TW201739733A - Arylcarboxamides and uses thereof - Google Patents

Abstract

The present disclosure is directed to compounds of formula (I): or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof. Compounds of formula (I) are inhibitors of NOX4 and are useful in the treatment of fibrotic diseases such as scleroderma; lung disease, such as pulmonary fibrosis including idiopathic pulmonary fibrosis (IPF); heart disease, such as heart failure due to ischaemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and hypertension; liver disease, such as cirrhosis of the liver; and kidney disease, such as progressive kidney disease glomerulonephritis and diabetic nephropathy; and eye disease such as diabetic retinopathy; skin or subcutaneous scarring, such as keloids, adhesions, hypertrophic scarring or cosmetic scarring; or as an adjuvant or anti-fibrotic in pancreatic cancer to increase chemotherapeutic drug penetration by reducing the density of the connective tissue stroma.

Description

Arylcarmine and its use

Disclosed herein are aryl carbamide compounds, pharmaceutical compositions containing aryl methamine, and methods of treating diseases using aryl carbamide. In some embodiments, the condition to be treated is a fibrotic disease. In some embodiments, arylcarbamide modulates the activity or function of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) NOX4.

The NADPH oxidase (NOX) family contains cellular enzymes that transfer electrons from NADPH to molecular oxygen, thereby producing superoxide anions, as well as reactive oxygen species (ROS). Oxygen-derived small molecules in different types of ROS, including oxygen radical superoxide (O ₂ •-), hydroxyl (•OH), hydrogen peroxide (RO2•) and alkoxy (RO•) and as oxidant itself And/or various non-radicals which can be readily converted to free radicals, such as hypochlorous acid (HOCl), ozone (O ₃ ), singlet oxygen ( ¹ O ₂ ) and most particularly hydrogen peroxide. ROS production usually begins with superoxide, which rapidly disproportionates into hydrogen peroxide via spontaneous formation or via the action of superoxide dismutase. In addition, there are other ROS production pathways, including: 1) reacting superoxide with nitric oxide to form peroxynitrite, 2) peroxidase-mediated formation of hypochlorous acid from hydrogen peroxide, and 3) iron-catalyzed fen Fenton reaction, which causes hydroxyl radical formation (Bedard and Krause, 2007). Currently, there are seven mammalian NOX isoforms: NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2. The phagocytic NOX, renamed NOX2, is found in neutrophils and represents a classical NOX isoform. NOX2 contains a heterodimeric membrane-bound flavocytochrome b558 complex consisting of a catalytic gp91 ^phox subunit located in the membrane and a regulatory p22 ^phox subunit. For complete activation, NOX2 requires the Rho family of GTPases, Rac, and the regulatory subunits p47 ^phox , p40 ^phox, and p67 ^phox , which are translocated from cytosol to membrane-bound complexes following agonist stimulation (Paik et al., 2013). These same tissue features are not shared by all NOX family members, such that only NOX1, NOX3 and NOX4 and p22 ^phox form heterodimers (Nauseef, 2008). Furthermore, unlike the regulatory subunit-dependent NOX1, NOX2 and NOX3 or the EF hand containing NOX5 and DUOX1 and 2, NOX4 showed constitutive activity. In general, all NOX can catalyze the reduction of molecular oxygen to superoxide. However, there are inherent differences in their performance, cellular localization, activation patterns, and upstream and downstream signaling pathways (Bedard and Krause, 2007). In general, ROS is associated with many reversible and irreversible regulatory processes that can have physiological and pathological consequences. NOX2-derived ROS is a major component of innate immunity and plays an important biological role in killing pathogens as part of host defense. In contrast, ROS made by other NOX isoforms can irreversibly destroy or alter the function of many molecular targets and are key contributors to cellular and tissue damage via oxidative stress. In lung tissue, oxidants are continuously produced by endogenous metabolic reactions (such as mitochondrial respiration, via activation and recruitment of inflammatory cells) or by exogenous sources (such as cigarette smoke and airborne pollutants). Based on its large surface area and blood supply, the lungs experience higher oxygen tension relative to other tissues and are more sensitive to ROS-mediated damage than other organs. NOX-mediated ROS production has been described for a number of lung cells, including endothelial and smooth muscle cells, and NOX activation is associated with respiratory conditions such as pulmonary hypertension, increased pulmonary vasoconstriction, and interstitial lung disease. In particular, recent evidence supports that NOX4-derived ROS play a role in lung inflammation, fibroblast activation, and collagen accumulation in pulmonary fibrosis environments (Thannickal VJ, 2012). NOX4 is up-regulated in the lungs of mice after injury and is increased in lung tissue from patients with idiopathic pulmonary fibrosis (IPF). Furthermore, in a mouse model of pulmonary fibrosis, genetic deletion of NOX4 eliminates fibrogenesis (Hecker et al., 2009). NOX4 is also associated with vascular remodeling and associated pulmonary hypertension (Barman, 2014). In the liver, oxidative stress is a major player in the onset and progression of liver fibrosis, thereby promoting the conversion of hepatic stellate cells (HSC) to myofibroblasts and promoting apoptosis in hepatocytes. The accumulation of evidence that NADPH oxidase, which is also fully associated with inflammation of the liver, is a major contributor to ROS production in this tissue (Crosas-Molist and Fabregat, 2015). Elevated ROS concentrations contribute to cell death, whereas sublethal concentrations enhance HSC activation, proliferation, and collagen production (Paik et al., 2013). It is well known that the profibrotic factor TGFβ increases HSC activation and NOX4 expression, and these changes are attenuated by the NOX4 blocking gene. In a mouse model of steatosis hepatitis, loss of NOX4 in hepatocytes also reduces oxidative stress, lipid peroxidation, and liver fibrosis, and in patients with nonalcoholic fatty liver disease (NASH), an increase in NOX4 levels has been observed. (Bettaieb et al., 2015). Similarly, upregulation of NOX4 was observed in samples from patients with HCV-derived fibrosis (Sancho et al., 2012) to further determine the pro-fibrotic effects of NOx-induced oxidative stress in the clinical setting. Although a large body of evidence indicates its ability to regulate renal function and pathology, the role of ROS and certain NOX isoforms in the kidney remains somewhat puzzling. In the context of hyperglycemia and in response to increased angiotensin II signaling, increased ROS production can adversely affect renal structure and function. Furthermore, by regulating sodium reabsorption and renal hemodynamics, ROS appears to play a key pathological role in blood pressure regulation (Sedeek et al., 2013). ROS is also involved in diabetic retinopathy, whereby elevated ROS in the retina can impair metabolism, impair DNA and mitochondrial function, and compromise electron transport systems (Ellis et al., 2000). It is worth noting that antioxidants can target multiple aspects of oxidative stress and mitochondrial damage and improve retinopathy in a rat diabetic model (Kowluru and Mishra, 2015). ROS and Nox also involve glomerular disease (Mao and Huang, 2013). Similar to its role in the lungs and liver, NOX4-mediated ROS production also appears to be a pathogen of renal fibrosis. Progressive formation of fibrotic tissue is the terminal component of kidney disease, which ultimately impairs organ function and leads to eventual renal failure. Interestingly, several researchers have suggested the ability to protect NOX4 in the kidney (Nlandu Khodo et al., 2012; Babelova et al., 2012). However, such studies are limited and directly contradictory to a large body of literature, suggesting that increased Nox activity and ROS production are the main drivers in a range of renal pathological conditions (Jha et al., 2014; Sedeek et al., 2010; Holterman et al. People, 2015). Therefore, ROS derived from NADPH oxidase are involved in the pathogenesis of disease in a variety of organs including lung, liver, kidney, heart and eye (Jiang et al., 2014). In particular, Xianxin ROS is the main driver of tissue damage and subsequent fibrosis in the terminal organ failure. By definition, fibrosis is the accumulation of excess fibrous connective tissue in tissues and organs, resulting in significant remodeling of the tissue structure and the development of progressive organ dysfunction and failure (Friedman et al., 2013). Currently, it is estimated that almost 45% of all disease-related deaths in industrialized societies are caused by some forms of fibrotic disease (Wynn, 2008). Despite this huge unmet medical need, there are still few approved treatments for fibrosis. Therefore, the development of specific NADPH oxidase inhibitors for clinical applications in the treatment of fibrotic diseases is extremely beneficial.

The present invention provides compounds and pharmaceutical compositions suitable for the treatment of fibrotic and fibrotic diseases. A method of treating fibrotic and fibrotic diseases is also provided. In some embodiments, a compound of formula (I) is provided: Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein A is -C(R ¹ )=C(R ¹ )-C(R ¹ )=C(R ¹ )-, -SC(R ^1a )=C(R ^1a )-, -C(R ^1a )=C(R ^1a )-S- or -(CH ₂ ) _3-4 -; X ¹ series -CH-, -C( Halogen)- or -N-; X ² -CH- or -N-; X ³ -N- or -C(R ⁴ )-; each R ^{1 is} independently H, halogen, cyano, C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl, halo, -C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{1 - 6} alkoxy group or halo -C _{1 - 6} alkoxy, which is limited to at least two R ¹ H; each R ^{1a is} independently H, C _{1 - 6} alkyl or aryl; R ² is CO ₂ H, -C(O)NHSO ₂ R ⁵ , -NHSO ₂ R ⁵ , , , , , or R ³ is halogen, cyano or OR ⁶ ; R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{3 - 6} cycloalkyl, optionally 1 to 3 identical or a different halogen atom-substituted aryl group, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR ⁷ R ⁸ or cyano; or R ³ and R ⁴ together -O-CF ₂ -O- or -O-(CH ₂ ) _p -O-; R ⁵ is C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl or C _{3 - 6} cycloalkyl; each R ⁶ independently Is a C _{1 - 6} alkyl group, a halo-C _{1 - 6} alkyl group, a C _{3 - 6} cycloalkyl-(C _{0 - 2} alkyl group), a heterocyclic group or a benzyl group; R ⁷ and R ⁸ are each independently Is selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and p is 1, 2 or 3; the following compounds are not included: (A) , (B) Wherein R ^1B is H or OCH ₃ : R ^3B is Br, Cl or I and R ^4B is H; or R ^3B and R ^{4B are} each OCH ₃ ; or R ^3B is OCH ₃ and R ^4B is O(CH ₂ ) ₂ OCH ₃ ; or R ^3B and R ^4B together are -O-(CH ₂ ) ₂ -O- or -O-(CH ₂ ) ₃ -O-, (C) Wherein R ^3C is OCH ₃ , Br, Cl or I and R ^4C is H; or wherein R ^3C and R ^{4C are} each OCH ₃ ; or wherein R ^3C is OCH ₃ and R ^4C is O(CH ₂ ) ₂ OCH ₃ Or wherein R ^3C and R ^{4C are} together -O-(CH ₂ ) ₂ -O- or -O-(CH ₂ ) ₃ -O-, and (D) Wherein R ^3D is Br or Cl and R ^4D is H; or wherein R ^3D and R ^{4D are} each OCH ₃ ; or wherein R ^3D is OCH ₃ and R ^4D is O(CH ₂ ) ₂ OCH ₃ ; or wherein R ^3D and R ^{4D is} together -O-(CH ₂ ) ₂ -O- or -O-(CH ₂ ) ₃ -O-. In some embodiments of compounds of formula (I), A is based ^{-CH = CH-C (R 1} ) = CH- *, wherein * indicates the carbon adjacent to X ¹ of the connector. In some embodiments of the compound of Formula (I), X ¹ is -N-. In some embodiments of the compound of Formula (I), X ¹ is -CH-. In some embodiments of compounds of formula (I), A is based ^{-CH = CH-C (R 1} ) = CH- *, wherein * indicates the carbon adjacent to X ¹ of the connector, and X ¹ based -N-. In some embodiments of compounds of formula (I), A is based ^{-CH = CH-C (R 1} ) = CH- *, wherein * indicates the carbon adjacent to X ¹ of the connector, and ^a line X -CH-. In some embodiments of the compound of Formula (I), X ³ is -CR ⁴ -. In some embodiments of the compound of Formula (I), X ³ is -CR ⁴ - and X ² is -CH-. In some embodiments of the compound of Formula (I), X ³ is -CR ⁴ - and X ² is -N-. In some embodiments of the compounds of formula (I), R ² is CO ₂ H, , or . In some embodiments of the compounds of formula (I), R ² is CO ₂ H, or . In some embodiments, the compound of Formula (I) has Formula Ia: Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein R ³ is halogen, cyano or OR ⁶ ; and R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkynyl, C _{3 a 6-} cycloalkyl group, an aryl group substituted by 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR ⁷ R ⁸ or Cyano group. In some embodiments of the compound of Formula (Ia), R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkane a C _{1 - 6} alkoxy-C _{1 - 6} alkyl group, a C _{2 - 6} alkynyl group, a C _{3 - 6} cycloalkyl group, an aryl group optionally substituted with 1 to 3 identical or different halogen atoms, Heteroaryl, halogen, NR ⁷ R ⁸ or cyano group substituted by the same or different halogen atoms, as the case may be. In some embodiments of compounds of formula (Ia), A is based ^{-CH = CH-C (R 1} ) = CH- *, wherein * indicates the carbon adjacent to the connection of X ^1. In some embodiments of the compound of Formula (Ia), X ¹ is -N-. In some embodiments of the compound of Formula (Ia), X ¹ is -CH-. In some embodiments of compounds of formula (Ia), A is based ^{-CH = CH-C (R 1} ) = CH- *, wherein * indicates the carbon adjacent to X ¹ of the connector, and X ¹ based -N-. In some embodiments of compounds of formula (Ia), A is based ^{-CH = CH-C (R 1} ) = CH- *, wherein * indicates the carbon adjacent to X ¹ of the connector, and ^a line X -CH-. In some embodiments of the compound of Formula (Ia), X ² is -CH-. In some embodiments of the compound of Formula (Ia), X ² is -N-. In some embodiments of the compound of Formula (Ia), R ² is CO ₂ H, , or . In some embodiments of the compound of Formula (Ia), R ² is CO ₂ H, or . In some embodiments, the compound of Formula (I) has Formula Ib: Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein R ² is CO ₂ H, , or R ³ is halogen, cyano or OR ⁶ ; in some embodiments of the compound of formula (Ib), R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo- C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkynyl, C _{3 - 6} cycloalkyl, optionally a heteroaryl group substituted with three identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR ⁷ R ⁸ or cyano; and each R ⁶ independently C _{1 - 6} alkyl, fluoro-C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl-C _{0 - 1} alkyl, benzyl or . In some embodiments of the compound of Formula (Ib), X ¹ is -CH-. In some embodiments of the compound of Formula (Ib), R ² is CO ₂ H, or . In some embodiments of the compound of Formula (Ib), R ³ is halogen or OR ⁶ . In some embodiments of the compound of Formula (Ib), R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkane a C _{1 - 6} alkoxy-C _{1 - 6} alkyl group, a C _{2 - 6} alkynyl group, a C _{3 - 6} cycloalkyl group, an aryl group optionally substituted with 1 to 3 identical or different halogen atoms, A heteroaryl group, a halogen, NR ⁷ R ⁸ or a cyano group substituted by 1 to 3 identical or different halogen atoms, as the case may be. In some embodiments of the compound of Formula (Ib), R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkane A C _{1 - 6} alkoxy-C _{1 - 6} alkyl group, a C _{2 - 6} alkynyl group, a C _{3 - 6} cycloalkyl group, a halogen, NR ⁷ R ⁸ or a cyano group. In some embodiments of the compound of Formula (Ib), X ² is -CH-. In some embodiments of the compound of Formula (Ib), X ² is -N-. In some embodiments of the compound of Formula (Ib), X ¹ and X ^{2 are} each -CH-. In some embodiments of the compound of Formula (Ib), R ¹ is H, F or Cl. In some embodiments of the compound of Formula (Ib), R ² is CO ₂ H, or R ³ is halogen or OR ⁶ ; R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkynyl, C _{3 - 6} cycloalkyl, optionally substituted by 1 to 3 identical or different halogen atoms, optionally 1 to 3 heteroaryl groups which are the same or different to give a halogen atom, halogen, NR ⁷ R ⁸ or cyano; and each R ^{6 is} independently C _{1 - 6} alkyl, fluoro-C _{1 - 6} alkyl, C _3--6 cycloalkyl, C _3--6 cycloalkyl -C _{1 - 6} alkyl, benzyl or . In some embodiments of the compound of Formula (Ib), R ² is CO ₂ H, or R ³ is halogen or OR ⁶ ; R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkynyl, C _{3 - 6} cycloalkyl, optionally substituted by 1 to 3 identical or different halogen atoms, optionally 1 to 3 heteroaryl groups substituted with the same or different halogen atoms, halogen, NR ⁷ R ⁸ or cyano; each R ^{6 is} independently C _{1 - 6} alkyl, fluoro-C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, -C _{1 - 6} alkyl, benzyl or ; and X ² series -CH-. In some embodiments of compounds of formula (Ib), R ¹ is based H, halogen, C _{1 - 3} alkyl, fluoro -C _{1 - 3} alkyl, C _{3 - 6} cycloalkyl, fluoro -C _{1 - 3} alkyl oxy, cyano or C _{2 - 3} alkynyl group; R ² based CO ₂ H, , or ; R ³ based halo, cyano, C _{1 - 3} alkoxy or fluoro -C _{1 - 3} alkoxy group; R ⁴ lines _{^{H, OR 6, C 1 -}} 3 alkyl, fluoro -C _{1 - 3} alkyl _{, S (O) n -C 1} - 3 alkyl, hydroxy -C _{1 - 3} alkyl, C _{1 - 3} alkoxy, -C _{1 - 3} alkyl, C _{2 - 3} alkynyl, C _{3 - 6} cycloalkyl alkyl, optionally substituted by 1-2 of fluorine atoms, phenyl, pyridyl, halogen, NR ⁷ R ⁸ or cyano; each R ⁶ is independently line C _{1 - 3} alkyl, fluoro -C _{1 - 3} alkyl group, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, -C _{1 - 2} alkyl, benzyl or And R ¹ and R ⁸ are each independently selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and X ¹ and X ^{2 are} independently selected from -CH- and -N-. In some embodiments of the compound of Formula (Ib), R ¹ is H or halogen; R ² is CO ₂ H, , or ; R ³ based halo or cyano; R ⁴ based OR ^6, C _{1 - 3} alkyl, fluoro -C _{1 - 3 alkyl, S (O) n -C 1} - 3 alkyl, hydroxy -C _{1 - 3} alkyl group, C _{1 - 3} alkoxy, -C _{1 - 3} alkyl, C _{2 - 3} alkynyl, C _{3 - 6} cycloalkyl, halogen, cyano or NR ⁷ R ^8; R ⁶ line C _{1 - 3} alkoxy , fluoro -C _{1 - 3} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, -C _{1 - 2} alkyl, benzyl or And R ¹ and R ⁸ are each independently selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and X ₁ and X _{2 are} independently selected from -CH- and -N-. In some embodiments, R ² is CO ₂ H. In some embodiments, the R ² system . In some embodiments, the R ² system . In some embodiments, the R ² system . In some embodiments, the compound of formula (I) is selected from the group consisting of: N- (4-chloro-2-(methylsulfonylamino)phenyl)-2-naphthylamine; N- (4 -Chloro-2-( 2H -tetrazol-5-yl)phenyl)-2-naphthylamine; 5-chloro-2-(quinoline-3-carboxamido)benzoic acid; 5-chloro- 2-(6-fluoro-2-naphthylamino)benzoic acid; 2-(2-naphthylamino)-5-chloro-4-fluorobenzoic acid; 2-(2-naphthylamino)-5 -chloronicotinic acid; 2-(2-naphthylamino)-4,5-dichlorobenzoic acid; 5-chloro-2-(7-fluoroquinoline-3-carboxamido)benzoic acid; -(6-bromo-2-naphthylamino)-5-chlorobenzoic acid; 5-chloro-2-(7-methylquinolin-3-carboxamido)benzoic acid; 2-(2-naphthalene Amidino)-4-bromo-5-chlorobenzoic acid; 5-chloro-2-(6-(trifluoromethyl)-2-naphthylamino)benzoic acid; 2-(6-bromo-2- Naphthylamino)-4,5-dichlorobenzoic acid; 5-chloro-4-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acid; 2-(2-naphthylamino) -5-chloro-4-methoxybenzoic acid; 2-(benzo[b]thiophene-5-carbamimidino)-5-chlorobenzoic acid; 4,5-difluoro-2-(6-fluoro 2-naphthylamino)benzoic acid; 2-(2-naphthylamino)-4,5-difluorobenzoic acid; 2-(2-naphthylamino)-5-cyanobenzoic acid; ,5-Dichloro-2-(6-ethyl-2-naphthylamino) Formic acid; 2-(benzo[b]thiophene-5-carbamimidino)-5-chloro-4-fluorobenzoic acid; 2-(6-bromo-2-naphthylamino)-5-cyanobenzene Formic acid; 5-bromo-2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6-ethyl-2-naphthylamino)-4-methoxybenzoic acid 5-cyano-2-(6-ethyl-2-naphthylamino)benzoic acid; 5-chloro-2-(6-ethyl-2-naphthylamino)-4-fluorobenzoic acid; 2-(6-ethyl-2-naphthylamino)-4,5-difluorobenzoic acid; 5-chloro-2-(7-bromoquinoline-3-carboxamido)benzoic acid; 5- Chloro-2-(3-methylbenzo[b]thiophene-5-carbamimidino)benzoic acid; 2-(benzo[b]thiophene-6-carboxamido)-5-chlorobenzoic acid; 5-chloro-2-(thieno[2,3-b]pyridine-5-carboxamido)benzoic acid; N- (4-chloro-2-(5-sideoxy-4,5-dihydro) -1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; N- (4-chloro-2-(1 H -tetrazol-5-yl)phenyl)-7-fluoroquinoline 3-carbamamine; N- (4-chloro-2-(1 H -tetrazol-5-yl)phenyl)-6-fluoro-2-naphthylamine; N- (4-chloro-2- (5-Sideoxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro-2-(6-fluoro-2 -naphthylamino)-4-methoxybenzoic acid; N- (4-chloro-2-(5-o-oxy-4,5-dihydro-1,2,4-oxadiazol-3- Base) phenyl)- 2-naphthylamine; 5-chloro-4-methoxy-2-(2-phenylbenzo[b]thiophene-5-carbamido)benzoic acid; 5-chloro-2-(6-fluoro -2-naphthylamino)-4-(trifluoromethyl)benzoic acid; N- (4-chloro-2-(5-tertiaryoxy-4,5-dihydro-1 H -tetrazole-1 -yl)phenyl)-2-methylbenzo[b]thiophene-5-carboxamide; 5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-5- Methionine)benzoic acid; N- (4-chloro-5-fluoro-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6 -fluoro-2-naphthylamine; N- (4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)quinoline Benzyl-3-carboxamide; N- (4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6 -fluoro-2-naphthylamine; N- (4-chloro-2-(5-sidedoxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)- 6-ethynyl-2-naphthylamine; N- (4-chloro-2-(5-o-oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl -6-ethyl-2-naphthylamine; 5-fluoro-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acid; 4-chloro-5-fluoro-2- (6-fluoro-2-naphthylamino)benzoic acid; 6-(2-naphthylamino)benzo[d][1,3]dioxazole-5-carboxylic acid; N -(4,5- difluoro -2- (1 H - tetrazol-5-yl) phenyl) -6-fluoro-2-naphthyl Amides; N - (4,5- Fluor-2-(5-sided oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro- 2-(6-chloro-2-naphthylamino)benzoic acid; 6-fluoro- N- (4-fluoro-5-methoxy-2-(5-sideoxy-4,5-dihydro- 1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; 5-chloro-4-ethyl-2-(6-fluoro-2-naphthylamino)benzoic acid; 4-(benzene Methoxy)-5-chloro-2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(oxa) Cyclobutane-3-yloxy)benzoic acid; N- (4-chloro-5-methoxy-2-(5-sided oxy-4,5-dihydro-1 H -tetrazole-1- Phenyl)-6-fluoro-2-naphthylamine; 2-(2-naphthylamino)-5-(difluoromethoxy)benzoic acid; 2-(6-fluoro-2-naphthoquinone Amino)-4,5-dimethoxybenzoic acid; 7-(6-fluoro-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine- 6-formic acid; 5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-6-carbamimidino)benzoic acid; 5-cyano-2-(6-fluoro- 2-naphthylamino)-4-methoxybenzoic acid; 5-chloro-4-ethynyl-2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6 -fluoro-2-naphthylamino)-4-((tetrahydro-2 H -piperidin-4-yl)oxy)benzoic acid; 5-chloro-4-cyclopropyl-2-(6-fluoro -2-naphthylamino)benzoic acid; N- (4,5-difluoro-2-(5-sided oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro-2-(7-fluoroquinoline-3-carbamimidino)-4-(oxetan-3-yloxy)benzoic acid; 5-chloro-2-(6-fluoro- 2-naphthylamino)-4-(hydroxymethyl)benzoic acid; N- (4-chloro-5-(oxetan-3-yloxy)-2-(5-sideoxy)- 4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro-2-(6-fluoro-2-naphthylamino)- 4-(2,2,2-trifluoroethoxy)benzoic acid; N- (4-chloro-5-methoxy-2-((methylsulfonyl)aminecarbamyl)phenyl)-6 -fluoro-2-naphthylamine; 6-chloro- N- (4-chloro-2-(5-o-oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)- 2-naphthylamine; 6-(6-chloro-2-naphthylamino)-2,2-difluorobenzo[d][1,3]dioxazole-5-carboxylic acid; 2-(2- Naphthylamino)-5-chloro-6-methoxynicotinic acid; 2-(2-naphthylamino)-5-chloro-6-ethoxynicotinic acid; N- (4,5- Difluoro-2-((methylsulfonyl)amine-carbamoyl)phenyl)-6-fluoro-2-naphthylamine; N- (4-chloro-2-((difluoromethyl)sulfonate) Ethyl indenyl)-5-methoxyphenyl)-6-fluoro-2-naphthylamine; 2-(6-chloro-2-naphthylamino)-5-(difluoromethoxy) 4-fluorobenzoic acid; 5-cyano-2-(6-fluoro-2-naphthylamine Benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyanobenzoic acid; 5-cyano-2-(6-fluoro-2-naphthylamino)-4-methyl Benzoic acid; 5-cyano-2-(6-chloro-2-naphthylamino)-4-methylbenzoic acid; N- (4-(difluoromethoxy)-2-(5-side) Oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 6-chloro- N- (4-(difluoromethoxy) -2-(5-Sideoxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; 6-chloro- N- (4-chloro-5- Methoxy-2-(5-sided oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; N- (4-chloro-5-B Oxy-2-(5-o-oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 6-chloro- N- ( 4-chloro-5-ethoxy-2-(5-sided oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; N -(4 -chloro-5-methoxy-2-(5-sided oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-(trifluoromethyl)-2- Naphthylamine; N- (4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6- N- (4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl) -6-cyclopropyl-2-naphthylamine; N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-cyano-2-naphthylamine; 2,2-difluoro-6-(6-fluoro-2-naphthylamino)benzo[d][ 1,3]dicarbazole-5-carboxylic acid; 2-(2-naphthylamino)-5-chloro-4-(methoxymethyl)benzoic acid; N- (4-chloro-5-methoxy 2-(5-sided oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-7-fluoroquinoline-3-carboxamide; N - (4-Bromo-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine ; N- (4-bromo-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-chloro-2- Naphthylamine; N- (4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-6-fluoro-2 -naphthylamine; 7-(6-chloro-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 7-(6-cyanide 5-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 5-cyano-4-ethoxy-2-(6- Fluoro-2-naphthylamino)benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-methoxybenzoic acid 7-(7-fluoroquinoline-3- Methionamine)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 5-chloro-4-methoxy-2-(6-methyl-2- Naphthylamino)benzoic acid; 5-chloro-2-(6-cyclopropyl-2-naphthylamino)-4-methoxybenzene Acid; 5-chloro-2-(6-(difluoromethyl)-2-naphthylamino)-4-methoxybenzoic acid; 5-chloro-4-methoxy-2-(6-( Trifluoromethyl)-2-naphthylamino)benzoic acid; 5-chloro-2-(6-(difluoromethoxy)-2-naphthylamino)-4-methoxybenzoic acid; -Chloro-4-methoxy-2-(6-(trifluoromethoxy)-2-naphthylamino)benzoic acid; N- (4-chloro-2-(5-sideoxy-4, 5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-methyl-2-naphthylamine; N- (4-chloro-2-(5-sideoxy-4,5-) Dihydro-1 H -tetrazol-1-yl)phenyl)-6-cyclopropyl-2-naphthylamine; N- (4-chloro-2-(5-sideoxy-4,5-di) Hydrogen-1 H -tetrazol-1-yl)phenyl)-6-(trifluoromethoxy)-2-naphthylamine; 5-cyano-2-(6-fluoro-2-naphthylamino) -4-(oxetan-3-yloxy)benzoic acid; 5-cyano-2-(7-fluoroquinoline-3-carboxamido)-4-(oxetane) -3-yloxy)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(methoxymethyl)benzoic acid; 5-cyano-4-methoxy 2-(2-methylbenzo[b]thiophene-5-carbamimidino)benzoic acid; 8-(6-fluoro-2-naphthylamino)-3,4-dihydro-2 H -benzo[b][1,4]dioxin-7-carboxylic acid; 5-(difluoromethoxy)-2-(6-fluoro-2-naphthylamino)-4-methoxybenzene Formic acid; 5- Fluor-2-(6-fluoro-2-naphthylamino)-4-(oxetan-3-yloxy)benzoic acid; 2-(2-naphthylamino)-5-cyano -4-(oxetan-3-yloxy)benzoic acid; 2-chloro-2'-fluoro-5-(6-fluoro-2-naphthylamino)-[1,1'-linked Benzene]-4-carboxylic acid; N- (4-cyano-2-(5-sidedoxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-7 -fluoroquinoline-3-carboxamide; 5-chloro-2-(6-chloro-2-naphthylamino)-4-methoxybenzoic acid; 5-cyano-4-fluoro-2-( 6-fluoro-2-naphthylamino)benzoic acid; 4-cyano-5-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acid; 2-(6-chloro-2-naphthalene Amidino)-5-(difluoromethoxy)benzoic acid; 7-(2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6- Formic acid; 7-(6-(trifluoromethyl)-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 2-(2 -naphthylamino)-5-cyano-4-methoxybenzoic acid; 5-cyano-4-methoxy-2-(6-(trifluoromethyl)-2-naphthylamino) Benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-ethoxybenzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)- 4-(pyridin-4-yl)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridin-3-yl)benzoic acid; 5-chloro-2-( 6-fluoro-2-naphthylamino)-6- Methoxynicotinic acid; 5-chloro-6-ethoxy-2-(6-fluoro-2-naphthylamino)nicotinic acid; 5-chloro-2-(6-chloro-2-naphthoquinone Amino)-6-ethoxynicotinic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridin-2-yl)benzoic acid; 2-chloro-5- (6-fluoro-2-naphthylamino)isonicotinic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-isopropoxybenzoic acid; 5-chloro-4 -Cyano-2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6-chloro-2-naphthylamino)-4-isopropoxybenzoic acid; -(6-chloro-2-naphthylamino)-5-fluoro-4-methoxybenzoic acid; 4-chloro-2-(6-chloro-2-naphthylamino)-5-cyanobenzene Formic acid; 6-fluoro- N- (4-fluoro-5-(oxetan-3-yloxy)-2-(5-sideoxy-4,5-dihydro-1,2,4 -oxadiazol-3-yl)phenyl)-2-naphthylamine; 6-fluoro- N- (4-fluoro-5-methoxy-2-(5-sideoxy-4,5-di Hydrogen-1,2,4-oxadiazol-3-yl)phenyl)-2-naphthylamine; 2-(6-chloro-2-naphthylamino)-5-cyano-4-(cyclo) Propyl methoxy)benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-cyclobutoxybenzoic acid; 2-(6-chloro-2-naphthylamine 5-(cyano-4-(methylthio)benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-isopropoxybenzoic acid; N- ( 4-fluoro-5-A 2-(5-sided oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-2-naphthylamine; 5-chloro-2-(6 -chloro-2-naphthylamino)-6-methoxynicotinic acid; 5-cyano-4-methoxy-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamidine Amino)benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-(methylsulfinyl)benzoic acid; 2-(6-chloro-2-naphthylamine 5-(cyano-4-(difluoromethoxy)benzoic acid; N- (4-cyano-5-methoxy-2-(5-sidedoxy-4,5-dihydro-) 1,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthylamine; and 2-(6-chloro-2-naphthylamino)-5-cyano-4 -(dimethylamino)benzoic acid; or a pharmaceutically acceptable salt, solvate or salt thereof. In some embodiments, a pharmaceutical composition comprising a compound of any of the above embodiments, or a pharmaceutically acceptable salt, solvate or solvate thereof, and a pharmaceutically acceptable compound Carriers In some embodiments, a method of treating fibrosis comprising administering to a patient in need thereof the above pharmaceutical composition or a therapeutically effective amount of a compound of any of the above examples, or a pharmaceutically acceptable thereof a salt, a solvate or a solvate of the salt. In some embodiments of the method of treating fibrosis, the fibrosis is selected from the group consisting of scleroderma, fibrosis of the lungs, fibrosis of the kidney, and fibrosis of the liver. In some embodiments, a method of treating fibrosis comprising administering a therapeutically effective amount of a compound of Formula I' to a patient in need thereof is provided: Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein A is -C(R ¹ )=C(R ¹ )-C(R ¹ )=C(R ¹ )-, -SC(R ^1a )=C(R ^1a )-, -C(R ^1a )=C(R ^1a )-S- or -(CH ₂ ) _3-4 -; X ¹ series -CH-, -C( Halogen)- or -N-; X ² -CH- or -N-; X ³ -N- or -C(R ⁴ )-; each R ^{1 is} independently H, halogen, cyano, C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl, halo, -C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{1 - 6} alkoxy group or halo -C _{1 - 6} alkoxy, which is limited to at least two R ¹ H; each R ^{1a is} independently H, C _{1 - 6} alkyl or aryl; R ² is CO ₂ H, -C(O)NHSO ₂ R ⁵ , -NHSO ₂ R ⁵ , , , , , or R ³ is halogen, cyano or OR ⁶ ; R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{3 - 6} cycloalkyl, optionally 1 to 3 identical or a different halogen atom-substituted aryl group, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR ⁷ R ⁸ or cyano; or R ³ and R ⁴ together -O-CF ₂ -O- or -O-(CH ₂ ) _p -O-; R ⁵ is C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl or C _{3 - 6} cycloalkyl; R ⁶ C _{1 - 6} alkyl, halo -C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl _- (C ₀ - ₂ alkyl), benzyl, or a heterocyclic group; R ⁷ and R ⁸ are each independently selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and p is 1, 2 or 3.

