, 100% acetonitrile

[0129] Method B: Instrument: Shimadzu Prominence HPLC coupled to a Shimadzu LCMS-2020 mass spectrometer Linear gradient from 0 to 100% B over 3 min, hold at 100% B for 0.75 min UV visualization at 220 nm Column: Waters Xbridge C18, 2.1 x 50 mm, 1.7 um particles Flow rate: 1 mL / min Mobile phase A: 10 mM ammonium acetate, 95:5 water:acetonitrile Mobile phase B: 10 mM ammonium acetate, 5:95 water:acetonitrile

[0130] Method C: Instrument: Shimadzu Prominence HPLC coupled to a Shimadzu LCMS-2020 mass spectrometer Linear gradient from 0 to 100% B over 3 min, hold at 100% B for 0.75 min UV visualization at 220 nm Column: Waters Xbridge C18, 2.1 x 50 mm, 1.7 um particles Flow rate: 1 mL / min Mobile phase A: 0.1% TFA, 95:5 water:acetonitrile Mobile phase B: 0.1% TFA, 5:95 water:acetonitrile

[0131] Method D: Instrument: Agilent 1200 / 6140 LCMS single quadrupole mass spectrometer 4. Linear gradient from 20% B to 100% B over 6 min, then hold at 20% B for 0.4 min UV visualization at 254 nm Column: Kinetex XB C18 75x3 mm, 2.6 μM Flow rate: 1 mL / min for the first 4 min; 1.5 mL / min for 0.6 min, then 1 mL / min for 0.4 min Mobile phase A: 10 mM NH4COOH / water Mobile phase B: ACN

[0132] Method E: Instrument: Agilent 1290 infinity II coupled to a G6135B mass spectrometer Linear gradient from 0% B to 100% B over 3 min UV visualization at 220 nm Column: Xbridge BEH XP C18 50 x 2.1 mm, 2.5 μM Flow rate: 1.1 mL / min at 50°C Mobile phase A: 10 mM NH4OAc in water:ACN (95:05) Mobile phase B: 10 mM NH4OAc in water:ACN (05:95)

[0133] Method F: Instrument: Agilent 1290 infinity II coupled to a G6135B mass spectrometer Linear gradient from 0% B to 100% B over 3 min UV visualization at 220 nm Column: Xbridge BEH XP C18 50 x 2.1 mm, 2.5 μM Flow rate: 1.1 mL / min at 50°C Mobile phase A: 0.1% TFA in water:ACN (95:05) Mobile phase B: 0.1% TFA in water:ACN (05:95)

[0134] Method G: Instrument: Agilent 1200 / 6140 LCMS single quadrupole mass spectrometer Linear gradient from 60% B to 100% B over 4 min, then hold at 100% B for 0.6 min UV visualization at 220 nm Column: Xbridge BEH XP C18 50 x 2.1 mm, 2.5 μM Flow rate: 1.0 mL / min for the first 4 minutes, then 1.5 mL / min for the next 0.6 minutes Mobile phase A: 0.1% HCOOH / water Mobile phase B: ACN

[0135] NMR used for characterization of the examples: 1H NMR spectra were obtained on Bruker or JEOL® Fourier transform spectrometers operating at the following frequencies: 1H NMR: 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®), Bruker Avance III 300 MHz, Bruker Avance Neo 400 MHz, Bruker Avance III 400 MHz. Spectral data are reported in the format of chemical shift (multiplicity, coupling constant, number of hydrogens). Chemical shifts are specified in ppm downfield of the internal standard of tetramethylsilane (d units, tetramethylsilane = 0 ppm) and / or referenced to the solvent peaks appearing in the 1H NMR spectrum at 2.51 ppm (DMSO-d6), 3.30 ppm (CD3OD), 1.94 ppm (CD3CN) and 7.24 ppm (CDCl3).

[0136] Intermediate 1: Preparation of 5-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methylbenzo[d]thiazole-6-carboxamide [ka] Preparation of Intermediate 1-1: 6-Bromo-4-chloro-2-methylbenzo[d]thiazol-5-amine Intermediate 1-1 (0.85 g, 3.10 mmol, 25% yield) was prepared by the method described in Masuda, K, et al, PCT Int Appl, 2010044441, 2010. 1 H NMR (400 MHz, CDCl3) δ 7.83(s, 1H), 4.66(br s, 2H), 2.86(s, 3H). MS (ESI) m / z 279.1 (M+H, Br isotope peaks seen).

[0137] Preparation of Intermediate 1-2: Methyl 5-amino-4-chloro-2-methylbenzo[d]thiazole-6-carboxylate To a steel reaction vessel was added 1-1 (0.9 g, 3 mmol), followed by TEA (0.5 mL, 3.2 mmol), PdOAc2 (0.2 g, 0.6 mmol), dppf (0.5 g, 0.9 mmol), DMSO (12 mL) and MeOH (8 mL). The reaction vessel was sealed, pressurized with 70 psi CO gas and heated to 80 °C for 24 h. The reaction vessel was cooled to room temperature and the contents were partitioned between water (20 mL) and EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to give an oil. The residue was purified by normal phase chromatography eluting with hexanes / EtOAc to give 1-2 (0.7 g, 3 mmol, 90% yield) as a pale yellow solid. 1 H NMR(400 MHz, CDCl3) δ 8.35(s, 1H), 6.34(br s, 2H), 3.96(s, 3H), 2.89(s, 3H). MS(ESI)m / z 257.0(M+H) + .

[0138] Intermediate 1-3: 5-amino-4-chloro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methylbenzo[d]thiazole-6-carboxamide To 4-fluoro-3-(trifluoromethyl)aniline (1.2 g, 7.0 mmol) in a microwave vial was added toluene (8 mL) and the solution was cooled to 0° C. To this solution was added trimethylaluminum (3.5 mL, 7.0 mmol, 2 M in toluene). After 10 min, a solution of 1-2 (0.6 g, 2.3 mmol) in toluene (6 mL) was added, followed by more toluene (32 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 30 min. The cooled reaction mixture was quenched with 1 N HCl (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic portions were washed with brine (15 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by normal phase chromatography eluting with hexane / EtOAc to give 1-3 (0.8 g, 2 mmol, 90% yield) as an orange solid. 1 H NMR(400 MHz, CDCl3) δ 7.94(br d, J=1.8 Hz, 1H), 7.91(s, 1H), 7.89(dd, J=6.2, 2.6 Hz, 1H), 7.84(dt, J=8.8, 3.5 Hz, 1H), 5.92(br s, 2H), 2.92 - 2.89(m, 3H). MS(ESI)m / z 404.1(M+H) + .

[0139] Intermediate 1: In a microwave vial was added palladium(II) acetate (56 mg, 0.2 mmol), [1,1'-biphenyl]-2-yldi-tert-butylphosphane (0.15 g, 0.50 mmol), and sodium formate (0.2 g, 3 mmol) in degassed (under N2) MeOH (10 mL). The mixture was degassed under N2 for 3 min and stirred for 10 min before adding 1-2 / THF (1 mL). The vial was sealed and the reaction mixture was heated to 130 °C under microwave irradiation for 1 h. The solvent was removed in vacuo and the residue was purified by normal phase chromatography eluting with hexane / EtOAc to give intermediate 1 (0.14 g, 0.38 mmol, 61% yield) as a brown solid.1 H NMR(500 MHz, CDCl3) δ 8.07(br s, 1H), 7.99(s, 1H), 7.89(dd, J=6.1, 2.7 Hz, 1H), 7.83(dt, J=8.9, 3.5 Hz, 1H), 7.33 - 7.30(m, 1H), 7.25(t, J=9.2 Hz, 1H), 5.31(br s, 2H), 2.84(s, 3H). MS(ESI)m / z 370.1(M+H) + .

[0140] Intermediate 2: Preparation of 5-(3-hydroxy-3-methylbutyl)-2-methoxybenzoic acid [ka] Intermediate 2-1: Methyl 5-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methoxybenzoate In a large microwave vial was added methyl 5-bromo-2-methoxybenzoate (1.7 g, 6.9 mmol), 2-methylbut-3-yn-2-ol (0.58 g, 6.9 mmol), Pd(Ph3P)4 (0.4 g, 0.35 mmol), copper(I) iodide (13 mg, 69 mmol) and TEA (15 mL). The reaction mixture was degassed (vac / N2), sealed and heated at 80 °C for 18 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4) and then purified by normal phase silica chromatography eluting with hexane / EtOAc to give 2-1 (1.2 g, 4.8 mmol, 70% yield). MS(ESI)m / z:249(M+H) + .

[0141] Intermediate 2-2: Methyl 5-(3-hydroxy-3-methylbutyl)-2-methoxybenzoate A Parr bottle was charged with 2-1 (1.2 g, 4.8 mmol), followed by EtOH (25 mL) and wet 10% Pd / C (0.2 g). The flask was sealed and hydrogenated at 20 psi for 18 h, the reaction mixture was filtered through Celite®, and the filtrate was concentrated in vacuo. The residue was purified by normal phase silica chromatography eluting with hexane / EtOAc to give 2-2 (0.7 g, 3 mmol, 60% yield) as a pale yellow oil. 1 H NMR(400 MHz, CDCl3)δ 7.67(d, J=2.4 Hz, 1H), 7.33(dd, J=8.4, 2.4 Hz, 1H), 6.94(d, J=8.4 Hz, 1H), 3.92(s, 3H), 3.92(s, 3H), 2.88 - 2.59(m, 2H), 1.86 - 1.69(m, 2H), 1.32(s, 6H), 1.25(s, 1H).

[0142] Intermediate 2: To 2-2 (0.7 g, 3 mmol) in THF (21 ml) was added water (7 ml), followed by aqueous LiOH (2M, 1.4 ml, 2.8 mmol). The reaction mixture was stirred at room temperature for 14 h. An additional equivalent of LiOH solution was added and the reaction mixture was stirred for 4 h. The reaction mixture was acidified with HCl (0.1 N) and extracted with EtOAc (2×25 mL). The combined organic portions were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give intermediate 2 (0.6 g, 3 mmol, 90% yield), which was used without further purification. MS (ESI) m / z: 239.2 (M+H). + .

[0143] Preparation of intermediates 3-6 and 3-7: 2-Methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoic acid (homochiral analogue): [ka]

[0144] Preparation of intermediate 3-1: methyl (E)-5-((hydroxyimino)methyl)-2-methoxybenzoate Commercially available methyl 5-formyl-2-methoxybenzoate (1.16 g, 6 mmol) was dissolved in DCM (5 mL) and to this solution was added HONH2-HCl (415 mg, 6 mmol) followed by TEA (1 mL) and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2×25 mL). The combined organic portions were dried (MgSO4) and concentrated in vacuo to give 3-1 (1.2 g, 5.7 mmol, 95% yield) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 8.13(s, 1H), 8.03(d, J=2.4 Hz, 1H), 7.78 - 7.67(m, 1H), 7.03(d, J=8.8 Hz, 1H), 3.97(s, 3H), 3.93(s, 3H). MS(ESI)m / z:= 210.1(M+H) + .

[0145] Intermediate 3-2: Preparation of methyl (Z)-5-(chloro(hydroxyimino)methyl)-2-methoxybenzoate Intermediate 3-1 (23 g, 0.10 mol) was dissolved in DMF (100 mL), NCS (15 g, 0.10 mol) was added to the solution, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water (300 mL), and the solid formed was collected by filtration and dried under vacuum to give 3-2 (23 g, 95 mmol, 86% yield) as a pale yellow solid. 1 H NMR(500 MHz, CDCl3) δ 8.32 - 8.30(m, 1H), 7.99 - 7.96(m, 1H), 7.80 - 7.78(m, 1H), 7.05 - 7.02(d, 1H), 3.98(s, 3H), 3.94(s, 3H).MS(ESI)m / z:= 244.1(M+H) + .

[0146] Intermediate 3-3: Preparation of methyl 2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoate To intermediate 3-2 (0.4 g, 2 mmol) and 2,5-dihydrofuran (1.2 g, 17 mmol) in DCM (10 mL) was added TEA (0.7 mL, 5 mmol) and the reaction mixture was stirred for 24 h. The solvent was removed in vacuo and the residue was directly purified by normal phase silica gel chromatography eluting with hexane / EtOAc to give 3-3 (0.4 g, 80% yield). 1 H NMR(500 MHz, CDCl3) δ 7.98(d, J=2.3 Hz, 1H), 7.86(dd, J=8.8, 2.4 Hz, 1H), 7.04(d, J=8.7 Hz, 1H), 5.38(dd, J=9.2, 3.9 Hz, 1H), 4.34 - 4.26(m, 2H), 4.20 - 4.09(m, 1H), 3.96(s, 3H), 3.91(s, 3H), 3.83 - 3.76(m, 1H), 2.92 - 2.70(m, 1H). MS(ESI)m / z = 278.3(M+H) + .

[0147] Intermediate 3-4 and Intermediate 3-5: The following chiral intermediates were separated by chiral SFC from racemic 3-3 by the following preparative chromatographic method: Apparatus: PIC Solution SFC Column: Chiralpak IA, 30 x 250 mm, 5 micron, Mobile phase: 20% MeOH / 80% CO2, Flow conditions: 90 mL / min, 150 Bar, 40°C, Detection wavelength: 220 nm; Analytical method: Apparatus: Shimadzu Nexera SFC, Column Chiralpak IA 4.6 x 100 mm, 5 micron, Mobile phase: 25% MeOH / 75% CO2, Flow conditions: 2 mL / min, 150 Bar, 40°C, Detection wavelength: 220 nm to obtain homochiral intermediate 3-4 (Peak-1, Yield 28%, RT=1.83 min., >99% ee) and homochiral intermediate 3-5 (Peak-2, Yield 28%, RT=3.83 min, >99% ee).

[0148] Intermediate 3-6: Preparation of 2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoic acid To a solution of intermediate 3-4 (75 mg, 0.3 mmol) in THF (3 mL) was added MeOH (0.6 mL) followed by LiOH (2M, 0.4 mL, 0.8 mmol). After 4 h, the reaction mixture was diluted with water, acidified with HCl (1 M) and extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSO4) and concentrated under reduced pressure to give intermediate 3-6 (71 mg, 100% yield). 1H NMR(400 MHz, CD3OD) δ 7.78(d, J=2.3 Hz, 1H), 7.71(dd, J=8.7, 2.3 Hz, 1H), 7.09(d, J=8.8 Hz, 1H), 5.33(dd, J=9.2, 3.6 Hz, 1H), 4.44(ddd, J=8.9, 7.2, 1.3 Hz, 1H), 4.18(d, J=10.6 Hz, 1H), 4.08(dd, J=9.4, 1.0 Hz, 1H), 3.91 - 3.88(m, 3H), 3.86(dd, J=9.4, 6.9 Hz, 1H), 3.73(dd, J=10.7, 3.7 Hz, 1H).MS(ESI)m / z:= 264.1(M+H) + .

[0149] Intermediate 3-7: Preparation of 2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoic acid Intermediate 3-7 (52 mg, 0.20 mmol, 100% yield) was prepared in a similar manner to intermediate 3-6, using intermediate 3-5 instead of intermediate 3-4. 1 H NMR(500 MHz, CD3OD)δ 8.10(d, J=2.4 Hz, 1H), 7.87(dd, J=8.8, 2.4 Hz, 1H), 7.23(d, J=8.7 Hz, 1H), 5.38(dd, J=9.2, 3.7 Hz, 1H), 4.47(ddd, J=8.9, 7.2, 1.2 Hz, 1H), 4.22(d, J=10.7 Hz, 1H), 4.12(q, J=7.1 Hz, 1H), 4.07(dd, J=9.5, 0.9 Hz, 1H), 3.97(s, 3H), 3.88(dd, J=9.5, 6.9Hz, 1H), 3.76(dd, J=10.8, 3.6 Hz, 1H). MS(ESI)m / z:= 264.1(M+H) + .

[0150] Intermediate 4: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]-isoxazol-3-yl)-2-methoxybenzoic acid [ka] Preparation of Intermediate 4-1: Methyl 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoate Intermediate 3-2 (3.0 g, 12 mmol) was dissolved in DCM (123 mL) and cyclopent-3-en-1-ylmethanol (4.8 g, 49 mmol) was added thereto, followed by TEA (5.2 mL, 37 mmol) and the reaction mixture was stirred at room temperature. After stirring for 14 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by normal phase chromatography eluting with hexane / EtOAc to give 4-1 (2.8 g, 9.2 mmol, 75% yield) as an oily mass. LC-MS RT = 0.95 min; MS(ESI)m / z = 306.3(M+H). + [Method A]

[0151] Diastereomeric intermediate 4-2: Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 4-1 (88 mg, 0.29 mmol) was dissolved in THF (1 mL) / MeOH (1 mL) and treated with LiOH monohydrate (36 mg, 0.86 mmol) in HO (1 mL) at room temperature. After 3 h, the reaction mixture was diluted with HO (5 mL) and the pH of the aqueous layer was adjusted to pH 7 with 1M aqueous HCl and extracted with EtOAc (2 x 25 mL). The combined organic portions were washed with brine, dried (NaSO), filtered and concentrated in vacuo to give 4-2 (62 mg, 74% yield). Intermediate 4-2 was used without further purification. LC-MS RT = 0.85 min; MS(ESI)m / z = 292.3(M+H) + [Method A]

[0152] Intermediates 4-3 to 4-10 Intermediates 4-3, 4-5, 4-7, and 4-9 were obtained by chiral SFC separation of the diastereomeric mixture of intermediate 4-1 (525 mg, 1.72 mmol). Chiral SFC preparative chromatography conditions: Apparatus; Berger MG II (SFC); Column: Chiralpak AD-H, 21 x 250 mm, 5 micron; Mobile phase: 15% MeOH / 85% CO2; Flow conditions: 45 mL / min, 150 Bar, 40°C; Detection wavelength: 210 nm; Injection details: 0.5 mL of ~35 mg / mL in MeOH. Analytical chromatographic conditions: Instrument; Shimazu Nexera SFC; Column: Chiralpak AD-H, 4.6 x 100 mm, 3 micron; Mobile phase: 15% MeOH / 85% CO2; Flow conditions: 2.0 mL / min, 150 Bar, 40 °C; Detection wavelength: 220 nm; Injection details: Inject 5 μL of ~1 mg / mL in MeOH.

