CROSS REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of U.S. provisional patent application no. 61/312,768 filed March 1 1, 2010.

BACKGROUND OF THE INVENTION The disclosure generally relates to the novel compounds of formula I, including their salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV. The disclosure also relates to compositions and methods of using these compounds. Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated

170 million persons worldwide - roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.; Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5 '-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV. The HCV NS5B protein is described in "Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides

(Bressanelli; S. et al, Journal of Virology 2002, 3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7, 211-242.

Currently, the most effective HCV therapy employs a combination of alpha- interferon and ribavirin, leading to sustained efficacy in 40% of patients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N. Engl. J. Med. 2000, 343, 1666-1672). However, even with experimental therapeutic regimens involving combinations of pegylated alpha- interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and important need to develop effective therapeutics for treatment of HCV infection. HCV-796, an HCV NS5B inhibitor, showed an ability to reduce HCV RNA levels in patients. The viral RNA levels decreased transiently and then rebounded during dosing when treatment was with the compound as a single agent but levels dropped more robustly when combined with the standard of care which is a form of interferon and ribavirin. The development of this compound was suspended due to hepatic toxicity observed during exteneded dosing of the combination regimens. US patent 7,265, 152 and the corresponding PCT patent application WO2004/041201A2 describe compounds of the HCV-796 class. The invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

DESCRIPTION OF THE INVENTION One aspect of the invention is a compound of formula I,

I

R ¹ is phenyl substituted with 1 CON(R ⁵ )(R ⁶ ); and where said phenyl is also substituted with 0-2 substituents selected from the group consisting of halo, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (carboxy)alkyl, alkoxy,

hydroxyalkyloxy, alkoxyalkyloxy, benzyloxy, (CON(R ⁷ )(R ⁸ ))alkyloxy,

tetrahydropyranyloxy, carboxy, alkoxycarbonyl, alkylsulfonyl, (carboxy)alkenyl, (alkoxycarbonyl)alkenyl, alkylcarboxamido, alkoxycarboxamido, alkylsulfamido, (alkylsulfamido)alkyl, Ar ² , and S0 ₂ N(R ⁷ )(R ⁸ ); and where said phenyl is also substituted with 0-2 substituents selected from the group consisting of halo; nitro; alkyl; cycloalkyl; haloalkyl; aminoalkyl; hydroxyalkyl; alkoxyalkyl; hydroxy;

alkoxy; 0(R ⁹ ); cycloalkoxy; amino; alkylamino; dialkylamino; alkylcarboxamido; alkoxycarboxamido; alkoxyalkylcarboxamido; furanyl, thienyl, pyrazolyl substituted with 0-2 alkyl substituents; pyridinyl substituted with 0-2 halo, cyano, alkyl, hydroxy, alkoxy, amino, or alkylaminocarbonyl substituents; pyrimidinyl;

pyrimidinedionyl; aminopyrimidinyl; indolyl; isoquinolinyl; and phenyl substituted with 0-2 substituents selected from the group consisting of halo, alkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, amino, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarboxamido, carboxyalkenyl, and phenyl; R ² is hydrogen, halo, nitro, amino, phenyl, or (R ¹⁰ )(R ⁿ )N;

R ³ is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl,

CON(R ¹² )(R ¹³ ), (R ¹² )(R ¹³ )NCONH, triazolyl, thiazolyl, or tetrazolyl;

R ⁴ is phenyl substituted with 0-2 halo, alkoxy, phenoxy, or halophenoxy substituents;

_R 14 _R 15 R14 _R 15

R ⁵ is * Ar ¹ , *^ ^Ar1 , or ;

R ⁶ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; R ⁷ is hydrogen, alkyl, hydroxyalkyl, cycloalkyl, or benzyl; R ⁸ is hydrogen or alkyl; or R ⁷ and R ⁸ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

R ⁹ is haloalkyl, cyanoalkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (R ¹⁶ )alkyl, (Ar ³ )alkyl, alkynyl, or aminocycloalkyl; R ¹⁰ is hydrogen, alkyl, or alkylsulfonyl;

R ¹¹ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or alkylsulfonyl; R is hydrogen, alkyl, or cycloalkyl;

R is hydrogen, alkyl, or cycloalkyl; or R and R taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

R ¹⁴ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; R ¹⁵ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or R ¹⁴ and R ¹⁵ taken together is ethylene, propylene, butylene, pentylene, or hexylene; R ¹⁶ is CONH2, H2NCONH, dibenzylamino, phthalimido, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is substituted with 0- 3 alkyl or alkoxycarbonyl substituents; R ¹⁷ is hydrogen, halo, alkyl, or alkoxy;

R ¹⁸ is hydrogen, halo, alkyl, or alkoxy;

Ar ¹ is azaindolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,

oxazolopyridinyl, imidazopyridinyl, quinazolinyl, pyridopyrimidinyl or

naphthyridinyl, and is substituted with 0-2 substituents selected from halo, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxy, alkoxy, amino, alkylamino,

dialkylamino, aminocarbonyl, pyridinyl, phenyl, halophenyl, alkylphenyl, and alkoxyphenyl;

Ar ² is phenyl, biphenyl, or pyridinyl and is substituted witlh 0-2 substituents selected from halo, alkyl, cyano, hydroxy, alkoxy, and carboxy; and Ar ³ is furanyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, indolyl, or phenyl and is substituted with 0-2 substituents selected from halo, alkyl, haloalkyl, hydroxyl, and alkoxy; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where

R ¹ is phenyl substituted with 1 CON(R ⁵ )(R ⁶ ) and 1 alkyl substituent;

R ² is hydrogen or halo; R ³ is CON(R ¹² )(R ¹³ ); R ⁴ is phenyl substituted with 0-2 halo substituents;

R ¹ * _R 15

R ⁵ is ^ r^ . R ⁶ is hydrogen;

R ¹² is alkyl; R ¹³ is hydrogen; R ¹⁴ and R ¹⁵ taken together is ethylene; and Ar ¹ is azaindolyl or naphthyridinyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R ² is hydrogen or halo, R ¹⁷ is hydrogen, and R ¹⁸ is hydrogen. Another aspect of the invention is a compound of formula I where R ¹ is phenyl substituted with 1 CON(R ⁵ )(R ⁶ ) and 0-2 halo, alkyl, alkoxy, or

(CON(R ⁷ )(R ⁸ ))alkyloxy substituents; R ² is hydrogen or halo;

R ³ is CON(R ¹² )(R ¹³ );

R ⁴ is phenyl substituted with 0-2 halo substituents;

R ¹ < R ¹⁵

R ⁵ is ^ r^ ;

R ⁶ is hydrogen; R ⁷ is hydrogen or alkyl;

R ⁸ is hydrogen or alkyl;

R ¹² is hydrogen or alkyl;

R ¹³ is hydrogen or alkyl;

R ¹⁴ is hydrogen or alkyl; R ¹⁵ is hydrogen or alkyl; or R ¹⁴ and R ¹⁵ taken together is ethylene; and

Ar ¹ is azaindolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, oxazolopyridinyl, imidazopyridinyl, quinazolinyl, pyridopyrimidinyl or naphthyridinyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R ¹ is R ¹ is phenyl substituted with 1 CON(R ⁵ )(R ⁶ ) and 1-2 fluoro, methyl, methoxy, or (CONH ₂ )CH ₂ 0

2 3 12 13 4

substituents; R is hydrogen or fluoro; R is CON(R )(R ); R is phenyl substituted with 1 fluoro substituent; R ⁵ is * ^Al"1 ; R ⁶ is hydrogen; R ¹² is methyl; R ¹³ is hydrogen; R ¹⁴ is methyl, R ¹⁵ is hydrogen; or R ¹⁴ and R ¹⁵ taken together is ethylene; and Ar ¹ is azaindolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, oxazolopyridinyl, imidazopyridinyl, quinazolinyl, pyridopyrimidinyl or

naphthyridinyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R ¹ is phenyl substituted with 1 CON(R ⁵ )(R ⁶ ) and 1-2 fluoro, methyl, or methoxy substituents; R ²

R ¹ ^ _R 15 is hydrogen or fluoro; R ³ is CON(R ¹² )(R ¹³ ); R ⁴ is 4-fluorophenyl; R ⁵ is * ^Ar ' ; R ⁶ is hydrogen; R ¹² is methyl; R ¹³ is hydrogen; R ¹⁴ and R ¹⁵ taken together is ethylene; and Ar ¹ is azaindolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, oxazolopyridinyl, imidazopyridinyl, quinazolinyl, pyridopyrimidinyl or

naphthyridinyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R ¹ is phenyl substituted with 1 CON(R ⁵ )(R ⁶ ); and where said phenyl is also substituted with 0-2 substituents selected from the group consisting of halo, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (carboxy)alkyl, alkoxy, hydroxyalkyloxy,

alkoxyalkyloxy, benzyloxy, (CON(R ⁷ )(R ⁸ ))alkyloxy, tetrahydropyranyloxy, carboxy, alkoxycarbonyl, alkylsulfonyl, (carboxy)alkenyl, (alkoxycarbonyl)alkenyl, alkylcarboxamido, alkoxycarboxamido, alkylsulfamido, (alkylsulfamido)alkyl, Ar ² , and S0 ₂ N(R ⁷ )(R ⁸ ); and where said phenyl is also substituted with 0-2 substituents selected from the group consisting of halo; nitro; alkyl; cycloalkyl; haloalkyl;

aminoalkyl; hydroxyalkyl; alkoxyalkyl; hydroxy; alkoxy; 0(R ⁹ ); cycloalkoxy; amino alkylamino; dialkylamino; alkylcarboxamido; alkoxycarboxamido;

alkoxy alkylcarboxamido; furanyl, thienyl, pyrazolyl substituted with 0-2 alkyl substituents; pyridinyl substituted with 0-2 halo, cyano, alkyl, hydroxy, alkoxy, amino, or alkylaminocarbonyl substituents; pyrimidinyl; pyrimidinedionyl;

aminopyrimidinyl; indolyl; isoquinolinyl; and phenyl substituted with 0-2 substituents selected from the group consisting of halo, alkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, amino, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarboxamido, carboxyalkenyl, and phenyl; R ² is hydrogen, halo, or (R ¹⁰ )(R ⁿ )N; R ³ is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl,

CON(R ¹² )(R ¹³ ), (R ¹² )(R ¹³ )NCONH, triazolyl, thiazolyl, or tetrazolyl; R ⁴ is phenyl alo, alkoxy, phenoxy, or halophenoxy substituents; R ⁵ is , or Ar ¹ ; R ⁶ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; R ⁷ is hydrogen, alkyl, hydroxyalkyl, cycloalkyl, or benzyl; R ⁸ is hydrogen or alkyl; or R ⁷ and R ⁸ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; R ⁹ is haloalkyl, cyanoalkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (R ¹⁶ )alkyl, (Ar ³ )alkyl, alkynyl, or aminocycloalkyl; R ¹⁰ is alkylsulfonyl; R ¹¹ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; R ¹² is hydrogen, alkyl, or cycloalkyl; R ¹³ is hydrogen, alkyl, or cycloalkyl; or R ¹² and R ¹³ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; R ¹⁴ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; R ¹⁵ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or R ¹⁴ and R ¹⁵ taken together is ethylene, propylene, butylene, pentylene, or hexylene; R ¹⁶ is CONH2, H2NCONH, dibenzylamino, phthalimido, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is substituted with 0-3 alkyl or

alkoxycarbonyl substituents; R ¹⁷ is hydrogen, fluoro, or chloro; R ¹⁸ is hydrogen, fluoro, or chloro; Ar ¹ is azaindolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, oxazolopyridinyl, imidazopyridinyl, quinazolinyl, pyridopyrimidinyl or naphthyridinyl, and is substituted with 0-2 substituents selected from halo, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, pyridinyl, phenyl, halophenyl, alkylphenyl, and alkoxyphenyl; Ar ² is phenyl, biphenyl, or pyridinyl and is substituted witlh 0-2 substituents selected from halo, alkyl, cyano, hydroxy, alkoxy, and carboxy; and Ar ³ is furanyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, indolyl, or phenyl and is substituted with 0-2 substituents selected from halo, alkyl, haloalkyl, hydroxyl, and alkoxy; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of this formula where R ¹⁷ and R ¹⁸ are hydrogen.

Another aspect of the invention is a compound of formula I where R ¹ is phenyl ssuubbssttiittuutteedd wwiitthh 11 CCOON(R ⁵ )(R ⁶ ) substituent and also substituted with 0-2 halo, alkyl, or alkoxy substituents

Another aspect of the invention is a compound of formula I where where R ⁵ is * ^Al_ and R ¹⁴ and R ¹⁵ is ethylene or propylene. Another aspect of the invention is a compound of formula I where where R ⁵ is

R ¹ ^ _R 15

* ^Ar and R ¹⁴ and R ¹⁵ is ethylene.

Another aspect of the invention is a compound of formula I where where R ⁵ is

R^R ¹⁵

* ^Al_ and at least one of R ¹⁴ and R ¹⁵ is not hydrogen.

Another aspect of the invention is a compound of formula I where Ar ¹ is azaindolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, oxazolopyridinyl,

imidazopyridinyl, quinazolinyl, pyridopyrimidinyl or naphthyridinyl, and is substituted with 0-2 substituents selected from halo, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, pyridinyl, phenyl, halophenyl, alkylphenyl, and alkoxyphenyl..

Another aspect of the invention is a compound of formula I where Ar ¹ is azaindolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, oxazolopyridinyl,

imidazopyridinyl, quinazolinyl, pyridopyrimidinyl or naphthyridinyl. Another aspect of the invention is a compound of formula I where R ³ is

CON(R ⁿ )(R ¹² ).

Another aspect of the invention is a compound of formula I where R ³ is

CON(H)(alkyl).

Another aspect of the invention is a compound of formula I where R ⁴ is halophenyl.

Another aspect of the invention is a compound of formula I where R ⁴ is phenyl or mono fluorophenyl.

Another aspect of the invention is a compound of formula I where Ar ¹ is phenyl.

Any scope of any variable, including R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , Ar ¹ , Ar ² , or Ar ³ can be used independently with the scope of any other instance of a variable.

Unless specified otherwise, these terms have the following meanings.

