AU2011329486A1 - Compounds - Google Patents

Abstract

The present invention features compounds of formula (I): and salts thereof, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections.

Description

WO 2012/067664 PCT/US2011/024825 COMPOUNDS FIELD OF THE INVENTION 5 The present invention relates to novel compounds useful as anti-viral agents, specifically Hepatitis C Virus (HCV) inhibitors, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections. BACKGROUND OF THE INVENTION 10 Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be 15 infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010. Due to the high degree of variability in the viral surface antigens, existence of multiple 20 viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by 25 ribavirin (Lindsay, K.L. (1997) Hepatology 26 (suppl 1): 71S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) 30 and, of those treated, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon, both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement 35 in the management of this disease. First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359 362), hepatitis C virus (HCV) is now widely accepted as the most common causative agent of 1 WO 2012/067664 PCT/US2011/024825 post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral 5 proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, C.M. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931-960; Raven Press, N.Y.). The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) 10 EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al. (2000) Journal of Virology, 74(4), p.2046 2051). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to 15 cure HCV infection. Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit replication of both genotype 1a and genotype lb of HCV. SUMMARY OF THE INVENTION 20 The present invention provides compounds substituted at the 6-position with a boron containing moiety, pharmaceutical compositions comprising said compounds, methods of synthesis and uses of such compounds in treating and/or preventing viral infections, such as flavivirus infections, for example, HCV infections. DETAILED DESCRIPTION OF THE INVENTION 25 The present invention provides a compound of formula (1): 0 R2 0 3 O N NN R R 4 (I) wherein: 30 R 1 is one or more substituents independently selected from the group consisting of hydrogen, halogen, C 1

.

6 alkyl, hydroxyC 1

.

6 alkyl, alkoxy, -CN, and -CF 3 ;

R

2 is NR 5

R

6 2 WO 2012/067664 PCT/US2011/024825

R

5 is hydrogen;

R

6 is hydrogen or C 1

.

6 alkyl;

R

3 is C 1

.

6 alkyl, C 3

.

6 cycloalkyl, C 1

.

6 alkoxy, or heterocyclyl;

R

4 is 5 (a) aryl substituted with B(OR 7 )(OR) and additionally substituted with one or more substituents selected from the group consisting of C 1

.

6 alkyl, C 3

.

6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ; (b) Het substituted with hydroxyl on the boron atom and additionally substituted with one or more substituents selected from the group consisting of halogen and 10 C 1

.

6 alkyl; or (c) R 9

OR

9

B(OR

7 )(OR) wherein R 9 is alkylene;

R

7 and R3 are both hydrogen or C 1

.

6 alkyl or when R 7 and R3 are C 1

.

6 alkyl, R 7 and R3 together with the oxygen atoms to which they are attached form a 5 to 8-membered ring; X and Z are independently CH or N, provided that both X and Z are not N; 15 or a pharmaceutically acceptable salt thereof. The term "alkyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C 1

.

6 alkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, 20 isopropyl, t-butyl and 1,1-dimethylpropyl. However, when a moiety is defined such that alkyl bears a substituent it will be clear to the skilled person from the context that alkyl may include alkylene, for example methylene (CH 2 ), ethylene (CH 2

CH

2 ) and propylene (CH 2

CH

2

CH

2 ). The term "alkylene" refers to a straight or branched chain saturated hydrocarbon linker groups. Examples of alkylene groups include methylene (CH 2 ), ethylene (CH 2

CH

2 ) and 25 propylene (CH 2

CH

2

CH

2 ). The term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, C 1

.

6 alkoxy means a straight or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1 30 oxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy. The term "aryl" refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, particularly 6 - 10 carbon atoms. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the 35 like. Unless otherwise indicated, the term "aryl" also includes each possible positional isomer of an aromatic hydrocarbon radical, such as 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6 3 WO 2012/067664 PCT/US2011/024825 tetrahydronaphthyl, 1-phenathridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenathridinyl, 9-phenanthridinyl and 10-phenanthridinyl. The term "halogen" or "halo" refers to a fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br) or iodine (iodo, 1) atom. 5 The term "hydroxy" or "hydroxyl" refers to a radical or substituent of the formula OH. The term "cycloalkyl" refers to a saturated cyclic group containing 3 to 6 carbon ring atoms (unless otherwise specified). Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "Het" refers to a 3- to 7-membered monocyclic heterocyclic ring or 8- to 11 10 membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused. Each "Het" contains one or more carbon atoms, one boron atom substituted with hydroxy, and additionally contains one or more oxygen atoms. Preferred Het are oxaborolanyl, benzoxaborolyl, and dihyrobenzoxaborolyl. 15 The term "heterocyclyl" refers to a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, partially saturated or unsaturated- Each heterocycle consists of one or more carbon atoms and one or more oxygen, nitrogen, or sulfur atoms. The heterocycle may be attached at any carbon or N atom, provided that the attachment results in the creation of a stable structure. When the heterocycle has substituents, it is understood 20 that the substituents may be attached to any atom in the ring, provided that a stable chemical structure results. Preferred heterocycles are furanyl and pyrazolyl. The present invention provides a compound of formula (1): O R 2 0 3 0 O N N y R1 R 4 25 (1) wherein:

