Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
ARYLCARBOXAMIDES AND USES THEREOF
Document Type and Number:
WIPO Patent Application WO/2017/192304
Kind Code:
A1
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.

Inventors:
JACINTHO, Jason, Duarte (5871 Oberlin Drive, Suite 100San Diego, CA, 92121, US)
CLARK, Ryan, Christopher (5871 Oberlin Drive, Suite 100San Diego, CA, 92121, US)
SHENG, Tao (5871 Oberlin Drive, Suite 100San Diego, CA, 92121, US)
OBALLA, Renata, Marcella (5871 Oberlin Drive, Suite 100San Diego, CA, 92121, US)
STOCK, Nicholas, Simon (5871 Oberlin Drive, Suite 100San Diego, CA, 92121, US)
ROPPE, Jeffrey, Roger (5871 Oberlin Drive, Suite 100San Diego, CA, 92121, US)
Application Number:
US2017/029369
Publication Date:
November 09, 2017
Filing Date:
April 25, 2017
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
INCEPTION 1, INC. (5871 Oberlin Drive, Suite 100San Diego, CA, 92121, US)
International Classes:
C07D213/80; C07C233/76; C07C311/15; C07D213/55; C07D215/54; C07D257/04; C07D271/07; C07D305/08; C07D309/12; C07D317/68; C07D319/18; C07D321/08; C07D333/54; C07D409/12; C07D413/12; C07D495/04
Domestic Patent References:
WO2008135524A22008-11-13
WO2005085188A22005-09-15
WO2004018414A22004-03-04
Foreign References:
EP2990057A12016-03-02
US20030073862A12003-04-17
Other References:
S. M. BERGE: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
"Remington's Pharmaceutical Sciences, 17th ed.", 1985, MACK PUBLISHING COMPANY, pages: 1418
JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 2
WERMUTH, C. G. AND STAHL, P. H.: "Pharmaceutical Salts: Properties, Selection, and Use. A Handbook", 2002, VERLAG HELVETICA CHIMICA ACTA, ISBN: 3-906390-26-8
REICHARDT, C.; WELTON T.: "Solvents and Solvent Effects in Organic Chemistry", 2011, JOHN WILEY & SONS, ISBN: 978-3-527-32473-6
H. BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
FREIREICH, CANCER CHEMOTHER. REP., vol. 50, 1966, pages 219
"Scientific Tables, Geigy Pharmaceuticals", 1970, ARDSLEY, pages: 537
ABO M. ET AL.: "Development of a highly sensitive fluorescence probe for hydrogen peroxide", J AM CHEM SOC, vol. 133, no. 27, 2011, pages 10629 - 37
BARMAN S. ET AL.: "Nox4 is Expressed in Pulmonary Artery Adventitia and Contributes to Hypertensive Vascular Remodeling.", ARTERIOSCLER THROMB VASE BIOL. AUG, vol. 34, no. 8, 2014, pages 1704 - 1715
BABELOVA A. ET AL.: "Role of NOX4 in murine models of kidney disease.", FREE RADIC BIOL MED, vol. 53, no. 4, 2012, pages 842 - 53
BEDARD K.; KRAUSE K-H.: "The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.", PHYSIOL REV, vol. 87, 2007, pages 245 - 313
BETTAIEB A. ET AL.: "Hepatocyte NADPH oxidase 4 regulates stress signaling, fibrosis, and insulin sensitivity during development of steatohepatitis in mice", GASTROENTEROLOGY, vol. 149, no. 2, 2015, pages 468 - 480
CROSAS-MOLIST E.; FABREGAT, I.: "Role of NADPH oxidases in the redox biology of liver fibrosis.", REDOX BIOL, vol. 6, 2015, pages 106 - 111
ELLIS E.A. ET AL.: "Increased H 0 , vascular endothelial growth factor and receptors in the retina of the BBZ/WOR diabetic rat.", FREE RAD BIOL MED, vol. 28, no. 1, 2000, pages 91 - 101
FRIEDMAN S.L. ET AL.: "Therapy for fibrotic diseases: nearing the starting line.", SCI TRANSL MED, vol. 5, no. 167, 2013, pages 167srl
HECKER L. ET AL.: "NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury", NAT MED, vol. 15, no. 9, 2009, pages 1077 - 81
HOLTERMAN C.E. ET AL.: "NOX and renal disease", CLIN SCI (LOND, vol. 128, no. 8, 2015, pages 465 - 81
IKAWA Y. ET AL.: "Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-beta-induced mouse fibrosis", J CELL PHYSIOL, vol. 216, no. 3, 2008, pages 680 - 7
JHA J.C. ET AL.: "Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy", J AM SOC NEPHROL, vol. 25, no. 6, 2014, pages 1237 - 54
JIANG F. ET AL.: "NADPH oxidase-dependent redox signaling in TGF-p-mediated fibrotic responses.", REDOX BIOL, vol. 2, 2014, pages 267 - 72
KOWLURU R.A.; MISHRA M.: "Oxidative stress, mitochondrial damage and diabetic retinopathy.", BIOCHIM BIOPHYS ACTA, vol. 1852, no. 11, 2015, pages 2474 - 83, XP029277071, DOI: doi:10.1016/j.bbadis.2015.08.001
MAO S.; HUANG S.: "The signaling pathway of NADPH oxidase and its role in glomerular diseases", J RECEPTORS AND SIGNAL TRANSDUCTION, vol. 34, no. 1, 2014, pages 6 - 11
NAUSEEF W.M.: "Biological roles for the NOX family NADPH oxidases", J BIOL CHEM, vol. 283, no. 25, 2008, pages 16961 - 5
NLANDU KHODO S. ET AL.: "NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury.", J AM SOC NEPHROL, vol. 23, no. 12, 2012, pages 1967 - 76
PAIK Y.H. ET AL.: "Role of NADPH oxidases in liver fibrosis.", ANTIOXID REDOX SIGNAL, vol. 20, no. 17, 2013, pages 2854 - 2872
SANCHO P. ET AL.: "NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.", PLOS ONE, vol. 7, no. 9, 2012, pages e45285
SEDEEK M. ET AL.: "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, vol. 299, no. 6, 2010, pages F1348 - 58, XP055041888, DOI: doi:10.1152/ajprenal.00028.2010
SEDEEK M. ET AL.: "NADPH oxidases, reactive oxygen species, and the kidney: friend and foe", J AM SOC NEPHROL, vol. 24, no. 10, 2013, pages 1512 - 8
SERRANDER L. ET AL.: "NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation", BIOCHEM J, vol. 406, 2007, pages 105 - 114
THANNICKAL V.J.: "Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase.", FIBROGENESIS TISSUE REPAIR, vol. 5, no. 1, 2012, pages S23, XP021096018, DOI: doi:10.1186/1755-1536-5-S1-S23
WYNN T. A.: "Cellular and molecular mechanisms of fibrosis", J PATHOL, vol. 214, no. 2, 2008, pages 199 - 210, XP002553819, DOI: doi:10.1002/path.2277
Attorney, Agent or Firm:
MALLON, Joseph, J. (Knobbe, Martens Olson & Bear LLP,2040 Main Street, Fourteenth Floo, Irvine CA, 92614, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:

1. A compound having the formula (I):

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

X1 is -CH-, -C(halogen)- or -N-;

X2 is -CH- or -N-;

X3 is -N- or -C(R4)-;

each R1 is independently H, halogen, cyano, Ci-6alkyl, C3-6Cycloalkyl, halo-Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy or halo-Ci-6alkoxy, with the proviso that at least two Rx's are H;

each Rla is independently H, Ci-6alkyl or aryl;

R2 is C02H, -C(0)NHS02R5, -NHS02R5, °r i

R3 is halogen, cyano or OR6;

R4 is H, OR6, S(0)nR6, Ci-6alkyl, halo-Ci-6alkyl, hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR7R8 or cyano; or

R3 and R4 together is -0-CF2-0- or -0-(CH2)p-0-; R is Ci-6alkyl, halo-Ci-6alkyl or C3-6Cycloalkyl;

each R6 is independently Ci-6alkyl, halo-Ci-6alkyl, C3-6Cycloalkyl-(Co.

heterocyclyl or benzyl;

R 7 and R 8 are each independently selected from H and Ci-6alkyl; n is 0, 1 or 2; and

p is 1, 2 or 3;

excluding the following compounds:

where R is H or OCH3: R is Br, CI or I and R is H; or

Ria and R4U are each OCH3; or Ria is OCH3 and R4U is 0(CH2)2OCH3; or Ria and R4U taken together is -0-(CH2)2-0- or -0-(CH2)3-0-,

a. nd R , 4C are each OC¾; or where RJU is OC¾ and R4C is 0(CH2)2OCH3; or where R3C and R4C taken together is -0-(CH2)2-0- or -0-(CH2)3-0-, and

where R is Br or CI and R is H; or where R and R are each OCH3; or where RiU is OCH3 and R4D is 0(CH2)2OCH3; or where R3D and R4D taken gether is -0-(CH2)2-0- or -0-(CH2)3

2. The compound of Claim 1 wherein A is -CH=CH-C(R1)=CH-*, wherein * indicates attachment to the carbon adjacent to X1.

3. The compound of Claim 1 wherein X1 is -N-.

4. The compound of Claim 1 wherein X1 is -CH-.

5. The compound of Claim 2 wherein X1 is -N-.

6. The compound of Claim 2 wherein X1 is -CH-.

7. The compound of Claim 1 wherein X3 is -CR4-

8. The compound of Claim 7 wherein X2 is -CH-.

9. The compound of Claim 7 wherein X2 is -N-. mpound of Claim 1 wherein R

The compound of Claim 10 wherein R2 is C02H,

The compound of Claim 1 having the formula la:

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

R3 is halogen, cyano, or OR6; and

R4 is H, OR6, S(0)„R6, Ci-6alkyl, halo-Ci-6alkyl, hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkynyl, C3-6Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 , or cyano.

13. The compound of Claim 12 wherein R4 is OR6, S(0)nR6, Ci-6alkyl, halo-Ci-6alkyl, hydroxyl-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkynyl, C3-6Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 , or cyano.

14. The compound of Claim 13 wherein A is -CH=CH-C(R1)=CH-*, wherein * indicates attachment to the carbon adjacent to X1.

15. The compound of Claim 13 wherein X1 is -N-.

16. The compound of Claim 13 wherein X1 is -CH-.

17. The compound of Claim 14 wherein X1 is -N-.

18. The compound of Claim 14 wherein X1 is -CH-.

19. The compound of Claim 12 wherein X is -CH-.

20. The compound of Claim 12 wherein X2 is -N-.

21. The compound of Claim 12 wherein R2 is C02H, The compound of Cl

The compound of Claim 1 having the formula lb:

lb

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

R is halogen, cyano, or OR ;

R4 is H, OR6, S(0)„R6, Ci-6alkyl, halo-Ci-6alkyl, hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkynyl, C3-6Cycloalkyl, aryl optionally substituted with 1 -3 same or different halogen atoms, heteroaryl optionally substituted with 1 -3 same or

7 8

different halogen atoms, halogen, NR R , or cyano; and

each R6 is independently Ci-6alkyl, fluoro-Ci-6alkyl, C3-6Cycloalkyl,

C3-6Cycloalkyl-Co-ialkyl, benzyl or ~' 0-2

The compound of Claim 23 wherein 1 is -CH-

25. The compound of Claim 23 wherein or

26. The compound of Claim 23 wherein R3 is halogen or OR6

27. The compound of Claim 23 wherein R4 is OR6, S(0)nR6, Ci-6alkyl, halo-Ci-6alkyl, hydroxyl-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkynyl, C3-6Cycloalkyl, aryl optionally substituted with 1 -3 same or different halogen atoms, heteroaryl optionally substituted with 1 -3 same or

7 8

different halogen atoms, halogen, NR R , or cyano.

28. The compound of Claim 23 wherein R4 is OR6, S(0)nR6, Ci-6alkyl,

hydroxyl-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkynyl, C3-6Cycloalkyl, halogen, NR7R8 or cyano.

29. The compound of Claim 23 wherein X2 is -CH-.

30. The compound of Claim 23 wherein X is -N-.

1 2

31. The compound of 23 wherein X and X are each -CH-.

32. The compound of Claim 23 wherein R1 is H, F or CI.

33. The compound of Claim 24 wherein:

R2 is C02H, or R3 is halogen or OR6;

R4 is OR6, S(0)„R6, Ci-6alkyl, halo-Ci-6alkyl, hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkynyl, C3-6Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR7R8, or cyano; and

each R6 is independently Ci-6alkyl, fluoro-Ci-6alkyl, C3-6Cycloalkyl,

C3-6Cycloalkyl-Ci-6alkyl, benzyl or

34. The compound of Claim 33 wherein X is -CH-.

35. The compound of Claim 23 wherein:

R1 is H, halogen, Ci-3alkyl, fluoro-Ci-3alkyl, C3-6Cycloalkyl, fluoro-Ci-3alkoxy, cyano or C2-3alkynyl;

halogen, cyano, Ci-3alkoxy or fluoro-Ci-3alkoxy;

R4 is H, OR6, Ci-3alkyl, fluoro-Ci-3alkyl, S(0)„-Ci.3alkyl, hydroxy-Ci-3alkyl, Ci-3alkoxy-Ci-3alkyl, C2-3alkynyl, C3-6Cycloalkyl, phenyl optionally substituted with 1-2

7 8

fluorine atoms, pyridyl, halogen, NR R or cyano;

each R6 is independently Ci-3alkyl, fluoro-Ci-3alkyl, C3-6Cycloalkyl,

C3-6Cycloalkyl-Ci-2alkyl, benzyl or

R 7 8

and R are each independently selected from H and Ci-6alkyl; n is 0, 1 or 2; and

X1 and X2 are independently selected from -CH- and -N-.

36. The compound of Claim 23 wherein

R1 is H or halogen;

R3 is halogen or cyano;

R4 is OR6, Ci-3alkyl, fluoro-Ci-3alkyl, S(0)„-Ci-3alkyl, hydroxy-Ci-3alkyl,

7 8

alkoxy-Ci-3alkyl, C2-3alkynyl, C3-6Cycloalkyl, halogen, NR R or cyano;

6 is Ci-3alkyl, fluoro-Ci-3alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl-Ci-2alkyl, benzyl

1 8

R and R are each independently selected from H and Ci-6alkyl;

n is 0, 1 or 2; and

X1 and X2 are independently selected from -CH- and -N-.

37. The compound of Claim 23, wherein

R1 is H;

R2 is C02H;

R is halogen or cyano;

R4 is OR6;

R6 is Ci-3alkyl; and

X1 and X2 are -CH-.

38. The compound of any of Claims 1 - 37 wherein 2 is C02H.

39. The compound of any of Claims 1 - 37 wherein

40. The compound of any of Claims 1 - 37 wherein

41. The compound of any of Claims 1 - 37 wherein

42. The compound of Claim 1 selected from the group consisting of:

N-(4-chloro-2-(methylsulfonamido)phenyl)-2-naphthamide;

N-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-2-naphthamide;

5-chloro-2-(quinoline-3-carboxamido)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)benzoic acid; 2-(2-naphthamido)-5-chloro-4-fluorobenzoic acid;

2-(2-naphthamido)-5-chloronicotinic acid;

2-(2-naphthamido)-4,5-dichlorobenzoic acid;

5-chloro-2-(7-fluoroquinoline-3-carboxamido)benzoic acid;

2-(6-bromo-2-naphthamido)-5-chlorobenzoic acid;

5-chloro-2-(7-methylquinoline-3-carboxamido)benzoic acid;

2-(2-naphthamido)-4-bromo-5-chlorobenzoic acid;

5-chloro-2-(6-(trifluoromethyl)-2-naphthamido)benzoic acid;

2-(6-bromo-2-naphthamido)-4,5-dichlorobenzoic acid;

5-chloro-4-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(2-naphthamido)-5-chloro-4-methoxybenzoic acid;

2-(benzo[b]thiophene-5-carboxamido)-5-chlorobenzoic acid;

4, 5 -difluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(2-naphthamido)-4,5-difluorobenzoic acid;

2-(2-naphthamido)-5-cyanobenzoic acid;

4,5-dichloro-2-(6-ethyl-2-naphthamido)benzoic acid;

2-(benzo[b]thiophene-5-carboxamido)-5-chloro-4-fluorobenzoic acid;

2-(6-bromo-2-naphthamido)-5-cyanobenzoic acid;

5-bromo-2-(6-fluoro-2-naphthamido)benzoic acid;

5-chloro-2-(6-ethyl-2-naphthamido)-4-methoxybenzoic acid;

5-cyano-2-(6-ethyl-2-naphthamido)benzoic acid;

5-chloro-2-(6-ethyl-2-naphthamido)-4-fluorobenzoic acid;

2-(6-ethyl-2-naphthamido)-4,5-difluorobenzoic acid;

5-chloro-2-(7-bromoquinoline-3 -carboxamido)benzoic acid;

5-chloro-2-(3-methylbenzo[b]thiophene-5-carboxamido)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-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-2-naphthamide;

N-(4-chloro-2-(lH-tetrazol-5-yl)phenyl)-7-fluoroquinoline-3-carboxamide;

N-(4-chloro-2-(lH-tetrazol-5-yl)phenyl)-6-fluoro-2-naphthamide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2-naphthamide; 5-chloro-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid;

N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-2-naphthamide;

5-chloro-4-methoxy-2-(2-phenylbenzo[b]thiophene-5-carboxamido)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(trifluoromethyl)benzoic acid;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-2-methylbenzo[b]thiophene-5- carboxamide;

5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxamido)benzoic acid;

N-(4-chloro-5-fluoro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2- naphthamide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)quinoline-3-carboxamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-6-ethynyl-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-6-ethyl-2-naphthamide;

5- fluoro-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid;

4- chloro-5-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

6- (2-naphthamido)benzo[d] [1,3] dioxole-5 -carboxy lie acid;

N-(4,5-difluoro-2-(lH-tetrazol-5-yl)phenyl)-6-fluoro-2-naphthamide;

N-(4,5-difluoro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2-naphthamide;

5- chloro-2-(6-chloro-2-naphthamido)benzoic acid;

6- fluoro-N-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-2- naphthamide;

5-chloro-4-ethyl-2-(6-fluoro-2-naphthamido)benzoic acid;

4- (benzyloxy)-5-chloro-2-(6-fluoro-2-naphthamido)benzoic acid;

5- chloro-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)benzoic acid;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2- naphthamide;

2-(2-naphthamido)-5-(difluoromethoxy)benzoic acid;

2-(6-fluoro-2-naphthamido)-4,5-dimethoxybenzoic acid;

7- (6-fluoro-2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid;

5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-6-carboxamido)benzoic acid;

5-cyano-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid; 5-chloro-4-ethynyl-2-(6-fluoro-2-naphthamido)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid; 5-chloro-4-cyclopropyl-2-(6-fluoro-2-naphthamido)benzoic acid;

N-(4,5-difluoro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2-naphthamide; 5-chloro-2-(7-fluoroquinoline-3-carboxamido)-4-(oxetan-3-yloxy)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(hydroxymethyl)benzoic acid;

N-(4-chloro-5-(oxetan-3-yloxy)-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2- naphthamide;

5- chloro-2-(6-fluoro-2-naphthamido)-4-(2,2,2-trifluoroethoxy)benzoic acid;

N-(4-chloro-5-methoxy-2-((methylsulfonyl)carbamoyl)phenyl)-6-fluoro-2-naphthamide;

6- chloro-N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-2-naphthamide; 6-(6-chloro-2-naphthamido)-2,2-difluorobenzo [d] [1,3] dioxole-5 -carboxylic acid;

2-(2-naphthamido)-5-chloro-6-methoxynicotinic acid;

2-(2-naphthamido)-5-chloro-6-ethoxynicotinic acid;

N-(4,5-difluoro-2-((methylsulfonyl)carbamoyl)phenyl)-6-fluoro-2-naphthamide;

N-(4-chloro-2-(((difluoromethyl)sulfonyl)carbamoyl)-5-methoxyphenyl)-6-fluoro-2- naphthamide;

2-(6-chloro-2-naphthamido)-5-(difluoromethoxy)-4-fluorobenzoic acid;

5-cyano-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyanobenzoic acid;

5-cyano-2-(6-fluoro-2-naphthamido)-4-methylbenzoic acid;

5- cyano-2-(6-chloro-2-naphthamido)-4-methylbenzoic acid;

N-(4-(difluoromethoxy)-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2- naphthamide;

6- chloro-N-(4-(difluoromethoxy)-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-2- naphthamide;

6-chloro-N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-2- naphthamide;

N-(4-chloro-5-ethoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2- naphthamide;

6-chloro-N-(4-chloro-5-ethoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-2- naphthamide;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-(trifluoromethyl)- 2-naphthamide;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-methyl-2- naphthamide;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-cyclopropyl-2- naphthamide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-cyano-2-naphthamide;

2,2-difluoro-6-(6-fluoro-2-naphthamido)benzo[d][l,3]dioxole-5-carboxylic acid;

2-(2-naphthamido)-5-chloro-4-(methoxymethyl)benzoic acid;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-7- fluoroquinoline-3-carboxamide;

N-(4-bromo-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-fluoro-2- naphthamide;

N-(4-bromo-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-chloro-2- naphthamide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)-6-fluoro-2-naphthamide; 7-(6-chloro-2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid;

7-(6-cyano-2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid;

5-cyano-4-ethoxy-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-methoxybenzoic acid

7-(7-fluoroquinoline-3-carboxamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid; 5-chloro-4-methoxy-2-(6-methyl-2-naphthamido)benzoic acid;

5-chloro-2-(6-cyclopropyl-2-naphthamido)-4-methoxybenzoic acid;

5-chloro-2-(6-(difluoromethyl)-2-naphthamido)-4-methoxybenzoic acid;

5-chloro-4-methoxy-2-(6-(trifluoromethyl)-2-naphthamido)benzoic acid;

5-chloro-2-(6-(difluoromethoxy)-2-naphthamido)-4-methoxybenzoic acid;

5-chloro-4-methoxy-2-(6-(trifluoromethoxy)-2-naphthamido)benzoic acid;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-methyl-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-cyclopropyl-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6-(trifluoromethoxy)-2- naphthamide;

5-cyano-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)benzoic acid;

5-cyano-2-(7-fluoroquinoline-3-carboxamido)-4-(oxetan-3-yloxy)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(methoxymethyl)benzoic acid;

5-cyano-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxamido)benzoic acid; 8-(6-fluoro-2-naphthamido)-3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic ack 5-(difluoromethoxy)-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid;

5-fluoro-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)benzoic acid;

2-(2-naphthamido)-5-cyano-4-(oxetan-3-yloxy)benzoic acid;

2-chloro-2'-fluoro-5-(6-fluoro-2-naphthamido)-[l, -biphenyl]-4-carboxylic acid; N-(4-cyano-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-7-fluoroquinoline-3- carboxamide;

5-chloro-2-(6-chloro-2-naphthamido)-4-methoxybenzoic acid;

5-cyano-4-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

4- cyano-5-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-(difluoromethoxy)benzoic acid;

7-(2-naphthamido)-2,3 -dihydrobenzo [b] [ 1 ,4] dioxine-6-carboxylic acid;

7-(6-(trifluoromethyl)-2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic 2-(2-naphthamido)-5-cyano-4-methoxybenzoic acid;

5- cyano-4-methoxy-2-(6-(trifluoromethyl)-2-naphthamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-ethoxybenzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(pyridin-4-yl)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(pyridin-3-yl)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-6-methoxynicotinic acid;

5-chloro-6-ethoxy-2-(6-fluoro-2-naphthamido)nicotinic acid;

5-chloro-2-(6-chloro-2-naphthamido)-6-ethoxynicotinic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(pyridine-2-yl)benzoic acid;

2-chloro-5-(6-fluoro-2-naphthamido)isonicotinic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-isopropoxybenzoic acid;

5-chloro-4-cyano-2-(6-fluoro-2-naphthamido)benzoic acid;

5-chloro-2-(6-chloro-2-naphthamido)-4-isopropoxybenzoic acid; 2-(6-chloro-2-naphthamido)-5-fluoro-4-methoxybenzoic acid;

4- chloro-2-(6-chloro-2-naphthamido)-5-cyanobenzoic acid;

6-fluoro-N-(4-fluoro-5-(oxetan-3-yloxy)-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)- 2-naphthamide;

6-fluoro-N-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-2- naphthamide;

2-(6-chloro-2-naphthamido)-5-cyano-4-(cyclopropylmethoxy)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-cyclobutoxybenzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-(methylthio)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-isopropoxybenzoic acid;

N-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-2-naphthamide;

5- chloro-2-(6-chloro-2-naphthamido)-6-methoxynicotinic acid;

5-cyano-4-methoxy-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-(methylsulfinyl)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-(difluoromethoxy)benzoic acid;

N-(4-cyano-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-2- naphthamide; and

2-(6-chloro-2-naphthamido)-5-cyano-4-(dimethylamino)benzoic acid;

or a pharmaceutically acceptable salt, solvate or salt of the solvate thereof.

43. A pharmaceutical composition comprising a compound of any one of Claims 1-42 or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof and a pharmaceutically acceptable carrier.

44. A method for the treatment of fibrosis comprising administering to a patient in need thereof the pharmaceutical composition of Claim 43 or a therapeutically effective amount of a compound of any one of Claims 1-42 or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof.

45. The method of Claim 44 wherein said fibrosis is selected from the group consisting of scleroderma, fibrosis of the lung, fibrosis of the kidney, and fibrosis of the liver.

46. A method for the treatment of fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula Γ:

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

A is -CfR^CfR^-qR^CiR1)-, -S-C(Rla)=C(Rla)-, -C(Rla)=C(Rla)-S- or

X1 is -CH-, -C(halogen)- or -N-;

X2 is -CH- or -N-;

X3 is -N- or -C(R4)-;

each R1 is independently H, halogen, cyano, Ci-6alkyl, C3-6Cycloalkyl, halo-Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy or halo-Ci-6alkoxy, with the proviso that at least two Rx's are H;

each Rla is independently H, Ci-6alkyl or aryl;

R3 is halogen, cyano or OR6;

R4 is H, OR6, S(0)„R6, Ci-6alkyl, halo-Ci-6alkyl, hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR7R8 or cyano; or

R3 and R4 together is -0-CF2-0- or -0-(CH2)p-0-;

R5 is Ci-6alkyl, halo-Ci-6alkyl or C3-6Cycloalkyl; R6 is Ci-ealkyl, halo-Ci-6alkyl, C3-6cycloalkyl-(C0-2alkyl), heterocyclyl or benzyl; R7 and R8 are each independently selected from H and Ci-6alkyl;

n is 0, 1 or 2; and

p is 1, 2 or 3.

Description:
ARYLCARBOXAMIDES AND USES THEREOF

BACKGROUND

FIELD

[0001] Disclosed herein are arylcarboxamide compounds, pharmaceutical compositions containing arylcarboxamides, and methods of treating diseases using arylcarboxamides. In some embodiments the diseases to be treated are fibrotic diseases. In some embodiments the arylcarboxamides modulate the activity or function of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) NOX4.

DESCRIPTION

[0002] The NADPH oxidase (NOX) family is comprised of cellular enzymes that transfer electrons from NADPH to molecular oxygen, thereby producing superoxide anion, as well as reactive oxygen species (ROS). Among the different types of ROS are oxygen-derived small molecules, including the oxygen radicals superoxide (0 2 ·-), hydroxyl (·ΟΗ), peroxyl (R02 » ), and alkoxyl(RO » ) and various nonradicals that are either oxidizing agents themselves and/or can easily be converted into radicals, such as hypochlorous acid (HOC1), ozone (O 3 ), singlet oxygen O2), and most notably, hydrogen peroxide. ROS generation typically begins with the formation of superoxide, which rapidly dismutates to become hydrogen peroxide, either through spontaneous formation or via the action of superoxide dismutase. In addition, there are other routes of ROS generation including: 1) the reaction of superoxide with nitric oxide to form peroxynitrite, 2) peroxidase-mediated formation of hypochlorous acid from hydrogen peroxide, and 3) the iron-catalyzed Fenton reaction which results in the formation of hydroxyl radical (Bedard & Krause, 2007).