"Alkyl" means a straight or branched alkyl group composed of 1 to 6 carbons.

"Alkenyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. "Cycloalkyl" means a monocyclic ring system composed of 3 to 7 carbons. "Hydroxy alkyl," "alkoxy" and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. "Halo" includes all halogenated isomers from monohalo substituted to perhalo substituted in substituents defined with halo, for example, "Haloalkyl" and "haloalkoxy", "halophenyl", "halophenoxy." "Aryl" includes carbocyclic and heterocyclic aromatic substituents. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. Substituents which are illustrated by chemical drawing to bond at variable positions on a multiple ring system (for example a bicyclic ring system) are intended to bond to the ring where they are drawn to append. For example, substituents R ¹ and R ² of formula IV are intended to bond to the benzene ring of formula IV and not to the thiophene ring.

Ethylene means ethanediyl or -(¾(¾-; propylene means propanediyl or -CH ₂ CH ₂ CH ₂ -; butylene means butanediyl or -CH ₂ CH ₂ CH ₂ CH ₂ -; pentylene means pentanediyl or -CH2CH2CH2CH2CH2-.

Dioxothiazinyl means The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms. The invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art. The use of wedges or hashes in the depictions of molecular structures in the following schemes and tables is intended only to indicate relative stereochemistry, and should not be interpreted as implying absolute stereochemical assignments. The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³ C and ¹⁴ C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

Synthetic Methods

The compounds may be made by methods known in the art including those described below. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using commercially available materials. The variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make and are not to be confused with variables used in the claims or in other sections of the specification. Abbreviations used within the schemes generally follow conventions used in the art. Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: "NaHMDS" for sodium bis(trimethylsilyl)amide; "DMF" for ,N- dimethylformamide; "MeOH" for methanol; "NBS" for N-bromosuccinimide; "Ar" for aryl; "TFA" for trifluoroacetic acid; "LAH" for lithium aluminum hydride;

"BOC", "DMSO" for dimethylsulfoxide; "h" for hours; "rt" for room temperature or retention time (context will dictate); "min" for minutes; "EtOAc" for ethyl acetate; "THF" for tetrahydrofuran; "EDTA" for ethylenediaminetetraacetic acid; "Et20" for diethyl ether; "DMAP" for 4-dimethylaminopyridine; "DCE" for 1,2-dichloroethane; "ACN" for acetonitrile; "DME" for 1,2-dimethoxyethane; "HOBt" for 1- hydroxybenzotriazole hydrate; "DIEA" for diisopropylethylamine, "Nf ' for CF ₃ (CF ₂ ) ₃ S0 ₂ -; and "TMOF" for trimethylorthoformate. As shown in Scheme I, some compounds of the invention may be prepared by coupling a benzofuran triflate or halide to a substituted phenyl boronic acid that in some examples contains a carboxylic acid or carboxylic acid ester. Other coupling techniques and conditions are also known in the art as are other carbon-carbon bond forming reactions. Acids and esters may be converted to amides by methods known in the art.

Scheme 1.

Biological Methods

The compounds demonstrated activity against HCV NS5B as determined the following HCV RdRp assays. HCVNS5B RdRp cloning, expression, and purification. The cDNA encoding the NS5B protein of HCV, genotype lb, was cloned into the pET21a expression vector. The protein was expressed with an 18 amino acid C-terminal truncation to enhance the solubility. The E. coli competent cell line BL21(DE3) was used for expression of the protein. Cultures were grown at 37 °C for ~ 4 hours until the cultures reached an optical density of 2.0 at 600 nm. The cultures were cooled to 20 °C and induced with 1 mM IPTG. Fresh ampicillin was added to a final concentration of 50 μg/ml and the cells were grown overnight at 20 °C. Cell pellets (3L) were lysed for purification to yield 15-24 mgs of purified

NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500 mM NaCl, 0.5% triton X-100, 1 mM DTT, ImM EDTA, 20% glycerol, 0.5 mg/ml lysozyme, 10 mM MgC12, 15 ug/ml deoxyribonuclease I, and Complete TM protease inhibitor tablets (Roche). After addition of the lysis buffer, frozen cell pellets were resuspended using a tissue homogenizer. To reduce the viscosity of the sample, aliquots of the lysate were sonicated on ice using a microtip attached to a Branson sonicator. The sonicated lysate was centrifuged at 100,000 x g for lhr at 4 °C and filtered through a 0.2 μιη filter unit (Corning). The protein was purified using three sequential chromatography steps:

Heparin sepharose CL-6B, polyU sepharose 4B, and Hitrap SP sepharose

(Pharmacia). The chromatography buffers were identical to the lysis buffer but contained no lysozyme, deoxyribonuclease I, MgC12 or protease inhibitor and the NaCl concentration of the buffer was adjusted according to the requirements for charging the protein onto the column. Each column was eluted with a NaCl gradient which varied in length from 5-50 column volumes depending on the column type. After the final chromatography step, the resulting purity of the enzyme is >90% based on SDS-PAGE analysis. The enzyme was aliquoted and stored at -80 °C. Standard HCVNS5B RdRp enzyme assay. HCV RdRp genotype lb assays were run in a final volume of 60 μΐ in 96 well plates (Costar 3912). The assay buffer is composed of 20 mM Hepes, pH 7.5, 2.5 mM KC1, 2.5 mM MgC12, 1 mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.1 mg/ml BSA (Promega R3961), and 2 % glycerol. All compounds were serially diluted (3 -fold) in DMSO and diluted further in water such that the final concentration of DMSO in the assay was 2%. HCV RdRp genotype lb enzyme was used at a final concentration of 28 nM. A polyA template was used at 6 nM, and a biotinylated oligo-dT12 primer was used at 180 nM final concentration. Template was obtained commercially (Amersham 27- 41 10). Biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 μθί (0.29 μΜ total UTP). Reactions were initiated by the addition of enzyme, incubated at 30 °C for 60 min, and stopped by adding 25 μΐ of 50 mM EDTA containing SPA beads (4 μg/μl, Amersham RPNQ 0007). Plates were read on a Packard Top Count NXT after >lhr incubation at room temperature.

Modified HCVNS5B RdRp enzyme assay. A modified enzyme assay was performed essentially as described for the standard enzyme assay except for the following: The biotinylated oligo dT12 primer was precaptured on streptavidin- coated SPA beads by mixing primer and beads in assay buffer and incubating at room temperature for one hour. Unbound primer was removed after centrifugation. The primer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 and used in the assay at final concentrations of 20 nM primer and 0.67 μg/μl beads. Order of addition in the assay: enzyme (14 nM) was added to diluted compound followed by the addition of a mixture of template (0.2 nM), 3H-UTP (0.6 μθί, 0.29 μΜ), and primer-bound beads, to initiate the reaction; concentrations given are final. Reactions were allowed to proceed for 4 hours at 30° C.

IC5 ₀ values for compounds were determined using seven different [I]. IC5 ₀ values were calculated from the inhibition using the formula y = A+((B- A)/(l+((C/x)-D))).

FRET Assay Preparation. To perform the HCV FRET screening assay, 96- well cell culture plates were used. The FRET peptide (Anaspec, Inc.) (Taliani et al, Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor, DABCYL, near the other end. The fluorescence of the peptide is quenched by intermolecular resonance energy transfer (RET) between the donor and the acceptor, but as the NS3 protease cleaves the peptide the products are released from RET quenching and the fluorescence of the donor becomes apparent. The assay reagent was made as follows: 5X cell Luciferase cell culture lysis reagent from Promega (#E153A) diluted to IX with dH ₂ 0, NaCl added to 150 mM final, the FRET peptide diluted to 20 μΜ final from a 2 mM stock.

To prepare plates, HCV replicon cells, with or without a Renilla luciferase reporter gene, were trypsinized and placed into each well of a 96-well plate with titrated test compounds added in columns 3 through 12; columns 1 and 2 contained a control compound (HCV protease inhibitor), and the bottom row contained cells without compound. The plates were then placed in a CO ₂ incubator at 37 °C.

Assays. Subsequent to addition of the test compounds described above (FRET Assay Preparation), at various times the plate was removed and Alamar blue solution (Trek Diagnostics, #00-100) was added per well as a measure of cellular toxicity. After reading in a Cyto flour 4000 instrument (PE Biosystems), plates were rinsed with PBS and then used for FRET assay by the addition of 30 ul of the FRET peptide assay reagent described above (FRET Assay Preparation) per well. The plate was then placed into the Cytoflour 4000 instrument which had been set to 340 excite/490 emission, automatic mode for 20 cycles and the plate read in a kinetic mode. Typically, the signal to noise using an endpoint analysis after the reads was at least three-fold. Alternatively, after Alamar blue reading, plates were rinsed with PBS, 50 ul of DMEM (high glucose) without phenol red was added and plates were then used for luciferase assay using the Promega Dual-Glo Luciferase Assay System. Compound analysis was determined by quantification of the relative HCV replicon inhibition and the relative cytotoxicity values. To calculate cytoxicity values, the average Alamar Blue fluorescence signals from the control wells were set as 100% non-toxic. The individual signals in each of the compound test wells were then divided by the average control signal and multiplied by 100% to determine percent cytotoxicity. To calculate the HCV replicon inhibition values, an average background value was obtained from the two wells containing the highest amount of HCV protease inhibitor at the end of the assay period. These numbers were similar to those obtained from naive Huh-7 cells. The background numbers were then subtracted from the average signal obtained from the control wells and this number was used as 100% activity. The individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity. EC5 ₀ values for a protease inhibitor titration were calculated as the concentration which caused a 50% reduction in FRET or luciferase activity. The two numbers generated for the compound plate, percent cytoxicity and percent activity were used to determine compounds of interest for further analysis.

HCV Replicon Luciferase Reporter Assay

The HCV replicon luciferase assay was developed to monitor the inhibitory effects of compounds described in the disclosure on HCV viral replication.

Utilization of a replicon luciferase reporter assay was first described by Krieger et al (Krieger N, Lohmann V, and Bartenschlager R, J. Virol. 75(10):4614-4624 (2001)). HUH-7 cells, constitutively expressing the HCV replicon, were grown in Dulbecco's Modified Eagle Media (DMEM) (Gibco-BRL) containing 10%> Fetal calf serum (FCS) (Sigma) and 1 mg/ml G418 (Gibco-BRL). Compounds were serially diluted 3 folds in DMSO for a twenty-point titration and subsequently transferred to sterile 384-well tissue-culture treated plates (Corning cat # 3571). The plates were then seeded with 50 μΐ of cells at a density of 3.0 x 10 ³ cells/well in DMEM containing 4 % FCS (final DMSO concentration at 0.5 %). After 3 days incubation at 37°C, cells were analyzed for Renilla Luciferase activity using the EnduRen as substrate (Promega cat #E6485). The EnduRen substrate was diluted in DMEM and then added to the plates to a final concentration of 7.5 μΜ. The plates were incubated for 2 hrs at 37°C and then read immediately for 30 seconds with Viewlux Imager

(PerkinElmer) using a luminescence program. To assess cytotoxicity of compounds, CC5 ₀ values were generated by multiplexing the EnduRen-containing plates with Cell Titer-Blue (Promega, cat # G8082). 3 μΐ of Cell-Titer Blue was added to each well and incubated for 8 hrs at 37°C. The fluorescence signal from each well was read, with an excitation wavelength at 525/10 nm and an emission wavelength of 598/10 nm, using the Viewlux Imager. Representative data for compounds are reported in Table 1.

Table 1.

If no data is entered use the following key: A 0.002 or less to 0.25 μΜ; B >0.25 μΜ - <1.0 μΜ; C 1.0 μΜ - 10.0 μΜ; D >0.67 μΜ but an exact value was not determined; E >10.0 μΜ; F >0.4 μΜ; but an exact value was not determined; G > 1.39 μΜ but an exact value was not determined; H >0.62 μΜ but an exact value was not determined; I >4 μΜ but an exact value was not determined; J>3.7 μΜ but an exact value was not determined; K >1.23 μΜ but an exact value was not determined; L >4.17 μΜ but an exact value was not determined; M > 0.5 μΜ but an exact value was not determined. Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.

Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon. Another aspect of the invention is where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'- monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin. Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of inhibiting the function of the

HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. In another embodiment the compound is effective to inhibit the function of the HCV replicon. In another embodiment the compound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.

Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon.

Another aspect of the invention is the method where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin is cyclosporin A.

Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine. Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.

"Therapeutically effective" means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection. "Patient" means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.

"Treatment," "therapy," "regimen," "HCV infection," and related terms are used as understood by practitioners in the field of hepatitis and HCV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example,

Remington 's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985. Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.

Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally.

The specific dosing regime, however, will be determined by a physician using sound medical judgement.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection. In these combination methods, the compound will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods are listed in Table 2. Table 2.