R

1 is one or more substituents independently selected from the group consisting of hydrogen, halogen, C1.

6 alkyl, hydroxyC 1

.

6 alkyl, alkoxy, -CN, and -CF 3 ;

R

2 is NR 5

R

6 ; 30 R 5 is hydrogen;

R

6 is hydrogen or C 1

.

6 alkyl;

R

3 is C 1

.

6 alkyl, C 3

.

6 cycloalkyl, C 1

.

6 alkoxy, or heterocyclyl; 4 WO 2012/067664 PCT/US2011/024825

R

4 is (a) aryl substituted with B(OR 7 )(OR") and additionally substituted with one or more substituents selected from the group consisting of C 1

.

6 alkyl, C 3

.

6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ; or 5 (b) Het substituted with hydroxyl on the boron atom and additionally substituted with one or more substituents selected from the group consisting of halogen and

C

1

.

6 alkyl;

R

7 and R3 are both hydrogen or C 1

.

6 alkyl or when R 7 and R3 are C 1

.

6 alkyl, R 7 and R3 together with the oxygen atoms to which they are attached form a 5 to 8-membered ring; 10 X and Z are independently CH or N, provided that both X and Z are not N; or a pharmaceutically acceptable salt thereof. The present invention features a compound of formula (1) wherein:

R

1 is halogen;

R

2 is NR 5

R

6 ; 15 R 5 is hydrogen;

R

6 is hydrogen or C 1

.

6 alkyl;

R

3 is C 3

-

6 cycloalkyl;

R

4 is aryl substituted with B(OR 7 )(OR") and additionally substituted with one or 20 more substituents selected from the group consisting of C 1

.

6 alkyl, C 3

.

6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ;

R

7 and R3 are both hydrogen or C 1

.

6 alkyl; X and Z are independently CH or N, provided that both X and Z are not N; or a pharmaceutically acceptable salt thereof. 25 The present invention also features a compound of formula (1) wherein:

R

1 is halogen;

R

2 is NR 5

R

6 ;

R

5 is hydrogen;

R

6 is hydrogen or C1.

6 alkyl; 30 R 3 is C 3

.

6 cycloalkyl;

R

4 is Het substituted with hydroxy on the boron atom and additionally substituted with one or more substituents selected from the group consisting of halogen and C1.

6 alkyl; X and Z are independently CH or N, provided that both X and Z are not N; or a pharmaceutically acceptable salt thereof. 35 The present invention features a compound of formula (1) as described above wherein X and Z are both CH. The present invention features a compound of formula (la) 5 WO 2012/067664 PCT/US2011/024825 0

R

2 0// / N "OH

R

9 B OH (la) wherein:

R

1 is halogen; 5 R 2 is NR 5

R

6 ;

R

5 is hydrogen;

R

6 is hydrogen or C 16 alkyl;

R

9 is one or more substituents independently selected from the group consisting of C1. 6 alkyl, C 3