[0003] 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 classic NOX isoform. NOX2 contains a heterodimeric membrane- bound flavocytochrome b558 complex, consisting of the catalytic gp91 phox subunit and the regulatory p22 phox subunit located in the membrane. For full activation NOX2 requires the Rho family GTPase, Rac, as well as the regulatory subunits p47 phox , p40 phox and p67 phox , which translocate from the cystosol to the membrane-bound complex following agonist stimulation (Paik et al, 2013). These same organizational features are not shared by all of the NOX family members, such that only NOX1, NOX3 and NOX4 form heterodimers with p22 phox (Nauseef,

2008) . Furthermore, unlike the regulatory subunit dependent NOX1, NOX2 and NOX3 or EF- hand containing NOX5 and DUOX1 and 2, NOX4 displays constitutive activity. Collectively, all NOX's can catalyze the reduction of molecular oxygen to superoxide. However, there are intrinsic differences in their expression, cellular localization, mode of activation and up- and down-stream signaling pathways (Bedard & Krause, 2007).

[0004] In general, ROS are involved in numerous reversible and irreversible regulatory processes that can have both physiological and pathological outcomes. NOX2- derived ROS are an integral component of innate immunity, and play a vital biological role in the killing of pathogens as part of host defense. In contrast, ROS produced by other NOX isoforms can irreversibly destroy or alter the function of numerous molecular targets and are key contributors to cell and tissue damage through oxidative stress.

[0005] In lung tissue, oxidants are continuously generated either by endogenous metabolic reactions, such as mitochondrial respiration, through activation and recruitment of inflammatory cells, or by exogenous sources such as cigarette smoke and airborne pollutants. Based on their large surface area and blood supply, the lungs encounter much higher oxygen tensions relative to other tissues and are more susceptible to ROS-mediated injury, as compared to other organs. NOX-mediated ROS generation has been described for numerous lung cells, including endothelial and smooth muscle cells, and NOX activation is linked to respiratory disorders such as pulmonary hypertension, increased pulmonary vasoconstriction and interstitial lung disease. In particular, recent evidence supports a role for NOX4-derived-ROS generation in pulmonary inflammation, fibroblast activation and collagen accumulation in the setting of lung fibrosis (Thannickal V.J., 2012). NOX4 is upregulated in the lungs of mice following injury and is increased in lung tissue from patients with idiopathic pulmonary fibrosis (IPF). Furthermore, genetic deletion of NOX4 abrogates fibrogenesis in mouse models of lung fibrosis (Hecker et al,

2009) . NOX4 is also linked to vascular remodeling and associated pulmonary hypertension (Barman, 2014).

[0006] In the liver, oxidative stress is a major player in both the initiation and the progression of liver fibrosis, whereby it promotes transformation of hepatic stellate cells (HSC) into myofibroblasts and promotes hepatocyte apoptosis. There is accumulating evidence that NADPH oxidases, which are also integrally involved in hepatic inflammation, are the primary contributors to ROS production in this tissue (Crosas-Molist & Fabregat, 2015). Elevated concentrations of ROS promote cell death whereas sub-lethal concentrations can enhance activation, proliferation and collagen production by HSC (Paik et al, 2013). TGFP, the well- known pro-fibrotic factor, increased HSC activation and NOX4 expression levels and these changes are attenuated by NOX4 knockdown. Deletion of NOX4 in hepatocytes also decreased oxidative stress, lipid peroxidation and liver fibrosis in a mouse model of steatohepatitis and NOX4 has been found in increased levels in patients with nonalcoholic fatty liver disease (NASH) (Bettaieb et al, 2015). Similarly, upregulation of NOX4 was observed in samples from patients with HCV-derived fibrosis (Sancho et al, 2012), further confirming the profibrotic role of NOX-driven oxidative stress in the clinical setting.

[0007] Despite the large amount of evidence for their ability to regulate renal function and pathobiology, the roles for ROS and certain NOX isoforms in the kidney are still somewhat enigmatic. In the setting of hyperglycemia and in response to increased angiotensin II signaling, increased ROS production can negatively impact renal structure and function. Furthermore, via the regulation of sodium resorption and renal hemodynamics, ROS appear to play a key pathological role in blood pressure regulation (Sedeek et al, 2013). ROS have also been implicated in diabetic retinal disorders whereby elevated ROS in the retina can impair metabolism, damage DNA and mitochondrial function, and compromise the electron transport system (Ellis et al, 2000). Notably, antioxidants are able to target multiple aspects of oxidative stress and mitochondrial damage and can ameliorate retinopathy in rat diabetic models (Kowluru & Mishra, 2015). ROS and Nox are also implicated in glomerular diseases (Mao & Huang, 2013). Similar to its role in the lung and liver, NOX4-mediated ROS production also appears to be a causative agent in renal fibrosis. Progressive formation of fibrotic tissue is an end-stage component of kidney disease which ultimately compromises organ function and leads to eventual renal failure. Interestingly, several researchers have proposed a protective capacity for NOX4 in the kidney (Nlandu Khodo et al, 2012; Babelova et al, 2012). However, these studies are limited and lie in direct contradiction to the large body of literature demonstrating that increased Nox activity and ROS production are primary drivers in a diverse array of renal pathological conditions (Jha et al, 2014; Sedeek et al, 2010; Holterman et al, 2015). Thus, ROS derived from NADPH oxidases are linked to disease pathogenesis in multiple organs including the lung, liver, kidneys, heart and eyes (Jiang et ah, 2014). In particular, ROS are believed to be a major driver in tissue damage and the subsequent fibrosis that culminates in end- stage organ failure. By definition, fibrosis is the accumulation of excess fibrous connective tissue in an organ of tissue, leading to dramatic remodeling of tissue architecture and resulting in progressive organ dysfunction and failure (Friedman et ah, 2013). Currently, it is estimated that nearly 45% of all disease-related deaths in industrialized society result from some form of fibrotic disease (Wynn, 2008). Despite this huge unmet medical need there are currently few approved treatments for fibrosis. Therefore, it would be highly beneficial to develop specific NADPH oxidase inhibitors for clinical application in the treatment of fibrotic diseases.

SUMMARY OF THE I VENTION

[0008] The present disclosure provides compounds and pharmaceutical compositions that are useful in the treatment of fibrosis and fibrotic diseases. A method of treatment of fibrosis and fibrotic diseases is also provided.

[0009] In some embodiments a compound is provided having the formula I :

wherein

X 1 is -CH-, -C(halogen)- or -N-;

X 2 is -CH- or -N-;

X 3 is -N- or -C(R 4 )-; each R 1 is independently H, halogen, cyano, Ci- 6 alkyl, C3- 6 Cycloalkyl, halo-Ci- 6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, Ci- 6 alkoxy or halo-Ci- 6 alkoxy, with the proviso that at least two R u s are H;

each R la is independently H, Ci- 6 alkyl or aryl;

halogen, cyano or OR 6 ,

R is H, OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; or

R 3 and R 4 together is -0-CF 2 -0- or -0-(CH 2 ) p -0-;

R 5 is Ci- 6 alkyl, halo-Ci- 6 alkyl or C3- 6 Cycloalkyl;

each R 6 is independently Ci -6 alkyl, C3. 6 cycloalkyl-(Co -2 alkyl), heterocyclyl or benzyl;

R 7 and R 8 are each independently selected from H and Ci- 6 alkyl;

n is 0, 1 or 2; and

p is 1, 2 or 3;

excluding the following compounds:

(B) R 1U is H or OCH 3 : R ia is Br, CI or I and

R 4U is H; or R ia and R 4U are each OCH 3 ; or R ia is OCH 3 and R 4U is 0(CH 2 ) 2 OCH 3 ; or R 3B and R 4B taken to ether is -0-(CH 2 ) 2 -0- or -0-(CH 2 ) 3 -0-,

where R 3U is OCH 3 , Br, CI or I and R 4U is H; or where R and R are each OCH 3 ; or where R is OCH 3 and R is 0(CH 2 ) 2 OCH 3 ; or where R 3C and R 4C taken to ether is -0-(CH 2 ) 2 -0- or -0-(CH 2 ) 3 -0-, and

where R is Br or CI and R is H; or where R 3D and R 4U are each OCH 3 ; or where R 3U is OCH 3 and R 4U is 0(CH 2 ) 2 OCH 3 ; or where R 3U and R 4D taken together is -0-(CH 2 ) 2 -0- or -0-(CH 2 ) 3 -0- .

[0010] In some embodiments of the compound of formula (I), A is -CH=CH- C(R 1 )=CH-*, wherein * indicates attachment to the carbon adjacent to X 1 .

[0011] In some embodiments of the compound of formula (I), X 1 is -N-.

[0012] In some embodiments of the compound of formula (I), X 1 is -CH-.

[0013] In some embodiments of the compound of formula (I), A is -CH=CH- C(R 1 )=CH-*, wherein * indicates attachment to the carbon adjacent to X 1 andX 1 is -N-.

[0014] In some embodiments of the compound of formula (I), A is -CH=CH- C(R 1 )=CH-*, wherein * indicates attachment to the carbon adjacent to X 1 andX 1 is -CH-.

3 4

[0015] In some embodiments of the compound of formula (I), X is -CR -.

[0016] In some embodiments of the compound of formula (I), X 3 is -CR 4 - and X 2 is -

CH-. [0017] In some embodiments of the compound of formula (I), X 3 is -CR 4 - and X 2 is

N-

[0018] In some embodiments of the compound of formula (I), R is CO 2 H,

mbodiments of the compound of formula (I), R is CO 2 H,

[0020] In some embodiments, the compound of formula (I) has the formula la:

(la)

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

R 3 is halogen, cyano, or OR 6 ; and

R 4 is H, OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci. 6 alkoxy-Ci. 6 alkyl, C 2 - 6 alkynyl, C3. 6 cycloalkyl, aryl optionally substituted with 1 -3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 , or cyano.

[0021] In some embodiments of the compound of formula (la), R 4 is OR 6 , S(0) n R 6 , Ci- 6 alkyl, halo-Ci- 6 alkyl, hydroxyl-Ci- 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2 - 6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally

7 8

substituted with 1-3 same or different halogen atoms, halogen, NR R , or cyano.

[0022] In some embodiments of the compound of formula (la), A is -CH=CH- C(R 1 )=CH-*, wherein * indicates attachment to the carbon adjacent to X 1 . [0023] In some embodiments of the compound of formula (la), X 1 is -N-.

[0024] In some embodiments of the compound of formula (la), X 1 is -CH-.

[0025] In some embodiments of the compound of formula (la), A is -CH=CH- C(R 1 )=CH-*, wherein * indicates attachment to the carbon adjacent to X 1 andX 1 is -N-.

[0026] In some embodiments of the compound of formula (la), A is -CH=CH- C(R 1 )=CH-*, wherein * indicates attachment to the carbon adjacent to X 1 andX 1 is -CH-.

[0027] In some embodiments of the compound of formula (la), X 2 is -CH-.

[0028] In some embodiments of the compound of formula (la), X 2 is -N-.

2 of the compound of formula (la), R is CO 2 H,

2 mbodiments of the compound of formula (la), R is CO 2 H,

[0031] In some embodiments, the compound of formula I) has the formula lb:

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

R is halogen, cyano, or OR ;

In some embodiments of the compound of formula (lb), R 4 is H, OR 6 , S(0) n R 6 , Ci- 6 alkyl, halo-Ci- 6 alkyl, hydroxy-Ci- 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C2- 6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen,

7 8

NR R , or cyano; and

each R 6 is independently Ci- 6 alkyl, fluoro-Ci- 6 alkyl, C3- 6 Cycloalkyl,

C3- 6 Cycloalkyl-Co-ialkyl, benzyl or ~' 0 - 2 _

[0032] In some embodiments of the compound of formula (lb), X 1 is -CH-.

[0033] In some embodiments of the compound of formula (lb), R is C0 2 H,

[0034] In some embodiments of the compound of formula (lb), R is halogen or OR .

[0035] In some embodiments of the compound of formula (lb), R 4 is OR 6 , S(0) n R 6 , Ci- 6 alkyl, halo-Ci- 6 alkyl, hydroxyl-Ci- 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 , or cyano.

[0036] In some embodiments of the compound of formula (lb), R 4 is OR 6 , S(0) n R 6 , Ci- 6 alkyl, halo-Ci- 6 alkyl, hydroxyl-Ci- 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkynyl, C3- 6 Cycloalkyl,

7 8

halogen, NR R or cyano.

[0037] In some embodiments of the compound of formula (lb), X is -CH-.

[0038] In some embodiments of the compound of formula (lb), X 2 is -N-.

[0039] In some embodiments of the compound of formula (lb), X 1 and X 2 are each -

CH-.

[0040] In some embodiments of the compound of formula (lb), R 1 is H, F or CI. [0041] In some embodiments of the compound of formula (lb),

R 3 is halogen or OR 6 ;

R 4 is OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C2- 6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 , or cyano; and

each R 6 is independ 6 alkyl, fluoro-Ci- 6 alkyl, C3- 6 Cycloalkyl,

C3- 6 Cycloalkyl-Ci- 6 alkyl, benzyl or

[0042] In some embodiments of the compound of formula (lb),

R 3 is halogen or OR 6 ;

R 4 is OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 , or cyano;

each R 6 is independently Ci- 6 alkyl, fluoro-Ci- 6 alkyl, C3- 6 Cycloalkyl,

C3- 6 Cycloalkyl-Ci- 6 alkyl, benzyl or

and X 2 is -CH-.

[0043] In some embodiments of the compound of formula (lb),

R 1 is H, halogen, Ci- 3 alkyl, fluoro-Ci- 3 alkyl, C3- 6 Cycloalkyl, fluoro-Ci cyano or C 2-3 alkynyl;

R 3 is halogen, cyano, Ci-3alkoxy or fluoro-Ci-3alkoxy;

R 4 is H, OR 6 , Ci -3 alkyl, fluoro-Ci -3 alkyl, S(0)„-Ci -3 alkyl, hydroxy-Ci -3 alkyl, Ci- 3 alkoxy-Ci -3 alkyl, C 2-3 alkynyl, C 3-6 Cycloalkyl, phenyl optionally substituted with 1 -2

7 8

fluorine atoms, pyridyl, halogen, NR R or cyano;

each R 6 is independently Ci -3 alkyl, fluoro-Ci -3 alkyl, C 3-6 Cycloalkyl,

C 3-6 Cycloalkyl-Ci- 2 alkyl, benzyl or .

R 7 and R 8 are each independently selected from H and Ci- 6 alkyl;

n is 0, 1 or 2; and

X 1 and X 2 are independently selected from -CH- and -N-.

[0044] In some embodiments of the compound of formula (lb), R 1 is H or halogen;

R 3 is halogen or cyano;

R 4 is OR 6 , Ci -3 alkyl, fluoro-Ci -3 alkyl, S(0)„-Ci -3 alkyl, hydroxy-Ci -3 alkyl, Ci- 3 alkoxy-Ci -3 alkyl, C 2-3 alkynyl, C 3-6 Cycloalkyl, halogen, NR 7 R 8 or cyano;

6 is Ci -3 alkyl, fluoro-Ci -3 alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-Ci- 2 alkyl, benzyl

R 7 and R 8 are each independently selected from H and Ci_

n is 0, 1 or 2; and

X 1 and X 2 are independently selected from -CH- and -N-.

2

[0045] In some embodiments

[0046] In some embodiment, [0047] In some embodiments,

[0048] In some embodiments, R 2 is

[0049] In some embodiments the compound of formula (I) is selected from the group consisting of:

N-(4-chloro-2-(methylsulfonamido)phenyl)-2-naphthamide;

N-(4-chloro-2-(2H-tetrazol-5-yl)phenyl)-2-naphthamide;

5-chloro-2-(quinoline-3-carboxamido)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(2-naphthamido)-5-chloro-4-fluorobenzoic acid;

2-(2-naphthamido)-5-chloronicotinic acid;

2-(2-naphthamido)-4,5-dichlorobenzoic acid;

5-chloro-2-(7-fluoroquinoline-3-carboxamido)benzoic acid;

2-(6-bromo-2-naphthamido)-5-chlorobenzoic acid;

5-chloro-2-(7-methylquinoline-3-carboxamido)benzoic acid;

2-(2-naphthamido)-4-bromo-5-chlorobenzoic acid;

5-chloro-2-(6-(trifluoromethyl)-2-naphthamido)benzoic acid;

2-(6-bromo-2-naphthamido)-4,5-dichlorobenzoic acid;

5-chloro-4-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(2-naphthamido)-5-chloro-4-methoxybenzoic acid;

2-(benzo[b]thiophene-5-carboxamido)-5-chlorobenzoic acid;

4, 5 -difluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(2-naphthamido)-4,5-difluorobenzoic acid;

2-(2-naphthamido)-5-cyanobenzoic acid;

4,5-dichloro-2-(6-ethyl-2-naphthamido)benzoic acid;

2-(benzo[b]thiophene-5-carboxamido)-5-chloro-4-fluorobenz oic acid;

2-(6-bromo-2-naphthamido)-5-cyanobenzoic acid;

5-bromo-2-(6-fluoro-2-naphthamido)benzoic acid; 5-chloro-2-(6-ethyl-2-naphthamido)-4-methoxybenzoic acid;

5-cyano-2-(6-ethyl-2-naphthamido)benzoic acid;

5-chloro-2-(6-ethyl-2-naphthamido)-4-fluorobenzoic acid;

2-(6-ethyl-2-naphthamido)-4,5-difluorobenzoic acid;

5-chloro-2-(7-bromoquinoline-3 -carboxamido)benzoic acid;

5-chloro-2-(3-methylbenzo[b]thiophene-5-carboxamido)benzo ic 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-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl) -2-naphthamide;

N-(4-chloro-2-(lH-tetrazol-5-yl)phenyl)-7-fluoroquinoline -3-carboxamide;

N-(4-chloro-2-(lH-tetrazol-5-yl)phenyl)-6-fluoro-2-naphth amide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl) -6-fluoro-2-naphthamide;

5-chloro-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid;

N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phe nyl)-2-naphthamide;

5-chloro-4-methoxy-2-(2-phenylbenzo[b]thiophene-5-carboxa mido)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(trifluoromethyl)be nzoic acid;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl) -2-methylbenzo[b]thiophene-5- carboxamide;

5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxamid o)benzoic acid;

N-(4-chloro-5-fluoro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)p henyl)-6-fluoro-2- naphthamide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl )quinoline-3-carboxamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl )-6-fluoro-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl )-6-ethynyl-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl )-6-ethyl-2-naphthamide;

5- fluoro-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid;

4- chloro-5-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

6- (2-naphthamido)benzo[d] [1,3] dioxole-5 -carboxy lie acid;

N-(4,5-difluoro-2-(lH-tetrazol-5-yl)phenyl)-6-fluoro-2-na phthamide;

N-(4,5-difluoro-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)ph enyl)-6-fluoro-2-naphthamide;

5- chloro-2-(6-chloro-2-naphthamido)benzoic acid; 6- fluoro-N-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazo l-l-yl)phenyl)-2- naphthamide;

5-chloro-4-ethyl-2-(6-fluoro-2-naphthamido)benzoic acid;

4- (benzyloxy)-5-chloro-2-(6-fluoro-2-naphthamido)benzoic acid;

5- chloro-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)benzoic acid;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l- yl)phenyl)-6-fluoro-2- naphthamide;

2-(2-naphthamido)-5-(difluoromethoxy)benzoic acid;

2-(6-fluoro-2-naphthamido)-4,5-dimethoxybenzoic acid;

7- (6-fluoro-2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-c arboxylic acid;

5-chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-6-carboxa mido)benzoic acid;

5-cyano-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid;

5-chloro-4-ethynyl-2-(6-fluoro-2-naphthamido)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-((tetrahydro-2H-pyran- 4-yl)oxy)benzoic acid; 5-chloro-4-cyclopropyl-2-(6-fluoro-2-naphthamido)benzoic acid;

N-(4,5-difluoro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl )-6-fluoro-2-naphthamide; 5-chloro-2-(7-fluoroquinoline-3-carboxamido)-4-(oxetan-3-ylo xy)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(hydroxymethyl)benz oic acid;

N-(4-chloro-5-(oxetan-3-yloxy)-2-(5-oxo-4,5-dihydro-lH-te trazol-l-yl)phenyl)-6-fluoro-2- naphthamide;

5- chloro-2-(6-fluoro-2-naphthamido)-4-(2,2,2-trifluoroethoxy)b enzoic acid;

N-(4-chloro-5-methoxy-2-((methylsulfonyl)carbamoyl)phenyl )-6-fluoro-2-naphthamide;

6- chloro-N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phe nyl)-2-naphthamide; 6-(6-chloro-2-naphthamido)-2,2-difluorobenzo [d] [1,3] dioxole-5 -carboxylic acid;

2-(2-naphthamido)-5-chloro-6-methoxynicotinic acid;

2-(2-naphthamido)-5-chloro-6-ethoxynicotinic acid;

N-(4,5-difluoro-2-((methylsulfonyl)carbamoyl)phenyl)-6-fluor o-2-naphthamide;

N-(4-chloro-2-(((difluoromethyl)sulfonyl)carbamoyl)-5-methox yphenyl)-6-fluoro-2- naphthamide;

2-(6-chloro-2-naphthamido)-5-(difluoromethoxy)-4-fluorobenzo ic acid;

5-cyano-2-(6-fluoro-2-naphthamido)benzoic acid; 2-(6-chloro-2-naphthamido)-5-cyanobenzoic acid;

5-cyano-2-(6-fluoro-2-naphthamido)-4-methylbenzoic acid;

5- cyano-2-(6-chloro-2-naphthamido)-4-methylbenzoic acid;

N-(4-(difluoromethoxy)-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl )phenyl)-6-fluoro-2- naphthamide;

6- chloro-N-(4-(difluoromethoxy)-2-(5-oxo-4,5-dihydro-lH-tetraz ol-l-yl)phenyl)-2- naphthamide;

6-chloro-N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetra zol-l-yl)phenyl)-2- naphthamide;

N-(4-chloro-5-ethoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)p henyl)-6-fluoro-2- naphthamide;

6- chloro-N-(4-chloro-5-ethoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol -l-yl)phenyl)-2- naphthamide;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl) phenyl)-6-(trifluoromethyl)- 2-naphthamide;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl) phenyl)-6-methyl-2- naphthamide;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl) phenyl)-6-cyclopropyl-2- naphthamide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6- cyano-2-naphthamide;

2,2-difluoro-6-(6-fluoro-2-naphthamido)benzo[d][l,3]dioxo le-5-carboxylic acid;

2-(2-naphthamido)-5-chloro-4-(methoxymethyl)benzoic acid;

N-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazo l-3-yl)phenyl)-7- fluoroquinoline-3-carboxamide;

N-(4-bromo-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)p henyl)-6-fluoro-2- naphthamide;

N-(4-bromo-5-methoxy-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)p henyl)-6-chloro-2- naphthamide;

N-(4-chloro-2-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl )-6-fluoro-2-naphthamide;

7- (6-chloro-2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-c arboxylic acid;

7-(6-cyano-2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine -6-carboxylic acid; 5-cyano-4-ethoxy-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-methoxybenzoic acid

7- (7-fluoroquinoline-3-carboxamido)-2,3-dihydrobenzo[b][l,4]di oxine-6-carboxylic acid; 5-chloro-4-methoxy-2-(6-methyl-2-naphthamido)benzoic acid;

5-chloro-2-(6-cyclopropyl-2-naphthamido)-4-methoxybenzoic acid;

5-chloro-2-(6-(difluoromethyl)-2-naphthamido)-4-methoxybe nzoic acid;

5-chloro-4-methoxy-2-(6-(trifluoromethyl)-2-naphthamido)b enzoic acid;

5-chloro-2-(6-(difluoromethoxy)-2-naphthamido)-4-methoxyb enzoic acid;

5-chloro-4-methoxy-2-(6-(trifluoromethoxy)-2-naphthamido) benzoic acid;

N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl) -6-methyl-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6- cyclopropyl-2-naphthamide; N-(4-chloro-2-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-6- (trifluoromethoxy)-2- naphthamide;

5-cyano-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)benzoic acid;

5-cyano-2-(7-fluoroquinoline-3-carboxamido)-4-(oxetan-3-y loxy)benzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(methoxymethyl)benz oic acid;

5-cyano-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxam ido)benzoic acid;

8- (6-fluoro-2-naphthamido)-3,4-dihydro-2H-benzo[b][l,4]dioxepi ne-7-carboxylic acid; 5-(difluoromethoxy)-2-(6-fluoro-2-naphthamido)-4-methoxybenz oic acid;

5-fluoro-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)ben zoic acid;

2-(2-naphthamido)-5-cyano-4-(oxetan-3-yloxy)benzoic acid;

2-chloro-2'-fluoro-5-(6-fluoro-2-naphthamido)-[l, -biphenyl]-4-carboxylic acid;

N-(4-cyano-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phen yl)-7-fluoroquinoline-3- carboxamide;

5-chloro-2-(6-chloro-2-naphthamido)-4-methoxybenzoic acid;

5-cyano-4-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

4-cyano-5 -fluoro-2-(6-fluoro-2-naphthamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-(difluoromethoxy)benzoic acid;

7-(2-naphthamido)-2,3-dihydrobenzo[b][l,4]dioxine-6-carbo xylic acid;

7-(6-(trifluoromethyl)-2-naphthamido)-2,3-dihydrobenzo[b] [l,4]dioxine-6-carboxylic acid; 2-(2-naphthamido)-5-cyano-4-methoxybenzoic acid; 5-cyano-4-methoxy-2-(6-(trifluoromethyl)-2-naphthamido)benzo ic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-ethoxybenzoic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(pyridin-4-yl)benzo ic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(pyridin-3-yl)benzo ic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-6-methoxynicotinic acid;

5-chloro-6-ethoxy-2-(6-fluoro-2-naphthamido)nicotinic acid;

5-chloro-2-(6-chloro-2-naphthamido)-6-ethoxynicotinic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-(pyridine-2-yl)benz oic acid;

2-chloro-5-(6-fluoro-2-naphthamido)isonicotinic acid;

5-chloro-2-(6-fluoro-2-naphthamido)-4-isopropoxybenzoic acid;

5-chloro-4-cyano-2-(6-fluoro-2-naphthamido)benzoic acid;

5- chloro-2-(6-chloro-2-naphthamido)-4-isopropoxybenzoic acid;

2-(6-chloro-2-naphthamido)-5-fluoro-4-methoxybenzoic acid;

4- chloro-2-(6-chloro-2-naphthamido)-5-cyanobenzoic acid;

6- fluoro-N-(4-fluoro-5-(oxetan-3-yloxy)-2-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)phenyl)- 2-naphthamide;

6-fluoro-N-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-ox adiazol-3-yl)phenyl)-2- naphthamide;

2-(6-chloro-2-naphthamido)-5-cyano-4-(cyclopropylmethoxy)ben zoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-cyclobutoxybenzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-(methylthio)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-isopropoxybenzoic acid;

N-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3 -yl)phenyl)-2-naphthamide;

5- chloro-2-(6-chloro-2-naphthamido)-6-methoxynicotinic acid;

5-cyano-4-methoxy-2-(5,6,7,8-tetrahydronaphthalene-2-carb oxamido)benzoic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-(methylsulfinyl)benz oic acid;

2-(6-chloro-2-naphthamido)-5-cyano-4-(difluoromethoxy)ben zoic acid;

N-(4-cyano-5-methoxy-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol -3-yl)phenyl)-6-fluoro-2- naphthamide; and

2-(6-chloro-2-naphthamido)-5-cyano-4-(dimethylamino)benzoic acid;

or a pharmaceutically acceptable salt, solvate or salt of the solvate thereof. [0050] In some embodiments, a pharmaceutical composition is provided comprising a compound any of the above embodiments or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof and a pharmaceutically acceptable carrier

[0051] In some embodiments, a method for the treatment of fibrosis is provided comprising administering to a patient in need thereof the above pharmaceutical composition or a therapeutically effective amount of a compound of any one of the above embodiments or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof.