All publications and patent applications mentioned in this specification are hereby incorporated by reference in their entirety in the extent of the extent Into the general. In one aspect, the invention provides a compound of formula (I):(I) or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein A-C(R)¹ )=C(R¹ )-C(R¹ )=C(R¹ )-,-S-C(R^1a )=C(R^1a )-, -C(R^1a )=C(R^1a )-S- or-(CH₂ )_3-4 -; X¹ -CH-, -C(halogen)- or -N-; X² Department -CH- or -N-; X³ Department-N- or -C(R⁴ )-; Each R¹ Independently H, halogen, cyano, C_{1 - 6} Alkyl, C_{3 - 6} Cycloalkyl, halo-C_{1 - 6} Alkyl, C_{2 - 6} Alkenyl, C_{2 - 6} Alkynyl, C_{1 - 6} Alkoxy or halo-C_{1 - 6} Alkoxy group, the restriction condition is at least two R¹ H; each R^1a Independently H, C_{1 - 6} Alkyl or aryl; R² CO₂ H,-C(O)NHSO₂ R⁵ -NHSO₂ R⁵ ,,,,,or; R³ Halogen, cyano or OR⁶ ; R⁴ H, OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C_{1 - 6} alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkenyl, C_{2 - 6} Alkynyl, C_{3 - 6} a cycloalkyl group, an aryl group substituted with 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR⁷ R⁸ Or cyano; or R³ And R⁴ Together -O-CF₂ -O- or -O-(CH₂ )_p -O-; R⁵ Department C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl or C_{3 - 6} Cycloalkyl; R⁶ Department C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, C_{3 - 6} Cycloalkyl-(C_{0 - 2} Alkyl), heterocyclic or benzyl; R⁷ And R⁸ Each is independently selected from H and C_{1 - 6} Alkyl; n is 0, 1 or 2; and p is 1, 2 or 3; does not include the following compounds: (A), (B), where R^1B H or OCH₃ :R^3B Br Br, Cl or I and R^4B H; or R^3B And R^4B OCH₃ ; or R^3B Department OCH₃ And R^4B Department O (CH₂ )₂ OCH₃ ; or R^3B And R^4B Together -O-(CH₂ )₂ -O- or -O-(CH₂ )₃ -O-, (C), where R^3C Br Br, Cl or I and R^4C H; or where R^3C And R^4C OCH₃ Or or where R^3C Department OCH₃ And R^4C Department O (CH₂ )₂ OCH₃ Or or where R^3C And R^4C Together -O-(CH₂ )₂ -O- or -O-(CH₂ )₃ -O-, and (D), where R^3D Br Br or Cl and R^4D H; or where R^3D And R^4D OCH₃ Or or where R^3D Department OCH₃ And R^4D Department O (CH₂ )₂ OCH₃ Or or where R^3D And R^4D Together -O-(CH₂ )₂ -O- or -O-(CH₂ )₃ -O-. Within this aspect, there exists a first group, where A is -CH=CH-C (R¹ )=CH-*, where * indicates proximity X¹ The carbon is connected, and all other variables are as defined for formula (I). Within this aspect, there is a second group, where X¹ -N-, and all other variables are as defined for formula (I) or as defined in the first group. Within this aspect, there is a third group, where X¹ -CH-, and all other variables are as defined for formula (I) or as defined in the first group. Within this aspect, there is a fourth group, where X³ Department-CR⁴ - and all other variables are as defined with respect to formula (I) or as defined in any of the first to third groups. Within this aspect, there is a fifth group, where X² -CH-, and all other variables are as defined with respect to formula (I) or as defined in any of the first to fourth groups. Within this aspect, there is a sixth group, where X² -N-, and all other variables are as defined with respect to formula (I) or as defined in any of the first to fourth groups. Within this aspect, there is a seventh group, where R² CO₂ H,,orAnd all other variables are as defined with respect to formula (I) or as defined in any of the first to sixth groups. Within this aspect, there is an eighth group, where R² CO₂ H,orAnd all other variables are as defined with respect to formula (I) or as defined in any of the first to sixth groups. Within this aspect, there is a ninth group having the formula (Ia):Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein R³ Halogen, cyano or OR⁶ ; R⁴ H, OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C₁ -₆ alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkynyl, C_{3 - 6} a cycloalkyl group, an aryl group substituted with 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR⁷ R⁸ Or cyano; and all other variables are as defined for formula (I) or as defined in any of the first to eighth groups. Within this aspect, there is a tenth group, where R³ Halogen, cyano or OR⁶ ;R⁴ OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C_{1 - 6} alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkynyl, C_{3 - 6} a cycloalkyl group, an aryl group substituted with 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR⁷ R⁸ Or cyano; and all other variables are as defined for formula (I) or as defined in any of the first to eighth groups. Within this aspect, there is an eleventh group having the formula (Ib):Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein R² CO₂ H,,or; R³ Halogen, cyano or OR⁶ ; R⁴ H, OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C_{1 - 6} alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkynyl, C_{3 - 6} a cycloalkyl group, an aryl group substituted with 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR⁷ R⁸ Or cyano; and R⁶ Department C_{1 - 6} Alkyl, fluorine-C_{1 - 6} Alkyl, C_{3 - 6} Cycloalkyl, C_{3 - 6} cycloalkyl-C_{0 - 1} Alkyl, benzyl orAnd other variables are as defined with respect to formula (I) or as defined in any of the second, third, fifth or sixth groups. Within this eleventh group, there is a first subgroup, where R² CO₂ H,orAnd other variables are as defined for equation (Ib). Within this eleventh group, there is a second subgroup, where R³ Halogen or OR⁶ And other variables are as defined for equation (Ib) or as defined in the first subgroup. Within this eleventh group, there is a third subgroup, where R³ Cyano group; R¹ Hydrogen, halogen or halo-C_{1 - 3} Alkyl; and other variables as defined for formula (Ib) or as defined in the first subgroup. Within this eleventh group, there is a fourth subgroup, where R⁴ OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C_{1 - 6} alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkynyl, C_{3 - 6} a cycloalkyl group, an aryl group substituted with 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR⁷ R⁸ Or cyano; and other variables are as defined for formula (Ib) or as defined in the first to third subgroups. Within this eleventh group, there is a fifth subgroup, where R⁴ OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C_{1 - 6} alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkynyl, C_{3 - 6} Cycloalkyl, halogen, NR⁷ R⁸ Or cyano; and other variables are as defined for formula (Ib) or as defined in the first to third subgroups. Within this eleventh group, there is a sixth subgroup, where X¹ And X² Each line CH; and other variables are as defined for formula (Ib) or as defined in the first to fifth subgroups. Within this eleventh group, there is a seventh subgroup, where R¹ H, F or Cl; and other variables as defined for formula (Ib) or as defined in the first to sixth subgroups. Within this eleventh group, there is an eighth subgroup, where R³ Halogen or cyano; R⁴ OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C_{1 - 6} alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkynyl, C_{3 - 6} Cycloalkyl, halogen, NR⁷ R⁸ Or cyano; and other variables are as defined for formula (Ib) or as defined in the first and sixth to seventh subgroups. Within this eleventh group, there is a ninth subgroup, where: R¹ H, halogen, C_{1 - 3} Alkyl, fluorine-C_{1 - 3} Alkyl, C_{3 - 6} Cycloalkyl, fluoro-C_{1 - 3} Alkoxy, cyano or C_{2 - 3} Alkynyl; R² CO₂ H,,or; R³ Halogen, cyano, C_{1 - 3} Alkoxy or fluoro-C_{1 - 3} Alkoxy; R⁴ H, OR⁶ , C_{1 - 3} Alkyl, fluorine-C_{1 - 3} Alkyl, S(O)_n -C_{1 - 3} Alkyl, hydroxy-C_{1 - 3} Alkyl, C_{1 - 3} alkoxy-C_{1 - 3} Alkyl, C_{2 - 3} Alkynyl, C_{3 - 6} Cycloalkyl, phenyl, pyridyl, halogen, NR substituted by 1 to 2 fluorine atoms, as the case may be⁷ R⁸ Or cyano; R⁶ Department C_{1 - 3} Alkyl, fluorine-C_{1 - 3} Alkyl, C_{3 - 6} Cycloalkyl, C_{3 - 6} cycloalkyl-C_{1 - 2} Alkyl, benzyl or; R⁷ And R⁸ Each is independently selected from H and C_{1 - 6} Alkyl; n is 0, 1 or 2; and X¹ And X² Independently selected from -CH- and -N-. Within this eleventh group, there is a tenth subgroup, where: R¹ H or halogen; R² CO₂ H,,or; R³ Halogen or cyano; R⁴ OR⁶ , C_{1 - 3} Alkyl, fluorine-C_{1 - 3} Alkyl, S(O)_n -C_{1 - 3} Alkyl, hydroxy-C_{1 - 3} Alkyl, C_{1 - 3} alkoxy-C_{1 - 3} Alkyl, C_{2 - 3} Alkynyl, C_{3 - 6} Cycloalkyl, halogen, NR⁷ R⁸ Or cyano; R⁶ Department C_{1 - 3} Alkyl, fluorine-C_{1 - 3} Alkyl, C_{3 - 6} Cycloalkyl, C_{3 - 6} cycloalkyl-C_{1 - 2} Alkyl, benzyl or; R⁷ And R⁸ Each is independently selected from H and C_{1 - 6} Alkyl; n is 0, 1 or 2; and X¹ And X² Independently selected from -CH- and -N-. Within this eleventh group, there is an eleventh subgroup, where: R¹ H;R² CO₂ H;R³ Halogen or cyano; R⁴ OR⁶ ;R⁶ Department C_{1 - 3} Alkyl; and X¹ And X² Department -CH-. Within this group and the groups and subgroups provided above, there is a category in which R² CO₂ H. Within this group and the groups and subgroups provided above, there is a category in which R² system. Within this group and the groups and subgroups provided above, there is a category in which R² system. Within this group and the groups and subgroups provided above, there is a category in which R² system. Within this group and the groups and subgroups provided above, there is a category in which R³ Chlorine. Within this group and the groups and subgroups provided above, there is a category in which R³ Is a cyano group. Within this group and the groups and subgroups provided above, there is a category in which R⁶ Is a methyl group. In a second aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. In a third aspect, the invention provides (i) a method of treating fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') as provided below, or a pharmaceutically acceptable compound thereof a salt, a solvate or a solvate of the salt; (ii) a compound of the formula (I'), or a pharmaceutically acceptable salt, solvate or solvate thereof, as provided below, It is for the treatment of fibrosis; (iii) the use of a compound of the formula (I'), or a pharmaceutically acceptable salt, solvate or solvate thereof, as provided below, for the manufacture thereof The agent used to treat fibrosis:Where A is -C(R¹ )=C(R¹ )-C(R¹ )=C(R¹ )-,-S-C(R^1a )=C(R^1a )-, -C(R^1a )=C(R^1a )-S- or-(CH₂ )_3-4 -; X¹ -CH-, -C(halogen)- or -N-; X² Department -CH- or -N-; X³ Department-N- or -C(R⁴ )-; Each R¹ Independently H, halogen, cyano, C_{1 - 6} Alkyl, C_{3 - 6} Cycloalkyl, halo-C_{1 - 6} Alkyl, C_{2 - 6} Alkenyl, C_{2 - 6} Alkynyl, C_{1 - 6} Alkoxy or halo-C_{1 - 6} Alkoxy group, the restriction condition is at least two R¹ H; each R^1a Independently H, C_{1 - 6} Alkyl or aryl; R² CO₂ H,-C(O)NHSO₂ R⁵ -NHSO₂ R⁵ ,,,,,or; R³ Halogen, cyano or OR⁶ ; R⁴ H, OR⁶ , S(O)_n R⁶ , C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, hydroxy-C_{1 - 6} Alkyl, C_{1 - 6} alkoxy-C_{1 - 6} Alkyl, C_{2 - 6} Alkenyl, C_{2 - 6} Alkynyl, C_{3 - 6} a cycloalkyl group, an aryl group substituted with 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR⁷ R⁸ Or cyano; or R³ And R⁴ Together -O-CF₂ -O- or -O-(CH₂ )_p -O-; R⁵ Department C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl or C_{3 - 6} Cycloalkyl; R⁶ Department C_{1 - 6} Alkyl, halo-C_{1 - 6} Alkyl, C_{3 - 6} Cycloalkyl-(C_{0 - 2} Alkyl), heterocyclic or benzyl; R⁷ And R⁸ Each is independently selected from H and C_{1 - 6} An alkyl group; n is 0, 1 or 2; and p is 1, 2 or 3. Within the third aspect, there is a first group, wherein the compound of formula (I') is a first aspect or a group, subgroup, class of compounds within the first aspect or a pharmaceutically acceptable compound thereof a salt, a solvate or a salt of the solvate. Within the third aspect and its first group, there is a second group in which the fibrosis is scleroderma, fibrosis of the lung, fibrosis of the liver, or fibrosis of the kidney. Any of the features of the embodiments, aspects, groups or sub-groups are applicable to all embodiments, aspects, groups or sub-groups identified herein. Furthermore, any of the features of the embodiments, aspects, groups, or subgroups can be independently combined in any manner with other embodiments, aspects, groups, or subgroups described herein in part or in whole, such as a Two or three or more embodiments, aspects, groups or sub-groups may be combined in whole or in part. Furthermore, any of the features of the embodiments, aspects, groups, or subgroups may be selected for other embodiments, aspects, groups, or subgroups. Any embodiment, aspect, group or subgroup of methods may comprise another embodiment, aspect, group or subgroup of compounds, and any embodiment, aspect, group or subgroup of compounds may be grouped State to perform another embodiment, aspect, group, or subgroup. Definitions The term "patient" includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans. The term "halo" or "halogen" means any fluoro, chloro, bromo or iodo group. The term "alkyl" refers to a saturated hydrocarbon chain which may be a straight or branched chain containing the specified number of carbon atoms. For example, C_{1 - 6} The alkyl group indicates a group which may have 1 to 6 (including 1 and 6) carbon atoms. Any carbon atom may be substituted, for example, by one or more substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and t-butyl. The term "haloalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms is replaced by a halo group. In some embodiments, more than one hydrogen atom (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) is replaced with a halo group. In such embodiments, the hydrogen atoms may each be replaced by the same halogen (e.g., fluorine) or the hydrogen atoms may be replaced by a combination of different halogens (e.g., fluorine and chlorine). "Haloalkyl" also includes alkyl moieties in which all hydrogen has been halosubstituted (sometimes referred to herein as perhaloalkyl, such as perfluoroalkyl, such as trifluoromethyl). Any carbon atom may be substituted, for example, by one or more substituents. As referred to herein, the term "alkoxy" refers to a radical of the formula -O-(alkyl). The alkoxy group can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, pentyloxy, 2-pentyloxy, 3- Pentyloxy or hexyloxy. Similarly, the term "thioalkoxy" refers to a radical of the formula -S-(alkyl). The terms "haloalkoxy" and "halothioalkoxy" mean -O-(haloalkyl) and -S-(haloalkyl), respectively. The term "mercapto" refers to -SH. The term "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One carbon of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Any ring or chain atom may be substituted, for example, by one or more substituents. Non-limiting examples of "aralkyl" include benzyl, 2-phenylethyl and 3-phenylpropyl. The term "alkenyl" refers to a straight or branched chain hydrocarbon chain containing the specified number of carbon atoms and having one or more carbon-carbon double bonds. Any carbon atom may be substituted, for example, by one or more substituents. The alkenyl group may include, for example, a vinyl group, an allyl group, a 1-butenyl group, and a 2-hexenyl group. The term "alkynyl" refers to a straight or branched chain hydrocarbon chain containing the specified number of carbon atoms and having one or more carbon-carbon reference bonds. Any carbon atom may be substituted, for example, by one or more substituents. Alkynyl groups can include, for example, ethynyl, propargyl, 1-propynyl, and 2-butynyl. As used herein, the term "heterocycle" or "heterocycle", as used herein, means a stable 4, 5, 6 or 7 membered monocyclic ring comprising at least one non-aromatic (ie saturated or partially unsaturated) ring or a stable 6, 7, 8, 9, 10, 11 or 12 membered fused bicyclic heterocyclic ring system consisting of carbon atoms and one to four heteroatoms selected from the group consisting of N, O and S, wherein nitrogen and sulfur The heteroatoms may be oxidized as appropriate, and wherein the nitrogen heteroatoms may be quaternized in four stages. In the case of a "heterocycle" which is a bicyclic group, the second ring may also be a non-aromatic group consisting of a carbon atom and one to four heteroatoms selected from the group consisting of N, O and S as defined above. The ring, or the second ring, may be a benzene ring or a "cycloalkyl" or "cycloalkenyl" as defined hereinafter. Examples of such heterocyclic groups include, but are not limited to, azetidine, &lt;134381; alkane, dihydrofuran, dihydropentan, dioxane, dioxolane, hexahydrozine, Imidazolium, imidazoline, porphyrin, iso- &lt;134381; alkane, isoporphyrin, isothiazoline, isothiazolidine, isoxazoline, isoxazole, morpholine, oxazoline, oxazolidine , oxetane, piperazine, piperidine, piperazine, pyrazole, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorph, thiazoline, thiazopyridine, thio? Porphyrin and its N-oxide. The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon radical. Any carbon atom may be substituted, for example, by one or more substituents. The ring carbon acts as a point of attachment of the cycloalkyl group to another moiety. The cycloalkyl moiety can include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1]heptyl). The term "cycloalkenyl" refers to a partially unsaturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon radical. The point of attachment of a cyclocarbon (e.g., saturated or unsaturated) cycloalkenyl substituent. Any carbon atom may be substituted, for example, by one or more substituents as defined herein. The cycloalkenyl moiety can include, for example, cyclopentenyl, cyclohexenyl, cyclohexadienyl or norbornene. As used herein, the term "cycloalkylene" refers to a divalent monocyclic cycloalkyl group having the specified number of ring atoms. As used herein, "heterocycloalkylene" refers to a divalent monocyclic heterocyclic group having the indicated number of ring atoms. As used herein, the term "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring having up to 6 members in each ring, at least one of which is an aromatic ring. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl. As used herein, the term "heteroaryl", as used herein, denotes a stable 5, 6 or 7 membered monocyclic or stable 9 or 10 membered fused bicyclic ring system comprising at least one aromatic ring derived from a carbon atom. And one to three hetero atoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms are optionally oxidized, and the nitrogen heteroatoms may be quaternized by quaternary conditions. In the case where the nitrogen system has only heteroatoms, there may be four nitrogens. In the case of a "heteroaryl" group which is a bicyclic group, the second ring need not be an aromatic ring and does not need to contain a hetero atom. Thus, "heteroaryl" includes, for example, a stable 5, 6 or 7 membered monocyclic aromatic ring consisting of a carbon atom and one to four heteroatoms as defined above, fused to a benzene ring or fused to the above. "Heterocycle", "cycloalkyl" or "cycloalkenyl" as defined. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, Benzooxazole, porphyrin, porphyrin, furan, furazan, imidazole, oxazole, hydrazine, pyridazine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, hydrazine Azine, acridine, anthracene, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole and Its N-oxide. As used herein, the term "mercapto" refers to a group derived from an organic acid by removal of the hydroxyl portion of the acid. Thus, fluorenyl is intended to include, for example, ethyl, propyl, butyl, decyl, pentylene, benzhydryl, and the like. The term "treating/treat/treatment" generally refers to controlling, alleviating, ameliorating a specified condition, slowing the progression of a given condition, or eliminating a specified condition once the condition has been determined. The term "prevention" generally refers to preventing the specified condition, delaying the onset of a specified condition, or reducing the risk of developing a specified condition or causing a course of the condition, or preventing the recurrence of the condition. The term "therapeutically effective amount" or "effective amount" is an amount sufficient to achieve a beneficial or desired clinical result. An effective amount can be administered one or more times. An effective amount is usually sufficient to alleviate, ameliorate, stabilize, reverse, slow or delay the progression of a disease condition. Compound Forms and Salts The compounds of the present invention may contain one or more asymmetric centers, and thus racemates and racemic mixtures, enantiomeric enriched mixtures, single enantiomers, individual diastereomeric The form of isomers and diastereomeric mixtures appears. The compounds of the invention may exist in the form of isomers (enantiomers, diastereomers) by the nature of the asymmetric center or by limited rotation. Any isomer may be present in which the asymmetric center is in the (R)-, (S)- or (R, S)-configuration. It will also be appreciated that when two or more asymmetric centers are present in a compound of the invention, several diastereomers and enantiomers of the exemplified structure are generally possible, and pure diastereomers. And pure enantiomers represent preferred embodiments. Pure stereoisomers, pure diastereomers, pure enantiomers and mixtures thereof are intended to be within the scope of the invention. All isomers of the compounds of the invention which are isolated, pure, partially pure or in the form of a racemic mixture are encompassed within the scope of the invention. Purification of such isomers and separation of such isomeric mixtures can be accomplished by standard techniques known in the art. For example, diastereomeric mixtures can be separated into individual isomers by chromatography or crystallization, and the racemates can be separated into individual pairs by chromatographic chromatography or by resolution. isomer. The compounds of the invention include all cis, trans, ipsilateral, contralateral, E (E) and Z (Z) isomers, as well as suitable mixtures thereof. The compounds of the invention may also be represented in a variety of tautomeric forms, in which case the compounds of the invention expressly include all tautomeric forms of the compounds described herein, but may represent only a single tautomeric form. All such isomeric forms of such compounds are expressly included in the present invention. The compound of the present invention includes the compound itself as well as a salt, a solvate thereof, a solvate of the salt, and a prodrug thereof, as appropriate. The salt for the purpose of the present invention is preferably a pharmaceutically acceptable salt of the compound of the present invention (for example, see S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19). Also included are salts which are not themselves suitable for pharmaceutical use but which are useful, for example, for isolation or purification of the compounds of the invention. For example, a salt can be formed between an anion and a positively charged substituent (eg, an amine group) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate and acetate. Likewise, salts can also be formed between a cation and a negatively charged substituent (e.g., a carboxylic acid ester) on a compound described herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. When the compound of the present invention contains an acid group and a base, the compound of the present invention may also form an internal salt, and such a compound is within the scope of the present invention. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the parent compound which has been modified by the formation of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include such salts derived from inorganic acids; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, Lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxy maleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-Ethyloxybenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, naphthalene disulfonic acid, methanesulfonic acid, ethanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid And its analogues. When the compounds of the invention are basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Such inorganic acids include hydrochloric acid, hydrobromic acid, sulfonic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, and the like. Suitable organic acids include acetic acid, propionic acid, glycolic acid, stearic acid, ascorbic acid, hydroxy maleic acid, phenylacetic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-ethyloxybenzoic acid, benzenesulfonic acid , benzoic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, ethane disulfonic acid, oxalic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, Maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, p-toluenesulfonic acid and the like. When the compounds of the invention are acidic, the salts can be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Such salts which can be prepared include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, dicyclohexylamine salts, N-methyl-D-reducing glucosamine salts, ginseng (hydroxymethyl) methylamine salts. , arginine, per-amine and its analogues. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, page 1418; Journal of Pharmaceutical Science, 66, 2 (1977); and "Pharmaceutical Salts: Properties, Selection, and Use. A Handbook"; Wermuth, CG and Stahl, PH (ed.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8], each of which is incorporated herein by reference in its entirety. In the context of the present invention, solvates represent such forms of the compounds of the invention which form a complex in solid or liquid form by stoichiometric coordination with a solvent molecule. Hydrates are a specific form of solvates in which they coordinate with water. In the case of the present invention, hydrate is a preferred solvate. The formation of solvates is described in more detail in "Solvents and Solvent Effects in Organic Chemistry"; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6] The content is incorporated herein by reference in its entirety. Those skilled in the art will recognize the solvates of the present invention. The invention also encompasses all suitable isotopic variations of the compounds of the invention. It will be understood that an isotopic variation of a compound of the invention means that at least one atom in the compound of the invention has been exchanged for another atom having the same atomic number but different atomic mass than the atomic mass normally or predominantly present in nature. Compound. Examples of isotopes which may be incorporated into the compounds of the invention are such isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2H (氘), 3H (氚), 13C, 14C, 15N, 17O, 18O, 18F, 36Cl, 82Br, 123I, 124I, 125I, 129I and 131I. Particular isotopic variations of the compounds of the invention, especially those isotopically modified with one or more radioisotopes, may be useful, for example, to study the mechanism of action or the distribution of active compounds in vivo. Compounds labeled with 3H, 14C and/or 18F isotopes are particularly suitable for this purpose due to their relatively ease of preparation and detection. In addition, the incorporation of an isotope, such as incorporation into a sputum, may result in a particular therapeutic benefit due to the greater metabolic stability of the compound, such as an increase in the in vivo half-life or a desired reduction in the active dose. In some cases, such modifications of the compounds of the invention may therefore also constitute a preferred embodiment of the invention. Isotopic variants of the compounds of the invention may be prepared by methods known to those skilled in the art, for example by the methods and methods described below, by using specific reagents and/or starting compounds therein. The corresponding isotope is modified to prepare. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. In some embodiments, the compound of formula (I) is prepared in a prodrug form. Prodrugs are generally prodrugs which, upon administration to an individual and subsequent absorption, are converted to active or more active substances via processes such as conversion by metabolic pathways. Examples of prodrugs include carboxylic acid group C_{1 - 6} Alkyl esters which are capable of providing the active compound when administered to an individual. Pharmaceutical Compositions As used herein, the term "composition" is intended to encompass one or more of the compounds of the invention and the inert ingredients which comprise the carrier. The term "pharmaceutical composition" as used herein encompasses the preparation of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the salt, and a pharmaceutically acceptable carrier. Any composition. The term "pharmaceutically acceptable carrier" means a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and is not deleterious to the recipient. The invention includes, in its scope, prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound. Thus, in the method of treatment of the present invention, the term "administration of/administering a" compound shall encompass the conversion to a specified compound in vivo by the use of a specifically disclosed compound or by unspecified disclosure but after administration to a patient. The compounds treat different such conditions. Conventional procedures suitable for the selection and preparation of prodrug derivatives are described, for example, in "Design of Prodrugs", edited by H. Bundgaard, Elsevier, Amsterdam, NL, 1985. Metabolites of such compounds include the active species produced when the compounds of the invention are introduced into a biological environment. The amount of administration depends on the compound formulation, the route of administration, etc., and is generally determined by routine experimentation, and it is necessary to produce various changes depending on the target, the host, and the route of administration. In general, the amount of active compound in a unit dosage of the formulation may vary or be adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg depending on the particular application. For convenience, the total daily dose may be divided and dispensed in several portions during the day, if necessary. The pharmaceutical composition of the present invention for parenteral injection comprises a pharmaceutically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion and for reconstitution into a sterile injectable solution or dispersion upon use. Sterile powder. Examples of suitable aqueous and non-aqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol and the like), suitable mixtures thereof, vegetable oils (such as olive oil). And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the desired particle size in the case of dispersion and by the use of surfactants. These pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include an isotonic agent such as sugar, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin. Where necessary and for more efficient distribution, the compounds can be incorporated into slow release or targeted delivery systems, such as polymeric matrices, liposomes, and microspheres. The pharmaceutical composition as an injectable formulation can be sterilized, for example, by filtration through a bacterial retention filter or by incorporation into a sterilizing agent in the form of a sterile solid pharmaceutical composition, which may be dissolved or dispersed upon application. In sterile water or other sterile injectable media. The solid dosage forms of the pharmaceutical compositions of the present invention for oral administration include capsules, troches, pills, powders, and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) filler or extender Such as starch, lactose, sucrose, glucose, mannitol and citric acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants , such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain citrates and sodium carbonate, e) dissolution retarders, such as paraffin, f) absorption enhancers , such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, hard Magnesium citrate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may also contain a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose/milk sugar and high molecular weight polyethylene glycols and the like. . The solid dosage forms of the pharmaceutical compositions of the present invention may be prepared from coatings and shells, such as enteric coatings and other methods known in the art of pharmaceutical formulation, in the preparation of lozenges, dragees, capsules, pills, and granules. Coating. It may optionally contain an opacifying agent and may also be a formulation which, in a particular portion of the intestinal tract, will optionally release the active ingredient in a delayed manner. Examples of medical compositions that can be used for embedding include polymeric substances and waxes. The active compound may also be in microencapsulated form with one or more of the above-mentioned excipients, as appropriate. Liquid dosage forms for the pharmaceutical compositions of the present invention for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, cosolvents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzene. Benzyl formate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (in detail, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin , fatty acid esters of tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. Besides the inert diluent, the oral pharmaceutical compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents. In addition to the active compound, suspensions of the compounds of the invention may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar-agar and xanthine and mixtures thereof. A pharmaceutical composition for rectal or vaginal administration is preferably a suppository which can be prepared by solidifying the compound with ambient temperature, but liquid at body temperature and thus melting and releasing the active compound in the rectum or vaginal cavity It is prepared by mixing a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax. Dosage forms for topical administration of a compound or pharmaceutical composition of the invention include powders, patches, sprays, ointments and inhalants. The active compound can be admixed under sterile conditions with apharmaceutically acceptable carrier and any of the required preservatives, buffers or propellants. Uses In certain embodiments, the compounds of the invention are useful in the treatment of a disease or condition associated with fibrosis. In some embodiments, the compounds of the invention are useful for treating a disease or condition associated with or not associated with fibrosis, selected from the group consisting of scleroderma, lung disease, and conditions, such as pulmonary fibrosis, including idiopathic pulmonary fibrosis. (IPF), interstitial lung disease, idiopathic interstitial lung disease and pulmonary hypertension; heart disease and conditions, such as ischemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and Heart failure caused by hypertension; liver diseases and conditions, such as liver cirrhosis and NASH; and kidney diseases and conditions, such as progressive kidney disease glomerulonephritis, glomerular disease and diabetic nephropathy; eye diseases and Symptoms, such as diabetic retinopathy; skin or subcutaneous scar formation, such as keloids, adhesions, hypertrophic scar formation or cosmetic scar formation; or in the form of adjuvants or anti-fibrotic agents for pancreatic cancer, to borrow The penetration of the chemotherapeutic drug is increased by reducing the density of the connective tissue matrix. In one aspect, the invention disclosed herein relates to a compound of formula (I) suitable for use in the treatment of fibrotic diseases of the skin, lungs, liver, kidneys, heart, muscle tissue and eyes. In another aspect, the invention is directed to a method of preventing the onset and/or recurrence of such fibrotic diseases. The invention also includes pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. The invention also relates to a method of treating a fibrotic disease of the skin, lungs, liver, kidneys, heart, muscle tissue and eyes comprising administering a therapeutically effective amount of a compound of formula (I). Such methods comprise administering to a subject an effective amount of a compound of formula (I) (and/or any of the other formulae described herein) as defined herein, or a salt thereof (eg, a pharmaceutical) Learnably acceptable salt). In another aspect, a compound of formula (I) (and/or a compound of any of the other formulae described herein) as defined herein, or a salt thereof (eg, a pharmaceutically acceptable salt) Use in the preparation or use as a medicament for the treatment or prevention of one or more diseases, disorders or conditions caused by fibrosis or associated with fibrosis. Administration of the compounds and pharmaceutical compositions described herein can be, for example, oral, parenteral (e.g., subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and By intracranial injection or infusion technique), by inhalation spray, topical, transrectal, nasal, buccal, transvaginal, via an implantable reservoir, by injection, subdermal, intraperitoneal, transmucosal or By eye preparation, from about 0.01 mg/kg to about 1000 mg/kg per 4 to 120 hours (eg, from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, Dosages ranging from about 1 to about 10 mg/kg are administered according to the requirements of the particular drug. The interrelationship between doses for animals and humans (in milligrams per square meter of body surface) is described by Freireich et al, Cancer Chemother. Rep. 50, 219 (1966). The body surface area can be roughly determined by the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the pharmaceutical composition is administered by oral administration or by injection. The methods herein encompass the administration of an effective amount of a compound or a pharmaceutical composition comprising one or more compounds to achieve a desired or prescribed effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day, or administered as a continuous infusion. Such administration can be used in the form of chronic or acute therapy. A dose lower or higher than the above-mentioned required dose may be required. The specific dosage and treatment regimen for any particular patient will depend on a number of factors, including the activity, age, weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, disease, condition, or symptom of the particular compound used. The severity and duration of the disease, the patient's treatment of the disease and the diagnosis of the treating physician. The dosage form comprises from about 0.05 mg to about 2,000 mg (eg, from about 0.1 mg to about 1,000 mg, from about 0.1 mg to about 500 mg, from about 0.1 mg to about 250 mg, from about 0.1 mg to about 100 mg, from about 0.1 mg to about 50 mg) Or from about 0.1 mg to about 25 mg of a compound of formula (I) (and/or a compound of any of the other formulae described herein) as defined herein, or a salt thereof (eg, pharmaceutically acceptable) The dosage form may further comprise a pharmaceutically acceptable carrier and/or other therapeutic agent. However, the actual dosage concentration and duration of administration of the active ingredient in the pharmaceutical compositions of the present invention may vary to achieve a certain amount. The active ingredient, the amount of the active ingredient is effective for obtaining a desired therapeutic response for a particular patient, pharmaceutical composition and mode of administration and is non-toxic to the patient. Therefore, when appropriate, it is necessary to deviate from the prescribed amount, in particular with age, sex, weight, The general health status of the diet and the patient, the route of administration, the individual response to the active ingredient, the nature of the preparation, and the time or interval over which the administration takes place. Therefore, in some cases It is desirable to use below the minimum amount described above, however in other cases the upper limit must be exceeded. In the case of larger doses, it is advisable to divide these larger amounts into individual doses of the day. In one aspect, the compound or pharmaceutical composition of the invention may be combined with one or more additional anti-fibrotic agents and/or one or more agents to alleviate, ameliorate, stabilize, reverse, slow or delay progression of the fibrotic disease. Administration. Certain additional agents may be used to treat fibrosis in a particular organ. For example, for pulmonary fibrosis, such agents may include, but are not limited to, corticosteroids, such as prednisone (prednisone); , such as cyclophosphamide, azathioprine, methotrexate and cyclosporine; mycophenolate mofetil; N-acetylcysteine; pirfenidone; Nintedanib and its analogs. Other agents that can be used in combination with the compound of formula (I) for conditions of fibrotic diseases such as diabetic nephropathy, diabetic pulmonary fibrosis, myelofibrosis include another NOx inhibitor, such as GKT137831 (Genkyotex, SA, Switzerland); galectin-3 inhibitors such as TD-139 (Galecto Biotech, Denmark); LPA1 receptor antagonists such as BMS-986020 (Bristol-Myers Squibb, New York, USA); Human PTX-2, such as PRM-151 (Promedior, Massachusetts, USA); and antibodies targeting IL-3 (such as lebrikizumab (Genentech, California, USA) and tarotinumab ( Tralokinumab) (AstraZeneca, UK), LOXL2 (such as simtuzumab (Gilead Sciences, California, USA)), CTGF (such as FG-3019 (FibroGen, California, USA), integrin αvβ6 (such as STX- 100, Biogen, Massachusetts, USA) and IL-3/IL-4 (such as SAR156597 (Sanofi, France)). In certain embodiments, the additional agent can be part of a plurality of dosing regimens with a compound of the invention (eg, one or more compounds of formula (I) and/or any of the other formulae, including any subgenus thereof or Specific compounds) are administered separately (eg, sequentially; through different overlapping time courses). In other embodiments, such agents may be part of a single dosage form, mixed with a compound of the invention in a single pharmaceutical composition. In another embodiment, such agents may be administered in separate doses, with the administration of one or more compounds of formula (I) (and/or any of the other formulae, including any subgenus or specific compound thereof Substantially the same time (e.g., administration with the administration of one or more compounds of formula (I) (and/or any of the other formulae, including any subgenus or specific compound thereof). When a pharmaceutical composition of the invention comprises a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, the compound and the additional agent may be administered between about 1 and 100% of the dosage typically administered in a monotherapy regimen. And preferably at a dose concentration between about 5 and 95%. The pharmaceutical compositions of the present invention may contain any of the conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, base or buffer to enhance the stability of the formulated compound or its delivery form. The pharmaceutical compositions of the present invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, troches, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, conventional carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in a capsule form, suitable diluents include lactose and dried corn starch. When the aqueous suspension and/or emulsion is administered orally, the active ingredient can be suspended or dissolved in the oil phase and then combined with emulsifying and/or suspending agents. Some sweeteners and/or flavoring and/or coloring agents may be added as necessary.Biological function Material DMEM (Dulbecco's modified Eagle's medium), fetal bovine serum, blasticidin, neomycin (G418, geneticin), tetracycline, acuzyme and amp Amplex Red was purchased from Invitrogen (Carlsbad, CA). TGFβ1 was purchased from R & D Systems (Minneapolis, MN). Production of stable cell lines NOX4 expressing cell lines were generated according to minor modifications of the above method (Serrander, 2007). The full-length human NOX4 cDNA vector (Accession No.: BC040105; Pure Line ID: 5590269) was purchased from Dharmacon (Lafayette, CO). The NOX4 gene was cloned into the pcDNA4/TO vector (Invitrogen). Overexpression of tetracycline receptors (T-REx) transfected with a tet-on (TO) vector containing NOX4^TM ; Invitrogen) HEK-293 (human embryonic kidney) cells and a positive pure line was selected with neomycin. At 37 ° C in air at 5% CO₂ Next, supplemented with 10% fetal bovine serum and 100 units/ml penicillin and 100 μg/ml streptomycin, and selected antibiotic blasticidin (5 μg/ml) and homomycin (200 μg/ml) HEK-293 cells stably expressing NOX4 were cultured in a growth medium of DMEM. NOX4 expression was induced by the addition of 1 μg/mL tetracycline and non-inducible cells (-tetracycline) served as a negative control. Cell-based H₂ O₂ Analysis One day prior to the start of the analysis, NOX4 HEK cells were seeded in 96-well plates at 20,000 cells/well in 0.1 mL cell culture medium with or without 1 μg/ml tetracycline (Corning^TM Costar^TM No. 3603). Twenty four hours later, the cells were washed with PBS and the NOX4 overexpressing cells were preincubated for 3 hours with increasing concentrations (30 pM to 30 μM) of the inhibitor compound. Then use H by fluorescence₂ O₂ The selective probe NBzF (Abo, 2011) measures NOX4 enzyme activity. Fluorescence measurements were performed on a FlexStation 3 multi-mode micro-quantitative disc reader (Molecular Devices, LLC., Sunnyvale, CA, USA). Fluorescence at 2 different time points was measured to calculate the enzyme activity rate (RFU/min). Membrane based H₂ O₂ Analysis To prepare membranes, human NOX4 was induced with tetracycline (1 μg/mL) for 24 hours and cells were harvested using accutase. The cells were resuspended in an equal volume of growth medium to inactivate apozyme and then the cells were assembled by centrifugation at 1450 xg for 10 min at 4 °C. The medium was aspirated and the cells were solubilized in a portion of the separation buffer (1X PBS, by sonication (four 10-second pulses at a power of 10 using an XL-2000 Series sonic processor (Qsonica, LLC, Newtown, CT)). 250 mM sucrose, 1 mM EDTA). The lysate was kept on ice for 20 minutes and then the nucleus was partially agglomerated by centrifugation at 800 x g for 10 minutes. The supernatant layer was transferred to a fresh collection tube and sonicated again as described above. Discard the nuclear agglomerates. The supernatant layer was then centrifuged at 20,000 x g for 10 min at 4 °C to partially agglomerate the mitochondria. The supernatant layer was transferred to a fresh collection tube and the mitochondrial aggregates were discarded. To obtain the membrane fraction, the supernatant layer was subjected to ultracentrifugation (100,000 x g) for 1 hour at 4 °C. The remaining agglomerates consisting of membrane fractions were resuspended in a portion of the separation buffer containing 20% glycerol and the protein concentration was determined using BSA as a standard using the BioRad Protein Assay Kit. The ROS activity was then determined using the Ample Red method. For this, the membrane was diluted with PBS containing 4 μM FAD to obtain an assay concentration of 50 μg/ml. Forty-five microliters of this membrane stock was added to each well of a 96-well plate. The DMSO stock solution of the NOX4 inhibitor compound was diluted with a buffer (PBS) at a 10-fold concentration. Ten microliters of vehicle (0.1% DMSO/PBS) or NOx4 inhibitor compound was then added to the wells and pre-incubated with NOX4 overexpressing membrane for 30 min at room temperature. After the drug was incubated, 10 μL of 30 μM cytochrome C was added to reduce the Ample Red background. Apulle red solution (4x) was prepared according to the manufacturer's recommendations and 25 μL of Ampere red solution was added to each well. The reaction was initiated by the addition of 10 μL of 500 μM NADPH to yield a final concentration of 50 μM/well and the rate of enzyme activity was determined according to the manufacturer's recommendations. In vivo pharmacodynamic analysis of 4 female C57BL/6 mice (20-25 g, obtained from Harlan Laboratory, Livermore, CA) in cages, allowing free access to food and water and adapting them to the new environment before the test begins 7 days. After the adaptation phase, use isoflurane (at 100% O)₂ 3.0-3.5% of the mice were lightly anesthetized and scraped off the hair in the upper region of the dorsal side. A 3.0 μg/mL TGFβ solution was prepared by sterile filtration of PBS, and 0.1 mL of this solution (300 ng TGFß/site) was subcutaneously administered to each shaved area using a modification of the previous method (Ikawa, 2008). Repeat this procedure for 3 days every day. Test compound or vehicle is delivered orally (PO) once or twice daily starting on day 0. On the fourth day of the study, using CO₂ All animals were sacrificed and an 8 mm tissue biopsy was obtained for subsequent PCR analysis of the effect of the drug on TGF-stimulated gene expression. Blood was also collected via cardiac puncture into an EDTA tube for analysis of drug content. Information on representative compounds in the cell and membrane based assays described above is reported in the table below. In this table, the example numbers correspond to such numbers as the example compounds described herein below. abbreviation Alkyl: Me = methyl; Et = ethyl; Pr = propyl; i-Pr = isopropyl; n-Bu = n-butyl; t-Bu = tert-butyl synthesis starting material for synthesis It is synthesized or obtained from commercially available sources using methods known in the chemical arts, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, and the like. General methods for preparing compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the structures provided herein. In the experiments, the instruments used included the Shimadzu LCMS-2020 system and the Shimadzu Prominence HPLC system (Shimadzu, Columbia, Maryland). In some embodiments, the compounds described herein were prepared as outlined in the general synthetic scheme below. In Scheme 1, an ortho-amino benzoate group1 (and its heteroaryl derivatives) and (hetero) aryl chloride2 Condensation in the presence of a base such as triethylamine or pyridine to give the guanamine ester3 . Typical ester hydrolysis conditions (e.g., lithium hydroxide monohydrate, water, THF) provide compound I(i) which, when treated with sulfonamide in the presence of a coupling agent such as CDI, gives the corresponding N-mercaptosulfonamide I (ii) ). The starting (hetero)arylamines for compounds I(iii)-I(v) can be prepared using the general methods shown in Schemes 2 and 3. Amino substituted (hetero) aryl carbonitrile4 When treated with sodium azide and ammonium chloride, the corresponding 5-tetrazolyl (hetero)arylamine is obtained.5 And treatment with hydroxylamine in the presence of a base such as sodium methoxide, followed by treatment with diethyl carbonate to give the corresponding (hetero)arylamine substituted with 1,2,4-oxadiazolone6 . (hetero)arylamine substituted with tetrazolone11 Can be prepared as follows: from nitro (hetero) arylamine8 Using bis or triphosgene, trimethyldecyl azide and heating to obtain a nitro compound10 , which gives an amine compound when hydrogenated in the presence of Muni Ni11 . In addition, a compound substituted with a nitro group10 Nitro(hetero)arylcarboxylic acid9 It is prepared by sequentially treating with ethylene dichloride, aluminum chloride and sodium azide. amine5 ,6 and11 Use of acid chloride under typical amidine reaction conditions2 Deuteration, or use acid in the presence of a coupling agent such as HATU, as appropriate7 Purification gives the corresponding compounds I(iii), I(iv) and I(v). In Scheme 4, dichloric acid12 Conversion to the corresponding ether acid using the appropriate alcohol and base13 . Make acid13 Conversion to an ester and the use of oxonium phosphine/Pd catalytic conditions for the halide14 With guanamine15 Coupling16 , followed by chlorination with NCS and subsequent hydrolysis of the ester to give the compoundI ( I ' ) .General synthetic procedure for exemplary compounds Process 1Process 2Process 3Process 4Preparation of intermediates Intermediate 1. 6-chloro-2-naphthoic acidCombine 6-bromo-2-naphthoic acid (9.00 g, 35.85 mmol) and DMF (140 mL), stir and subsurface N₂ After degassing for 10 minutes, CuCl (35.49 g, 358.50 mmol) and CuI (6.96 g, 36.57 mmol) were then added. The reaction vessel was covered with aluminum foil and refluxed for 5 hours under a nitrogen atmosphere. The mixture was cooled to 60 ° C and then filtered through celite. The filtrate was diluted with EtOAc and 1 M HCl. The organic phase was washed again with 1 M EtOAc EtOAc (EtOAc) The resulting crude solid was suspended in EtOAc (EtOAc m.) Intermediate 2. 2-Amino-5-cyano-4-methoxybenzoic acid methyl esterstep 1:2- Amine -5- Cyano -4- Fluorobenzoic acid Add CuCN (3.5 g, 39.2 mmol) to a solution of 2-amino-5-bromo-4-fluorobenzoic acid (8.33 g, 35.6 mmol) in N-methylpyrrolidone (22 mL) The sealed vessel was heated to 205 ° C for 6 hours. After cooling, the mixture was partitioned between EtOAc and EtOAc.₄ ), filtered and evaporated in vacuo. The crude material 2-amino-5-cyano-4-fluorobenzoic acid was obtained by wet-purification from DCM, which was used without further purification. Step 2:2- Amine -5- Cyano -4- Methoxybenzoic acid . Add Cs to a solution of 2-amino-5-cyano-4-fluorobenzoic acid (12.0 g, 66.6 mmol) in MeOH (150 mL)₂ CO₃ (65 g, 199 mmol) and the reaction mixture was heated in a sealed vessel at 80 ° C for 16 h. The suspension was filtered and the residue was washed with MeOH. The combined organic phases were evaporated to half volume and slowly neutralized with 1N HCl until pH ~4. The resulting precipitate was filtered, washed with water and dried in vacuo. The isolated solid was dissolved in acetone and filtered to remove any residual inorganic solids and evaporated to give 11.7 g of 2-amino-5-cyano-4-methoxybenzoic acid as a white solid. Step 3:2- Amine -5- Cyano -4- Methyl methoxybenzoate To 2-Amino-5-cyano-4-methoxybenzoic acid (11.7 g, 60.9 mmol) and K₂ CO₃ Methyl iodide (3.79 mL, 60.9 mmol) was slowly added to the cooled solution in DMF (75 mL). After the addition was complete, the reaction was stirred at ambient temperature for 16 hours with the addition of saturated NH.₄ The aqueous solution of Cl (100 mL) and water (100 mL) were quenched and stirred for 15 min. The resulting precipitate was filtered, washed with EtOAcqqqqq Intermediate 3. 1-(2-Amino-5-chlorophenyl)-1H -tetrazole-5 (4H )-ketonestep 1:1-(5- chlorine -2- Nitrophenyl )-1H- Tetrazole -5(4H)- ketone 4-Chloro-2-isocyanato-1-nitro-benzene (1.50 g, 7.55 mmol) and trimethyldecyl azide (1.99 ml, 15.1 mmol) in a sealed vial at 95 ° C Heat for 16 hours. After cooling, the resulting solid was stirred vigorously in MeOH (10 mL) for 30 min and then filtered. The filtrate was collected and evaporated to give a crude material which was purified from EtOAc EtOAc. Yield = 1.5 g (82%). Step 2:1-(2- Amine -5- Chlorophenyl )-1H- Tetrazole -5(4H)- ketone To 1-(5-chloro-2-nitrophenyl)-1 in THF (10 mL)H -tetrazole-5 (4H A ketone (500 mg, 2.07 mmol) was added with a slurry of Raney nickel (about 0.3 mL) and stirred under hydrogen (1 atm) for 24 hours. The suspension was filtered through EtOAc <RTI ID=0.0></RTI> to <RTI ID=0.0> Intermediate 4. 