[0153] Intermediate 4-3 (Peak-1, RT = 4.07 min; >99% ee) was obtained as a film (150 mg, 29% yield). 1 H NMR(600 MHz, CDCl3) δ 8.04(d, J=2.3 Hz, 1H), 7.87(dd, J=8.7, 2.3 Hz, 1H), 7.01(d, J=8.8 Hz, 1H), 5.23(dd, J=8.8, 5.1 Hz, 1H), 4.10(t, J=8.7 Hz, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.72 - 3.66(m, 1H), 3.61(dt, J=10.5, 5.2 Hz, 1H), 2.30 - 2.16(m, 2H), 2.05(dd, J=13.0, 6.1Hz, 1H), 1.76(ddd, J=12.9, 11.5, 9.4 Hz, 1H), 1.68 - 1.62(m, 1H), 1.39(br t, J=4.8 Hz, 1H).

[0154] Preparation of intermediate 4-4: 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid. Intermediate 4-4 (100 mg, 78% yield) was prepared in a similar manner to intermediate 4-2 by hydrolysis of intermediate 4-3. LC-MS RT = 0.85 min; MS(ESI)m / z = 292.3(M+H). + .[Method A]

[0155] Intermediate 4-5 (Peak-2, RT = 4.55 min; >99% ee) was obtained as a film (33 mg, 6.3% yield). 1 H NMR(600 MHz, CDCl3)δ 8.05(d, J=2.3 Hz, 1H), 7.87(dd, J=8.8, 2.3 Hz, 1H), 7.02(d, J=8.8 Hz, 1H), 5.25(ddd, J=10.1, 6.2, 4.2 Hz, 1H), 4.04 - 3.98(m, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.63 - 3.57(m, 1H), 3.56 - 3.50(m, 1H), 2.38 - 2.26(m, 3H), 1.92 - 1.85(m, 1H), 1.73 - 1.66(m, 1H), 1.51(t, J=5.3 Hz, 1H).

[0156] Preparation of Intermediate 4-6: 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 4-6 (20.2 mg, 92% yield) was prepared in a similar manner to intermediate 4-2 by hydrolysis of intermediate 4-5. LC-MS RT = 0.83 min; MS(ESI) m / z: 292.3 (M+H). + .[Method A]

[0157] Intermediate 4-7 (Peak-3, RT = 5.66 min; >99% ee) was obtained as a film (161 mg, 30.6% yield). 1H NMR:(600 MHz, CDCl3)δ 8.05 - 8.03(m, 1H), 7.86(dd, J=8.7, 2.3 Hz, 1H), 7.01(d, J=8.8 Hz, 1H), 5.23(dd, J=8.7, 5.2 Hz, 1H), 4.10(t, J=8.7 Hz, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.69(br dd, J=10.6, 5.2 Hz, 1H), 3.63 - 3.58(m, 1H), 2.28 - 2.17(m, 2H), 2.05(br dd, J=12.9, 6.2 Hz, 1H), 1.76(ddd, J=13.0, 11.5, 9.4 Hz, 1H), 1.64 - 1.60(m, 1H), 1.49(br s, 1H).

[0158] Preparation of Intermediate 4-8: 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 4-8 (120 mg, 85% yield) was prepared in a similar manner to intermediate 4-2 by hydrolysis of intermediate 4-7. LC-MS RT = 0.83 min; MS(ESI) m / z: 292.3 (M+H). + .[Method A]

[0159] Intermediate 4-9 (Peak-4, RT = 9.81 min; >99% ee) was obtained as a film (47 mg, 9.0% yield). 1H NMR:(600 MHz, CDCl3) δ 8.04(d, J=2.3 Hz, 1H), 7.87(dd, J=8.7, 2.3 Hz, 1H), 7.02(d, J=8.8 Hz, 1H), 5.24(ddd, J=10.1, 6.2, 4.2 Hz, 1H), 4.03 - 3.98(m, 1H), 3.94(s, 3H), 3.90(s, 3H), 3.63 - 3.57(m, 1H), 3.56 - 3.49(m, 1H), 2.38 - 2.25(m, 3H), 1.91 - 1.85(m, 1H), 1.72 - 1.66(m, 1H), 1.55(br s, 1H).

[0160] Intermediate 4-10. Preparation of 5-(5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 4-10 (18 mg, 52% yield) was prepared in a similar manner to intermediate 4-2 by hydrolysis of intermediate 4-9. LC-MS RT = 0.84 min; MS(ESI) m / z: 292.3 (M+H). + .[Method A]

[0161] Intermediate 5: Preparation of 5-(5-(2-hydroxyacetyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid [ka] Preparation of Intermediate 5-1: Methyl 2-methoxy-5-(3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)benzoate Intermediates 5-1 and 5-2 were prepared and isolated in a similar manner as described for intermediate 3-3, substituting tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate for 2,5-dihydrofuran in the cycloaddition step, and the resulting diastereomers were subjected to SFC separation of the isomers using the following preparative chromatographic method; Apparatus: Jasco SFC Prep Column: Regis Whelk 21 x 250 mm ID, 5 μm, Temperature: 40°C; Flow rate: 45 mL / min, 150 Bar; Mobile phase: Gradient 80 / 20 CO2 / MeOH; Detection wavelength: 220 nm; Injection volume: 0.5 mL to give intermediate 5-1 (Peak-1, 0.36 g, 0.95 mmol, 23% yield, >99% ee, analytical RT = 8.80 min) and intermediate 5-2 (Peak-2, 0.36 g, 0.95 mmol, 23% yield, >99% ee, analytical RT = 9.86 min. Analytical chromatographic conditions: Instrument: Shimadzu Nexera SFC, Column: Regis Whelk-01, 4.6 x 100 mm ID, 3 μm; Temperature: 40°C, Flow rate: 2.0 mL / min, 150 Bar; Mobile phase: Gradient 80 / 20 CO2 / MeO.

[0162] Intermediate 5-3: To intermediate 5-2 (Peak-2) (0.36 g, 0.96 mmol) in THF (10 mL) was added 4N HCl / dioxane (2.4 mL) and the reaction mixture was stirred for 14 h. The solvent was removed under reduced pressure to give 5-3 (0.3 g, 0.96 mmol, 100% yield). 1H NMR(500 MHz, DMSO-d6) δ 7.95(d, J=2.4 Hz, 1H), 7.85(dd, J=8.8, 2.4 Hz, 1H), 7.26(d, J=8.9 Hz, 1H), 5.43(dd, J=9.3, 4.7 Hz, 1H), 4.67(td, J=9.0, 1.7 Hz, 1H), 3.88(s, 3H), 3.80(s, 3H), 3.63(br d, J=13.3 Hz, 1H), 3.54 - 3.42(m, 2H), 3.39 - 3.33(m, 2H). MS(ESI) m / z 277.1 (M+H) + .

[0163] Intermediate 5: Preparation of 5-(5-(2-hydroxyacetyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid To intermediate 5-3 (78 mg, 0.30 mmol) was added glycolic acid (57 mg, 0.75 mmol), 1-HOBt (51 mg, 0.30 mmol) and EDC (57 mg, 0.30 mmol) in DCM (5 ml), followed by TEA (70 μl, 0.5 mmol). After 1 h, the reaction mixture was partitioned between HCl (1 N, 5 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a solution of THF (2 mL) / MeOH (0.5 mL) and cooled to 0 °C, followed by the addition of aqueous LiOH (2 M, 0.4 ml, 0.7 mmol). The solvent was removed under reduced pressure and the residue was lyophilized to give intermediate 5 (80 mg, 0.25 mmol, 100% yield), which was used in the next step without purification. MS(ESI) m / z 321.1(M+H). +

[0164] Preparation of intermediate 6: 5-(5,5-dioxido-3a,4,6,6a-tetrahydrothieno[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid: [ka] Preparation of intermediates 6-1 and 6-2: methyl 5-(5,5-dioxido-3a,4,6,6a-tetrahydrothieno[3,4-d]isoxazol-3-yl)-2-methoxybenzoate Intermediates 6-1 and 6-2 were prepared in a similar manner as described for intermediate 3-3, substituting 2,5-dihydrofuran for 2,5-dihydrothiophene 1,1-dioxide in the cycloaddition step, followed by chiral SFC separation of the diastereomers using the following preparative chromatographic method: Apparatus: PIC Solution SFC Prep 200, Column: Chiralcel OD-H 21 x 250 mm ID, 5 μm; Temperature: 40°C; Flow rate: 45 mL / min, 150 Bar; Mobile phase: Gradient 75 / 25 CO2 / MeOH; Detection wavelength: 271 nm; Injection volume: 1 mL; to give intermediate 6-1 (peak-1, 0.1g, 0.33 mmol, 18% yield, >99% ee, analytical RT = 3.79 min) and intermediate 6-2 (peak-2, 0.1g, 0.33 mmol, 18% yield, >99% ee, analytical RT = 3.79 min). % yield, >99% ee, analytical RT = 5.67 min. Analytical chromatographic conditions: Instrument: Shimadzu Nexera SFC; Column: Chiralcel OD-H, 4.6 x 100 mm ID, 3 μm; Temperature: 40°C; Flow rate: 2.0 mL / min, 150 Bar; Mobile phase: Gradient 85 / 15 CO2 / MeOH; Detection wavelength: 220 nm. Intermediate 6-1: 1 H NMR(400 MHz, CDCl3)δ 7.96(d, J=2.4 Hz, 1H), 7.85(dd, J=8.8, 2.2 Hz, 1H), 7.07(d, J=9.0 Hz, 1H), 5.43(ddd, J=10.1, 7.2, 4.1 Hz, 1H), 4.52 - 4.44(m, 1H), 3.97(s, 3H), 3.92(s, 3H), 3.66 - 3.47(m, 3H), 3.14(dd, J=13.6, 8.1 Hz, 1H). Intermediate 6-2: 1H NMR(400 MHz, CDCl3) δ 7.96(d, J=2.4 Hz, 1H), 7.85(dd, J=8.8, 2.2 Hz, 1H), 7.06(d, J=8.8 Hz, 1H), 5.42(ddd, J=10.1, 7.2, 4.1 Hz, 1H), 4.52 - 4.44(m, 1H), 3.97(s, 3H), 3.91(s, 3H), 3.66 - 3.46(m, 3H), 3.14(dd, J=13.6, 8.4 Hz, 1H).

[0165] Intermediate 6: Preparation of 5-(5,5-dioxido-3a,4,6,6a-tetrahydrothieno[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid Intermediate 6 (82 mg, 0.26 mmol, 79% yield) was prepared from intermediate 6-1 (peak-1) in a similar manner as described for intermediate 3-6. MS(ESI) m / z 312.3 (M+H) + .

[0166] Intermediate 7: Preparation of 5-((4S,6R)-4,6-bis((tert-butyldimethylsilyl)oxy)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid [ka]

[0167] Preparation of Intermediate 7-1: Methyl 5-((4S,6R)-4,6-bis((tert-butyldimethylsilyl)oxy)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoate To intermediate 3-2 (1.2 g, 5.0 mmol) in DCM (10 mL) was added (1R,3S)-cyclopent-4-ene-1,3-diol (0.5 g, 5 mmol) followed by TEA (0.5 g, 5 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSO4) and concentrated in vacuo. Purification on normal phase silica using hexane / EtOAc as eluent gave the cycloadduct diol, which was redissolved in DCM (10 mL) and then tert-butyldimethylsilyl trifluoromethanesulfonate (2.6g, 10 mmol) was added followed by 2,6-lutidine (1.6g, 15 mmol). After 24 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSO4) and concentrated in vacuo and the residue was purified on normal phase silica eluting with hexanes / EtOAc to give intermediate 7-1 (Peak-1, >99% ee, Analytical RT = 4.69 min, 344 mg, 13% yield) and intermediate 7-2 (Peak-2, >99% ee, Analytical RT = 6.32 min, 364 mg, 14% yield) via chiral SFC separation using the following preparative chromatography method: Apparatus: PIC Solution SFC Prep 200, Column: Chiralcel OD-H 30 x 250 mm ID, 5 μm, Temperature: 40 °C, Flow: 90 mL / min, 150 Bar, Mobile phase: Gradient 80 / 20 CO2 / IPA, Detection wavelength: 270 nm, Injection volume: 0.5 mL). Analytical chromatographic conditions: Instrument: Shimadzu Nexera SFC, Column: Chiralpak IC, 4.6 x 100 mm ID, 3 μm, Temperature: 40°C, Flow rate: 2.0 mL / min, 150 Bar, Mobile phase: Gradient 90 / 10 CO2 / IPA, Detection wavelength: 220 nm. Intermediate 7-1: 11H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 2.3 Hz, 1H), 7.89 (dd, J = 8.8, 2.3 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.01 (dd, J = 10.4, 2.8 Hz, 1H), 4.29 (td, J = 6.0, 2.8 Hz, 1H), 4.19 (td, J = 5.7, 4.0 Hz, 1H), 4.06 (dd, J = 10.3, 3.7 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.06 (dt, J = 13.2, 5.8 Hz, 1H), 1.80 (dt, J = 12.9, 6.2 Hz, 1H), 0.93 (s, 9H), 0.91 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.02 (s, 3H), -0.05 (s, 3H). MS(ESI) m / z: 536.6 (M + H) + . Intermediate 7-2: 1 1H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 2.3 Hz, 1H), 7.89 (dd, J = 8.8, 2.3 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.01 (dd, J = 10.4, 2.8 Hz, 1H), 4.29 (td, J = 6.0, 2.8 Hz, 1H), 4.19 (td, J = 5.7, 4.0 Hz, 1H), 4.06 (dd, J = 10.3, 3.7 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.06 (dt, J = 13.2, 5.8 Hz, 1H), 1.80 (dt, J = 12.9, 6.2 Hz, 1H), 0.93 (s, 9H), 0.91 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.02 (s, 3H), -0.05 (s, 3H). MS(ESI) m / z: 536.6 (M + H) + .

[0168] Intermediate 7: To intermediate 7-1 (30 mg, 56 μmol) in THF (1 mL) was added MeOH (1 mL), HO (0.5 mL), followed by LiOH (4 mg, 0.17 mmol). After 4 h, the reaction mixture was diluted with water acidified with HCl (1N) and extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSO) and concentrated in vacuo to give intermediate 7 (18 mg, 34 μmol, 62% yield). 1 H NMR(500 MHz, CDCl3)δ 8.48 - 8.46(m, 1H), 8.04 - 8.00(m, 1H), 7.10 - 7.05(m, 1H), 5.06 - 5.02(m, 1H), 4.33 - 4.29(m, 1H), 4.23 - 4.18(s, 3H), 4.15 - 4.13(m, 1H), 4.12 - 4.10(m, 1H), 4.00 - 3.94(m, 1H), 1.29 - 1.24(m, 1H), 0.93(s, 18H), 0.12(s, 3H), 0.12 - 0.03(m, 3H), 0.03(s, 1H), 0.02(s, 3H), -0.05 - 0.06(m, 3H). MS(ESI)m / z:522.5(M+H) + .

[0169] Intermediate 8-2 (chiral peak 1), 8-3 (chiral peak 2), 8-4 (chiral peak 3), 8-5 (chiral peak 4): 5-(5-hydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid. The title compounds were prepared according to the scheme outlined below: [ka]

[0170] Intermediate 8-1. Preparation of 5-(5-hydroxy-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid Methyl 5-formyl-2-methoxybenzoate (24.9 g, 128 mmol) was dissolved in DCM (500 mL). To the solution was added triethylamine (17.9 mL, 128 mmol) followed by hydroxylamine hydrochloride (8.91 g, 128 mmol). The reaction mixture was stirred at room temperature for 14 h and concentrated in vacuo to give a white solid. The solid was dissolved in water (200 mL) and the aqueous portion was extracted with EtOAc (2 x 100 mL). The combined organic portions were dried (MgSO4), filtered and concentrated in vacuo to give a white solid (27.1 g, 100% yield). The solid was redissolved in DMF (200 mL) and the solution was added NCS (17.2 g, 128 mmol) and stirred at room temperature for 14 h. The reaction mixture was quenched by the addition of excess water to precipitate a white solid. The solid was isolated by filtration, washed with excess water, and dried under vacuum to give a white solid of intermediate 8-1 (287 g, 89% yield). 1 H NMR(500 MHz, CDCl3)δ 8.32 - 8.30(m, 1H), 7.99 - 7.96(m, 1H), 7.80 - 7.78(m, 1H), 7.05 - 7.02(d, 1H), 3.98(s, 3H), 3.94(s, 3H).