[0052] In some embodiments of the method for the treatment of fibrosis, the fibrosis is selected from the group consisting of scleroderma, fibrosis of the lung, fibrosis of the kidney, and fibrosis of the liver.

[0053] In some embodiments, a method for the treatment of fibrosis is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula Γ :

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

A is -CfR^CfR^-qR^CiR 1 )-, -S-C(R la )=C(R la )-, -C(R la )=C(R la )-S- or

X 1 is -CH-, -C(halogen)- or -N-;

X 2 is -CH- or -N-;

X 3 is -N- or -C(R 4 )-;

each R 1 is independently H, halogen, cyano, Ci- 6 alkyl, C3- 6 Cycloalkyl, halo-Ci- 6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, Ci- 6 alkoxy or halo-Ci- 6 alkoxy, with the proviso that at least two R x 's are H;

each R la is independently H, Ci- 6 alkyl or aryl; R is C0 2 H, -C(0)NHS0 2 R 5 , -NHS0 2 R 5 ,

R 3 is halogen, cyano or OR 6 ;

R 4 is H, OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; or

R 3 and R 4 together is -0-CF 2 -0- or -0-(CH 2 ) p -0-;

R 5 is Ci- 6 alkyl, halo-Ci- 6 alkyl or C3- 6 Cycloalkyl;

R 6 is Ci- 6 alkyl, halo-Ci- 6 alkyl, C3- 6 Cycloalkyl-(Co -2 alkyl), heterocyclyl or benzyl;

R 7 and R 8 are each independently selected from H and Ci- 6 alkyl;

n is 0, 1 or 2; and

p is 1, 2 or 3.

INCORPORATION BY REFERENCE

[0054] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRD7TION OF THE INVENTION

[0055] In one aspect the present disclosure provides compounds having the formula

(I):

(I)

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

X 1 is -CH-, -C(halogen)- or -N-;

X 2 is -CH- or -N-;

X 3 is -N- or -C(R 4 )-;

each R 1 is independently H, halogen, cyano, Ci- 6 alkyl, C3- 6 Cycloalkyl, halo-Ci- 6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, Ci- 6 alkoxy or halo-Ci- 6 alkoxy, with the proviso that at least two R u s are H;

each R la is independently H, Ci- 6 alkyl or aryl;

halogen, cyano or OR

R is H, OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; or

R 3 and R 4 together is -0-CF 2 -0- or -0-(CH 2 ) p -0-;

R 5 is Ci- 6 alkyl, halo-Ci- 6 alkyl or C3- 6 Cycloalkyl;

R 6 is Ci- 6 alkyl, halo-Ci- 6 alkyl, C3- 6 Cycloalkyl-(Co -2 alkyl), heterocyclyl or benzyl; R 7 and R 8 are each independently selected from H and Ci- 6 alkyl;

n is 0, 1 or 2; and

p is 1, 2 or 3;

excluding the following compounds: ( B) where R ia is H or OCH 3 : R ia is Br, CI or I and

R 4U is H; or R ia and R 4U are each OCH 3 ; or R ia is OCH 3 and R 4U is 0(CH 2 ) 2 OCH 3 ; or R 3B and R 4B taken to ether is -0-(CH 2 ) 2 -0- or -0-(CH 2 ) 3 -0-,

where R is Br, CI or I and R is H; or where R 3C and R are each OCH 3 ; or where R is OCH 3 and R is 0(CH 2 ) 2 OCH 3 ; or where R and R 4C taken to ether is -0-(CH 2 ) 2 -0- or -0-(CH 2 ) 3 -0-, and

where R is Br or CI and R is H; or where R 3D and R 4U are each OCH 3 ; or where R iU is OCH 3 and R 4U is 0(CH 2 ) 2 OCH 3 ; or where R iU and R 4D taken together is -0-(CH 2 ) 2 -0- or -0-(CH 2 ) 3 -0- .

[0056] Within this aspect there is a first group wherein A is -CH=CH-C(R 1 )=CH-*, wherein * indicates attachment to the carbon adjacent to X 1 , and all other variables are as defined for formula (I).

[0057] Within this aspect there is a second group wherein X 1 is -N-, and all other variables are as defined for formula (I) or as defined in the first group.

[0058] Within this aspect there is a third group wherein X 1 is -CH-, and all other variables are as defined for formula (I) or as defined in the first group. [0059] Within this aspect there is a fourth group wherein X 3 is -CR 4 -, and all other variables are as defined for formula (I) or as defined in any of the first through third groups.

[0060] Within this aspect there is a fifth group wherein X is -CH-, and all other variables are as defined for formula (I) or as defined in any of the first through fourth groups.

[0061] Within this aspect there is a sixth group wherein X 2 is -N-, and all other variables are as defined for formula (I) or as defined in any of the first through fourth groups.

[0062] Within this aspect there is a seventh group wherein R 2 is C0 2 H,

N or and all other variables are as defined for formula

(I) or as defined in any of the first through sixth groups.

Within this aspect there is an eighth group wherein R is C0 2 H,

or 5 and all other variables are as defined for formula (I) or as defined in any of the first through sixth groups.

[0064] Within this aspect there is a ninth group having the formula (la):

(la)

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

R 3 is halogen, cyano or OR 6 ;

R 4 is H, OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; and all other variables are as defined for formula (I) or as defined in any of the first through eighth groups.

[0065] Within this aspect there is a tenth group wherein R 3 is halogen, cyano or OR 6 ; R 4 is OR 6 , S(0) n R 6 , Ci- 6 alkyl, halo-Ci- 6 alkyl, hydroxy-Ci- 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C2- 6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; and all other variables are as defined for formula (I) or as defined in any of the first through eighth groups.

[0066] Within this aspect there is an eleventh group having the formula (lb):

or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof;

wherein

R 3 is halogen, cyano or OR 6 ;

R 4 is H, OR 6 , S(0) n R 6 , Ci -6 alkyl, halo-C h alky-, hydroxy-Ci -6 alkyl, Ci -6 alkoxy- Ci- 6 alkyl, C2- 6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; and - 6 alkyl, fluoro-Ci- 6 alkyl, C3- 6 Cycloalkyl, C3- 6 Cycloalkyl-Co-ialkyl, benzyl or omer variables are as defined for formula (I) or as defined in any of the second, third, fifth or sixth group.

[0067] Within this eleventh group there is a first subgroup wherein R is C0 2 H, ;; aanndd tthhee ootthheerr vvaarriiaabblleess aarree aass ddeeffiinneedd ffoorr ffoorrmmuullaa ((llbb)).

[0068] Within this eleventh group there is a second subgroup wherein R 3 is halogen or OR 6 ; and the other variables are as defined for formula (lb) or as defined in the first subgroup.

3 1

[0069] Within this eleventh group there is a third subgroup wherein R is cyano; R is hydrogen, halogen or halo-Ci- 3 alkyl; and the other variables are as defined for formula (lb) or as defined in the first subgroup.

[0070] Within this eleventh group there is a fourth subgroup wherein R 4 is OR 6 , S(0) n R 6 , Ci- 6 alkyl, halo-Ci- 6 alkyl, hydroxy-Ci- 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C2- 6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1 -3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; and the other variables are as defined for formula (lb) or as defined in the first through third subgroups.

[0071] Within this eleventh group there is a fifth subgroup wherein R 4 is OR 6 , S(0) n R 6 , Ci -6 alkyl, C2- 6 alkynyl, C3- 6 cycloalkyl, halogen, NR 7 R 8 or cyano; and the other variables are as defined for formula (lb) or as defined in the first through third subgroups.

[0072] Within this eleventh group there is a sixth subgroup wherein X 1 and X 2 are each CH; and the other variables are as defined for formula (lb) or as defined in the first through fifth subgroups.

[0073] Within this eleventh group there is a seventh subgroup wherein R 1 is H, F or CI; and the other variables are as defined for formula (lb) or as defined in the first through sixth subgroups.

[0074] Within this eleventh group there is an eighth subgroup wherein R 3 is halogen or cyano; R 4 is OR 6 , S(0) n R 6 , Ci- 6 alkyl, halo-Ci- 6 alkyl, hydroxy-Ci- 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C2- 6 alkynyl, C3- 6 Cycloalkyl, halogen, NR 7 R 8 or cyano; and the other variables are as defined for formula (lb) or as defined in the first, and sixth through seventh subgroups.

[0075] Within this eleventh group there is a ninth subgroup wherein:

R 1 is H, halogen, Ci- 3 alkyl, fluoro-Ci- 3 alkyl, C3- 6 Cycloalkyl, fluoro-Ci- 3 alkoxy, cyano or C2- 3 alkynyl;

R is halogen, cyano, Ci- 3 alkoxy or fluoro-Ci- 3 alkoxy;

R 4 is H, OR 6 , Ci -3 alkyl, fluoro-Ci -3 alkyl, S(0)„-Ci. 3 alkyl, hydroxy-Ci -3 alkyl, Ci- 3 alkoxy-Ci- 3 alkyl, C 2 - 3 alkynyl, C3- 6 Cycloalkyl, phenyl optionally substituted with 1-2 fluorine atoms, pyridyl, halogen, NR 7 R 8 or cyano;

6 is Ci- 3 alkyl, fluoro-Ci- 3 alkyl, C3- 6 Cycloalkyl, C3- 6 Cycloalkyl-Ci -2 alkyl, benzyl

R 7 and R 8 are each independently selected from H and Ci- 6 alkyl;

n is 0, 1 or 2; and

1 2

X 1 and X z are independently selected from -CH- and -N-.

Within this eleventh group there is a tenth subgroup wherein:

1 is H or halogen;

R is halogen or cyano;

R 4 is OR 6 , Ci -3 alkyl, fluoro-Ci -3 alkyl, S(0)„-Ci. 3 alkyl, hydroxy-Ci -3 alkyl, alkoxy-Ci NR 7 R 8

- 3 alkyl, C 2-3 alkynyl, C3- 6 Cycloalkyl, halogen, or cyano;

R 6 is Ci- 3 alkyl, fluoro-Ci- 3 alkyl, C3- 6 Cycloalkyl, C3- 6 Cycloalkyl-Ci -2 alkyl, benzyl or /0-2

R 7 and R 8 are each independently selected from H and Ci- 6 alkyl; n is 0, 1 or 2; and

1 2

X 1 and X z are independently selected from -CH- and -N-.

1 2

Within this eleventh group there is an eleventh subgroup wherein: R is H; R z is C0 2 H; R 3 is halogen or cyano; R 4 is OR 6 ; R 6 is Ci-3alkyl; and ,Χ 1 and X 2 are -CH-.

[0076] Within this aspect and the groups and subgroups provided above, there is a class wherein R 2 is C0 2 H.

[0077] Within this aspect and the groups and subgroups provided above, there is a

class wherein

[0078] Within this aspect and the groups and subgroups provided above, there is a

H class wherein R 2 is (L N

spect and the groups and subgroups provided above, there is a

Within this aspect and the groups and subgroups provided above, there is a class wherein

R 3 is chloro. Within this aspect and the groups and subgroups provided above, there is a class wherein R is cyano. Within this aspect and the groups and subgroups provided above, there is a class wherein R 6 is methyl.

[0080] In a second aspect the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0081] In a third aspect the present disclosure provides (i) a method for the treatment of fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (Γ) as provided below, or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof; (ii) a compound of formula (Γ) as provided below, or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof for use in the treatment of fibrosis; (iii) the use of a compound of formula (Γ) as provided below, or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof for the manufacture of a medicament for the treatment of fibrosis:

(Γ)

wherein

A is -CfR^CfR^-qR^CiR 1 )-, -S-C(R la )=C(R la )-, -C(R la )=C(R la )-S- or

X 1 is -CH-, -C(halogen)- or -N-;

X 2 is -CH- or -N-;

X 3 is -N- or -C(R 4 )-;

each R 1 is independently H, halogen, cyano, Ci- 6 alkyl, C3- 6 Cycloalkyl, halo-Ci- 6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, Ci- 6 alkoxy or halo-Ci- 6 alkoxy, with the proviso that at least two R x 's are H;

each R la is independently H, Ci- 6 alkyl or aryl;

R 3 is halogen, cyano or OR 6 ;

R 4 is H, OR 6 , S(0)„R 6 , Ci -6 alkyl, halo-Ci -6 alkyl, hydroxy-Ci -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6 Cycloalkyl, aryl optionally substituted with 1-3 same or different halogen atoms, heteroaryl optionally substituted with 1-3 same or different halogen atoms, halogen, NR 7 R 8 or cyano; or

R 3 and R 4 together is -0-CF 2 -0- or -0-(CH 2 ) p -0-;

R 5 is Ci- 6 alkyl, halo-Ci- 6 alkyl or C3- 6 Cycloalkyl;

R 6 is Ci- 6 alkyl, halo-Ci- 6 alkyl, C3- 6 Cycloalkyl-(Co -2 alkyl), heterocyclyl or benzyl; R 7 and R 8 are each independently selected from H and Ci- 6 alkyl;

n is 0, 1 or 2; and

p is 1, 2 or 3.

[0082] Within the third aspect there is a first group wherein said compound of formula (Γ) is a compound of the first aspect or a group, subgroup, class within said first aspect, or a pharmaceutically acceptable salt, solvate or salt of the solvate thereof.

[0083] Within the third aspect and the first group thereof there is a second group wherein said fibrosis is scleroderma, fibrosis of the lung, fibrosis of the liver or fibrosis of the kidney.

[0084] Any of the features of an embodiment, aspect, group, or subgroup is applicable to all embodiments, aspects, groups, or subgroups identified herein. Moreover, any of the features of an embodiment, aspect, group, or subgroup is independently combinable, partly or wholly with other embodiments, aspects, groups, or subgroups described herein in any way, e.g., one, two, or three or more embodiments, aspects, groups, or subgroups may be combinable in whole or in part. Further, any of the features of an embodiment, aspect, group, or subgroup may be made optional to other embodiments, aspects, groups, or subgroups. Any embodiment, aspect, group, or subgroup of a method can comprise another embodiment, aspect, group, or subgroup of a compound, and any embodiment, aspect, group, or subgroup of a compound can be configured to perform a method of another embodiment, aspect, group, or subgroup.

Definitions

[0085] The term "patient" includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.

[0086] The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

[0087] The term "alkyl" refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci- 6 alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any carbon atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert- butyl. [0088] The term "haloalkyl" refers to an alkyl group, in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). "Haloalkyl" also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Any carbon atom can be optionally substituted, e.g., by one or more substituents.

[0089] As referred to herein, the term "alkoxy" refers to a group of formula -O-(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec- butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term "thioalkoxy" refers to a group of formula -S-(alkyl). The terms "haloalkoxy" and "halothioalkoxy" refer to -O-(haloalkyl) and -S-(haloalkyl), respectively. The term "sulfhydryl" refers to -SH.

[0090] The term "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Any ring or chain atom can be optionally substituted e.g., by one or more substituents. Non-limiting examples of "aralkyl" include benzyl, 2-phenylethyl, and 3-phenylpropyl groups.

[0091] The term "alkenyl" refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Any carbon atom can be optionally substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl.

[0092] The term "alkynyl" refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. Any carbon atom can be optionally substituted, e.g., by one or more substituents. Alkynyl groups can include, e.g., ethynyl, propargyl, 1-propynyl, and 2-butynyl.

[0093] The term "heterocycle" or "heterocyclic", as used herein except where noted, represents a stable 4-, 5-, 6- or 7-membered monocyclic- or stable 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered fused bicyclic heterocyclic ring system which comprises at least one non-aromatic (i.e. saturated or partially unsaturated) ring which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and wherein the nitrogen heteroatom may optionally be quaternized. In the case of a "heterocycle" which is a bicyclic group, the second ring may also be a non-aromatic ring which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, as defined above, or the second ring may be a benzene ring, or a "cycloalkyl", or a "cycloalkenyl", as defined immediately below. Examples of such heterocyclic groups include, but are not limited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, thiazoline, thiazolidine, thiomorpholine, and N-oxides thereof.

[0094] The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. Any carbon atom can be optionally substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicycle[2.2.1]heptyl).

[0095] The term "cycloalkenyl" refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Any carbon atom can be optionally substituted e.g., by one or more substituents as defined herein. Cycloalkenyl moieties can include, e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl.

[0096] The term "cycloalkylene", as used herein, refers to a divalent monocyclic cycloalkyl group having the indicated number of ring atoms.

[0097] The term "heterocycloalkylene", as used herein, refers to a divalent monocyclic heterocyclyl group having the indicated number of ring atoms.

[0098] The term "aryl" as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 6 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl. [0099] The term "heteroaryl", as used herein except where noted, represents a stable 5-, 6- or 7-membered monocyclic- or stable 9 or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In the instance where nitrogen is the only heteroatom, there may be four nitrogens. In the case of a "heteroaryl" which is a bicyclic group, the second ring need not be aromatic and need not comprise a heteroatom. Accordingly, "heteroaryl" includes, for example, a stable 5-, 6- or 7-membered monocyclic aromatic ring consisting of carbon atoms and from one to four heteroatoms, as defined immediately above, fused to a benzene ring, or fused to a "heterocycle", a "cycloalkyl", or a "cycloalkenyl", as defined above. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxides thereof.

[0100] The term "acyl", as used herein, refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.

[0101] The terms "treating", "treat", or "treatment" refer generally to controlling, alleviating, ameliorating, slowing the progress of or eliminating a named condition once the condition has been established. The term "prophylaxis" refers generally to preventing or delaying the onset of, or reducing the risk of developing a named condition or of a process that can lead to the condition, or the recurrence of symptoms of a condition.

[0102] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state. Compound Forms and Salts

[0103] The compounds of the present disclosure may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. The compounds of the present disclosure may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration.

[0104] It will also be appreciated that when two or more asymmetric centers are present in the compounds of the present disclosure, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the invention. All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this of the present disclosure are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art. For example, diastereomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.

[0105] The compounds of the present disclosure include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. The compounds of the present disclosure may also be represented in multiple tautomeric forms, in such instances, the compounds of the present disclosure expressly include all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds are expressly included in the present invention.

[0106] The compounds of the present disclosure include the compounds themselves, as well as their salts, solvates, solvates of the salts and their prodrugs, if applicable. Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure (for example, see S. M. Berge et ah, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19). Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the present disclosure are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. When the compounds of the present disclosure contain an acidic group as well as a basic group the compounds of the present disclosure may also form internal salts, and such compounds are within the scope of the invention.

[0107] As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the 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 those derived from inorganic acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0108] When the compound of the present disclosure is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such inorganic acids include hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic, phosphoric, nitric and the like. Suitable organic acids include acetic, propionic, glycolic, stearic, ascorbic, hydroxymaleic, phenylacetic, salicylic, sulfanilic, 2-acetoxybenzoic, benzenesulfonic, benzoic, naphthalenedisulfonic, camphorsulfonic, citric, ethanesulfonic, ethanedisulfonic, oxalic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid, and the like. [0109] When the compound of the present disclosure is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Such salts that may be prepared include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, dicyclohexylamine salt, N-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and the like.

[0110] Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; Journal of Pharmaceutical Science, 66, 2 (1977); and "Pharmaceutical Salts: Properties, Selection, and Use. A Handbook"; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3- 906390-26-8] each of which is incorporated herein by reference in their entireties.

[0111] Solvates in the context of the present disclosure are designated as those forms of the compounds according to the present disclosure which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present disclosure. The formation of solvates is described in greater 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 contents of which is incorporated herein by reference in its entirety. A person of ordinary skill in the art would recognize the solvates of the present disclosure.

[0112] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 18F, 36C1, 82Br, 1231, 1241, 1251, 1291 and 1311. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Due to comparatively easy preparability and detectability, especially compounds labelled with 3H, 14C and/or 18F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. Such modifications of the compounds according to the present disclosure may therefore in some cases also constitute a preferred embodiment of the present disclosure. Isotopic variants of the compounds according to the present disclosure can be prepared by processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the invention.

[0113] In some embodiments, compounds of formula (I) are prepared as prodrugs. Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Examples of prodrugs include C 1-6 alkyl esters of carboxylic acid groups, which, upon administration to a subject, are capable of providing active compounds.

Pharmaceutical Compositions

[0114] The term "composition" as used herein is intended to encompass one or more of the instant compounds combined with the inert ingredient(s) that make up the carrier. The term "pharmaceutical composition" as used herein encompasses any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0115] The present disclosure includes within its scope prodrugs of the compounds of the present disclosure. In general, such prodrugs will be functional derivatives of the compounds of the present disclosure which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present disclosure, the terms "administration of or "administering a" compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, Amsterdam, NL, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of the present disclosure into the biological milieu.

[0116] The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0117] Pharmaceutical compositions of the present disclosure for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0118] These pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. [0119] The pharmaceutical compositions that are injectable formulations can be sterilised, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilising agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0120] Solid dosage forms of the instant pharmaceutical compositions for oral administration include capsules, tablets, 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) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0121] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0122] The solid dosage forms of the instant pharmaceutical compositions of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding pharmaceutical compositions which can be used include polymeric substances and waxes.

[0123] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0124] Liquid dosage forms of the instant pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0125] Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring, and perfuming agents.

[0126] Suspensions of the instant compounds, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0127] Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0128] Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.

Uses

[0129] In certain embodiments, compounds of the present disclosure may be used to treat a disease or condition associated with fibrosis. In some embodiments, compounds of the present disclosure may be used to treat a disease or condition, whether or not associated with fibrosis, selected from scleroderma, lung diseases and conditions, such as pulmonary fibrosis including idiopathic pulmonary fibrosis (IPF), interstitial lung disease, idiopathic interstitial lung disease, and pulmonary hypertension; heart diseases and conditions, such as heart failure due to ischaemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and hypertension; liver diseases and conditions, such as cirrhosis of the liver and NASH; kidney diseases and conditions, such as progressive kidney disease glomerulonephritis, glomerular disease, and diabetic nephropathy; eye diseases and conditions 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.

[0130] In one aspect the present disclosure disclosed herein is directed to compounds of formula (I) which are useful in the treatment of fibrotic diseases of the skin, lung, liver, kidney, heart, musculature and eyes. In another aspect, the present disclosure is directed to a method of preventing the onset of and/or recurrence of said fibrotic diseases. The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof. The present disclosure is also directed to methods of treating fibrotic diseases of the skin, lung, liver, kidney, heart, musculature and eyes comprising administration of a therapeutically effective amount of a compound of formula (I). The methods include administering to the subject an effective amount of a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to the patient. In another aspect, the use of a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein in the preparation of, or for use as, a medicament for the treatment or prevention of one or more diseases, disorders, or conditions caused by, or associated with, fibrosis.

Administration

[0131] The compounds and pharmaceutical compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., 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, from about 1 to about 10 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et ah, Cancer Chemother. Rep. 50, 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the pharmaceutical compositions are administered by oral administration or by injection. The methods herein contemplate administration of an effective amount of compound or pharmaceutical composition comprising one or more compounds to achieve the desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

[0132] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, and the judgment of the treating physician.

[0133] Dosage forms include from about 0.05 milligrams to about 2,000 milligrams (e.g., from about 0.1 milligrams to about 1,000 milligrams, from about 0.1 milligrams to about 500 milligrams, from about 0.1 milligrams to about 250 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams, or from about 0.1 milligrams to about 25 milligrams) of a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.

[0134] Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, pharmaceutical composition and mode of administration, without being toxic to the patient. It may therefore be necessary where appropriate to deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the patient, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day.

[0135] In another aspect the compounds or pharmaceutical compositions of the present disclosure may be co-administered with one or more additional anti-fibrotic agents, and/or one or more agents used to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the fibrotic disease state. The particular additional agents may be used in the therapy for fibrosis of specific organ(s). For example, for pulmonary fibrosis such agents may include, but are not limited to corticosteroids such as prednisone; immunosuppressants such as cyclophosphamide, azathioprine, methotrexate and cyclosporine; mycophenolate mofetil; N- acetylcysteine; pirfenidone; nintedanib, and the like. Other agents that may be used in combination with a compound of formula (I) for fibrotic disease state such as diabetic nephropathy, idipathic pulmonary fibrosis, myelofibrosis, include another NOX inhibitor such as GKT137831 (Genkyotex, S.A., Switzerland); galectin-3 inhibitor such as TD-139 (Galecto Biotech, Denmark); LPA1 receptor antagonist such as BMS-986020 (Bristol-Myers Squibb, New York, USA); recombinant human PTX-2 such as PRM-151(Promedior, Massachusetts, USA); and antibodies targeting IL-3 (such as lebrikizumab (Genentech, California, USA) and tralokinumab (AstraZeneca, UK), LOXL2 (such as simtuzumab (Gilead Sciences, California, USA)), CTGF (such as FG-3019 (FibroGen, California, USA), lntegnn ανβό (such as STX-100, Biogen, Massachusetts, USA), and IL-3/IL-4 (such as SARI 56597 (Sanofi, France)).

[0136] In certain embodiments, the additional agents may be administered separately (e.g., sequentially; on different overlapping schedules), as part of a multiple dose regimen, from the compounds of the present disclosure (e.g., one or more compounds of formula (I) and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof). In other embodiments, these agents may be part of a single dosage form, mixed together with the compounds of the present disclosure in a single pharmaceutical composition. In still another embodiment, these agents can be given as a separate dose that is administered at about the same time as that of one or more compounds of formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof) are administered (e.g., simultaneously with the administration of one or more compounds of formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof)). When the pharmaceutical compositions of the present disclosure include a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

[0137] The pharmaceutical compositions of the present disclosure may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

[0138] The pharmaceutical compositions of the present disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase and then combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

BIOLOGICAL FUNCTION

Materials

[0139] DMEM (Dulbecco's modified Eagle's medium), fetal calf serum, blasticidin, neomycin (G418, geneticin), tetracycline, accutase and Amplex Red were purchased from Invitrogen (Carlsbad, CA). TGFpi was purchased from R &D Systems (Minneapolis, MN). Generation of stable cell lines

[0140] A NOX4-expressing cell line was generated based on a slight modification of previously described methods (Serrander, 2007). Full-length human NOX4 cDNA vector (Accession: BC040105; Clone ID: 5590269) was purchased from Dharmacon (Lafayette, CO). The NOX4 gene was cloned into a pcDNA4/TO vector (Invitrogen). HEK-293 (human embryonic kidney) cells overexpressing a tetracycline receptor (T-REx™; Invitrogen) were transfected with the NOX4-containing tet-on (TO) vector and positive clones were selected with neomycin. HEK-293 cells stably expressing NOX4 and were cultured in growth media containing DMEM supplemented with 10% fetal calf serum and 100 units/ml penicillin and 100 μg/ml streptomycin, and the selecting antibiotics blasticidin (5 μg/ml) and Zeocin (200 μg/ml), at 37°C in air with 5% C0 2 . NOX4 expression was induced by adding 1 μg/mL tetracycline and non-induced cells (-tetracycline) served as a negative control.

Cell-Based H assays

[0141] One day prior to assay initiation, NOX4 HEK cells were plated in a 96-well plate (Corning™ Costar™ #3603) at 20,000 cells/well in 0.1 mL of cell culture media with or without tetracycline at ^g/ml. Twenty four hours later, cells were washed with PBS and NOX4 overexpressing cells were pre-incubated with increasing concentrations (30 pM - 30 μΜ) of inhibitor compound for 3 hr. NOX4 enzyme activity was then determined by fluorescence using the H2O2- selective probe, NBzF (Abo, 2011). Fluorescence measurements were conducted on a FlexStation 3 Multi-Mode Microplate Reader (Molecular Devices, LLC, Sunnyvale, CA, USA). Fluorescence was measured at 2 different time points and the rate of enzyme activity was calculated (RFU/min).