Type of Inhibitor or

Brand Name Source Company

Target

InterMune

Infergen A IF alfacon-1 Pharmaceuticals Inc.,

Brisbane, CA

ISIS Pharmaceuticals Inc, Carlsbad, CA/Elan

ISIS 14803 antisense

Phamaceuticals Inc., New York, NY

Japan Tobacco Inc.,

JTK-003 RdRp inhibitor

Tokyo, Japan

PEGylated IFN-a2a/ Maxim Pharmaceuticals

Pegasys and Ceplene

immune modulator Inc., San Diego, CA

Maxim Pharmaceuticals

Ceplene immune modulator

Inc., San Diego, CA

Nabi

HCV IgG

Civacir Biopharmaceuticals Inc., immunosuppressant

Boca Raton, FL

RegeneRx

Biopharmiceuticals Inc., Bethesda, MD/

Intron A and Zadaxin IFN-a2b/al -thymosin

SciClone

Pharmaceuticals Inc, San Mateo, CA

Ribapharm Inc., Costa

Levovirin IMPDH inhibitor

Mesa, CA

Ribapharm Inc., Costa

Viramidine Ribavirin Prodrug

Mesa, CA

Ribozyme

Heptazyme ribozyme Pharmaceuticals Inc.,

Boulder, CO Type of Inhibitor or

Brand Name Source Company

Target

Schering-Plough

Intron A IFN-a2b Corporation,

Kenilworth, NJ

Schering-Plough

PEG-Intron PEGylated IFN-a2b Corporation,

Kenilworth, NJ

Schering-Plough

Rebetron IFN-a2b/ribavirin Corporation,

Kenilworth, NJ

Schering-Plough

Ribavirin ribavirin Corporation,

Kenilworth, NJ

Schering-Plough

PEGylated IFN-

PEG-Intron / Ribavirin Corporation,

a2b/ribavirin

Kenilworth, NJ

SciClone

Zadazim Immune modulator Pharmaceuticals Inc.,

San Mateo, CA

Serono, Geneva,

Rebif IFN-pia

Switzerland

Transition Therapeutics

IFN-β and EMZ701 IFN-P and EMZ701

Inc., Ontario, Canada

Tularik Inc., South San

Batabulin (T67) β-tubulin inhibitor

Francisco, CA

Merimepodib Vertex Pharmaceuticals

IMPDH inhibitor

(VX-497) Inc., Cambridge, MA

Vertex Pharmaceuticals

Telaprevir NS3 serine protease Inc., Cambridge, MA/

(VX-950, LY-570310) inhibitor Eli Lilly and Co. Inc.,

Indianapolis, IN Type of Inhibitor or

Brand Name Source Company

Target

Viragen Inc., Plantation,

Omniferon natural IFN-a

FL

XTL

XTL-6865 (XTL-002) monoclonal antibody Biopharmaceuticals

Ltd., Rehovot, Isreal

NS5B Replicase

HCV-796 Wyeth / Viropharma

Inhibitor

NS5B Replicase

NM-283 Idenix / Novartis

Inhibitor

NS5B Replicase

GL-59728 Gene Labs / Novartis

Inhibitor

NS5B Replicase

GL-60667 Gene Labs / Novartis

Inhibitor

NS5B Replicase

2'C MeA Gilead

Inhibitor

NS5B Replicase

PSI 6130 Roche

Inhibitor

NS5B Replicase

R1626 Roche

Inhibitor

SCH 503034 serine protease inhibitor Schering Plough

NIM811 Cyclophilin Inhibitor Novartis

Suvus Methylene blue Bioenvision

Multiferon Long lasting IFN Viragen/V alentis

Actilon (CPG10101) TLR9 agonist Coley

Interferon-β Interferon-P-la Serono

Zadaxin Immunomodulator Sciclone Type of Inhibitor or

Brand Name Source Company

Target

Pyrazolopyrimidine

compounds and salts

From WO- HCV Inhibitors Arrow Therapeutics Ltd. 2005047288

26 May 2005

NS5B Replicase

2'C Methyl adenosine Merck

Inhibitor

GS-9132 (ACH-806) HCV Inhibitor Achillion / Gilead

DESCRIPTION OF SPECIFIC EMBODIMENTS

1 -(1 ,8-naphthyridin-2-yl)cyclopropanamine was prepared according to the four step synthesis as briefly depicted below.

tert-butyl l-(methoxy(methyl)carbamoyl)cyclopropylcarbamate. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50 mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. White solid, 58.7% yield. LCMS m/z 245.2 (M + H), rt = 1.768 min., 100% purity. ' ^{H NMR} ( ^{400 MHz} > DMSO-i/6) δ ppm 0.70 - 0.94 (m, 2 H), 1.09 - 1.24 (m, 2 H), 1.38 (s, 9 H), 3.06 (s, 3 H), 3.64 (s, 3 H), 7.55 (br. s., 1 H). tert-butyl 1-acetylcyclopropylcarbamate. White solid, 91% yield, 90% purity. *H NMR (400 MHz, DMSO-i¾) δ ppm 0.99 (q, J=4.10 Hz, 2 H), 1.29 (q, J=4.10 Hz, 2 H), 1.39 (s, 9 H), 2.13 (s, 3 H), 7.73 (br. s., 1 H). tert-butyl l-(l,8-naphthyridin-2-yl)cyclopropylcarbamate. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50 mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. White solid, 47.2% yield. LCMS rt = 1.573min, m/z

286.2 (M+H), 100% purity. *H NMR (400 MHz, CD3OD) δ ppm 1.40 - 1.47 (m, 2

H), 1.56 (s, 9 H), 1.88 - 1.98 (m, 2 H), 7.60 (dd, J=8.03, 4.52 Hz, 1 H), 7.82 (d, J=8.53 Hz, 1 H), 8.38 (d, J=8.53 Hz, 1 H), 8.44 (d, J=8.03 Hz, 1 H), 9.01 (dd, J=4.27, 1.76 Hz, 1 H). l-(l,8-naphthyridin-2-yl)cyclopropanamine, HCl. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50 mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. White solid, 97% yield. LCMS rt = 0.435min, m/z 186.1

(M+H), 99.4% purity. *H NMR (400 MHz, DMSO-i/ ₆ ) δ ppm 1.95 (d, J=2.51 Hz, 4 H), 7.76 (d, J=9.03 Hz, 1 H), 8.25 (dd, J=8.28, 5.52 Hz, 1 H), 8.89 (d, J=8.78 Hz, 1 H), 9.35 (dd, J=8.28, 1.51 Hz, 1 H), 9.41 (dd, 1 H).

1-(1, 7-naphthyridin-2-yl)cyclopropanamine, HCl. 1 -( 1 ,7-naphthyridin-2- yl)cyclopropanamine, HCl was synthesized in a similar fashion.

The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3 μιη C 18, 2 x 50 mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. Tan solid, 52.6% yield. LCMS rt = 0.460 min., m/z 186.1(M + H), 98.3% purity. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.91 (s, 4 H), 7.86 (d, J=9.03 Hz, 1 H), 8.65 (d, J=6.27 Hz, 1 H), 8.75 - 8.90 (m, 2 H),

5-(5-(l-(l,8-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-me thylphenyl)-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide. To a 1 dram vial was added 3- (2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-me thylbenzoic acid (30.3 mg, 0.075 mmol) in DMF (1 mL) along with N-ethyl-N-isopropylpropan-2- amine (0.065 mL, 0.375 mmol), l-(l,8-naphthyridin-2-yl)cyclopropanamine, HCI (31.1 mg, 0.113 mmol) and finally HATU (2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- 1, 1,3,3-tetramethyl isouronium hexafluorophosphate(V), (114 mg, 0.300 mmol). The vial was sealed and the tan mixture shaken overnight at room temperature. The crude product was purified using a Shimadzu preparative HPLC employing

acetonitrile/water/ trifluoroacetic acid where solvent A was 10% acetonitrile / 90% water/ 0.1% trifluoroacetic acid and solvent B was 10% water / 90% acetonitrile/ 0.1% trifluoroacetic acid with a Waters Sunfire 5μιη C18 19 x 150mm column at a gradient of 20-100% B and a flow rate of 25 mL/min. over 22 minutes with a 8 minute hold. The solvent was removed giving 45.0mgs (87% yield) of 5-(5-(l-(l,8- naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4 -fluorophenyl)-N- methylbenzofuran-3-carboxamide, TFA as a tan solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10- 100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Xbridge Phenyl CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. *Η NMR (400 MHz, THF-dS) δ ppm 1.44 (q, J=4.18 Hz, 2 H), 1.90 - 1.98 (m, 2 H), 2.30 (s, 3 H), 2.89 (d, J=4.77 Hz, 3 H), 7.18 - 7.26 (m, 2 H), 7.29 (dd, J=8.28, 1.76 Hz, 1 H), 7.34 - 7.39 (m, 1 H), 7.50 (dd, J=8.03, 4.52 Hz, 2 H), 7.57 (d, J=8.53 Hz, 1 H), 7.69 (d, J=1.25 Hz, 1 H), 7.74 (d, J=8.53 Hz, 1 H), 7.85 - 7.91 (m, 2 H), 8.07 - 8.14 (m, 2 H), 8.18 (d, J=8.53 Hz, 1 H), 8.34 (dd, J=8.03, 1.76 Hz, 1 H), 8.73 (s, 1 H), 9.04 (dd, 1 H). LCMS rt = 1.430 min., m/z 571.3 (M + H), 98.3% purity. HPLC (Sunfire C18) rt = 6.93 lmin, 99.4% purity and (XBridge Phenyl C18) rt = 1 1.521min., 100% purity.

5-(5-(l-(l, 7-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2- (4- fluorophenyl)-N-methylbenzofuran-3-carboxamide. 5-(5-(l-(l,7-naphthyridin-2- yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)- N-methylbenzofuran-

3-carboxamide was synthesized in a similar fashion. H NMR (400 MHz, THF-i/5) δ ppm 1.51 - 1.59 (m, 2 H), 1.90 - 1.95 (m, 2 H), 2.32 (s, 3 H), 2.89 (d, J=4.77 Hz, 3 H), 7.18 - 7.27 (m, 2 H), 7.32 (dd, J=8.41, 1.63 Hz, 1 H), 7.36 - 7.42 (m, 1 H), 7.46 (d, J=4.27 Hz, 1 H), 7.59 (d, J=8.28 Hz, 1 H), 7.70 (d, J=1.25 Hz, 1 H), 7.86 - 7.93 (m, 2 H), 8.03 - 8.17 (m, 3 H), 8.28 (br. s., 1 H), 8.40 (d, J=9.04 Hz, 1 H), 8.63 (br. s., 1 H), 8.79 (s, 1 H), 9.51 (s, 1 H). LCMS rt = 2.603 min., m/z 571.3 (M + H), 98.4% purity. HPLC rt = 7.121 min. (Sunfire CI 8), 99.3 % purity and 11.708 min. (XBridge Phenyl C18), 95.9 % purity.

5-(5-(l-(l,8-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-me thylphenyl)-4- fluoro-2-(4-fluoro phenyl)-N-methylbenzofuran-3-carboxamide. To a 25mL RBF was added 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran -5-yl)-4- methylbenzoic acid (20.5 mg, 0.049 mmol) in DMF (1 mL) along with N-ethyl-N- isopropylpropan-2 -amine (0.042 mL, 0.243 mmol), l-(l,8-naphthyridin-2- yl)cyclopropanamine, HC1 (20.17 mg, 0.073 mmol) and finally 5 eq. of HATU, 2- (3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethyli souronium

hexafluorophosphate(V) (74.0 mg, 0.195 mmol). The flask was sealed with a septa, placed under nitrogen and the mixture stirred overnight at room temperature. The crude product was purified using a Shimadzu preparative HPLC employing methanol/water/ trifluoroacetic acid where solvent A was 10% methanol / 90% water/ 0.1% trifluoroacetic acid and solvent B was 10% water / 90% methanol/ 0.1% trifluoroacetic acid with a Phenomenex Luna ΙΟμιη C18 30 x 100mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 12 minutes with a 13 minute hold. The solvent was removed giving 33.3mgs (96% yield) of 5-(5-(l-(l,8- naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-4-fl uoro-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide, TFA as a yellow powder. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Xbridge Phenyl C18 3.0μιη 4.6 x 150mm column employing water/methanol/lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. *Η NMR (400 MHz, THF-dS) δ ppm 1.40 - 1.49 (m, 2 H), 1.95 (m, 2 H), 2.25 (s, 3 H), 2.88 (m, 3 H), 7.17 - 7.29 (m, 3 H), 7.37 - 7.47 (m, 2 H), 7.50 (dd, J=8.03, 4.52 Hz, 1 H), 7.74 (d, J=8.53 Hz, 2 H), 7.85 - 7.97 (m, 2 H), 8.03 - 8.09 (m, 2 H), 8.18 (d, J=8.53 Hz, 1 H), 8.33 - 8.39 (m, 1 H), 8.74 (s, 1 H), 9.05 (dd, J=4.27, 1.76 Hz, 1 H). LCMS rt = 2.475min, m/z 589.3 (M+H), 95.7% purity. HPLC rt = 6.728min. (Sunfire C18), 100% purity and 1 1.261min. (XBridge CI 8), 99.0 % purity.

5-(5-(l-(lH-pyrrolo[3,2-c]pyridin-4-yl)cyclopropylcarbamo yl)-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. This example was prepared from the coupling of 3-(4-fluoro-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid with l-(lH-pyrrolo[3,2- c]pyridin-4-yl)cyclopropanamine (obtained from lH-pyrrolo[3,2-c]pyridine-4- carbonitrile by the reaction using Ti(OiPr)4/EtMgBr/BF30Et ₂ ). Purification was performed by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A = 10% MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90% MeOH- 10% H ₂ O-0.1% TFA, Start %B = 10, Final %B = 100, Gradient time = 10 min, Stop time = 12 min, Flow Rate = 25 mL/min, Column: Sunfire Prep C18 19 x 100 5um, Fraction Collection: 7.86 - 8.40 min. (UV detection at 220 nm). The material obtained was further purified by preparative TLC (500 um x 20 x 20 cm plate, 10% MeOH/CH ₂ Cl ₂ ). Analytical TLC Rf = 0.30 (10% MeOH/CH ₂ Cl ₂ ). H NMR (500 MHz, CD ₃ OD) δ 8.05 (d, J= 5.80, 1H), 7.94 (m, 2H), 7.86 (d, J= 7.93, 1H), 7.80 (s, 1H), 7.53 (d, J= 8.55, 1H), 7.46 (d, J= 8.24, 1H), 7.37 (d, J= 3.36, 2H), 7.31-7.27 (overlapping m, 3H), 6.93 (d, J= 3.05, 1H), 2.95 (s, 3H), 2.28 (s, 3H), 1.77 (m, 2H), 1.47 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A = 10%

MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90% MeOH-10%H ₂ O-0.1% TFA, Start %B = 0, Final %B = 100, Gradient time = 2 min, Stop time = 3 min, Flow Rate = 5 ml/min, Column: Phenomenex-Luna, 3.0 x 50 mm, S10; (ES+) m/z (M+H) ⁺ = 577.25, HPLC R _t = 1.427 min. Analytical HPLC were performed by using

Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A = 5% MeCN-95% H ₂ O-0.1% TFA, Solvent B = 95% MeCN-5%H ₂ O-0.1% TFA, Start %B = 20, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min, Column: Sunfire C18, 3.5 um, 4.6 x 150 mm, R _t = 8.06 min; Column: Xbridge Phenyl 3.5 um, 4.6 x 150 mm, R _t = 8.78 min. Analytical HPLC method: Solvent A = 5% MeOH-95% H ₂ O-10 mM NH ₄ HCO ₃ , Solvent B = 95% MeOH-5%H ₂ O-10 mM NH ₄ HCO ₃ , Start %B = 50, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6 x 150 mm, R _t = 10.20 min.