3-(2-Amino-5-chlorophenyl)-1,2,4-oxadiazol-5 (4H )-ketonestep 1:2- Amine -5- chlorine -N'- Hydroxybenzamide . Add sodium methoxide to a mixture of 2-amino-5-chlorobenzonitrile (5.0 g, 32.8 mmol) and hydroxylamine hydrochloride (2.56 g, 36.8 mmol) in water (1 mL) and EtOH (30 mL) (25 wt% solution; 9 mL) and the mixture was heated to reflux for 16 h. After cooling, 3M NaOH solution (75 mL) was added and the volatiles were removed in vacuo. The remaining aqueous phase was washed with DCM, separated and then adjusted to a pH of about 4 by addition of 1N HCl solution. Filtration and washing of the subsequent precipitates with water afforded N-hydroxybenzidine as a colorless solid which was used without further purification. Step 2:3-(2- Amine -5- Chlorophenyl )-1,2,4- Oxadiazole -5 (4 H)- ketone Dissolving 2-amino-5-chloro-N'-hydroxybenzimidamide (2.03 g, 10.9 mmol) in a mixture of EtOH (50 mL) and sodium methoxide (25 wt% solution; 5 mL) Diethyl carbonate (5.7 mL, 47 mmol) was added and the mixture was heated to reflux for 16 h. After cooling, the solution was evaporated to dryness, and the obtained solid was dissolved in water (200 mL) and acidified with concentrated HCl to pH 3. The resulting precipitate was filtered, washed with water and dried in vacuo to give oxadione. Intermediate 5. 6-fluoro-2-naphthoquinone chlorideDMF (about 10 μL) was added to a solution of 6-fluoro-2-naphthoic acid (250 mg, 1.31 mmol) in DCM (10 mL), followed by the dropwise addition of hexanes (300 μL, 3.5 mmol). After stirring for 1 hour, the solvent was removed in vacuo and the obtained acid chloride was used without further analysis or purification. Example 1:N -(4-chloro-2-(methylsulfonylamino)phenyl)-2-naphthylaminestep 1:N-(2- Amine -5- Chlorophenyl ) Methionamide . willN -(5-Chloro-2-nitrophenyl)methanesulfonamide (0.80 g, 3.20 mmol), acetic acid (1.10 mL, 19.23 mmol) and methanol (50 mL) combined and stirred at 0 ° C, then powder Zinc (1.26 g, 19.23 mmol). The resulting mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 2 hours. The reaction was filtered through celite and the filtrate was evaporated to dry. With EtOAc and saturated NaHCO₃ Dilute the residue in aqueous solution, separate the organic phase, wash with water (2 times), brine, Na₂ SO₄ Dry, filter and concentrate in vacuo. containN The crude solid obtained from (2-amino-5-chlorophenyl)methanesulfonamide was used without further purification. Step 2: The title compound was prepared in a similar manner to Step 2 of Example 2 using 2-naphthoquinone chloride, TEA and THF, and N-(2-amino-5-chlorophenyl)methanesulfonamide. LC-MS: 375 (M+H)⁺ . Example 2.N -(4-chloro-2-(2H -tetrazol-5-yl)phenyl)-2-naphthylaminestep 1.4- chlorine -2-(2H- Tetrazole -5- base ) aniline Add sodium azide (639 mg, 9.83 mmol) and ammonium chloride (425 mg, to a solution of 2-amino-5-chlorobenzonitrile (1.0 g, 6.55 mmol) in DMF (6 mL) 7.94 mmol). The resulting mixture was heated at 100 ° C for 16 hours in a resealable vial. After completion of the reaction as determined by LC-MS, the mixture was cooled and 1N HCl and water were sequentially added to give a precipitate. Filter and vacuum dry. The intermediate tetrazole was obtained which was used without further purification or analysis. Step 2. Add Et to the previously prepared tetrazole (500 mg, 2.15 mmol) in THF (15 mL)₃ N (1.5 mL, 10.7 mmol), 2-naphthoquinone chloride (410 mg, 2.15 mmol). The resulting mixture was stirred with EtOAc (EtOAc) EtOAc.₄ ), filtered and evaporated in vacuo. The obtained solid was purified by wet-purified from DCM/hexane to afford the title compound. LC-MS: 350 (M+H)⁺ . Example 3. 5-Chloro-2-(quinoline-3-carboxamido)benzoic acidstep 1.5- chlorine -2-( quinoline -3- Methionine ) Methyl benzoate . To a solution of quinoline-3-carboxylic acid (300 mg, 1.73 mmol) in DCM (15 mL) was added DMF (catalyzed, approx. 10 μL) and ethane chloride (about 300 μL, 3.5 mmol; 2 equivalents) . After stirring at ambient temperature for 2 hours, the solvent was removed in vacuo. A solution of 2-amino-5-chlorobenzoic acid methyl ester (321 mg, 1.73 mmol) in pyridine (2 mL). The resulting mixture was stirred for 16 hr then evaporated to dryness crystals crystals crystals The precipitate was filtered and washed with water to give a crude intermediate, which was purified from EtOAc EtOAc. Step 2.5- chlorine -2-( quinoline -3- Methionine ) benzoic acid The isolated methyl 5-chloro-2-(quinolin-3-carbamoyl)benzoate was suspended in a mixture of p-dioxane (7 mL), water (2 mL) and MeOH (2 mL) , adding LiOH·H to it₂ O (125 mg, 3 mmol), and the reaction mixture was stirred at ambient temperature until LC-MS analysis confirmed the ester hydrolysis was completed. The title compound was obtained as a white solid. LC-MS: 327 (M+H)⁺ . Example 4. 5-Chloro-2-(6-fluoro-2-naphthylamino)benzoic acidThe title compound was prepared in a similar manner as described in Example 3 using 6-fluoro-2-naphthoquinone chloride (Intermediate 5). LC-MS: 342 (M-H)^- . Example 5. 2-(2-Naphthylamino)-5-chloro-4-fluorobenzoic acidThe title compound was prepared in a similar manner to that described in Example 3 using methyl 2-amino-5-chloro-4-fluorobenzoate and 2-naphthoquinone chloride, followed by typical ester hydrolysis conditions. LC-MS: 342 (M-H)^- . Example 6: 2-(2-naphthylamino)-5-chloronicotinic acidThe title compound was prepared in a similar manner to Example 3 using 2-naphthoic acid and a base of TEA and 2-amino-5-chloronicotinate, followed by typical ester hydrolysis conditions. LC-MS: 325 (M-H)^- . Example 7: 2-(2-naphthylamino)-4,5-dichlorobenzoic acid2-Amino-4,5-dichlorobenzoic acid (103 mg, 0.5 mmol, 1 eq.) and 2-naphthoquinone chloride (123 mg, 0.5 mmol, 1 eq.) in dioxane (2 mL) Triethylamine (0.2 mL, 1.5 mmol, 3 eq.) was added to the solution. After stirring for 1 h, the solvent was evaporated in vacuo tolululululululululululululululululu LC-MS: 358 (M-H)^- . Example 8: 5-Chloro-2-(7-fluoroquinoline-3-carboxamido)benzoic acidThe title compound was used in a similar manner to Example 3 using 7-fluoroquinoline-3-carboxylic acid and DCM as solvent and methyl 2-amino-5-chlorobenzoate, followed by typical ester hydrolysis conditions. To prepare. LC-MS: 345 (M+H)⁺ . Example 9: 2-(6-Bromo-2-naphthylamino)-5-chlorobenzoic acidThe title compound was prepared in a similar manner to Example 7 using 6-bromo-2-naphthoquinone chloride. LC-MS: 402 (M-H)^- . Example 10: 5-Chloro-2-(7-methylquinolin-3-carboxamido)benzoic acidThe title compound was used in a similar manner to Example 3 using 7-methylquinoline-3-carboxylic acid, TEA as a base and DCM as solvent and methyl 2-amino-5-chlorobenzoate, followed by hydrolysis with a typical ester. Conditions to prepare. LC-MS: 339 (M-H)^- . Example 11: 2-(2-Naphthylamino)-4-bromo-5-chlorobenzoic acidThe title compound was prepared in a similar manner to Example 3 using 2-naphthoquinone chloride and TEA as base and methyl 2-amino-4-bromo-5-chlorobenzoate, followed by typical ester hydrolysis conditions. LC-MS: 404 (M-H)^- . Example 12: 5-Chloro-2-(6-(trifluoromethyl)-2-naphthylamino)benzoic acidstep 1:6-( Trifluoromethyl )-2- Methyl naphthoate Will Pd(OAc)₂ (0.082 g, 0.37 mmol), 2-bromo-6-(trifluoromethyl)naphthalene (1.00 g, 3.64 mmol), DPPP (0.153 g, 0.37 mmol), methanol (2.95 mL, 72.8 mmol), TEA (1.01) The combination of mL, 7.28 mmol) and DMF (30 mL) was stirred at 90 ° C for 72 hours under a CO atmosphere. The reaction was cooled to rt and diluted with EtOAc & brine. Wash the organics with water (3 times), brine, via Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue containing methyl 6-(trifluoromethyl)-2-naphthoate was used without further purification. Step 2:6-( Trifluoromethyl )-2- Naphthoic acid To a solution of methyl 6-(trifluoromethyl)-2-naphthoate (0.85 g, 3.34 mmol) in EtOAc (EtOAc) ). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was diluted with EtOAc EtOAc. The organic layer was extracted with EtOAc (EtOAc)EtOAc. The resulting solid containing 6-(trifluoromethyl)-2-naphthoic acid was used directly in the next step. Step 3: title compound using 6-(trifluoromethyl)-2-naphthoic acid and DCM as solvent and methyl 2-amino-5-chlorobenzoate in a similar manner to Example 3, followed by a typical ester Prepared by hydrolysis conditions. LC-MS: 392 (M-H)^- . Example 13: 2-(6-Bromo-2-naphthylamino)-4,5-dichlorobenzoic acidThe title compound was prepared in a similar manner to Example 7 using 6-bromo-2-naphthoquinone chloride. LC-MS: 436 (M-H)^- . Example 14. 5-Chloro-4-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acidThe title compound used methyl 2-amino-5-chloro-4-fluorobenzoate and 6-fluoro-2-naphthoquinone chloride (intermediate 5) in a similar manner to that described in Example 3, followed by a typical ester. Prepared by hydrolysis conditions. LC-MS: 360 (M-H)^- . Example 15. 2-(2-Naphthylamino)-5-chloro-4-methoxybenzoic acid2-Amino-5-chloro-4-methoxybenzoic acid (250 mg, 1.24 mmol) in THF (8 mL)₃ 2-naphthoquinone chloride (236 mg, 1.24 mmol) was added to a solution of N (1 mL, 7.2 mmol) and the obtained mixture was stirred at ambient temperature for 16 hr. The reaction was quenched with 1N EtOAc (10 mL) and stirred 1 hr. The precipitate was filtered to give a crude acid which was purified from EtOAc EtOAc. LC-MS: 356 (M+H)⁺ . Example 16. 2-(Benzo[b]thiophene-5-carboxamido)-5-chlorobenzoic acidThe title compound was prepared in a similar manner as described in Example 3 using benzo[b]thiophene-5-carboxylic acid. LC-MS: 330 (M-H)^- . Example 17: 4,5-Difluoro-2-(6-fluoro-2-naphthylamino)benzoic acidThe title compound was prepared in a similar manner to Example 7 using 6-fluoro-2-naphthoquinone chloride (Intermediate 5) and 2-amino-4,5-difluorobenzoic acid. LC-MS: 344 (M-H)^- . Example 18: 2-(2-naphthylamino)-4,5-difluorobenzoic acidThe title compound was prepared in a similar manner to Example 7 using 2-naphthoquinone chloride and 2-amino-4,5-difluorobenzoic acid. LC-MS: 326 (M-H)^- . Example 19: 2-(2-Naphthylamino)-5-cyanobenzoic acidThe title compound was prepared in a similar manner to Example 3 using 2-naphthoquinone chloride and TEA as a base and methyl 2-amino-5-cyanobenzoate, followed by typical ester hydrolysis conditions. LC-MS: 315 (M-H)^- . Example 20: 4,5-Dichloro-2-(6-ethyl-2-naphthylamino)benzoic acidstep 1:6- Vinyl -2- Methyl naphthoate . Heating methyl 6-bromo-2-naphthoate (1.02 g, 3.84 mmol), vinyl trifluoride at 80 ° C in a microwavePotassium acid (514 mg, 3.83 mmol), hydrazine (triphenylphosphine) palladium (0) (443 mg, 0.384), sodium carbonate (1.2 g, 11.5 mmol) in DME (5 mL) and water (5 mL) The solution was allowed to stand for 30 minutes. After extraction with EtOAc, EtOAc was evaporated Column chromatography (SiO₂ Purification by gradient 0 to 10% EtOAc (EtOAc) Step 2:6- Ethyl -2- Methyl naphthoate . Add Pd/C (14 mg) to a solution of methyl 6-vinyl-2-naphthoate (287 mg, 1.35 mmol) in EtOH (13 mL).₂ 2 hours. The solution was filtered through EtOAc (EtOAc)EtOAc. Step 3:6- Ethyl -2- Naphthoic acid A solution of 6-ethyl-2-naphthoic acid methyl ester (283 mg, 1.3 mmol) in MeOH (2 mL) After 16 h, 1N HCl (2 eq.).₄ Filtration and concentration in vacuo gave 6-ethyl-2-naphthoic acid (257 mg, yield 97%). Step 4:6- Ethyl -2- Naphthoquinone chloride . A mixture of 6-ethyl-2-naphthoic acid (97 mg, 0.49 mmol) and sulfinium chloride (1.6 mL) was heated at 80 °C for 2 hours. The reaction mixture was concentrated in vacuo to give 6-ethyl <RTI ID=0.0>#</RTI> </RTI> <RTIgt; Step 5: To 6-ethyl-2-naphthoquinone chlorideN ,N 2-Amino-4,5-dichlorobenzoic acid (100 mg, 0.48 mmol) was added to a solution of dimethylacetamide (4 mL), and the mixture was stirred for 16 hr. Water was added slowly and the resulting solid was filtered to give the title compound. LC-MS: 386 (M-H)^- . Example 21. 2-(Benzo[b]thiophene-5-carboxamido)-5-chloro-4-fluorobenzoic acidThe title compound was used in a similar manner to that described in Example 3 using 2-amino-5-chloro-4-fluorobenzoic acid methyl ester and benzo[b]thiophene-5-carboxylic acid, which was then prepared using typical ester hydrolysis conditions. LC-MS: 348 (M-H)^- . Example 22: 2-(6-Bromo-2-naphthylamino)-5-cyanobenzoic acidThe title compound was prepared using methyl 2-amino-5-cyanobenzoate and 6-bromo-2-naphthoic acid in a similar manner as described in Steps 4 and 5 of Example 20, followed by typical ester hydrolysis conditions. LC-MS: 393 (M-H)^- . Example 23: 5-Bromo-2-(6-fluoro-2-naphthylamino)benzoic acidThe title compound was used in a similar manner as described in Step 5 of Example 20, using 2-amino-5-bromobenzoic acid methyl ester and 6-fluoro-2-naphthoquinone chloride (intermediate 5), followed by typical ester hydrolysis conditions. To prepare. LC-MS: 386 (M-H)^- . Example 24: 5-Chloro-2-(6-ethyl-2-naphthylamino)-4-methoxybenzoic acidThe title compound was used in a similar manner to that described in Steps 4 and 5 of Example 20, using 2-amino-5-chloro-4-methoxybenzoic acid methyl ester and 6-ethyl-2-naphthoic acid, followed by typical Prepared by ester hydrolysis conditions. LC-MS: 382 (M-H)^- . Example 25: 5-Cyano-2-(6-ethyl-2-naphthylamino)benzoic acidThe title compound was prepared using methyl 2-amino-5-cyanobenzoate and 6-ethyl-2-naphthoic acid in a similar manner as described in Steps 4 and 5 of Example 20, followed by typical ester hydrolysis conditions. . LC-MS: 343 (M-H)^- . Example 26: 5-Chloro-2-(6-ethyl-2-naphthylamino)-4-fluorobenzoic acidThe title compound was used in a similar manner as described in Steps 4 and 5 of Example 20, using 2-amino-5-chloro-4-fluorobenzoic acid methyl ester and 6-ethyl-2-naphthoic acid, followed by hydrolysis with a typical ester. Conditions to prepare. LC-MS: 370 (M-H)^- . Example 27: 2-(6-ethyl-2-naphthylamino)-4,5-difluorobenzoic acidThe title compound was used in a similar manner as described in Steps 4 and 5 of Example 20, using methyl 2-amino-4,5-difluorobenzoate and 6-ethyl-2-naphthoic acid, followed by typical ester hydrolysis conditions. To prepare. LC-MS: 354 (M-H)^- . Example 28: 5-Chloro-2-(7-bromoquinolin-3-carboxamido)benzoic acidThe title compound was prepared in a similar manner to Example 3 using 7-bromoquinoline-3-carboxylic acid and DCM, and 2-amino-5-chlorobenzoic acid methyl ester, followed by typical ester hydrolysis conditions. LC-MS: 405 (M-H)^- . Example 29: 5-Chloro-2-(3-methylbenzo[b]thiophene-5-carboxamido)benzoic acidstep 1:3- Methyl benzo [b] Thiophene -5- Methyl formate . Will Pd(OAc)₂ (0.099 g, 0.44 mmol), 5-bromo-3-methylbenzo[b]thiophene (1.00 g, 4.40 mmol), DPPP (0.181 g, 0.44 mmol), methanol (3.57 mL, 88.00 mmol), TEA ( 1.22 mL, 8.80 mmol) and DMF (40 mL) were combined and stirred at 90 ° C for 16 hours under a CO atmosphere. The reaction was cooled to rt and diluted with EtOAc & brine. Wash the combined organic phase with water (3 times), brine, Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue containing methyl 3-methylbenzo[b]thiophene-5-carboxylate was used without further purification. Step 2:3- Methyl benzo [b] Thiophene -5- Formic acid . A solution of methyl 3-methylbenzo[b]thiophene-5-carboxylate (0.87 g, 4.22 mmol) in EtOAc (30 mL ). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was diluted with EtOAc EtOAc. Extract the organic layer with water (3 times) and brine.₂ SO₄ Dry, filter and concentrate in vacuo. The resulting solid containing 3-methylbenzo[b]thiophene-5-carboxylic acid was used directly in the next step. Step 3: title compound using 3-methylbenzo[b]thiophene-5-carboxylic acid and DCM and methyl 2-amino-5-chlorobenzoate in a similar manner as in Example 3, followed by typical ester hydrolysis conditions To prepare. LC-MS: 344 (M-H)^- . Example 30: 2-(Benzo[b]thiophene-6-carboxamido)-5-chlorobenzoic acidstep 1:Benzo [b] Thiophene -6- Methyl formate Will Pd(OAc)₂ (0.070 g, 0.31 mmol), 6-bromobenzo[b]thiophene (0.70 g, 3.08 mmol), DPPP (0.128 g, 0.31 mmol), methanol (2.50 mL, 61.60 mmol), TEA (0.86 mL, 6.16 mmol) And DMF (30 mL) were combined and stirred at 90 ° C for 16 hours under a CO atmosphere. The reaction was cooled to rt and diluted with EtOAc & brine. Wash the organics with water (3 times), brine, via Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue containing methyl benzo[b]thiophene-6-carboxylate was used without further purification. Step 2:Benzo [b] Thiophene -6- Formic acid To a solution of benzo[b]thiophene-6-carboxylic acid methyl ester (0.50 g, 2.60 mmol) in EtOAc (EtOAc) (EtOAc) The resulting mixture was stirred at room temperature for 16 hours. Evaporate the solvent and use Et₂ O and water to dilute the residue. The organic phase was discarded and the basic aqueous layer was acidified with EtOAc and 1M aqueous HCI. The organic phase was extracted with water (2×), EtOAc evaporated The resulting solid containing benzo[b]thiophene-6-carboxylic acid was used directly in the next step. Step 3: The title compound was obtained in a similar manner to Example 3 using benzo[b]thiophene-6-carboxylic acid and DCM and 2-amino-5-chlorobenzoic acid methyl ester. LC-MS: 330 (M-H)^- . Example 31: 5-Chloro-2-(thieno[2,3-b]pyridine-5-carbamido)benzoic acidThe title compound was used in a similar manner to Example 3 using thieno[2,3-b]pyridine-5-carboxylic acid and DCM as solvent and methyl 2-amino-5-chlorobenzoate, followed by typical ester hydrolysis conditions. To prepare. LC-MS: 331 (M-H)^- . Example 32.N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-2-naphthylamineTo 1-(2-amino-5-chlorophenyl)-1H -tetrazole-5 (4H Adding Et to the ketone (200 mg, 0.95 mmol) in THF (7 mL)₃ N (1 mL), 2-naphthoquinone chloride (180 mg, 0.95 mmol), and the mixture was stirred at room temperature for 48 hr. 1N HCl (about 5 mL), water (10 mL) were added sequentially and stirred for 30 minutes. The resulting precipitate was isolated by filtration. LC-MS: 366 (M+H)⁺ . Example 33:N -(4-chloro-2-(1)H -tetrazol-5-yl)phenyl)-7-fluoroquinoline-3-carboxamideThe title compound was prepared in a similar manner to Step 1 of Example 3 using 7-fluoroquinoline-3-carboxylic acid and DCM and 4-chloro-2-(1H-tetrazol-5-yl)aniline. LC-MS: 367 (M-H)^- . Example 34:N -(4-chloro-2-(1)H -tetrazol-5-yl)phenyl)-6-fluoro-2-naphthylamineThe title compound was prepared in a similar manner to Step 1 of Example 3 using 6-fluoro-2-naphthoic acid and DCM and 4-chloro-2-(1H-tetrazol-5-yl)aniline. LC-MS: 366 (M-H)^- . Example 35:N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamineThe title compound used 6-fluoro-2-naphthoquinone chloride (Intermediate 5) and DCM and 1-(2-amino-5-chlorophenyl)-1 in a similar manner to Example 32.H -tetrazole-5 (4H )-ketone to prepare. LC-MS: 382 (M-H)^- . Example 36: 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acidThe title compound was used in a similar manner to Example 3 using 6-fluoro-2-naphthoic acid and DCM and &lt;EMI ID=9.1&gt;&gt; 2-amino-5-chloro-4-methoxybenzoic acid methyl ester, followed by typical ester hydrolysis conditions. LC-MS: 372 (M-H)^- . Example 37.N -(4-Chloro-2-(5-sided oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-2-naphthylamineTo 3-(2-Amino-5-chlorophenyl)-1,2,4-oxadiazol-5 (4H Adding Et to the ketone (intermediate 4,250 mg, 1.19 mmol) in THF (10 mL)₃ N (1 mL), 2-naphthoquinone chloride (226 mg, 1.19 mmol) and the mixture was stirred 16 hr. 1 N HCl (10 mL) was added and stirred vigorously for 10 min to give a precipitate which was obtained, which was filtered and washed with water. The title compound was obtained as a colorless solid. LC-MS: 364 (M-H)^- . Example 38: 5-Chloro-4-methoxy-2-(2-phenylbenzo[b]thiophene-5-carboxamido)benzoic acidstep 1:2- Boron based Benzo [b] Thiophene -5- Formic acid Add to a stirred solution of benzo[b]thiophene-5-carboxylic acid (1.00 g, 5.61 mmol) in THF (30 mL) at -78 °Ct -BuLi (8.25 mL, 14.03 mmol, 1.7 M in pentane). The mixture was removed from the dry ice bath, stirred at room temperature for 40 minutes and then cooled back to -78 °C. Add triisopropyl borate (1.93 mL, 8.42 mmol) and stir the solution at -78 °C for 10 minutes, stir at ambient temperature for 1 hour, and pour to 1:1 10% KHSO₄ Aqueous solution: saturated NH₄ Quenched in aqueous Cl solution. The resulting quenched mixture was stirred at room temperature for 1 h and partitioned between EtOAc and brine. Organic phase via Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue was triturated with diisopropyl ether, and the obtained solid was filtered to give 2-bromobenzo[b]thiophen-5-carboxylic acid. Step 2:2- Phenylbenzo [b] Thiophene -5- Formic acid . Add bromobenzene (0.35 mL, 3.27 mmol) and saturated NaHCO to a solution of 2-bromobenzo[b]thiophene-5-carboxylic acid (0.66 g, 2.97 mmol) in dioxane (10 mL)₃ Aqueous solution (5 mL). The resulting mixture was sparged with nitrogen, followed by hydrazine(triphenylphosphine)palladium(0) (0.172 g, 0.05 mmol). The reaction was then sealed and heated at 100 °C for 16 hours. The reaction mixture was cooled to room rt and partitioned between EtOAc and 1 M EtOAc. Extract the organic phase with water (2 times), brine, and Na₂ SO₄ Dry, filter and concentrate in vacuo. The crude residue was taken up in 2-phenylbenzo[b]thiophene-5-carboxylic acid and used without further purification. Step 3: Title compound 2-Phenylbenzo[b]thiophene-5-carboxylic acid and DCM and methyl 2-amino-5-chloro-4-methoxybenzoate were used in a similar manner to Example 3. It is prepared by typical ester hydrolysis conditions. LC-MS: 436 (M-H)^- . Example 39. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(trifluoromethyl)benzoic acidstep 1:Double third Butoxycarbonyl 2- bromine -4- chlorine -5-( Trifluoromethyl ) aniline To a solution of 2-bromo-4-chloro-5-(trifluoromethyl)aniline (5.1 g, 18.6 mmol) in THF (100 mL), EtOAc (10.1 mL, 44.0 mmol), DMAP (455 mg, 3.7 mmol). After stirring at ambient temperature for 16 h, EtOAc EtOAcqqqqqqq substance. Step 2:2-(( Third butoxycarbonyl ) Amine )-5- chlorine -4-( Trifluoromethyl ) Tert-butyl benzoate . Add to the -78 ° C solution of the previously synthesized protected aniline (5.0 g, 10.5 mmol) in anhydrous THF (100 mL)n - BuLi (2.5 M hexane solution; 5.0 mL, 12.5 mmol). After stirring at -78 ° C for 1 hour, add saturated NH₄ The reaction was quenched with aqueous Cl. And warm it to ambient temperature. The reaction mixture was diluted with EtOAc, washed with water and dried₄ ), filtered and evaporated in vacuo. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut Tert-butyl 4-(trifluoromethyl)benzoate. Step 3:2- Amine -5- chlorine -4-( Trifluoromethyl ) benzoic acid The previously isolated ester (3.0 g, 7.6 mmol) in DCM (50 mL) wasEtOAc. The solvent is removed in vacuo to give the carboxylic acid as a TFA salt which can be used without further analysis or purification. Step 4:2- Amine -5- chlorine -4-( Trifluoromethyl ) Ethyl benzoate . Add K to 2-amino-5-chloro-4-(trifluoromethyl)benzoic acid TFA salt (7.6 mmol) in DMF (15 mL)₂ CO₃ (3.2 g, 22.8 mmol) and ethyl iodide (0.74 mL, 9.12 mmol). The suspension was stirred at ambient temperature for 16 h then diluted with EtOAc EtOAc EtOAc.₄ ), filtered and evaporated to dryness. The isolated solid was used without further purification. Step 5:5- chlorine -2-(6- fluorine -2- Naphthylamine )-4-( Trifluoromethyl ) Ethyl benzoate Prepared in a similar manner to Step 1 of Example 3 using 6-fluoro-2-naphthoic acid. The resulting ester was purified by silica gel elution with a gradient of 0 to 50% of DCM in hexane. Step 6.5- chlorine -2-(6- fluorine -2- Naphthylamine )-4-( Trifluoromethyl ) benzoic acid Prepared in a similar manner to step 2 of Example 3 to give the title compound as a colourless solid. LC-MS: 410 (M-H)^- . Example 40:N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-2-methylbenzo[b]thiophene-5-carboxamidestep 1:2- Methyl benzo [b] Thiophene -5- Formic acid Add to a stirred solution of benzo[b]thiophene-5-carboxylic acid (1.00 g, 5.61 mmol) in THF (50 mL) at -78 °Ct -BuLi (7.26 mL, 12.34 mmol, 1.7 M pentane). The mixture was removed from the dry ice bath, stirred at room temperature for 40 minutes and then cooled back to -78 °C. Methyl iodide (0.42 mL, 6.73 mmol) was added and the solution was stirred at -78 °C for 10 min then stirred at ambient temperature for 1 hour. By pouring into 1:1 10% KHSO₄ Aqueous solution: saturated NH₄ The reaction was quenched in aqueous Cl. The resulting mixture was stirred at rt for 1 h to partition between EtOAc and brine. Organic phase via Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue was triturated with 4:1 EtOAc: hexanes and filtered to afford 2-methylbenzo[b]thiophene-5-carboxylic acid. Step 2: The title compound was used in a similar manner to Example 32 using 2-methylbenzo[b]thiophene-5-methylhydrazine chloride (as described for Intermediate 5, prepared from isolated acid and succinyl chloride) and -(2-amino-5-chlorophenyl)-1H -tetrazole-5 (4H )-ketone to prepare. LC-MS: 384 (M-H)^- . Example 41: 5-Chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxamido)benzoic acidThe title compound was used in a similar manner to Example 3 using 2-methylbenzo[b]thiophene-5-carboxylic acid (Example 40, Step 1) and DCM and 2-amino-5-chloro-4-methoxybenzoic acid The methyl ester is then prepared using typical ester hydrolysis conditions. LC-MS: 374 (M-H)^- . Example 42.N -(4-chloro-5-fluoro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylaminestep 1:1- chlorine -2- fluorine -5- Isocyanate -4- Nitrobenzene 5-Chloro-4-fluoro-2-nitroaniline (1.0 g, 5.25 mmol) was dissolved in EtOAc (30 mL). Solution. The resulting solution was heated to reflux for 16 h, then the solvent was evaporated in vacuo and EtOAcqqqqqq Step 2:1-(2- Amine -5- chlorine -4- Fluorophenyl )-1H- Tetrazole -5 (4 H)- ketone . Prepared in a manner similar to that described for Intermediate 2, Step 2. Step 3: The title compound was isolated as shown in Example 32. Purification by hydrazine (0 to 100% EtOAc in EtOAc) LC-MS: 400 (M-H)^- . Example 43.N -(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)quinoline-3-carboxamideThe title compound was prepared in a similar manner as in Example 37 using quinoline-3-methane chloride (as described in Example 3, from the respective carboxylic acid and succinyl chloride). LC-MS: 367 (M+H)⁺ . Example 44.N -(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthylamineThe title compound was prepared in a similar manner to Example 37 using 6-fluoro-2-naphthoquinone chloride (Intermediate 5). The final product was wet milled from acetone. LC-MS: 382 (M-H)^- . Example 45.N -(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-ethynyl-2-naphthylaminestep 1:6-(( Trimethyldecyl ) Ethynyl )-2- Methyl naphthoate Add ethynyl trimethyl decane (0.64 mL, 4.5 mmol), triethylamine (1.1 mL) to a solution of methyl 6-bromo-2-naphthoate (1 g, 3.8 mmol) in MeCN (9 mL) , 7.5 mmol), bis(triphenylphosphine)palladium(II) chloride (106 mg, 0.15 mmol) and CuI (86 mg, 0.45 mmol). The solution was sparged with nitrogen and heated at 80 ° C for 16 hours. Add EtOAc and water and extract the aqueous layer with EtOAc (3times). The combined organic extracts were washed with brine (2×) and dried (MgSO₄ And concentrated in vacuo to give the crude material. Column chromatography (SiO₂ Purification with a gradient of 0 to 10% EtOAc in hexanes afforded 6-((trimethyl decyl) ethynyl)-2-naphthalic acid methyl ester (875 mg, yield 83%). Step 2:6- Ethynyl -2- Naphthoic acid . To a suspension of methyl 6-((trimethyldecyl)ethynyl)-2-naphthoate (440 mg, 1.6 mmol) in MeOH EtOAc (1 N, 6 mL) hour. The reaction was quenched with EtOAc (3 mL)EtOAc. The combined organic extracts were washed with brine (1×) and dried (MgSO₄ The title compound (314 mg, quantitative yield) was obtained. Step 3:6- Ethynyl -2- Naphthoquinone chloride To a suspension of 6-ethynyl-2-naphthoic acid (200 mg, 1 mmol) in DCM (2 mL) EtOAc (EtOAc) DMF (30 μL) was added and the reaction was stirred at room temperature for 10 min. The solution was concentrated in vacuo to give the product which was used in the next step without purification. Step 4: Add 3-(2-Amino-5-chlorophenyl)-1,2,4-oxadiazole to a solution of 6-ethynyl-2-naphthoquinone chloride in DMAc (4 mL) -5 (4H a solution of the ketone (intermediate 4, 216 mg, 1 mmol) in pyridine (0.6 mL). The solution was concentrated in vacuo to give a crude material. By column chromatography (C18 reverse phase, water + 0.1% NH₃ •H₂ O -> MeCN + 0.1% NH₃ •H₂ O) Purification afforded the title compound. LC-MS: 388 (M-H)^- . Example 46.N -(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-ethyl-2-naphthylamineThe title compound was prepared in a similar manner as described in Example 37 using 6-ethyl-2-naphthoquinone chloride (Example 20). LC-MS: 392 (M-H)^- . Example 47. 