Membrane Based H¾Q¾ assays

[0142] To prepare membranes, human NOX4 was induced with tetracycline (1 μg/mL) over a 24 hr period and cells were harvested using accutase. Cells were re-suspended in an equal volume of growth media to inactivate the accutase enzyme and then the cells were pelleted by centrifugation at 1450 x g for 10 min at 4 °C. The media was aspirated and the cells were lysed in fractionation buffer (IX PBS, 250 mM sucrose, 1 mM EDTA) by sonication (four, 10 sec pulses at power 10 using an XL-2000 series sonicator (Qsonica, LLC, Newtown, CT). The lysate was kept on ice for 20 minutes and then the nuclear fraction was pelleted by centrifugation at 800 x g for 10 minutes. The supernatant was removed into a fresh collection tube and sonicated again as described above. The nuclear pellet was discarded. The supernatant was then centrifuged at 20,000 x g for 10 min at 4 °C to pellet the mitochondrial fraction. The supernatant was removed into a fresh collection tube and the mitochondrial pellet was discarded. To obtain the membrane fraction, the supernatant was subjected to ultracentrifugation (100,000 x g) for 1 hour at 4 °C. The remaining pellet, consisting of the membrane fraction, was re- suspended in fractionation buffer containing 20% glycerol and the protein concentration was determined using the BioRad protein determination kit with BSA as a standard. ROS activity was then determined using the Amplex Red method. To do this, membranes were diluted in PBS containing 4 μΜ FAD to obtain a 50 μg/ml assay concentration. Forty-five microliters of this membrane stock were added to each well of a 96 well plate. DMSO stocks of the NOX4 inhibitor compounds were diluted in buffer (PBS) at a lOx concentration. Ten microliters of vehicle (0.1% DMSO/PBS) or NOX4 Inhibitor compounds were then added to the wells and allowed to pre- incubate with NOX4-overexpressing membranes for 30 min at room temperature. Following drug incubation, 10 μL of 30 μΜ cytochrome C was added to reduce the Amplex Red background. Amplex Red solution (4X) was formulated according to manufacturer's recommendations and 25 μL of the Amplex Red solution was added to each well. The reaction was initiated by adding 10 μL of 500 μΜ NADPH to yield 50 μΜ /well final concentration and the rate of enzyme activity was determined according to manufacturer's recommendations.

In vivo Pharmacodynamic assay

[0143] Female C57BL/6 mice (20-25g, obtained from Harlan Laboratory, Livermore, CA) were housed 4 per cage, given free access to food and water and allowed to acclimate for at least 7 days prior to test initiation. After the habituation phase, mice were lightly anesthetized with isoflurane (3.0-3.5% in 100% 0 2 ) and shaved in the upper dorsal region. A 3.0 μg/mL solution of TGFB was prepared in sterile filtered PBS and 0.1 mL of this solution (300 ng TGFB/site) was administered subcutaneously to each shaved region using a modification of previous methods (Ikawa, 2008). This procedure was repeated daily over a period of 3 days. Test compound or vehicle was delivered orally (PO), once or twice daily, beginning on day 0. On day 4 of the study, all animals were sacrificed using C0 2 and an 8 mm tissue biopsy was taken for subsequent PCR analysis of the drug effects on TGF-stimulated gene expression. Blood was also collected via cardiac puncture into EDTA tubes for analysis of drug levels.

[0144] Data for representative compounds in the cell-based and membrane-based assays described above are reported in the table below. In this table, the Example Nos. correspond to those for the Example Compounds described herein below.

Example

NOX4 Membrane IC 50

Compound NOX4 Cell : 50 (μΜ)

(μΜ)

No.

22 0.016 0.006

23 0.070 0.028

24 0.190 0.170

25 0.090 0.210

26 0.120 0.150

27 0.320 0.190

28 0.340 0.062

29 0.330 0.098

30 0.170 0.120

31 1.760 0.750

32 0.520 0.140

33 12.200 0.200

34 0.180 0.056

35 0.120 0.056

36 0.009 0.007

37 0.150 0.043

38 1.360 0.150

39 0.430 0.290

40 0.960 0.480

41 0.018 0.093

42 0.150 0.120

43 0.530 0.190

44 0.080 0.011

45 0.080 0.054

46 0.310 0.490

47 0.030 0.011

48 0.050 0.018 Example

NOX4 Membrane IC 50

Compound NOX4 Cell : 50 (μΜ)

(μΜ)

No.

49 0.770 0.520

50 0.350 0.140

51 0.070 0.008

52 0.010 0.017

53 0.650 0.430

54 0.020 0.020

55 1.700 0.240

56 0.080 0.046

57 0.210 0.047

58 0.790 0.290

59 0.990 0.150

60 0.170 0.024

61 0.060 0.053

62 0.006 0.001

63 0.050 0.013

64 0.290 0.220

65 0.040 0.032

66 0.640 0.078

67 1.060 0.200

68 0.030 0.010

69 0.800 0.190

70 0.060 0.059

71 0.050 0.005

72 0.070 0.010

73 0.120 0.086

74 0.090 0.069

75 0.400 0.120 Example

NOX4 Membrane IC 50

Compound NOX4 Cell : 50 (μΜ)

(μΜ)

No.

76 0.280 0.020

77 0.100 0.016

78 0.440 0.280

79 0.021 0.007

80 0.010 0.006

81 0.005 0.006

82 0.004 0.004

83 0.350 0.154

84 0.140 0.043

85 0.130 0.049

86 >30 0.520

87 >30 0.390

88 0.060 0.920

89 0.650 0.400

90 0.330 0.790

91 0.340 0.060

92 0.170 0.054

93 1.090 0.200

94 0.140 0.026

95 0.630 0.086

96 0.050 0.078

97 >30 0.750

98 0.060 0.026

99 0.550 0.840

100 0.020 0.010

101 0.004 0.002

102 0.650 0.240 Example

NOX4 Membrane IC 50

Compound NOX4 Cell : 50 (μΜ)

(μΜ)

No.

103 0.030 0.095

104 0.080 0.240

105 0.042 0.167

106 0.030 0.078

107 0.050 0.140

108 0.050 0.094

109 0.390 0.590

110 >30 0.660

111 >30 0.850

112 0.040 0.038

113 0.290 0.340

114 0.060 0.038

115 0.020 0.010

116 >30 0.650

117 0.110 0.026

118 0.170 0.074

119 0.220 0.071

120 >30 0.500

121 >30 0.032

122 0.006 0.016

123 0.011 0.004

124 0.140 0.120

125 0.044 0.034

126 >30 0.648

127 >30 0.650

128 0.010 0.005

129 0.038 0.022 Example

NOX4 Membrane IC 50

Compound NOX4 Cell : 50 (μΜ)

(μΜ)

No.

130 0.010 0.013

131 1.580 0.980

132 0.320 0.300

133 0.020 0.013

134 0.040 0.023

135 0.020 0.017

136 0.260 0.160

137 0.160 0.130

138 1.160 0.380

139 0.010 0.005

140 0.590 0.180

141 0.007 0.012

142 0.010 0.007

143 0.160 0.046

144 0.017 0.005

145 0.050 0.061

146 0.060 0.059

147 0.008 0.007

148 0.158 0.090

149 0.034 0.024

150 0.007 0.011

151 0.040 0.024

152 0.040 0.024

153 0.010 0.035

154 0.006 0.001

155 0.02 0.016 Abbreviations

Alkyl: Me=methyl; Et=ethyl; Pr=propyl; i-Pr=isopropyl; n-Bu=n-butyl; t-Bu=tert-butyl Synthesis

[0145] The starting materials used for the synthesis are either synthesized using methods known in the chemical art, or obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific and the like. General methods for the preparation of compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the structures as provided herein. In the experiments, instruments used include the Shimadzu LCMS-2020 system, and the Shimadzu Prominence HPLC system (Shimadzu, Columbia, Maryland)

[0146] In some embodiments, compounds described herein are prepared as outlined in the following general synthetic schemes. In Scheme 1 an anthranilate \ (as well as heteroaryl derivatives thereof) is condensed with (hetero)aroyl chloride 2 in the presence of a base such as triethylamine or pyridine to provide the amide ester 3. Typical ester hydrolysis conditions (e.g. lithium hydroxide monohydrate, water, THF) provides the compound I(i), which upon treatment with a sulfonamide in the presence of a coupling agent such as CDI, provides the corresponding N-acylsulfonamide I(ii).

[0147] The starting (hetero)arylamines for compounds I(iii) - I(v) may be prepared using general methods shown in Schemes 2 and 3. An amino-substituted (hetero)arylcarbonitrile 4 provides the corresponding 5-tetrazolyl (hetero)arylamine 5 upon treatment with sodium azide and ammonium chloride, and the corresponding 1 ,2,4-oxadiazolone substituted (hetero)arylamine 6 upon treatment with hydroxylamine in the presence of a base (such as sodium methoxide), followed by treatment with diethylcarbonate. The tetrazolone substituted (hetero)arylamine II can be prepared from nitro(hetero)arylamine 8 using di- or triphosgene, followed by trimethylsilylazide and heat to provide nitro compound K ) , which upon hydrogenation in the presence of Raney Ni provides the amine compound 1_L Alternatively, nitro substituted compound K ) may be prepared from nitro (hetero)arylcarboxylic acid 9 by treatment with oxalyl chloride, followed by aluminum chloride and sodium azide. The amines 5, 6, and ϋ are acylated under typical amide formation conditions using an acid chloride 2 or, where appropriate, an acid 7 in the presence of a coupling agent such as HATU, to give the corresponding compounds I(iii), I(iv) and I(v). [0148] In Scheme 4, the dichloro acid 12 is converted to the corresponding ether acid

13 using an appropriate alcohol and a base. The acid 13 is converted to an ester, and this halide

14 is coupled with the amide 15 using Xantphos/Pd-catalytic conditions to yield the amide 16, followed by chlorination with NCS and subsequent ester hydrolysis to afford compound Ki'Y

GENERAL SYNTHETIC SCHEME FOR EXEMPLARY COMPOUNDS

Scheme 1

Scheme 3 heme 4

Preparation of Intermediates

Intermediate 1. 6-Chloro-2-naphthoic acid

[0149] 6-Bromo-2-naphthoic acid (9.00 g, 35.85 mmol) and DMF (140 mL) were combined, stirred, and degassed with subsurface N 2 for 10 minutes before adding CuCl (35.49 g, 358.50 mmol) and Cul (6.96 g, 36.57 mmol). The reaction vessel was wrapped in aluminum foil and refluxed for 5 h under a nitrogen atmosphere. The mixture was allowed to cool to 60 °C then filtered through celite. The filtrate was diluted with EtOAc and 1 M HCl. The organic phases were washed once more with 1 M HCl, water (2X) and concentrated in vacuo. The resulting crude solid was suspended in acetonitrile, stirred for 1 hr, and filtered to afford 6-chloro-2-naphthoic acid as a white solid. Intermediate 2. Methyl 2-amino-5-cvano-4-methoxybenzoate

[0150] Step 1 : 2-Amino-5-cyano-4-fluorobenzoic acid. To a solution of 2-amino-5- bromo-4-fluorobenzoic acid (8.33 g, 35.6 mmol) in N-methylpyrrolidinone (22 niL) was added CuCN (3.5 g, 39.2 mmol) and heated to 205 °C in a sealed vessel for 6 hrs. After cooling, the mixture was partitioned between EtOAc and IN HCl, stirred vigorously for 1 hr, the organic phase separated, washed with water, dried (MgS0 4 ), filtered and evaporated in vacuo. Trituration from DCM afforded crude 2-amino-5-cyano-4-fluorobenzoic acid, which was used without further purification.

[0151] Step 2: 2-Amino-5-cyano-4-methoxybenzoic acid. To a MeOH solution (150 mL) of 2-amino-5-cyano-4-fluorobenzoic acid (12.0 g, 66.6 mmol) was added CS2CO3 (65 g, 199 mmol) and the reaction mixture heated at 80 °C in a sealed vessel for 16 hrs. The suspension was filtered and the residue washed with MeOH. The combined organic phase was evaporated to half volume and slowly neutralized with IN HCl until pH ~ 4. The resulting precipitate was filtered, washed with water and dried in vacuo. The isolated solid was taken up in acetone and filtered to remove any remaining inorganic solids, and evaporated to yield 11.7 g of 2-amino-5-cyano-4- methoxybenzoic acid as an off-white solid.

[0152] Step 3: Methyl 2-amino-5-cyano-4-methoxybenzoate. To a cooled solution of 2-amino-5-cyano-4-methoxybenzoic acid (11.7 g, 60.9 mmol) and K2CO3 in DMF (75 mL) was slowly added iodomethane (3.79 mL, 60.9 mmol). After complete addition, the reaction was stirred at ambient temperature for 16 hrs, quenched upon addition of sat'd. aq. NH 4 C1 solution (100 mL) and water (100 mL) and stirred for 15 minutes. The resulting precipitate was filtered, washed with water and dried in vacuo to furnish 9 g of the title material as a tan solid.

Intermediate 3. l-(2-Amino-5-chlorophenylMH-tetrazol-5(4H)-one

[0153] Step 1 : l-(5-Chloro-2-nitrophenyl)-lH-tetrazol-5(4H)-one. 4-Chloro-2- isocyanato-l-nitro-benzene (1.50 g, 7.55 mmol) and trimethylsilylazide (1.99 ml, 15.1 mmol) were heated in a sealed vial at 95 °C for 16 hrs. After cooling, the resulting solid was stirred vigorously in MeOH (10 mL) for 30 minutes and then filtered. The filtrate was collected and evaporated to afford the crude product which was purified via trituration from DCM. Yield = 1.5 g (82%).

[0154] Step 2: l-(2-Amino-5-chlorophenyl)-lH-tetrazol-5(4H)-one. To l-(5-chloro-2- nitrophenyl)-lH-tetrazol-5(4H)-one (500 mg, 2.07 mmol) in THF (10 mL) was added a slurry of Raney Nickel (~ 0.3 mL) and the suspension stirred under hydrogen gas (1 atm) for 24 hrs. The suspension was filtered through celite and the solvent evaporated to afford the desired aniline which was used without further purification.

Intermediate 4. 3-(2- Amino-5-chlorophenyi)- 1 ,2,4-oxadiazol-5( H)-one

[0155] Step 1 : 2-Amino-5-chloro-N'-hydroxybenzimidamide. 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) was added sodium methoxide (25% wt. soln; 9 mL) and the mixture heated to reflux for 16 hrs. After cooling, 3M NaOH solution was added (75 mL) and the volatiles removed in vacuo. The remaining aqueous phase was washed with DCM, separated and then adjusted to pH~4 by the addition of IN HC1 solution. Filtration and washing of the subsequent precipitate with water gave the N-hydroxybenzimidamide as a colorless solid used without further purification.

[0156] Step 2: 3-(2-Amino-5-chlorophenyl)-l,2,4-oxadiazol-5(4H)-one. 2-Amino-5- chloro-N'-hydroxybenzimidamide (2.03 g, 10.9 mmol) was dissolved in a mixture of EtOH (50 mL) and sodium methoxide (25% wt. soln.; 5 mL) to which was added diethyl carbonate (5.7 mL, 47 mmol) and the mixture heated to reflux for 16 hrs. After cooling, the solution was evaporated to dryness, the resulting solid dissolved in water (200 mL) and acidified with cone. HCl to pH~3. The precipitate afforded was filtered, washed with water and dried in vacuo to yield the oxadiazolone which was used without further purification.

Intermediate 5. 6-Fluoro-2-naphthoyl chloride

[0157] To a solution of 6-fluoro-2-naphthoic acid (250 mg, 1.31 mmol) in DCM (10 mL) was added DMF (-10 μΐ.) followed by slow addition of oxalyl chloride (300 μΐ ^ , 3.5 mmol). After stirring for 1 hr, the solvent was removed in vacuo and the resulting acid chloride used without further analysis or purification.

Example 1 ; iV-(4-Chloro-2-(methylsulfonamido)phenvn-2-naphthamide

[0158] Step 1 : N-(2-amino-5-chlorophenyl)methanesulfonamide. N-(5-Chloro-2- nitrophenyl)methanesulfonamide (0.80 g, 3.20 mmol), acetic acid (1.10 mL, 19.23 mmol) and methanol (50 mL) were combined and stirred at 0 °C followed by addition of powdered 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 hrs. The reaction was filtered through celite and the filtrate was evaporated to dryness. The residue was diluted with EtOAc and a saturated aq. solution of NaHCC , the organic phases separated, washed with water (2X), brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo. The resulting crude solid containing N-(2-amino-5- chlorophenyl)methanesulfonamide was used without further purification.

[0159] Step 2: The title compound was prepared in an analogous manner to Example 2, Step 2 using 2-naphthoyl chloride, TEA, and THF with N-(2-amino-5- chlorophenyl)methanesulfonamide. LC-MS: 375 (M+H) + .

[0160] Step 1. 4-Chloro-2-(2H-tetrazol-5-yl)aniline. To a solution of 2-amino-5-chlorobenzonitrile (1.0 g, 6.55 mmol) in DMF (6 mL) was added sodium azide (639 mg, 9.83 mmol) and ammonium chloride (425 mg, 7.94 mmol). The resulting mixture was heated in a re-sealable vial at 100 °C for 16 hrs. After completion of the reaction as determined by LC-MS, the mixture was cooled and IN HC1 was added followed by water to afford a precipitate. Filtration and drying in vacuo afforded the intermediate tetrazole which was used without further purification or analysis.

[0161] Step 2. To a solution of the previously synthesized tetrazole (500 mg, 2.15 mmol) in THF (15 mL) was added Et3N (1.5 mL, 10.7 mmol) followed by 2-naphthoyl chloride (410 mg, 2.15 mmol). The resulting mixture was stirred vigorously under nitrogen for 16 hrs, diluted with EtOAc and the combined organic phase washed with IN HC1 and water, dried (MgS0 4 ) filtered and evaporated in vacuo. The resulting solid was purified by trituration from DCM/Hexanes to afford the title compound. LC-MS: 350 (M+H) + .

Example 3. 5-Chloro-2-(quinoline-3-carboxamido)benzoic acid

[0162] Step 1. Methyl 5-chloro-2-(quinoline-3-carboxamido)benzoate. To a solution of quinoline-3-carboxylic acid (300 mg, 1.73 mmol) in DCM (15 mL) was added DMF (cat. ~ 10iL) and oxalyl chloride (-300 iL, 3.5 mmol; 2 eq.). After stirring at ambient temperature for 2 hrs, the solvent was removed in vacuo. To the isolated acid chloride in THF (8 mL) was added a solution of methyl 2-amino-5-chlorobenzoate (321 mg, 1.73 mmol) in pyridine (2 rriL). The resulting mixture was stirred for 16 hrs, evaporated to dryness and the solids stirred in a mixture of IN HC1 (10 mL) and THF (10 rriL) to yield a white precipitate. Filtration of the precipitate and washing with water yielded the crude intermediate ester which was purified by trituration from a DCM/Hexanes mixture.

[0163] Step 2. 5-Chloro-2-(quinoline-3-carboxamido)benzoic acid. The isolated methyl 5-chloro-2-(quinoline-3-carboxamido)benzoate was suspended in a mixture of/7-dioxane (7 mL), water (2 mL) and MeOH (2 mL) to which was added LiOH H 2 0 (125 mg, 3 mmol), and the reaction mixture stirred at ambient temperature until LC-MS analysis confirmed complete ester hydrolysis. Addition of IN HC1 to the reaction mixture and filtration of the precipitate afforded the title compound as a white solid. LC-MS: 327 (M+H) + .

Example 4. 5-Chloro-2-(6-fluoro-2-naphthamido)benzoic acid

[0164] The title compound was prepared in an analogous manner to that described for Example 3 using 6-fluoro-2-naphthoyl chloride (Intermediate 5). LC-MS: 342 (M-H) " .

Example 5. 2-(2-Naphthamido)-5-chloro-4-fluorobenzoic acid

[0165] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-chloro-4-fluorobenzoate and 2-naphthoyl chloride followed by typical ester hydrolysis conditions. LC-MS: 342 (M-H) " . Example 6; 2-(2-Naphthamido)-5-chloronicotinic acid

[0166] The title compound was prepared in an analogous manner to Example 3 using 2-naphthoic acid and TEA as base with methyl 2-amino-5-chloronicotinate followed by typical ester hydrolysis conditions. LC-MS: 325 (M-H) " .

Example 7; 2-(2-Naphthamido)-4,5-dichlorobenzoic acid

[0167] To a solution of 2-amino-4,5-dichlorobenzoic acid (103 mg, 0.5 mmol, 1 eq) and 2-naphthoyl chloride (123 mg, 0.5 mmol, 1 eq) in dioxane (2 mL) was added triethylamine (0.2 mL, 1.5 mmol, 3 eq). After stirring for 1 hr the solvent was removed in vacuo and the residue purified on a reverse phase C-18 column eluting with water, 0.1% formic acid -> MeCN, 0.1% formic acid to afford the title compound. LC-MS: 358 (M-H) " .

Example 8; 5-Chloro-2-(7-fluoroquinoline-3-carboxamido)benzoic acid

[0168] The title compound was prepared in an analogous manner to Example 3 using 7-fluoroquinoline-3-carboxylic acid and DCM as solvent with methyl 2-amino- 5 -chlorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 345 (M+H) + .

Example 9; 2-(6-Bromo-2-naphthamido)-5-chlorobenzoic acid

[0169] The title compound was prepared in an analogous manner to Example 7 using 6-bromo-2-naphthoyl chloride. LC-MS: 402 (M-H) " .

Example 10; 5-Chloro-2-(7-methylquinoline-3-carboxamido)benzoic acid

[0170] The title compound was prepared in an analogous manner to Example 3 using 7-methylquinoline-3-carboxylic acid, TEA as base and DCM as solvent with methyl 2-amino-5- chlorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 339 (M-H) " .

Example 11; 2-(2-Naphthamido)-4-bromo-5-chlorobenzoic acid

[0171] The title compound was prepared in an analogous manner to Example 3 using 2-naphthoyl chloride and TEA as base with 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-naphthamido)benzoic acid

[0172] Step 1 : Methyl 6-(trifluoromethyl)-2-naphthoate. 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 mL, 7.28 mmol) and DMF (30 mL) were combined and stirred under a CO atmosphere at 90 °C for 72 hrs. The reaction was cooled to rt and diluted with EtOAc and brine. The organics were washed with water (3X), brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo. The residue, containing methyl 6-(trifluoromethyl)- 2-naphthoate was used without further purification.

[0173] Step 2: 6-(Trifluoromethyl)-2-naphthoic acid. To a solution of methyl 6- (trifluoromethyl)-2-naphthoate (0.85 g, 3.34 mmol) in THF (23 mL) and MeOH (23 mL) was added 1M aq. LiOH (23.41 mL, 23.41 mmol). The resulting mixture was stirred at rt for 16 hrs. The solvents were evaporated and the residue diluted with EtOAc and aq. 1M HCl. The organic layer was extracted with water (2X), concentrated in vacuo, and co-evaporated several times with EtOAc. The resulting solid containing 6-(trifluoromethyl)-2-naphthoic acid was used directly in the next step.

[0174] Step 3: The title compound was prepared in an analogous manner to Example 3 using 6-(trifluoromethyl)-2-naphthoic acid and DCM as solvent with methyl 2-amino-5- chlorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 392 (M-H) " . Example 13; 2-(6-Bromo-2-naphthamido)-4,5-dichlorobenzoic acid

[0175] The title compound was prepared in an analogous manner to Example 7 using 6-bromo-2-naphthoyl chloride. LC-MS: 436 (M-H) " .

Example 14. 5-Chloro-4-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid

[0176] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-chloro-4-fluorobenzoate and 6-fluoro-2-naphthoyl chloride (Intermediate 5) followed by typical ester hydrolysis conditions. LC-MS: 360 (M-H) " .

Example 15. 2-(2-Naphthamido)-5-chloro-4-methoxybenzoic acid

[0177] To a solution of 2-amino-5-chloro-4-methoxybenzoic acid (250 mg, 1.24 mmol) in THF (8 mL) and Et 3 N (1 mL, 7.2 mmol) was added 2-naphthoyl chloride (236 mg, 1.24 mmol) and the resulting solution stirred at ambient temperature for 16 hrs. The reaction was quenched with addition of IN HCl (10 mL) and stirred for 1 hr. Filtration of the precipitate afforded crude product acid which was purified by trituration from hot EtOAc. LC-MS: 356 (M+H) + .

Example 16. 2-(Benzo[b]thiophene-5-carboxamido)-5-chlorobenzoic acid

[0178] The title compound was prepared in an analogous manner to that described for Example 3 using benzo[b]thiophene-5-carboxylic acid. LC-MS: 330 (M-H) " .

Example 17; 4,5-Difluoro-2-(6-fluoro-2-naphthamido)benzoic acid

[0179] The title compound was prepared in an analogous manner to Example 7 using 6-fluoro-2-naphthoyl chloride (Intermediate 5) and 2-amino-4,5-difluorobenzoic acid. LC-MS: 344 (M-H) " .

Example 18; 2-(2-Naphthamido)-4,5-difluorobenzoic acid

[0180] The title compound was prepared in an analogous manner to Example 7 using 2-naphthoyl chloride and 2-amino-4,5-difluorobenzoic acid. LC-MS: 326 (M-H) " . Example 19; 2-(2-Naphthamido)-5-cyanobenzoic acid

[0181] The title compound was prepared in an analogous manner to Example 3 using 2-naphthoyl chloride and TEA as base with 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-naphthamido)benzoic acid

[0182] Step 1 : Methyl 6-vinyl-2-naphthoate. A solution of methyl 6-bromo-2- naphthoate (1.02 g, 3.84 mmol), potassium vinyl trifluoroborate (514 mg, 3.83 mmol), tetrakis(triphenylphosphine)palladium(0) (443 mg, 0.384), sodium carbonate (1.2 g, 11.5 mmol), in DME (5 mL) and water (5 mL) was heated in a microwave at 80 °C for 30 minutes. After extraction with EtOAc the organic phases were concentrated in vacuo to afford a crude oil. Purification by column chromatography (Si0 2 , gradient 0 to 10% EtOAc in Hexanes) afforded methyl 6-vinyl-2-naphthoate (543 mg, 54% yield).

[0183] Step 2: Methyl 6-ethyl-2-naphthoate. To a solution of methyl 6-vinyl-2- naphthoate (287 mg, 1.35 mmol) in EtOH (13 mL) was added Pd/C (14 mg) followed by bubbling H 2 for 2 hrs. The solution was filtered through celite and concentrated in vacuo to afford methyl 6-ethyl-2-naphthoate (283 mg, 98% yield).

[0184] Step 3: 6-Ethyl-2-naphthoic acid. To a solution of methyl 6-ethyl-2- naphthoate (283 mg, 1.3 mmol) in MeOH (2 mL) and THF (2 mL) was added IN aq. LiOH (2 mL, 2 mmol). After 16 hrs, IN HCl was added (2 eq.) and the mixture extracted with EtOAc, the organic layer was separated, dried (MgS0 4 ), filtered and concentrated in vacuo to afford 6-ethyl- 2-naphthoic acid (257 mg, 97% yield).

[0185] Step 4: 6-Ethyl-2-naphthoyl chloride. A mixture of 6-ethyl-2-naphthoic acid (97 mg, 0.49 mmol) and thionyl chloride (1.6 mL) was heated at 80 °C for 2 hrs. The reaction mixture was concentrated in vacuo to afford 6-ethyl-2-naphthoyl chloride, which was used in next step without purification.