5-(5-(l-(lH-pyrrolo[3,2-b]pyridin-5-yl)cyclopropylcarbamo yl)-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. This example was prepared from the coupling of 3-(4-fluoro-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid with l-(lH-pyrrolo[3,2- &]pyridin-5-yl)cyclopropanamine (obtained from lH-pyrrolo[3,2-/?]pyridine-5- carbonitrile by the reaction using Ti(OiPr)4/EtMgBr/BF30Et ₂ ). Purification was performed by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A = 10% MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90% MeOH- 10% H ₂ O-0.1% TFA, Start %B = 10, Final %B = 100, Gradient time = 10 min, Stop time = 12 min, Flow Rate = 25 mL/min, Column: Sunfire Prep C18 19 x 100 5um, Fraction Collection: 7.86 - 8.38 min. (UV detection at 220 nm). The material obtained was further purified by preparative TLC (500 um x 20 x 20 cm plate, 5% MeOH/CH ₂ Cl ₂ ). Analytical TLC Rf = 0.30 (5% MeOH/CH ₂ Cl ₂ ). H NMR (500 MHz, CD ₃ OD) δ 7.96 (m, 2H), 7.90 (dd, J= 7.93, 2.14, 1H), 7.83 (d, J= 1.83, 1H), 7.72 (dd, J= 8.55, 0.92, 1H), 7.54 (d, J= 8.55, 1H), 7.51 (d, J= 3.36, 1H), 7.48 (d, J = 7.93, 1H), 7.34-7.27 (overlapping m, 4H), 6.55 (dd, J= 3.36, 0.92, 1H), 2.96 (s, 3H), 2.29 (s, 3H), 1.69 (m, 2H), 1.38 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A = 10% MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90% MeOH-10%H ₂ O-0.1% TFA, Start %B = 0, Final %B = 100, Gradient time = 2 min, Stop time = 3 min, Flow Rate = 5 ml/min, Column: Phenomenex-Luna, 3.0 x 50 mm, S10; (ES+) m/z (M+H) ⁺ = 577.19, HPLC R _t = 1.433 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A = 5% MeCN-95% H ₂ O-0.1% TFA, Solvent B = 95% MeCN-5%H ₂ O-0.1% TFA, Start %B = 20, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min, Column: Sunfire C18, 3.5 um, 4.6 x 150 mm, R _t = 7.74 min; Column: Xbridge Phenyl 3.5 um, 4.6 x 150 mm, R _t = 8.42 min. Analytical HPLC method: Solvent A = 5% MeOH-95% H ₂ O-10 mM NH ₄ HCO ₃ , Solvent B = 95% MeOH-5%H ₂ O-10 mM NH ₄ HCO ₃ , Start %B = 50, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6 x 150 mm, R _t = 9.87 min. tert-butyl l-(l,6-naphthyridin-2-yl)cyclopropylcarbamate was synthesized in a similar fashion then converted to l-(l,6-naphthyridin-2-yl)cyclopropanamine using the following approach. tert-butyl l-(l, 6-naphthyridin-2-yl)cyclopropylcarbamate. Light yellow solid, 59.4% yield. *H NMR (400 MHz, CD ₃ OD) δ ppm 1.35 (br. s., 2 H), 1.44 (m, 2

H), 1.53 (m, 7 H), 1.87 (m, 2 H), 7.85 (m, 2 H), 8.46 (d, J=9 Hz, 1 H), 8.64 (d, J=6 Hz, 1 H), 9.26 (s, 1 H). LCMS retention time (rt) = 2.415min, m/z 286.2 (M+H) & m/z 284.3 (M-H). HPLC rt = 5.126 min. (Sunfire C18), 100 % purity and 10.336 min. (Gemini CI 8), 100 % purity. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ lOmM ammonium acetate / 10% HPLC grade water), (A = 90% HPLC grade water / lOmM ammonium acetate / 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute.

HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. l-(l, 6-naphthyridin-2-yl)cyclopropanamine. To a 250mL RBF was added tert-butyl l-(l,6-naphthyridin-2-yl)cyclopropylcarbamate (770.5 mg, 2.70 mmol) in 30mL of DCM along with Hunig's Base (1.2mL, 6.75 mmol) under a nitrogen atmosphere. The mixture was cooled to 0°C in an ice bath. To the cold mixture was added drop wise TMS-triflate (975 μΐ, 5.40 mmol) and the mixture was stirred for 1 hour then allowed to reach room temperature. The mixture was re-cooled to 0°C, and the reaction quenched with 30mL of saturated sodium bicarbonate. The mixture was diluted with 75mL of diethyl ether, extracted, washed with brine, dried over sodium sulfate, decanted and evaporated to dryness. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50 mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1%TFA with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. Yellow solid, 75% yield. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.36 (m, 2 H), 1.57 (m, 2 H), 7.78 (d, J=8.78 Hz, 1 H), 7.92 (d, J=6.02 Hz, 1 H), 8.47 (d, J=8.78 Hz, 1 H), 8.67 (d, J=6.02 Hz, 1 H), 9.27 (s, 1 H). LCMS rt = 0.415 min., m/z 186.1 (M + H), 98.2% purity. tert-butyl l-(l,5-naphthyridin-2-yl)cyclopropylcarbamate was synthesized in a similar fashion then converted to l-(l,5-naphthyridin-2-yl)cyclopropanamine using the following approach. tert-butyl l-(l,5-naphthyridin-2-yl)cyclopropylcarbamate. LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade methanol/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. Yellow solid, 71% yield. ^X H NMR (400 MHz, CD ₃ OD) 8 ppm 1.39 (m, 2 H), 1.55 (m, 2 H), 7.78 (ddd, J=8.78, 2.13, 1.88 Hz, 2 H), 8.36 (d, J=9.03 Hz, 1 H), 8.44 (d, J=8.03 Hz, 1 H), 8.91 (dd, J=4.27, 1.51 Hz, 1 H). LCMS rt = 1.868min, m/z 286.2 (M+H). HPLC rt = 10.316 min. (Gemini C18), 98.7 % purity. l-(l,5-naphthyridin-2-yl)cyclopropanamine. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50 mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. Tan solid, 67% yield. ¾ NMR (400 MHz, CD ₃ OD) δ ppm 1.39 (m, 2 H), 1.55 (m, 2 H), 7.78 (ddd, J=8.78, 2.13, 1.88 Hz, 2 H), 8.36 (d, J=9.03 Hz, 1 H), 8.44 (d, J=8.03 Hz, 1 H), 8.91 (dd, J=4.27, 1.51 Hz, 1 H). LCMS rt = 0.505min., m/z 186.1(M + H), 99.1% purity. tert-butyl l-(pyrido[4,3-d]pyrimidin-2-yl)cyclopropylcarbamate. To a microwave vial was added 4-aminonicotinaldehyde (500mg, 4.09 mmol), tert-butyl 1-carbamimidoylcyclopropylcarbamate, HC1 (965 mg, 4.09 mmol), N-ethyl-N- is opropylpropan-2 -amine (1.426 mL, 8.19 mmol) and 15mL of ethanol. The vessel was sealed and the mixture subjected to microwave heating (1 10°C) for 8 hours. The crude reaction mixture was purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Phenomenex Luna ΙΟμιη CI 8 30x100mm column at a gradient of 0-100% B and a flow rate of 30 mL/min. over 8 minutes with a 4 minute hold. Upon solvent evaporation, 837mgs (64% yield) of tert-butyl 1- (pyrido[4,3-d]pyrimidin-2-yl)cyclopropylcarbamate was obtained as a tan solid H NMR (400 MHz, CD ₃ OD) δ ppm 1.28 (br. s., 1 H), 1.45 (m, 2 H), 1.51 (br. s., 8 H), 1.82 (m, 2 H), 7.78 (d, J=6.02 Hz, 1 H), 8.80 (d, J=6.02 Hz, 1 H), 9.37 (s, 1 H), 9.57 (s, 1 H). LCMS rt = 1.560 min., m/z 287.31 (M + H), 97.1% purity. HPLC rt = 3.968 min. (Sunfire C18), 99.3 % purity and 9.326 min. (Gemini C18), 97.5 % purity. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+/-) at 220nm using the following set of conditions: Phenomenex Luna 3mm C 18, 2 x 50mm column, with a gradient of 0- 100%B (B = 95% HPLC grade acetonitrile/ lOmM ammonium acetate/ 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium acetate/ 5% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire CI 8 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. tert-Butyl l-(pyrido[3,4-d]pyrimidin-2-yl)cyclopropylcarbamate was synthesized and analyzed in an analogous fashion. tert-butyl l-(pyrido[3,4-d]pyrimidin-2-yl)cyclopropylcarbamate. Tan solid, 61% yield. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.35 (br. s., 1 H), 1.49 (m, 2 H), 1.55 (br. s., 8 H), 1.85 (m, 2 H), 8.00 (d, J=5.52 Hz, 1 H), 8.71 (d, J=5.52 Hz, 1 H), 9.36 (s, 1 H), 9.59 (s, 1 H). LCMS rt = 2.332 min., m/z 287.3 (M + H), 94.8% purity. l-(pyrido[4,3-d]pyrimidin-2-yl)cyclopropanamine, 2 HCl. To a 25mL RBF at 0 °C, under a nitrogen atmosphere, was added tert-butyl l-(pyrido[4,3-d] pyrimidin-2-yl)cyclopropylcarbamate (60 mg, 0.210 mmol), dioxane (5 mL) and a 4M solution of hydrochloric acid (0.524 mL, 2.095 mmol) in dioxane. The solution was stirred for 5 minutes at 0 °C then allowed to warm to room temperature and stirred for 3 hrs. Volatiles were removed en vacuo to give 54mgs (98% yield) of 1- (pyrido[4,3-d]pyrimidin-2-yl)cyclopropanamine, 2 HCl as a light yellow solid. The LC/MS data was obtained on a Shimadzu analytical LCMS (ESI+/-) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%>B (B = 95%> HPLC grade methanol/ lOmM ammonium acetate/ 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium acetate/ 5% HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS rt = 1.91 1 min., m/z 187.1 (M + H), 90% purity. l-(pyrido[3,4-d]pyrimidin-2-yl)cyclopropanamine, 2 HCl. To a 25mL RBF at 0 °C, under a nitrogen atmosphere, was added tert-butyl l-(pyrido[3,4-d] pyrimidin-2-yl)cyclopropylcarbamate (60 mg, 0.210 mmol), dioxane (5 mL) and a 4M solution of hydrochloric acid (0.524 mL, 2.095 mmol) in dioxane. The solution was stirred for 5 minutes at 0 °C then allowed to warm to room temperature and stirred for 3 hrs. Volatiles were removed en vacuo to give 54mgs (98% yield) of 1- (pyrido[3,4-d]pyrimidin-2-yl)cyclopropanamine, 2 HCl as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+/-) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 95% HPLC grade acetonitrile/ lOmM ammonium acetate/ 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium acetate/ 5% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS rt = 2.317 min., m/z 187.1 (M + H), 90% purity.

The bicyclic oxazolopyridine intermediate was made in a similar manner. tert-butyl l-(4-hydroxypyridin-3-ylcarbamoyl)cyclopropylcarbamate. To a large screw cap vial was added 3-aminopyridin-4-ol (0.440 g, 4.0 mmol) in DMF (lOmL) along with triethylamine (1.561 mL, 1 1.2 mmol), \-(tert- butoxycarbonylamino)cyclopropanecarboxylic acid (0.845 g, 4.2 mmol) and finally TBTU, o-Benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (1.605 g, 5.0 mmol). The vial was sealed and the brown mixture was shaken for 24 hours at room temperature. The reaction mixture was concentrated to an oil, taken up in acetonitrile and purified using a Shimadzu preparative HPLC employing

acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Phenomenex-Luna ΙΟμιη C18 30x100mm column at a gradient of 0-100% B and a flow rate of 30mL/min. over 10 minutes with a 5 minute hold. Solvent was removed giving l.Ogram (81% yield) of tert-butyl l-(4- hydroxypyridin-3-ylcarbamoyl) cyclopropyl carbamate as a light yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μηι CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire CI 8 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100%) B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.17 (m, 2 H), 1.51 (s, 9 H), 1.59 (m, 2 H), 6.55 (d, J=7.03 Hz, 1 H), 7.74 (dd, J=7.03, 1.51 Hz, 1 H), 7.79 (br. s., 1 H), 8.89 (d, 1 H). LCMS rt =1.682, min., m/z 294.3(M + H). HPLC rt = 5.621min. (Sunfire C18), 94.9% purity and 7.961min. (Gemini C18), 100 % purity. tert-butyl l-(3-hydroxypyridin-4-ylcarbamoyl)cyclopropylcarbamate was synthesized in an analogous fashion. Tan solid, 69% yield. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.19 (m, 2 H), 1.53 (br. s., 9 H), 1.60 (m, 2 H), 7.85 (d, J=5.52 Hz, 1 H), 7.90 (br. s., 1 H), 8.30 (d, J=5.52 Hz, 1 H). LCMS rt =1.557, min., m/z 294.3(M + H), 91% purity. tert-butyl l-(oxazolo[4,5-c]pyridin-2-yl)cyclopropylcarbamate. To a lOOmL RBF was added hexachloroethane (296 mg, 1.250 mmol), DCM (5 mL), triphenyl phosphine (393 mg, 1.500 mmol) and triethylamine (0.558 mL, 4.00 mmol). The mixture was stirred for 5 minutes at room temperature. Neat tert-butyl l-(4- hydroxypyridin-3-ylcarbamoyl)cyclopropyl carbamate (147 mg, 0.5 mmol) was then added. The solution was stirred for 3 hours at room temperature then further diluted with 20mL of DCM, washed sequentially with 5mL of saturated ammonium chloride, 5mL of saturated sodium bicarbonate, 5mL of brine. The resulting solution was dried over sodium sulfate, decanted and evaporated to an oil. The crude reaction mixture was taken up in 6 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Phenomenex-Luna ΙΟμιη C18 30x100mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 10 minutes with a 10 minute hold. Solvent was removed giving 1 1 lmgs (79% yield) of a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.38 (br. s., 2 H), 1.51 (m, 9 H), 1.78 (m, 2 H), 7.70 (d, J=5.52 Hz, 1 H), 8.51 (d, J=5.52 Hz, 1 H), 8.89 (s, 1 H). LCMS rt = 1.638 min., m/z 276.3 (M + H), 98.0% purity. tert-butyl l-(oxazolo[5,4-c]pyridine-2-yl)cyclopropylcarbamate was synthesized in an analogous fashion. Yellow solid, 50% yield. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.25 - 1.39 (2 H, m), 1.42 - 1.57 (9 H, m), 1.72 - 1.82 (2 H, m), 7.67 (1 H, d, J=5.3 Hz), 8.45 (1 H, d, J=5.5 Hz), 8.83 (1 H, s). LCMS rt = 2.153min., m/z 276.2 (M + H). HPLC rt = 4.511 min. (Sunfire CI 8), 95.8 % purity and 8.058min. (Gemini C18), 97.1% purity. l-(oxazolo[4,5-c]pyridin-2-yl)cyclopropanamine, 2 HCl. To a small RBF was added tert-butyl l-(oxazolo[4,5-c]pyridin-2-yl)cyclopropylcarbamate (107 mg, 0.389 mmol) in dioxane (3 mL) at room temperature along with a 4M dioxane solution of hydrochloric acid (0.972 mL, 3.89 mmol). The mixture was stirred for 3 hours. Volatiles were removed giving 108mgs (95% yield) of l-(oxazolo[4,5- c]pyridin-2-yl)cyclopropanamine, 2 HC1 as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.94 (m, 2 H), 2.07 (m, 2 H), 8.43 (d, J=6.53 Hz, 1 H), 8.96 (d, J=6.53 Hz, 1 H), 9.55 (s, 1 H). LCMS rt = 0.288min., m/z 176.1(M + H), 86% purity. l-(oxazolo[5,4-c]pyridin-2- yl)cyclopropanamine, 2 HC1. White solid, 95% yield. LCMS rt = 0.295min., m/z 176.1(M + H), 84% purity.

(R)- 1 -(oxazolo[4,5-c]pyridin-2-yl)ethanamine and (S)- 1 -(oxazolo[4,5- c]pyridin-2-yl)ethanamine were synthesized in a similar fashion.

(S)-l-(oxazolo[4,5-c]pyridin-2-yl)ethanamine, 2HCI. Yellow solid, 68% yield. LCMS rt = 0.262, m/z 164.17 (M+H), 60% purity. (R)-l-(oxazolo[4,5-c]pyridin-2-yl)ethanamine, 2methanesulfonic acid salt.

Tan solid, 98% yield. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.44 (d, J=7.03 Hz, 3 H), 4.18 (d, J=7.03 Hz, 1 H), 7.21 (d, J=6.53 Hz, 1 H), 8.21 (dd, J=6.65, 1.13 Hz, 1 H), 9.26 (d, J=1.00 Hz, 1 H). LCMS rt = 0290min., m/z 164.1(M + H), 98% purity. l-(lH-imidazo[ 4, 5-c]pyridin-2-yl)cyclopropanamine was synthesized using the following approach. l-(Benzyloxycarbonylamino)cyclopropanecarboxylic acid. To a solution of N-(Benzyloxycarbonyloxy)succinimide (1.80g, 7.23 mmol) in THF (9 mL) was added 1-aminocyclopropanecarboxylic acid, HC1 (722 mg, 5.24 mmol) in water

(1.4mL). The mixture was cooled to 0°C and shaken for 5 minutes. To this mixture was added at 0°C an aqueous solution of sodium bicarbonate (2.46 g, 29.3 mmol)) in 5mL of water. The mixture was allowed to warm to room temperature and shaken overnight. The product mixture was filtered and the solids set aside. Volatiles were evaporated to near dryness then the crude mixture was diluted with lOmL of water and 40mL of DCM. The mixture was extracted and the DCM layer was set aside. The resulting aqueous layer was cooled in an ice bath then acidified with lOmL of acetic acid. The solid was filtered, washed with lmL of water x2 then dried under vaccuum for 2 hours giving 856mgs of l-(benzyloxycarbonylamino)

cyclopropanecarboxylic acid as a fluffy white solid (63% yield). ^X H NMR (400 MHz, DMSO-i/6) δ ppm 0.93 - 1.10 (m, 2 H), 1.26 - 1.37 (m, 2 H), 5.02 (s, 2 H), 7.25 - 7.44 (m, 5 H), 7.89 (s, 1 H), 12.44 (d, 1 H). LCMS rt = 2.1 12min., m/z 236.1(M + H), 90% purity. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute.

Benzyl l-(4-aminopyridin-3-ylcarbamoyl)cyclopropylcarbamate and benzyl l-(3-aminopyridin-4-ylcarbamoyl)cyclopropylcarbamate. To a lOOmL RBF was added pyridine-3,4-diamine (327 mg, 3.00 mmol) in DMF (30 mL) along with 1- (benzyloxycarbonylamino)cyclopropanecarboxylic acid (706 mg, 3.00 mmol), triethylamine. (1.20 mL, 8.40 mmol), and TBTU, 2-(lH-benzo[d][l,2,3]triazol-l-yl)- 1, 1,3,3-tetramethylisouronium tetrafluoroborate (1.20 mg, 3.75 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with 50mL of DCM and extracted; the organics were washed with lOmL of water, lOmL of brine, dried over magnesium sulfate, decanted and evaporated to dryness to give 949mgs of a mixture of benzyl l-(4-aminopyridin-3- ylcarbamoyl)cyclopropylcarbamate and benzyl l-(3-aminopyridin-4- ylcarbamoyl)cyclopropylcarbamate as a yellow solid (68% yield). ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.12 - 1.19 (m, 2 H), 1.52 - 1.60 (m, 2 H), 5.13 (s, 2 H), 7.23 - 7.43 (m, 6 H), 7.82 (d, J=5.5 Hz, 1 H), 8.06 (s, 1 H). LCMS rt = 1.880min., m/z 327.1(M + H), 71% purity. Benzyl l-(lH-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamate. To a medium size microwave vial was added 5mL of acetic acid and 850mgs of the crude reaction mixture prepared in the previous step (benzyl l-(4-aminopyridin-3- lcarbamoyl)cyclopropylcarbamate and benzyl l-(3-aminopyridin-4- ylcarbamoyl)cyclopropylcarbamate). The vial was sealed and the mixture heated at 120°C for 70minutes in the microwave. The vessel was cooled to near 0°C and 50mL of cold saturated sodium carbonate was added along with lOOmL of 10: 1 DCM/methanol. The product was extracted; the organics washed with brine, dried over magnesium sulfate and evaporated. The product mixture was taken up in 15 mL of methanol and purified using a Shimadzu preparative HPLC employing methanol/water/ trifluoroacetic acid where solvent A was 10% methanol / 90% water / 0.1% trifluoroacetic acid and solvent B was 10% water / 90% methanol / 0.1% trifluoroacetic acid with a Phenomenex-Luna ΙΟμιη CI 8 30x100mm column at a gradient of 0-100% B and a flow rate of 40 mL/min. over 15 minutes with a 10 minute hold. Solvent was removed giving a 70% yield of benzyl l-(lH-imidazo[4,5-

1

c]pyridin-2-yl)cyclopropylcarbamate as a light yellow solid. H NMR (400 MHz, CD ₃ OD) δ ppm 1.44 - 1.59 (m, 2 H), 1.68 - 1.83 (m, 2 H), 5.05 - 5.14 (m, 2 H), 6.99

- 7.14 (m, 1 H), 7.19 - 7.41 (m, 4 H), 7.88 - 7.97 (m, 1 H), 8.40 (d, J=6.5 Hz, 1 H), 8.97 (s, 1 H). LCMS rt = 1.483min., m/z 309.2(M + H), 94.5% purity. l-(lH-imidazo[4,5-c]pyridin-2-yl)cyclopropanamine. To a small RBF was added benzyl l-(lH-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamate (939mg, 3.05 mmol) in methanol (13 ml). The flask was sealed with a septa and the solution was degassed and flushed with nitrogen several times. To the solution was then added 10% Palladium(II) on carbon (97 mg, 91 μιηοΐ), and a balloon of hydrogen was added to the top of the flask. The mixture was stirred overnight at room temperature. The mixture was pushed through a plug of celite in a Whatman Autovial (equipped with a 0.45uM nylon membrane and a glass microfiber prefilter). Volatiles were removed giving 640mgs (100% yield) of l-(lH-imidazo[4,5-c]pyridin-2- yl)cyclopropanamine as a yellow solid. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.67 - 1.72 (m, 2 H), 1.73 - 1.80 (m, 2 H), 7.92 (m, 1 H), 8.40 (d, J=7.0 Hz, 1 H), 9.05 (s, 1 H). LCMS rt = 0.293min., m/z 175.1(M + H), 90.7% purity.

5-(5-(l-(l,6-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-me thylphenyl)-2-(4-

1 fluorophenyl)-N-methylbenzofuran-3-carboxamide. Yellow solid, 43% yield. H NMR (400 MHz, THF-i/5) δ ppm 1.43 (m, 2 H), 1.89 (m, 2 H), 2.32 (s, 3 H), 2.89 (d, J=4.77 Hz, 3 H), 7.23 (m, 2 H), 7.33 (dd, J=8.53, 1.76 Hz, 1 H), 7.39 (d, J=8.53 Hz, 1 H), 7.44 (d, J=4.27 Hz, 1 H), 7.60 (d, J=8.53 Hz, 1 H), 7.66 (d, J=5.77 Hz, 1 H), 7.71 (d, J=1.25 Hz, 1 H), 7.73 (d, J=8.78 Hz, 1 H), 7.89 (m, 2 H), 8.11 (m, 2 H), 8.21 (d, J=8.78 Hz, 1 H), 8.59 (d, J=5.77 Hz, 2 H), 9.14 (s, 1 H). LCMS rt = 2.626 min., m/z 571.2(M + H). HPLC rt = 7.391 min. (Sunfire C18), 100 % purity and 11.914 min. (Gemini CI 8), 99.9 % purity.

5-(5-(l-(l,5-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methy lphenyl)-2-(4-

1 fluorophenyl)-N-methylbenzofuran-3-carboxamide. Yellow solid, 43% yield. H NMR (400 MHz, THF-i/5) δ ppm 1.40 (m, 2 H), 1.86 (m, 2 H), 2.31 (s, 3 H), 2.89 (d, J=4.52 Hz, 3 H), 7.22 (m, 2 H), 7.32 (dd, J=8.53, 1.76 Hz, 1 H), 7.37 (d, J=8.78 Hz, 1 H), 7.48 (d, J=4.02 Hz, 1 H), 7.57 (m, 2 H), 7.71 (d, J=1.25 Hz, 1 H), 7.82 (d, J=8.78 Hz, 1 H), 7.89 (m, 2 H), 8.11 (m, 2 H), 8.18 (m, 2 H), 8.64 (s, 1 H), 8.80 (d, J=2.76 Hz, 1 H). LCMS rt = 4.233 min., m/z 571.5 (M + H). HPLC rt = 8.111 min. (Sunfire CI 8), 98.1 % purity and 12.031 min. (Gemini CI 8), 98.1 % purity.

5-(5-(l-(l, 7-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-4- -2-(4-fluoro phenyl)-N-methylbenzofuran-3-carboxamide. Yellow solid, 20% yield. H NMR (400 MHz, T F-dS) δ ppm 1.41 (q, J=4.18 Hz, 2 H), 1.88 (q, J=4.10 Hz, 2 H), 2.26 (s, 3 H), 2.88 (d, J=4.77 Hz, 3 H), 7.23 (m, 3 H), 7.41 (d, J=8.03 Hz, 1 H), 7.46 (d, J=8.53 Hz, 1 H), 7.61 (d, J=5.52 Hz, 1 H), 7.69 (d, J=4.27 Hz, 1 H), 7.81 (d, J=8.53 Hz, 1 H), 7.85 (d, J=1.76 Hz, 1 H), 7.91 (dd, J=7.91, 1.88 Hz, 1 H), 8.07 (m, 3 H), 8.44 (d, J=5.52 Hz, 1 H), 8.61 (s, 1 H), 9.21 (s, 1 H). LCMS rt = 2.543 min., m/z 589.2 (M + H). HPLC rt = 7.126 min. (Sunfire CI 8), 100 % purity and 11.469 min. (Gemini CI 8), 100 % purity.

5-(5-(l-(l,6-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-me thylphenyl)-4- -2-(4-fluoro phenyl)-N-methylbenzofuran-3-carboxamide. Yellow solid, 34% yield. H NMR (400 MHz, T F-dS) δ ppm 1.42 (q, J=4.02 Hz, 2 H), 1.89 (m, 2 H), 2.26 (s, 3 H), 2.88 (d, J=4.77 Hz, 3 H), 7.24 (m, 3 H), 7.41 (d, J=7.78 Hz, 1 H), 7.47 (d, J=8.53 Hz, 1 H), 7.67 (m, 2 H), 7.73 (d, J=8.53 Hz, 1 H), 7.85 (d, J=1.76 Hz, 1 H), 7.92 (dd, J=8.03, 1.76 Hz, 1 H), 8.07 (m, 2 H), 8.21 (d, J=8.78 Hz, 1 H), 8.59 (d, J=5.77 Hz, 2 H), 9.14 (s, 1 H). LCMS rt = 2.555 min., m/z 589.2 (M + H). HPLC rt = 7.098 min. (Sunfire C18), 98.9 % purity and 11.484 min. (Gemini C18), 100 % purity.