5-Fluoro-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acidstep 1:(2- bromine -4- fluorine -5- Methoxyphenyl ) Di-tert-butyl diamine dicarboxylate Add to a stirred solution of 2-bromo-4-fluoro-5-methoxyaniline (0.50 g, 2.27 mmol) and DMAP (0.055 g, 0.45 mmol) in THF (30 mL) (Boc)₂ O (1.19 g, 5.45 mmol). The mixture was stirred at room temperature for 16 hours, and the solvent was evaporated. The crude material was purified by EtOAc (EtOAc) eluting elute . Step 2:2-(( Third butoxycarbonyl ) Amine )-5- fluorine -4- Tert-butyl methoxybenzoate . A stirred solution of (2-bromo-4-fluoro-5-methoxyphenyl)dicarbamic acid di-t-butyl ester (0.83 g, 1.97 mmol) in THF (20 mL) at -78 °C Add drop by dropn -BuLi (1.48 mL, 12.34 mmol, 1.6 M in hexanes). The mixture was stirred at -78 ° C for 1 hour, followed by the addition of saturated NH.₄ The Cl aqueous solution was quenched. The resulting mixture was partitioned between EtOAc EtOAc m. The crude material was purified by chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc Third butyl ester. Step 3:2- Amine -5- fluorine -4- Methoxybenzoic acid . tert-Butyl 2-((t-butoxycarbonyl)amino)-5-fluoro-4-methoxybenzoate (0.59 g, 1.73 mmol) with DCM (10 mL) and TFA (4 mL) The premixed solutions were combined and stirred at room temperature for 16 hours. The solvent was evaporated and the residue was co- evaporated with toluene and heptane. The obtained solid 2-amino-5-fluoro-4-methoxybenzoic acid was used without further purification. Step 4:2- Amine -5- fluorine -4- Methyl methoxybenzoate To 2-Amino-5-fluoro-4-methoxybenzoic acid (0.40 g, 2.16 mmol), K at room temperature₂ CO₃ (0.896 g, 6.48 mmol) iodomethane (0.14 mL, 2.16 mmol) was added to a stirred solution in DMF (20 mL). The mixture was stirred at room temperature for 16 h then partitioned between EtOAc and brine. Wash the organics with water (3 times), brine, via Na₂ SO₄ Dry, filter and concentrate in vacuo. The crude material obtained was used without further purification. Step 5: title compound using 6-fluoro-2-naphthoic acid and DCM and methyl 2-amino-5-fluoro-4-methoxybenzoate in a similar manner to Example 3, followed by typical ester hydrolysis conditions To prepare. LC-MS: 356 (M-H)^- . Example 48. 4-Chloro-5-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acidThe title compound was used in a similar manner to Example 3 using 6-fluoro-2-naphthoquinone chloride (Intermediate 5) and DCM and 2-amino-4-chloro-5-fluorobenzoic acid methyl ester, followed by a typical ester. Prepared by hydrolysis conditions. LC-MS: 360 (M-H)^- . Example 49. 6-(2-Naphthylamino)benzo[d][1,3]dioxazole-5-carboxylic acidAdd 2-naphthoquinone chloride (263) to a solution of 6-aminobenzo[d][1,3]dioxazole-5-carboxylic acid (250 mg, 1.38 mmol) in THF (8 mL) Mg, 1.38 mmol), Et₃ N (1 mL). The suspension was stirred at ambient temperature for 16 hours, after which time 1N HCl was added and the resulting precipitate was filtered and dried. The title compound was obtained as a colorless solid. LC-MS: 336 (M+H)⁺ . Example 50.N -(4,5-difluoro-2-(1H -tetrazol-5-yl)phenyl)-6-fluoro-2-naphthylaminestep 1:2- Amine -4,5- Difluorobenzonitrile . Add ruthenium (triphenylphosphine) palladium (0) (400 mg, 0.34 mmol) and cyanide to a solution of 2-bromo-4,5-difluoroaniline (1.2 g, 4.3 mmol) in DMF (4 mL) Zinc (800 mg, 6.8 mmol). The solution was sparged with nitrogen and heated in a Biotage microwave reactor at 120 °C for 30 minutes. The resulting suspension was filtered and concentrated in vacuo to give crude material. By column chromatography (C18 reverse phase, water + 0.1% NH₃ •H₂ O -> MeCN + 0.1% NH₃ •H₂ O) Purification affords the desired 2-amino-4,5-difluorobenzonitrile. Step 2:4,5- Difluoro -2-(2 H- Tetrazole -5- base ) aniline . Add sodium azide (1.04 g, 16 mmol) and ammonium chloride (856) to a solution of 2-amino-4,5-difluorobenzonitrile (250 mg, 1.6 mmol) in DMF (8 mL) Mg, 16 mmol). The mixture was heated at 100 &lt;0&gt;C for 16 h and then filtered and the filtrate was concentrated in vacuo to give crude. By column chromatography (C18 reverse phase, water + 0.1% NH₃ •H₂ O -> MeCN + 0.1% NH₃ •H₂ O) Purification affords the title product. Step 3: Add 4,5-difluoro-2-(1H-tetrazole) to a solution of 6-fluoro-2-naphthoquinone chloride (intermediate 5, 125 mg, 0.6 mmol) in DCM (3 mL) A solution of -5-yl)aniline (92 mg, 0.6 mmol) elut elut elut By column chromatography (C18 reverse phase, water + 0.1% NH₃ •H₂ O -> MeCN + 0.1% NH₃ •H₂ O) Purification afforded the title compound. LC-MS: 368 (M-H)^- . Example 51.N -(4,5-difluoro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthalene Guanaminestep 1:2- Amine -4,5- Difluoro -N- Hydroxybenzamide To a solution of 2-amino-4,5-difluorobenzonitrile (100 mg, 0.65 mmol) in EtOH (2 mL), EtOAc (EtOAc) Mg, 3.25 mmol). The solution was heated at 50 ° C for 16 hours and then concentrated in vacuo to give a crude material. By column chromatography (C18 reverse phase, water + 0.1% NH₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification affords the desired product. Step 2:3-(2- Amine -4,5- Difluorophenyl )-1,2,4- Oxadiazole -5(4H)- ketone To 2-amino-4,5-difluoro-N Methyl methoxide (86 mg, 1.6 mmol) and diethyl carbonate (250 mg, 2.1 mmol) were added to a suspension of hydroxybenzhydrazide (100 mg, 0.53 mmol) in EtOH (2 mL). The solution was heated to reflux for 16 hours, allowed to cool and water and 1N HCl were added sequentially to adjust pH to pH 7. The resulting solid was filtered, washed with water then dried in vacuo to give the desired material. Step 3: The title compound was prepared in a similar manner to Step 3 of Example 50. LC-MS: 384 (M-H)^- . Example 52. 5-Chloro-2-(6-chloro-2-naphthylamino)benzoic acidThe title compound was prepared in a similar manner to Example 3 using 6-chloro-2-naphthoic acid ( Intermediate 1). LC-MS: 360 (M+H)⁺ . Example 53. 6-Fluoro-N -(4-fluoro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-2-naphthylamineThe title compound used 6-fluoro-2-naphthoquinone chloride (Intermediate 5) and DCM and 1-(2-amino-5-fluoro-4-methoxyphenyl)-1 in a similar manner to Example 32.H -tetrazole-5 (4H - Ketone (prepared by using 5-fluoro-4-methoxy-2-nitroaniline and the conditions outlined in Example 42). LC-MS: 396 (M-H)^- . Example 54. 5-Chloro-4-ethyl-2-(6-fluoro-2-naphthylamino)benzoic acidstep 1:2- Amine -5- chlorine -4- Vinyl benzoic acid . To a solution of 2-amino-4-bromo-5-chlorobenzoic acid (500 mg, 2 mmol) in DME (5 mL) and water (5 mL)Potassium acid (804 mg, 6 mmol), XPhos-Pd-G2 (0.04 equivalent) and sodium carbonate (848 mg, 8 mmol). The solution was sparged with nitrogen, heated in a microwave reactor at 100 ° C for 30 minutes, and then the solution was concentrated in vacuo to give a crude material. By column chromatography (C18 reverse phase, water, 0.1% NH₃ H₂ O -> MeCN, 0.1% NH₃ H₂ O) Purification affords the desired product. Step 2:2- Amine -5- chlorine -4- Ethyl benzoic acid Add Niobium Nickel (1 mL Suspension) to a solution of 2-amino-5-chloro-4-vinylbenzoic acid (180 mg, 0.9 mmol) in water (15 mL) MeOH (15 mL) . The solution was bubbled with hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give a crude material. By column chromatography (C18 reverse phase, water, 0.1% NH₃ H₂ O -> MeCN, 0.1% NH₃ H₂ O) Purification affords the desired product. Step 3: The title compound was prepared in a similar manner to Example 7 using 6-fluoro-2-naphthoquinone chloride (Intermediate 5). LC-MS: 370 (M-H)^- . Example 55. 4-(Benzyloxy)-5-chloro-2-(6-fluoro-2-naphthylamino)benzoic acidstep 1:2- Amine -4-( Benzyloxy )-5- Chlorobenzoic acid . 2-Amino-5-chloro-4-fluorobenzoic acid (250 mg, 1.32 mmol), benzyl alcohol (2 g, 18.5 mmol) and cesium carbonate (1 g, 3 mmol) were combined and heated at 120 ° C 16 hour. By column chromatography (C18 reverse phase, water + 0.1% NH₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification of the crude reaction mixture to give the desired product. Step 2: The title compound was prepared in a similar manner to Step 3 of Example 50 using 6-fluoro-2-naphthoquinone chloride (Intermediate 5). LC-MS: 448 (M-H)^- . Example 56. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(oxetan-3-yloxy)benzoic acidThe title compound was prepared in a similar manner to Example 55 using oxetane-3-ol. LC-MS: 414 (M-H)^- . Example 57.N -(4-chloro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamineThe title compound used 6-fluoro-2-naphthoquinone chloride (Intermediate 5) and DCM and 1-(2-amino-5-chloro-4-methoxyphenyl)-1 in a similar manner to Example 32.H -tetrazole-5 (4H -ketone (using 5-chloro-4-methoxy-2-nitroaniline and Example 42 Step 1 and preparation of the intermediate 1-(2-amino-5-chlorophenyl)-1H -tetrazole-5 (4H Prepared by the conditions outlined in the -ketone. LC-MS: 412 (M-H)^- . Example 58. 2-(2-Naphthylamino)-5-(difluoromethoxy)benzoic acidStep 1: Methyl 2-(2-naphthylamino)-5-hydroxybenzoate was used in a similar manner to Step 1 of Example 3 using 2-amino-5-hydroxybenzoic acid methyl ester and 2-naphthic acid as Start with the substance to prepare. Step 2: Add 2-bromo-2 to a stirred solution of methyl 2-(2-naphthylamino)-5-hydroxybenzoate (307 mg, 0.96 mmol) in anhydrous DMF (4 mL) Ethyl 2-difluoroacetate (150 μL, 1.15 mmol). The resulting mixture was stirred at 80 &lt;0&gt;C for 13 h, cooled to rt, filtered and purified by &lt;RTI ID=0.0&gt;&gt;&gt; The product containing the dissolved fraction was concentrated to give methyl 2-(2-naphthylamino)-5-(difluoromethoxy)benzoate. Step 3: The title compound was prepared in a similar manner to Step 2 of Example 3 using methyl 2-(2-naphthylamino)-5-(difluoromethoxy)benzoate as starting material. LC-MS: 356 (M-H)^- . Example 59. 2-(6-Fluoro-2-naphthylamino)-4,5-dimethoxybenzoic acidThe title compound was prepared in a similar manner as described in Example 49 using 2-amino-4,5-dimethoxybenzoic acid and 6-fluoro-2-naphthoquinone chloride (Intermediate 5). The isolated solid was stirred with a mixture of EtOAc, EtOAc (EtOAc &lt;RTI ID=0.0&gt;&gt; 1N HCl was added to the reaction mixture to give the title compound. LC-MS: 370 (M+H)⁺ . Example 60. 7-(6-Fluoro-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acidThe title compound was prepared in a similar manner to Example 59 using 7-amino-2,3-dihydrobenzo[b][1,4]dioxazin-6-carboxylic acid. LC-MS: 368 (M+H)⁺ . Example 61. 5-Chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-6-carboxamido)benzoic acidStep 1: 2-Methylbenzo[b]thiophene-6-carboxylic acid was prepared using benzo[b]thiophene-6-carboxylic acid and the procedure of Example 1 Step 1. Step 2: Title compound 2-methylbenzo[b]thiophene-6-carboxylic acid and DCM and ethyl 2-amino-5-chloro-4-methoxybenzoate were used in a similar manner to Example 3. It is prepared by typical ester hydrolysis conditions. LC-MS: 374 (M-H)^- . Example 62. 5-cyano-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acidThe title compound used methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 6-fluoro-2-naphthoic acid in a similar manner as described in Example 3, followed by typical Prepared by ester hydrolysis conditions. LC-MS: 363 (M-H)^- . Example 63. 5-Chloro-4-ethynyl-2-(6-fluoro-2-naphthylamino)benzoic acidstep 1:2- Amine -5- chlorine -4-(( Trimethyldecyl ) Ethynyl ) Methyl benzoate Prepared in a similar manner to that described in Step 1 of Example 45 using methyl 2-amino-4-bromo-5-chlorobenzoate as the starting material. Step 2:5- chlorine -2-(6- fluorine -2- Naphthylamine )-4-(( Trimethyldecyl ) Ethynyl ) Methyl benzoate Prepared in a manner similar to that described in Example 50, Step 3. Step 3: To a solution of methyl 5-chloro-2-(6-fluoro-2-naphthylamino)-4-((trimethyldecyl)ethynyl)benzoate (60 mg, 0.13 mmol) in MeOH ( NaOH (1 M, 0.5 mL, 0.5 mmol) was added to a solution of 2 mL) and THF (1 mL). After stirring for 30 minutes, the solution was concentrated in vacuo to give a crude material. By column chromatography (C18 reverse phase, water + 0.1% NH₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification afforded the title compound. LC-MS: 366 (M-H)^- . Example 64. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-((tetrahydro-2)H -piperidin-4-yl)oxy)benzoic acidThe title compound used tetrahydro-2 in a similar manner as described in Example 55.H -pipetam-4-ol to prepare. LC-MS: 442 (M-H)^- . Example 65. 5-Chloro-4-cyclopropyl-2-(6-fluoro-2-naphthylamino)benzoic acid (5203)step 1:2- Amine -5- chlorine -4- Cyclopropylbenzoic acid Using a cyclopropyl group in a similar manner to that described in Step 1 of Example 54Acid to prepare. Step 2: The title compound was prepared in a similar manner as described in Step 3 of Example 50. LC-MS: 382 (M-H)^- . Example 66.N -(4,5-difluoro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylaminestep 1:1,2- Difluoro -4- Isocyanate -5- Nitrobenzene Add a phosgene (2.95 g, 15 mmol) to a suspension of 4,5-difluoro-2-nitroaniline (1.7 g, 10 mmol) in toluene (40 mL) and warm the mixture to reflux. 16 hours. The solution was concentrated in vacuo to give a crude oil which was used without further purification. Step 2:1-(4,5- Difluoro -2- Nitrophenyl )-1,4- Dihydrogen -5 H- Tetrazole -5- ketone 1. 1,2-Difluoro-4-isocyanato-5-nitrobenzene (1.3 g, 6.5 mmol) was mixed with azide trimethyl decane (2 mL) and heated at 100 ° C for 16 hours. The solution is concentrated in vacuo and the residue is chromatographed by column chromatography (SiO₂ Purification by gradient hexane->EtOAc to give the desired product. Step 3:1-(2- Amine -4,5- Difluorophenyl )-1H- Tetrazole -5 (4 H)- ketone . To 1-(4,5-difluoro-2-nitrophenyl)-1,4-dihydro-5H To a solution of tetrazol-5-one (150 mg, 0.62 mmol) in MeOH (20 mL) EtOAc (1 mL, as a suspension). The hydrogen was bubbled for four hours while stirring vigorously and the solution was filtered through celite and concentrated in vacuo to give product. Step 4: The title compound was then obtained in a similar manner as described in Step 3 of Example 50. LC-MS: 384 (M-H)^- . Example 67. 5-Chloro-2-(7-fluoroquinoline-3-carbamimidino)-4-(oxetan-3-yloxy)benzoic acidThe title compound was prepared in a similar manner to Example 55 using oxetane-3-ol and 7-fluoroquinoline-3-carboxylic acid as the decylamine coupling. LC-MS: 415 (M-H)^- . Example 68. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(hydroxymethyl)benzoic acidstep 1:2- Amine -4-((( Third butyl dimethyl decyl ) Oxyl ) methyl )-5- Methyl chlorobenzoate Add a solution of methyl 2-amino-4-bromo-5-chlorobenzoate (100 mg, 0.38 mmol) in dioxane (1 mL) in butyl dimethyl ((tributylstannane) Methoxy) decane (165 mg, 0.38 mmol) and hydrazine (triphenylphosphine) palladium (0) (20 mg, 0.017 mmol). The solution was sparged with nitrogen and heated at 150 ° C for 3 hours. After the reaction is completed, the solution is concentrated in vacuo and the residue is chromatographed by column chromatography (SiO₂ Purification by gradient hexane -> EtOAc) gave the desired material. Step 2:4-((( Third butyl dimethyl decyl ) Oxyl ) methyl )-5- chlorine -2-(6- fluorine -2- Naphthylamine ) Methyl benzoate 2-Amino-4-(((tert-butyldimethylmethylalkyl)oxy)methyl)-5-chlorobenzoic acid methyl ester and 6-fluoro-2 were used as described in Step 3 of Example 50. -Naphthoquinone chloride (Intermediate 5) was prepared. Step 3:4-((( Third butyl dimethyl decyl ) Oxyl ) methyl )-5- chlorine -2-(6- fluorine -2- Naphthylamine ) benzoic acid To 4-(((tert-butyldimethylmethylalkyl)oxy)methyl)-5-chloro-2-(6-fluoro-2-naphthylamino)benzoic acid methyl ester (100 mg, NaOH (5N, 200 μL) was added to a solution of MeOH (3 mL) and THF (3 mL). The solution was concentrated in vacuo and the residue was chromatographed by column chromatography (C-18 reverse phase, water + 0.1% NH₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification to give the desired product. Step 4: To 4-(((t-butyldimethyl)alkyl)oxy)methyl)-5-chloro-2-(6-fluoro-2-naphthylamino)benzoic acid (30 mg, 0.06 mmol) TBAF (1M in THF; 2 mL, 2.0 mmol) was added in THF (100 uL). After 1 h, the solution was concentrated in vacuo and purified title crystalljjjjlililililililililililili LC-MS: 372 (M-H)^- . Example 69.N -(4-chloro-5-(oxetan-3-yloxy)-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylaminestep 1:1-(5- chlorine -2- Nitro -4-( Oxetane -3- Baseoxy ) Phenyl )-1 H- Tetrazole -5 (4 H)- ketone Oxybutane-3-ol and 1-(5-chloro-4-fluoro-2-nitrophenyl)-1 were used in a similar manner to that described in Example 55.H -tetrazole-5 (4H )-ketone (see Example 42) was prepared. Step 2:1-(2- Amine -5- chlorine -4-( Oxetane -3- Baseoxy ) Phenyl )-1 H- Tetrazole -5 (4 H)- ketone 1-(5-Chloro-2-nitro-4-(oxetan-3-yloxy)phenyl)-1H-tetrazole-5 (4) was used in a similar manner to that described for Intermediate 3.H - Ketone is prepared as a starting material. Step 3: title compound using 1-(2-amino-5-chloro-4-(oxetan-3-yloxy)phenyl)-1 in a similar manner as described in Step 3 of Example 50H -tetrazole-5 (4H )-ketone and 6-fluoro-2-naphthoquinone chloride (intermediate 5) were prepared. LC-MS: 456 (M+H)⁺ . Example 70: 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(2,2,2-trifluoroethoxy)benzoic acidThe title compound was prepared in a similar manner as described in Example 55 using 2,2,2-trifluoroethanol. LC-MS: 440 (M-H)^- . Example 71.N -(4-chloro-5-methoxy-2-((methylsulfonyl)amine-methyl)phenyl)-6-fluoro-2-naphthylamineAdd 1,1'- to a solution of 5-chloro-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acid (180 mg, 0.48 mmol) in THF (10 mL) Carbonyldiimidazole (156 mg, 1 mmol) and the solution was heated at 40 ° C for 1 hour. Sodium hydride (60% in mineral oil, 23 mg, 0.58 mmol) and THF (1 mL) were added to each vial and stirred for 30 min. Methanesulfonamide (46 mg, 0.48 mmol) was then added. After stirring for 30 minutes, the CDI solution was added to the sodium salt and heated at 50 ° C for 1 hour. The reaction mixture was cooled and acidified with EtOAc EtOAc (EtOAc)EtOAc.₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification to give the title compound. LC-MS: 449 (M-H)^- . Example 72. 6-Chloro-N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-2-naphthylamineThe title compound used 6-chloro-2-naphthoic acid (Intermediate 1) and DCM and 1-(2-amino-5-chlorophenyl)-1 in a similar manner as in Step 3 of Example 3.H -tetrazole-5 (4H )-ketone (Intermediate 3) to prepare. LC-MS: 398 (M-H)^- . Example 73. 6-(6-Chloro-2-naphthylamino)-2,2-difluorobenzo[d][1,3]dioxazole-5-carboxylic acidstep 1:2,2- Difluoro -6- iodine Benzo [d][1,3] Dicarbazole -5- amine Add to a stirred solution of 2,2-difluorobenzo[d][1,3]dioxazole-5-amine (1 g, 5.78 mmol) in dry DMF (60 mL)N - Iodobutane diimine (1.37 g, 6.07 mmol). The resulting mixture was stirred at room temperature for 7 hours and then diluted with EtOAc and water. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc) 5-amine. Step 2:6- Amine -2,2- Difluorobenzo [d][1,3] Dicarbazole -5- Methyl formate To a stirred solution of 2,2-difluoro-6-iodobenzo[d][1,3]dioxazole-5-amine (1.12 g, 3.75 mmol) in anhydrous DMSO (15 mL) Add anhydrous MeOH (9 mL), TEA (530 μL, 3.75 mmol), potassium carbonate (1.6 g, 11.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium ( II) (411 mg, 0.562 mmol). Carbon monoxide was bubbled through the reaction mixture for 15 minutes. The resulting mixture was stirred at 70 ° C under 1 atmosphere of CO for 2 hr then diluted with EtOAc and water. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc - Dicarbazole-5-carboxylic acid methyl ester. Step 3: title compound using 6-amino-2,2-difluorobenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester and 6-chloro-2- in a similar manner as in Example 3. Naphthoic acid (Intermediate 1) was then prepared using typical ester hydrolysis conditions. LC-MS: 404 (M-H)^- . Example 74. 2-(2-Naphthylamino)-5-chloro-6-methoxynicotinic acidstep 1:2- chlorine -6- Methoxynicotinic acid . 2,6-Dichloropyridine-3-carboxylic acid (5.0 g, 26.04 mmol), methanol (30 mL) and potassium butoxide (5.86 g, 52.22 mmol) were placed in a 250 mL round bottom flask. The resulting solution was stirred at 65 ° C for 4 days in an oil bath. The resulting mixture was concentrated in vacuo. The residue was dissolved in 30 mL of water and the pH of the solution was adjusted to 3 to 4 with HCl. The obtained precipitate was collected by filtration to yield 4.6 g (yield: 94%) of 2-chloro-6-methoxypyridine-3-carboxylic acid as a white solid. Step 2:2- chlorine -6- Methoxypyridine -3- Methyl formate Place 2-chloro-6-methoxypyridine-3-carboxylic acid (900 mg, 4.80 mmol), dichloromethane (10 mL), N,N-dimethylformamide in a 50 mL round bottom flask (about 15 μL) and sulfoxide (2 mL, 24.0 mmol). The resulting solution was stirred at 40 ° C for 2.5 hours in an oil bath. The resulting mixture was concentrated in vacuo. Thereafter, methanol (10 mL) was added dropwise at 0 ° C with stirring. The resulting solution was stirred at room temperature for 1 hour and the resulting mixture was concentrated in vacuo. The residue was purified with a pad of silica gel eluting with ethyl acetate / petroleum ether (1/19). This gave 720 mg (74%) of 2-chloro-6-methoxypyridine-3-carboxylic acid methyl ester as a colorless oil. Step 3:6- Methoxy -2-( Naphthalene -2- Amidoxime ) Pyridine -3- Methyl formate 2-Chloro-6-methoxypyridine-3-carboxylic acid methyl ester (720 mg, 3.57 mmol), naphthalene-2-carboxamide, placed in a 50 mL round bottom flask purged and maintained under an inert nitrogen atmosphere (700 mg, 4.09 mmol), potassium carbonate (1.105 g, 8.00 mmol), tetrahydrofuran (10 mL), Pd (OAc)₂ (92 mg, 0.41 mmol) and oxaphosphonium (473 mg, 0.82 mmol). The resulting solution was stirred at 65 ° C for 20 hours in an oil bath. The resulting mixture was concentrated in vacuo. The resulting mixture was partitioned between water and EtOAc.₂ SO₄ Dry, filter and concentrate in vacuo. The residue was purified by dissolving with a pad of silica gel eluting with ethyl acetate / petroleum ether (1/4). This gave 620 mg (52%) of methyl 6-methoxy-2-(naphthalen-2-indole)pyridine-3-carboxylate as a pale yellow solid. Step 4:5- chlorine -6- Methoxy -2-( Naphthalene -2- Amidoxime ) Pyridine -3- Methyl formate Place a 6-methoxy-2-(naphthalen-2-indenyl)pyridine-3-carboxylic acid methyl ester (620 mg, 1.84 mmol) in THF (15 mL) in a 50 mL round bottom flask.N - Chlorobutane diimine (319 mg, 2.39 mmol). The resulting solution was stirred at 70 ° C for 1 day in an oil bath. The resulting mixture was concentrated in vacuo and the residue was purified mjjjjjjj This gave 240 mg (purity 91%) and 280 mg (crude solid) of 5-chloro-6-methoxy-2-(naphthalen-2-indenyl)pyridine-3-carboxylic acid as a pale yellow solid. ester. Step 5: Place methyl 5-chloro-6-methoxy-2-(naphthalen-2-indenyl)pyridine-3-carboxylate in water (1.5 mL) in a 50 mL round bottom flask (180) Mg, 0.49 mmol), ethanol (5 mL) and LiOH (58 mg, 2.42 mmol). The resulting solution was stirred at 25 ° C for 3 hours. The resulting mixture was concentrated in vacuo and the residue was dissolved in 10 mL water. The pH of the aqueous solution was adjusted to 3 to 4 with an aqueous HCl solution (6 mol/L). The solid was collected by filtration. The title compound was obtained as a colorless solid. LC-MS: 357 (M+H)⁺ . Example 75. 2-(2-Naphthylamino)-5-chloro-6-ethoxynicotinic acidThe title compound was prepared in step 1 using ethanol in a similar manner as in Example 74. LC-MS: 371 (M+H)⁺ . Example 76.N -(4,5-difluoro-2-((methylsulfonyl)amine)methyl)phenyl)-6-fluoro-2-naphthylamineThe title compound was prepared in a similar manner as described in Example 71. LC-MS: 421 (M-H)^- . Example 77:N -(4-Chloro-2-(((difluoromethyl))sulfonyl)amine)-methoxy)-5-methoxyphenyl)-6-fluoro-2-naphthylamineThe title compound was prepared in a similar manner as described in Example 71 using difluoromethanesulfonamide. LC-MS: 485 (M-H)^- . Example 78: 2-(6-Chloro-2-naphthylamino)-5-(difluoromethoxy)-4-fluorobenzoic acidStep 1: Methyl 2-(6-chloro-2-naphthylamino)-4-fluoro-5-hydroxybenzoate. 2-Amino-4-fluoro-5- was used in a similar manner to Step 1 in Example 3. Methyl hydroxybenzoate and 6-chloro-2-naphthoic acid (Intermediate 1) were prepared. Step 2: Methyl 2-(6-chloro-2-naphthylamino)-5-(difluoromethoxy)-4-fluorobenzoate was used in a similar manner to step 2 of Example 58 using 2-(6- Methyl chloro-2-naphthylamino)-4-fluoro-5-hydroxybenzoate was prepared as a starting material. Step 3: The title compound was used in a similar manner to Step 2 of Example 3 using methyl 2-(6-chloro-2-naphthylamino)-5-(difluoromethoxy)-4-fluorobenzoate as a starting point. Substance to prepare. LC-MS: 408 (M-H)^- . Example 79. 5-cyano-2-(6-fluoro-2-naphthylamino)benzoic acidThe title compound was used in a similar manner to that described in Example 3 using 2-amino-5-cyanobenzoic acid methyl ester and 6-fluoro-2-naphthoic acid, followed by the usual ester hydrolysis conditions. LC-MS: 333 (M-H)^- . Example 80. 2-(6-Chloro-2-naphthylamino)-5-cyanobenzoic acidThe title compound was used in a similar manner to that described in Example 3 using 2-amino-5-cyanobenzoic acid methyl ester and 6-chloro-2-naphthoic acid (Intermediate 1), followed by typical ester hydrolysis conditions. LC-MS: 349 (M-H)^- . Example 81. 5-cyano-2-(6-fluoro-2-naphthylamino)-4-methylbenzoic acidThe title compound was prepared in a similar manner to that described in Example 3 using methyl 2-amino-5-cyano-4-methylbenzoate and 6-fluoro-2-naphthoic acid, and then using typical ester hydrolysis conditions. LC-MS: 347 (M-H)^- . Example 82. 5-cyano-2-(6-chloro-2-naphthylamino)-4-methylbenzoic acidThe title compound used methyl 2-amino-5-cyano-4-methylbenzoate and 6-chloro-2-naphthoic acid (Intermediate 1) in a similar manner as described in Example 3, followed by a typical ester. Prepared by hydrolysis conditions. LC-MS: 363 (M-H)^- . Example 83.N -(4-(difluoromethoxy)-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylaminestep 1:5-( Difluoromethoxy )-2- Nitroaniline Add ammonia (26 mL, 53.1 mmol, to a stirred solution of 4-(difluoromethoxy)-2-fluoro-1-nitrobenzene (1.1 g, 5.31 mmol) in EtOH (4 mL) 2.0 M EtOH solution). The resulting mixture was stirred at 70 ° C for 48 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc and water. Wash the organic layer with brine over MgSO₄ Drying and concentration in vacuo gave 5-(difluoromethoxy)-2-nitroaniline. Step 2:1-(5-( Difluoromethoxy )-2- Nitrophenyl )-1H- Tetrazole -5 (4 H)- ketone Prepared in a similar manner to Intermediate 3, Step 2, using 5-(difluoromethoxy)-2-nitroaniline as the starting material. Step 3:1-(2- Amine -5-( Difluoromethoxy ) Phenyl )-1H- Tetrazole -5 (4 H)- ketone . To 1-(5-(difluoromethoxy)-2-nitrophenyl)-1 under nitrogen atmosphereH -tetrazole-5 (4H To a solution of the ketone (210 mg, 0.769 mmol) in EtOAc (10 mL) EtOAc (EtOAc) Hydrogen gas was bubbled through the resulting mixture for 15 minutes and then heated to 60 ° C under 1 atmosphere of hydrogen for 8 hours. The reaction mixture was cooled to room temperature, filtered over EtOAc EtOAc (EtOAc)EtOAc. . Step 4: title compound using 1-(2-amino-5-(difluoromethoxy)phenyl)-1 in a similar manner as Example 32H -tetrazole-5 (4H The ketone and 6-fluoro-2-naphthoquinone chloride (intermediate 5) were prepared as starting materials. LC-MS: 414 (M-H)^- . Example 84. 