[0171] Intermediate 8-1 (mixture of diastereomers): Alternatively, (E)-5-((hydroxyimino)methyl)-2-methoxybenzoic acid (620 mg, 3.18 mmol) was dissolved in DMF (5 mL) and NCS (424 mg, 3.18 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 4 h. Water (100 mL) was added to the reaction mixture and the solution was extracted with EtOAc (2 x 25 mL), dried (MgSO4) and concentrated in vacuo to give an oil. The resulting oil was redissolved in DCM (10 mL) and cyclopent-3-en-1-ol (2.67 g, 31.8 mmol) was added followed by TEA (0.44 mL) and the reaction mixture was stirred at room temperature for 14 h. The resulting solution was filtered through a plug of silica gel and concentrated in vacuo to give a diastereomeric mixture of intermediate 8-1 (227 mg, 26% yield). 1 H NMR(600 MHz, CDCl3) δ 8.04(d, J=2.3 Hz, 1H), 7.85(dd, J=8.8, 2.3 Hz, 1H), 7.03(d, J=8.8 Hz, 1H), 5.30(ddd, J=9.4, 6.2, 2.9 Hz, 1H), 4.50(quin, J=5.9 Hz, 1H), 4.19(td, J=9.3, 4.7 Hz, 1H), 3.92(s, 3H), 2.33 - 2.27(m, 1H), 2.18 - 2.06(m, 3H). LC-MS RT = 0.83 min;MS(ESI) m / z:278.1 (M+H) + .[Method A]

[0172] The chiral intermediates of 8-1 were separated by chiral SFC with the following preparative chromatography method; Instrument: Berger SFC; Column: IC 25 x 3 cm ID, 5 μm; Temperature: 40°C; Flow rate: 85 mL / min; Mobile phase: Gradient: 75 / 25 CO2 / MeOH for 12 min, then gradient to 45% MeOH; Detection wavelength: 235 nm; Injection volume: 1000 μL; to give chiral 8-2 (Peak-1, >99% ee, Analytical RT = 8.80 min), chiral 8-3 (Peak-2, >95% ee, Analytical RT = 9.86 min) and chiral 8-4 (Peak-3, >99% ee, Analytical RT = 13.53 min) and chiral 8-5 (Peak-4, >99% ee, Analytical RT = 16.67 min). Analytical chromatographic conditions: Instrument: Agilent SFC; Column: IC 250 x 4.6 mm ID, 5 μm; Temperature: Ambient; Flow rate: 2 mL / min; Mobile phase: 75 / 25 CO2 / MeOH 12 min, then gradient to 45% MeOH. Analytical data for peaks-1-4: 1 H NMR(600 MHz, CD3OD) δ 8.07(d, J=2.2 Hz, 1H), 7.82(dd, J=8.7, 2.1 Hz, 1H), 7.18(d, J=8.8 Hz, 1H), 5.21(ddd, J=9.2, 6.2, 2.5 Hz, 1H), 13C NMR (151 MHz, CD3OD)δ 169.5, 161.6, 160.0, 133.2, 131.4, 122.6(2C), 113.9, 87.3, 72.7, 56.8, 51.5, 44.1, 40.3.

[0173] Intermediate 9: Preparation of 5-(5-(((di-tert-butoxyphosphanyl)oxy)methyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid [ka] To intermediate 4 (50 mg, 0.16 mmol) in ACN (1.4 mL) and DCM (1 mL) was added 1H-tetrazole (23 mg, 0.32 mmol) followed by di-tert-butyl N,N-diisopropyl phosphoramidite (0.1 mL, 30 mmol) dropwise. The reaction mixture was cooled to 0° C. and 2-hydroperoxy-2-methylpropane (47 μL, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure, EtOAc (20 mL) was added and washed with potassium phosphate dibasic solution (1.0M, 20 mL). The organic layer was extracted with EtOAc (2 x 25 mL) and the combined organic layers were washed with H2O (25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in a solution of THF / MeOH (1:1, 4 mL), cooled to 0 °C, and LiOH (34 mg, 0.82 mmol) / H2O (1 mL) was added. After 3 h, the reaction mixture was acidified with HCl (1.0 M) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4) and concentrated in vacuo to give intermediate 9 (79 mg, 0.16 mmol, 100% yield), which was used in the next reaction without further purification. MS (ESI) m / z: 484.5 (M+H). + .

[0174] Intermediate 10: Preparation of 5-(3a,4,5,6,7,7a-hexahydro-4,7-methanobenzo[d]isoxazol-3-yl)-2-methoxybenzoic acid [ka]

[0175] Intermediates 10-1 and 10-2: Preparation of methyl 5-(3a,4,5,6,7,7a-hexahydro-4,7-methanobenzo[d]isoxazol-3-yl)-2-methoxybenzoate: Intermediates 10-1 and 10-2 were prepared in a similar manner as described for Intermediate 3-3, substituting bicyclo[2.2.1]hept-2-ene for 2,5-dihydrofuran, followed by chiral SFC separation of the diastereomers using the following preparative chromatographic method; Apparatus: Berger MG II; Column: Chiralcel OD-H 21 x 250 mm ID, 5 μm; Temperature: 40 °C; Flow rate: 45 mL / min, 150 Bar; Mobile phase: Gradient 93 / 7 CO2 / MeOH; Detection wavelength: 240 nm; Injection volume: 0.5 mL; to give Intermediate 10-1 (Peak-1, 0.16 g, 0.52 mmol, 38 % yield, >99% ee, analytical RT = 4.42 min) and Intermediate 10-2 (Peak-2, 0.16 g, 0.52 mmol, 38 % yield, >99% ee, analytical RT = 4.42 min). % yield, >99% ee, analytical RT = 5.52 min. Analytical chromatographic conditions: Instrument: Shimadzu Nexera SFC, Column: Chiralcel OD-H, 4.6 x 100 mm ID, 3 μm; Temperature: 40°C; Flow rate: 2.0 mL / min, 150 Bar; Mobile phase: Gradient 93 / 7 CO2 / MeOH; Detection wavelength: 220 nm. Intermediate 10-1: 1 H NMR(500 MHz, CDCl3)δ 8.09(d, J=2.3 Hz, 1H), 7.89(dd, J=8.8, 2.4 Hz, 1H), 7.03(d, J=8.7 Hz, 1H), 4.66(d, J=8.2 Hz, 1H), 3.96(s, 3H), 3.93(s, 3H), 3.50(d, J=7.8 Hz, 1H), 2.65(br d, J=3.7 Hz, 1H), 2.53(br s, 1H), 1.71 - 1.59(m, 2H), 1.56 - 1.49(m, 1H), 1.45 - 1.34(m, 1H), 1.26 - 1.13(m, 2H).MS(ESI)m / z:302(M+H) + Intermediate 10-2:1 H NMR(500 MHz, CDCl3) δ 8.09(d, J=2.3 Hz, 1H), 7.89(dd, J=8.9, 2.3 Hz, 1H), 7.03(d, J=8.9 Hz, 1H), 4.66(d, J=8.4 Hz, 1H), 3.96(s, 3H), 3.93(s, 3H), 3.50(d, J=7.6 Hz, 1H), 2.65(br d, J=3.8 Hz, 1H), 2.53(br s, 1H), 1.65 - 1.58(m, 2H), 1.54(br d, J=10.5 Hz, 1H), 1.43 - 1.29(m, 1H), 1.24 - 1.10(m, 2H).MS(ESI)m / z:302(M+H) + .

[0176] Intermediate 10: To intermediate 10-1 (72 mg, 0.24 μmol) in THF (1.5 mL) was added MeOH (0.1 mL) followed by LiOH (2 M, 0.4 mL, 0.7 mmol). After 4 h, the reaction mixture was diluted with water, acidified with HCl (1 N), and then extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (MgSO4) and concentrated in vacuo to give intermediate 10 (68 mg, 0.23 μmol, 99% yield). 1 H NMR(400 MHz, CDCl3) δ 11.11 - 9.94(m, 1H), 8.38 - 8.27(m, 1H), 8.16(dd, J=8.8, 2.4 Hz, 1H), 7.14(d, J=9.0 Hz, 1H), 4.69(d, J=8.1 Hz, 1H), 4.20 - 4.03(m, 3H), 3.55(d, J=8.1 Hz, 1H), 2.66(br d, J=3.3 Hz, 1H), 2.55(br s, 1H), 1.67 - 1.59(m, 2H), 1.52(dt, J=10.7, 1.6 Hz, 1H), 1.47 - 1.40(m, 1H), 1.27 - 1.06(m, 2H).

[0177] Preparation of Intermediate 11-3: 5-(5-(2-hydroxypropan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoic acid [ka]

[0178] Preparation of Intermediate 11-1: 5-(5-(2-hydroxypropan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoic acid Intermediate 11-1 was prepared in a similar manner to intermediate 4-1 by substituting 2-(cyclopent-3-en-1-yl)propan-2-ol for cyclopent-3-en-1-ylmethanol, followed by hydrolysis similar to that described for intermediate 3-6 (181 mg, 100% yield). 1 H NMR(400 MHz, CDCl3)δ 8.13(d, J=2.2 Hz, 1H), 7.98(dd, J=8.8, 2.2 Hz, 1H), 7.05(d, J=9.0 Hz, 1H), 4.58(dd, J=11.0, 8.8 Hz, 1H), 4.05(s, 3H), 3.39(dd, J=16.9, 8.8 Hz, 1H), 3.27(dd, J=16.7, 11.0 Hz, 1H), 1.35(s, 3H), 1.22(s, 3H).

[0179] Intermediate 11-1 (0.18 g, 0.65 mmol) was separated by chiral SFC using the following preparative chromatography method: Preparative Chromatography Conditions; Apparatus: Berger MG II Column: Chiralpak AD-H, 21 x 250 mm, 5 micron; Mobile phase: 40% MeOH / 60% CO2; Flow conditions: 45 mL / min, 150 Bar, 40°C; Detection wavelength: 220 nm; Injection details: ~65 mg / mL in MeOH (0.5 mL). Chiral separation afforded chiral intermediate 11-2 (peak 1, 64 mg, 0.23 mmol, 35% yield, >95% ee, analytical RT = 5.51 min) and intermediate 11-3 (peak 2, 71 mg, 0.25 mmol, 39% yield, >95% ee, analytical RT = 7.7 min). Analytical chromatographic conditions; Instrument: Shimadzu Nexera SFC; Column: Chiralpak AD-H, 4.6 x 100 mm, 3 micron; Mobile phase: 35% MeOH / 65% CO2; Flow conditions: 2.0 mL / min, 150 Bar, 40 °C; Detection wavelength: 220 nm; Injection details: 5 μL of ~1 mg / mL in MeOH. 11-2 (Peak-2) 1 H NMR(600 MHz, CD3OD)δ 8.07(d, J=2.2 Hz, 1H), 7.82(dd, J=8.7, 2.1 Hz, 1H), 7.18(d, J=8.8 Hz, 1H), 5.21(ddd, J=9.2, 6.2, 2.5 Hz, 1H), 4.27(m, 1H), 4.24(td, J=9.4, 4.0 Hz, 1H), 3.94(s, 3H), 2.16(m, 1H), 2.05(m, 1H), 2.00(m, 1H), 1.99(m, 1H). Homochiral intermediate 11-3 (peak-2): 1H NMR(600 MHz, CD3OD) δ 8.10(d, J=1.8 Hz, 1H), 7.86(dd, J=8.7, 1.9 Hz, 1H), 7.19(d, J=8.7 Hz, 1H), 5.21(ddd, J=9.6, 6.4, 2.2 Hz, 1H), 4.32(m, 1H), 4.18(td, J=9.6, 3.1 Hz, 1H), 3.94(s, 3H), 2.21(m, 1H), 2.17(m, 1H), 2.14(m, 1H), 1.98(dd, J=13.7, 1.5 Hz, 1H).

[0180] Intermediate 12-2 and 12-3: Preparation of 2-Methoxy-5-(5-(1-(2-methoxyethoxy)cyclopropyl)-4,5-dihydroisoxazol-3-yl)benzoic acid [ka]

[0181] Intermediate 12-1 (0.27 g, 0.77 mmol, 87% yield) was prepared in a similar manner as described for intermediate 3-3, substituting 1-(2-methoxyethoxy)-1-vinylcyclopropane for 2,5-dihydrofuran, followed by ester hydrolysis as described for intermediate 3-6. Chiral SFC separation of the isomers was performed using the following preparative chromatographic method; Instrument: Berger MG II Column: Chiralpak IC 21 × 250 mm ID, 5 μm; Temperature: 40 °C; Flow rate: 45 mL / min, 150 Bar; Mobile phase: Gradient 75 / 25 CO2 / MeOH; Detection wavelength: 220 nm; Injection volume: 0.5 mL; to give intermediate 12-2 (77 mg, 0.22 mmol, 30% yield) (peak-1, >99% ee, analytical RT = 5.04 min) and intermediate 12-3 (79 mg, 0.23 mmol, 31% yield) (peak-2, >99% ee, analytical RT = 6.48 min). Analytical chromatographic conditions: Instrument: Shimadzu Nexera SFC; Column: Chiralpak, 4.6 x 100 mm ID, 3 μm; Temperature: 40° C.; Flow rate: 2.0 mL / min, 150 Bar; Mobile phase: gradient 75 / 25 CO2 / MeOH; Detection wavelength: 220 nm. Intermediate 12-2: 1 H NMR(500 MHz, CDCl3)δ 10.61 - 10.34(m, 1H), 8.35(d, J=2.1 Hz, 1H), 8.12(dd, J=8.8, 2.2 Hz, 1H), 7.15(d, J=8.9 Hz, 1H), 4.59(dd, J=10.9, 8.3 Hz, 1H), 4.16(s, 3H), 3.91 - 3.83(m, 1H), 3.80 - 3.74(m, 1H), 3.69(dd, J=16.9, 8.3 Hz, 1H), 3.48 - 3.39(m, 2H), 3.30(s, 3H), 1.13 - 1.02(m, 1H), 1.00 - 0.93(m, 1H), 0.90 - 0.79(m, 2H), 0.78 - 0.69(m, 1H). Intermediate 12-3: 1H NMR(500 MHz, CDCl3)δ 8.35(d, J=2.3 Hz, 1H), 8.12(dd, J=8.7, 2.3 Hz, 1H), 7.15(d, J=8.9 Hz, 1H), 4.58(dd, J=10.9, 8.3 Hz, 1H), 4.16(s, 3H), 3.90 - 3.84(m, 1H), 3.81 - 3.74(m, 1H), 3.71 - 3.66(m, 1H), 3.52(s, 1H), 3.43 - 3.40(m, 2H), 3.32 - 3.28(m, 3H), 1.06(ddd, J=10.7, 6.5, 5.3 Hz, 1H), 1.00 - 0.93(m, 1H), 0.87 - 0.79(m, 1H), 0.77 - 0.69(m, 1H).

[0182] Intermediate 13: Preparation of 5-(4-(hydroxymethyl)-2-oxopyrrolidin-1-yl)-2-methoxybenzoic acid [ka] To a solution containing 4-(hydroxymethyl)pyrrolidinone (50 mg, 0.43 mmol), methyl 5-iodo-2-methoxybenzoate (127 mg, 0.434 mmol), Xantphos (25 mg, 0.043 mmol), and Cs2CO3 (0.28 g, 0.87 mmol) was added dioxane (2 mL) and the reaction mixture was purged with N2 for 10 min, followed by the addition of Pd2(dba)3 (20 mg, 22 μmol). The resulting reaction mixture was heated at 100 °C for 15 h. MS (ESI) m / z: 280.2 (M+H). +A silicycle Pd trap was added to the cooled reaction flask and the reaction mixture was filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic portions were washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo. THF (3 mL) was added to the residue followed by a solution of MeOH (0.5 mL) in water (1 mL) and the reaction mixture was cooled to 0°C. Aqueous LiOH (2M, 0.7 mL, 1.3 mmol) was added and the reaction mixture was stirred for 3 h before being acidified (1N HCl) and concentrated in vacuo. The residue was lyophilized to give intermediate 13 as a brown solid which was used in the next step without further purification. MS (ESI) m / z: 266.1 (M+H) + .

[0183] Intermediate 14: Preparation of 2-methoxy-5-(5-oxo-3a,4,5,6,7,7a-hexahydro-4,7-methanoisoxazole[5,4-c]pyridin-3-yl)benzoic acid [ka] In a similar manner to intermediate 3-3, by substituting (1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3-one for 2,5-dihydrofuran and (Z)-5-(chloro(hydroxyimino)methyl)-2-methoxybenzoic acid for intermediate 3-2, intermediate 14 (0.17 g, 0.60 mmol, 86% yield) was prepared and used without purification. MS(ESI) m / z: 303.3(M+H). + .