-

6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ; 10 or a pharmaceutically acceptable salt thereof. The present invention features a compound of formula (1) or (la) wherein R 1 is fluoro or chloro. The present invention features a compound of formula (1) or (la) wherein R 6 is C1. 6 alkyl. 15 The present invention features a compound of formula (1) or (la) wherein R 9 is one or more halogen. The present invention also features a compound of formula (1) selected from the group consisting of: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 20 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 6-(N-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5 yl)methyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1,5 a]pyridine-3-carboxamide; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 25 yl)methylsu lfonamido)methyl)-2-(trifluoromethoxy)phenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(pyrid in-3-yl)pyrazolo[1 , 5-a]pyrid in-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 6 WO 2012/067664 PCT/US2011/024825 4-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(pyrid in-4-yl)pyrazolo[1, 5-a]pyrid in-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 5 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)H-pyrazolo[1,5-a]pyridin 6-yl)methan-1 6-ylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-chlorophenylboronic acid; 2-chloro-4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 10 a]pyridin-6-yl)methylsulfonamido)methyl)phenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-methylphenylboronic acid; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-methylphenylboronic acid; 15 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid; 2-chloro-4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5 20 a]pyridin-6-yl)methylsulfonamido)methyl)phenylboronic acid ; 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid; 2-fluoro-4-((N-(2-(4-fluorophenyl)-5-(furan-3-yl)-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)phenylboronic acid; 25 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluoro-3-(trifluoromethyl)phenylboronic acid; 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((1 -hydroxy-7-(trifl uoromethyl)- 1,3 dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3 carboxamide; 30 and pharmaceutically acceptable salts thereof. Certain compounds of formula (1) and (la) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention also extends to conformational isomers of compounds of 35 formula (1) and (la) and any geometric (cis and/or trans) isomers of said compounds. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to 7 WO 2012/067664 PCT/US2011/024825 those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention. Diastereoisomeric mixtures of compounds of formula (1) and (Ia) may be separated according to methods well known in the literature, for example by preparative HPLC or by 5 chromatographic purifications. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention. 10 It is understood that compounds of formula (1) and (Ia) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention. It will also be appreciated that compounds of the invention which exist as polymorphs, and mixtures thereof, are within the scope of the present invention. 15 The present invention also features a compound of formula (1) or (Ia) or a pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use. The term "pharmaceutically acceptable" when used in relation to an ingredient which may be included in a pharmaceutical composition for administration to a patient, refers to that ingredient being 20 acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical composition and not being deleterious to the recipient thereof. Salts of compounds of formula (1) or (Ia) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non pharmaceutically acceptable counterions are within the scope of the present invention, for 25 example, for use as intermediates in the preparation of other compounds of formula (1) or (Ia) and their pharmaceutically acceptable salts. It will be appreciated that for use in medicine the salts of formula (1) or (Ia) should be physiologically (i.e. pharmaceutically) acceptable. The compounds of the present invention may be in the form of their free base or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically 30 acceptable esters thereof. Also included in the present invention are pharmaceutically acceptable salt complexes. The present invention also covers the pharmaceutically acceptable salts of the compounds of formula (1) and (Ia). As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and 35 exhibit minimal undesired toxicological effects. For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base 8 WO 2012/067664 PCT/US2011/024825 addition salts. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. The salt may precipitate from solution and be collected by filtration or may be recovered by 5 evaporation of the solvent. Therefore, according to a further aspect, the invention provides a pharmaceutically acceptable salt of a compound of formula (1) or (Ia) and embodiments thereof. In certain embodiments, compounds of formula (1) and (Ia) may contain an acidic functional group and may therefore be capable of forming pharmaceutically acceptable base 10 addition salts by treatment with a suitable base. A pharmaceutically acceptable base addition salt may be formed by reaction of a compound of formula (1) or (Ia) with a suitable strong base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which may be isolated for example by crystallisation and filtration. Pharmaceutically acceptable base salts include ammonium salts (for example ammonium or 15 tetraalkylammonium), metal salts, for example alkali-metal or alkaline-earth-metal salts (such as hydroxides, sodium, potassium, calcium or magnesium), organic amines (such as tris [also known as