5-(5-(l-(l,5-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-me thylphenyl)-4- -2-(4-fluoro phenyl)-N-methylbenzofuran-3-carboxamide. Yellow solid, 42% yield. H NMR (400 MHz, T F-dS) δ ppm 1.40 (m, 2 H), 1.85 (m, 2 H), 2.26 (s, 3 H), 2.88 (d, J=4.77 Hz, 3 H), 7.24 (m, 3 H), 7.40 (d, J=8.03 Hz, 1 H), 7.46 (d, J=8.28 Hz, 1 H), 7.55 (dd, J=8.53, 4.02 Hz, 1 H), 7.72 (d, J=4.27 Hz, 1 H), 7.82 (d, J=9.03 Hz, 1 H), 7.86 (d, J=1.76 Hz, 1 H), 7.92 (dd, J=7.91, 1.88 Hz, 1 H), 8.07 (m, 2 H), 8.17 (m, 2 H), 8.64 (s, 1 H), 8.80 (dd, 1 H). LCMS rt = 3.385 min., m/z 589.3 (M + H). HPLC rt = 7.743 min. (Sunfire CI 8), 98.1 % purity and 11.546 min. (Gemini C18), 98.1 % purity.

5-(5-(l-(l,8-naphthyridin-2-yl)cyclopropylcarbamoyl)-3-fluor o-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. To a 1 dram vial was added DMF (1.3 ml), l-(l,8-naphthyridin-2-yl)cyclopropanamine, 2 HC1 (38.7 mg, 0.150 mmol), N-ethyl-N-isopropylpropan-2-amine (87 μΐ, 0.500 mmol), 3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-5- yl)-4-methylbenzoic acid (43.9 mg, 0.1 mmol) and finally HATU, 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, l,3,3-tetramethylisouronium

hexafluorophosphate(V) (152 mg, 0.400 mmol). The vial was capped and shaken overnight. The crude product was purified using a Shimadzu preparative HPLC employing methanol/water/ trifluoroacetic acid where solvent A was 10% methanol / 90% water/ 0.1% trifluoroacetic acid and solvent B was 10% water / 90% methanol/ 0.1% trifluoroacetic acid with a Phenomenex Luna ΙΟμιη CI 8 30 x 100mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 12 minutes with a 13 minute hold. The solvent was removed giving 33.3mgs (54% yield) of 5-(5-(l-(l,8- naphthyridin-2-yl)cyclopropylcarbamoyl)-3-fluoro-2-methylphe nyl)-4-fluoro-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide as a light yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Xbridge Phenyl C18 3.0μιη 4.6 x 150mm column employing water/methanol/lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. *Η NMR (400 MHz, THF-dS) δ ppm 1.42 (m, 2 H), 1.93 (m, 2 H), 2.17 (d, J=1.00 Hz, 3 H), 2.90 (m, 3 H), 7.23 (m, 3 H), 7.37 (dd, J=8.03, 4.27 Hz, 1 H), 7.44 (d, J=8.28 Hz, 1 H), 7.65 (d, J=8.28 Hz, 1 H), 7.75 (m, 3 H), 8.08 (m, 3 H), 8.18 (dd, J=8.03, 2.01 Hz, 1 H), 8.84 (s, 1 H), 8.93 (dd, J=4.02, 1.76 Hz, 1 H). LCMS rt = 2.595 min., m/z 607.3 (M + H), 99.5% purity. HPLC rt = 7.160 min. (Sunfire C18), 98.7 % purity and 1 1.701min(Gemini C18), 99.2 % purity.

5-(5-(l-(l, 7-naphthyridin-2-yl)cyclopropylcarbamoyl)-3-fluoro-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide.

Yellow solid, 46% yield. *Η NMR (400 MHz, T F-dS) δ ppm 1.42 (m, 2 H), 1.88 (m, 2 H), 2.18 (d, J=1.51 Hz, 3 H), 2.88 (d, J=4.77 Hz, 3 H), 7.25 (m, 3 H), 7.49 (d, J=8.53 Hz, 1 H), 7.62 (d, J=5.52 Hz, 1 H), 7.73 (m, 3 H), 7.79 (d, J=8.78 Hz, 1 H), 8.07 (m, 3 H), 8.45 (d, J=5.52 Hz, 1 H), 8.71 (s, 1 H), 9.21 (s, 1 H). LCMS rt = 2.626 min., m/z 607.3 (M + H), 96.1% purity. HPLC rt = 7.348 min. (Sunfire CI 8), 98.6 % purity and 11.881 min. (Gemini CI 8), 97.9 % purity.

5-(5-(l-(l,6-naphthyridin-2-yl)cyclopropylcarbamoyl)-3-fl uoro-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide.

Orange solid, 77% yield. H NMR (400 MHz, T F-dS) δ ppm 1.43 (m, 2 H), 1.89 (q, J=4.10 Hz, 2 H), 2.18 (d, J=1.25 Hz, 3 H), 2.89 (d, J=4.77 Hz, 3 H), 7.25 (m, 3 H), 7.49 (d, J=8.53 Hz, 1 H), 7.70 (m, 5 H), 8.07 (m, 2 H), 8.22 (d, J=8.53 Hz, 1 H), 8.60 (d, J=5.77 Hz, 1 H), 8.69 (s, 1 H), 9.15 (s, 1 H). LCMS rt = 2.625 min., m/z 607.3 (M + H), 96.4% purity. HPLC rt = 7.358 min. (Sunfire CI 8), 100 % purity and 11.869 min. (Gemini CI 8), 98.2% purity.

5-(5-(l-(l,5-naphthyridin-2-yl)cyclopropylcarbamoyl)-3-fl uoro-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide.

Orange solid, 76% yield. H NMR (400 MHz, T F-dS) δ ppm 1.40 (m, 2 H), 1.84 (m, 2 H), 2.17 (s, 3 H), 2.88 (d, J=4.77 Hz, 3 H), 7.24 (m, 3 H), 7.46 (d, J=8.28 Hz, 1 H), 7.55 (dd, J=8.53, 4.02 Hz, 1 H), 7.77 (m, 4 H), 8.05 (m, 2 H), 8.17 (m, 2 H), 8.79 (dd, J=4.27, 2.76 Hz, 2 H). LCMS rt = 3.588 min., m/z 607.3 (M + H), 98.8% purity. HPLC rt = 8.284 min. (Sunfire CI 8), 97.6 % purity and 11.793 min. (Gemini CI 8), 98.4 % purity.

5-(5-(l-(l,6-naphthyridin-2-yl)cyclopropylcarbamoyl)-4-me thoxy-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. To a 50mL RBF was added 5-(4-fluoro-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzo ic acid (57.0 mg, 0.1263 mmol) in DMF (4 mL) along with Hunig'sBase (110 μΐ, 0.632 mmol), 1-(1,6- naphthyridin-2-yl)cyclopropanamine (37.4 mg, 0.202 mmol) and HATU, 0-(7- Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (192 mg, 0.505 mmol). The vessel was sealed, placed under nitrogen, and stirred overnight at room temperature. The crude product was purified using a Shimadzu preparative HPLC employing methanol/water/ trifluoroacetic acid where solvent A was 10% methanol / 90% water/ 0.1% trifluoroacetic acid and solvent B was 10% water / 90% methanol/ 0.1% trifluoroacetic acid with a Phenomenex Luna ΙΟμιη CI 8 30 x 100mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 12 minutes with a 13 minute hold. The solvent was removed giving 39.1mgs (40% yield) of 5-(5-(l-(l,6-naphthyridin-2-yl)cyclopropylcarbamoyl)-4-metho xy-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methyl Benzofuran-3-carboxamide as a tan solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Xbridge Phenyl CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF- dS) δ ppm 1.51 (m, 2 H), 1.96 (m, 2 H), 2.27 (s, 3 H), 2.87 (d, J=4.77 Hz, 3 H), 4.07 (s, 3 H), 7.14 (s, 1 H), 7.21 (m, 3 H), 7.44 (d, J=8.53 Hz, 1 H), 7.70 (d, J=4.52 Hz, 1 H), 7.91 (m, 3 H), 8.08 (m, 2 H), 8.40 (d, J=8.53 Hz, 1 H), 8.70 (m, 2 H). LCMS rt = 2.525 min., m/z 619.4 (M + H), 96.4% purity. HPLC rt = 7.201 min. (Sunfire C18), 93.4% purity and 11.724 min. (Gemini CI 8), 96.3 % purity.

5-(5-(l-(l, 7-naphthyridin-2-yl)cyclopropylcarbamoyl)-4-methoxy-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. Yellow solid, 82% yield. ^X H NMR (400 MHz, T F-dS) δ ppm 1.43 (m, 2 H), 1.90 (m, 2 H), 2.26 (s, 3 H), 2.87 (d, J=4.77 Hz, 3 H), 4.06 (s, 3 H), 7.12 (s, 1 H), 7.21 (m, 3 H), 7.43 (d, J=8.53 Hz, 1 H), 7.62 (d, J=5.52 Hz, 1 H), 7.72 (d, J=4.52 Hz, 1 H), 7.87 (d, J=8.78 Hz, 1 H), 7.94 (s, 1 H), 8.08 (m, 3 H), 8.44 (d, J=5.52 Hz, 1 H), 8.69 (s, 1 H), 9.22 (s, 1 H). LCMS rt = 2.412 min., m/z 619.5 (M + H), 97.8% purity. HPLC rt = 7.273 min. (Sunfire C18), 100 % purity and 11.658 min. (Gemini C18), 98.9 % purity.

5-(5-(l-(l, 7-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-(2-amino-2- oxoethoxy)-4-methoxy phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide. To a small RBF was added 4-(2-amino-2-oxoethoxy)-5-(2-(4- fluorophenyl)-3-(methylcarbamoyl) benzofuran-5-yl)-2-methoxybenzoic acid (40.5 mg, 0.082 mmol), DMF (3 mL), N-ethyl-N-diisopropylpropan-2-amine (0.086 mL, 0.493 mmol), l-(l,7-naphthyridin-2-yl)cyclopropanamine, 2 HC1 (34.0 mg, 0.132 mmol) and HATU, 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, 1,3,3- tetramethylisouronium hexafluorophosphate(V) (125 mg, 0.329 mmol). The reaction mixture was stirred over night at room temperature. The crude reaction mixture was then evacuated to near dryness, taken up in 6 mL of methanol and purified using a Shimadzu preparative HPLC employing methanol/water/ trifluoroacetic acid where solvent A was 10% methanol / 90% water / 0.1% trifluoroacetic acid and solvent B was 10% water / 90% methanol / 0.1% trifluoroacetic acid with a Phenomenex-Luna ΙΟμιη C18 30x100mm column at a gradient of 40-100%) B and a flow rate of 40 mL/min. over 12 minutes with a 13 minute hold. Solvent was removed giving

26.1mgs (46.6% yield) of 5-(5-(l-(l,7-naphthyridin-2-yl)cyclopropylcarbamoyl)-2- (2-amino-2-oxoethoxy)-4-methoxy phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran- 3-carboxamide as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, DMF-cl7) δ ppm 1.54 (m, 2 H), 1.90 (m, 2 H), 2.96 (d, J=3.51 Hz, 3 H), 4.19 (s, 3 H), 4.81 (s, 2 H), 7.06 (s, 1 H), 7.28 (br. s., 1 H), 7.41 (t, J=8.91 Hz, 2 H), 7.46 (br. s., 1 H), 7.71 (m, 2 H), 7.87 (d, J=5.27 Hz, 1 H), 7.95 (s, 1 H), 8.03 (m, 2 H), 8.11 (dd, J=8.91, 5.40 Hz, 2 H), 8.31 (d, J=4.27 Hz, 1 H), 8.39 (d, J=8.78 Hz, 1 H), 8.57 (d, J=4.52 Hz, 1 H), 9.05 (s, 1 H), 9.28 (br. s., 1 H). LCMS rt = 2.097 min., m/z 660.5(M + H). HPLC rt = 6.203 min. (Sunfire C18), 96.8 % purity and 10.883 min. (Gemini C18), 96.8 % purity.

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-( l-(pyrido[ 4, 3- d]pyrimidin-2-yl)cyclo- propylcarbamoyl)phenyl)benzofuran-3-carboxamide, 2 TFA. To a 25mL RBF flask containing freshly made l-(pyrido[4,3-d]pyrimidin-2-yl)cyclo propanamine, 2 HC1 was added DMF (1.8mL) and Hunig'sBase (122 μΐ, 0.700 mmol). The mixture was stirred for 5 minutes at room temperature followed by the addition of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran -5-yl)-4- methylbenzoic acid (29.5 mg, 0.07 mmol) in DMF (1.8mL) along with HATU (106 mg, 0.280 mmol). The reaction was stirred overnight at room temperature. The crude product mixture was evaporated to a tan oil, diluted with methanol and purified using a Shimadzu preparative HPLC employing methanol/water/ trifluoroacetic acid where solvent A was 10% methanol / 90% water / 0.1% trifluoroacetic acid and solvent B was 10% water / 90% methanol / 0.1% trifluoroacetic acid with a

Phenomenex-Luna ΙΟμιη C18 30x100mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 15 minutes with a 10 minute hold. Solvent was removed giving 14.2mgs (24% yield) of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2- methyl-5-(l-(pyrido[4,3-d]pyrimidin-2-yl)cyclo- propylcarbamoyl)phenyl)benzofuran-3-carboxamide, 2 TFA as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire CI 8 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100%) B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF-dS) δ ppm 1.24 (m, 2 H), 1.65 (m, 2 H), 2.27 (s, 3 H), 2.88 (d, J=4.77 Hz, 3 H), 7.26 (m, 2 H), 7.39 (m, 1 H), 7.46 (m, 2 H), 7.54 (m, 1 H), 7.67 (m, 2 H), 7.86 (d, J=1.76 Hz, 1 H), 7.94 (dd,

J=7.91, 1.88 Hz, 1 H), 8.07 (m, 2 H), 8.61 (d, J=7.03 Hz, 1 H), 8.68 (m, 1 H), 9.88 (s, 1 H). LCMS rt = 2.325min., m/z 590.40 (M + H). HPLC rt = 6.496min. (Sunfire C18), 95.1% purity and 11.088min. (Gemini C18), 95.8% purity.