[0186] Step 5: To a solution of 6-ethyl-2-naphthoyl chloride in N,N- dimethylacetamide (4 mL) was added 2-amino-4,5-dichlorobenzoic acid (100 mg, 0.48 mmol), and the reaction mixture stirred for 16 hrs. Water was slowly added and the resulting solid was filtered to yield the title compound. LC-MS: 386 (M-H) " .

Example 21. 2-(Benzo[b]thiophene-5-carboxamido)-5-chloro-4-fluorobenzoic acid

[0187] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-chloro-4-fluorobenzoate and benzo[b]thiophene-5- carboxylic acid followed by typical ester hydrolysis conditions. LC-MS: 348 (M-H) " .

Example 22; 2-(6-Bromo-2-naphthamido)-5-cyanobenzoic acid

[0188] The title compound was prepared in an analogous manner to that described for Example 20, Steps 4 and 5 using methyl 2-amino-5-cyanobenzoate and 6-bromo-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 393 (M-H) " . Example 23; 5-Bromo-2-(6-fluoro-2-naphthamido)benzoic acid

[0189] The title compound was prepared in an analogous manner to that described for Example 20, Step 5 using methyl 2-amino-5-bromobenzoate and 6-fluoro-2-naphthoyl chloride (Intermediate 5) followed by typical ester hydrolysis conditions. LC-MS: 386 (M-H) " .

Example 24; 5-Chloro-2-(6-ethyl-2-naphthamido)-4-methoxybenzoic acid

[0190] The title compound was prepared in an analogous manner to that described for Example 20, Steps 4 and 5 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-ethyl-2- naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 382 (M-H) " .

Example 25; 5-Cvano-2-(6-ethyl-2-naphthamido)benzoic acid

[0191] The title compound was prepared in an analogous manner to that described for Example 20, Steps 4 and 5 using methyl 2-amino-5-cyanobenzoate and 6-ethyl-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 343 (M-H) " . Example 26; 5-Chloro-2-(6-ethyl-2-naphthamido)-4-fluorobenzoic acid

[0192] The title compound was prepared in an analogous manner to that described for Example 20, Steps 4 and 5 using methyl 2-amino-5-chloro-4-fluorobenzoate and 6-ethyl-2- naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 370 (M-H) " .

Example 27; 2-(6-Ethyl-2-naphthamido)-4,5-difluorobenzoic acid

[0193] The title compound was prepared in an analogous manner to that described for Example 20, Steps 4 and 5 using methyl 2-amino-4,5-difluorobenzoate and 6-ethyl-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 354 (M-H) " .

Example 28; 5-Chloro-2-(7-bromoquinoline-3-carboxamido)benzoic acid

[0194] The title compound was prepared in an analogous manner to Example 3 using 7-bromoquinoline-3-carboxylic acid and DCM with methyl 2-amino-5-chlorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 405 (M-H) " . Example 29; 5-Chloro-2-(3-methylbenzo[b]thiophene-5-carboxamido)benzoic acid

[0195] Step 1 : Methyl 3-methylbenzo[b]thiophene-5-carboxylate. 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 under a CO atmosphere at 90 °C for 16 hrs. The reaction was cooled to rt and diluted with EtOAc and brine. The combined organic phases were washed with water (3X), brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo. The residue, containing methyl 3- methylbenzo[b]thiophene-5-carboxylate was used without further purification.

[0196] Step 2: 3-Methylbenzo[b]thiophene-5-carboxylic acid. To a solution of methyl 3-methylbenzo[b]thiophene-5-carboxylate (0.87 g, 4.22 mmol) in THF (30 mL) and MeOH (30 mL) was added 1M aq. LiOH (29.53 mL, 29.53 mmol). The resulting mixture was stirred at rt for 16 hrs. The solvents were evaporated and the residue diluted with EtOAc and aq. 1 M citric acid. The organic layer was extracted with water (3X), brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo. The resulting solid containing 3-methylbenzo[b]thiophene-5-carboxylic acid was used directly in the next step.

[0197] Step 3: The title compound was prepared in an analogous manner to Example 3 using 3-methylbenzo[b]thiophene-5-carboxylic acid and DCM with methyl 2-amino-5- chlorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 344 (M-H) " .

Example 30; 2-(Benzo[b]thiophene-6-carboxamido)-5-chlorobenzoic acid

[0198] Step 1 : Methyl benzo[b]thiophene-6-carboxylate. 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 under a CO atmosphere at 90 °C for 16 hrs. The reaction was cooled to rt and diluted with EtOAc and brine. The organics were washed with water (3X), brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo. The residue, containing methyl benzo[b]thiophene-6- carboxylate was used without further purification.

[0199] Step 2: Benzo[b]thiophene-6-carboxylic acid. To a solution of methyl benzo[b]thiophene-6-carboxylate (0.50 g, 2.60 mmol) in THF (26 mL) and MeOH (26 mL) was added IM aq. LiOH (26.00 mL, 29.53 mmol). The resulting mixture was stirred at rt for 16 hrs. The solvent was evaporated and the residue diluted with Et 2 0 and water. The organic phase was discarded and the basic aqueous layer acidified by dilution with EtOAc and aq. IM HCl. The organic phase was extracted with water (2X), concentrated in vacuo and co-evaporated several times with EtOAc. The resulting solid containing benzo[b]thiophene-6-carboxylic acid was used directly in the next step.

[0200] Step 3 : The title compound was prepared in an analogous manner to Example 3 using benzo[b]thiophene-6-carboxylic acid and DCM with methyl 2-amino-5-chlorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 330 (M-H) " .

Example 31; 5-Chloro-2-(thieno[2,3-b1pyridine-5-carboxamido)benzoic acid

[0201] The title compound was prepared in an analogous manner to Example 3 using thieno[2,3-b]pyridine-5-carboxylic acid and DCM as solvent with methyl 2-amino-5- chlorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 331 (M-H) " . Example 32. iV-(4-Chloro-2-(5-oxo-4,5-dihvdro- lH-tetrazol- l-vDphenvD-2-naphthamide

[0202] To a solution of l-(2-amino-5-chlorophenyl)-lH-tetrazol-5(4H)-one (200 mg, 0.95 mmol) in THF (7 mL) was added Et3N (1 mL) followed by 2-naphthoyl chloride (180 mg, 0.95 mmol) and the mixture stirred at room temperature for 48 hrs. IN HC1 was added (~ 5 mL) followed by water (10 mL) and stirred for 30 min. The resulting precipitate was isolated by filtration, the solid washed with DCM and dried to afford the title compound. LC-MS: 366 (M+H) + .

[0203] The title compound was prepared in an analogous manner to Example 3, Step 1 using 7-fluoroquinoline-3-carboxylic acid and DCM with 4-chloro-2-(lH-tetrazol-5-yl)aniline. LC-MS: 367 (M-H) " .

[0204] The title compound was prepared in an analogous manner to Example 3, Step 1 using 6-fluoro-2-naphthoic acid and DCM with 4-chloro-2-(lH-tetrazol-5-yl)aniline. LC-MS: 366 (M-H) " .

Example 35; iy-(4-Chloro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-yl)phenvn-6- fluoro-2- naphthamide

[0205] The title compound was prepared in an analogous manner to Example 32 using 6-fluoro-2-naphthoyl chloride (Intermediate 5) and DCM with l-(2-amino-5- chlorophenyl)-lH-tetrazol-5(4H)-one. LC-MS: 382 (Μ-Η) " .

Example 36; 5-Chloro-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid

[0206] The title compound was prepared in an analogous manner to Example 3 using 6-fluoro-2-naphthoic acid and DCM with methyl 2-amino-5-chloro-4-methoxybenzoate followed by typical ester hydrolysis conditions. LC-MS: 372 (Μ-Η) " .

Example 37. iy-(4-Chloro-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vnphenyl )-2-naphthamide

[0207] To a solution of 3-(2-amino-5-chlorophenyl)-l,2,4-oxadiazol-5(4H)-one (Intermediate 4, 250 mg, 1.19 mmol) in THF (10 mL) was added Et 3 N (1 mL) followed by 2- naphthoyl chloride (226 mg, 1.19 mmol) and the resulting mixture stirred for 16 hrs. Addition of IN HC1 (10 mL) and vigorous stirring for 10 minutes afforded a precipitate which upon filtration and washing with water provided the crude product. Trituration from DCM afforded the title compound as a colorless solid. LC-MS: 364 (M-H) " .

Example 38; 5-Chloro-4-methoxy-2-(2-phenylbenzo[b]thiophene-5-carboxamid o)benzoic acid

[0208] Step 1 : 2-Boronobenzo[b Jthiophene-5-carboxylic acid. To a stirring solution of benzo[b]thiophene-5-carboxylic acid (1.00 g, 5.61 mmol) in THF (30 mL) at -78 °C was added i-BuLi (8.25 mL, 14.03 mmol, 1.7 M solution in pentane). The mixture was removed from the dry ice bath, stirred at rt for 40 minutes, then cooled back down to -78 °C. Triisopropylborate (1.93 mL, 8.42 mmol) was added and the solution was stirred at -78 °C for 10 minutes, ambient temperature 1 hr, and quenched by pouring into a 1 : 1 10% aq. KHS0 4 : saturated aq. NH C1 solution. The resulting quenched mixture was stirred for 1 hr at rt and partitioned between EtOAc and brine. The organic phase was dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and the resulting solid was filtered to afford 2-boronobenzo[b]thiophene-5-carboxylic acid. [0209] Step 2: 2-Phenylbenzo[b]thiophene-5-carboxylic acid. To a solution of 2- boronobenzo[b]thiophene-5-carboxylic acid (0.66 g, 2.97 mmol) in dioxane (10 niL) was added bromobenzene (0.35 mL, 3.27 mmol) and sat. aq. NaHCC (5 mL). The resulting mixture was sparged with nitrogen gas before tetrakis(triphenylphosphine) palladium(O) (0.172 g, 0.05 mmol) was added. The reaction was then sealed and heated at 100 °C for 16 hrs. The reaction mixture was allowed to cool to rt and partitioned between EtOAc and 1 M HC1 (aq.). The organic phase was extracted with water (2X), brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The crude residue afforded 2-phenylbenzo[b]thiophene-5-carboxylic acid and was used without further purification.

[0210] Step 3: The title compound was prepared in an analogous manner to Example 3 using 2-phenylbenzo[b]thiophene-5-carboxylic acid and DCM with methyl 2-amino-5-chloro- 4-methoxybenzoate followed by typical ester hydrolysis conditions. LC-MS: 436 (M-H) " .

Example 39. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(trifluoromethyl)benzo ic acid

[0211] Step 1 : Bis-tertbutoxycarbonyl 2-bromo-4-chloro-5-(trifluoromethyl)aniline. To a solution of 2-bromo-4-chloro-5-(trifluoromethyl)aniline (5.1 g, 18.6 mmol) in THF (100 mL) was added di-feri-butyl dicarbonate (10.1 mL, 44.0 mmol) followed by DMAP (455 mg, 3.7 mmol). After stirring for 16 hrs at ambient temperature, the reaction mixture was evaporated to dryness and the residue purified directly via column chromatography on silica gel eluting with a gradient of 0 to 5% EtOAc in Hexanes to afford the fos-Boc material as a colorless solid.

[0212] Step 2: tert-Butyl 2-((tert-butoxycarbonyl)amino)-5-chloro-4- (trifluoromethyl)benzoate. To a -78 °C solution of the previously synthesized protected aniline (5.0 g, 10.5 mmol) in anhydrous THF (100 mL) was added w-BuLi (2.5M soln. in Hexanes; 5.0 mL, 12.5 mmol) dropwise. After stirring at -78 °C for 1 hr, the reaction was quenched upon addition of aqueous sat'd. NH 4 C1 soln. and allowed to warm to ambient temperature. The reaction mixture was diluted with EtOAc, washed with water, dried (MgS0 4 ), filtered and evaporated in vacuo. The residue was purified via column chromatography on silica gel eluting with a gradient of 0 to 10% EtOAc in Hexanes to afford 3.0 g (72%) of tert-buty\ 2-((tert- butoxycarbonyl)amino)-5-chloro-4-(trifluoromethyl)benzoate.

[0213] Step 3: 2-Amino-5-chloro-4-(trifluoromethyl)benzoic acid. The previously isolated ester (3.0 g, 7.6 mmol) in DCM (50 mL) was treated with TFA (20 mL) and stirred at ambient temperature for 16 hrs. The solvent was removed in vacuo to afford the carboxylic acid as the TFA salt, which was used without further analysis or purification.

Step 4: Ethyl 2-amino-5-chloro-4-(trifluoromethyl)benzoate. To 2-amino-5-chloro-4- (trifluoromethyl)benzoic acid TFA salt (7.6 mmol) in DMF (15 mL) was added K 2 CO 3 (3.2 g, 22.8 mmol) and iodoethane (0.74 mL, 9.12 mmol). The suspension was stirred for 16 hrs at ambient temperature after which the reaction mixture was diluted with EtOAc, washed with water (2x), the organic phase separated, dried (MgS0 4 ), filtered and evaporated to dryness. The isolated solid was used without further purification.

[0214] Step 5: Ethyl 5-chloro-2-(6-fluoro-2-naphthamido)-4-

(trifluoromethyl)benzoate was prepared in an analogous fashion to Example 3, Step 1, using 6- fluoro-2-naphthoic acid. The resulting ester was purified on silica gel eluting with a gradient of 0 to 50% DCM in Hexanes.

Step 6. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(trifluoromethyl)benzo ic acid was prepared in an analogous fashion to Example 3, Step 2 to afford the title compound as a colorless solid. LC-MS: 410 (M-H) " .

Example 40; iV-(4-Chloro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnphenvn-2- methylbenzo[b]thiophene-5-car xamide

[0215] Step 1 : 2-Methylbenzo[b]thiophene-5-carboxylic acid. To a stirring solution of benzo[b]thiophene-5-carboxylic acid (1.00 g, 5.61 mmol) in THF (50 mL) at -78 °C was added i-BuLi (7.26 mL, 12.34 mmol, 1.7 M solution in pentane). The mixture was removed from the dry ice bath, stirred at rt for 40 minutes, then cooled back down to -78 °C. lodomethane (0.42 mL, 6.73 mmol) was added and the solution was stirred at -78 °C for 10 minutes then at ambient temperature for 1 hr. The reaction was quenched by pouring into a 1 : 1 10% aq. KHS0 4 : saturated aq. NH 4 CI solution. The resulting mixture was stirred for 1 hr at rt and partitioned between EtOAc and brine. The organic phase was dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The residue was triturated in 4: 1 EtOAc:Hexanes and the resulting solid was filtered to afford 2-methylbenzo[b]thiophene-5-carboxylic acid.

[0216] Step 2: The title compound was prepared in an analogous manner to Example 32 using 2-methylbenzo[b]thiophene-5-carbonyl chloride (prepared from the isolated acid and oxalyl chloride as described for Intermediate 5) with l-(2-amino-5-chlorophenyl)-lH-tetrazol- 5(4H)-one. LC-MS: 384 (Μ-Η) " .

Example 41; 5-Chloro-4-methoxy-2-(2-methylbenzo[blthiophene-5-carboxamid o)benzoic acid

[0217] The title compound was prepared in an analogous manner to Example 3 using 2-methylbenzo[b]thiophene-5-carboxylic acid (Example 40, Step 1) and DCM with methyl 2- amino-5-chloro-4-methoxybenzoate followed by typical ester hydrolysis conditions. LC-MS: 374 (Μ-Η) " .

Example 42. iV-(4-Chloro-5-fluoro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnp henvn-6-fluoro- 2-naphthamide

[0218] Step 1 : l-Chloro-2-fluoro-5-isocyanato-4-nitrobenzene. 5-Chloro-4-fluoro-2- nitroaniline (1.0 g, 5.25 mmol) was dissolved in EtOAc (30 mL) to which a solution of triphosgene (850 mg, 2.9 mmol) in EtOAc (20 mL) was added. The resulting solution was heated to reflux for 16 hrs after which the solvent was evaporated in vacuo and the resulting solid triturated with hot Hexanes, filtered and the filtrate evaporated to furnish the crude isocyanate which was used without further purification.

[0219] Step 2: l-(2-Amino-5-chloro-4-fluorophenyl)-lH-tetrazol-5(4H)-one. Prepared in an analogous manner to that described for Intermediate 3, Step 2.

Step 3: The title compound was isolated as illustrated in Example 32. Purification on silica gel (0 to 100% EtOAc in Hexanes) afforded a colorless solid. LC-MS: 400 (M-H) " .

Example 43. iy-(4-Chloro-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vnphenyl )quinoline-3- carboxamide

[0220] The title compound was prepared in an analogous manner to Example 37 using quinoline-3-carbonyl chloride (generated from the respective carboxylic acid and oxalyl chloride as described in Example 3). LC-MS: 367 (M+H) + .

Example 44. iy-(4-Chloro-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vnphenyl )-6-fluoro-2- naphthamide

[0221] The title compound was prepared in an analogous manner to Example 37 using 6-fluoro-2-naphthoyl chloride (Intermediate 5). Final product was triturated from acetone. LC-MS: 382 (M-H) " .

Example 45. iy-(4-Chloro-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vnphenyl )-6-ethvnyl-2- naphthamide

[0222] Step 1 : Methyl 6-((trimethylsilyl)ethynyl)-2-naphthoate. To a solution of methyl 6-bromo-2-naphthoate (1 g, 3.8 mmol) in MeCN (9 rriL) was added ethynyltrimethylsilane (0.64 mL, 4.5 mmol), triethyl amine (1.1 mL, 7.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (106 mg, 0.15 mmol) and Cul (86 mg, 0.45 mmol). The solution was sparged with nitrogen and heated at 80 °C for 16 hrs. EtOAc and water were added and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with brine (2x), dried (MgS0 4 ) and concentrated in vacuo to afford the crude product. Purification by column chromatography (Si0 2 , gradient 0 to 10% EtOAc in Hexanes) yielded methyl 6-((trimethylsilyl)ethynyl)-2-naphthoate (875 mg, 83 % yield).

[0223] Step 2: 6-Ethynyl-2 -naphthoic acid. To a suspension of methyl 6- ((trimethylsilyl)ethynyl)-2-naphthoate (440 mg, 1.6 mmol) in MeOH was added NaOH (IN, 6 mL) and stirred at rt for 48 hrs. Reaction was quenched with IN HC1 (8 mL) and extracted with EtOAc (3x). The combined organic extracts were washed with brine (lx), dried (MgS0 4 ) and concentrated in vacuo to afford the title compound (314 mg, quantitative yield).

Step 3: 6-Ethynyl-2-naphthoyl chloride. To a suspension of 6-ethynyl-2-naphthoic acid (200 mg, 1 mmol) in DCM (2 mL) was added oxalyl chloride (0.35 mL, 4 mmol). DMF (30 μΕ) was added and the reaction stirred for 10 minutes at rt. The solution was concentrated in vacuo to afford the product which was used in the next step without purification. [0224] Step 4: To a solution of 6-ethynyl-2-naphthoyl chloride in DMAc (4 mL) was added a solution of 3-(2-amino-5-chlorophenyl)-l,2,4-oxadiazol-5(4H)-one (Intermediate 4, 216 mg, 1 mmol) in pyridine (0.6 mL). The solution was concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water + 0.1% ΝΗ 3 Ή 2 Ο -> MeCN + 0.1% ΝΗ 3 ·Η 2 0) afforded the title compound. LC-MS: 388 (Μ-Η) " .

Example 46. iV-(4-Chloro-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vnphenvn -6-ethyl-2- naphthamide

[0225] The title compound was prepared in an analogous way to that described for Example 37 using 6-ethyl-2-naphthoyl chloride (Example 20). LC-MS: 392 (Μ-Η) " .

Example 47. 5-Fluoro-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid

[0226] Step 1 : Di-tert-butyl (2-bromo-4-fluoro-5-methoxyphenyl)dicarbamate. To a stirring solution of 2-bromo-4-fluoro-5-methoxyaniline (0.50 g, 2.27 mmol) and DMAP (0.055 g, 0.45 mmol) in THE (30 mL) at rt was added (Boc) 2 0 (1.19 g, 5.45 mmol). The mixture was stirred at rt for 16 hrs and the solvents were evaporated. The resulting crude material was purified on silica gel eluting with a solvent gradient of 0% to 30% EtOAc in Hexanes to afford di-teri-butyl (2-bromo-4-fluoro-5-methoxyphenyl)dicarbamate.

[0227] Step 2: tert-Butyl 2-((tert-butoxycarbonyl)amino)-5-fluoro-4- methoxybenzoate. To a stirring solution of di-feri-butyl (2-bromo-4-fluoro-5- methoxyphenyl)dicarbamate (0.83 g, 1.97 mmol) in THF (20 mL) at -78 °C was added w-BuLi (1.48 mL, 12.34 mmol, 1.6 M solution in Hexanes) dropwise. The mixture was stirred at -78 °C for lhr then quenched by adding a saturated aq. NH 4 C1 solution. The resulting mixture was partitioned between EtOAc and water, the organic phase was separated, washed with water, concentrated, and co-evaporated with EtOAc. The resulting crude material was purified on silica gel eluting with a solvent gradient of 0% to 30% EtOAc in Hexanes to afford tert-butyl 2-((tert- butoxycarbonyl)amino)-5-fluoro-4-methoxybenzoate.

[0228] Step 3: 2-Amino-5-fluoro-4-methoxybenzoic acid. tert-Butyl 2-((tert- butoxycarbonyl)amino)-5-fluoro-4-methoxybenzoate (0.59 g, 1.73 mmol) was combined with a premixed solution of DCM (10 mL) and TFA (4 mL) and stirred at rt for 16 hrs. The solvent was evaporated and the residue was co-evaporated with toluene and heptanes. The resulting solid 2- amino-5-fluoro-4-methoxybenzoic acid was used without further purification.

[0229] Step 4: Methyl 2-amino-5-fluoro-4-methoxybenzoate. To a stirring solution of 2-amino-5-fluoro-4-methoxybenzoic acid (0.40 g, 2.16 mmol), K 2 CO 3 (0.896, 6.48 mmol) in DMF (20 mL) at rt was added iodomethane (0.14 mL, 2.16 mmol). The mixture was stirred for 16 hrs at rt then partitioned between EtOAc and brine. The organics were washed with water (3X), brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo. The resulting crude material was used without further purification.

[0230] Step 5: The title compound was prepared in an analogous manner to Example 3 using 6-fluoro-2-naphthoic acid and DCM with methyl 2-amino-5-fluoro-4-methoxybenzoate followed by typical ester hydrolysis conditions. LC-MS: 356 (M-H) " .

Example 48. 4-Chloro-5-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid

[0231] The title compound was prepared in an analogous manner to Example 3 using 6-fluoro-2-naphthoyl chloride (Intermediate 5) and DCM with methyl 2-amino-4-chloro-5- fluorobenzoate followed by typical ester hydrolysis conditions. LC-MS: 360 (M-H) " . Example 49. 6-(2-Naphthamido)benzo[dl [l,31dioxole-5-carboxylic acid

[0232] To a solution of 6-aminobenzo[d][l,3]dioxole-5-carboxylic acid (250 mg, 1.38 mmol) in THF (8 mL), was added 2-naphthoyl chloride (263 mg, 1.38 mmol) followed by Et 3 N (1 mL). The suspension was stirred at ambient temperature for 16 hrs after which IN HCl was added and the resulting precipitate filtered and dried. Trituration of the isolated solid with MeOH/DCM afforded the title compound as a colorless solid. LC-MS: 336 (M+H) + .

Example 50. iV-(4,5-Difluoro-2-( -tetrazol-5-vnphenvn-6-fluoro-2-naphthamide

[0233] Step 1 : 2-Amino-4,5-difluorobenzonitrile. To a solution of 2-bromo-4,5- difluoroaniline (1.2 g, 4.3 mmol) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.34 mmol) and zinc cyanide (800 mg, 6.8 mmol). The solution was sparged with nitrogen and heated at 120 °C for 30 minutes in a Biotage microwave reactor. The resulting suspension was filtered and concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) afforded the desired 2-Amino-4,5-difluorobenzonitrile.

[0234] Step 2: 4,5-Difluoro-2-(2W-tetrazol-5-yl)aniline. To a solution of 2-amino- 4,5-difluorobenzonitrile (250 mg, 1.6 mmol) in DMF (8 mL) was added sodium azide (1.04 g, 16 mmol) and ammonium chloride (856 mg, 16 mmol). The mixture was heated at 100 °C for 16 hrs and then filtered and the filtrate was concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) afforded the title product.

[0235] Step 3: To a solution of 6-fluoro-2-naphthoyl chloride (Intermediate 5, 125 mg, 0.6 mmol) in DCM (3 rriL) was added a solution of 4,5-difluoro-2-(lH-tetrazol-5-yl)aniline (92 mg, 0.6 mmol) in pyridine (1 mL), stirred for 1 hr and concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) afforded the title compound. LC-MS: 368 (M-H) " .

Example 51. iy-(4,5-Difluoro-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-yl)p henvn-6-fluoro-2- naphthamide

[0236] Step 1 : 2-Amino-4,5-difluoro-N-hydroxybenzimidamide. To a solution of 2- amino-4,5-difluorobenzonitrile (100 mg, 0.65 mmol) in EtOH (2 mL), was added hydroxylamine hydrochloride (226 mg, 3.25 mmol) and sodium methoxide (175 mg, 3.25 mmol). The solution was heated at 50 °C for 16 hrs and then concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) afforded the desired product.

[0237] Step 2: 3-(2-Amino-4,5-difluorophenyl)-l,2,4-oxadiazol-5(4H)-one. To a suspension of 2-amino-4,5-difluoro-N-hydroxybenzimidamide (100 mg, 0.53 mmol) in EtOH (2 mL) was added sodium methoxide (86 mg, 1.6 mmol) and diethyl carbonate (250 mg, 2.1 mmol). The solution was heated to reflux for 16 hrs, allowed to cool and water was added followed by IN HC1 such that the pH was adjusted to pH 7. The resulting solid was filtered, washed with water and then dried in vacuo to yield the desired product.

Step 3: The title compound was prepared in an analogous manner as described in Example Step 3. LC-MS: 384 (M-H) " . Example 52. 5-Chloro-2-(6-chloro-2-naphthamido)benzoic acid

[0238] The title compound was prepared in an analogous manner to that for Example 3 using 6-chloro-2-naphthoic acid (Intermediate 1). LC-MS: 360 (M+H) + .

Example 53. 6-Fluoro-iV-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetr azol-l- vDphenyr)-2-naphthamide

[0239] The title compound was prepared in an analogous manner to Example 32 using 6-fluoro-2-naphthoyl chloride (Intermediate 5) and DCM with l-(2-amino-5-fluoro-4- methoxyphenyl)-lH-tetrazol-5(4H)-one (made by using 5-fluoro-4-methoxy-2-nitroaniline and conditions outlined in Example 42). LC-MS: 396 (Μ-Η) " .

Example 54. 5-Chloro-4-ethyl-2-(6-fluoro-2-naphthamido)benzoic acid

[0240] Step 1 : 2-Amino-5-chloro-4-vinylbenzoic acid. To a solution of 2-amino-4- bromo-5-chlorobenzoic acid (500 mg, 2 mmol) in DME (5 mL) and water (5 mL), was added potassium vinyl trifluoroborate (804 mg, 6 mmol), XPhos-Pd-G2 (0.04 eq) and sodium carbonate (848 mg, 8 mmol). The solution was sparged with nitrogen, heated at 100 °C for 30 minutes in a microwave reactor, then the solution was concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water 0.1% NH 3 H 2 O -> MeCN 0.1% NH 3 H 2 O) afforded the desired product.