[0184] Intermediate 15: Preparation of 6-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methylbenzo[d]thiazole-5-carboxamide [ka]

[0185] Intermediate 15-1: Preparation of methyl 2-methyl-6-nitrobenzo[d]thiazole-5-carboxylate To methyl 2-methylbenzo[d]thiazole-5-carboxylate (0.1g, 0.5 mmol) was added H2SO4 (0.5 mL) and the reaction mixture was cooled to 0 °C. To this solution was added a cold (0 °C) solution of KNO3 (59 mg, 0.60 mmol) in H2SO4 (1 mL). After 24 h, ice water was added to the reaction mixture and the solution was extracted with DCM (4 x 20 mL). Hexane was added to the organic layer to precipitate a solid that was collected by filtration, although most of the desired product was in the aqueous layer. The aqueous layer was concentrated under vacuum and the resulting residue was purified by normal phase chromatography eluting with hexane / EtOAc to give 15-1 (46 mg, 38 % yield): 1 H NMR (400 MHz, CDCl3) δ 8.49(s, 1H), 8.26(s, 1H), 4.00(s, 3H), 2.96(s, 3H); and 15-2 (15 mg, 12% yield): 1 H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 1.3 Hz, 1H), 8.93 (d, J = 1.3 Hz, 1H), 4.07 (s, 3H), 2.96 (s, 3H).

[0186] Preparation of Intermediate 15-3: 2-Methyl-6-nitrobenzo[d]thiazole-5-carboxylic acid Hydrolysis of intermediate 15-1 (46 mg, 0.18 mmol) was carried out in THF (2 mL) / MeOH (0.5 mL) / water (0.5 mL) and LiOH (2M, 0.5 ml, 0.5 mmol) for 24 h. The solvent was reduced in vacuo and the residue was dissolved in dilute HCl (2 mL). The solution was extracted with EtOAc (2 x 10 mL) and the combined organic portions were dried (MgSO4) and concentrated under reduced pressure to give intermediate 15-3 (39 mg, 0.16 mmol, 90% yield) as a yellow solid. 1H NMR(400 MHz, DMSO-d6)δ 14.44 - 13.28(m, 1H), 8.87(s, 1H), 8.28(s, 1H), 2.92(s, 3H).

[0187] Intermediate 15-4: Preparation of N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-6-nitrobenzo[d]thiazole-5-carboxamide To 15-3 (49 mg, 0.21 mmol), 4-fluoro-3-(trifluoromethyl)aniline (37 mg, 0.21 mmol) and pyridine (166 μL, 2.00 mmol) in DCM (1 mL) cooled to 0 °C was added POCl3 (19 μL, 0.21 mmol). After 24 h, the reaction mixture was quenched with NaHCO3(aq) (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO4). Purification by normal phase silica gel chromatography gave intermediate 15-4 (41 mg, 0.10 mmol, 50% yield). 1 H NMR(400 MHz, DMSO-d6) δ 11.10(s, 1H), 9.08(s, 1H), 8.34(s, 1H), 8.21(dd, J=6.6, 2.4 Hz, 1H), 8.01 - 7.93(m, 1H), 7.58(t, J=9.8 Hz, 1H), 2.94(s, 3H). MS(ESI) m / z 399.8(M+H) + .

[0188] Intermediate 15: Intermediate 15-4 (41 mg, 0.1 mmol) was hydrogenated in EtOH (4 mL) at 55 psi in the presence of 10% Pd / C (10 mg). After 4 h, the catalyst was filtered off and the reaction mixture was concentrated under reduced pressure to give Intermediate 15 (34 mg, 92 μmol, 90% yield). 1H NMR(400 MHz, DMSO-d6)δ 10.54(s, 1H), 8.29 - 8.26(m, 1H), 8.07(m, 2H), 7.57 - 7.49(m, 2H), 6.39(s, 2H), 2.72(s, 3H). MS(ESI)m / z 370(M+H) + .

[0189] Intermediate 16-6: 5'-(2-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)-2-oxoethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0190] Intermediate 16-1: Preparation of tert-butyl 2-(3-bromo-4-fluorophenyl)acetate Intermediate 16-1 was prepared by the general method described in Ludwig, J.; Lehr, M. Syn. Comm. 2004, 34, 3691-3695, except that the reaction temperature was maintained at 80° C. for 12 hours. 1 H NMR(500 MHz, CDCl3)δ 7.49(dd, J=6.6, 2.2 Hz, 1H), 7.20(ddd, J=8.3, 4.6, 2.2 Hz, 1H), 7.13 - 7.03(m, 1H), 3.49(s, 2H), 1.46(s, 9H).

[0191] Intermediate 16-2: Preparation of tert-butyl 2-bromo-2-(3-bromo-4-fluorophenyl)acetate To a 20 mL reaction vial containing intermediate 16-1 (266 mg, 0.92 mmol), NBS (0.2 g, 1 mmol), carbon tetrachloride (10 mL), and AIBN (15 mg, 90 mmol) were added. The solution was stirred at 77 °C for 3 h. The solution was concentrated under reduced pressure and purified by normal phase silica gel chromatography to give intermediate 16-2 (0.3 g, 0.8 mmol, 91% yield).1 H NMR(500 MHz, CDCl3) δ 7.79(dd, J=6.5, 2.3 Hz, 1H), 7.55 - 7.46(m, 1H), 7.18 - 7.10(m, 1H), 5.18(s, 1H), 1.50(s, 9H).

[0192] Preparation of Intermediate 16-3: tert-Butyl 2-(3-bromo-4-fluorophenyl)-2-((tert-butoxycarbonyl)amino)acetate To intermediate 16-2 (60 mg, 0.16 mmol) was added ammonia (0.5 mL, 4 mmol, in MeOH). After stirring at room temperature for 12 h, the reaction mixture was concentrated in vacuo. DCM (1 mL) was then added to the residue, followed by BOC anhydride (0.11 mL, 0.49 mmol) and DIEA (57 μL, 0.33 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography to give 16-3 (42 mg, 0.1 mmol, 63% yield). LC-MS RT = 1.14 min; MS (ESI) m / z: 406.0 (M+H). + .[Method A]

[0193] Intermediates 16-5 and 16-6: To a reaction vessel containing intermediate 16-3 (330 mg, 0.816 mmol) was added 5-borono-2-methoxybenzoic acid (208 mg, 1.061 mmol), PdCl2(dppf)-DCM adduct (100 mg, 0.122 mmol) and Na2CO3 (346 mg, 3.27 mmol) in THF (12 mL). The reaction mixture was degassed by bubbling N2 for 10 min, sealed and stirred at 60 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC purification to give intermediate 16-4 (25 mg, 53 mmol, 52% yield). 1H NMR (500 MHz, CDCl3) δ 8.38(d, J=1.9 Hz, 1H), 7.80(dt, J=8.7, 2.0 Hz, 1H), 7.46(dd, J=7.4, 2.5 Hz, 1H), 7.36(dddd, J=8.8, 4.4, 2.2, 1.1 Hz, 1H), 7.19 - 7.13(m, 2H), 5.67(br d, J=5.2 Hz, 1H), 5.25(br d, J=6.3 Hz, 1H), 4.16(s, 3H), 1.46(br s, 9H), 1.44(s, 9H). Intermediate 16-4 was separated into its enantiomers using chiral SFC. Preparative chromatographic conditions: Instrument: Berger MG II; Column: Chiralpak ID, 21 x 250 mm, 5 micron; Mobile phase: 20% MeOH / 80% CO2; Flow conditions: 45 mL / min, 120 Bar, 40°C; Detection wavelength: 209 nm; Injection details: 49 injections in MeOH. Analytical chromatographic conditions: Instrument: Waters UPC2 analytical SFC; Column: Chiralpak IC, 4.6 x 100 mm, 3 micron; Mobile phase: 25% MeOH / 75% CO2; Flow conditions: 2 mL / min, 150 Bar, 40°C; Detection wavelength: 220 nm. Intermediate 16-5: (Peak 1, RT = 4.22 min, 95.7% ee). Intermediate 16-6 (Peak 2, RT = 5.11 min, >99% ee).

[0194] Intermediate 17: Preparation of (S)-5'-(1-((cyclobutylcarbamoyl)oxy)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0195] Preparation of Intermediate 17-1: 1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol 3-Bromo-4-fluorobenzaldehyde (0.2 g, 1 mmol) was dissolved in DMF (3.5 mL) and to this solution was added (trifluoromethyl)trimethylsilane (0.3 mL, 2 mmol) and K2CO3 (8.0 mg, 58 μmol). The reaction mixture was stirred at room temperature for 60 min and HCl (2N, 3 mL) was added. After stirring at room temperature for an additional 1 h, the reaction mixture was diluted with EtOAc (15 mL) and the solution was washed with saturated NH4Cl (25 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL) and the combined organic portions were dried (Na2SO4), concentrated under reduced pressure and the residue was purified by silica gel chromatography using hexane / EtOAc as eluent to give intermediate 17-1 (0.2 g, 0.8 mmol, 70% yield). 1 H NMR(500 MHz, CDCl3) δ 7.74(dd, J=6.5, 2.1 Hz, 1H), 7.43(ddd, J=8.4, 4.8, 2.2 Hz, 1H), 7.19(t, J=8.4 Hz, 1H), 5.11 - 4.98(m, 1H), 2.69(d, J=4.4 Hz, 1H).

[0196] Preparation of Intermediate 17-2: (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethan-1-ol (S)-2-Phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole (0.4 g, 2 mmol) and intermediate 17-1 (11 g, 40 mmol) were dissolved in diisopropyl ether (134 mL) and cooled to 0°C to -20°C. The solution was treated with isobutyl anhydride (4 mL, 20 mmol) and transferred to a freezer (-20°C) for 18 h. The reaction was quenched with MeOH (1 mL) and phosphate buffer. The resulting solution was extracted with EtOAc (2 x 25 mL), dried (MgSO4), and concentrated in vacuo to give a residue that was purified by normal phase chromatography using hexanes / EtOAc as eluent to give intermediate 17-2 (5 g, 20 mmol, 44% yield, >99% ee). 1H NMR(500 MHz, CDCl3) δ 7.74(dd, J=6.3, 1.9 Hz, 1H), 7.50 - 7.39(m, 1H), 7.18(t, J=8.4 Hz, 1H), 6.71 - 5.53(m, 1H), 5.03(q, J=6.5 Hz, 1H).

[0197] Intermediate 17-3: Preparation of (S)-1-(3-bromo-4-fluorophenyl)-2,2,2-trifluoroethyl cyclobutylcarbamate Intermediate 17-2 (0.3 g, 1 mmol), pyridine (0.4 mL, 6 mmol) and DMAP (13 mg, 0.10 mmol) were dissolved in DCM (20 mL) and 4-nitrophenyl carbonochloridate (1 g, 6 mmol) was added. The reaction mixture was stirred for 1 h, after which cyclobutanamine (0.78 g, 11 mmol) was added. After 2 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by normal phase chromatography using hexane / EtOAc as eluent to give 17-3 (0.35 g, 0.90 mmol, 85% yield) as a white solid. MS(ESI) m / z: 371.7 (M+H, Br isotope peaks were seen)+

[0198] Intermediate 17: Preparation of (S)-5'-(1-((cyclobutylcarbamoyl)oxy)-2,2,2-trifluoroethyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid To a vial was added 17-3 (30 mg, 0.080 mmol), 5-borono-2-methoxybenzoic acid (21 mg, 0.10 mmol), PdCl2(dppf)-DCM (9 mg, 0.01 mmol), Na2CO3 (34 mg, 0.32 mmol), THF (1 mL) and H2O (0.25 mL). The reaction mixture was degassed by bubbling N2 for 10 min, sealed and stirred at 65 °C for 3 h. After cooling to room temperature, the reaction was quenched with HCl (1N) and extracted with EtOAc (2 x 25 mL). The combined organic portions were dried (Na2SO4), concentrated under reduced pressure, and purified by reverse-phase chromatography using a gradient of Solvent A: 20% ACN-80% HO-0.1% TFA; Solvent B: 80% ACN-20% HO-0.1% TFA to give Intermediate 17 (24 mg, 0.050 mmol, 66% yield). 1 H NMR(400 MHz, CDCl3) δ 8.39(d, J=1.5 Hz, 1H), 7.83(br d, J=8.6 Hz, 1H), 7.56(br d, J=6.4 Hz, 1H), 7.45(br s, 1H), 7.25 - 7.10(m, 2H), 7.02 - 6.44(m, 1H), 6.10(q, J=6.5 Hz, 1H), 5.26(br d, J=7.5 Hz, 1H), 4.17(s, 3H), 2.54 - 2.25(m, 2H), 2.08 - 1.88(m, 2H), 1.83 - 1.46(m, 2H) MS(ESI)m / z:442.0(M+H) + .

[0199] Intermediate 18: Preparation of 6-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzo[d]thiazole-5-carboxamide [ka] Intermediate 18 (33 mg, 93 μmol, 80% yield) was prepared in a similar manner to intermediate 15, substituting methyl 2-methylbenzo[d]thiazole-5-carboxylate with methylbenzo[d]thiazole-5-carboxylate. 1 H NMR(400 MHz, CDCl3) δ 8.72(s, 1H), 8.61 - 8.47(m, 1H), 8.30(s, 1H), 8.00(dd, J=6.2, 2.6 Hz, 1H), 7.82(dt, J=8.6, 3.5 Hz, 1H), 7.24(s, 1H), 7.20(s, 1H), 5.55(s, 2H). MS(ESI) m / z:356.2(M+H) + .

[0200] Intermediate 19: Preparation of 5-amino-N-cyclopentyl-2-methylbenzo[d]thiazole-6-carboxamide [ka] Intermediate 19 (51 mg, 190 μmol, 73% yield) was prepared in a similar manner to intermediate 1, substituting 4-fluoro-3-(trifluoromethyl)aniline with cyclopentanamine. 1 H NMR(500 MHz, CDCl3) δ 7.86 - 7.69(m, 1H), 7.23(s, 1H), 5.42 - 5.34(m, 2H), 4.45 - 4.34(m, 1H), 2.80(s, 3H), 2.16 - 2.08(m, MS(ESI)m / z:276(M+H) + .

[0201] Intermediate 20: Preparation of 6-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(trifluoromethyl)benzo[d]thiazole-5-carboxamide [ka]

[0202] Intermediate 20-1: Preparation of dimethyl 4,4'-disulfanediylbis(3-aminobenzoate) Benzo[d]thiazole-5-carboxylic acid (1 g, 5.58 mmol) and NaOH (0.67 g, 17 mmol) in ethylene glycol (25 mL) and water (25 mL) were heated to 140° C. for 4 h. The reaction mixture was cooled to room temperature and partitioned with water (20 mL) and EtOAc (50 mL). The pH of the aqueous layer was adjusted to 4 with HCl and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO4). The organic layer was concentrated in vacuo and to the collected solid in MeOH (50 mL) was added thionyl chloride (0.4 mL, 6 mmol) and the reaction mixture was heated to 60° C. for 24 h. The reaction mixture was cooled and triturated with DCM and hexanes and the solid was filtered. The solid was treated with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM / 0-10% MeOH to give intermediate 20-1 (0.9 g, 2.5 mmol, 32% yield) as a light yellow solid, which was used without further purification. MS (ESI) m / z: 365.2 (M+H). + .

[0203] Intermediate 20-2: Preparation of methyl 2-(trifluoromethyl)benzo[d]thiazole-5-carboxylate (Du, G. et.al. Het. 2015, 9, 1723) To intermediate 20-1 (0.28 g, 0.77 mmol) in toluene (4 mL) was added TFA (0.6 mL, 8 mmol), PCl3 (3.8 mL, 7.7 mmol), and the reaction mixture was heated at 100° C. for 2 h and then stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography eluting with hexane / EtOAc to give intermediate 20-2 (0.2 g, 0.8 mmol, 100% yield) as a white solid. 1 H NMR(400 MHz, CDCl3)δ 8.91(d, J=1.3 Hz, 1H), 8.27(dd, J=8.6, 1.5 Hz, 1H), 8.09(d, J=8.6 Hz, 1H), 4.04(s, 3H). MS(ESI)m / z:262.1(M+H) + .

[0204] Intermediate 20-3: Preparation of methyl 6-nitro-2-(trifluoromethyl)benzo[d]thiazole-5-carboxylate Intermediate 20-3 (98 mg, 0.32 mmol, 42% yield) was prepared in a similar manner to 15-1, substituting methyl 2-methylbenzo[d]thiazole-5-carboxylate with 20-2. For 20-4: 1 H NMR(600 MHz, CDCl3) d 8.25(d, J=8.6 Hz, 1H), 8.20(d, J=8.6 Hz, 1 H), 3.99(s, 3H). MS(ESI)m / z:307.0(M+H) + The material thus obtained also contained the regioisomer 20-4 (30 mg, 0.1 mmol, 26% yield).

[0205] Preparation of Intermediate 20-5 and 20-6: Methyl 6-amino-2-(trifluoromethyl)benzo[d]thiazole-5-carboxylate and Methyl 7-amino-2-(trifluoromethyl)benzo[d]thiazole-5-carboxylate Intermediates 20-3 and 20-4 (98 mg, 0.32 mmol) were hydrogenated in the presence of 10% Pd / C (15 mg) at 55 psi for 5 h. The reaction mixture was filtered to give a yellow film containing 20-5 and 20-6 (80 mg, 0.29 mmol, 90% yield), which was used without purification. MS (ESI) m / z: 277.1 (M+H). + .

[0206] Intermediate 20 (24 mg, 0.056 mmol, 77% yield) was prepared in the same general manner as 1-3, substituting intermediates 20-5 and 20-6 for 1-2. This material was purified by reverse phase HPLC. 1 H NMR (400 MHz, CDCl3) δ 8.33(s, 1H), 8.05 - 7.93(m, 2H), 7.78(dt, J=9.1, 3.5 Hz, 1H), 7.29 - 7.24(m, 1H), 7.22(s, 1H). No protons seen in NMR, probably due to overlap with solvent peaks. MS(ESI) m / z: 424.2(M+H). + .