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-(py rido[3,4- dJpyrimidin-2-yi) cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide was synthesized and analyzed in an analogous fashion. The LC/MS data was obtained a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF-dS) δ ppm 1.50 (m, 2 H), 1.83 (m, 2 H), 2.26 (s, 3 H), 2.88 (d, J=4.77 Hz, 3 H), 7.24 (m, 3 H), 7.38 (d, J=8.03 Hz, 1 H), 7.46 (d, J=8.28 Hz, 1 H), 7.71 (d, J=4.27 Hz, 1 H), 7.77 (m, 1 H), 7.85 (d, J=1.51 Hz, 1 H), 7.91 (dd, J=7.91, 1.88 Hz, 1 H), 8.08 (m, 2 H), 8.54 (s, 1 H), 8.60 (d, J=5.52 Hz, 1

H), 9.23 (s, 1 H), 9.41 (s, 1 H). LCMS rt = 2.497 min., m/z 590.4(M + H). HPLC rt = 7.205min. (Sunfire C18), 99.0% purity and 1 1.124min. (Gemini C18), 97.2% purity.

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-( l-(oxazolo[ 4, 5- c]pyridin-2-yl)cyclopropyl carbamoyl)phenyl)benzofuran-3-carboxamide. To a screw cap vial was added, at room temperature, 3-(4-fluoro-2-(4-fluorophenyl)-3- (methyl carbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (31.6 mg, 0.075 mmol) DMF (1.8mL) along with N-ethyl-N,N-diisopropylpropan-2-amine (79 μΐ, 0.450 mmol), l-(oxazolo[4,5-c]pyridin-2-yl)cyclopropanamine, 2 HC1 (27.9 mg, 0.113 mmol), and finally HATU, 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, 1,3,3- tetramethylisouronium hexafluorophosphate(V) (1 14 mg, 0.300 mmol). The vial was sealed and the mixture shaken at room temperature overnight. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Waters Sunfire 5μιη CI 8 30x150mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 20 minutes with a 10 minute hold. Solvent was removed giving 6mgs (13% yield) of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-(oxazo lo[4,5-c]pyridin-2- yl)cyclo propylcarbamoyl)phenyl)benzofuran-3-carboxamide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100%) B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (500 MHz, THF-dS) δ ppm 1.50 (m, 2 H), 1.79 (m, 2 H), 2.26 (s, 3 H), 2.89 (m, 3 H), 7.25 (m, 3 H), 7.41 (d, J=8.24 Hz, 1 H), 7.48 (m, 2 H), 7.71 (d, J=4.88 Hz, 1 H), 7.80 (d, J=1.83 Hz, 1 H), 7.87 (dd, J=7.93, 1.83 Hz, 1 H), 8.08 (m, 2 H), 8.41 (d, J=5.49 Hz, 1 H), 8.70 (s, 1 H), 8.80 (s, 1 H). LCMS rt = 2.327min., m/z 579.3(M + H), 94.5% purity. HPLC rt = 6.696min.

(Sunfire CI 8), 98.0 % purity and 10.403 min. (Gemini CI 8), 98.6% purity.

4-fluoro-5-(3-fluoro-2-methyl-5-( l-(oxazolo[ 4, 5-c]pyridin-2- yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylb enzofuran-3- carboxamide. To a screw cap vial was added, at room temperature, 3-fluoro-5-(4- fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl )-4-methylbenzoic acid (33.0 mg, 0.075 mmol) in DMF (1.8mL) along with N-ethyl-N,N- diisopropylpropan-2-amine (79 μΐ, 0.450 mmol), l-(oxazolo[4,5-c]pyridin-2- yl)cyclopropanamine, 2 HC1 (27.9 mg, 0.1 13 mmol), and finally HATU, 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, l,3,3-tetramethylisouronium

hexafluorophosphate(V) (114 mg, 0.300 mmol). The vial was sealed and the mixture shaken at room temperature overnight. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Waters Sunfire 5μιη CI 8 30x150mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 20 minutes with a 10 minute hold. Solvent was removed giving lOmgs (21% yield) of 4-fluoro- 5-(3-fluoro-2-methyl-5-(l-(oxazolo[4,5-c]pyridin-2-yl)cyclop ropylcarbamoyl) phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 -carboxamide as a white solid.

The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100%) B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF-dS) δ ppm 1.52 (m, 2 H), 1.79 (m, 2 H), 2.18 (d, J=1.51 Hz, 3 H), 2.89 (d, J=4.77 Hz, 3 H), 7.25 (m, 3 H), 7.48 (m, 2 H), 7.69 (m, 3 H), 8.07 (m, 2 H), 8.41 (d, J=5.52 Hz, 1 H), 8.80 (m, 2 H). LCMS rt = 2.407min., m/z 597.3(M + H), 94.7% purity. HPLC rt = 6.933min.

(Sunfire CI 8), 97.4 % purity and 10.876 min. (Gemini CI 8), 97.4% purity.

4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(l-(o xazolo[4,5- c]pyridin-2-yl)cyclopropyl carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide. To a screw cap vial was added, at room temperature, 5-(4-fluoro-2-(4-fluorophenyl)- 3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoi c acid (33.9 mg, 0.075 mmol) in DMF (1.8mL) along with N-ethyl-N,N-diisopropylpropan-2-amine (79 μΐ, 0.450 mmol), l-(oxazolo[4,5-c]pyridin-2-yl)cyclopropanamine, 2 HC1 (27.9 mg, 0.1 13 mmol), and finally HATU, 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- 1, 1,3,3-tetramethylisouronium hexafluorophosphate(V) (1 14 mg, 0.300 mmol). The vial was sealed and the mixture shaken at room temperature overnight. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Waters Sunfire 5μιη C18 30x150mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 20 minutes with a 10 minute hold. Solvent was removed giving 18.5mgs (41% yield) of 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(l- (oxazolo [4,5-c]pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylben zofuran-3- carboxamide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF-dS) δ ppm 1.53 (m, 2 H), 1.80 (m, 2 H), 2.26 (s, 3 H), 2.87 (d, J=4.52 Hz, 3 H), 4.06 (s, 3 H), 7.12 (s, 1 H), 7.20 (m, 3 H), 7.43 (d, J=8.28 Hz, 1 H), 7.47 (d, J=5.52 Hz, 1 H), 7.68 (d, J=4.52 Hz, 1 H), 7.96 (s, 1 H), 8.09 (m, 2 H), 8.40 (d, J=5.52 Hz, 1 H), 8.71 (s, 1 H), 8.80 (d, 1 H). LCMS rt =

2.405min., m/z 609.3(M + H), 97.2% purity. HPLC rt = 6.878min. (Sunfire C18), 100 % purity and 10.719min. (Gemini CI 8), 100% purity.

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-( l-(oxazolo[ 4, 5-c]pyridin-2- yl)cyclopropyl carbamoyl)phenyl)benzofuran-3-carboxamide. To a screw capped vial was added 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4- methylbenzoic acid (40.3 mg, 0.1 mmol) in DMF (1.7 mL) along with N-ethyl-N,N- diisopropylpropan-2-amine (0.087 mL, 0.500 mmol), l-(oxazolo[4,5-c]pyridin-2-yl) cyclopropanamine, 2 HC1 (39.7 mg, 0.160 mmol) and finally HATU, 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, l,3,3-tetramethylisouronium

hexafluorophosphate(V) (152 mg, 0.400 mmol). The vial was capped and the mixture shaken over night at room temperature. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Waters Sunfire 5μιη C18

30x150mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 20 minutes with a 10 minute hold. Solvent was removed giving 29.5mgs (52% yield) of 2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-(oxazolo[4,5-c] pyridin-2-yl) cyclopropyl carbamoyl)phenyl)benzofuran-3-carboxamide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC

(ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a

Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF-dS) δ ppm 1.47 - 1.53 (m, 2 H), 1.76 - 1.81 (m, 2 H), 2.31 (s, 3 H), 2.87 - 2.91 (m, 3 H), 7.20 - 7.27 (m, 2 H), 7.32 (dd, J=8.5, 1.8 Hz, 1 H), 7.37 (d, J=7.5 Hz, l H), 7.47 (dd, J=5.5, 1.0 Hz, 1 H), 7.51 (d, J=4.5 Hz, 1 H), 7.60 (d, J=8.3 Hz, 1 H), 7.70 (d, J=1.3 Hz, 1 H), 7.80 - 7.87 (m, 2 H), 8.08 - 8.16 (m, 2 H), 8.41 (d, J=5.5 Hz, 1 H), 8.74 (s, 1 H), 8.80 (s, 1 H). LCMS rt = 2.472min., m/z 561.3(M + H). HPLC rt = 6.888 min. (Sunfire C18), 99.0 % purity and 10.934min. (Gemini CI 8), 100 % purity.

5-(3-fluoro-2-methyl-5-( l-(oxazolo[ 4, 5-c]pyridin-2- yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylb enzofuran-3- carboxamide. To a screw capped vial was added added 3-fluoro-5-(2-(4- fluorophenyl)-3-(methylcarbamoyl) benzofuran-5-yl)-4-methylbenzoic acid (42.1 mg, 0.1 mmol) in DMF (1.7 mL) along with N-ethyl-N,N-diisopropylpropan-2-amine (0.087 mL, 0.500 mmol), l-(oxazolo[4,5-c]pyridin-2-yl) cyclopropanamine, 2 HC1 (39.7 mg, 0.160 mmol) and finally HATU, 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- 1, 1,3,3-tetramethylisouronium hexafluorophosphate(V) (152 mg, 0.400 mmol). The vial was capped and the mixture shaken over night at room temperature. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Waters Sunfire 5μιη C18 30x150mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 20 minutes with a 10 minute hold. Solvent was removed giving 25.7mgs (44% yield) of 5-(3-fluoro-2-methyl-5-(l-(oxazolo[4,5-c]pyridin-2- yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylb enzofuran-3- carboxamide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF-dS) δ ppm 1.49 - 1.54 (m, 2 H), 1.76 - 1.83 (m, 2 H), 2.23 (d, J=2.5 Hz, 3 H), 2.89 (d, J=4.8 Hz, 3 H), 7.20 - 7.28 (m, 2 H), 7.33 (dd, J=8.5, 1.8 Hz, 1 H), 7.48 (dd, J=5.5, 1.0 Hz, 1 H), 7.51 (d, J=4.3 Hz, 1 H), 7.60 - 7.68 (m, 2 H), 7.71 (dd, J=12.4, 1.4 Hz, 2 H), 8.08 - 8.16 (m, 2 H), 8.41 (d, J=5.5 Hz, 1 H), 8.78 - 8.86 (m, 2 H). LCMS rt = 2.572min., m/z 579.2(M + H). HPLC rt = 7.168min. (Sunfire C18), 97.4 % purity and 11.323min. (Gemini C18), 100 % purity.

2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(l-(oxazolo[4, 5-c]pyridin-2- yl)cyclopropyl carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide. To a screw capped vial was added 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)- 2-methoxy-4-methylbenzoic acid (43.3 mg, 0.1 mmol) in DMF (1.7 mL) along with N-ethyl-N,N-diisopropylpropan-2-amine (0.087 mL, 0.500 mmol), l-(oxazolo[4,5- c]pyridin-2-yl) cyclopropanamine, 2 HCl (39.7 mg, 0.160 mmol) and finally HATU, 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, l,3,3-tetramethylisouronium

hexafluorophosphate(V) (152 mg, 0.400 mmol). The vial was capped and the mixture shaken overnight at room temperature. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Waters Sunfire 5μιη C18

30x150mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 20 minutes with a 10 minute hold. Solvent was removed giving 18.7mgs (31% yield) of 2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(l-(oxazolo[4,5-c ]pyridin-2- yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxa mide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass

Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF- dS) 5 ppm 1.51 - 1.57 (m, 2 H), 1.77 - 1.83 (m, 2 H), 2.31 (s, 3 H), 2.88 (d, J=4.8 Hz, 3 H), 4.05 (s, 3 H), 7.09 (s, 1 H), 7.17 - 7.29 (m, 3 H), 7.48 (d, J=6.3 Hz, 1 H), 7.50 - 7.58 (m, 2 H), 7.62 (d, J=1.3 Hz, 1 H), 8.00 (s, 1 H), 8.09 - 8.18 (m, 2 H), 8.41 (d, J=5.5 Hz, 1 H), 8.74 (s, 1 H), 8.77 - 8.84 (m, 1 H). LCMS rt = 2.543 min., m/z 591.3 (M + H). HPLC rt = 7.158min. (Sunfire C18), 97.9 % purity and 1 1.306min. (Gemini CI 8), 100% purity.

4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(l-(o xazolo[5,4- c]pyridin-2-yl)cyclopropyl carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide. To a screw capped vial was added 5-(4-fluoro-2-(4-fluorophenyl)-3- (methylcarbamoyl) benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (45.1 mg, 0.1 mmol) in DMF (1.7 mL) along with N-ethyl-N,N-diisopropylpropan-2-amine (0.087 mL, 0.500 mmol), freshly prepared l-(oxazolo[4,5-c]pyridin-2-yl)cyclopropanamine, 2 HC1 (0.040 g, 0.160 mmol) and finally HATU, 2-(3H-[l,2,3]triazolo[4,5- b]pyridin-3-yl)-l, l,3,3-tetramethylisouronium hexafluorophosphate(V) (152 mg, 0.400 mmol). The vial was capped and the mixture shaken over night at room temperature. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing

acetonitrile/water/ammonium acetate where solvent A was 5% acetonitrile / 95% water / 10 mM ammonium acetate and solvent B was 5% water / 95% acetonitrile / 10 mM ammonium acetate with a Waters Sunfire 5μιη CI 8 30x150mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 20 minutes with a 10 minute hold. Solvent was removed giving 19.7mgs (31.8% yield) of 4-fluoro-2-(4- fluorophenyl)-5-(4-methoxy-2-methyl-5-(l-(oxazolo [5,4-c]pyridin-2- yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxa mide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. ^X H NMR (400 MHz, THF- dS) δ ppm 1.13 - 1.20 (m, 2 H), 1.59 - 1.65 (m, 2 H), 2.25 (s, 3 H), 2.87 (d, J=4.5 Hz, 3 H), 4.02 (s, 3 H), 7.09 (s, 1 H), 7.16 - 7.28 (m, 3 H), 7.44 (d, J=8.5 Hz, 1 H), 7.76 (t, J=4.4 Hz, 1 H), 7.87 (s, 1 H), 7.90 (d, J=5.3 Hz, 1 H), 7.99 (s, 1 H), 8.02 - 8.12 (m, 3 H), 8.51 (s, 1 H). LCMS rt = 2.537min., m/z 609.2(M + H). HPLC rt = 7.045min. (Sunfire C18), 98.5% purity and 10.943min. (Gemini C18), 97.8% purity.