[0241] Step 2: 2-Amino-5-chloro-4-ethylbenzoic acid. To a solution of 2-amino-5- chloro-4-vinylbenzoic acid (180 mg, 0.9 mmol) in water (15 mL) and MeOH (15 mL), was added Raney-Nickel (1 mL suspension). The solution was bubbled with hydrogen for 1 hr. The solution was filtered and concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water 0.1% NH 3 H 2 0 -> MeCN 0.1% NH 3 H 2 0) afforded the desired product.

[0242] Step 3: The title compound was prepared in an analogous manner to that for Example 7 using 6-fluoro-2-naphthoyl chloride (Intermediate 5). LC-MS: 370 (M-H) " .

Example 55. 4-(Benzyloxy)-5-chloro-2-(6-fluoro-2-naphthamido)benzoic acid

[0243] Step 1 : 2-Amino-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 for 16 hrs. Purification of the crude reaction mixture by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 O -> MeCN + 0.1% NH 3 H 2 O) afforded the desired product.

[0244] Step 2: The title compound was prepared in an analogous manner to that for Example 50, Step 3 using 6-fluoro-2-naphthoyl chloride (Intermediate 5). LC-MS: 448 (M-H) " . Example 56. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)benzoi c acid

[0245] The title compound was prepared in an analogous manner to that for Example 55 using oxetan-3-ol. LC-MS: 414 (M-H) " .

Example 57. iV-(4-Chloro-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-yl )phenyl)-6- fluoro-2-naphthamide

[0246] The title compound was prepared in an analogous manner to Example 32 using 6-fluoro-2-naphthoyl chloride (Intermediate 5) and DCM with l-(2-amino-5-chloro-4- methoxyphenyl)-lH-tetrazol-5(4H)-one (made by using 5-chloro-4-methoxy-2-nitroaniline and conditions outlined in Example 42, Step 1 and the preparation of Intermediate l-(2-amino-5- chlorophenyl)-lH-tetrazol-5(4H)-one). LC-MS: 412 (Μ-Η) " .

Example 58. 2-(2-Naphthamido)-5-(difluoromethoxy)benzoic acid

[0247] Step 1 : Methyl 2-(2-naphthamido)-5-hydroxybenzoate was prepared in an analogous manner to Example 3, Step 1 using methyl 2-amino-5-hydroxybenzoate and 2- naphthoic acid as starting materials.

[0248] Step 2: To a stirring solution of methyl 2-(2-naphthamido)-5-hydroxybenzoate (307 mg, 0.96 mmol) in anhydrous DMF (4 mL) was added ethyl 2-bromo-2,2-difluoroacetate (150 μΐ ^ , 1.15 mmol). The resulting mixture was stirred at 80 °C for 13 hrs, cooled to rt, filtered and purified by HPLC (C-18 column, water + 0.1% TFA -> MeCN + 0.1% TFA). Product containing fractions were concentrated to afford methyl 2-(2-naphthamido)-5- (difluoromethoxy)benzoate.

[0249] Step 3 : The title compound was prepared in an analogous manner to Example 3, Step 2 using methyl 2-(2-naphthamido)-5-(difluoromethoxy)benzoate as a starting materials. LC-MS: 356 (M-H) " .

Example 59. 2-(6-Fluoro-2-naphthamido)-4,5-dimethoxybenzoic acid

[0250] The title compound was prepared in an analogous manner to that described for Example 49 using 2-amino-4,5-dimethoxybenzoic acid and 6-fluoro-2-naphthoyl chloride (Intermediate 5). The isolated solid was stirred with LiOH monohydrate (5 equiv) in a mixture of MeOH, water and dioxane (~8 mL of a 1 : 1 : 1 mixture) until complete conversion to the acid was apparent by LC-MS analysis. Addition of IN HC1 to this reaction mixture afforded a colorless precipitate which was filtered, washed with water and dried in vacuo to afford the title compound. LC-MS: 370 (M+H) + . Example 60. 7-(6-Fluoro-2-naphthamido)-2,3-dihydrobenzo[bl [l,4]dioxine-6-carboxylic acid

[0251] The title compound was prepared in an analogous manner to Example 59, using 7-amino-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid. LC-MS: 368 (M+H) + .

Example 61. 5-Chloro-4-methoxy-2-(2-methylbenzo[b]thiophene-6-carboxamid o)benzoic acid

[0252] Step 1 : 2-Methylbenzo[b]thiophene-6-carboxylic acid was prepared using benzo[b]thiophene-6-carboxylic acid and the procedure in Example 40, Step 1.

[0253] Step 2: The title compound was prepared in an analogous manner to Example 3 using 2-methylbenzo[b]thiophene-6-carboxylic acid and DCM with ethyl 2-amino-5-chloro-4- methoxybenzoate followed by typical ester hydrolysis conditions. LC-MS: 374 (M-H) " .

Example 62. 5-Cvano-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid

[0254] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 6-fluoro-2- naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 363 (M-H) " .

Example 63. 5-Chloro-4-ethvnyl-2-(6-fluoro-2-naphthamido)benzoic acid

[0255] Step 1 : Methyl 2-amino-5-chloro-4-((trimethylsilyl)ethynyl)benzoate was prepared in an analogous manner to that described for Example 45 Step 1 using methyl 2-amino- 4-bromo-5-chlorobenzoate as starting material.

[0256] Step 2: Methyl 5-chloro-2-(6-fluoro-2-naphthamido)-4-

((trimethylsilyl)ethynyl)benzoate was prepared in an analogous manner to that described for Example 50, Step 3.

[0257] Step 3: To a solution of methyl 5-chloro-2-(6-fluoro-2-naphthamido)-4- ((trimethylsilyl)ethynyl)benzoate (60 mg, 0.13 mmol) in MeOH (2 rriL) and THF (1 rriL) was added NaOH (1M, 0.5 rriL, 0.5 mmol). After stirring for 30 minutes the solution was concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) afforded the title compound. LC-MS: 366 (M-H) " .

Example 64. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-((tetrahvdro-2H-pyran- 4- vDoxy)benzoic acid

[0258] The title compound was prepared in an analogous manner to that described for Example 55 using tetrahydro-2H-pyran-4-ol. LC-MS: 442 (Μ-Η) " .

Example 65. 5-Chloro-4-cvclopropyl-2-(6-fluoro-2-naphthamido)benzoic acid (5203)

[0259] Step 1 : 2-Amino-5-chloro-4-cyclopropylbenzoic acid was prepared in an analogous manner to that described for Step 1 of Example 54 using cyclopropylboronic acid. Step 2: The title compound was prepared in an analogous manner to that described for Step 3 of Example 50. LC-MS: 382 (Μ-Η) " .

Example 66. iy-(4,5-Difluoro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-yl)phenv n-6-fluoro-2- naphthamide

[0260] Step 1 : l,2-Difluoro-4-isocyanato-5-nitrobenzene. To a suspension of 4,5- difluoro-2-nitroaniline (1.7 g, 10 mmol) in toluene (40 rriL) was added diphosgene (2.95 g, 15 mmol) and the reaction mixture heated to reflux for 16 hrs. The solution was concentrated in vacuo to afford the crude oil, which was used without further purification.

[0261] Step 2: l-(4,5-difluoro-2-nitrophenyl)-l,4-dihydro-5Yi-tetrazol-5-on e. 1,2- Difluoro-4-isocyanato-5-nitrobenzene (1.3 g, 6.5 mmol) was mixed with trimethylsilyl azide (2 mL) and heated at 100 °C for 16 hrs. The solution was concentrated in vacuo and the residue purified by column chromatography (Si0 2 , gradient Hexanes -> EtOAc) to afford the desired product. [0262] Step 3: l-(2-Amino-4,5-difluorophenyl)-lH-tetrazol-5(4K)-one. To a solution of l-(4,5-difluoro-2-nitrophenyl)-l,4-dihydro-5H-tetrazol-5-one (150 mg, 0.62 mmol) in MeOH (20 mL) was added Raney-Nickel (1 mL as suspension). Hydrogen gas was bubbled with vigorous stirring for four hrs and the solution was filtered through celite and concentrated in vacuo to afford the product.

[0263] Step 4: The title compound was then obtained in an analogous manner to that described for Step 3 of Example 50. LC-MS: 384 (M-H) " .

Example 67. 5-Chloro-2-(7-fluoroquinoline-3-carboxamido)-4-(oxetan-3-ylo xy)benzoic acid

[0264] The title compound was prepared in an analogous manner to Example 55 using oxetan-3-ol and 7-fluoroquinoline-3-carboxylic acid as amide coupling partner. LC-MS: 415 (M-H) " .

Example 68. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(hvdroxymethyl)benzoic acid

[0265] Step 1 : Methyl 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-5- chlorobenzoate . To a solution of methyl 2-amino-4-bromo-5-chlorobenzoate (100 mg, 0.38 mmol) in dioxane (1 mL) was added teri-butyldimethyl((tributylstannyl)methoxy)silane (165 mg, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017). The solution was sparged with nitrogen and heated at 150 °C for 3 hrs. After completion of reaction, the solution was concentrated in vacuo and the residue purified by column chromatography (Si0 2 , gradient Hexanes -> EtOAc) to afford the desired product. [0266] Step 2: Methyl 4-(((tQrt-butyldimethylsilyl)oxy)methyl)-5-chloro-2-(6-fluor o-2- naphthamido)benzoate was prepared as described in Step 3 of Example 50 using methyl 2- amino-4-(((ieri-butyldimethylsilyl)oxy)methyl)-5-chlorobenzo ate and 6-fluoro-2-naphthoyl chloride (Intermediate 5).

[0267] Step 3: 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-2-(6-fluor o-2- naphthamido)benzoic acid. To a solution of methyl 4-(((teri-butyldimethylsilyl)oxy)methyl)-5- chloro-2-(6-fluoro-2-naphthamido)benzoate (100 mg, 0.2 mmol) in MeOH (3 mL) and THF (3 mL) was added NaOH (5N, 200 μΕ) and the mixture stirred for 1 hr. The solution was concentrated in vacuo and the residue purified by column chromatography (C-18 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) to yield the desired product.

[0268] Step 4: To a solution of 4-(((ieri-butyldimethylsilyl)oxy)methyl)-5-chloro-2- (6-fluoro-2-naphthamido)benzoic acid (30 mg, 0.06 mmol) in THF (100 μΕ) was added TBAF (1M solution in THF; 2 mL, 2.0 mmol). After 1 hr, the solution was concentrated in vacuo and the residue purified by column chromatography (C-18 reverse phase, water + 0.1% formic acid - > MeCN + 0.1% formic acid) yielding the title compound. LC-MS: 372 (M-H) " .

Example 69. iV-(4-Chloro-5-(oxetan-3-yloxy)-2-(5-oxo-4,5-dihvdro-lH-tetr azol-l- vDphenyr)-6-fluoro-2-naphthami

[0269] Step 1 : l-(5-Chloro-2-nitro-4-(oxetan-3-yloxy)phenyl)-lYi-tetrazol-5 (4K)-one was prepared in an analogous manner to that described as for Example 55 using oxetan-3-ol and l-(5-chloro-4-fluoro-2-nitrophenyl)-lH-tetrazol-5(4H)-one (see Example 42).

[0270] Step 2: l-(2-amino-5-chloro-4-(oxetan-3-yloxy)phenyl)-lH-tetrazol-5( 4H)- one was prepared in an analogous manner to that described for the Intermediate 3 using l-(5- chloro-2-nitro-4-(oxetan-3-yloxy)phenyl)-lH-tetrazol-5(4H)-o ne as starting material. [0271] Step 3: The title compound was prepared in an analogous manner to that described for Example 50 Step 3 using l-(2-amino-5-chloro-4-(oxetan-3-yloxy)phenyl)-lH- tetrazol-5(4H)-one and 6-fluoro-2-naphthoyl chloride (Intermediate 5). LC-MS: 456 (M+H) + .

Example 70; 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(2,2,2-trifluoroethoxy )benzoic acid

[0272] The title compound was prepared in an analogous manner to that described for Example 55 using 2,2,2-trifluoroethanol. LC-MS: 440 (M-H) " .

Example 71. iV-(4-Chloro-5-methoxy-2-((methylsulfonvncarbamoyl)phenvn-6- fluoro-2- naphthamide

[0273] To a solution of 5-chloro-2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid (180 mg, 0.48 mmol) in THE (10 mL) was added Ι,Γ-carbonyldiimidazole (156 mg, 1 mmol) and the solution was heated at 40 °C for 1 hr. In a separate vial was added sodium hydride (60% in mineral oil, 23 mg, 0.58 mmol) and THF (1 mL) and stirred for 30 minutes. 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 hr. The reaction mixture was allowed to cool and acidified with HC1 (IN, 5 mL), concentrated in vacuo and the residue purified by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 O -> MeCN + 0.1% NH 3 H 2 O) to afford the title compound. LC-MS: 449 (M-H) " . Example 72. 6-Chloro-iV-(4-chloro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnp henvn-2- naphthamide

[0274] The title compound was prepared in an analogous manner to Example 3, Step 1 using 6-chloro-2-naphthoic acid (Intermediate 1) and DCM with l-(2-amino-5-chlorophenyl)- lH-tetrazol-5(4H)-one (Intermediate 3). LC-MS: 398 (Μ-Η) " .

Example 73. 6-(6-Chloro-2-naphthamido)-2,2-difluorobenzo[dl [l,3]dioxole-5-carboxylic acid

[0275] Step 1 : 2,2-Difluoro-6-iodobenzo[d][l,3]dioxol-5-amine. To a stirring solution of 2,2-difluorobenzo[d][l,3]dioxol-5-amine (1 g, 5.78 mmol) in anhydrous DMF (60 mL) was added N-iodosuccinimide (1.37 g, 6.07 mmol). The resulting mixture was stirred at rt for 7 hrs and then diluted with EtOAc and water. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 30% EtOAc in Hexanes to provide 2,2-difluoro-6- iodobenzo[d][l,3]dioxol-5-amine.

[0276] Step 2: Methyl 6-amino-2,2-difluorobenzo[d] [l,3]dioxole-5-carboxylate. To a stirring solution of 2,2-difluoro-6-iodobenzo[d][l,3]dioxol-5-amine (1.12 g, 3.75 mmol) in anhydrous DMSO (15 mL) was added anhydrous MeOH (9 mL), TEA (530 \iL, 3.75 mmol), potassium carbonate (1.6 g, 11.3 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II) (411 mg, 0.562 mmol). Carbon monoxide was bubbled through the reaction mixture for 15 min. The resulting mixture was stirred at 70 °C under 1 atm of CO for 2 hrs then diluted with EtOAc and water. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EtOAc in Hexanes to provide methyl 6-amino-2,2- difluorobenzo[d][l,3]dioxole-5-carboxylate.

[0277] Step 3 : The title compound was prepared in an analogous manner to Example 3 using methyl 6-amino-2,2-difluorobenzo[d][l,3]dioxole-5-carboxylate and 6-chloro-2- naphthoic acid (Intermediate 1) followed by typical ester hydrolysis conditions. LC-MS: 404 (M- H)-.

Example 74. 2-(2-Naphthamido)-5-chloro-6-methoxynicotinic acid

[0278] Step 1 : 2-chloro-6-methoxynicotinic acid. Into a 250-mL round-bottom flask, was placed 2,6-dichloropyridine-3-carboxylic acid (5.0 g, 26.04 mmol), methanol (30 mL) and (tert-butoxy)potassium (5.86 g, 52.22 mmol). The resulting solution was stirred for 4 days at 65 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of water and the pH value of the solution adjusted to 3-4 with HC1. The resulting precipitate was collected by filtration resulting in 4.6 g (94%) of 2-chloro-6- methoxypyridine-3-carboxylic acid as a white crude solid.

[0279] Step 2: Methyl 2-chloro-6-methoxypyridine-3-carboxylate. Into a 50-mL round-bottom flask was placed 2-chloro-6-methoxypyridine-3-carboxylic acid (900 mg, 4.80 mmol), dichloromethane (10 mL), Ν,Ν-dimethylformamide (~15 μΕ) and thionyl chloride (2 mL, 24.0 mmol). The resulting solution was stirred for 2.5 hr at 40 °C in an oil bath. The resulting mixture was concentrated under vacuum. This was followed by the addition of methanol (10 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 1 hr at room temperature and the resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/19). This resulted in 720 mg (74%) of methyl 2-chloro-6-methoxypyridine-3-carboxylate as a colorless oil.

[0280] Step 3: Methyl 6-methoxy-2-(naphthalene-2-amido)pyridine-3-carboxylate. Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-chloro-6-methoxypyridine-3-carboxylate (720 mg, 3.57 mmol), naphthalene-2-carboxamide (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 Xantphos (473 mg, 0.82 mmol). The resulting solution was stirred for 20 hrs at 65 °C in an oil bath. The resulting mixture was concentrated under vacuum. The resulting mixture was partitioned between water and EtOAc and the organic phase separated and dried with anhydrous Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1/4). This resulted in 620 mg (52%) of methyl 6-methoxy-2- (naphthalene-2-amido)pyridine-3-carboxylate as a light yellow solid.

[0281] Step 4: Methyl 5-chloro-6-methoxy-2-(naphthalene-2-amido)pyridine-3- carboxylate. Into a 50-mL round-bottom flask was placed methyl 6-methoxy-2-(naphthalene-2- amido)pyridine-3-carboxylate (620 mg, 1.84 mmol), THF (15 mL) and N-chlorosuccinimide (319 mg, 2.39 mmol). The resulting solution was stirred for 1 day at 70 °C in an oil bath. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column with dichloromethane/methanol (20/1). This resulted in 240 mg (91% purity) and 280 mg (crude solid) of methyl 5-chloro-6-methoxy-2-(naphthalene-2-amido)pyridine-3-carboxy late as a light yellow solid.

[0282] Step 5: Into a 50-mL round-bottom flask, was placed methyl 5-chloro-6- methoxy-2-(naphthalene-2-amido)pyridine-3-carboxylate (180 mg, 0.49 mmol), ethanol (5 mL) and LiOH (58 mg, 2.42 mmol) in water (1.5 mL). The resulting solution was stirred for 3 hrs at 25 °C. The resulting mixture was concentrated under vacuum and the residue was dissolved in 10 mL of water. The pH of the solution was adjusted to 3-4 with aqueous HC1 (6 mol/L). The solids were collected by filtration. This afforded the title compound as a colorless solid. LC-MS: 357 (M+H) + . Example 75. 2-(2-Naphthamido)-5-chloro-6-ethoxynicotinic acid

[0283] The title compound was prepared in an analogous fashion to Example 74 using ethanol in Step 1. LC-MS: 371 (M+H) + .

Example 76. iV-(4,5-Difluoro-2-((methylsulfonvncarbamoyl)phenvn-6-fluoro -2- naphthamide

[0284] The title compound was prepared in an analogous manner to that described for Example 71. LC-MS: 421 (M-H) " .

Example 77; iV-(4-Chloro-2-(((difluoromethyl)sulfonyl)carbamovn-5-methox yphenvn-6- fluoro-2-naphthamide

[0285] The title compound was prepared in an analogous manner to that described for Example 71 using difluoromethanesulfonamide. LC-MS: 485 (M-H) " . Example 78; 2-(6-Chloro-2-naphthamido)-5-(difluoromethoxy)-4-fluorobenzo ic acid

[0286] Step 1 : Methyl 2-(6-chloro-2-naphthamido)-4-fluoro-5-hydroxybenzoate was prepared in an analogous manner to Example 3, Step 1 using methyl 2-amino-4-fluoro-5- hydroxybenzoate and 6-chloro-2-naphthoic acid (Intermediate 1).

[0287] Step 2: Methyl 2-(6-chloro-2-naphthamido)-5-(difluoromethoxy)-4- fluorobenzoate was prepared in an analogous manner to Example 58, Step 2 using methyl 2-(6- chloro-2-naphthamido)-4-fluoro-5-hydroxybenzoate as a starting material.

[0288] Step 3 : The title compound was prepared in an analogous manner to Example 3, Step 2 using methyl 2-(6-chloro-2-naphthamido)-5-(difluoromethoxy)-4-fluorobenzo ate as starting material. LC-MS: 408 (M-H) " .

Example 79. 5-Cvano-2-(6-fluoro-2-naphthamido)benzoic acid

[0289] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-cyanobenzoate and 6-fluoro-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 333 (M-H) " . Example 80. 2-(6-Chloro-2-naphthamido)-5-cyanobenzoic acid

[0290] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-cyanobenzoate 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-naphthamido)-4-methylbenzoic acid

[0291] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-cyano-4-methylbenzoate and 6-fluoro-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 347 (M-H) " .

Example 82. 5-Cyano-2-(6-chloro-2-naphthamido)-4-methylbenzoic acid

[0292] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-cyano-4-methylbenzoate and 6-chloro-2-naphthoic acid (Intermediate 1) followed by typical ester hydrolysis conditions. LC-MS: 363 (M-H) " . Example 83. iy-(4-(Difluoromethoxy)-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-y l)phenvn-6- fluoro-2-naphthamide

[0293] Step 1 : 5-(Difluoromethoxy)-2-nitroaniline. To a stirring solution of 4- (difluoromethoxy)-2-fluoro-l -nitrobenzene (1.1 g, 5.31 mmol) in EtOH (4 rriL) was added ammonia (26 mL, 53.1 mmol, 2.0 M in EtOH). The resulting mixture was stirred at 70 °C for 48 hrs. Volatiles were removed in vacuo and the residue was diluted with EtOAc and water. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo to provide 5- (difluoromethoxy)-2-nitroaniline.

[0294] Step 2: l-(5-(Difluoromethoxy)-2-nitrophenyl)-lH-tetrazol-5(4H)-one was prepared in an analogous manner to Intermediate 3, Step 2 using 5-(difluoromethoxy)-2- nitroaniline as a starting material.

[0295] Step 3: l-(2-Amino-5-(difluoromethoxy)phenyl)-lH-tetrazol-5( H)-one. To a stirring solution of l-(5-(difluoromethoxy)-2-nitrophenyl)-lH-tetrazol-5(4H)-one (210 mg, 0.769 mmol) in EtOAc (10 mL) under a nitrogen atmosphere was added Pd/C (20 mg, 10% Pd w/w). Hydrogen was bubbled through the resulting mixture for 15 min before heating to 60 °C under 1 atm of hydrogen for 8 hrs. The reaction mixture was cooled to rt, filtered through celite and concentrated in vacuo to provide l-(2-amino-5-(difluoromethoxy)phenyl)-lH-tetrazol-5(4H)- one.

[0296] Step 4: The title compound was prepared in an analogous manner to Example 32 using l-(2-amino-5-(difluoromethoxy)phenyl)-lH-tetrazol-5(4H)-one and 6-fluoro-2- naphthoyl chloride (Intermediate 5) as starting materials. LC-MS: 414 (Μ-Η) " . Example 84. 6-Chloro-iV-(4-(difluoromethoxy)-2-(5-oxo-4,5-dihvdro-lH-tet razol-l- vDphenyr)-2-naphthamide

[0297] The title compound was prepared in an analogous manner to Example 32 using l-(2-amino-5-(difluoromethoxy)phenyl)-lH-tetrazol-5(4H)-one prepared in Example 83, Step 3 and 6-chloro-2-naphthoyl chloride (prepared as for Intermediate 5 from the corresponding acid) LC-MS: 430 (M-H) " .

Example 85. 6-Chloro-iV-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetr azol-l- vDphenyr)-2-naphthamide

[0298] The title compound was prepared in an analogous manner to Example 86 using iodomethane in Step 1 and 6-chloro-2-naphthoyl chloride (prepared analogously to Intermediate 5). LC-MS: 428 (M-H) " .

Example 86. iV-(4-Chloro-5-ethoxy-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnp henvn-6-fluoro- 2-naphthamide

[0299] Step 1 : 4-Ethoxy-2-nitroaniline. To a stirring solution of 4-amino-3- nitrophenol (3.00 g, 12.2 mmol), Cs 2 C0 3 (7.98, 24.5 mmol) in DMF (100 mL) at 0 °C was added bromoethane (0.96 mL, 12.9 mmol). The mixture was stirred for 16 hrs at rt and the reaction was found to be 50% complete. Additional bromoethane (0.96 mL, 12.9 mmol) was added and the reaction was continued stirring for 36 hrs. The mixture was partitioned between EtOAc and brine and the organics were washed once more with brine, water (2X), saturated aq. Na 2 C03 (2X), brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo. The resulting crude material was sufficiently pure and was used without further purification.

[0300] Step 2: 4-Ethoxy-l -isocyanato-2-nitrobenzene . To a stirring solution of EtOAc (100 mL) at 0 °C was added diphosgene (1.53 mL, 12.8 mmol) followed by slow addition of 4-ethoxy-2-nitroaniline (3.10 g, 17.0 mmol) dissolved in a minimal amount of EtOAc. The resulting mixture was stirred at reflux for 16 hrs and the solvents were evaporated. The resulting crude material was stirred in a 20: 1 mixture of Hexanes: EtOAc at 60 °C for 1 hr and then filtered through filter paper. The filtrate was evaporated to afford 4-ethoxy-l-isocyanato-2-nitrobenzene which was carried on to the next step.

[0301] Step 3: l-(4-Ethoxy-2-nitrophenyl)-lYi-tetrazol-5(4R)-one. 4-Ethoxy-l- isocyanato-2-nitrobenzene (3.50 g, 16.8 mmol) was combined with TMSN 3 (5.50 mL, 42.0 mmol) and heated to 100 °C inside of a sealed vessel for 16 hrs. The solvents were evaporated and the resulting crude material was purified on silica gel eluting with a solvent gradient of 10% to 60% EtOAc in Hexanes (the EtOAc and Hexanes were spiked with 2.5% acetic acid) to afford the desired product. [0302] Step 4: l-(2-Amino-4-ethoxyphenyl)-lYi-tetrazol-5(4R)-one. 1 -(4-Ethoxy-2- nitrophenyl)-lH-tetrazol-5(4H)-one (1.90 g, 7.56 mmol) was stirred in THF (40 mL) and Raney Nickel (2800, slurry in H 2 0, 1.6 mL) was added. The resulting mixture was stirred under a ¾ atmosphere at rt for 96 hrs. The reaction was filtered through celite, the solvent evaporated in vacuo to yield the desired product which was used without further purification.

[0303] Step 5: l-(2-Amino-5-chloro-4-ethoxyphenyl)-lii-tetrazol-5(4H)-one. To a stirring solution of l-(2-amino-4-ethoxyphenyl)-lH-tetrazol-5(4H)-one (0.40 g, 1.81 mmol), in acetic acid (20 mL) at rt was added NCS (0.29 mg, 2.17 mmol). The mixture was stirred for 16 hrs at rt and then evaporated. The resulting crude material was purified on a CI 8 column eluting with a solvent gradient of 10% to 100% C¾CN in water (the C¾CN and water were spiked with 0.1% formic acid) to afford l-(2-amino-5-chloro-4-ethoxyphenyl)-lH-tetrazol-5(4H)-one formic acid salt. The resulting formic acid salt was neutralized with a minimum amount of saturated NaHCC (aq.) then diluted with n-BuOH and saturated NH 4 C1. The organic phases were washed with water (2X), concentrated, and then co-evaporated with heptanes to afford the desired product.

[0304] Step 6: The title compound was prepared in an analogous manner to Example 32 using 6-fluoro-2-naphthoyl chloride (Intermediate 5) with l-(2-amino-5-chloro-4- ethoxyphenyl)-lH-tetrazol-5(4H)-one. LC-MS: 426 (M-H) " .