[0207] Intermediate 21: Preparation of 5-(4-(((tert-butoxycarbonyl)amino)methyl)-2-oxopyrrolidin-1-yl)-2-methoxybenzoic acid [ka] Intermediate 21 (0.17 g, 0.46 mmol, 81% yield) was prepared in a similar manner to intermediate 13, substituting tert-butyl ((5-oxopyrrolidin-2-yl)methyl)carbamate for 4-(hydroxymethyl)pyrrolidinone, and was used without further purification. MS (ESI) m / z: 309.3 (M+H-tBu).

[0208] Intermediate 22: Preparation of 5-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-methylbenzo[d]isoxazole-6-carboxamide [ka]

[0209] Intermediate 22-1: Preparation of (Z)-1-(4-bromo-2-hydroxyphenyl)ethan-1-one oxime To a solution of 1-(4-bromo-2-hydroxyphenyl)ethan-1-one (6 g, 30 mmol) in EtOH (8 mL) and water (2 mL) was added hydroxylamine hydrochloride (5.8 g, 84 mmol) and sodium acetate (3.4 g, 42 mmol). The reaction mixture was then refluxed under inert atmosphere for 2 h and then cooled to room temperature. The solvent was concentrated under vacuum to give a residue which was subjected to silica gel column chromatography using hexane and EtOAc as eluents to give 22-1 (6.0 g, 93% yield). MS(ESI)m / z:229.9(M+H) + .

[0210] Preparation of Intermediate 22-2: 6-Bromo-3-methylbenzo[d]isoxazole To a mixture of 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (11.8 g, 52.0 mmol) and triphenylphosphine (13.7 g, 52.0 mmol) in dry DCM (100 mL) was added 22-1 (6 g, 30 mmol) at room temperature and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was subjected to silica gel column chromatography using hexane and EtOAc as eluents to give intermediate 22-2 (2.0 g, 58% yield). MS (ESI) m / z: 211.9 (M+H) + .

[0211] Preparation of Intermediate 22-3: 6-Bromo-3-methyl-5-nitrobenzo[d]isoxazole Intermediate 22-2 (1.4 g, 6.6 mmol) was added to sulfuric acid (0.53 ml, 9.9 mmol) pre-cooled at 0° C., and the reaction mixture was stirred for 10 min. Nitric acid (0.4 ml, 10 mmol) was added to the reaction mixture, and the reaction mixture was stirred for 2 h. The reaction mixture was then poured onto crushed ice to form a precipitate, which was extracted with EtOAc (20 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under vacuum to give a residue, which was subjected to silica gel column chromatography using hexane and EtOAc as eluents to give intermediate 22-3 (1.3 g, 77% yield). MS (ESI) m / z: 359.3 (M+2H)+.

[0212] Preparation of Intermediate 22-4: 6-Bromo-3-methylbenzo[d]isoxazol-5-amine To a stirred solution of intermediate 22-3 (500 mg, 1.9 mmol) in EtOH (3 mL) was added a solution of ammonium chloride (312 mg, 5.80 mmol) in water (3 mL). The reaction mixture was then heated to 50° C. and iron (543 mg, 9.70 mmol) was added. The reaction temperature was then increased to 80° C. and the reaction mixture was stirred for 14 h. The reaction mixture was cooled to rt and then filtered through Celite® and washed with EtOAc. The solution was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20 mL) and washed with water (20 mL). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography using hexane and EtOAc as eluents to give intermediate 22-4 (400 mg, 91% yield). MS (ESI) m / z: 227.0 (M+H) + .

[0213] Intermediate 22-5: Preparation of methyl 5-amino-3-methylbenzo[d]isoxazole-6-carboxylate A solution of intermediate 22-4 (1.1g, 4.8 mmol) in MeOH (100 mL) was added to the reactor, followed by DMF (100 mL). The reaction mixture was purged with nitrogen gas, followed by the addition of diacetoxypalladium (0.22 g, 0.97 mmol), dppf (0.8g, 1 mmol) and TEA (10.1 mL, 73.0 mmol). The reaction mixture was purged with nitrogen gas, followed by stirring at 100° C. for 18 h under carbon monoxide atmosphere. The reaction mixture was then cooled to room temperature and concentrated under vacuum to give a residue which was subjected to silica gel chromatography using hexanes and EtOAc as eluents to give intermediate 22-5 (700 mg, 70% yield). MS (ESI) m / z: 207.1 (M+H) + .

[0214] Intermediate 22: To a stirred solution of intermediate 22-5 (50 mg, 0.24 mmol) in THF (2 mL), bis(trimethylaluminum)-1,4-diazabicyclo[2,2,2]octane adduct (62 mg, 0.24 mmol) was added and the reaction mixture was stirred for 10 min. Then, 4-fluoro-3-(trifluoromethyl)aniline (0.03 mL, 0.24 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. To this mixture, a saturated solution of sodium potassium tartrate was added and the solution was stirred for 10 min and then extracted with EtOAc (5 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give a residue that was purified by silica gel chromatography to give intermediate 22 (60 mg, 70% yield). MS(ESI)m / z: 354.1(M+H) + .

[0215] Intermediate 23: Preparation of 5'-(tert-butoxycarbonyl)-2'-fluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0216] Intermediate 23: To the vial was added 5-borono-2-methoxybenzoic acid (500 mg, 2.55 mmol), tert-butyl 3-bromo-4-fluorobenzoate (842 mg, 3.06 mmol), tert-butyl 3-bromo-4-fluorobenzoate (842 mg, 3.06 mmol), K2CO3 (1.76 g, 12.8 mmol), PdCl2(dppf)-CH2Cl2 adduct (313 mg, 0.380 mmol) and THF (22 mL). The reaction mixture was degassed with nitrogen for 2 min and then heated at 80 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with 1N hydrochloric acid (25 mL) and the solution was extracted with EtOAc (3 x 25 mL). The combined organic portions were dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was dissolved in DMF and purified by preparative RP-HPLC to give Intermediate 23 (586 mg, 1.69 mmol, 66% yield). 1 H NMR(500 MHz, DMSO-d6) δ 12.78(br s, 1H), 7.98(dd, J=7.7, 2.2 Hz, 1H), 7.93(ddd, J=8.5, 4.8, 2.3 Hz, 1H), 7.84 - 7.79(m, 1H), 7.73(dt, J=8.7, 1.7 Hz, 1H), 7.45(dd, J=10.5, 8.5 Hz, 1H), 7.28(d, J=8.8 Hz, 1H), 3.89(s, 3H), 1.57(s, 9H);MS(ESI)m / z:347.1(M+H) + .

[0217] Intermediate 24: Preparation of 6-amino-2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide [ka]

[0218] Preparation of Intermediate 24-1: 6-Bromo-2,2-difluorobenzo[d][1,3]dioxol-5-amine To a stirred suspension of 5-amino-2,2-difluoro-1,3-benzodioxole (9.4 g, 54 mmol) in DMF (100 mL) was added NBS (10.63 g, 59.70 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown gum, which was subjected to silica gel chromatography to give 24-1 (11.3 g, 43.9 mmol, 81% yield). MS (E - ) m / z = 252.2 (M+2H) + .

[0219] Intermediate 24-2: Preparation of methyl 6-amino-2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate To a degassed solution of 24-1 (5.5 g, 22 mmol) in MeOH (120 mL) and DMF (120 mL) was added TEA (30.4 mL, 218 mmol), palladium(II) acetate (1.47 g, 6.55 mmol) and dppf (4.84 g, 8.73 mmol). The reaction mixture was then stirred at 100° C. for 16 h under an atmosphere of carbon monoxide gas. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc (40 mL) and water (40 mL). The organic layer was further washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown gum which was subjected to silica gel chromatography using hexanes and EtOAc as eluents to give 24-2 (4.0 g, 17 mmol, 78% yield). MS (E-) m / z = 232.2 (M+H) + .

[0220] Intermediate 24: To a solution of 24-2 (1.7 g, 7.4 mmol) in toluene (20 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (1.32 g, 7.35 mmol) and bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (1.89 g, 7.35 mmol). The reaction mixture was then heated at 100° C. for 8 h. The reaction mixture was cooled and concentrated under vacuum, and the resulting residue was dissolved in saturated ammonium chloride (25 mL), EtOAc (25 mL) and 0.5 N aqueous hydrochloric acid (15 mL) and stirred for 5 h. The organic layer was further washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown gum which was subjected to silica gel chromatography using hexanes and EtOAc as eluents to give Intermediate 24 (1.1 g, 2.8 mmol, 38% yield). MS (ESI) m / z: 379.1 (M+H) + .

[0221] Intermediate 25: Preparation of 5-(5-(tert-butoxycarbonyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzoic acid [ka]

[0222] Preparation of Intermediate 25-1: tert-Butyl 3-(4-methoxy-3-(methoxycarbonyl)phenyl)-3a,4,6,6a-tetrahydro-5H-pyrrolo[3,4-d]isoxazole-5-carboxylate 25-1 (500 mg, 46% yield) was prepared in a similar manner to intermediate 3-3, substituting tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate for 2,5-dihydrofuran. MS(ESI) m / z: 277.1 (M+H-Boc).

[0223] Intermediate 25: To a solution of 25-1 (2.1 g, 5.6 mmol) in MeOH (20 mL) was added 2N aqueous LiOH (0.40 g, 17 mmol) at 0° C. and the reaction mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo, acidified to pH 4 with 1.5 N HCl, and the solid was collected by filtration and dried under high vacuum to give intermediate 25 (1.7 g, 4.7 mmol, 84% yield). MS(ESI) m / z: 361.2(M+H). + .

[0224] Intermediate 26: Preparation of 5-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methoxybenzoic acid [ka] Preparation of Intermediate 26-1: tert-butyl 3-(4-methoxy-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate To a degassed solution of methyl 5-bromo-2-methoxybenzoate (2 g, 8 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2.65 g, 8.98 mmol) in dioxane and water was added PdCl2(dppf)-DCM adduct (0.66 g, 0.80 mmol) and potassium phosphate tribasic monohydrate (5.64 g, 25.0 mmol). The reaction mixture was stirred at 100° C. for 4 h in a sealed tube. The reaction mixture was cooled to room temperature and diluted with EtOAc (25 mL). The organic layer was then washed with brine (20 mL) and dried over sodium sulfate to give a residue which was subjected to silica gel chromatography using 25-35% EtOAc / petroleum ether to give 26-1 (2.2 g, 6.6 mmol, 81% yield). MS(E-) m / z = 278.1(M+H-tBu).

[0225] Preparation of Intermediate 26-2: tert-butyl 3-(4-methoxy-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate To a degassed solution of 26-1 (2.2 g, 6.6 mmol) in MeOH (100 mL), Pd-C (1.7 g, 16.5 mmol) was added and stirred at room temperature under a hydrogen balloon for 12 h. The reaction mixture was then filtered over a pad of Celite® and washed with excess MeOH. The combined layers were concentrated in vacuo to give 26-2 (1.7 g, 5.0 mmol, 77% yield). MS (E-) m / z = 280.2 (M+H-tBu).

[0226] Intermediate 26: To a solution of 26-2 (2.0 g, 5.96 mmol) in MeOH (10 mL) and THF (10 mL) was added a solution of LiOH (1.43 g, 59.6 mmol) / HO (5 mL). The reaction mixture was stirred for 5 h, then concentrated in vacuo and acidified with hydrochloric acid. The precipitated solid was then collected by filtration and dried under vacuum to give intermediate 26 (1.5 g, 4.7 mmol, 78% yield). MS (ESI) m / z: 320.2(MH). - .

[0227] Intermediate 27: Preparation of 5-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methoxybenzoic acid [ka]

[0228] Preparation of Intermediate 27-1: Methyl 5-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methoxybenzoate A slurry of methyl 5-bromo-2-methoxybenzoate (1.7 g, 6.9 mmol), 2-methylbut-3-yn-2-ol (0.58 g, 6.9 mmol), Pd(Ph3p)4 (401 mg, 0.350 mmol) and CuI (13 mg, 0.070 mmol) in TEA (15 mL) was degassed, backfilled under nitrogen and heated at 80° C. for 14 h. The reaction mixture was dissolved in water (20 mL) and the solution was extracted with EtOAc (20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was subjected to silica gel chromatography with hexane and EtOAc to give intermediate 27-1 (1.2 g, 4.83 mmol, 70% yield). MS(ESI) m / z: 248.9 (M+H) + .

[0229] Intermediate 27: To a solution of intermediate 27-1 (158 mg, 0.640 mmol) in THF (4.8 mL) and water (1.5 mL), LiOH (27 mg, 0.64 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was then concentrated and acidified with 1N hydrochloric acid. The residue was then extracted with EtOAc (6 mL) and concentrated under reduced pressure to give intermediate 27 (149 mg, 0.64 mmol, 100% yield). MS(ESI)m / z: 248.9(M+H) + .

[0230] Intermediate 28: Preparation of 5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-methoxybenzoic acid [ka]

[0231] Preparation of Intermediate 28-1: tert-Butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate To a slurry of CuBr2 (297 mg, 1.33 mmol) in anhydrous ACN (3 mL) was added tert-butyl nitrate (0.181 mL, 1.371 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature for 10 minutes. A suspension of tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (200 mg, 0.78 mmol) in anhydrous ACN (4 mL) was added dropwise. The reaction mixture was again stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, the residue was diluted with EtOAc (8 mL) and 1N HCl was added. The organic layer was collected and washed with 0.5 N HCl (2X), saturated NaHCO3, brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was dissolved in chloroform and purified by silica gel chromatography using hexanes and EtOAc as eluents to give 28-1 (85 mg, 0.26 mmol, 34% yield). 1 H NMR(500MHz, CD3CN) δ 4.56(t, J=1.8 Hz, 2H), 3.70(t, J=5.8 Hz, 2H), 2.81 - 2.76(m, 2H), 1.47(s, 9H).

[0232] Intermediate 28: Intermediate 30 was prepared in a similar manner to Intermediate 26-1, substituting Intermediate 28-1 for methyl 5-bromo-2-methoxybenzoate to give Intermediate 28 (750 mg, 1.92 mmol, 38% yield). MS(ESI) m / z: 391.3(M+H). + .

[0233] Preparation of Intermediate 29: 5-(7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2-methoxybenzoic acid [ka]

[0234] Preparation of Intermediate 29-1: tert-Butyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate A round bottom flask was charged with tert-butyl 3-oxopiperazine-1-carboxylate (5.06 g, 25.3 mmol), DCM (10 mL), mesitylene (10 mL) and tin(IV) chloride (0.89 mL, 7.6 mmol). The reaction mixture was refluxed and then aminoacetaldehyde diethyl acetal (7.4 mL, 51 mmol) was added slowly. The reaction mixture was heated at reflux for 84 h and then cooled to room temperature. The reaction mixture was diluted with DCM (50 mL) and filtered through activated charcoal. The filtrate was concentrated under vacuum and subjected to silica gel chromatography using EtOAc and MeOH as eluents to give 29-1 (0.768 g, 3.44 mmol, 14% yield). MS(ESI)m / z:224.1(M+H) + .

[0235] Preparation of Intermediate 29-2: tert-Butyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate A round-bottom flask was charged with intermediate 29-1 (768 mg, 3.44 mmol), N-bromosuccinimide (612 mg, 3.44 mmol) and CCl4 (10 mL). The reaction mixture was heated to reflux for 30 min and cooled to room temperature. The organic layer was concentrated under vacuum and the residue was subjected to silica gel chromatography using hexanes and EtOAc as eluents to give 29-2 (513 mg, 1.70 mmol, 49% yield).

[0236] Intermediate 29: Intermediate 29 was prepared in the same manner as Intermediate 26-1, substituting Intermediate 29-2 for methyl 5-bromo-2-methoxybenzoate to give Intermediate 29 (350 mg, 0.94 mmol, 37% yield). MS (ESI) m / z: (M+H) + .

[0237] Intermediate 30: Preparation of 2-methoxy-5-((oxetan-3-yloxy)methyl)benzoic acid [ka] To a solution of methyl 5-(bromomethyl)-2-methoxybenzoate (20 mg, 0.080 mmol) and oxetan-3-ol (17 mg, 0.23 mmol) in DMSO (1 mL) was added KOH (13 mg, 0.23 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then acidified with 1N HCl and extracted with EtOH (4 mL). The organic layer was concentrated under vacuum to give intermediate 30, which was used without further purification (90 mg, 0.37 mmol, 98% yield). MS(ESI)m / z:237.2(M+H) + .

[0238] Intermediate 31: Preparation of 2-methoxy-5-(3-morpholino-1,2,4-oxadiazol-5-yl)benzoic acid [ka]

[0239] Intermediate 31-1: Preparation of morpholine-4-carbonitrile To a stirred solution of morpholine (2 mL, 20 mmol) in CHCl3 (20 mL) was added cyanogen bromide (2.92 g, 27.5 mmol) followed by TEA (6.4 mL, 46 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then concentrated in vacuo and diluted with water. The aqueous layer was extracted with EtOAc (30 mL) and the organic layer was concentrated in vacuo to give 31-1, which was used without further purification (2.44 g, 21.8 mmol, 95% yield). MS(ESI) m / z: 130.2 (M+18).