6-Chloro-N -(4-(difluoromethoxy)-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-2-naphthylamineThe title compound was used in a similar manner to Example 32 using 1-(2-amino-5-(difluoromethoxy)phenyl)-1H-tetrazole-5(4H)-one as prepared in Step 3 of Example 83. And 6-chloro-2-naphthoquinone chloride (as intermediate 5 is prepared from the corresponding acid). LC-MS: 430 (M-H)^- . Example 85. 6-Chloro-N -(4-chloro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-2-naphthylamineThe title compound was prepared in a similar manner as in Example 86 using iodomethane in step 1 and using 6-chloro-2-naphthoquinone chloride (prepared analogously to intermediate 5). LC-MS: 428 (M-H)^- . Example 86.N -(4-chloro-5-ethoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylaminestep 1:4- Ethoxy -2- Nitroaniline To 4-amino-3-nitrophenol (3.00 g, 12.2 mmol), Cs at 0 °C₂ CO₃ (7.98 g, 24.5 mmol) bromoethane (0.96 mL, 12.9 mmol) was added to a stirred solution in DMF (100 mL). The mixture was stirred at room temperature for 16 hours and the reaction was considered to be 50% complete. Additional bromoethane (0.96 mL, 12.9 mmol) was added and the reaction was stirred further 36 h. The mixture was partitioned between EtOAc and brine and again brine, water (2) water, sat. Na₂ CO₃ Aqueous solution (2 times), brine washed organics, Na₂ SO₄ Dry, filter and concentrate in vacuo. The crude material obtained was of sufficient purity and was used without further purification. Step 2:4- Ethoxy -1- Isocyanate -2- Nitrobenzene Add diphosgene (1.53 mL, 12.8 mmol) to a stirred solution of EtOAc (100 mL) at 0 ° C, then slowly add 4-ethoxy-2-nitro Aniline (3.10 g, 17.0 mmol). The resulting mixture was stirred under reflux for 16 hours and the solvent was evaporated. The crude material was stirred at 60 ° C in a 20:1 mixture of hexane:EtOAc for 1 hour and then filtered thru filter paper. The filtrate was evaporated to give 4-ethoxy-1-isocyanato-2-nitrobenzene which was used in the next step. Step 3:1-(4- Ethoxy -2- Nitrophenyl )-1 H- Tetrazole -5 (4 H)- ketone . 4-Ethoxy-1-isocyanato-2-nitrobenzene (3.50 g, 16.8 mmol) with TMSN₃ (5.50 mL, 42.0 mmol) was combined and heated to 100 ° C in a sealed vessel for 16 hours. The solvent was evaporated and the crude material was purified eluting eluting eluting eluting eluting eluting eluting Step 4:1-(2- Amine -4- Ethoxyphenyl )-1 H- Tetrazole -5 (4 H)- ketone Stirring 1-(4-ethoxy-2-nitrophenyl)-1 in THF (40 mL)H -tetrazole-5 (4H )-ketone (1.90 g, 7.56 mmol) with the addition of Raney nickel (2800 in H)₂ Slurry in O, 1.6 mL). In H₂ The resulting mixture was stirred at room temperature for 96 hours under an atmosphere. The reaction was filtered through EtOAc (EtOAc)EtOAc. Step 5:1-(2- Amine -5- chlorine -4- Ethoxyphenyl )-1 H- Tetrazole -5 (4 H)- ketone To 1-(2-Amino-4-ethoxyphenyl)-1 at room temperatureH -tetrazole-5 (4H N-N (0.29 mg, 2.17 mmol) was added to a stirred solution of ketone (0.40 g, 1.81 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 16 hours and then evaporated. The obtained crude material is passed through a C18 column with 10% to 100% CH in water.₃ CN solvent gradient (CH₃ Purification by elution of CN and water plus 0.1% formic acid) gave 1-(2-amino-5-chloro-4-ethoxyphenyl)-1H -tetrazole-5 (4H )-keto formate. The resulting formate is saturated with a minimum amount of saturated NaHCO₃ Neutralization (aqueous solution) followed by n-BuOH and saturated NH₄ Diluted with Cl. The organic phase is washed with water (2 times), concentrated, and then co- evaporated with heptane to give the desired product. Step 6: The title compound used 6-fluoro-2-naphthoquinone chloride (intermediate 5) and 1-(2-amino-5-chloro-4-ethoxyphenyl)- in a similar manner as in Example 32. 1H - Tetrazolium-5(4H)-one is prepared. LC-MS: 426 (M-H)^- . Example 87. 6-Chloro-N -(4-chloro-5-ethoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-2-naphthylamineThe title compound was prepared in a similar manner to Example 86 using 6-chloro-2-naphthoquinone chloride (prepared from Intermediate 5). LC-MS: 442 (M-H)^- . Example 88.N -(4-chloro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-(trifluoromethyl)-2-naphthylaminestep 1:6-( Trifluoromethyl )-2- Naphthoic acid Add to a stirred solution of 2-bromo-6-(trifluoromethyl)naphthalene (5 g, 18.2 mmol) in dry THF (50 mL) at -78 °Cn -BuLi (12 mL, 20 mmol, 1.6 M in hexanes) and the mixture was stirred for 15 min. Anhydrous carbon dioxide was bubbled through the reaction mixture for 15 minutes and the mixture was allowed to warm to room temperature. The volatiles were removed in vacuo andqqqqqqqqq Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The obtained solid was wet-milled with DCM to give 6-(trifluoromethyl)-2-naphthic acid. Step 2: Add HATU (84 mg, 0.220 mmol) to a solution of 6-(trifluoromethyl)-2-naphthoic acid (44 mg, 0.183 mmol) in dry DMF (2 mL) The resulting mixture was stirred under heating for 15 minutes. Then 1-(2-amino-5-chloro-4-methoxyphenyl)-1H-tetrazole-5(4H)-one (45 mg, 0.183 mmol) was added to the mixture in a similar manner as in Example 32. Prepared using 5-chloro-4-methoxy-2-nitroaniline and the conditions outlined in Preparation Intermediate 3), then added after 10 minutesN , N - Diisopropylethylamine (96 μL, 0.549 mmol), and the mixture was stirred at room temperature for 14 hr. Next, 1 mL of 3N aqueous NaOH solution was added to the mixture, followed by the addition of 3 mL of 5N aqueous HCl solution after 20 minutes. The resulting mixture was then diluted with EtOAc and 1N aqueous HCI. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by EtOAc (EtOAc) elut LC-MS: 462 (M-H)^- . Example 89.N -(4-chloro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-methyl-2-naphthylaminestep 1:6- methyl -2- Methyl naphthoate Add methyl to a stirred solution of methyl 6-bromo-2-naphthoate (3 g, 11.3 mmol) in dry 1,4-dioxane (100 mL)Acid (2.04 g, 34.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (830 mg, 1.13 mmol) and cesium fluoride (5.8 g, 38.5) Mm). The resulting mixture was stirred at 100 ° C for 7 hours and then cooled to room temperature. The volatiles were removed in vacuo and the residue was diluted with EtOAc and water. The organic layer was washed with aq. EtOAc EtOAc.₄ Dry and concentrate in vacuo. The resulting solid was triturated with MeOH to give methyl 6-methyl-2-naphthalate. Step 2:6- methyl -2- Naphthoic acid To a stirred suspension of methyl 6-methyl-2-naphthoate (1.76 g, 8.79 mmol) in MeOH (10 mL) The mixture was heated to 50 &lt;0&gt;C for 3 h, diluted with aq. Wash the organic layer with brine over MgSO₄ Dry and concentrated in vacuo to give 6-methyl-2-naphthic acid. Step 3: title compound using 1-(2-amino-5-chloro-4-methoxyphenyl)-1H-tetrazole-5(4H)-one and 6-A in a similar manner as Example 88 Step 2. Base-2-naphthoic acid was prepared as a starting material. LC-MS: 408 (M-H)^- . Example 90.N -(4-chloro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-cyclopropyl-2-naphthylamineStep 1: 6-Cyclopropyl-2-naphthoic acid using cyclopropyl in a similar manner to Steps 1 and 2 of Example 89The acid is prepared as a starting material. Step 2: title compound using 1-(2-amino-5-chloro-4-methoxyphenyl)-1 in a similar manner as in Example 88 Step 2.H -tetrazole-5 (4H The ketone and 6-cyclopropyl-2-naphthoic acid were prepared as starting materials. LC-MS: 434 (M-H)^- . Example 91.N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-cyano-2-naphthylamineThe title compound was prepared in a similar manner as described in Example 32 using 6-cyano-2-naphthoquinone chloride (prepared from Intermediate 5). The desired material was isolated by precipitating the crude product from DMSO with water. LC-MS: 391 (M+H)⁺ . Example 92. 2,2-Difluoro-6-(6-fluoro-2-naphthylamino)benzo[d][1,3]dioxazole-5-carboxylic acid (NXT5416)The title compound was used in a similar manner to Example 3 using methyl 6-amino-2,2-difluorobenzo[d][1,3]dicarbazole-5-carboxylate (described in Example 73) and 6- Fluor-2-naphthoic acid is then prepared using typical ester hydrolysis conditions. LC-MS: 388 (M-H)^- . Example 93. 2-(2-Naphthylamino)-5-chloro-4-(methoxymethyl)benzoic acidstep 1:2- Amine -5- chlorine -4-( Methoxymethyl ) Methyl benzoate Add hydrazine (triphenylphosphine) palladium (0) to a solution of methyl 2-amino-4-bromo-5-chlorobenzoate (200 mg, 0.75 mmol) in dioxane (2 mL) 50 mg, 0.043 mmol) and tributyl(methoxymethyl)stannane (253 mg, 0.75 mmol). The solution was degassed with nitrogen and heated at 150 ° C for four days. The solution is concentrated in vacuo and the residue is chromatographed by column chromatography (SiO₂ Purification by gradient hexane->EtOAc to give the desired product. Step 2:2-(2- Naphthylamine )-5- chlorine -4-( Methoxymethyl ) Methyl benzoate Prepared using 2-naphthoquinone chloride in a similar manner to that described in Step 3 of Example 50. Step 3: To a solution of methyl 2-(2-naphthylamino)-5-chloro-4-(methoxymethyl)benzoate (90 mg, 0.23 mmol) in THF (1 mL) and MeOH (1 mL LiOH (1 M, 1 mL, 1 mmol) was added to the solution. The solution was concentrated in vacuo and the residue was chromatographed by column chromatography (C-18 reverse phase, water, 0.1% NH₃ H₂ O -> MeCN, 0.1% NH₃ H₂ O) Purification to give the title compound. LC-MS: 368 (M-H)^- . Example 94.N -(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-7-fluoroquin Porphyrin-3-carboxamidestep 1.2- Amine -5- chlorine -4- Methoxybenzonitrile Place 2-amino-4-methoxybenzonitrile (2.0 g, 13.50 mmol) in tetrahydrofuran (40 mL) in a 100 mL round bottom flask.N - Chlorobutane diimine (2.7 g, 20.2 mmol). The resulting solution was stirred at 60 ° C for 16 hours. The resulting solution was extracted with ethyl acetate and the organic phases were combined. The combined organics were evaporated in vacuo and EtOAc EtOAc m. This gave 1.54 g (62%) of 2-amino-5-chloro-4-methoxybenzonitrile as a light red solid. Step 2.2- Amine -5- chlorine -N- Hydroxyl -4- Methoxybenzene -1- Hyperthyroidism . 2-Amino-5-chloro-4-methoxybenzonitrile (1.54 g, 8.43 mmol), NH was placed in a 100 mL round bottom flask₂ OH·HCl (1.16 g, 16.9 mmol), ethanol (30 mL), and DIEA (3.27 g, 25.3 mmol). The resulting solution was stirred at 80 ° C for 16 hours in an oil bath. The mixture was concentrated with EtOAc EtOAc m. The residue was purified via hydrazine gel column eluting with ethyl acetate / petroleum ether (2/3). This gave 1.3 g (71%) of 2-amino-5-chloro-N-hydroxy-4-methoxybenzene-1-carboxamidine as a pale yellow solid. Step 3.3-(2- Amine -5- chlorine -4- Methoxyphenyl )-4,5- Dihydrogen -1,2,4- Oxadiazole -5- ketone Ethanol (50 mL) and sodium metal (1.03 g, 44.5 mmol) were placed in a 250 mL round bottom flask and the solution was stirred in water/ice bath for 3 hours. Add 2-amino-5-chloro-N-hydroxy-4-methoxybenzene-1-carboxamidine (1.2 g, 5.56 mmol) and stir the resulting solution for 1 hour while maintaining at 80 ° C in an oil bath. temperature. Diethyl carbonate (5.26 g, 44.5 mmol) was added and the resulting solution was maintained at 80 ° C for 16 hours in an oil bath. The resulting mixture was concentrated in vacuo. The solid was collected by filtration and washed with water and dried in vacuo. This gave 810 mg (60%) of 3-(2-amino-5-chloro-4-methoxyphenyl)-4,5-dihydro-1,2,4-oxo as a pale yellow solid. Oxazol-5-one. Step 4. Place 7-fluoroquinoline-3-carboxylic acid (100 mg, 0.52 mmol), DCE (4 mL), 3-(2-amino-5-chloro-4-methyl) in a 25 mL round bottom flask. Oxyphenyl)-4,5-dihydro-1,2,4-oxadiazol-5-one (138.8 mg, 0.57 mmol), HATU (258.6 mg, 0.68 mmol) and DIEA (202.6 mg, 1.57 mmol) . The resulting solution was stirred at 60 ° C for 12 hours in an oil bath. The resulting mixture was concentrated in vacuo and washed with 10 mL MeOH. The title compound was obtained as a pale yellow solid. LC-MS 415 (M+H)⁺ . Example 95:N -(4-bromo-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamineThe title compound was prepared in a similar manner as in Example 86 using methyl iodide in step 1, NBS/DMF in step 5, and 6-fluoro-2-naphthoquinone chloride (intermediate 5) in the final step. LC-MS: 456 (M-H)^- . Example 96.N -(4-bromo-5-methoxy-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-chloro-2-naphthylamineThe title compound was used in the same manner as in Example 86 using methyl iodide in step 1, NBS/DMF in step 5, and 6-chloro-2-naphthoquinone chloride in the final step (similar to intermediate 5). To prepare. LC-MS: 474 (M-H)^- . Example 97.N -(4-chloro-2-(5-o-oxy-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-6-fluoro-2-naphthylaminestep 1:5- chlorine -2- Nitrobenzopyrene . To a solution of 5-chloro-2-nitrobenzoic acid (4.03 g, 20.0 mmol) in THF (100 mL), EtOAc. The resulting mixture was stirred for 45 minutes, after which time hydrazine monohydrate (3.5 mL, 72.0 mmol) was added and stirring was continued for a further 2 hours. The volatiles were then removed by rotary evaporation and the crude residue was crystallised eluted with EtOAc₃ Wash with aqueous solution (3 x 50 mL), water (100 mL) and brine (50 mL). The combined aqueous layers were then back extracted with EtOAc (100 mL). Combined EtOAc layers over MgSO₄ Dry, filter and concentrate to dryness to give 5-chloro-2-nitrobenzoindole as a white solid. Step 2:5-(5- chlorine -2- Nitrophenyl )-1,3,4- Oxadiazole -2(3 H)- ketone Add carbonyldiimidazole to a solution of 5-chloro-2-nitrobenzoindole (0.417 g, 1.94 mmol) and triethylamine (0.94 mL, 6.79 mmol) in THF (20 mL). (0.346 g, 2.13 mmol). The mixture was stirred for 2 h, diluted with EtOAc (EtOAc) (EtOAc)EtOAc.₄ Dry, filter and concentrate to dryness to give 5-(5-chloro-2-nitrophenyl)-1,3,4-oxadiazole-2 as a white solid.H )-ketone. Step 3:5-(2- Amine -5- Chlorophenyl )-1,3,4- Oxadiazole -2(3 H)- ketone To 5-(5-chloro-2-nitrophenyl)-1,3,4-oxadiazole-2 (3H To a stirred solution of the ketone (0.372 g, 1.54 mmol) in dry ethanol (15 mL), EtOAc (EtOAc, EtOAc. The resulting mixture was heated to 60 ° C and stirred for 15 minutes at which time TLC and LC-MS analysis showed 5-(5-chloro-2-nitrophenyl)-1,3,4-oxadiazole-2 (3H) - The ketone starting material is completely consumed. The reaction mixture was cooled to EtOAc EtOAc (EtOAc)EtOAc.₄ Dry, filter and concentrate to give 5-(2-amino-5-chlorophenyl)-1,3,4-oxadiazole-2 as a white solid.H )-ketone. Step 4:N-(4- chlorine -2-(5- Side oxy -4,5- Dihydrogen -1,3,4- Oxadiazole -2- base ) Phenyl )-6- fluorine -2- Naphthylamine . The title compound was prepared in a similar manner as described in Step 1 of Example 3 using 5-(2-amino-5-chlorophenyl)-1,3,4-oxadiazole-2 (3H) - Ketone and 6-fluoro-2-naphthoic acid to give the title compound. LC-MS: 382 (M-H)^- . Example 98: 7-(6-Chloro-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acidThe title compound used 7-amino-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid and 6-chloro-2-naphthoquinone chloride in a similar manner to Example 59. Prepared by similar preparation to Intermediate 5. LC-MS: 384 (M+H)⁺ . Example 99: 7-(6-Cyano-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid (NXT 5476)step 1:6- Cyano -2- Naphthoic acid Add LiOH.H to a suspension of methyl 6-cyano-2-naphthoate (1.0 g, 4.73 mmol) in p-dioxane (20 mL) and water (10 mL)₂ O (500 mg, 11.9 mmol). The turbid suspension was dissolved over a period of 2 hours and thereafter hydrolyzed by LC-MS analysis. 1N HCl (20 mL) was added to a stirred solution for 10 min then filtered, washed with water and dried in vacuo to give the desired acid. Step 2: The title compound was used in a similar manner to Example 59 using 7-amino-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid and 6-cyano-2-naphthalene. Formamidine chloride (prepared in the same manner as Intermediate 5) was prepared. LC-MS 375 (M+H)⁺ . Example 100. 5-cyano-4-ethoxy-2-(6-fluoro-2-naphthylamino)benzoic acidstep 1:2- Ethoxy -4- Nitrobenzonitrile . Potassium carbonate (4.2 g, 30.3 mmol) and ethyl iodide (1.3 mL, 16.3) were added sequentially to a solution of 2-hydroxy-4-nitrobenzonitrile (2.5 g, 15.2 mmol) in DMF (20 mL) Mm). After stirring at ambient temperature for 16 hours, the mixture was diluted with water and EtOAc. The combined organic phases were washed with water, separated and dried (MgSO₄ ), filtered and evaporated in vacuo. The isolated compound was used without further purification. Step 2:4- Amine -2- Ethoxy Benzoonitrile . 2-Ethoxy-4-nitrobenzonitrile (2.1 g, 10.93 mmol) was dissolved in EtOH (50 mL), Pd/C (10% aqueous; 150 mg) was added and the solution was spouted with hydrogen and Stir under hydrogen for 3 hours. Dichloromethane was added to the solution and filtered through diatomaceous earth. Evaporation of the solvent gave aniline which was used without further purification. Step 3:4- Amine -2- Ethoxy -5- iodine Benzoonitrile . Add to a solution of 4-amino-2-ethoxybenzonitrile (1.92 g, 11.8 mmol) in acetic acid (25 mL)N - Iodobutane diimine (2.7 g, 12.0 mmol) and stirred at ambient temperature until completion of the reaction as judged by TLC analysis. Water (50 mL) was added and the obtained crystals were crystalljjjjjjjjjjjjj Step 4:double Third butoxycarbonyl (2- iodine -4- Cyano -5- Ethoxy ) aniline . 4-Amino-2-ethoxy-5-iodobenzonitrile (2.8 g, 9.72 mmol) was dissolved in THF (60 mL), and DMAP (250 mg, catalyzed) and didicarbonate were added thereto. Tributyl ester (5.4 mL, 23.3 mmol) and the solution was stirred at ambient temperature for 48 hours. The reaction mixture was evaporated to dryness crystals crystals crystals₄ Filtration and evaporation in vacuo gave the desired compound. Step 5:2-(( Third butoxycarbonyl ) Amine )-5- Cyano -4- Tert-butyl ethoxybenzoate . Add to a solution of bis-tert-butoxycarbonyl (2-iodo-4-cyano-5-ethoxy)aniline (2.06 g, 4.21 mmol) in THF (100 mL) cooled to -78 °Cn -BuLi (2.5 M hexane solution; 2.2 mL, 5.5 mmol). After stirring at -78 ° C for 1.5 hours, add saturated NH₄ Aq. Cl was added and the mixture was evaporated w~~~~~ The organic phase was separated and dried (MgSO₄ ), filtered and evaporated in vacuo. The residue is purified by silica gel eluting with a gradient of 0 to 50% of EtOAc in hexane to afford the desired compound. Step 6:2- Amine -5- Cyano -4- Ethoxybenzoic acid . Add 3 to a solution of tert-butyl 2-((t-butoxycarbonyl)amino)-5-cyano-4-ethoxybenzoate (2.0 g, 5.52 mmol) in DCM (30 mL) Fluoroacetic acid (20 mL). After stirring for 16 hours at rt. Step 7:2- Amine -5- Cyano -4- Methyl ethoxybenzoate . The previously isolated acid (1.06 g, 3.31 mmol) was dissolved in DMF (11 mL), and then potassium carbonate (1. 4 g, 10.1 mmol), methylene chloride (220 μL, 3.5 mmol). After stirring for 16 hours, the reaction mixture was diluted with water and EtOAc.₄ ), filtered and evaporated in vacuo. The residue was triturated with EtOAc / EtOAc (EtOAc) Step 8: title compound The above 2-amino-5-cyano-4-ethoxybenzoic acid methyl ester and 6-fluoro-2-naphthoic acid were used in a similar manner to that described in Example 3, followed by a typical ester. Prepared by hydrolysis conditions. LC-MS 379 (M+H)⁺ . Example 101. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-methoxybenzoic acidThe title compound used methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 6-chloro-2-naphthoic acid (Intermediate 1) in a similar manner as described in Example 3. It is then prepared using typical ester hydrolysis conditions. LC-MS 379 (M-H)^- . Example 102. 7-(7-Fluoroquinoline-3-carbamimidino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acidThe title compound was used in a similar manner as described in Example 59 using 7-fluoroquinoline-3-carbochlorobenzene and 7-amino-2,3-dihydrobenzo[b][1,4]dioxazine-6. - Preparation of formic acid. LC-MS 369 (M+H)⁺ . Example 103. 5-Chloro-4-methoxy-2-(6-methyl-2-naphthylamino)benzoic acidThe title compound was used in a similar manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-methyl-2-naphthoic acid (prepared in Step 2 of Example 89). It is prepared by typical ester hydrolysis conditions. LC-MS: 368 (M-H)^- . Example 104. 5-Chloro-2-(6-cyclopropyl-2-naphthylamino)-4-methoxybenzoic acidThe title compound was used in a similar manner to Example 3 to give methyl 2-amino-5-chloro-4-methoxybenzoate and 6-cyclopropyl-2-naphthoic acid (prepared in Step 1 of Example 90). ), followed by typical ester hydrolysis conditions. LC-MS: 394 (M-H)^- . Example 105. 5-Chloro-2-(6-(difluoromethyl)-2-naphthylamino)-4-methoxybenzoic acidstep 1:2- bromine -6-( Difluoromethyl ) Naphthalene To a stirred solution of 6-bromo-2-naphthaldehyde (3.7 g, 15.7 mmol) in DCM (50 mL), DAST (2.4 mL, 18.1 mmol). The resulting mixture was stirred at 30 ° C for 48 hr then diluted with aq. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by silica gel chromatography eluting with hexane to give 2-bromo-6-(difluoromethyl)naphthalene. Step 2:6-( Difluoromethyl )-2- Methyl naphthoate To 2-bromo-6-(difluoromethyl)naphthalene (2.8 g, 10.9 mmol), palladium (II) acetate (122 mg, 0.545 mmol) and 1,3-bis(diphenylphosphino)propane (225 To a stirred solution of anhydrous DMF (100 mL) and dry MeOH (9 mL). Carbon monoxide was bubbled through the resulting mixture for 15 minutes at room temperature, then heated to 70 ° C under 1 atmosphere of CO for 14 hours. After cooling to room temperature, the mixture was diluted with EtOAc and water. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by EtOAc (EtOAc) elut elut elut elut Step 3: 6-(Difluoromethyl)-2-naphthoic acid was prepared in a similar manner to Step 2 of Example 89 using methyl 6-(difluoromethyl)-2-naphthalate as starting material. Step 4: The title compound was used in a similar manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-(difluoromethyl)-2-naphthoic acid. Prepared by ester hydrolysis conditions. LC-MS: 404 (M-H)^- . Example 106. 5-Chloro-4-methoxy-2-(6-(trifluoromethyl)-2-naphthylamino)benzoic acidThe title compound was obtained in a similar manner as in Example 3 using 2-amino-5-chloro-4-methoxybenzoic acid methyl ester and 6-(trifluoromethyl)-2-naphthoic acid. ), followed by preparation with typical ester hydrolysis conditions. LC-MS: 422 (M-H)^- . Example 107. 5-Chloro-2-(6-(difluoromethoxy)-2-naphthylamino)-4-methoxybenzoic acidStep 1: Methyl 6-(difluoromethoxy)-2-naphthoate was prepared in a similar manner to Step 2 of Example 58 using methyl 6-hydroxy-2-naphthalate as starting material. Step 2: 6-(Difluoromethoxy)-2-naphthoic acid was prepared in a similar manner to Step 2 of Example 89 using methyl 6-(difluoromethoxy)-2-naphthalate as starting material. Step 3: The title compound was used in a similar manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-(difluoromethoxy)-2-naphthoic acid. The ester hydrolysis conditions are prepared. LC-MS: 420 (M-H)^- . Example 108. 5-Chloro-4-methoxy-2-(6-(trifluoromethoxy)-2-naphthylamino)benzoic acidstep 1:6-( Bromodifluoromethoxy )-2- Methyl naphthoate To a solution of methyl 6-hydroxy-2-naphthoate (1.2 g, 6.0 mmol) in anhydrous DMF (12 mL) EtOAc. 60% of the mineral oil and the resulting mixture was stirred for 10 minutes, after which potassium butoxide (740 mg, 6.6 mmol) and dibromodifluoromethane (5 g, 23.8 mmol) were added. The sealed container was heated to 70 ° C for 15 hours. After cooling to room temperature, the mixture was diluted with EtOAc and 1N aqueous HCI. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc EtOAc The product containing the fraction was further purified by C18 chromatography using a gradient of 5% to 100% in water + 0.1% formic acid in MeCN + 0.1% formic acid to afford 6-(bromodifluoromethoxy)-2-naphthalene. Methyl formate. Step 2:6-( Trifluoromethoxy )-2- Methyl naphthoate Add silver tetrafluoroborate (475 mg, to a stirred solution of 6-(bromodifluoromethoxy)-2-naphthalate (367 mg, 1.11 mmol) in anhydrous DCM at -78 °C. 2.44 mmol). The resulting mixture was stirred at room temperature for 14 hr then diluted with EtOAc EtOAc. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by chromatography eluting with EtOAc EtOAc EtOAc EtOAc Step 3: 6-(Trifluoromethoxy)-2-naphthoic acid was prepared in a similar manner to Step 2 of Example 89 using methyl 6-(trifluoromethoxy)-2-naphthalate as starting material. Step 4: The title compound was used in a similar manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-(trifluoromethoxy)-2-naphthoic acid, followed by typical The ester hydrolysis conditions are prepared. LC-MS: 438 (M-H)^- . Example 109.N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-methyl-2-naphthylamineThe title compound was prepared in a similar manner to Example 32 using 6-methyl-2-naphthoquinone chloride (similarly prepared using the corresponding acid prepared in Step 2 of Example 89 as Intermediate 5) as starting material. LC-MS: 378 (M-H)^- . Example 110.N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-cyclopropyl-2-naphthylamineThe title compound was prepared in a similar manner to Example 32 using 6-cyclopropyl-2-naphthoquinone chloride (similarly prepared using the corresponding acid prepared in Step 1 of Example 90 as Intermediate 5) as starting material. . LC-MS: 404 (M-H)^- . Example 111.N -(4-chloro-2-(5-sideoxy-4,5-dihydro-1H -tetrazol-1-yl)phenyl)-6-(trifluoromethoxy)-2-naphthylamineThe title compound was obtained in a similar manner to Example 32 using 6-(trifluoromethoxy)-2-naphthoic acid (i.e., as described in Intermediate 5 using the corresponding acid prepared in Step 3 of Example 108) as starting material. To prepare. LC-MS: 448 (M-H)^- . Example 112. 5-cyano-2-(6-fluoro-2-naphthylamino)-4-(oxetan-3-yloxy)benzoic acidstep 1:2- Amine -5- Cyano -4- Fluorobenzoic acid To a solution of 2-amino-5-bromo-4-fluorobenzoic acid (1.87 g, 8 mmol, 1 eq.) in NMP (4 mL), CuCN (1.2 g, 13.4 mmol). The solution was heated to 200 ° C for 2 hours. After cooling to 60 ° C, add FeCl₃ (10 g) in water (10 mL) and HCl (36%, 1.5 mL). After stirring for 1 hour, the suspension was filtered to give a crude solid. By column chromatography (C18 reverse phase, water, 0.1% NH₃ H₂ O -> MeCN, 0.1% NH₃ H₂ O) Purification affords the desired product. Step 2: 2-Amino-5-cyano-4-(oxetan-3-yloxy)benzoic acid was used in a similar manner as described in Step 1 of Example 55 using oxetane-3- The alcohol is prepared by preparing 2-amino-5-cyano-4-fluorobenzoic acid. Step 3: title compound using 6-fluoro-2-naphthoquinone chloride (Intermediate 5) and 2-amino-5-cyano-4-(oxo-heterocycle) in a similar manner as described in Step 50, Example 50 Butane-3-yloxy)benzoic acid was prepared. LC-MS: 405 (M-H)^- . Example 113. 5-cyano-2-(7-fluoroquinoline-3-carbamimidino)-4-(oxetan-3-yloxy)benzoic acidThe title compound was used in a similar manner as described in Step 3, Example 3, using 2-amino-5-cyano-4-(oxe-butane-3-yloxy)benzoic acid (Example 112, Step 1) and - Fluoroquinoline-3-methane chloride (prepared in a similar manner to Intermediate 5). LC-MS: 406 (M-H)^- . Example 114. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(methoxymethyl)benzoic acidThe title compound was prepared in a similar manner as described in Example 93 using 6-fluoro-2-naphthoic acid. LC-MS: 386 (M-H)^- . Example 115. 