Example 87. 6-Chloro-iV-(4-chloro-5-ethoxy-2-(5-oxo-4,5-dihvdro-lH-tetra zol-l- vDphenyr)-2-naphthamide

[0305] The title compound was prepared in an analogous manner to Example 86 using 6-chloro-2-naphthoyl chloride (prepared analogously to Intermediate 5). LC-MS: 442 (M-

H)-. Example 88. iy-(4-Chloro-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-yl )phenvn-6- (trifluoromethvD-2-naphthami

[0306] Step 1 : 6-(Trifluoromethyl)-2-naphthoic acid. To a stirring solution of 2- bromo-6-(trifluoromethyl)naphthalene (5 g, 18.2 mmol) in anhydrous THF (50 mL) at -78 °C was added w-BuLi (12 mL, 20 mmol, 1.6 M in Hexanes) and the resulting mixture was stirred for 15 minutes. Anhydrous carbon dioxide was bubbled through the reaction mixture for 15 minutes and the mixture was warmed to rt. Volatiles were removed in vacuo and the residue was diluted with EtOAc and IN aqueous HC1. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The resulting solid was triturated with DCM to provide 6- (trifluoromethyl)-2-naphthoic acid.

[0307] Step 2: To a stirring solution of 6-(trifluoromethyl)-2-naphthoic acid (44 mg, 0.183 mmol) in anhydrous DMF (2 mL) was added HATU (84 mg, 0.220 mmol) and the resulting mixture was stirred at rt for 15 minutes. To the mixture was then added l-(2-amino-5- chloro-4-methoxyphenyl)-lH-tetrazol-5(4H)-one (45 mg, 0.183 mmol, prepared in an analogous manner to Example 32 by using 5-chloro-4-methoxy-2-nitroaniline and conditions outlined in the preparation of Intermediate 3, followed after 10 minutes by N,N-diisopropylethylamine (96 μΕ, 0.549 mmol) and the mixture was stirred at rt for 14 hrs. To the mixture was then added 1 mL of 3N aqueous NaOH followed after 20 minutes by 3 mL of 5N aqueous HC1. The resulting mixture was then diluted with EtOAc and IN aqueous HC1. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by trituration with DCM to provide the title compound. LC-MS: 462 (M-H) " . Example 89. iy-(4-Chloro-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-yl )phenvn-6- methyl-2-naphthamide

[0308] Step 1 : Methyl 6-methyl-2-naphthoate. To a stirring solution of methyl 6- bromo-2-naphthoate (3 g, 11.3 mmol) in anhydrous 1,4-dioxane (100 mL) was added methylboronic acid (2.04 g, 34.0 mmol), [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II) (830 mg, 1.13 mmol) and cesium fluoride (5.8 g, 38.5 mmol). The resulting mixture was stirred at 100 °C for 7 hrs and then cooled to rt. Volatiles were removed in vacuo and the residue was diluted with EtOAc and water. The organic layer was washed with IN aqueous HCl, saturated aqueous sodium bicarbonate, brine, dried over MgS0 4 and concentrated in vacuo. The resulting solid was triturated with MeOH to provide methyl 6-methyl-2- naphthoate.

[0309] Step 2: 6-Methyl-2-naphthoic acid. To a stirring suspension of methyl 6- methyl-2-naphthoate (1.76 g, 8.79 mmol) in MeOH (10 mL) and THF (10 mL) was added 3N aqueous NaOH (10 mL). The resulting mixture was heated to 50 °C for 3hrs, diluted with IN aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo to provide 6-methyl-2-naphthoic acid.

[0310] Step 3: The title compound was prepared in an analogous manner to Example 88, Step 2 using l-(2-amino-5-chloro-4-methoxyphenyl)-lH-tetrazol-5(4H)-one and 6-methyl-2- naphthoic acid as starting materials. LC-MS: 408 (M-H) " . Example 90. iy-(4-Chloro-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-yl )phenvn-6- cyclopropyl-2-naphthamide

[0311] Step 1 : 6-Cyclopropyl-2-naphthoic acid was prepared in an analogous manner to Example 89, Steps 1 and 2 using cyclopropylboronic acid as starting material.

[0312] Step 2: The title compound was prepared in an analogous manner to Example 88, Step 2 using l-(2-amino-5-chloro-4-methoxyphenyl)-lH-tetrazol-5(4H)-one and 6- cyclopropyl-2-naphthoic acid as starting materials. LC-MS: 434 (Μ-Η) " .

Example 91. iV-(4-Chloro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnphenvn-6-c vano-2- naphthamide

[0313] The title compound was prepared in an analogous manner to that described for Example 32 using 6-cyano-2-naphthoyl chloride (prepared analogously to Intermediate 5). The desired material was isolated by precipitation of crude product from a DMSO solution with water. LC-MS: 391 (M+H) + . Example 92. 2,2-Difluoro-6-(6-fluoro-2-naphthamido)benzo[dl [l,3]dioxole-5-carboxylic acid (NXT5416)

[0314] The title compound was prepared in an analogous manner to Example 3 using methyl 6-amino-2,2-difluorobenzo[d][l,3]dioxole-5-carboxylate (described in Example 73) and 6-fluoro-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 388 (M-H) " .

Example 93. 2-(2-Naphthamido)-5-chloro-4-(methoxymethyl)benzoic acid

[0315] Step 1 : Methyl 2-amino-5-chloro-4-(methoxymethyl)benzoate. To a solution of methyl 2-amino-4-bromo-5-chlorobenzoate (200 mg, 0.75 mmol) in dioxane (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043mmol) 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 was concentrated in vacuo and the residue purified by column chromatography (Si0 2 , gradient Hexanes -> EtOAc) to afford the desired product.

[0316] Step 2: Methyl 2-(2-naphthamido)-5-chloro-4-(methoxymethyl)benzoate was prepared in an analogous fashion as that described for Step 3 of Example 50, using 2-naphthoyl chloride.

[0317] Step 3: To a solution of methyl 2-(2-naphthamido)-5-chloro-4- (methoxymethyl)benzoate (90 mg, 0.23 mmol) in THF (1 mL) and MeOH (1 mL) was added LiOH (1M, 1 mL, 1 mmol). The solution was concentrated in vacuo and the residue purified by column chromatography (CI 8 reverse phase, water 0.1% NH 3 H 2 0 -> MeCN 0.1% NH 3 H 2 0) to afford the title compound. LC-MS: 368 (M-H) " .

Example 94. iy-(4-chloro-5-methoxy-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol- 3-vnphenyl)-7- fluoroquinoline-3-carboxamide

[0318] Step 1. 2-Amino-5-chloro-4-methoxybenzonitrile. Into a 100-mL round- bottom flask, was placed 2-amino-4-methoxybenzonitrile (2.0 g, 13.50 mmol), tetrahydrofuran (40 mL) and N-chlorosuccinimide (2.7 g, 20.2 mmol). The resulting solution was stirred for 16 hrs at 60 °C. The resulting solution was extracted with ethyl acetate and the organic phases combined. The combined organics were evaporated in vacuo and the residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 1.54 g (62%) of 2- amino-5-chloro-4-methoxybenzonitrile as a light red solid.

[0319] Step 2. 2-Amino-5-chloro-N-hydroxy-4-methoxybenzene-l-carboximidamid e. Into a 100-mL round-bottom flask, was placed 2-amino-5-chloro-4-methoxybenzonitrile (1.54 g, 8.43 mmol), NH 2 OH HC1 (1.16 g, 16.9 mmol), ethanol (30 mL) and DIEA (3.27 g, 25.3 mmol). The resulting solution was stirred for 16 hrs at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum, diluted with EtOAc, washed with 15 mL of water, the organic phases dried, filtered and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (2/3). This resulted in 1.3 g (71%) of 2-amino-5- chloro-N-hydroxy-4-methoxybenzene-l-carboximidamide as a light yellow solid.

[0320] Step 3. 3-(2-Amino-5-chloro-4-methoxyphenyl)-4,5-dihydro-l,2,4-oxadi azol- 5-one. Into a 250-mL round-bottom flask, was placed ethanol (50 mL) and sodium metal (1.03 g, 44.5 mmol) and the resulting solution stirred for 3 hrs in a water/ice bath. 2-Amino-5-chloro-N- hydroxy-4-methoxybenzene-l-carboximidamide (1.2 g, 5.56 mmol) was added and the resulting solution was stirred for an additional 1 hr while the temperature was maintained at 80 °C in an oil bath. Diethyl carbonate (5.26 g, 44.5 mmol) was added and the resulting solution was maintained at 80 °C in an oil bath for 16 hrs. The resulting mixture was concentrated under vacuum. The solids were collected by filtration and washed with water and dried in vacuo. This resulted in 810 mg (60%) of 3-(2-amino-5-chloro-4-methoxyphenyl)-4,5-dihydro-l,2,4- oxadiazol-5-one as a light yellow solid.

[0321] Step 4. Into a 25-mL round-bottom flask was placed 7-fluoroquinoline-3- carboxylic acid (100 mg, 0.52 mmol), DCE (4 mL), 3-(2-amino-5-chloro-4-methoxyphenyl)-4,5- dihydro-l,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 for 12 hrs at 60 °C in an oil bath. The resulting mixture was concentrated under vacuum and washed with 10 mL of methanol. The solids were collected by filtration to afford the title compound as a light yellow solid. LC-MS 415 (M+H) + .

Example 95; iy-(4-Bromo-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnp henyl)-6- fluoro-2-naphthamide

[0322] The title compound was prepared in an analogous manner to Example 86 using iodomethane in Step 1, NBS/DMF in Step 5, and 6-fluoro-2-naphthoyl chloride (Intermediate 5) in the final step. LC-MS: 456 (M-H) " .

Example 96. iy-(4-Bromo-5-methoxy-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-yl) phenvn-6- chloro-2-naphthamide

[0323] The title compound was prepared in an analogous manner to Example 86 using iodomethane in Step 1, NBS/DMF in Step 5, and 6-chloro-2-naphthoyl chloride (prepared analogously to Intermediate 5) in the final step. LC-MS: 474 (M-H) " .

Example 97. iV-(4-Chloro-2-(5-oxo-4,5-dihvdro-l,3.,4-oxadiazol-2-vnphenv n-6-fluoro-2- naphthamide

[0324] Step 1 : 5-Chloro-2-nitrobenzohydrazide. To a solution of 5-chloro-2- nitrobenzoic acid (4.03 g, 20.0 mmol) in THF (100 mL) at room temperature was added carbonyl diimidazole (3.56 g, 22.0 mmol). The resulting mixture was stirred for 45 min, after which time hydrazine monohydrate (3.5 mL, 72.0 mmol) was added, and stirring was continued for an additional 2 hrs. Volatiles were then removed by rotary evaporation, and the resulting crude residue was dissolved in EtOAc (300 mL) and washed with saturated aq. NaHCC (3 x 50 mL), water (100 mL), and brine (50 mL). The combined aqueous layers were then back-extracted with EtOAc (100 mL). The combined EtOAc layers were dried over MgS0 4 , filtered, and concentrated to dryness to afford 5-chloro-2-nitrobenzohydrazide as a white solid.

[0325] Step 2: 5-(5-Chloro-2-nitrophenyl)-l,3,4-oxadiazol-2(3Yi)-one. To a solution of 5-chloro-2-nitrobenzohydrazide (0.417 g, 1.94 mmol) and triethylamine (0.94 mL, 6.79 mmol) in THF (20 mL) at room temperature was added carbonyl diimidazole (0.346 g, 2.13 mmol). The resulting mixture was stirred for 2 hrs, diluted with EtOAc (75 mL), washed sequentially with IN HCl (20 mL), water (20 mL), and brine (20 mL), then dried over MgS0 4 , filtered and concentrated to dryness to afford 5-(5-chloro-2-nitrophenyl)-l,3,4-oxadiazol-2(3H)- one as a white solid.

[0326] Step 3: 5-(2-Amino-5-chlorophenyl)-l,3,4-oxadiazol-2(3Yi)-one. To a stirred solution of 5-(5-chloro-2-nitrophenyl)-l,3,4-oxadiazol-2(3H)-one (0.372 g, 1.54 mmol) in absolute ethanol (15 mL) was sequentially added tin(II) chloride (0.966 g, 5.09 mmol) and 12N aqueous HCl (1.28 mL, 15.4 mmol). The resulting mixture was heated to 60 °C and stirred for 15 min, at which time TLC and LC-MS analysis revealed full consumption of 5-(5-chloro-2- nitrophenyl)-l,3,4-oxadiazol-2(3H)-one starting material. The reaction mixture was cooled to room temperature, diluted with EtOAc (120 mL), washed with water (4 x 20 mL) and brine (20 mL), dried over MgS0 4 , filtered and concentrated to afford 5-(2-amino-5-chlorophenyl)-l,3,4- oxadiazol-2(3H)-one as an off-white solid.

[0327] Step 4: N-(4-Chloro-2-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl )-6- fluoro-2-naphthamide. The title compound was prepared in an analogous manner to that described in Example 3, Step 1 using the following starting materials: 5-(2-amino-5- chlorophenyl)-l,3,4-oxadiazol-2(3H)-one and 6-fluoro-2-naphthoic acid to afford the title compound. LC-MS: 382 (M-H) " .

Example 98; 7-(6-Chloro-2-naphthamido)-2,3-dihydrobenzo[b1 [l,4]dioxine-6-carboxylic acid

[0328] The title compound was prepared in an analogous manner to Example 59, using 7-amino-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid and 6-chloro-2-naphthoyl chloride (prepared analogously to Intermediate 5). LC-MS: 384 (M+H) + . Example 99; 7-(6-Cyano-2-naphthamido)-2,3-dihydrobenzo[bl [l,4]dioxine-6-carboxylic acid (NXT5476)

[0329] Step 1 : 6-Cyano-2 -naphthoic acid. To a suspension of methyl 6-cyano-2- naphthoate (1.0 g, 4.73 mmol) in /7-dioxane (20 mL) and water (10 mL) was added LiOH.H 2 0 (500 mg, 11.9 mmol). The cloudy suspension dissolves over a period of 2 hrs after which the hydrolysis is complete by LC-MS analysis. IN HC1 (20 mL) was added and the solution stirred for 10 mins after which the precipitate was filtered, washed with water and dried in vacuo to afford the desired acid used without further purification.

[0330] Step 2: The title compound was prepared in an analogous manner to Example 59, using 7-amino-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid and 6-cyano-2-naphthoyl chloride (prepared analogously to Intermediate 5). LC-MS 375 (M+H) + .

Example 100. 5-Cyano-4-ethoxy-2-(6-fluoro-2-naphthamido)benzoic acid

[0331] Step 1 : 2-Ethoxy-4-nitrobenzonitrile. To a solution of 2-hydroxy-4- nitrobenzonitrile (2.5 g, 15.2 mmol) in DMF (20 mL) was added potassium carbonate (4.2 g, 30.3 mmol) followed by iodoethane (1.3 mL, 16.3 mmol). After stirring at ambient temperature for 16 hrs, the mixture was diluted with water and extracted with EtOAc. The combined organic phases washed with water, separated, dried (MgS0 4 ), filtered and evaporated in vacuo. The isolated compound was used without further purification. [0332] Step 2: 4-Amino-2-ethoxybenzonitrile. 2-Ethoxy-4-nitrobenzonitrile (2.1 g, 10.93 mmol) was dissolved in EtOH (50 mL) to which was added Pd/C (10% wet; 150 mg) and the solution sparged with hydrogen gas and stirred under hydrogen for 3 hrs. Dichloromethane was added to the solution and filtered through celite. Evaporation of the solvent afforded the aniline which was used without further purification.

[0333] Step 3: 4-Amino-2-ethoxy-5-iodobenzonitrile. To a solution of 4-amino-2- ethoxybenzonitrile (1.92 g, 11.8 mmol) in acetic acid (25 mL) was added N-iodosuccinimide (2.7 g, 12.0 mmol) and stirred at ambient temperature until complete reaction as judged by TLC analysis. Water (50 mL) was added and the resulting precipitate filtered, washed with water and dried in vacuo to afford the iodobenzonitrile which was used without further purification.

[0334] Step 4: Bis-tert-butoxycarbonyl (2-iodo-4-cyano-5-ethoxy)aniline. 4-Amino-2- ethoxy-5-iodobenzonitrile (2.8 g, 9.72 mmol) was dissolved in THF (60 mL) to which was added DMAP (250 mg, cat.) and di-ieri-butyl dicarbonate (5.4 mL, 23.3 mmol) and the solution stirred at ambient temperature for 48 hrs. The reaction mixture was evaporated to dryness and the residue taken up in EtOAc, washed with water, separated, dried (MgS0 4 ), filtered and evaporated in vacuo to afford the desired compound.

[0335] Step 5: tert-Butyl 2-((tert-butoxycarbonyl)amino)-5-cyano-4-ethoxybenzoate. To a solution of bis-teri-butoxycarbonyl (2-iodo-4-cyano-5-ethoxy)aniline (2.06 g, 4.21 mmol) in THF (100 mL) cooled to -78 °C was added «-BuLi (2.5 M soln. in Hexanes; 2.2 mL, 5.5 mmol). After stirring at -78 °C for 1.5 hrs, sat'd. aq. NH 4 C1 soln. was added, and the reaction mixture allowed to warm to ambient temperature, diluted with EtOAc, and washed with water. The organic phase was separated, dried (MgS0 4 ), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 50% DCM in Hexanes to afford the desired compound.

[0336] Step 6: 2-Amino-5-cyano-4-ethoxybenzoic acid. To a solution of tert-butyl 2- ((tert-butoxycarbonyl)amino)-5-cyano-4-ethoxybenzoate (2.0 g, 5.52 mmol) in DCM (30 mL) was added trifluoroacetic acid (20 mL). After stirring for 16 hrs at ambient temperature the solvent was removed in vacuo to afford the title compound isolated as the TFA salt and used without further purification.

[0337] Step 7: Methyl 2-amino-5-cyano-4-ethoxybenzoate. The previously isolated acid (1.06 g, 3.31 mmol) was dissolved in DMF (11 mL) to which was added potassium carbonate (1.4 g, 10.1 mmol) followed by iodomethane (220 μΕ, 3.5 mmol). After stirring for 16 hrs, the reaction mixture was diluted with water and EtOAc; the organic phase separated, washed with water, dried (MgS0 4 ), filtered and evaporated in vacuo. Trituration of the residue with EtOAc/Hexanes afforded the desired material as a solid which was isolated by filtration.

[0338] Step 8: The title compound was prepared in an analogous manner to that described for Example 3 using the aforementioned methyl 2-amino-5-cyano-4-ethoxybenzoate and 6-fluoro-2-napthoic acid followed by typical ester hydrolysis conditions. LC-MS 379 (M+H) + .

Example 101. 2-(6-Chloro-2-naphthamido)-5-cvano-4-methoxybenzoic acid

[0339] The title compound was prepared in an analogous fashion to that described for Example 3 using methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 6-chloro-2- naphthoic acid (Intermediate 1) followed by typical ester hydrolysis conditions. LC-MS 379 (M- H)-.

Example 102. 7-(7-Fluoroquinoline-3-carboxamido)-2,3-dihydrobenzo[b1 [l,4]dioxine-6- carboxylic acid

[0340] The title compound was prepared in an analogous fashion to that described for Example 59 using 7-fluoroquinoline-3-carboxylic chloride and 7-amino-2,3- dihydrobenzo[b][l,4]dioxine-6-carboxylic acid. LC-MS 369 (M+H) + . Example 103. 5-Chloro-4-methoxy-2-(6-methyl-2-naphthamido)benzoic acid

[0341] The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-methyl-2-naphthoic acid (prepared in Example 89, Step 2) followed by typical ester hydrolysis conditions. LC-MS: 368 (M-H) " .

Example 104. 5-Chloro-2-(6-cvclopropyl-2-naphthamido)-4-methoxybenzoic acid

[0342] The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-cyclopropyl-2-naphthoic acid (prepared in Example 90, Step 1) followed by typical ester hydrolysis conditions. LC-MS: 394 (M-H) " .

Example 105. 5-Chloro-2-(6-(difluoromethvn-2-naphthamido)-4-methoxybenzoi c acid

[0343] Step 1 : 2-Bromo-6-(difluoromethyl)naphthalene. To a stirred solution of 6- bromo-2-naphthaldehyde (3.7 g, 15.7 mmol) in DCM (50 mL) was added DAST (2.4 mL, 18.1 mmol). The resulting mixture was stirred at 30 °C for 48 hrs then diluted with saturated aqueous sodium bicarbonate and extracted with DCM. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with Hexanes to provide 2-bromo-6-(difluoromethyl)naphthalene.

[0344] Step 2: Methyl 6-(difluoromethyl)-2-naphthoate . To a stirred solution of 2- bromo-6-(difluoromethyl)naphthalene (2.8 g, 10.9 mmol), palladium(II) acetate (122 mg, 0.545 mmol) and l,3-bis(diphenylphosphino)propane (225 mg, 0.545 mmol) in anhydrous DMF (100 mL) and anhydrous MeOH (9 mL) was added TEA (3 mL). Carbon monoxide was bubbled through the resulting mixture for 15 min at rt before heating to 70 °C under 1 atm of CO for 14 hrs. After cooling to rt the mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 20% EtOAc in Hexanes to provide methyl 6-(difluoromethyl)-2-naphthoate.

[0345] Step 3: 6-(Difluoromethyl)-2-naphthoic acid was prepared in an analogous manner to Example 89, Step 2 using methyl 6-(difluoromethyl)-2-naphthoate as a starting material.

[0346] Step 4: The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-(difluoromethyl)-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 404 (M-H) " .

Example 106. 5-Chloro-4-methoxy-2-(6-(trifluoromethyl)-2-naphthamido)benz oic acid

[0347] The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-(trifluoromethyl)-2-naphthoic acid (prepared in Example 88, Step 1) followed by typical ester hydrolysis conditions. LC-MS: 422 (M-H) " . Example 107. 5-Chloro-2-(6-(difluoromethoxy)-2-naphthamido)-4-methoxybenz oic acid

[0348] Step 1 : Methyl 6-(difluoromethoxy)-2-naphthoate was prepared in an analogous manner to Example 58, Step 2 using methyl 6-hydroxy-2-naphthoate as a starting material.

[0349] Step 2: 6-(Difluoromethoxy)-2-naphthoic acid was prepared in an analogous manner to Example 89, Step 2 using methyl 6-(difluoromethoxy)-2-naphthoate as a starting material.

[0350] Step 3 : The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-(difluoromethoxy)-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 420 (M-H) " .

Example 108. 5-Chloro-4-methoxy-2-(6-(trifluoromethoxy)-2-naphthamido)ben zoic acid

[0351] Step 1 : Methyl 6-(bromodifluoromethoxy)-2-naphthoate. To an anhydrous DMF (12 mL) solution of methyl 6-hydroxy-2-naphthoate (1.2 g, 6.0 mmol) at 0 °C in a pressure vessel was added sodium hydride (720 mg, 18 mmol, 60% in mineral oil) and the resulting mixture was stirred for 10 min followed by addition of potassium teri-butoxide (740 mg, 6.6 mmol) and dibromodifluoromethane (5 g, 23.8 mmol). The vessel was sealed and the mixture was heated to 70 °C for 15 hrs. After cooling to rt the mixture was diluted with EtOAc and IN aqueous HC1. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EtOAc in Hexanes. Product containing fractions were further purified by CI 8 chromatography eluting with a gradient of 5% to 100% MeCN + 0.1% formic acid in water + 0.1% formic acid to provide methyl 6-(bromodifluoromethoxy)-2-naphthoate.

[0352] Step 2: Methyl 6-(trifluoromethoxy)-2-naphthoate. To a stirring solution of 6- (bromodifluoromethoxy)-2-naphthoate (367 mg, 1.11 mmol) in anhydrous DCM at -78 °C was added silver tetrafluoroborate (475 mg, 2.44 mmol). The resulting mixture was stirred at rt for 14 hrs then diluted with EtOAc and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EtOAc in Hexanes to provide methyl 6-(trifluoromethoxy)-2-naphthoate.

[0353] Step 3: 6-(Trifluoromethoxy)-2-naphthoic acid was prepared in an analogous manner to Example 89, Step 2 using methyl 6-(trifluoromethoxy)-2-naphthoate as a starting material.

[0354] Step 4: The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-(trifluoromethoxy)-2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 438 (M-H) " .

Example 109. iV-(4-Chloro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnphenvn-6-m ethyl-2- naphthamide

[0355] The title compound was prepared in an analogous manner to Example 32 using 6-methyl-2-naphthoyl chloride (prepared analogously as described for Intermediate 5 using the corresponding acid prepared in Example 89, Step 2) as starting material. LC-MS: 378 (M-H) " Example 110. iy-(4-Chloro-2-(5-oxo-4,5-dihvdro-lH-tetrazol-l-vnphenyl)-6- cvclopropyl-2- naphthamide

[0356] The title compound was prepared in an analogous manner to Example 32 using 6-cyclopropyl-2-naphthoyl chloride (prepared analogously as described for Intermediate 5 using the corresponding acid prepared in Example 90, Step 1) as starting material. LC-MS: 404 (M-H) " .

Example 111. N-( 4-Chloro-2-( 5-oxo-4,5-dihydro- lH-tetrazol- l-vDphenvD-6-

(trifluoromethoxy)-2-naphthamide

[0357] The title compound was prepared in an analogous manner to Example 32 using 6-(trifluoromethoxy)-2-naphthoic acid (prepared analogously as described for Intermediate 5 using the corresponding acid prepared in Example 108, Step 3) as starting material. LC-MS: 448 (M-H) " . Example 112. 5-Cvano-2-(6-fluoro-2-naphthamido)-4-(oxetan-3-yloxy)benzoic acid

[0358] Step 1 : 2-Amino-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) was added CuCN (1.2 g, 13.4 mmol). The solution was heated to 200 °C for 2 hrs. After cooling to 60 °C a solution of FeC (10 g) in water (10 mL) and HC1 (36%, 1.5 mL) was added. After stirring for 1 hr, the suspension was filtered off to yield the solid crude product. Purification by column chromatography (C18 reverse phase, water 0.1% NH 3 H 2 0 -> MeCN 0.1% NH 3 H 2 0) afforded the desired product.

[0359] Step 2: 2-Amino-5-cyano-4-(oxetan-3-yloxy)benzoic acid was prepared in an analogous manner to that described in Example 55, Step 1 using oxetan-3-ol and 2-amino-5- cyano-4-fluorobenzoic acid.

[0360] Step 3: The title compound was prepared in an analogous manner to that described in Example 50, Step 3 using 6-fluoro-2-naphthoyl chloride (Intermediate 5) and 2- amino-5-cyano-4-(oxetan-3-yloxy)benzoic acid . LC-MS: 405 (M-H) " .

Example 113. 5-Cvano-2-(7-fluoroquinoline-3-carboxamido)-4-(oxetan-3-ylox y)benzoic acid

[0361] The title compound was prepared in a manner analogous to that described for Example 50, Step 3 using 2-amino-5-cyano-4-(oxetan-3-yloxy)benzoic acid (Example 112, Step 1) and 7-fluoroquinoline-3-carbonyl chloride (prepared in an analogous fashion to Intermediate 5). LC-MS: 406 (M-H) " .

Example 114. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(methoxymethvnbenzoic acid

[0362] The title compound was prepared in an analogous manner to that described for Example 93 using 6-fluoro-2-naphthoic acid. LC-MS: 386 (M-H) " .

Example 115. 5-Cvano-4-methoxy-2-(2-methylbenzo[b]thiophene-5-carboxamido )benzoic acid

[0363] The title compound was prepared in an analogous manner to Example 3 using 3-methylbenzo[b]thiophene-5-carboxylic acid (Example 40, Step 1) and DCM with methyl 2- amino-5-cyano-4-methoxybenzoate (Intermediate 2) followed by typical ester hydrolysis conditions. LC-MS: 365 (M-H) " .