[0240] Intermediate 31-2: Preparation of N-hydroxymorpholine-4-carboximidamide To a 50 mL round bottom flask was added 31-1 (250 mg, 2.23 mmol), followed by EtOH (20 mL) and hydroxylamine (295 mg, 4.46 mmol) (50% solution in water). The reaction mixture was then heated to reflux for 3 h. The cooled reaction mixture was concentrated in vacuo to give 31-2, which was used without further purification (341 mg, 2.23 mmol, 100% yield). 1 H NMR(400MHz, DMSO-d6) δ 8.33(s, 1H), 5.18(s, 2H), 3.63 - 3.54(m, 4H), 2.97 - 2.89(m, 4H).

[0241] Intermediate 31-3: Preparation of methyl 2-methoxy-5-(3-morpholino-1,2,4-oxadiazol-5-yl)benzoate To a stirred solution of 4-methoxy-3-(methoxycarbonyl)benzoic acid (250 mg, 1.19 mmol) in DMF (5 mL) was added intermediate 31-2 (207 mg, 1.43 mmol), followed by BOP (1.05 g, 2.38 mmol) and TEA (0.5 mL, 4 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (6 mL). The organic layer was then purified by silica gel chromatography using hexanes and EtOAc as eluents to give 31-3 (300 mg, 0.94 mmol, 79% yield). LCMS (ESI) m / z 320.3 (M+H) + .

[0242] Intermediate 31: Preparation of 2-methoxy-5-(3-morpholino-1,2,4-oxadiazol-5-yl)benzoic acid Intermediate 31 (160 mg, 0.52 mmol, 80% yield) was prepared in the same general manner as described above using the LiOH hydrolysis protocol as described for Intermediate 27. MS (ESI) m / z: 306.2 (M+H). + .

[0243] Intermediate 32: Preparation of (S)-5-((3-(hydroxymethyl)morpholino)sulfonyl)-2-methoxybenzoic acid [ka]

[0244] Preparation of Intermediate 32-1: 5-(chlorosulfonyl)-2-methoxybenzoic acid 2-Methoxybenzoic acid (5 g, 30 mmol) was dissolved in chlorosulfonic acid (11 mL, 160 mmol) at 0° C. The reaction mixture was heated to 50° C. for 1 h and then poured into ice-cold water. The formed precipitate was collected by filtration to give intermediate 32-1, which was used without further purification (3.42 g, 41.0% yield). 1 H NMR(500 MHz, CDCl3) δ 8.81(d, J=2.6 Hz, 1H), 8.25(dd, J=8.9, 2.7 Hz, 1H), 7.28(s, 1H), 4.20(s, 3H).

[0245] Intermediate 32: Preparation of (S)-5-((3-(hydroxymethyl)morpholino)sulfonyl)-2-methoxybenzoic acid To a solution of intermediate 32-1 (50 mg, 0.20 mmol) in DCM (2.5 mL) at 0° C. was added (S)-morpholin-3-ylmethanol (24 mg, 0.20 mmol) followed by TEA (0.11 mL, 0.80 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give intermediate 32, which was used without further purification (66 mg, 100% yield). MS (ESI) m / z: 332.6 (M+H). + .

[0246] Example 2: Preparation of N-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-methoxy-5-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzamido)-2-methylbenzo[d]thiazole-6-carboxamide [ka] To a mixture of intermediate 1 (2.53 mg, 6.84 μmol), intermediate 3-6 (1.8 mg, 6.84 μmol) and TCFH (1.9 mg, 6.84 μmol), ACN (1 mL) and 1-methyl-1H-imidazole (0.5 mg, 6.84 μmol) were added. After 24 hours, the reaction mixture was purified by reverse phase HPLC [5:95 ACN, water (with 0.05% TFA) to 95:5 ACN, water (with 0.05% TFA)] to give Example 2 (2.6 mg, 4.2 μmol, 62% yield). 1 H NMR(500 MHz, DMSO-d6) δ 11.73 - 11.50(m, 1H), 11.02(s, 1H), 9.08(s, 1H), 8.51(s, 1H), 8.38 - 8.29(m, 1H), 8.11 - 8.02(m, 1H), 7.91 - 7.83(m, 1H), 7.57(br t, J=9.8 Hz, 1H), 7.33(br d, J=8.9 Hz, 1H), 5.41 - 5.33(m, 1H), 4.55(br d, J=8.1 Hz, 1H), 4.11(br d, J=10.8 Hz, 1H), 4.06(s, 3H), 3.94 - 3.86(m, 1H), 3.83 - 3.77(m, 1H), 3.68 - 3.65(m, 1H), 3.17(d, J=5.2 Hz, 1H), 2.86(s, 3H);MS(ESI)m / z:615.1(M+H) + ;HPLC purity 100%, retention time 2.2 minutes. [Method B].

[0247] The compounds listed in Table 1 are compounds of the present invention that have been prepared, purified and isolated according to the methods described above. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0248] Example 30: Preparation of 2-(6-fluoro-3'-((5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylbenzo[d]thiazol-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)acetic acid [ka]

[0249] Example 30 To intermediate 15 (34 mg, 92 μmol) and intermediate 16-6 (44 mg, 92 μmol) in ACN (2 mL) was added DIEA (0.4 mL, 2.1 mmol) followed by HATU (42 mg, 0.11 mmol). After 24 h, the reaction mixture was purified by reverse phase HPLC. MS(ESI)m / z:827.2(M+H) +The solvent was removed and the residue was partially deprotected using HCl (4N / EtOAc) to give 2-amino-2-(6-fluoro-3'-((5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylbenzo[d]thiazol-6-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)acetic acid. The resulting intermediate residue was dissolved in DCM (1 mL) followed by the addition of DIEA (0.4 ml, 2.1 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (14 mg, 92 μmol) and stirring for 15 min. The solvent was removed under vacuum and the residue was treated with 50% TFA / DCM (1 mL). After 1 h, the solvent was removed in vacuum and the residue was purified by reverse phase HPLC to give Example 30 (2.6 mg, 3% yield). 1 H NMR(500 MHz, DMSO-d6) δ 11.76(s, 1H), 11.07(s, 1H), 9.20(s, 1H), 8.67(br d, J=7.8 Hz, 1H), 8.38(s, 2H), 8.23(s, 1H), 8.14 - 8.00(m, 1H), 7.77(br d, J=8.6 Hz, 1H), 7.62 - 7.53(m, 2H), 7.47 - 7.22(m, 3H), 5.41(d, J=7.5 Hz, 1H), 4.07(s, 3H), 3.92 - 3.77(m, 2H), 3.73 - 3.61(m, MS(ESI)m / z 804.87(M+H) + ;HPLC purity 86%. Analytical LC-MS: 2.12 min. [Method C]

[0250] Example 31: Preparation of 6-fluoro-3'-((6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-3-methylbenzo[d]isoxazol-5-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid [ka] To a stirred solution of intermediate 22 (100 mg, 0.28 mmol) and intermediate 23 (98 mg, 0.28 mmol) in ACN (2 mL) was added 1-methylimidazole (23 mg, 0.28 mmol) followed by N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (79 mg, 0.28 mmol) and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and purified using silica gel chromatography to give tert-butyl 6-fluoro-3'-((6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-3-methylbenzo[d]isoxazol-5-yl)carbamoyl)-4'-methoxy-[1,1'-biphenyl]-3-carboxylate, which was treated with TFA at 0° C. and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo to give a residue which was subjected to PREP HPLC to give Example 31 (16 mg, 14% yield). 1H NMR(400MHz, DMSO-d6) δ 11.69 - 11.57(m, 1H), 10.99 - 10.87(m, 1H), 8.82 - 8.73(m, 1H), 8.38 - 8.29(m, 1H), 8.26 - 8.21(m, 1H), 8.19 - 8.14(m, 1H), 8.11 - 8.02(m, 2H), 8.01 - 7.92(m, 1H), 7.85 - 7.77(m, 1H), 7.60 - 7.56(m, 1H), 7.48 - 7.41(m, 1H), 7.39 - 7.35(m, 1H), 4.10 - 4.02(m, 3H), 2.70 - 2.64(m, 3H), 2.72 - 2.63(m, 3H);MS(ESI)m / z:626.0(M+H) + ;HPLC RT = 2.24 min. [Method D]

[0251] Examples 32-34 were prepared using the general method described in Example 31. [Table 12]

[0252] Example 35: Preparation of N3-(2,2-difluoro-6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)-4-methoxy-N1-((1-(methylsulfonyl)cyclopropyl)methyl)isophthalamide [ka] Example 35-1: Preparation of tert-butyl 3-((2,2-difluoro-6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)carbamoyl)-4-methoxybenzoate To a solution of intermediate 24 (250 mg, 0.66 mmol), 5-(tert-butoxycarbonyl)-2-methoxybenzoic acid (333 mg, 1.32 mmol) in ACN (40 mL) at 0° C., chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (556 mg, 1.98 mmol) and 1-methylimidazole (326 mg, 3.97 mmol) were added and stirred at room temperature for 14 h. The reaction mixture was diluted with EtOAc (6 mL), washed with brine (6 mL) and dried over sodium sulfate. The solution was concentrated under vacuum and purified by silica gel chromatography using hexanes and EtOAc as eluents to give Example 35-1 (280 mg, 0.46 mmol, 69% yield). MS (ESI) m / z: 611.3(MH) - .

[0253] Example 35-2: Preparation of 3-((2,2-difluoro-6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)carbamoyl)-4-methoxybenzoic acid To a solution of Example 35-1 (280 mg, 0.46 mmol) in DCM (8 mL) was added TFA (1 mL, 10 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 4 h. The solution was concentrated under vacuum, and the residue was triturated with diethyl ether to produce a solid, which was dried to give Example 35-2 (210 mg, 0.37 mmol, 83% yield), which was used without further purification. MS (ESI) m / z: 555.2 (MH). - .

[0254] Example 35: To a solution of Example 35-2 (15 mg, 0.03 mmol), (1-(methylsulfonyl)cyclopropyl)methanamine hydrochloride (6 mg, 0.03 mmol) in DMF (2 mL), TEA (0.01 mL, 0.08 mmol) and HATU (12 mg, 0.03 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated in vacuo and subjected to PREP HPLC purification to give Example 35 (10 mg, 0.020 mmol, 53% yield). 1H NMR(400MHz, DMSO-d6) δ 11.79(s, 1H), 10.86(s, 1H), 8.75(t, J=6.0 Hz, 1H), 8.63 - 8.52(m, 2H), 8.30(dd, J=2.6, 6.5 Hz, 1H), 8.07(dd, J=2.4, 8.8Hz, 1H), 8.04 - 7.89(m, 2H), 7.56(t, J=9.7 Hz, 1H), 7.33(d, J=8.8 Hz, 1H), 4.06(s, 3H), 3.83(d, J=6.1 Hz, 2H), 3.07(s, 3H), 1.29 - 1.19(m, 2H), 1.18 -1.08(m, 2H);MS (ESI) m / z:688.2(M+H) + ;HPLC RT = 2.18 min. [Method E]

[0255] Examples 36-42 were prepared using the general method described in Example 35. [Table 13] [Table 14]

[0256] Example 43: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-methoxy-5-(3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)benzamide)benzo[d][1,3]dioxole-5-carboxamide [ka]

[0257] Example 43-1: Preparation of tert-butyl 3-(3-((2,2-difluoro-6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)carbamoyl)-4-methoxyphenyl)-3a,4,6,6a-tetrahydro-5H-pyrrolo[3,4-d]isoxazole-5-carboxylate To a solution of intermediate 24 (400 mg, 1.06 mmol) and intermediate 25 (575 mg, 1.58 mmol) in ACN (25 mL) at 0° C., chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (890 mg, 3.17 mmol) and 1-methylimidazole (521 mg, 6.35 mmol) were added. The reaction mixture was stirred at room temperature for 14 h and then concentrated in vacuo to give a residue which was chromatographed on silica gel using 40-50% EtOAc / petroleum ether to give example 43-1 (450 mg, 0.6 mmol, 59% yield). The isomers were separated by SFC and example 43-1 was peak-2 (RT = 6.1 min, >95% ee). Instrument: PIC Solution, Prep SFC; Column: Whelk (R,R) 250 x 30 mm, 5 micron; Mobile phase: 40% 0.2% methanolic ammonia / MeOH with 60% CO2; Flow conditions: 100 g / min; Back pressure: 100 bar; Temperature: 35°C; Detection wavelength: 272 nm; Analytical method: Column: Whelk (R,R) 250 x 4.6 mm, 5 micron; Mobile phase: 40% 0.2% methanolic ammonia / MeOH with 60% CO2; Flow conditions: 4.0 g / min; Back pressure: 100 bar; Temperature: 35°C; Detection wavelength: 272 nm gave peak-1 (RT = 5.2 min., >95% ee) and peak-2 (RT = 6.1 min., >95% ee). SFC purification gave peak-1 of Example 43-1 (140 mg, 0.19 mmol, 18% yield) and peak-2 of Example 43-1 (150 mg, 0.21 mmol, 20% yield). MS (ESI) m / z: 721.3 (MH) - .

[0258] Example 43: To a solution of Peak-2 (130 mg, 0.18 mmol) from Example 43-1 in DCM (10 mL) at 0° C. was added TFA (0.28 mL, 3.6 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure and the residue was subjected to reverse phase HPLC purification using a Waters XBridge C18 column, 19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 21-65% B over 25 min, then hold at 100% B for 5 min; flow rate: 15 mL / min to give Example 43 (15 mg, 0.020 mmol, 13% yield). 1 H NMR(400 MHz, DMSO-d6) δ 11.77(s, 1H), 10.87(s, 1H), 8.57(s, 1H), 8.34 - 8.25(m, 2H), 8.06 - 7.98(m, 1H), 7.96(s, 1H), 7.86(dd, J=8.7, 2.3 Hz, 1H), 7.57(t, J=9.8 Hz, 1H), 7.32(d, J=8.8 Hz, 1H), 5.26 - 5.18(m, 1H), 4.30 - 4.23(m, 1H), 4.05(s, 3H), 3.21 - 3.16(m, 1H), 3.04 - 2.88(m, 2H), 2.83 - 2.74(m, 1H). MS(ESI)m / z:623.2(M+H) + ;HPLC RT = 2.3 min. [Method E].

[0259] Example 44: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(5-(5-(2-hydroxyacetyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzamido)benzo[d][1,3]dioxole-5-carboxamide [ka] To a solution of Example 43 (20 mg, 0.03 mmol) and 2-hydroxyacetic acid (2.5 mg, 0.03 mmol) in DMF (2 mL) was added HATU (12 mg, 0.03 mmol) and TEA (0.02 mL, 0.16 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under vacuum and the residue was subjected to reverse phase HPLC purification using a Waters XBridge C18 column (19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 15-65% B over 25 min, then hold at 100% B for 5 min, flow rate of 15 mL / min) to give Example 44 (8 mg, 0.01 mmol, 40% yield). 1 H NMR(400 MHz, DMSO-d6)δ 11.77(br s, 1H), 10.87(s, 1H), 8.60 - 8.51(m, 1H), 8.35 - 8.25(m, 2H), 8.08 - 7.99(m, 1H), 7.96(s, 1H), 7.93 - 7.81(m, 1H), 7.57(t, J=9.9 Hz, 1H), 7.34(d, J=8.8 Hz, 1H), 5.42 - 5.28(m, 1H), 4.77 - 4.63(m, 1H), 4.60 - 4.46(m, 1H), 4.10 - 4.01(m, 3H), 3.99 - 3.93(m, 1H), 3.89 - 3.73(m, 2H), 3.69 - 3.55(m, 2H), 1.23(s, 2H). MS(ESI)m / z:695.2(M+H) + ;HPLC RT = 2.25 min. [Method E].

[0260] Example 45: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(5-(5-(2-hydroxy-2-methylpropyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazol-3-yl)-2-methoxybenzamido)benzo[d][1,3]dioxole-5-carboxamide [ka] A solution of peak 2 from Example 43-1 (20 mg, 0.03 mmol) and 2,2-dimethyloxirane (6 mg, 0.08 mmol) in EtOH (2 mL) was stirred at 55° C. for 15 h. The reaction mixture was concentrated in vacuo and then subjected to reverse phase HPLC purification using a Waters XBridge C18 column, 19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 30-75% B over 25 min, then hold at 100% B for 5 min, flow rate of 15 mL / min to give Example 45 (18 mg, 0.010 mmol, 81% yield). 1 H NMR(400 MHz, DMSO-d6) δ 11.78(s, 1H), 10.86(s, 1H), 8.57(s, 1H), 8.34 - 8.23(m, 2H), 8.07 - 7.99(m, 1H), 7.95(s, 1H), 7.85(dd, J=8.8, 2.2 Hz, 1H), 7.56(t, J=9.7 Hz, 1H), 7.31(d, J=9.0 Hz, 1H), 5.10(dd, J=9.5, 4.4 Hz, 1H), 4.34 - 4.22(m, 1H), 4.05(s, 4H), 3.21(d, J=10.8Hz, 1H), 3.09(br d, J=9.5 Hz, 1H), 2.45(br dd, J=11.5, 4.6 Hz, 1H), 2.34 - 2.27(m, 1H), 2.26 - 2.19(m, 1H), 1.01(s, 3H), 0.94(s, 3H). MS(ESI)m / z:695.3(M+H) + ;HPLC RT = 2.52 min. [Method E]

[0261] Example 46: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(5-(1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxybenzamido)benzo[d][1,3]dioxole-5-carboxamide [ka] To a solution of Example 54 (20 mg, 0.03 mmol) and 2-hydroxy-2-methylpropanoic acid (4 mg, 0.04 mmol) in DMF (2 mL) was added HATU (13 mg, 0.03 mmol) followed by TEA (0.03 mL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was then concentrated under vacuum and the residue was purified by reverse phase HPLC using the following conditions: Waters XBridge C18 column, 19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 15-55% B over 25 min, then 100% B held for 5 min at a flow rate of 15 mL / min to give Example 46 (14 mg, 0.020 mmol, 55% yield). 1 H NMR(400 MHz, DMSO-d6)δ 11.75 - 11.69(m, 1H), 10.85(s, 1H), 8.56(d, J=2.7 Hz, 1H), 8.34 - 8.27(m, 1H), 8.06 - 7.99(m, 1H), 7.97 - 7.90(m, 2H), 7.61 - 7.55(m, 1H), 7.55 - 7.46(m, 1H), 7.23 - 7.16(m, 1H), 5.16(d, J=3.4 Hz, 1H), 4.35 - 4.27(m, 1H), 4.11 - 4.05(m, 1H), 3.99(s,3H), 3.57 - 3.51(m, 1H), 3.17(d, J=5.1 Hz, 2H), 2.27 - 2.12(m, 2H), 1.97 - 1.75(m, 1H), 1.36 - 1.26(m, 4H), 1.23(s, 1H). MS(ESI)m / z:668.2(M+H) + ;HPLC RT = 2.34 min. [Method E].