5-Cyano-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxamido)benzoic acidThe title compound was used in a similar manner to Example 3 using 3-methylbenzo[b]thiophene-5-carboxylic acid (Example 40, Step 1) and DCM and 2-amino-5-cyano-4-methoxybenzene. Methyl formate (Intermediate 2) was then prepared using typical ester hydrolysis conditions. LC-MS: 365 (M-H)^- . Example 116. 8-(6-Fluoro-2-naphthylamino)-3,4-dihydro-2H -benzo[b][1,4]dioxin-7-carboxylic acidThe title compound used 8-amino-3,4-dihydro-2 in a similar manner as described in Example 49.H -Benzo[b][1,4]dioxin-7-carboxylic acid and 6-fluoro-2-naphthoquinone chloride (intermediate 5) were prepared. The isolated oxazinone and LiOH monohydrate (5 equivalents) were stirred in a mixture of MeOH, water and dioxane (a mixture of 1:8:1 1:1) until complete conversion to acid by LC-MS analysis . 1N HCl was added to the reaction mixture to give a colorless crystals, which was filtered, washed with water and dried in vacuo. Wet milling in acetone/hexane gave the pure product. LC-MS: 382 (M+H)⁺ . Example 117. 5-(Difluoromethoxy)-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acidThe title compound was prepared in a similar manner to Example 3 using 2-amino-5-(difluoromethoxy)-4-methoxybenzoic acid and 6-fluoro-2-naphthoic acid as starting materials. LC-MS: 404 (M-H)^- . Example 118. 5-Fluoro-2-(6-fluoro-2-naphthylamino)-4-(oxetan-3-yloxy)benzoic acidstep 1:2- Amine -5- fluorine -4-( Oxetane -3- Baseoxy ) benzoic acid . Prepared in a similar manner to that described in Example 55 using 2-amino-4,5-difluorobenzoic acid as the starting material. Step 2: The title compound was used in a similar manner to Example 3 using 2-amino-5-fluoro-4-(oxetan-3-yloxy)benzoic acid and 6-fluoro-2-naphthoic acid as Start with the substance to prepare. LC-MS: 398 (M-H)^- . Example 119. 2-(2-Naphthylamino)-5-cyano-4-(oxetan-3-yloxy)benzoic acidThe title compound was prepared in a similar manner as described in Example 112. LC-MS: 387 (M-H)^- . Example 120. 2-Chloro-2'-fluoro-5-(6-fluoro-2-naphthylamino)-[1,1'-biphenyl]-4-carboxylic acidstep 1:2- Amine -4- bromine -5- Methyl chlorobenzoate To 2-Amino-4-bromo-5-chlorobenzoic acid (5.00 g, 20.0 mmol) and K at room temperature₂ CO₃ (8.28, 59.88 mmol) iodomethane (1.23 mL, 20.0 mmol) was added to a stirred solution in DMF (100 mL). The mixture was stirred at room temperature for 16 h and partitioned between EtOAc and brine. The organics were washed again with brine, water (3times), concentrated and evaporated in vacuo. The resulting solid was sufficiently pure and was used without further purification. Step 2:4- bromine -5- chlorine -2-(6- fluorine -2- Naphthylamine ) Methyl benzoate Prepared in a similar manner to Step 1 of Example 3 using 6-fluoro-2-naphthoic acid and DCM and methyl 2-amino-4-bromo-5-chlorobenzoate to give 4-bromo-5-chloro-2. Methyl (6-fluoro-2-naphthylamino)benzoate. Step 3: Add to a solution of methyl 4-bromo-5-chloro-2-(6-fluoro-2-naphthylamino)benzoate (0.2 g, 0.46 mmol) in dioxane (12 mL) 2-fluorophenylAcid (0.071 mg, 0.50 mmol) and saturated NaHCO₃ Aqueous solution (3 mL). The resulting mixture was sparged with nitrogen, followed by the addition of bis(triphenylphosphine)palladium(0) (0.037 g, 0.032 mmol). The reaction was then sealed and heated at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered with EtOAc EtOAc EtOAc. The organic phase was extracted again with 1 M HCl, water (2 times), brine.₂ SO₄ Dry, filter and concentrate in vacuo. The crude residue was taken in EtOAc (EtOAc m. LC-MS: 436 (M-H)^- . Example 121.N -(4-cyano-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-7-fluoroquinoline-3-methyl Guanaminestep 1:2- Amine -5- bromine - N- Hydroxybenzene -1- Hyperthyroidism Add 2-amino-5-bromobenzonitrile (4.0 g, 20.30 mmol), hydroxylamine hydrochloride (2.82 g, 40.58 mmol), ethanol (45 mL), water (15) to a 250 mL round bottom flask. mL) and sodium bicarbonate (5.14 g, 61.18 mmol). The resulting solution was stirred at 80 ° C for 16 hours in an oil bath. The resulting mixture was concentrated in vacuo and washed with 3×25 mL water. The resulting solution was extracted with EtOAc (EtOAc) The isolated formazan was used without further purification. Step 2:3-(2- Amine -5- Bromophenyl )-4,5- Dihydrogen -1,2,4- Oxadiazole -5- ketone . Ethanol (60 mL), Na (2.0 g), 2-amino-5-bromo-N-hydroxybenzene-1-carboxamidine (2.5 g, 10.87 mmol) and diethyl carbonate were placed in a 250 mL round bottom flask. Ester (6.44 g, 54.52 mmol). The resulting solution was stirred at 0 ° C in an ice/salt bath for 1 hour and stirred for a further 16 hours while maintaining the temperature at 80 ° C in an oil bath. The resulting mixture was concentrated in vacuo and washed with 3×30 mL water. The solid was collected by filtration to give the desired 1,2,4-oxadiazol-5-one which was used without further purification. Step 3: N-(4- bromine -2-(5- Side oxy -4,5- Dihydrogen -1,2,4- Oxadiazole -3- base ) Phenyl )-7- Fluoroquinoline -3- Formamide 7. Place 7-fluoroquinoline-3-carboxylic acid (200 mg, 1.05 mmol), DCE (10 mL), 3-(2-amino-5-bromophenyl)-4 in a 25 mL round bottom flask. 5-Dihydro-1,2,4-oxadiazol-5-one (293.7 mg, 1.15 mmol), HATU (596.9 mg, 1.57 mmol), DIEA (405.2 mg, 3.14 mmol). The resulting solution was stirred at 60 ° C for 12 hours in an oil bath. The resulting solution was diluted with 10 mL of methanol. The solid was collected by filtration. This gives 290 mg (coarse) as a yellow solidN -[4-bromo-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-7-fluoroquinoline-3-carboxamidine amine. Step 4: Place in a 25 mL round bottom flaskN -[4-bromo-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-7-fluoroquinoline-3-carboxamidine Amine (290 mg, 0.68 mmol), N,N-dimethylformamide (10 mL), (t -Bu)₃ P (13.7 mg, 0.07 mmol), Pd₂ (dba)₃ ·CHCl₃ (70.1 mg, 0.06 mmol), Zn(CN)₂ (235.8 mg, 2.03 mmol). The resulting solution was stirred at 85 ° C for 5 hours in an oil bath. The reaction was then quenched by the addition of 10 mL of water. The solid was collected by filtration. The title compound was obtained as a pale yellow solid. LC-MS: 376 (M+H)⁺ . Example 122. 5-Chloro-2-(6-chloro-2-naphthylamino)-4-methoxybenzoic acidThe title compound used methyl 2-amino-5-chloro-4-methoxybenzoate and 6-chloro-2-naphthoic acid (Intermediate 1) in a similar manner to Example 3, followed by typical ester hydrolysis conditions To prepare. LC-MS: 388 (M-H)^- . Example 123. 5-cyano-4-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acidThe title compound was prepared in a similar manner to that described in Step 3 of Example 50 using 2-amino-5-cyano-4-fluorobenzoic acid and 6-fluoro-2-naphthoquinone chloride (Intermediate 5). LC-MS: 351 (M-H)^- . Example 124. 4-cyano-5-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acidstep 1:2- Amine -4- bromine -5- Fluorobenzoic acid To a solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (2.64 g, 10 mmol) in THF (20 mL), EtOAc (1 g). Hydrogen gas was bubbled into the solution for 3 hours. The suspension was filtered, the filtrate was concentrated in vacuo and the separated material was purified by column chromatography (C18 reverse phase, water 0.1% + NH₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification to give the desired product. Step 2:2- Amine -4- Cyano -5- Fluorobenzoic acid Prepared in a similar manner to Step 1 of Example 112. Step 3: The title compound was prepared using 2-amino-4-cyano-5-fluorobenzoic acid and 6-fluoro-2-naphthoquinone chloride (Intermediate 5) in a similar manner as described in Step 3 of Example 50. . LC-MS: 351 (M-H)^- . Example 125. 2-(6-Chloro-2-naphthylamino)-5-(difluoromethoxy)benzoic acidStep 1: Methyl 5-(difluoromethoxy)-2-nitrobenzoate was prepared in a similar manner to Step 2 of Example 58 using methyl 5-hydroxy-2-nitrobenzoate. Step 2:2- Amine -5-( Difluoromethoxy ) Methyl benzoate To a solution of methyl 5-(difluoromethoxy)-2-nitrobenzoate (516 mg, 2.1 mmol) in MeOH (20 mL). 6.9 mmol), concentrated HCl (1.7 mL). The resulting mixture was heated to 60 ° C for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and 1N aqueous EtOAc. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by EtOAc (EtOAc) elute Step 3: The title compound was used in a similar manner to Example 3 to give methyl 2-amino-5-(difluoromethoxy)benzoate and 6-chloro-2-naphthoic acid (Intermediate 1). Typical ester hydrolysis conditions. LC-MS: 390 (M-H)^- . Example 126. 7-(2-Naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acidThe title compound was prepared in a similar manner to Example 49 using 7-amino-2,3-dihydrobenzo[b][1,4]dioxazin-6-carboxylic acid. LC-MS: 348 (M-H)^- . Example 127. 7-(6-(Trifluoromethyl)-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acidThe title compound was used in a similar manner to Example 49 using 7-amino-2,3-dihydrobenzo[b][1,4]dioxazin-6-carboxylic acid and 6-(trifluoromethyl)-2- Naphthoic acid (prepared in Example 88, Step 1) was prepared as the starting material. LC-MS: 416 (M-H)^- . Example 128. 2-(2-Naphthylamino)-5-cyano-4-methoxybenzoic acidThe title compound was used in a similar manner to Example 3 using 2-amino-5-cyano-4-methoxybenzoic acid methyl ester (Intermediate 2) and 2-naphthic acid, which was then prepared using typical ester hydrolysis conditions. LC-MS: 345 (M-H)^- . Example 129. 5-Cyano-4-methoxy-2-(6-(trifluoromethyl)-2-naphthylamino)benzoic acidThe title compound was used in a similar manner to Example 3 using methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 6-(trifluoromethyl)-2-naphthoic acid (in Example 88, prepared in Step 1, followed by typical ester hydrolysis conditions. LC-MS: 413 (M-H)^- . Example 130. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-ethoxybenzoic acidThe title compound used 6-chloro-2-naphthoic acid (Intermediate 1) and methyl 2-amino-5-cyano-4-ethoxybenzoate in a similar manner to Example 3 (Example 100, Step 7) It is then prepared using typical ester hydrolysis conditions. LC-MS: 393 (M-H)^- . Example 131. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridin-4-yl)benzoic acidThe title compound was prepared in a similar manner as step 3 of Example 120 using pyridin-4-ylboronic acid. LC-MS: 419 (M-H)^- . Example 132. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridin-3-yl)benzoic acidThe title compound was used in a similar manner to Step 3 of Example 120 using pyridin-3-yl.Acid to prepare. LC-MS: 419 (M-H)^- . Example 133. 5-Chloro-2-(6-fluoro-2-naphthylamino)-6-methoxynicotinic acidThe title compound was prepared in step 3 using 6-fluoro-2-naphthylamine in a similar manner as in Example 74. LC-MS: 375 (M+H)⁺ . Example 134. 5-Chloro-6-ethoxy-2-(6-fluoro-2-naphthylamino) nicotinic acidThe title compound was prepared in a similar manner to Example 74 using ethanol in step 1 and 6-fluoro-2-naphthylamine in step 3. LC-MS: 389 (M+H)⁺ . Example 135. 5-Chloro-2-(6-chloro-2-naphthylamino)-6-ethoxynicotinic acidThe title compound was prepared in a similar manner to Example 74 using ethanol in step 1 and 6-chloro-2-naphthylamine in step 3. LC-MS: 405 (M+H)⁺ . Example 136. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridin-2-yl)benzoic acidstep 1:5- chlorine -2-(6- fluorine -2- Naphthylamine )-4-(4,4,5,5- Tetramethyl -1,3,2- Dioxonium -2- base ) Methyl benzoate 4-Bromo-5-chloro-2-(6-fluoro-2-naphthylamino)benzoic acid methyl ester (0.50 g, 1.15 mmol, from the intermediate of Step 2 of Example 120), bis (pinadol) Diborane (0.378 g, 1.49 mmol), KOAc (0.34 g, 3.45 mmol) suspended in dioxane (10 mL) with N₂ The resulting solution was subsurface purged for 5 minutes. Next, add Pd(dppf)Cl₂ (0.126 g, 0.17 mmol) and the resulting mixture was stirred at 95 ° C for 16 hours. The solution was cooled to room temperature and partitioned between EtOAc and brine. The organics were washed again with brine and water (2 times), filtered through Celite, and concentrated. The residue was used without further purification. Step 2: title compound using 2-bromopyridine and 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(4,4,5,5- in a similar manner as Example 120 Step 3. Methyl tetramethyl-1,3,2-dioxaboron-2-yl)benzoate is then prepared using typical ester hydrolysis conditions. LC-MS: 419 (M-H)^- . Example 137. 2-Chloro-5-(6-fluoro-2-naphthylamino)isonicotinic acidstep 1:2- chlorine -5-(6- fluorine -2- Naphthylamine ) Methyl isonicotinate . Stirring suspension of methyl 5-amino-2-chloroisonicotinate (200 mg, 1.07 mmol) and 6-fluoro-2-naphthoic acid (245 mg, 1.29 mmol) in DCM (10.7 mL) Methane sulfonium chloride (0.124 mL, 1.61 mmol) was added dropwise to the solution. Then, Hunigs base (0.560 mL, 3.22 mmol), DMAP (13.1 mg, 0.107 mmol) was added sequentially and the resulting solution was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was crystallised eluted elute The precipitate was collected by vacuum filtration and washed with diethyl ether to give the desired material. Step 2: To a solution of 2-chloro-5-(6-fluoro-2-naphthylamino)isonicotinic acid methyl ester (50 mg, 0.14 mmol) in THF (1.2 mL) and MeOH (0.8 mL) A 1 N aqueous NaOH solution (0.42 mL, 0.42 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was acidified with 1N HCl and the suspension was stirred at room temperature for 15 min then evaporated. The crude solid was triturated with EtOAc (EtOAc)EtOAc. LC-MS: 343 (M-H)^- . Example 138. 5-Chloro-2-(6-fluoro-2-naphthylamino)-4-isopropoxybenzoic acidstep 1:2- Amine -5- chlorine -4- Methyl isopropoxybenzoate Used in a similar manner as described in Example 100, Steps 3 through 7.N - Bromobutanediamine imideN - Iodobutane diimine was prepared using 4-chloro-3-isopropoxyaniline. Step 2: The title compound was prepared in a similar manner to that described in Example 3 using the above 2-amino-5-chloro-4-isopropoxybenzoic acid methyl ester and 6-fluoro-2-naphthoic acid. LC-MS 402 (M+H)⁺ . Example 139. 5-Chloro-4-cyano-2-(6-fluoro-2-naphthylamino)benzoic acidstep 1:2- Amine -4- chlorine -5- Methyl cyanobenzoate Used in a similar manner as described in Example 100, Steps 3 through 7.N - Bromobutanediamine imideN - Iodobutane diimine was prepared using 4-amino-2-chlorobenzonitrile. Step 2: The title compound was prepared in a similar manner to that described in Example 3 using methyl 2-amino-4-chloro-5-cyanobenzoate and 6-fluoro-2-naphthoic acid. LC-MS 367 (M-H)^- . Example 140. 5-Chloro-2-(6-chloro-2-naphthylamino)-4-isopropoxybenzoic acidThe title compound was used in a similar manner to that described in Example 3 using the above 2-amino-5-chloro-4-isopropoxybenzoic acid methyl ester (Example 138) and 6-chloro-2-naphthoic acid (Intermediate 1) To prepare. LC-MS 416 (M-H)^- . Example 141. 2-(6-Chloro-2-naphthylamino)-5-fluoro-4-methoxybenzoic acidThe title compound was used in a similar manner to Example 32 using 2-amino-5-fluoro-4-methoxybenzoic acid and 6-chloro-2-naphthoquinone chloride prepared in Step 3 of Example 47 (with intermediate 5) Prepared analogously as a starting material. LC-MS: 372 (M-H)^- . Example 142. 4-Chloro-2-(6-chloro-2-naphthylamino)-5-cyanobenzoic acidstep 1:2- Amine -4- chlorine -5- Methyl cyanobenzoate Prepared in a manner similar to that described in Steps 3 through 7 of Example 100 using N-bromosuccinimide in place of N-iodobutylimine and 4-amino-2-chlorobenzonitrile. Step 2: The title compound was used in a similar manner to that described in Example 3 using methyl 2-amino-4-chloro-5-cyanobenzoate and 6-chloro-2-naphthoquinone chloride (similar to Intermediate 5). Prepared from the corresponding acid). LC-MS 383 (M-H)^- . Example 143. 6-Fluoro-N -(4-fluoro-5-(oxetan-3-yloxy)-2-(5-sided oxy-4,5-dihydro-1,2,4-oxadiazol-3- Phenyl)-2-naphthylaminestep 1:2- Amine -5- fluorine -4-( Oxetane -3- Baseoxy ) Benzoonitrile Prepared in a similar manner to that described in Step 1 of Example 55 using 2-amino-4,5-difluorobenzonitrile and oxetane-3-ol. Step 2:2- Amine -5- fluorine - N- Hydroxyl -4-( Oxetane -3- Baseoxy ) Benzoquinone Add hydroxylamine hydrochloride to a solution of 2-amino-5-fluoro-4-(oxetan-3-yloxy)benzonitrile (270 mg, 1.3 mmol) in EtOH (5 mL) Salt (656 mg, 9.4 mmol) and sodium methoxide (512 mg, 9.4 mmol). The solution was heated at 80 ° C for 3 hours. By column chromatography (C18 reverse phase, water + 0.1% NH₃ •H₂ O -> MeCN + 0.1% NH₃ •H₂ O) Purification affords the desired product. Step 3:3-(2- Amine -5- fluorine -4-( Oxetane -3- Baseoxy ) Phenyl )-1,2,4- Oxadiazole -5(4H)- ketone To 2-amino-5-fluoro-N Add sodium methoxide (87 mg, 1.6 mmol) and carbonic acid to a solution of hydroxy-4-(oxetan-3-yloxy)benzimidamide (60 mg, 0.25 mmol) in EtOH (2 mL) Diethyl ester (260 mg, 2.2 mmol) was heated to reflux for 16 h. By column chromatography (C18 reverse phase, water + 0.1% NH₃ •H₂ O -> MeCN + 0.1% NH₃ •H₂ O) Purification affords the desired product. Step 4: title compound using 3-(2-amino-5-fluoro-4-(oxetan-3-yloxy)phenyl)-1 in a similar manner as described in Step 3 of Example 50 , 2,4-oxadiazol-5(4H)-one and 6-fluoro-2-naphthalene chloride were prepared. LC-MS: 438 (M-H)^- . Example 144: 6-Fluoro-N -(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-2-naphthoquinone amineThe title compound was prepared in a similar manner as described in Example 143. LC-MS: 396 (M-H)^- . Example 145. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-(cyclopropylmethoxy)benzoic acidstep 1:2- Amine -5- Cyano -4-( Cyclopropylmethoxy ) benzoic acid . 2-Amino-5-cyano-4-fluorobenzoic acid (0.25 g, 1.39 mmol), Cs₂ CO₃ (1.36 g, 4.16 mmol) and cyclopropylmethanol (10 mL) were combined in a sealed pressure vessel and stirred at 100 ° C for 16 hours. The solvent was evaporated and the residue was diluted with EtOAc EtOAc. The organic layer was extracted with EtOAc (EtOAc)EtOAc. Step 2.2- Amine -5- Cyano -4-( Cyclopropylmethoxy ) Methyl benzoate Prepared in a similar manner to Step 120 of Example 120 using 2-amino-5-cyano-4-(cyclopropylmethoxy)benzoic acid. Step 3. The title compound used 6-chloro-2-naphthoic acid (Intermediate 1) and DCM and 2-amino-5-cyano-4-(cyclopropylmethoxy)benzene in a similar manner as in Example 3. Methyl formate is then prepared using typical ester hydrolysis conditions. LC-MS: 419 (M-H)^- . Example 146. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-cyclobutoxybenzoic acidThe title compound used 6-chloro-2-naphthoic acid (Intermediate 1) and DCM and 2-amino-5-cyano-4-cyclobutoxybenzoic acid methyl ester in a similar manner to Example 3 145 is prepared in a similar manner using cyclobutanol in step 1, and is then prepared using typical ester hydrolysis conditions. LC-MS: 419 (M-H)^- . Example 147. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-(methylthio)benzoic acidThe title compound used 6-chloro-2-naphthoic acid (Intermediate 1) and DCM and 2-amino-5-cyano-4-(methylthio)benzoic acid methyl ester in a similar manner to Example 3 Example 145 was prepared in a similar manner using NaSMe in step 1 and DMSO as solvent, followed by typical ester hydrolysis conditions. LC-MS: 395 (M-H)^- . Example 148. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-isopropoxybenzoic acidThe title compound used 6-chloro-2-naphthoic acid (Intermediate 1) and DCM and 2-amino-5-cyano-4-isopropoxybenzoic acid methyl ester in a similar manner to Example 3 145 is prepared in a similar manner using isopropanol in step 1, and then prepared using typical ester hydrolysis conditions. LC-MS: 407 (M-H)^- . Example 149.N -(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-2-naphthoquinone amineThe title compound was prepared in a similar manner as described in Example 144 using 2-naphthic acid. LC-MS: 378 (M-H)^- . Example 150. 5-Chloro-2-(6-chloro-2-naphthylamino)-6-methoxynicotinic acidThe title compound was prepared in a similar manner to Example 74 using 6-chloro-2-naphthoic acid ( Intermediate 1). LC-MS: 391 (M+H)⁺ . Example 151. 5-cyano-4-methoxy-2-(5,6,7,8-tetrahydronaphthalen-2-carboxamido)benzoic acidThe title compound used methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 5,6,7,8, tetrahydronaphthalene-2 in a similar manner as described in Example 3. - Formic acid, which is then prepared using typical ester hydrolysis conditions. LC-MS: 349 (M-H)^- . Example 152. (racemic)-2-(6-chloro-2-naphthylamino)-5-cyano-4-(methylsulfinyl)benzoic acid2-(6-Chloro-2-naphthylamino)-5-cyano-4-(methylthio)benzoic acid (0.052 g, 0.12 mmol, m. It was treated with m-CPBA (0.062 g, 0.28 mmol) and stirred at 50 ° C for 96 hours. The solvent was evaporated and the residue was taken in MeOH and stirred 16 hr. The resulting white suspension was filtered and collected to give the title compound. LC-MS: 411 (M-H)^- . Example 153. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-(difluoromethoxy)benzoic acidStep 1: 2-(Difluoromethoxy)-4-nitrobenzonitrile was prepared in a similar manner to Step 2 of Example 58 using 2-hydroxy-4-nitrobenzonitrile as starting material. Step 2: 4-Amino-2-(difluoromethoxy)benzonitrile was started using 2-(difluoromethoxy)-4-nitrobenzonitrile in a similar manner to Step 3 of Example 83 Substance to prepare. Step 3:4- Amine -5- bromine -2-( Difluoromethoxy ) Benzoonitrile Add to 4-Amino-2-(difluoromethoxy)benzonitrile (358 mg, 1.94 mmol) in glacial acetic acid (20 mL).N - Bromobutanediamine (363 mg, 2.04 mmol). After 4 hours, the volatiles were removed in vacuo and residue was diluted with EtOAc and water. Wash the organic layer with brine over MgSO₄ Dry and concentrate in vacuo. The residue was purified by chromatography eluting with EtOAc EtOAc EtOAc Step 4: Methyl 2-amino-5-cyano-4-(difluoromethoxy)benzoate was used in a similar manner to Steps 47 to 4 of Example 47 using 4-amino-5-bromo-2- (Difluoromethoxy)benzonitrile to prepare. Step 5: title compound Methyl 2-amino-5-cyano-4-(difluoromethoxy)benzoate and 6-chloro-2-naphthoic acid (Intermediate 1) were used in a similar manner to Example 3. To prepare. LC-MS: 415 (M-H)^- . Example 154:N -(4-cyano-5-methoxy-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-fluoro -2-naphthylaminestep 1:2- Amine -5- bromine -4- fluorine Benzoonitrile N-Bromobutaneimine (23.8 g, 134 mmol) was added portionwise to a solution of 2-amino-4-fluorobenzonitrile (18.2 g, 134 mmol) in DMF (100 mL). The solution was stirred for 1 hour and poured into ice water (600 mL). The resulting solid was filtered off and dried to give the desired compound. Step 2:3-(2- Amine -5- bromine -4- Fluorophenyl )-1,2,4- Oxadiazole -5(4H)- ketone Prepared as described in Example 143, Step 2 and Step 3. Step 3: 4- Amine -2- fluorine -5-(5- Side oxy -4,5- Dihydrogen -1,2,4- Oxadiazole -3- base ) Benzoonitrile . To 3-(2-Amino-5-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (150 mg, 0.55 mmol) in DMF (3.8 mL) Add BrettPhos Palladacycle Gen. 3 (56 mg, 0.062 mmol) and zinc cyanide (450 mg, 3.8 mmol) to the solution. The solution was degassed and heated at 120 °C for 1.5 hours. Water (20 mL) was added and the resulting solid was filtered. The filtrate was concentrated in vacuo to give a crude material. By column chromatography (C18 reverse phase, water + 0.1% NH₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification affords the desired product. Step 4:4- Amine -2- Methoxy -5-(5- Side oxy -4,5- Dihydrogen -1,2,4- Oxadiazole -3- base ) Benzoonitrile 4-Amino-2-fluoro-5-(5-o-oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl was used in a similar manner to that described in Step 1 of Example 55. ) benzonitrile to prepare. Step 5: To 4-amino-2-methoxy-5-(5-o-oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzonitrile (60) To a solution of DMF (2 mL) was added 6-fluoro-2-naphthoic acid (180 mg, 0.94 mmol) and HATU (180 mg, 0.47 mmol). Then addN , N - Diisopropylethylamine (0.18 mL, 0.98 mmol) was heated at 80 ° C for 1.5 h. Water (20 mL) was added and the resulting solid was filtered. The filtrate was concentrated in vacuo to give a crude material which was purified by column chromatography (C18 reverse phase, water + 0.1% NH₃ H₂ O -> MeCN + 0.1% NH₃ H₂ O) Purification to give the title compound. LC-MS: 403 (M-H)^- . Example 155. 2-(6-Chloro-2-naphthylamino)-5-cyano-4-(dimethylamino)benzoic acidThe title compound used 6-chloro-2-naphthoic acid (Intermediate 1) and DCM and 2-amino-5-cyano-4-(dimethylamino)benzoic acid methyl ester in a similar manner as in Example 3. Similar to Example 145, use (Me) in step 1.₂ Prepared by NH.HCl and DMSO as a solvent, followed by typical ester hydrolysis conditions. LC-MS: 392 (M-H)^- . While the preferred embodiment of the invention has been shown and described herein, it will be understood that Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It will be appreciated that various alternatives to the embodiments of the invention described herein may be used in the practice of the invention. The scope of the invention is intended to be limited only by the scope of the invention and the scope of the invention and the scope of the invention. List of references Abo M.Et al. (2011). Development of a highly sensitive fluorescence probe for hydrogen peroxide. J Am Chem Soc, 133(27): 10629-37. Barman S.Et al. (2014). Nox4 is Expressed in Pulmonary Artery Adventitia and Contributes to Hypertensive Vascular Remodeling.Arterioscler Thromb Vasc Biol. Aug; 34(8): 1704-1715. Babelova A.Et al. (2012). Role of NOX4 in murine models of kidney disease. Free Radic Biol Med, 53(4): 842-53. Bedard K. & Krause KH. (2007). The NOX Family of ROS-Generating NADPH Oxidases: Physiology And Pathophysiology. Physiol Rev, 87:245-313. Bettaieb A.Et al. (2015). Hepatocyte NADPH oxidase 4 regulates stress signaling, fibrosis, and insulin sensitivity during development of steatohepatitis in mice. Gastroenterology, 149(2): 468-480. Crosas-Molist E. & Fabregat, I. (2015). Role Of NADPH oxidases in the redox biology of liver fibrosis. Redox Biol, 6:106-111. Ellis EAEt al. (2000). Increased H₂ O₂ , vascular endothelial growth factor and receptors in the retina of the BBZ/WOR diabetic rat. Free Rad Biol Med, 28(1): 91-101. Friedman S.L.Et al. (2013). Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med, 5(167):167sr1. Hecker L.Et al. (2009). NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med, 15(9): 1077-81. Holterman C.E.Et al. (2015). NOX and renal disease. Clin Sci (Lond), 128(8): 465-81. Ikawa Y.Et al. (2008). Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-beta-induced mouse fibrosis. J Cell Physiol, 216(3): 680-7. Jha J.C.Et al. (2014). Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy. J Am Soc Nephrol, 25(6): 1237-54. Jiang F.Et al. (2014). NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox Biol, 2:267-72. Kowluru RA & Mishra M. (2015). Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim Biophys Acta , 1852(11):2474-83. Mao S. & Huang S. (2014). The signaling pathway of NADPH oxidase and its role in glomerular diseases. J Receptors and Signal Transduction, 34(1): 6-11. Nauseef WM (2008). Biological roles for the NOX family NADPH oxidases. J Biol Chem, 283(25):16961-5. Nlandu Khodo S.Et al. (2012). NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury. J Am Soc Nephrol, 23(12): 1967-76. Paik Y.H.Et al. (2013). Role of NADPH oxidases in liver fibrosis. Antioxid Redox Signal, 20(17): 2854-2872. Sancho P.Et al. (2012). NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS One, 7(9):e45285. Sedeek M.Et al. (2010). Critical role of NOX4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol, 299(6): F1348-58. Sedeek M.Et al. (2013). NADPH oxidases, reactive oxygen species, and the kidney: friend and foe. J Am Soc Nephrol, 24(10): 1512-8. Serrander L.Et al. (2007). NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J, 406(Pt 1): 105-114. Thannickal VJ (2012). Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH Oxidase. Fibrogenesis Tissue Repair, 5(Suppl 1): S23. Wynn TA (2008). Cellular and molecular mechanisms of fibrosis. J Pathol, 214(2): 199-210.