4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-((S)-l-( oxazolo[4,5- cJpyridin-2-yi) ethyl carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide. White solid, 24% yield. ^X H NMR (400 MHz, T F-dS) δ ppm 1.73-1.82 (m, 3 H), 2.26 (s, 3 H), 2.87 (d, J=4.5 Hz, 3 H), 4.08 (s, 3 H), 5.59 (quin, J=7.1 Hz, 1 H), 7.12 (s, 1 H), 7.17 - 7.27 (m, 3 H), 7.44 (d, J=8.5 Hz, 1 H), 7.59 (d, J=5.5 Hz, 1 H), 7.74 (d, J=4.5 Hz, 1 H), 7.99 (s, 1 H), 8.07 - 8.15 (m, 2 H), 8.50 (d, J=5.5 Hz, 1 H), 8.73 (d, J=7.3 Hz, 1 H), 8.94 (s, 1 H). (Injectionl) LCMS rt = 2.91min., m/z 597.2(M + H), m/z 595.3(M - H). (Injection2) LCMS rt = 3.99min., m/z 597.2(M + H), m/z 595.3(M - H). Injection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7μιη; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 °C;

Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. Injection 2 conditions: Column: Waters BEH CI 8, 2.0 x 50 mm, 1.7-μιη; Mobile Phase A: 5:95 methanohwater with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanohwater with 10 mM ammonium acetate;

Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. HPLC rt = 7.025min. (Sunfire C18), 90.0% purity and 11.464min. (Gemini C18), 91.3% purity. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a

Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.

4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-((R)- l-(oxazolo[4,5- cJpyridin-2-yi) ethyl carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide. White solid, 17% yield. ^X H NMR (500 MHz, T F-dS) δ ppm 1.68 (s, 3 H), 2.27 (s, 3 H), 2.88 (d, J=4.58 Hz, 3 H), 4.09 (s, 3 H), 5.60 (q, J=7.10 Hz, 1 H), 7.13 (s, 1 H), 7.19 - 7.27 (m, 3 H), 7.46 (d, J=8.55 Hz, 1 H), 7.60 (dd, J=5.49, 0.92 Hz, 1 H), 7.75 (d, J=4.27 Hz, 1 H), 8.00 (s, 1 H), 8.08 - 8.15 (m, 2 H), 8.51 (d, J=5.49 Hz, 1 H), 8.74 (d, J=7.32 Hz, 1 H), 8.96 (s, 1 H). LCMS rt = 2.422min., m/z 597.3(M + H). HPLC rt = 6.965min. (Sunfire C18), 95.4% purity and 11.344min. (Gemini C18), 100% purity. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-( (S)-l-(oxazolof 4, 5- cJpyridin-2-yi) 'ethyl carbamoyl)phenyl)benzofuran-3-carboxamide. White solid, 10% yield. ^X H NMR (400 MHz, THF-i/5) δ ppm 1.70 (s, 3 H), 2.23 - 2.27 (m, 3 H), 2.84 - 2.91 (m, 3 H), 5.64 (quin, J=7.28 Hz, 1 H), 7.18 - 7.28 (m, 3 H), 7.39 (d, J=8.03 Hz, 1 H), 7.47 (d, J=8.28 Hz, 1 H), 7.56 (dd, J=5.52, 1.00 Hz, 1 H), 7.72 (d, J=4.52 Hz, 1 H), 7.80 (d, J=1.76 Hz, 1 H), 7.87 (dd, J=8.03, 2.01 Hz, 1 H), 8.03 - 8.13 (m, 2 H), 8.33 (d, J=8.03 Hz, 1 H), 8.48 (d, J=5.52 Hz, 1 H), 8.91 (d, J=0.75 Hz, 1 H).

(Injectionl) LCMS rt = 2.78min., m/z 567.2(M + H), m/z 565.3(M - H). (Injection2 ) LCMS rt = 3.89min., m/z 567.2(M + H), m/z 565.2(M - H). Injection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7μιη; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5

acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. Injection 2 conditions: Column: Waters BEH CI 8, 2.0 x 50 mm, 1.7-μιη; Mobile Phase A: 5:95 methanohwater with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. HPLC rt = 6.888min. (Sunfire C18), 91.7% purity and 1 1.066min. (Gemini CI 8), 99.2% purity. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire CI 8 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1%

trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100%) B (B = 95%> HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-( (R)-l-(oxazolo[ 4, 5- cJpyridin-2-yi) 'ethyl carbamoyl)phenyl)benzofuran-3-carboxamide. White solid, 15% yield. ^X H NMR (500 MHz, THF-i/5) δ ppm 1.70 (s, 3 H), 2.24 (s, 3 H), 2.87 (d, J=4.58 Hz, 3 H), 5.64 (q, J=7.25 Hz, 1 H), 7.17 - 7.29 (m, 3 H), 7.38 (d, J=7.93 Hz, 1 H), 7.47 (d, J=8.24 Hz, 1 H), 7.56 (dd, J=5.49, 0.92 Hz, 1 H), 7.73 (d, J=4.58 Hz, 1 H), 7.80 (d, J=1.53 Hz, 1 H), 7.87 (dd, J=7.93, 1.83 Hz, 1 H), 8.00 - 8.1 1 (m, 2 H), 8.34 (d, J=7.93 Hz, 1 H), 8.47 (d, J=5.49 Hz, 1 H), 8.90 (s, 1 H). LCMS rt =

2.327min., m/z 567.3(M + H). HPLC rt = 6.738min. (Sunfire C18), 94.0% purity and 1 1.1 13min. (Gemini CI 8), 98.2% purity. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη CI 8, 2 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.

4-fluoro-5-(3-fluoro-2-methyl-5-((S)-l-(oxazolo[4,5-c]pyr idin-2- yl)ethylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofu ran-3-carboxamide. White solid, 20% yield. ^X H NMR (400 MHz, T S-dS) δ ppm 1.70 - 1.73 (m, 3 H), 2.17 (d, J=1.3 Hz, 3 H), 2.87 - 2.90 (m, 3 H), 5.58 - 5.69 (m, 1 H), 7.21 - 7.30 (m, 3 H), 7.50 (d, J=8.5 Hz, 1 H), 7.57 (d, J=5.5 Hz, 1 H), 7.66 - 7.72 (m, 2 H), 7.75 (d, J=4.3 Hz, 1 H), 8.04 - 8.1 1 (m, 2 H), 8.42 - 8.51 (m, 2 H), 8.91 (s, 1 H). (Injection 1) LCMS rt = 2.88min., m/z 585.2(M + H), m/z 583.2(M - H). (Injection 2) LCMS rt = 3.99min., m/z 585.2(M + H), m/z 583.3(M - H). Injection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7μιη; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0- 100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min.

Injection 2 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7-μιη; Mobile Phase A: 5:95 methanol: water with 10 mM ammonium acetate; Mobile Phase B:

95:5 methanol: water with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. HPLC rt = 7.073min. (Sunfire CI 8), 94.4% purity and

11.393min. (Gemini CI 8), 96.4% purity. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini CI 8 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10-100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.

4-fluoro-5-(3-fluoro-2-methyl-5-( (R)-l-(oxazolo[ 4, 5-c]pyridin-2- yl)ethylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofu ran-3-carboxamide. White solid, 27% yield. 'H NMR (500 MHz, T S-dS) δ ppm 1.71 (s, 3 H), 2.16 (s, 3 H), 2.88 (d, J=4.58 Hz, 3 H), 5.63 (q, J=7.32 Hz, 1 H), 7.18 - 7.29 (m, 3 H), 7.48 (d, J=8.24 Hz, 1 H), 7.56 (dd, J=5.49, 0.61 Hz, 1 H), 7.65 - 7.73 (m, 2 H), 7.77 (d, J=4.58 Hz, 1 H), 8.02 - 8.10 (m, 2 H), 8.47 (d, J=5.49 Hz, 2 H), 8.90 (s, 1 H). LCMS rt = 2.420min., m/z 585.3(M + H). HPLC rt = 7.005min. (Sunfire CI 8), 95.5%purity and 11.364min. (Gemini CI 8), 97.6% purity. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.

5-(5-(l-(lH-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamoyl) -4-methoxy-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. To a screw cap vial was added 5-(4-fluoro-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-5-yl) 2-methoxy -4-methylbenzoic acid (45.1 mg, 0.1 mmol) in DMF (1.8mL) along with N-ethyl-N-isopropylpropan-2 -amine (0.087 mL, 0.500 mmol), l-(lH-imidazo[4,5-c]pyridin-2-yl) cyclopropanamine (26.1 mg, 0.150 mmol) and finally 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, 1,3,3- tetramethylisouronium hexafluorophosphate(V) (1 14 mg, 0.300 mmol). The vial was capped and shaken overnight at room temperature. The crude reaction mixture was further diluted with 2 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/ trifluoroacetic acid where solvent A was 10% acetonitrile / 90% water/ 0.1% trifluoroacetic acid and solvent B was 10% water / 90% acetonitrile/ 0.1% trifluoroacetic acid with a Phenomenex-Luna ΙΟμιη C18 30x100mm column at a gradient of 30-100% B and a flow rate of 30 mL/min. over 10 minutes with a 15 minute hold. The desired material was free based

(DCM/bicarb), dried over magnesium sulfate, decanted, and evaporated to dryness to give 30mgs (48% yield) of 5-(5-(l-(lH-imidazo[4,5-c]pyridin-2- yl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-4-fluoro- 2-(4-fluorophenyl)- N-methylbenzofuran-3-carboxamide as a yellow solid. ^X H NMR (500 MHz, CD ₃ OD) 8 ppm 1.49 - 1.59 (m, 2 H), 1.76 - 1.85 (m, 2 H), 2.25 (br. s., 3 H), 2.90 (s, 3 H), 3.99 - 4.06 (m, 3 H), 7.13 (s, 1 H), 7.16 - 7.28 (m, 3 H), 7.38 - 7.52 (m, 2 H), 7.81 - 7.92 (m, 3 H), 8.20 (d, J=5.80 Hz, 1 H), 8.69 (s, 1 H). LCMS rt = 2.325min., m/z

608.3(M + H). HPLC rt = 6.626min. (Sunfire CI 8), 96.5% purity and 10.973min. (Gemini CI 8), 99.5% purity. The LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Phenomenex Luna 3μιη C18, 2 x 50mm column, with a gradient of 0- 100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254nm and 256nm with a Waters Sunfire C18 3.5μιη 4.6 x 150mm column employing water/acetonitrile/ 0.1% trifluoroacetic acid with a gradient of 10-100% B (B = 95% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 5% HPLC grade water), (A = 95% HPLC grade water / 0.1% trifluoroacetic acid/ 5% HPLC grade acetonitrile), inlO minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Phenomenex Gemini C18 3.0μιη 4.6 x 150mm column employing water/methanol/ lOmM ammonium bicarbonate with a gradient of 10- 100% B (B = 95% HPLC grade methanol/ lOmM ammonium bicarbonate / 5% HPLC grade water), (A = 95% HPLC grade water / lOmM ammonium bicarbonate / 5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.

5-(5-(l-(lH-imidazo[ 4, 5-c]pyridin-2-yl)cyclopropylcarbamoyl)-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. Yellow solid, 28% yield. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.50 - 1.58 (m, 2 H),

1.74 - 1.81 (m, 2 H), 2.24 (s, 3 H), 2.88 - 2.93 (m, 3 H), 7.19 - 7.30 (m, 3 H), 7.43 (d, J=8.03 Hz, 1 H), 7.46 - 7.53 (m, 2 H), 7.83 (d, J=2.01 Hz, 1 H), 7.86 - 7.98 (m, 5 H), 8.20 (d, J=5.77 Hz, 1 H), 8.68 (d, J=0.75 Hz, 1 H). (Injection 1) LCMS rt =

2.96min., m/z 578.2(M + H), m/z 576.3(M - H). (Injection 2) LCMS rt = 3.80min., m/z 578.2(M + H), m/z 576.3(M - H). Iniection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7μιη; Mobile Phase A: 5:95 acetonitrile: water_with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. Iniection 2 conditions: Column: Waters BEH CI 8, 2.0 x 50 mm, 1.7-μιη; Mobile Phase A: 5:95 methanol: water_with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0- 100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. HPLC rt = 6.435min. (Sunfire CI 8), 94.5% purity and 10.733min. (Gemini CI 8), 96.6% purity.

5-(5-(l-(lH-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamo yl)-3-fluoro-2- methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide. Yellow solid, 35% yield. ^X H NMR (400 MHz, CD ₃ OD) δ ppm 1.49 - 1.57 (m, 2 H), 1.73 - 1.82 (m, 2 H), 2.15 (s, 3 H), 2.90 (s, 3 H), 7.19 - 7.31 (m, 3 H), 7.45 (dd,

J=5.77, 0.50 Hz, 1 H), 7.50 (d, J=8.53 Hz, 1 H), 7.66 - 7.72 (m, 2 H), 7.85 - 7.97 (m, 4 H), 8.18 (d, J=5.52 Hz, 1 H), 8.66 (d, J=0.50 Hz, 1 H). (Injection 1) LCMS rt = 2.64min., m/z 598.2(M + H), m/z 596.2(M - H). (Injection2) LCMS rt = 3.89min., m/z 598.2(M + H), m/z 596.2(M - H). Iniection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7μιη; Mobile Phase A: 5:95 acetonitrile: water_with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. Iniection 2 conditions: Column: Waters BEH CI 8, 2.0 x 50 mm, 1.7-μιη; Mobile Phase A: 5:95 methanol: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanohwater with 10 niM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0- 100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. HPLC rt = 6.666min. (Sunfire C18), 94.4% purity and 11.359min. (Gemini C18), 95.1% purity.

It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.