[0262] Example 47: Preparation of N3-(2,2-difluoro-6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)-6'-fluoro-4-methoxy-N3'-(methylsulfonyl)-[1,1'-biphenyl]-3,3'-dicarboxamide [ka] To a solution of Example 57 (130 mg, 0.2 mmol) in THF (6.0 mL) was added CDI (65 mg, 0.40 mmol) followed by TEA (0.14 mL, 0.99 mmol) at 0° C. and the reaction mixture was stirred at 80° C. for 4 h. The reaction mixture was then concentrated under vacuum and the residue (40 mg, 0.006 mmol) was dissolved in THF (2 mL) and cooled to 0° C. To this cooled solution was added methanesulfonamide (16 mg, 0.17 mmol) followed by TEA (0.04 mL, 0.29 mmol) and the reaction mixture was heated to 80° C. and stirred at that temperature for 2 h. The reaction mixture was then concentrated in vacuo and the residue was purified by reverse-phase HPLC using a Waters XBridge C18 column, 19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 15 to 55% B over 25 min at a flow rate of 15 mL / min, followed by a 5 min hold at 100% B) to give Example 47 (18 mg, 0.080 mmol, 41% yield). 1H NMR(400 MHz, DMSO-d6)δ 12.41 - 12.21(m, 1H), 11.83(s, 1H), 10.87(s, 1H), 8.59(s, 1H), 8.38 - 8.27(m, 2H), 8.17(dd, J=2.2, 7.6 Hz, 1H), 8.09- 7.93(m, 3H), 7.88(br d, J=8.8 Hz, 1H), 7.57(t, J=9.7 Hz, 1H), 7.49(dd, J=8.9, 10.4 Hz, 1H), 7.39(d, J=8.8 Hz, 1H), 4.08(s, 3H), 3.39(s, 3H). MS(ESI)m / z:728.2(M+H) + ;HPLC RT = 2.05 min. [Method E].

[0263] Example 48: Preparation of N3-(2,2-difluoro-6-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)-6'-fluoro-4-methoxy-N3'-(methylsulfonyl)-[1,1'-biphenyl]-3,3'-dicarboxamide [ka] To a solution of intermediate 24 (40 mg, 0.06 mmol) in THF (2 mL) at 0° C., 1H-pyrazol-3-amine (14 mg, 0.17 mmol) was added followed by TEA (0.04 mL, 0.3 mmol) and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was then concentrated under vacuum and the residue was purified by reverse phase HPLC using a Waters XBridge C18 column (19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 20-65% B over 25 min, then hold at 100% B for 5 min, flow rate 15 mL / min) to give Example 48 (6 mg, 0.01 mmol, 10% yield). 1H NMR(400 MHz, DMSO-d6) δ 11.83(s, 1H), 11.04(s, 1H), 10.88(s, 1H), 8.60(s, 1H), 8.38 - 8.29(m, 2H), 8.24(dd, J=2.2, 7.8 Hz, 1H), 8.04(dq, J=2.7, 5.3 Hz, 2H), 7.96(s, 1H), 7.91(br d, J=8.6 Hz, 1H), 7.67(d, J=2.0 Hz, 1H), 7.57(t, J=9.9 Hz, 2H), 7.49 - 7.34(m, 2H), 6.65(d, J=2.0 Hz, 1H), 4.08(s, 3H).MS(ESI)m / z:716.2(M+H) + ;HPLC RT = 2.42 min. [Method E]

[0264] Example 49: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-methoxy-5-(1-(methylsulfonyl)piperidin-3-yl)benzamido)benzo[d][1,3]dioxole-5-carboxamide [ka]

[0265] Example 49-1: Preparation of 6-(5-(1-benzyl-1,4,5,6-tetrahydropyridin-3-yl)-2-methoxybenzamido)-2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide Example 49-1 (400 mg, 0.56 mmol, 74% yield) was prepared in a similar manner to Example 43-1, replacing intermediate 25 with 5-(1-benzyl-1,4,5,6-tetrahydropyridin-3-yl)-2-methoxybenzoic acid, prepared in a similar manner to intermediate 27. MS (ESI) m / z = 684.3 (M+H). + .

[0266] Example 49-2: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-methoxy-5-(piperidin-3-yl)benzamido)benzo[d][1,3]dioxole-5-carboxamide To a solution of Example 49-1 (400 mg, 0.58 mmol) in MeOH (20 mL) was added Pd-C (156 mg, 1.46 mmol) and the reaction mixture was stirred at room temperature for 12 h under a hydrogen balloon. The reaction mixture was then filtered over a pad of Celite® and concentrated in vacuo to give a residue that was subjected to chiral separation. Separation of the isomers by SFC resulted in Example 49-2 being peak-2 (RT = 7.8 min, >95% ee): Apparatus: Thar SFC-80, Prep SFC Column: Luxcellulose-4 250 x 21.5 mm, 5 micron, Mobile phase: 75% CO2, 25% 4M methanolic ammonia / MeOH; Flow conditions: 80 g / min, back pressure: 0.5 MPa: 80 g / min, back pressure: 100 bar, temperature: 30°C, detection wavelength: 220 nm; Analytical method: Mobile phase: Luxcellulose-4 250 x 4.6 mm, 5 micron: Mobile phase: 75% CO2, 25% 4M methanolic ammonia / MeOH; Flow conditions: 4 g / min, back pressure: 100 bar, temperature: 30°C, detection wavelength: 220 nm. nm; Peak 1 (Peak-1, RT = 5.4 min, >95% ee) of Example 49-1 (40 mg, 0.006 mmol, 11% yield) and Peak 2 (Peak-2, RT = 7.8 min, >95% ee) of Example 49-2 (41 mg, 0.06 mmol, 11% yield).

[0267] Example 49: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-methoxy-5-(1-(methylsulfonyl)piperidin-3-yl)benzamido)benzo[d][1,3]dioxole-5-carboxamide: To a solution of peak 2 (10 mg, 0.02 mmol) of Example 49-2 and TEA (5 μL, 0.05 mmol) in DCM (2 mL) at 0° C., methanesulfonyl chloride (2.3 mg, 0.02 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then concentrated under vacuum and the residue was purified by reverse-phase HPLC using a Waters XBridge C18 column, 19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 15-65% B over 25 min, then hold at 100% B for 5 min; flow rate: 15 mL / min to give Example 49 (2 mg, 0.003 mmol, 20% yield). 1 H NMR(400 MHz, DMSO-d6) δ 11.73(s, 1H), 10.87(s, 1H), 8.57(s, 1H), 8.31(dd, J=2.7, 6.4 Hz, 1H), 8.07 - 7.99(m, 1H), 7.99 - 7.89(m, 2H), 7.63 -7.49(m, 2H), 7.20(d, J=8.6 Hz, 1H), 3.99(s, 3H), 3.61 - 3.54(m, 2H), 2.88(s, 3H), 2.86 - 2.70(m, 3H), 1.93 - 1.77(m, 2H), 1.66 - 1.50(m, 2H).MS(ESI) m / z:672.2(M+H) + ;HPLC RT = 2.48 min. [Method F]

[0268] Example 50: Preparation of 6-(5-(5-amino-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)-2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide [ka] Example 50-1 (70 mg, 0.11 mmols, 8% yield) was prepared in a similar manner to Example 43-1, substituting racemic 5-(5-((tert-butoxycarbonyl)amino)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzoic acid prepared as intermediate 3-3 for intermediate 25. The reaction mixture was diluted with EtOAc (6 mL) and washed with brine. The organic layer was then dried over sodium sulfate and purified by silica gel chromatography using hexane and petroleum ether as eluents to give a diastereomeric mixture which was subjected to SFC purification using the following conditions: Apparatus: Make / Model Thor SFC-350, Column / dimensions: Luxcellulose-2 (250 x 30) mm, 5u, %CO2: 50%, %co-solvent: 50% of 4M methanolic ammonia / MeOH, Total flow rate: 150.0 g / min, Back pressure: 100 bar, Temperature: 30°C, UV: 272 nm, Analytical SFC conditions: Column / dimensions: Luxcellulose-2 (250×4.6) mm, 5u, %CO2: 50% of 4M methanolic ammonia / MeOH, Total flow rate: 4g / min, Back pressure: 100 bar, Temperature: 30°C, UV: 272 nm to give the chiral (Peak-1, RT = 2.6 min, >95 %ee) and chiral (Peak-2, RT = 5.4 min, >95 %ee).Peak 1 obtained from the above SFC separation was further purified by SFC for a second time using the following SFC conditions: Apparatus: Make / Model: WATERS SFC-350, Column / Dimensions: Chiralpak AS-H (250 x 30) mm, 5u, %CO2: 80%, 20% co-solvent 0.2% 4M methanolic ammonia / MeOH, Total flow rate: 150g / min, Back pressure: 100 bar, Temperature: 30°C, UV: 271 nm; Analytical SFC Conditions: Column / Dimensions: Chiralpak AS-H (250 x 4.6) mm, 5u, %CO2: 80%, 20% co-solvent 0.2% 4M methanolic ammonia / MeOH, Total flow rate: 4g / min, Back pressure: 100 bar, Temperature: 30°C, UV: 271 nm; Peak-2, RT = 5.9 min, >95% ee) and chiral (peak-2, RT = 5.9 min, >95% ee). Peak 1 from the second SFC purification is 50-1 of the desired peak. MS (ESI) m / z = 735.0 (MH). - .

[0269] Example 50: Preparation of 6-(5-(5-amino-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)-2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide To a solution of Example 50-1 (isomer 3) (95 mg, 0.13 mmol) in DCM (10 mL) was added TFA (0.2 mL, 3 mmol) at 0° C. and stirred at room temperature for 4 h. The reaction mixture was then concentrated under vacuum and the residue was subjected to reverse-phase HPLC purification using a Waters XBridge C18 column, 19 x 150 mm, 5 micron; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 18-65% B over 25 min, then hold at 100% B for 5 min; flow rate 15 mL / min to give Example 50 (8 mg, 0.01 mmol, 9% yield). 1H NMR(400 MHz, DMSO-d6) δ 11.93 - 11.64(m, 1H), 8.57(s, 1H), 8.36 - 8.24(m, 2H), 8.07 - 7.98(m, 1H), 7.96(s, 1H), 7.87(dd, J=2.3, 8.9 Hz, 1H), 7.56(t, J=9.9 Hz, 1H), 7.33(d, J=8.6 Hz, 1H), 5.15 - 5.06(m, 1H), 4.15 - 3.99(m, 5H), 2.38 - 2.21(m, 3H), 1.90(s, 2H), 1.73 - 1.60(m, 1H), 1.53 - 1.41(m, 1H). MS(ESI)m / z:637.2(M+H) + ;HPLC RT = 2.08 min. [Method E].

[0270] Example 51: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(5-(5-(2-hydroxyacetamido)-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-3-yl)-2-methoxybenzamido)benzo[d][1,3]dioxole-5-carboxamide [ka] To a solution of Example 51 (20 mg, 0.03 mmol) and 2-hydroxyacetic acid (5 mg, 0.06 mmol) in DMF (2 mL) was added HATU (12 mg, 0.03 mmol) followed by TEA (0.02 mL, 0.16 mmol) and stirred at room temperature for 15 h. The reaction mixture was then concentrated under vacuum and the residue was subjected to reverse phase HPLC purification using a Waters XBridge C18 column, 19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 25-55% B over 25 min, then hold at 100% B for 5 min, flow rate: 15 mL / min to give Example 51 (3 mg, 0.004 mmol, 10% yield). 1H NMR(400 MHz, DMSO-d6)δ 11.94 - 11.73(m, 1H), 10.86(br d, J=17.9 Hz, 1H), 8.57(s, 1H), 8.34 - 8.21(m, 2H), 8.06 - 7.97(m, 1H), 7.95(s, 1H), 7.87(dd, J=2.4, 8.8 Hz, 1H), 7.82(d, J=8.3 Hz, 1H), 7.60 - 7.46(m, 1H), 7.32(d, J=9.0 Hz, 1H), 5.50 - 5.38(m, 1H), 5.18 - 5.04(m, 1H), 4.32 - 4.22(m, 1H), 4.13 - 3.98(m, 4H), 3.75(br s, 2H), 2.16 - 2.06(m, 1H), 2.01 - 1.82(m, 3H). MS(ESI)m / z:695.1(M+H) + ;HPLC RT = 2.24 min. [Method E].

[0271] Example 52: Preparation of 2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-methoxy-5-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)benzamide)benzo[d][1,3]dioxole-5-carboxamide [ka] Example 52 (8 mg, 0.01 mmol, 4% yield) was prepared in a similar manner to example 43-1 by replacing intermediate 25 with intermediate 28, followed by deprotection with 20% TFA / DCM. 1H NMR(400MHz, DMSO-d6)δ 11.77(br s, 1H), 10.84(br d, J=1.2 Hz, 1H), 8.56(s, 1H), 8.49(d, J=2.4 Hz, 1H), 8.30(dd, J=2.6, 6.5 Hz, 1H), 8.08 - 7.98(m, 2H), 7.93(s, 1H), 7.55(t, J=9.9 Hz, 2H), 7.32(d, J=8.8 Hz, 1H), 4.05(s, 3H), 3.93(s, 2H), 3.02(t, J=5.6 Hz, 2H), 2.79 - 2.68(m, 2H). MS(ESI)m / z:651.2(M+H) + ;HPLC RT = 2.31 min. [Method E].

[0272] Example 53: Preparation of 6-(5-(5-(2-amino-2-oxoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-methoxybenzamido)-2,2-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide [ka] To a solution of Example 52 (20 mg, 0.03 mmol) and 2-bromoacetamide (7 mg, 0.05 mmol) in DMF (0.5 mL) and THF (1.5 mL) was added TEA (0.021 mL, 0.15 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was then concentrated under vacuum and the residue was subjected to reverse phase HPLC purification using a Waters XBridge C18 column, 19 x 150 mm, 5 microns; mobile phase A: 10 mM NH4OAc; mobile phase B: ACN; gradient: 15-65% B over 25 min, then hold at 100% B for 5 min, flow rate: 15 mL / min to give Example 53 (1.2 mg, 0.0010 mmol, 5.0% yield). 1H NMR(400MHz, DMSO-d6)δ 11.87 - 11.71(m, 1H), 10.87(br s, 1H), 8.58(s, 1H), 8.52(d, J=2.5 Hz, 1H), 8.36 - 8.25(m, 1H), 8.11 - 7.99(m, 2H), 7.97(s, 1H), 7.57(t, J=9.8 Hz, 1H), 7.33 - 7.32(m, 1H), 7.40 - 7.25(m, 1H), 7.15(br s, 1H), 4.07(s, 3H), 3.81(s, 2H), 3.14(s, 2H), 2.96 - 2.81(m, 4H). MS(ESI)m / z:708.4(M+H) + ;HPLC RT = 2.3 min.[Method E].

[0273] The general methods described in Examples 54 to 97 and Example 52 were used for their production.