Example 116. 8-(6-Fluoro-2-naphthamido)-3,4-dihydro-2H-benzo[b1 [l,4]dioxepine-7- carboxylic acid

[0364] The title compound was prepared in an analogous manner to that described for Example 49 using 8-amino-3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid and 6- fluoro-2-naphthoyl chloride (Intermediate 5). The isolated oxazinone was stirred with LiOH monohydrate (5 equiv) in a mixture of MeOH, water and dioxane (~8 mL of a 1 : 1 : 1 mixture) until complete conversion to the acid was apparent by LC-MS analysis. Addition of IN HC1 to this reaction mixture afforded a colorless precipitate which was filtered, washed with water and dried in vacuo. Trituration in acetone/Hexanes afforded pure product. LC-MS: 382 (M+H) + .

Example 117. 5-(Difluorometho -2-(6-fluoro-2-naphthamido)-4-methoxybenzoic acid

[0365] The title compound was prepared in an analogous 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-naphthamido)-4-(oxetan-3-yloxy)benzoi c acid

[0366] Step 1 : 2-Amino-5-fluoro-4-(oxetan-3-yloxy)benzoic acid. Prepared in an analogous manner to that described for Example 55 using 2-amino-4,5-difluorobenzoic acid as starting material.

[0367] Step 2: The title compound was prepared in an analogous manner to Example 3 using 2-amino-5-fluoro-4-(oxetan-3-yloxy)benzoic acid and 6-fluoro-2-naphthoic acid as starting materials. LC-MS: 398 (M-H) " . Example 119. 2-(2-Naphthamido)-5-cvano-4-(oxetan-3-yloxy)benzoic acid

[0368] The title compound was prepared in an analogous manner to that described for Example 112. LC-MS: 387 (M-H) " .

Example 120. 2-Chloro-2'-fluoro-5-(6-fluoro-2-naphthamido)-[l,l'-biphenyl l-4-carboxylic acid

[0369] Step 1 : Methyl 2-amino-4-bromo-5-chlorobenzoate. To a stirring solution of 2-amino-4-bromo-5-chlorobenzoic acid (5.00 g, 20.0 mmol) and K 2 CO 3 (8.28, 59.88 mmol) in DMF (100 mL) at rt was added iodomethane (1.23 rriL, 20.0 mmol). The mixture was stirred for 16 hrs at rt and partitioned between EtOAc and brine. The organics were washed once more with brine, water (3X), concentrated, and co-evaporated with EtOAc in vacuo. The resulting solid was sufficiently pure and used without further purification.

[0370] Step 2: Methyl 4-bromo-5-chloro-2-(6-fluoro-2-naphthamido)benzoate was prepared in an analogous manner to Example 3, Step 1 using 6-fluoro-2-naphthoic acid and DCM with methyl 2-amino-4-bromo-5-chlorobenzoate to afford methyl 4-bromo-5-chloro-2-(6- fluoro-2-naphthamido)benzoate.

[0371] Step 3: To a solution of methyl 4-bromo-5-chloro-2-(6-fluoro-2- naphthamido)benzoate (0.2 g, 0.46 mmol) in dioxane (12 mL) was added 2-fluorophenylboronic acid (0.071 mg, 0.50 mmol) and sat. aq. NaHCC (3 mL). The resulting mixture was sparged with nitrogen gas before tetrakis(triphenylphosphine) palladium(O) (0.037 g, 0.032 mmol) was added. The reaction was then sealed and heated at 90 °C for 16 hrs. The reaction mixture was allowed to cool to rt, syringe filtered, and partitioned between EtOAc and 1 M HCl (aq.). The organic phase was extracted once more with 1 M HCl, water (2X), brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The crude residue was suspended in MeOH, stirred for 16 hrs, and filtered to afford the pure title compound. LC-MS: 436 (M-H) " .

Example 121. iV-(4-Cvano-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vnphenvn- 7- fluoroquinoline-3-carboxamide

[0372] Step 1 : 2-Amino-5-bromo-N-hydroxybenzene-l-carboximidamide. Into a 250- mL round-bottom flask, was placed 2-amino-5-bromobenzonitrile (4.0 g, 20.30 mmol), hydroxylamine hydrochloride (2.82 g, 40.58 mmol), ethanol (45 mL), water (15 mL) and sodium bicarbonate (5.14 g, 61.18 mmol). The resulting solution was stirred for 16 hrs at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum and was washed with 3x25 mL of water. The resulting solution was extracted with 3x50 mL of EtOAc and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The isolated carboximidamide was used without further purification.

[0373] Step 2: 3-(2-Amino-5-bromophenyl)-4,5-dihydro-l,2,4-oxadiazol-5-one. Into a 250-mL round-bottom flask, was placed ethanol (60 mL), Na (2.0 g), 2-amino-5-bromo-N- hydroxybenzene-1 -carboximidamide (2.5 g, 10.87 mmol,) and diethyl carbonate (6.44 g, 54.52 mmol). The resulting solution was stirred for 1 h at 0 °C in an ice/salt bath and for an additional 16 hrs while the temperature was maintained at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum and washed with 3x30 mL of water. The solids were collected by filtration to afford the desired l,2,4-oxadiazol-5-one used without further purification.

[0374] Step 3: ~ N-(4-bromo-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)p henyl)-7- fluoroquinoline-3-carboxamide. Into a 25-mL round-bottom flask was placed 7-fluoroquinoline- 3-carboxylic acid (200 mg, 1.05 mmol), DCE (10 mL), 3-(2-amino-5-bromophenyl)-4,5-dihydro- l,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 for 12 hrs at 60 °C in an oil bath. The resulting solution was diluted with 10 mL of methanol. The solids were collected by filtration. This resulted in 290 mg (crude) of N-[4-bromo-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl] -7- fluoroquinoline-3-carboxamide as a yellow solid.

[0375] Step 4: Into a 25-mL round-bottom flask, was placed N-[4-bromo-2-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl]-7-fluoroquinoline-3 -carboxamide (290 mg, 0.68 mmol), N,N-dimethylformamide (10 mL), (i-Bu) 3 P (13.7 mg, 0.07 mmol), Pd 2 (dba) 3 CHCl 3 (70.1 mg, 0.06 mmol), Zn(CN)2 (235.8 mg, 2.03 mmol). The resulting solution was stirred for 5 hrs at 85 °C in an oil bath. The reaction was then quenched by the addition of 10 mL of water. The solids were collected by filtration. This afforded the title compound as a light yellow solid. LC-MS: 376 (M+H) + .

Example 122. 5-Chloro-2-(6-chloro-2-naphthamido)-4-methoxybenzoic acid

[0376] The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-chloro-4-methoxybenzoate and 6-chloro-2-naphthoic acid (Intermediate 1) followed by typical ester hydrolysis conditions. LC-MS: 388 (M-H) " .

Example 123. 5-Cyano-4-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid

[0377] The title compound was prepared in an analogous manner to that described for Example 50, Step 3 using 2-amino-5-cyano-4-fluorobenzoic acid and 6-fluoro-2-naphthoyl chloride (Intermediate 5). LC-MS: 351 (M-H) " .

Example 124. 4-Cvano-5-fluoro-2-(6-fluoro-2-naphthamido)benzoic acid

[0378] Step 1 : 2-Amino-4-bromo-5-fluorobenzoic acid. To a solution of 4-bromo-5- fluoro-2-nitrobenzoic acid (2.64 g, 10 mmol) in THF (20 rriL) was added Raney-Nickel (1 g suspension). Hydrogen was bubbled into the solution for 3 hrs. The suspension was filtered, the filtrate was concentrated in vacuo and the isolated material purified by column chromatography (CI 8 reverse phase, water 0.1% + NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) to afford the desired product.

[0379] Step 2: 2-Amino-4-cyano-5-fluorobenzoic acid was prepared in an analogous fashion to Step 1 of Example 112.

[0380] Step 3: The title compound was prepared in an analogous manner to that described for Example 50, Step 3 using 2-amino-4-cyano-5-fluorobenzoic acid and 6-fluoro-2- naphthoyl chloride (Intermediate 5). LC-MS: 351 (M-H) " .

Example 125. 2-(6-Chloro-2-naphthamido)-5-(difluoromethoxy)benzoic acid

[0381] Step 1 : Methyl 5-(difluoromethoxy)-2-nitrobenzoate was prepared in an analogous manner to Example 58, Step 2 using methyl 5-hydroxy-2-nitrobenzoate. [0382] Step 2: Methyl 2-amino-5-(difluoromethoxy)benzoate. To a solution of methyl 5-(difluoromethoxy)-2-nitrobenzoate (516 mg, 2.1 mmol) in MeOH (20 mL) was added tin(II) chloride (1.3 g, 6.9 mmol) followed by concentrated HC1 (1.7 mL). The resulting mixture was heated to 60 °C for 1 hr. After cooling to rt the mixture was diluted with EtOAc and IN aqueous NaOH. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 30% EtOAc in Hexanes to provide methyl 2-amino-5-(difluoromethoxy)benzoate.

[0383] Step 3 : The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-(difluoromethoxy)benzoate and 6-chloro-2-naphthoic acid (Intermediate 1) followed by typical ester hydrolysis conditions. LC-MS: 390 (M-H) " .

Example 126. 7-(2-Naphthamido)-2,3-dihvdrobenzo[b1 [l,4]dioxine-6-carboxylic acid

[0384] The title compound was prepared in an analogous manner to Example 49 using 7-amino-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid. LC-MS: 348 (M-H) " .

Example 127. 7-(6-(Trifluoromethyl)-2-naphthamido)-2,3-dihydrobenzo[b1 [l,4]dioxine-6- carboxylic acid

[0385] The title compound was prepared in an analogous manner to Example 49 using 7-amino-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid and 6-(trifluoromethyl)-2- naphthoic acid (prepared in Example 88, Step 1) as starting materials. LC-MS: 416 (M-H) " . Example 128. 2-(2-Naphthamido)-5-cvano-4-methoxybenzoic acid

[0386] The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 2-naphthoic acid followed by typical ester hydrolysis conditions. LC-MS: 345 (M-H) " .

Example 129. 5-Cvano-4-methoxy-2-(6-(trifluoromethyl)-2-naphthamido)benzo ic acid

[0387] The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 6-(trifluoromethyl)-2- naphthoic acid (prepared in Example 88, Step 1) followed by typical ester hydrolysis conditions. LC-MS: 413 (M-H) " .

Example 130. 2-(6-Chloro-2-naphthamido)-5-cvano-4-ethoxybenzoic acid

[0388] The title compound was prepared in an analogous manner to Example 3 using 6-chloro-2-naphthoic acid (Intermediate 1) and methyl 2-amino-5-cyano-4-ethoxybenzoate (Example 100, Step 7) followed by typical ester hydrolysis conditions. LC-MS: 393 (M-H) " .

Example 131. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(pyridin-4-vnbenzoic acid

[0389] The title compound was prepared in an analogous manner to Example 3 using pyridin-4-ylboronic acid. LC-MS: 419 (M-H) " .

Example 132. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(pyridin-3-vnbenzoic acid

[0390] The title compound was prepared in an analogous manner to Example 3 using pyridine-3-ylboronic acid. LC-MS: 419 (M-H) " .

Example 133. 5-Chloro-2-(6-fluoro-2-naphthamido)-6-methoxynicotinic acid

[0391] The title compound was prepared in an analogous manner to Example 74 using 6-fluoro-2-naphthamide in Step 3. LC-MS: 375 (M+H) + . Example 134. 5-Chloro-6-ethoxy-2-(6-fluoro-2-naphthamido)nicotinic acid

[0392] The title compound was prepared in an analogous fashion to Example 74 using ethanol in Step 1 and 6-fluoro-2-naphthamide in Step 3. LC-MS: 389 (M+H) + .

Example 135. 5-Chloro-2-(6-chloro-2-naphthamido)-6-ethoxynicotinic acid

[0393] The title compound was prepared in an analogous fashion to Example 74 using ethanol in Step 1 and 6-chloro-2-naphthamide in Step 3. LC-MS: 405 (M+H) + .

Example 136. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-(pyridine-2-vDbenzoic acid

[0394] Step 1 : Methyl 5-chloro-2-(6-fluoro-2-naphthamido)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzoate. Methyl 4-bromo-5-chloro-2-(6-fluoro-2- naphthamido)benzoate (0.50 g, 1.15 mmol, Intermediate from Example 120, Step 2), bis(pinacolato)diborane (0.378 g, 1.49 mmol), KOAc (0.34 g, 3.45 mmol) were suspended in dioxane (10 mL) and the resulting solution was subsurface purged with N 2 for 5 minutes. Next, Pd(dppf)Cl 2 (0.126 g, 0.17 mmol) was added and the resulting mixture was stirred at 95 °C for 16 hrs. The solution was cooled to rt and partitioned between EtOAc and brine. The organics were washed once more with brine, water (2X), filtered through celite and concentrated. The residue was used without further purification.

[0395] Step 2: The title compound was prepared in an analogous manner to Example 120, Step 3 using 2-bromopyridine and methyl 5-chloro-2-(6-fluoro-2-naphthamido)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate followed by typical ester hydrolysis conditions. LC-MS: 419 (M-H) " .

Example 137. 2-Chloro-5-(6-fluoro-2-naphthamido)isonicotinic acid

[0396] Step 1 : Methyl 2-chloro-5-(6-fluoro-2-naphthamido)isonicotinate. To a 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 rriL) was added dropwise methanesulfonyl chloride (0.124 mL, 1.61 mmol). Hunigs base (0.560 rriL, 3.22 mmol) was then added, followed by DMAP (13.1 mg, 0.107 mmol) and the resulting solution was stirred at rt overnight. The solvent was evaporated in vacuo and the residue then re-suspended in DCM and ether. The precipitate was collected via vacuum filtration, washed with ether to furnish the desired material.

[0397] Step 2: To a stirring suspension of methyl 2-chloro-5-(6-fluoro-2- naphthamido)isonicotinate (50 mg, 0.14 mmol) in THF (1.2 mL) and MeOH (0.8 mL) was added aqueous IN NaOH solution (0.42 mL, 0.42 mmol) and the resulting solution was stirred overnight at room temperature. The reaction was acidified with IN HC1 and the suspension was stirred at rt for 15 minutes before the volatiles were evaporated. Trituration of the crude solid with water and collected via vacuum filtration and washing with water then ether yielded the title compound as a white solid. LC-MS: 343 (M-H) " . Example 138. 5-Chloro-2-(6-fluoro-2-naphthamido)-4-isopropoxybenzoic acid

[0398] Step 1 : Methyl 2-amino-5-chloro-4-isopropoxybenzoate was prepared in an analogous manner to that described in Example 100, Steps 3 to 7, using N-bromosuccinimide in place of N-iodosuccinimide with 4-chloro-3-isopropoxyaniline.

[0399] Step 2: The title compound was prepared in an analogous manner to that described for Example 3 using the aforementioned methyl 2-amino-5-chloro-4- isopropoxybenzoate and 6-fluoro-2-naphthoic acid. LC-MS 402 (M+H) + .

Example 139. 5-Chloro-4-cyano-2-(6-fluoro-2-naphthamido)benzoic acid

[0400] Step 1 : Methyl 2-amino-4-chloro-5-cyanobenzoate was prepared in an analogous manner to that described in Example 100, Steps 3 to 7, using N-bromosuccinimide in place of N-iodosuccinimide with 4-amino-2-chlorobenzonitrile.

[0401] Step 2: The title compound was prepared in an analogous manner to that described for Example 3 using the aforementioned 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-naphthamido)-4-isopropoxybenzoic acid

[0402] The title compound was prepared in an analogous manner to that described for Example 3 using the aforementioned methyl 2-amino-5-chloro-4-isopropoxybenzoate (Example 138) and 6-chloro-2-naphthoic acid (Intermediate 1). LC-MS 416 (M-H) " .

Example 141. 2-(6-Chloro-2-naphthamido)-5-fluoro-4-methoxybenzoic acid

[0403] The title compound was prepared in an analogous manner to Example 32 using 2-amino-5-fluoro-4-methoxybenzoic acid prepared in Example 47, Step 3 and 6-chloro-2- naphthoyl chloride (prepared analogously to Intermediate 5) as starting materials. LC-MS: 372 (M-H) " .

Example 142. 4-Chloro-2-(6-chloro-2-naphthamido)-5-cyanobenzoic acid

[0404] Step 1 : Methyl 2-amino-4-chloro-5-cyanobenzoate was prepared in analogous manner to that described in Example 100, Steps 3 to 7, using N-bromosuccinimide place of N-iodosuccinimide with 4-amino-2-chlorobenzonitrile. [0405] Step 2: The title compound was prepared in an analogous manner to that described for Example 3 using the aforementioned methyl 2-amino-4-chloro-5-cyanobenzoate and 6-chloro-2-naphthoyl chloride (prepared analogously to Intermediate 5 from the corresponding acid). LC-MS 383 (M-H) " .

Example 143. 6-Fluoro-iV-(4-fluoro-5-(oxetan-3-yloxy)-2-(5-oxo-4,5-dihvdr o-l,2,4- oxadiazol-3-vPphenvD-2-naphthamide

[0406] Step 1 : 2-Amino-5-fluoro-4-(oxetan-3-yloxy)benzonitrile. Prepared in an analogous method to that described in Step 1 of Example 55 using 2-amino-4,5- difluorobenzonitrile and oxetan-3-ol.

[0407] Step 2: 2-Amino-5-fl oro-N-hydroxy-4-(oxetan-3-yloxy)benzimidamide. To a solution of 2-amino-5-fluoro-4-(oxetan-3-yloxy)benzonitrile (270 mg, 1.3 mmol) in EtOH (5 mL) was added hydroxylamine hydrochloride (656 mg, 9.4 mmol) and sodium methoxide (512 mg, 9.4 mmol). The solution was heated at 80 °C for 3 hrs. Purification by column chromatography (C18 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% ΝΗ 3 Ή 2 0) afforded the desired product.

[0408] Step 3: 3-(2-Amino-5-fluoro-4-(oxetan-3-yloxy)phenyl)-l,2,4-oxadiazo l- 5(4H)-one. To a solution of 2-amino-5-fluoro-N-hydroxy-4-(oxetan-3-yloxy)benzimidamide (60 mg, 0.25 mmol) in EtOH (2 mL), was added sodium methoxide (87 mg, 1.6 mmol) and diethyl carbonate (260 mg, 2.2 mmol) and heated to reflux for 16 hrs. Purification by column chromatography (C18 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) afforded the desired product.

[0409] Step 4: The title compound was prepared in an analogous manner to that described in Step 3 of Example 50 using 3-(2-amino-5-fluoro-4-(oxetan-3-yloxy)phenyl)-l,2,4- oxadiazol-5(4H)-one and 6-fluoro-2-naphthyl chloride. LC-MS: 438 (M-H) " . Example 144; 6-Fluoro-iV-(4-fluoro-5-methoxy-2-(5-oxo-4,5-dihvdro-l,2,4-o xadiazol-3- vDphenvD-2-naphthamide

[0410] The title compound was prepared in an analogous manner to that described for Example 143. LC-MS: 396 (M-H) " .

Example 145. 2-(6-Chloro-2-naphthamido)-5-cvano-4-(cvclopropylmethoxy)ben zoic acid

[0411] Step 1 : 2-Amino-5-cyano-4-(cyclopropylmethoxy)benzoic acid. 2-Amino-5- cyano-4-fluorobenzoic acid (0.25 g, 1.39 mmol), CS2CO3 (1.36 g, 4.16 mmol) and cyclopropylmethanol (10 mL) were combined in a sealed pressure vessel and stirred for 16 hrs at 100 °C. The solvents were evaporated and the residue diluted with EtOAc and aq. 1 M citric acid. The organic layer was extracted with water (3X) and concentrated in vacuo to afford 2- amino-5-cyano-4-(cyclopropylmethoxy)benzoic acid which was used without further purification.

[0412] Step 2. Methyl 2-amino-5-cyano-4-(cyclopropylmethoxy)benzoate was prepared in an analogous manner to Example 120, Step 1 using 2-amino-5-cyano-4- (cyclopropylmethoxy)benzoic acid.

[0413] Step 3. The title compound was prepared in an analogous manner to Example 3 using 6-chloro-2-naphthoic acid (Intermediate 1) and DCM with methyl 2-amino-5-cyano-4- (cyclopropylmethoxy)benzoate, followed by typical ester hydrolysis conditions. LC-MS: 419 (M-H) " .

Example 146. 2-(6-Chloro-2-naphthamido)-5-cvano-4-cvclobutoxybenzoic acid

[0414] The title compound was prepared in an analogous manner to Example 3 using 6-chloro-2-naphthoic acid (Intermediate 1), and DCM with methyl 2-amino-5-cyano-4- cyclobutoxybenzoate (prepared in an analogous manner to Example 145 using cyclobutanol in Step 1) followed by typical ester hydrolysis conditions. LC-MS: 419 (M-H) " .

Example 147. 2-(6-Chloro-2-naphthamido)-5-cvano-4-(methylthio)benzoic acid

[0415] The title compound was prepared in an analogous manner to Example 3 using 6-chloro-2-naphthoic acid (Intermediate 1) and DCM with methyl 2-amino-5-cyano-4- (methylthio)benzoate (prepared in an analogous manner to Example 145 using NaSMe and DMSO as solvent in Step 1) followed by typical ester hydrolysis conditions. LC-MS: 395 (M-H) "

Example 148. 2-(6-Chloro-2-naphthamido)-5-cvano-4-isopropoxybenzoic acid

[0416] The title compound was prepared in an analogous manner to Example 3 using 6-chloro-2-naphthoic acid (Intermediate 1) and DCM with methyl 2-amino-5-cyano-4- isopropyloxybenzoate (prepared in an analogous manner to Example 145 using isopropanol in Step 1) followed by typical ester hydrolysis conditions. LC-MS: 407 (M-H) " .

Example 149. iV-(4-Fluoro-5-methoxy-2-(5-oxo-4,5-dihvdro- 1 ,2,4-oxadiazol-3-vDphenvD-2- naphthamide

[0417] The title compound was prepared in an analogous manner to that described for Example 144 using 2-naphthoic acid. LC-MS: 378 (M-H) " .

Example 150. 5-Chloro-2-(6-chloro-2-naphthamido)-6-methoxynicotinic acid

[0418] The title compound was prepared in an analogous manner to Example 74 using 6-chloro-2-naphthoic acid (Intermediate 1). LC-MS: 391 (M+H) + . Example 151. 5-Cvano-4-methoxy-2-(5,6,7,8-tetrahydronaphthalene-2- carboxamido)benzoic acid

[0419] The title compound was prepared in an analogous manner to that described for Example 3 using methyl 2-amino-5-cyano-4-methoxybenzoate (Intermediate 2) and 5,6,7,8,tetrahydronaphthalene-2-carboxylic acid followed by typical ester hydrolysis conditions. LC-MS: 349 (M-H) " .

Example 152. (rac)-2-(6-chloro-2-naphthamido)-5-cvano-4-(methylsulfinvnbe nzoic acid

[0420] 2-(6-Chloro-2-naphthamido)-5-cyano-4-(methylthio)benzoic acid (0.052 g, 0.12 mmol, title compound in Example 147) was treated with «¾-CPBA (0.062 g, 0.28 mmol) in THF (4 mL) and stirred for 96 hrs at 50 °C. The solvent was evaporated and the residue suspended in MeOH and stirred for 16hrs. The resulting white suspension was filtered and collected to afford the title compound. LC-MS: 411 (M-H) " .

Example 153. 2-(6-Chloro-2-naphthamido)-5-cvano-4-(difluoromethoxy)benzoi c acid

[0421] Step 1 : 2-(Difluoromethoxy)-4-nitrobenzonitrile was prepared in an analogous manner to Example 58, Step 2 using 2-hydroxy-4-nitrobenzonitrile as a starting material.

[0422] Step 2: 4-Amino-2-(difluoromethoxy)benzonitrile was prepared in an analogous manner to Example 83, Step 3 using 2-(difluoromethoxy)-4-nitrobenzonitrile as a starting material.

[0423] Step 3: 4-Amino-5-bromo-2-(difluoromethoxy)benzonitrile. To a stirring solution of 4-amino-2-(difluoromethoxy)benzonitrile (358 mg, 1.94 mmol) in glacial acetic acid (20 rriL) was added N-bromosuccinimide (363 mg, 2.04 mmol). After 4 hrs, volatiles were removed in vacuo and the residue was diluted with EtOAc and water. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 30% EtOAc in Hexanes to provide the desired benzonitrile.

[0424] Step 4: Methyl 2-amino-5-cyano-4-(difluoromethoxy)benzoate was prepared in an analogous manner to Example 47, Steps 1 through 4 using 4-amino-5-bromo-2- (difluoromethoxy)benzonitrile.

[0425] Step 5: The title compound was prepared in an analogous manner to Example 3 using methyl 2-amino-5-cyano-4-(difluoromethoxy)benzoate and 6-chloro-2-naphthoic acid (Intermediate 1). LC-MS: 415 (M-H) " .

Example 154; iy-(4-Cvano-5-methoxy-2-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3 -yl)phenvn-6- fluoro-2-naphthamide

[0426] Step 1 : 2-Amino-5-bromo-4-fluorobenzonitrile. To a solution of 2-amino-4- fluorobenzonitrile (18.2 g, 134 mmol) in DMF (100 mL), was added N-bromosuccinimide (23.8 g, 134 mmol) in several portions. The solution was stirred for 1 hr and poured into ice water (600 mL). The resulting solid was filtered off and dried to yield the desired compound. [0427] Step 2: 3-(2-Amino-5-bromo-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one was prepared as described for Example 143, Steps 2 and 3.

[0428] Step 3: 4-Amino-2-fluoro-5-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yljbenzonitrile. To a solution of 3-(2-amino-5-bromo-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (150 mg, 0.55 mmol) in DMF (3.8 mL) was added BrettPhos Palladacycle Gen. 3 (56 mg, 0.062 mmol) and zinc cyanide (450 mg, 3.8 mmol). The solution was degassed and heated at 120 °C for 1.5 hrs. Water (20 mL) was added and the resulting solid was filtered off. The filtrate was concentrated in vacuo to afford the crude product. Purification by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 0) afforded the intended product.

[0429] Step 4: 4-Amino-2-methoxy-5-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)benzonitrile was prepared in an analogous method to that described for Example 55, Step 1 using 4-amino-2-fluoro-5-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)b enzonitrile.

[0430] Step 5: To a solution of 4-amino-2-methoxy-5-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)benzonitrile (60 mg, 0.26 mmol) in DMF (2 mL) was added 6-fluoro-2-naphthoic acid (180 mg, 0.94 mmol) and HATU (180 mg, 0.47 mmol). N,N-diisopropylethylamine (0.18 mL, 0.98 mmol) was then added and the solution heated at 80 °C for 1.5 hrs. Water (20 mL) was added and the resulting solid was filtered. The filtrate was concentrated in vacuo to afford the crude product which was purified by column chromatography (CI 8 reverse phase, water + 0.1% NH 3 H 2 0 -> MeCN + 0.1% NH 3 H 2 O) to afford the title compound. LC-MS: 403 (M-H) " .

Example 155. 2-(6-Chloro-2-naphthamido)-5-cvano-4-(dimethylamino)benzoic acid

[0431] The title compound was prepared in an analogous manner to Example 3 using 6-chloro-2-naphthoic acid (Intermediate 1) and DCM with methyl 2-amino-5-cyano-4- (dimethylamino)benzoate (prepared in an analogous manner to Example 145, using (Me) 2 NH HCl and DMSO as solvent in Step 1) followed by typical ester hydrolysis conditions. LC-MS: 392 (M-H) " . [0432] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention described herein. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Reference List

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 Vase 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 K-H. (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 E.A. et al. (2000). Increased H2O2, 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): 167srl .

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-P-mediated fibrotic responses. Redox Biol, 2:267-72.

Kowluru R.A. & 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 W.M. (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 V.J. (2012). Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase. Fibrogenesis Tissue Repair, 5(Suppl 1):S23.

Wynn T. A. (2008). Cellular and molecular mechanisms of fibrosis. J Pathol, 214(2): 199-210.