no

Claims (46)

a compound having the formula (I): Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein A is -C(R ¹ )=C(R ¹ )-C(R ¹ )=C(R ¹ )-, -SC(R ^1a )=C(R ^1a )-, -C(R ^1a )=C(R ^1a )-S- or -(CH ₂ ) _3-4 -; X ¹ series -CH-, -C( Halogen)- or -N-; X ² -CH- or -N-; X ³ -N- or -C(R ⁴ )-; each R ^{1 is} independently H, halogen, cyano, C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl, halo, -C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{1 - 6} alkoxy group or halo -C _{1 - 6} alkoxy, which is limited to at least two R ¹ H; each R ^{1a is} independently H, C _{1 - 6} alkyl or aryl; R ² is CO ₂ H, -C(O)NHSO ₂ R ⁵ , -NHSO ₂ R ⁵ , , , , , or R ³ is halogen, cyano or OR ⁶ ; R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{3 - 6} cycloalkyl, optionally 1 to 3 identical or a different halogen atom-substituted aryl group, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR ⁷ R ⁸ or cyano; or R ³ and R ⁴ together -O-CF ₂ -O- or -O-(CH ₂ ) _p -O-; R ⁵ is C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl or C _{3 - 6} cycloalkyl; each R ⁶ independently Is a C _{1 - 6} alkyl group, a halo-C _{1 - 6} alkyl group, a C _{3 - 6} cycloalkyl-(C _{0 - 2} alkyl group), a heterocyclic group or a benzyl group; R ⁷ and R ⁸ are each independently Is selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and p is 1, 2 or 3; the following compounds are not included: (A) , (B) Wherein R ^1B is H or OCH ₃ : R ^3B is Br, Cl or I and R ^4B is H; or R ^3B and R ^{4B are} each OCH ₃ ; or R ^3B is OCH ₃ and R ^4B is O(CH ₂ ) ₂ OCH ₃ ; or R ^3B and R ^4B together are -O-(CH ₂ ) ₂ -O- or -O-(CH ₂ ) ₃ -O-, (C) Wherein R ^3C is OCH ₃ , Br, Cl or I and R ^4C is H; or wherein R ^3C and R ^{4C are} each OCH ₃ ; or wherein R ^3C is OCH ₃ and R ^4C is O(CH ₂ ) ₂ OCH ₃ Or wherein R ^3C and R ^{4C are} together -O-(CH ₂ ) ₂ -O- or -O-(CH ₂ ) ₃ -O-, and (D) Wherein R ^3D is Br or Cl and R ^4D is H; or wherein R ^3D and R ^{4D are} each OCH ₃ ; or wherein R ^3D is OCH ₃ and R ^4D is O(CH ₂ ) ₂ OCH ₃ ; or wherein R ^3D And R ^4D together are -O-(CH ₂ ) ₂ -O- or -O-(CH ₂ ) ₃ -O-. The compound of 1, wherein A is ^{-CH = CH-C (R 1} ) = CH- *, wherein * indicates the carbon adjacent to X it is connected to ^a requested item. The compound of claim 1, wherein X ¹ is -N-. The compound of claim 1, wherein X ¹ is -CH-. The compound of claim 2, wherein X ¹ is -N-. The compound of claim 2, wherein X ¹ is -CH-. The compound of claim 1, wherein X ³ is -CR ⁴ -. The compound of claim 7, wherein X ² is -CH-. The compound of claim 7, wherein X ² is -N-. The compound of claim 1, wherein R ² is CO ₂ H, , or . The compound of claim 10, wherein R ² is CO ₂ H, or . A compound of claim 1 which has the formula Ia: Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein R ³ is halogen, cyano or OR ⁶ ; and R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _2-6 alkynyl, C _{3 a 6-} cycloalkyl group, an aryl group substituted by 1 to 3 identical or different halogen atoms, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR ⁷ R ⁸ or Cyano group. The compound of claim 12, wherein R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _{1 -6} alkoxy -C _1-6 alkyl, C _2-6 alkynyl group, C _{3 - 6} cycloalkyl substituted alkyl, optionally substituted with 1 to 3 identical or different halogen atoms of an aryl group, optionally substituted with 1 Heteroaryl, halogen, NR ⁷ R ⁸ or cyano group substituted with 3 identical or different halogen atoms. The compound of claim 13, wherein A is -CH=CH-C(R ¹ )=CH-*, wherein * indicates a carbon bond to the adjacent X ¹ . The compound of claim 13, wherein X ¹ is -N-. The compound of claim 13, wherein X ¹ is -CH-. The compound of claim 14, wherein X ¹ is -N-. The compound of claim 14, wherein X ¹ is -CH-. The compound of claim 12, wherein X ² is -CH-. The compound of claim 12, wherein X ² is -N-. The compound of claim 12, wherein R ² is CO ₂ H, , or . The compound of claim 21, wherein R ² is CO ₂ H, or . A compound of claim 1 which has the formula Ib: Or a pharmaceutically acceptable salt, solvate or solvate thereof; wherein R ² is CO ₂ H, , or R ³ is halogen, cyano or OR ⁶ ; R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _{1- 6} alkyl, C _1-6 alkoxy -C _1-6 alkyl, C _2-6 alkynyl group, C _{3 - 6} cycloalkyl, optionally substituted with the same or different 1 to 3 halogen atoms of aryl a heteroaryl group, a halogen, an NR ⁷ R ⁸ or a cyano group substituted by 1 to 3 identical or different halogen atoms, and each R ^{6 is} independently a C _1-6 alkyl group, a fluorine-C _{1- 6} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, -C _0-1 alkyl, benzyl or . The compound of claim 23, wherein X ¹ is -CH-. The compound of claim 23, wherein R ² is CO ₂ H, or . The compound of claim 23, wherein R ³ is halogen or OR ⁶ . The compound of claim 23, wherein R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _{1 -6} alkoxy -C _1-6 alkyl, C _2-6 alkynyl group, C _{3 - 6} cycloalkyl substituted alkyl, optionally substituted with 1 to 3 identical or different halogen atoms of an aryl group, optionally substituted with 1 Heteroaryl, halogen, NR ⁷ R ⁸ or cyano group substituted with 3 identical or different halogen atoms. The compound of claim 23, wherein R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _{1 -6} alkoxy -C _1-6 alkyl, C _2-6 alkynyl group, C _{3 - 6} cycloalkyl, halogen, NR ⁷ R ⁸ or cyano. The compound of claim 23, wherein X ² is -CH-. The compound of claim 23, wherein X ² is -N-. The compound of claim 23, wherein X ¹ and X ^{2 are} each -CH-. The compound of claim 23, wherein R ¹ is H, F or Cl. The compound of claim 24, wherein: R ² is CO ₂ H, or R ³ is halogen or OR ⁶ ; R ⁴ is OR ⁶ , S(O) _n R ⁶ , C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C -C _1-6 alkyl _1-6 alkoxy, C _2-6 alkynyl group, C _{3 - 6} cycloalkyl substituted alkyl, optionally substituted with 1 to 3 identical or different halogen atoms of an aryl group, optionally substituted with 1 to 3 heteroaryl groups substituted with the same or different halogen atoms, halogen, NR ⁷ R ⁸ or cyano; and each R ^{6 is} independently C _1-6 alkyl, fluoro-C _1-6 alkyl, C _3--6 cycloalkyl, C _3--6 alkyl -C _1-6 cycloalkyl, benzyl or . The compound of claim 33, wherein X ² is -CH-. The compound according to item 23 of the request, wherein: R ¹ Department of H, halogen, C _{1 - 3} alkyl, fluoro -C _{1 - 3} alkyl, C _{3 - 6} cycloalkyl, fluoro -C _{1 - 3} alkoxy, Cyano or C _2-3 alkynyl; R ² is CO ₂ H, , or ; R ³ based halo, cyano, C _{1 - 3} alkoxy or fluoro -C _{1 - 3} alkoxy group; R ⁴ lines _{^{H, OR 6, C 1 -}} 3 alkyl, fluoro -C _{1 - 3} alkyl _{, S (O) n -C 1} - 3 alkyl, hydroxy -C _{1 - 3} alkyl, C _{1 - 3} alkoxy, -C _{1 - 3} alkyl, C _{2 - 3} alkynyl, C _{3 - 6} cycloalkyl alkyl, optionally substituted by 1-2 of fluorine atoms, phenyl, pyridyl, halogen, NR ⁷ R ⁸ or cyano; each R ⁶ is independently line C _{1 - 3} alkyl, fluoro -C _{1 - 3} alkyl group, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, -C _{1 - 2} alkyl, benzyl or And R ¹ and R ⁸ are each independently selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and X ¹ and X ^{2 are} independently selected from -CH- and -N-. The compound of claim 23, wherein R ¹ is H or halogen; R ² is CO ₂ H, , or ; R ³ based halo or cyano; R ⁴ based OR ^6, C _{1 - 3} alkyl, fluoro -C _{1 - 3 alkyl, S (O) n -C 1} - 3 alkyl, hydroxy -C _{1 - 3} alkyl group, C _{1 - 3} alkoxy, -C _{1 - 3} alkyl, C _{2 - 3} alkynyl, C _{3 - 6} cycloalkyl, halogen, NR ⁷ R ⁸ or a cyano group; R ⁶ line C _{1 - 3} alkyl, fluoro -C _{1 - 3} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, -C _{1 - 2} alkyl, benzyl or And R ¹ and R ⁸ are each independently selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and X ¹ and X ^{2 are} independently selected from -CH- and -N-. The compound of claim 23, wherein R ¹ is H; R ² is CO ₂ H; R ³ is halogen or cyano; R ⁴ is OR ⁶ ; R ⁶ is C _{1 - 3} alkyl; and X ¹ and X ² Department -CH-. The compound of any one of claims 1 to 37, wherein R ² is CO ₂ H. The compound of any one of claims 1 to 37, wherein the R ² is . The compound of any one of claims 1 to 37, wherein the R ² is . The compound of any one of claims 1 to 37, wherein the R ² is . The compound of claim 1, which is selected from the group consisting of: N- (4-chloro-2-(methylsulfonylamino)phenyl)-2-naphthylamine; N- (4-chloro- 2- (2 H - tetrazol-5-yl) phenyl) -2-naphthyl Amides; 5-chloro-2- (quinolin-3-acyl amino) benzoic acid; 5-chloro-2- ( 6-fluoro-2-naphthylamino)benzoic acid; 2-(2-naphthylamino)-5-chloro-4-fluorobenzoic acid; 2-(2-naphthylamino)-5-chlorofluoride Alkali acid; 2-(2-naphthylamino)-4,5-dichlorobenzoic acid; 5-chloro-2-(7-fluoroquinoline-3-carboxamido)benzoic acid; 2-(6 -bromo-2-naphthylamino)-5-chlorobenzoic acid; 5-chloro-2-(7-methylquinolin-3-carboxamido)benzoic acid; 2-(2-naphthylaminol) )-4-bromo-5-chlorobenzoic acid; 5-chloro-2-(6-(trifluoromethyl)-2-naphthylamino)benzoic acid; 2-(6-bromo-2-naphthylamine -4,5-dichlorobenzoic acid; 5-chloro-4-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acid; 2-(2-naphthylamino)-5- Chloro-4-methoxybenzoic acid; 2-(benzo[b]thiophene-5-carbamimidino)-5-chlorobenzoic acid; 4,5-difluoro-2-(6-fluoro-2- Naphthylamino)benzoic acid; 2-(2-naphthylamino)-4,5-difluorobenzoic acid; 2-(2-naphthylamino)-5-cyanobenzoic acid; 4,5- Dichloro-2-(6-ethyl-2-naphthylamino)benzoic acid ; 2-(benzo[b]thiophene-5-carbamimidino)-5-chloro-4-fluorobenzoic acid; 2-(6-bromo-2-naphthylamino)-5-cyanobenzoic acid ; 5-bromo-2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6-ethyl-2-naphthylamino)-4-methoxybenzoic acid; 5-cyano-2-(6-ethyl-2-naphthylamino)benzoic acid; 5-chloro-2-(6-ethyl-2-naphthylamino)-4-fluorobenzoic acid; -(6-ethyl-2-naphthylamino)-4,5-difluorobenzoic acid; 5-chloro-2-(7-bromoquinoline-3-carboxamido)benzoic acid; 5-chloro 2-(3-methylbenzo[b]thiophene-5-carbamimidino)benzoic acid; 2-(benzo[b]thiophene-6-carboxamido)-5-chlorobenzoic acid; -Chloro-2-(thieno[2,3-b]pyridine-5-carboxamido)benzoic acid; N- (4-chloro-2-(5-sideoxy-4,5-dihydro- 1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; N- (4-chloro-2-(1 H -tetrazol-5-yl)phenyl)-7-fluoroquinoline- 3-carbalamine; N- (4-chloro-2-(1 H -tetrazol-5-yl)phenyl)-6-fluoro-2-naphthylamine; N- (4-chloro-2-() 5-sided oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro-2-(6-fluoro-2- Naphthylamino)-4-methoxybenzoic acid; N- (4-chloro-2-(5-o-oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl) Phenyl)-2-naphthoquinone Amine; 5-chloro-4-methoxy-2-(2-phenylbenzo[b]thiophene-5-carbamido)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthalene) Amidino)-4-(trifluoromethyl)benzoic acid; N- (4-chloro-2-(5-o-oxy-4,5-dihydro-1 H -tetrazol-1-yl)benzene 2-methylbenzo[b]thiophene-5-carboxamide; 5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxamide Benzoic acid; N- (4-chloro-5-fluoro-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2 -naphthylamine; N- (4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)quinoline-3- Methionamine; N- (4-chloro-2-(5-sided oxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2 -naphthylamine; N -(4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-ethynyl -2-naphthylamine; N- (4-chloro-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6- Ethyl-2-naphthylamine; 5-fluoro-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acid; 4-chloro-5-fluoro-2-(6-fluoro -2-naphthylamino)benzoic acid; 6-(2-naphthylamino)benzo[d][1,3]dioxazole-5-carboxylic acid; N- (4,5-difluoro-2 -(1 H -tetrazol-5-yl)phenyl)-6-fluoro-2-naphthylamine; N -(4,5-difluoro-2- (5-Sideoxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro-2-(6 -Chloro-2-naphthylamino)benzoic acid; 6-fluoro- N- (4-fluoro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1 H -tetra Zin-1-yl)phenyl)-2-naphthylamine; 5-chloro-4-ethyl-2-(6-fluoro-2-naphthylamino)benzoic acid; 4-(benzyloxy) -5-chloro-2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(oxetane- 3-yloxy)benzoic acid; N- (4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl -6-fluoro-2-naphthylamine; 2-(2-naphthylamino)-5-(difluoromethoxy)benzoic acid; 2-(6-fluoro-2-naphthylamino)- 4,5-dimethoxybenzoic acid; 7-(6-fluoro-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-6-carboxamido)benzoic acid; 5-cyano-2-(6-fluoro-2-naphthoquinone) Amino)-4-methoxybenzoic acid; 5-chloro-4-ethynyl-2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6-fluoro-2 -naphthylamino)-4-((tetrahydro-2 H -piperidin-4-yl)oxy)benzoic acid; 5-chloro-4-cyclopropyl-2-(6-fluoro-2-naphthalene Amidino)benzoic acid; N -(4,5 -difluoro-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro-2- (7-fluoroquinolin-3-carboxamido)-4-(oxetan-3-yloxy)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino group -4-(hydroxymethyl)benzoic acid; N- (4-chloro-5-(oxetan-3-yloxy)-2-(5-sideoxy-4,5-dihydro) -1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(2,2 , 2-trifluoroethoxy)benzoic acid; N- (4-chloro-5-methoxy-2-((methylsulfonyl)aminomethane)phenyl)-6-fluoro-2-naphthalene Guanidine; 6-chloro- N- (4-chloro-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; 6-(6-chloro-2-naphthylamino)-2,2-difluorobenzo[d][1,3]dioxazole-5-carboxylic acid; 2-(2-naphthylamino)- 5-chloro-6-methoxynicotinic acid; 2-(2-naphthylamino)-5-chloro-6-ethoxynicotinic acid; N- (4,5-difluoro-2-() (Methanesulfonyl)amine,carinyl)phenyl)-6-fluoro-2-naphthylamine; N- (4-chloro-2-(((difluoromethyl)))sulfonyl) -5-methoxyphenyl)-6-fluoro-2-naphthylamine; 2-(6-chloro-2-naphthylamino)-5-(difluoromethoxy)-4-fluorobenzoic acid ; 5-cyano-2-(6-fluoro-2-naphthylamino)benzene Acid; 2-(6-chloro-2-naphthylamino)-5-cyanobenzoic acid; 5-cyano-2-(6-fluoro-2-naphthylamino)-4-methylbenzoic acid 5-cyano-2-(6-chloro-2-naphthylamino)-4-methylbenzoic acid; N- (4-(difluoromethoxy)-2-(5-sideoxy)- 4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 6-chloro- N- (4-(difluoromethoxy)-2- (5-Phenoxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; 6-chloro- N- (4-chloro-5-methoxy -2-(5-Sideoxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; N- (4-chloro-5-ethoxy- 2-(5-sided oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; 6-chloro- N- (4-chloro -5-ethoxy-2-(5-sided oxy-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-2-naphthylamine; N- (4-chloro- 5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-(trifluoromethyl)-2-naphthylamine ; N -(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-methyl-2 -naphthylamine; N- (4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6- Cyclopropyl-2-naphthylamine; N- (4-chloro-2-(5-sided oxy-4,5-dihydro-1 H -tetrazole- 1-yl)phenyl)-6-cyano-2-naphthylamine; 2,2-difluoro-6-(6-fluoro-2-naphthylamino)benzo[d][1,3] Dicarbazole-5-carboxylic acid; 2-(2-naphthylamino)-5-chloro-4-(methoxymethyl)benzoic acid; N- (4-chloro-5-methoxy-2- (5-Sideoxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-7-fluoroquinoline-3-carboxamide; N- (4-bromo) -5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-fluoro-2-naphthylamine; N -( 4-bromo-5-methoxy-2-(5-oxo-4,5-dihydro-1 H -tetrazol-1-yl)phenyl)-6-chloro-2-naphthylamine; N- (4-Chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-6-fluoro-2-naphthylamine 7-(6-Chloro-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 7-(6-cyano-2- Naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 5-cyano-4-ethoxy-2-(6-fluoro-2- Naphthylamino)benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-methoxybenzoic acid 7-(7-fluoroquinoline-3-carboxamide )-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 5-chloro-4-methoxy-2-(6-methyl-2-naphthylamino group) Benzoic acid; 5-chloro-2-(6-cyclopropyl-2-naphthylamino)-4-methoxybenzoic acid; 5-chloro-2-(6-(difluoromethyl)-2-naphthylamino)-4-methoxybenzoic acid; 5-chloro-4-methoxy-2-(6-(trifluoro) Methyl)-2-naphthylamino)benzoic acid; 5-chloro-2-(6-(difluoromethoxy)-2-naphthylamino)-4-methoxybenzoic acid; 5-chloro 4-methoxy-2-(6-(trifluoromethoxy)-2-naphthylamino)benzoic acid; N- (4-chloro-2-(5-sideoxy-4,5-) Dihydro-1 H -tetrazol-1-yl)phenyl)-6-methyl-2-naphthylamine; N- (4-chloro-2-(5-sideoxy-4,5-dihydro) -1 H -tetrazol-1-yl)phenyl)-6-cyclopropyl-2-naphthylamine; N- (4-chloro-2-(5-sideoxy-4,5-dihydro- 1 H -tetrazol-1-yl)phenyl)-6-(trifluoromethoxy)-2-naphthylamine; 5-cyano-2-(6-fluoro-2-naphthylamino)- 4-(oxetan-3-yloxy)benzoic acid; 5-cyano-2-(7-fluoroquinoline-3-carboxamido)-4-(oxeane-3 -yloxy)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(methoxymethyl)benzoic acid; 5-cyano-4-methoxy- 2-(2-methylbenzo[b]thiophene-5-carbamimidino)benzoic acid; 8-(6-fluoro-2-naphthylamino)-3,4-dihydro- 2H -benzene And [b][1,4]dioxin-7-carboxylic acid; 5-(difluoromethoxy)-2-(6-fluoro-2-naphthylamino)-4-methoxybenzoic acid; 5-fluoro-2-(6 -fluoro-2-naphthylamino)-4-(oxetan-3-yloxy)benzoic acid; 2-(2-naphthylamino)-5-cyano-4-(oxa) Cyclobutane-3-yloxy)benzoic acid; 2-chloro-2'-fluoro-5-(6-fluoro-2-naphthylamino)-[1,1'-biphenyl]-4-carboxylic acid N- (4-cyano-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-7-fluoroquinoline-3 -carbamamine; 5-chloro-2-(6-chloro-2-naphthylamino)-4-methoxybenzoic acid; 5-cyano-4-fluoro-2-(6-fluoro-2- Naphthylamino)benzoic acid; 4-cyano-5-fluoro-2-(6-fluoro-2-naphthylamino)benzoic acid; 2-(6-chloro-2-naphthylamino)-5 -(difluoromethoxy)benzoic acid; 7-(2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 7-(6 -(trifluoromethyl)-2-naphthylamino)-2,3-dihydrobenzo[b][1,4]dioxazine-6-carboxylic acid; 2-(2-naphthylamino) 5-5-cyano-4-methoxybenzoic acid; 5-cyano-4-methoxy-2-(6-(trifluoromethyl)-2-naphthylamino)benzoic acid; 2-( 6-chloro-2-naphthylamino)-5-cyano-4-ethoxybenzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridine-4 -yl)benzoic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridin-3-yl)benzoic acid; 5-chloro-2-(6-fluoro-2- Naphthylamino)-6-methoxy Nicotinic acid; 5-chloro-6-ethoxy-2-(6-fluoro-2-naphthylamino) nicotinic acid; 5-chloro-2-(6-chloro-2-naphthylamino) -6-ethoxy nicotinic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-(pyridin-2-yl)benzoic acid; 2-chloro-5-(6- Fluoro-2-naphthylamino)isonicotinic acid; 5-chloro-2-(6-fluoro-2-naphthylamino)-4-isopropoxybenzoic acid; 5-chloro-4-cyano -2-(6-fluoro-2-naphthylamino)benzoic acid; 5-chloro-2-(6-chloro-2-naphthylamino)-4-isopropoxybenzoic acid; 2-(6 -chloro-2-naphthylamino)-5-fluoro-4-methoxybenzoic acid; 4-chloro-2-(6-chloro-2-naphthylamino)-5-cyanobenzoic acid; -Fluoro- N- (4-fluoro-5-(oxetan-3-yloxy)-2-(5-sideoxy-4,5-dihydro-1,2,4-oxo Zin-3-yl)phenyl)-2-naphthylamine; 6-fluoro- N- (4-fluoro-5-methoxy-2-(5-sideoxy-4,5-dihydro-1) , 2,4-oxadiazol-3-yl)phenyl)-2-naphthylamine; 2-(6-chloro-2-naphthylamino)-5-cyano-4-(cyclopropylmethyl) Oxy)benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-cyclobutoxybenzoic acid; 2-(6-chloro-2-naphthylamino)- 5-cyano-4-(methylthio)benzoic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-isopropoxybenzoic acid; N- (4-fluoro -5-methoxy-2- (5-Sideoxy-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-2-naphthylamine; 5-chloro-2-(6-chloro-2 -naphthylamino)-6-methoxynicotinic acid; 5-cyano-4-methoxy-2-(5,6,7,8-tetrahydronaphthalen-2-carboxamido)benzene Formic acid; 2-(6-chloro-2-naphthylamino)-5-cyano-4-(methylsulfinyl)benzoic acid; 2-(6-chloro-2-naphthylamino)-5 -Cyano-4-(difluoromethoxy)benzoic acid; N- (4-cyano-5-methoxy-2-(5-sideoxy-4,5-dihydro-1,2, 4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthylamine; and 2-(6-chloro-2-naphthylamino)-5-cyano-4-(dimethyl Amino)benzoic acid; or a pharmaceutically acceptable salt, solvate or salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt, solvate or solvate thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition of claim 43 or a therapeutically effective amount of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt, solvate or solvate thereof, It is used in the manufacture of a medicament for the treatment of fibrosis. The use of claim 44, wherein the fibrosis is selected from the group consisting of scleroderma, fibrosis of the lung, fibrosis of the kidney, and fibrosis of the liver. A therapeutically effective amount of a compound of formula I': Or a pharmaceutically acceptable salt, solvate or solvate thereof, for use in the manufacture of a medicament for the treatment of fibrosis; wherein the A-C(R ¹ )=C(R ¹ ) -C(R ¹ )=C(R ¹ )-, -SC(R ^1a )=C(R ^1a )-, -C(R ^1a )=C(R ^1a )-S- or -(CH ₂ ) _{3 -4} -; X ¹ is -CH-, -C(halogen)- or -N-; X ² is -CH- or -N-; X ³ is -N- or -C(R ⁴ )-; ¹ independently H, halogen, cyano, C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl, halo-C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, a C _{1 - 6} alkoxy group or a halo-C _{1 - 6} alkoxy group, which is limited to at least two R ¹ systems H; each R ^{1a is} independently H, C _{1 - 6} alkyl or aryl; ² series CO ₂ H, -C(O)NHSO ₂ R ⁵ , -NHSO ₂ R ⁵ , , , , , or R ³ is halogen, cyano or OR ⁶ ; R ⁴ is H, OR ⁶ , S(O) _n R ⁶ , C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl, hydroxy-C _{1 - 6} alkyl, C _{1 - 6} alkoxy-C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{3 - 6} cycloalkyl, optionally 1 to 3 identical or a different halogen atom-substituted aryl group, optionally substituted with 1 to 3 identical or different halogen atoms, halogen, NR ⁷ R ⁸ or cyano; or R ³ and R ⁴ together -O-CF ₂ -O- or -O-(CH ₂ ) _p -O-; R ⁵ is C _{1 - 6} alkyl, halo-C _{1 - 6} alkyl or C _{3 - 6} cycloalkyl; R ⁶ C _{1 - 6} alkyl, halo -C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl _- (C ₀ - ₂ alkyl), benzyl, or a heterocyclic group; R ⁷ and R ⁸ are each independently selected from H and C _{1 - 6} alkyl; n is 0, 1 or 2; and p is 1, 2 or 3.