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

[0274] It will be apparent to those skilled in the art that the present invention is not limited to the following illustrative examples, but may be embodied in other specific forms without departing from its essential characteristics. The examples are therefore to be considered in all respects as illustrative and not restrictive, and it is desired to rely on the appended claims rather than on said examples, and therefore all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Ring A is O, S(=O) p , N and NR 1a and 0 to 4 R 1 is a 5-membered heterocyclyl substituted with R 1 is halo or C substituted with 0-5 halo or -OH 1-4 is alkyl; R 1a is H or C 1-3 is alkyl; R 2 is 0 to 3 R 3 and one R 5 phenyl substituted with 0-3 R 3 and 0 to 1 R 5 Bicyclic carbocyclyl substituted with, or O, S(=O) p , N and NR 2a and 0 to 3 R 3 and 0 to 1 R 5 is a 5- to 12-membered heterocyclyl substituted with R 2a , H, C 1-3 Alkyl, or C(=O)R b and R 3 , halo, CN, OH, C 1-4 Alkyl, or 0-5 halo, OH, -OC 1-4 -OC substituted with alkyl, aryl or heterocyclyl 1-4 is alkyl; R 4 is halo, CN, C substituted with 0-5 halo 1-4 -OC substituted with alkyl, OH or 0-5 halo 1-4 is alkyl; R 5 is -C(=O)NR 13 R 13 , -S(=O) p NR 13 R 13 , 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-8 alkenyl, 0-3 R 6 and 0 to 2 R 7 C replaced with 2-8 Alkynyl, 0-3 R 6 and 0 to 2 R 7 C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 3- to 12-membered heterocyclyl substituted with R 2 is phenyl and R 5 is heterocyclyl, said heterocyclyl is attached to the phenyl ring via a carbon or nitrogen atom; R 6 are halo, CN, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halo and OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-5 Alkyl, -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , -C(=O)NR a S(=O) p R c , 0 to 5 R e C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with R 8 is halo, -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a OR b or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a , -S(O) p R c , -OP(=O)(OH) 2 , 0 to 3 R e Substituted with -(CH 2 ) n -C 3-6 Carbocyclyl, or O, S(=O) p , N and NR d and 0 to 5 R e Substituted with -(CH 2 ) n -heterocyclyl; R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(O) p R c , 0 to 5 R e C replaced with 3-6 Carbocyclyl, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with R 11 is -OH, -C(=O)OH, -C(=O)NR a R a or aryl; R 12 , H, C 1-3 is alkyl or aryl; R 13 is H or 0 to 2 R 6 and 0 to 2 R 7 C replaced with 1-3 alkyl; or R 13 and R 13 Together with the nitrogen atom to which they are both bonded, they form O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 2 R 7 forming a heterocyclyl substituted with; R a is H, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0-5 R e C replaced with 2-6 Alkynyl, 0-5 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-5 R e Substituted with -(CH 2 ) n -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are both attached, they are 0 to 5 R e forming a heterocyclyl substituted with; R b is H, 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0-5 R e C replaced with 2-6 Alkynyl, 0-5 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-5 R e Substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 5 R e C replaced with 1-6 Alkyl, 0 to 5 R e C replaced with 2-6 Alkenyl, 0-5 R e C replaced with 2-6 Alkynyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-4 is alkyl; R e , Haro, CN, NO 2 , =O, 0 to 5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, 0-5 R g Substituted with -(CH 2 ) n -Carbocyclyl, 0-5 R g Substituted with -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , -C(=O)OR f , -C(=O)NR f R f , -NR f C(=O)R f , -S(=O) p R f , -S(=O) p NR f R f , -NR f S(=O) p R f , -NR f C(=O)OR f , -OC(=O)NR f R f or -(CH 2 ) n NR f R f and R f is H, 0 to 1 -OC 1-4 Alkyl-substituted C 1-6 Alkyl, C 3-6 cycloalkyl, aryl, or heterocyclyl; or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclyl; R g are halo, CN, OH, S(=O) 2 C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0, 1, 2 or 3; and p is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 2】 [In the formula, 【Chemistry 3】 teeth, 【Chemistry 4】 and R 1 is halo or C 1-3 is alkyl; R 3 Halo, C 1-3 -OC substituted with alkyl or 0 to 4 halo 1-4 is alkyl; R 4a is a halo; R 4b is C substituted with 0 to 4 halo 1-4 is alkyl; R 5 is -C(=O)NR 13 R 13 , -S(=O) p NR 13 R 13 , 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-7 alkenyl, 0-3 R 6 and 0 to 2 R 7 C replaced with 2-7 Alkynyl, 0-3 R 6 and 0 to 2 R 7 Phenyl substituted with, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 10-membered heterocyclyl substituted with R 6 are halo, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halo or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with R 8 is halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b , -S(=O) p NR a R a or -S(O) p R c and R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with R 11 is -OH, -C(=O)OH or aryl; R 12 , H, C 1-3 is alkyl or aryl; R 13 is H or 0 to 1 R 6 and 0 to 1 R 7 C replaced with 1-3 alkyl; or R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which is O, S(=O) p , N and NR 10 and 0-3 R 6 and 0 to 2 R 7 is replaced by; R a is H, 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-5 R e Substituted with -(CH 2 ) n -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are both attached, they are 0 to 5 R e forming a heterocyclyl substituted with; R b is H, 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0-5 R e C replaced with 2-5 Alkynyl, 0-5 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-5 R e Substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 5 R e C replaced with 1-5 Alkyl, 0 to 5 R e C replaced with 2-5 Alkenyl, 0-5 R e C replaced with 2-5 Alkynyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-3 is alkyl; R e is halo, CN, =O, 0-5 R g C replaced with 1-6 Alkyl, 0 to 5 R g C replaced with 2-6 Alkenyl, 0-5 R g C replaced with 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f , -C(=O)OR f or -S(=O) p R f and R f is H or 0 to 1 -OC 1-4 Alkyl-substituted C 1-3 is alkyl; R g , halo, CN, OH, C 1-6 Alkyl, C 3-6 is cycloalkyl or aryl; n is 0, 1, 2 or 3; and p is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

3. Formula (III): 【Chemistry 5】 [In the formula, R 1 is C 1-2 is alkyl; R 3 -OC 1-4 is alkyl; R 4a is a halo; R 4b is C substituted with 0 to 4 F 1-3 is alkyl; R 5 is -S(=O) p NR 13 R 13 , 0 to 3 R 6 and 0 to 2 R 7 Phenyl substituted with, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 10-membered heterocyclyl substituted with R 6 ,Haro,CN,C 1-3 Alkyl, -OH or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 4 R e is a 4- to 6-membered heterocyclyl substituted with R 8 is halo, -C(=O)OR b , -C(=O)NHR a or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -OC(=O)NR a OR b or -S(=O) p NR a R a and R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl or -C(=O)R b and R 13 and R 13 Together with the nitrogen atom to which they are both bonded, they form O, S(=O) p , N and NR 10 and 0-3 R 6 and 0 to 2 R 7 forming a heterocyclyl substituted with; R a is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-4 R e Substituted with -(CH 2 ) n -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are both attached, they are 0 to 4 R e forming a heterocyclyl substituted with; R b is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-4 R e Substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, 0-5 R g C replaced with 1-6 Alkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f OR -C(=O)OR f and R f is H or 0 to 1 -OC 1-4 Alkyl-substituted C 1-3 is alkyl; R g , halo, CN, OH, C 1-6 Alkyl or C 3-6 is cycloalkyl; n is 0, 1, 2 or 3; and p is 0, 1 or 2.

3. The compound of claim 2, having the formula:

4. R 1 But -CH 3 and R 3 But, -OCH 3 and R 4a is F; R 4b But CF 3 and R 5 But -S(=O) 2 NR 13 R 13 , 【Chemistry 6】 and R 6 But, Halo, C 1-4 Alkyl, -OH or -OC 1-4 is alkyl; R 7 But 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, -C(=O)NR a R a , or 0 to 2 R e C replaced with 3-6 is cycloalkyl; R 8 But halo, -C(=O)OC 1-4 Alkyl, or C 1-4 is alkyl; R 9 But -OR b , -NR a R a , -NR a C(=O)R b or -OC(=O)NR a R a and R 10 H, 0 to 2 R 11 C replaced with 1-3 Alkyl or -C(=O)R b and R 11 is -OH; R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which is O, S(=O) p and N, and 0-3 R 6 and 0 to 2 R 7 is replaced by; R a But, H, C 1-3 Alkyl, or C 3-6 is cycloalkyl; R b is H, 0 to 1 R e C replaced with 1-4 alkyl or heterocyclyl; R e But -OR f and R f is H or -OC 1-3 Alkyl-substituted C 1-3 is alkyl, 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof.

5. R 5 but, 【Chemistry 7】 and R 7 But 0 to 1 R 9 C replaced with 1-4 is alkyl; R 9 But -OR b and R 10 is H or -C(=O)R b and R b is H or 0-1 R e C replaced with 1-4 is alkyl; R e But -OR f and R f But H or C 1-2 is alkyl, 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof.

6. Formula (IV): 【Chemistry 8】 [In the formula, R 1 is C 1-2 is alkyl; R 3 -OC 1-4 is alkyl; R 4a is a halo; R 4b is C substituted with 0 to 4 F 1-3 is alkyl; R 5 is C substituted with OH 2-4 Alkynyl or 0-3 R 6 and 0 to 2 R 7 phenyl substituted with; R 6 ,Haro,CN,C 1-3 Alkyl, -OH or -OC 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-2 is alkyl; R 8 is halo or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -OC(=O)NR a R a or -OC(=O)NR a OR b and R a , H, C 1-3 Alkyl or C 3-6 is cycloalkyl; and R b is H or C 1-3 is alkyl] 3. The compound of claim 2 having the formula: or a pharma- ceutically acceptable salt thereof.

7. Formula (V): 【Chemistry 9】 [In the formula, R 1 is a halo; R 3 Halo, C 1-3 Alkyl or -OC 1-3 is alkyl; R 4a is a halo; R 4b is C substituted with 0 to 3 halo 1-3 is alkyl; R 5 is -C(=O)NR 13 R 13 , 0 to 3 R 6 and 0 to 2 R 7 C replaced with 2-6 alkenyl, 0-3 R 6 and 0 to 2 R 7 C replaced with 2-6 Alkynyl, 0-3 R 6 and 0 to 2 R 7 Phenyl substituted with, or O, S(=O) p , N and NR 10 and 0 to 3 R 6 and 0 to 1 R 7 is a 3- to 10-membered heterocyclyl substituted with R 6 are halo, =O, -OH, -OC 1-4 Alkyl or C substituted with 0-2 halo or OH 1-4 is alkyl; R 7 is 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-4 Alkyl, -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR a R a , -NR a S(=O) p R c , -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -C(=O)NR a S(=O) p R c , -OC(=O)R b , -S(=O) p R c , -S(=O) p NR a R a , -C(=O)NR a S(=O) p R c , 0 to 4 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR d and 0 to 4 R e is a 4- to 6-membered heterocyclyl substituted with R 8 is halo, -C(=O)OR b , -C(=O)NHR a , -C(=O)NHOR b or C substituted with 0-3 halo or OH 1-4 is alkyl; R 9 -OR b , -NR a R a , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a S(=O) p R c , -NR a S(O) p NR a R a , -OC(=O)NR a R a , -S(=O) p NR a R a or -S(O) p R c and R 10 is H, 0 to 2 R 11 C replaced with 1-4 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , -S(O) p R c , 0 to 5 R e C replaced with 3-6 Cycloalkyl, or O, S(=O) p , N and NR 12 and 0 to 5 R e is a 4- to 6-membered heterocyclyl substituted with R 11 is -OH, -C(=O)OH, -C(=O)NR a R a or aryl; R 12 , H, C 1-3 is alkyl or aryl; R 13 is H or 0 to 3 R 6 and 0 to 2 R 7 C replaced with 1-4 alkyl; or R 13 and R 13 together with the nitrogen atom to which they are both attached form a heterocyclyl, which includes O, S(=O), N, and NR 10 and 0-3 R 6 and 0 to 2 R 7 is substituted with; R a is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-4 R e Substituted with -(CH 2 ) n -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are both attached, they are 0 to 4 R e forming a heterocyclyl substituted with; R b is H, 0 to 4 R e C replaced with 1-5 Alkyl, 0 to 4 R e Substituted with -(CH 2 ) n -C 3-10 Carbocyclyl or 0-4 R e Substituted with -(CH 2 ) n -heterocyclyl; R c is 0 to 4 R e C replaced with 1-5 Alkyl, C 3-6 is carbocyclyl or heterocyclyl; R d is H or C 1-2 is alkyl; R e is halo, CN, =O, 0-5 R g C replaced with 1-6 Alkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n OR f OR -C(=O)OR f and R f is H or 0 to 1 -OC 1-4 Alkyl-substituted C 1-3 is alkyl; R g , halo, CN, OH, C 1-6 Alkyl or C 3-6 is cycloalkyl; n is 0, 1, 2 or 3; and p is 0, 1 or 2.

3. The compound of claim 2 having the formula: or a pharma- ceutically acceptable salt thereof.

8. Formula (VI): 【Chemistry 10】 [In the formula, R 1 is F; R 3 -OCH 3 and R 4a is F; R 4b CF 3 and R 6 is a halo; R 7 is -C(=O)OR b , -C(=O)NR a R a , -S(=O) p NR a R a or -C(=O)NR a S(=O) p C 1-4 is alkyl; R a is H, 0 to 5 R e C replaced with 1-3 Alkyl or 0 to 4 R e is heterocyclyl substituted with; R b is H or 0 to 5 R e C replaced with 1-3 is alkyl; and R e is halo, CN, =O or C 1-6 is alkyl] 8. The compound of claim 7, having the formula: or a pharma- ceutically acceptable salt thereof.

9. R 1 is F; R 3 But, -OCH 3 and R 4a is F; R 4b But CF 3 and R 5 but, 【Chemistry 11】 and R 6 is halo, -OH, or C substituted with 0-1 OH 1-4 is alkyl; R 7 But -NR a R a or -S(=O) 2 NR a R a and R 10 But H, -C(=O)R b , or 0 to 1 R 11 C replaced with 1-4 is alkyl; R 11 is -OH, -C(=O)OH or aryl; R a But H or C 1-3 alkyl; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl; and R b But H or C 1-3 is alkyl, 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof.

10. R 1 is F; R 3 But, -OCH 3 and R 4a is F; R 4b But CF 3 and R 5 but, 【Chemistry 12】 and R 6 But halo, =O, -OH, -OC 1-4 Alkyl, or C 1-4 is alkyl; R 7 But 0 to 1 R 8 and 0 to 1 R 9 C replaced with 1-3 Alkyl, -NR a R a or -NR a C(=O)R b and R 8 But -C(=O)OR b and R 9 is OH; R 10 H, 0 to 2 R 11 C replaced with 1-3 Alkyl, -C(=O)R b , -C(=O)OR b , -C(=O)NR a R a , or O, S(=O) p , N and NR 12 and 0 to 4 R e is a 4- to 6-membered heterocyclyl substituted with R 11 is -OH, -C(=O)OH, or C(=O)NR a R a and R 12 But H or C 1-3 is alkyl; R a But H or C 1-3 is alkyl; R b is H or 0 to 1 R e C replaced with 1-3 is alkyl; and R e is OH, 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof.

11. R 5 but, 【Chemistry 13】 and R 7 But 0 to 1 R 9 C replaced with 1-3 is alkyl; R 9 is -OH; R 10 H, 0 to 2 R 11 C replaced with 1-3 Alkyl or -C(=O)R b and R 11 is -OH; R b is H or 0-1 R e C replaced with 1-3 is alkyl; and R e is OH, 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof.

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

13. R 1 is F; R 3 But, -OCH 3 and R 4a is F; R 4b But CF 3 and R 5 But -C(=O)NR 13 R 13 and R 6 is halo, -OH, or C substituted with 0-1 OH 1-4 is alkyl; R 7 But -S(=O) 2 C 1-3 Alkyl or 0 to 2 R e C replaced with 3-6 is cycloalkyl; R 10 But H, -C(=O)R b , or 0 to 1 R 11 C replaced with 1-4 is alkyl; R 11 is -OH, -C(=O)OH or aryl; R 13 is H or 0 to 1 R 6 and 0 to 1 R 7 C replaced with 1-3 alkyl; or R 13 and R 13 together with the nitrogen atom to which they are both attached form: 【Chemistry 15】 forming a heterocyclyl selected from R b But H or C 1-6 is alkyl; and R e But -S(=O) 2 C 1-3 is alkyl, 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof.

14. R 5 -C(=O)NHR 13 and R 13 But 0 to 1 R 7 C replaced with 1-3 is alkyl; R 7 But 0 to 2 R e C replaced with 3-6 is cycloalkyl; and R e But -S(=O) 2 C 1-3 is alkyl, 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof.

15.

16. but, 【Chemistry 17】 and R 3 But, -OC 1-3 is alkyl; R 4a is F; R 4b But CF 3 and R 5 -C(=O)NHR 13 , 【Chemistry 18】 and R 7 But 0 to 1 R 9 C replaced with 1-3 Alkyl or 0 to 5 R e C replaced with 3-6 is cycloalkyl; R 8 But halo, -C(=O)OR b or C substituted with 0 to 3 halo 1-4 is alkyl; R 9 -OH, -NR a C(=O)R b or -OC(=O)NR a R a and R 10 H, 0 to 2 R 11 C replaced with 1-3 Alkyl or -C(=O)R b and R 11 is -OH; R 13 is H or 0 to 1 R 7 C replaced with 1-3 is alkyl; R b H, 0 to 5 R e C replaced with 1-3 alkyl or heterocyclyl; R e But -OR f or -S(=O) 2 C 1-3 is alkyl; and R f But H or C 1-3 is alkyl, 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof.

16. 13. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

17. A method for treating a relaxin-related disease, comprising administering to a patient in need of treatment a therapeutically effective amount of the pharmaceutical composition of claim 16.

18. 18. The method of claim 17, 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 iatrogenic damage.

19. 19. The method of claim 18, wherein the disease is heart failure.

20. 20. The method of claim 18, wherein the disease is fibrosis.

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