tromethamine or tris(hydroxymethyl)aminomethane], ethanolamine, diethylamine, triethanolamine, choline, isopropylamine, dicyclohexylamine or N-methyl-D glucamine), cationic amino acids (such as arginine, lysine or histidine) or bases for insoluble 20 salts (such as procaine or benzathine). In certain embodiments, compounds according to formula (1) or (Ia) may contain a basic functional group and may therefore be capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. A pharmaceutically acceptable acid addition salt may be formed by reaction of a compound of formula (1) or (Ia) with a suitable 25 strong inorganic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric or perchloric) or a suitable strong organic acid, for example, sulfonic acids [such as p toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, naphthalenesulfonic (e.g. 2-naphthalenesulfonic)], carboxylic acids (such as acetic, propionic, fumaric, maleic, benzoic, salicylic or succinic), anionic amino acids (such as 30 glutamaic or aspartic), hydroxyl acids (such as citric, lactic, tartaric or glycolic), fatty acids (such as caproic, caprylic, decanoic, oleic or stearic) or acids for insoluble salts (such as pamoic or resinic [e.g. polystyrene sulfonate]), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. In one embodiment, a pharmaceutically acceptable acid addition salt of a 35 compound of formula (1) or (Ia) is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt. 9 WO 2012/067664 PCT/US2011/024825 It will be appreciated by those skilled in the art that organoboronic acids and/or their organoboronate esters may form "ate" complex addition salts, such as organoborate complex addition salts, in the presence of suitable nucleophilic complexing reagents. Suitable nucleophilic complexing reagents include, but are not limited to alkali metal hydroxides, for 5 example lithium hydroxide, sodium hydroxide or potassium hydroxide, or fluoride. Examples of organoborate complex addition salts and methods for their preparation will be readily apparent. For example, one such suitable organoborate complex addition salt is an alkali metal trihydroxyorganoborate salt, such as a sodium trihydroxyorganoborate salt. By way of illustration, sodium trihydroxyarylborate and sodium trihydroxyalkylborate complex addition 10 salts and methods for their preparation are described in Cammidge, A.N. et al, Org. Lett., 2006, 8, 4071-4074. Pharmaceutically acceptable "ate" complex addition salts as described herein are also considered to be within the scope of this invention. The present invention features suitable pharmaceutically acceptable salts of the compounds of formula (1) or (Ia) including acid salts, for example sodium, potassium, 15 calcium, magnesium, ammonium, tetraalkylammonium and tris (tromethamine tris(hydroxymethyl)aminomethane) salts and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as 20 hydrochloric, sulfuric, phosphoric and sulfamic acids and the like. The present invention features pharmaceutically acceptable base addition salts of a compound of formula (1) or (Ia) which are salts of a strong base, for example, sodium, lysine, ammonium, N-methyl-D-glucamine, potassium, choline, arginine (for example L-arginine) or magnesium. In a further aspect the salt is sodium, lysine, ammonium, N-methyl-D 25 glucamine, potassium, choline or arginine (for example L-arginine). Other non-pharmaceutically acceptable salts, for example oxalates, may be used, for example in the isolation of compounds of formula (1) and (Ia) and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non 30 stoichiometric forms of the salts of the compounds of formula (1) and (Ia). The salts of a compound of formula (1) and (Ia) may be prepared by contacting appropriate stoichiometric amounts of the free acid with the appropriate base in a suitable solvent. The free acid of a compound of formula (1) or (Ia) may for example be in solution with the appropriate base added as a solid or both the free acid of a compound of formula (1) 35 or (Ia) and the appropriate acid may independently be in solution. Suitable solvents for solubilising a compound of formula (1) or (Ia) free acid include for example alcohols such as isopropanol; ketones such as acetone; acetonitrile or toluene. If 10 WO 2012/067664 PCT/US2011/024825 the base is to be added as a solution in a solvent, the solvent used may include acetone, methanol or water. The salts of a compound of formula (1) or (la) may be isolated in solid form by conventional means from a solution thereof obtained as above. For example, a non 5 crystalline salt may be prepared by precipitation from solution, spray drying or freeze drying of solutions, evaporating a solution to a glass, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid. The salts of a compound of formula (1) and (la) may be prepared by directly crystallising from a solvent in which the salt has limited solubility, or by triturating or otherwise 10 crystallising a non-crystalline salt. For example, organic solvents such as acetone, acetonitrile, butanone, 1-butanol, ethanol, 1-propanol or tetrahydrofuran or mixtures of such solvents may be used. An improved yield of the salts may be obtained by the evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, for example in stages. Careful control of the precipitation temperature and seeding 15 may be used to improve the reproducibility of the production process and the particle size distribution and form of the product. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a 20 complex with water is known as a "hydrate". Solvates of the compounds of formula (1) and (la) and solvates of the salts of the compounds of formula (1) and (la) are included within the scope of the present invention. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (1) or (la) or a salt thereof) and a 25 solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Most preferably the solvent used is water and the solvate may also be referred to as a hydrate. Solvates of compounds of formula (1) and (la) which are suitable for use in medicine 30 are those wherein the solvent is pharmaceutically acceptable. However, solvates having non pharmaceutically acceptable solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (1) and (la) and their pharmaceutically acceptable salts and solvates. Furthermore, some of the crystalline forms of the compounds of formula (1) or (la) or 35 salts and solvates thereof may exist in one or more polymorphic form, which are included in the present invention. 11 WO 2012/067664 PCT/US2011/024825 Prodrugs of the compounds of formula (1) and (Ia) are included within the scope of the present invention. It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (1) or (Ia), which may be made prior to a final deprotection stage, may not 5 possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds defined in the first aspect which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined in the first aspect are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of 10 the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. 15 Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds of formula (1) and (Ia). Suitable prodrugs for compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals 20 and ketals. The compounds of the invention have been found to exhibit antiviral activity, specifically HCV inhibitory activity, and may therefore useful in treating or preventing viral infections, such as HCV infections, or diseases associated with such infections. In vitro studies have been performed which demonstrate the usefulness of compounds described 25 herein as antiviral agents. The present invention provides a compound of formula (1) or (Ia) or a pharmaceutically acceptable salt thereof for use in medical therapy. The present invention provides the use of a compound of formula (1) or (Ia) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating 30 and/or preventing viral infections, such as HCV infections, and/or diseases associated with such infections. The present invention provides a compound of formula (1) or (Ia) or a pharmaceutically acceptable salt thereof for use in treating and/or preventing viral infections, such as HCV infections, and/or diseases associated with such infections. 35 The present invention provides a method for treating and/or preventing viral infections, such as HCV infections, or diseases associated with such infections which method 12 WO 2012/067664 PCT/US2011/024825 comprises administering to a subject, for example a human, a therapeutically effective amount of a compound of formula (1) or (Ia) or a pharmaceutically acceptable salt thereof. It will be appreciated that reference herein to therapy or treatment may include, but is not limited to prevention, retardation, prophylaxis, and cure of the disease. The present 5 invention provides compounds and pharmaceutical compositions for the treatment and prevention of viral infections, such as HCV infections, as well as diseases associated with viral infections in living hosts. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection include treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma. 10 Within the context of the present invention, the terms describing the indications used herein are classified in the Merck Manual of Diagnosis and Therapy, 17 th Edition and/or the International Classification of Diseases 1 0 th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Processes for the preparation of compounds of formula (1) form further aspects of the 15 invention. Throughout the specification, general formulae are designated by formulae 1 - 14. 0 2 N 0 2 N N H 2 N N 1 2 3 According to a process A, 4-chloro-3-nitropyridine can be readily converted to molecules of general formula 2 (wherein G 1 = alkyl, heteroaryl, or cyclopropyl) via treatment of 1 with a suitable catalyst (preferably a palladium catalyst such as PdCl 2 (dppf)), an alkyl- or 20 aryl- organometallic reagent (including an aryl or alkyl boronic acid or alkyl zinc, for example cyclopropylboronic acid), and a base (for example sodium carbonate) in a suitable solvent mixture (for example dioxane and water). Reduction of 2 to afford 3 can be accomplished readily by those skilled in the art by using a suitable reducing agent (for example hydrogen) in the presence of a suitable catalyst (for example palladium on activated carbon) in a solvent 25 (for example ethanol or THF). N N NH 2 o=s=o o~:s=o 1 12 G2 G 4 5 Functionalization of 3 can be readily accomplished using methods well known to those skilled in the art. For example, treatment of amine 3 with a suitable sulfonating agent (for example methanesulfonyl chloride, where G 2 = Me) in the presence of a suitable base 30 (for example Hunig's base) and a suitable solvent (for example dichloromethane) affords a bis-sulfonated amine which can be readily converted to the mono-sulfonated amine by 13 WO 2012/067664 PCT/US2011/024825 treatment with an aqueous base (for example potassium hydroxide). Subsequent functionalization as a suitably protected amine (for example P 1 = p-methoxybenzyl) can be accomplished by treatment with a suitable alkylating agent (for example p-methoxybenzyl chloride) in the presence of a suitable base (for example NaH) in solvent (for example THF). 5 Further functionalization of 4 to aminated product 5 can be accomplished using a suitable oxidant (for example MSH) in solvent (for example DCM). 0 0 O 3 P 3 G N N o=s=o 6 7 Combination of aminated pyridine 5 with a suitable alkyne coupling partner (for example 6, where G3 = suitably substituted aryl or heteroaryl or alkyl, for example methyl, 3 10 (4-fluorophenyl)-2-propynoate) and a base (for example potassium carbonate) in solvent (for example DMF) affords adduct 7. HN HN 0 0 P 3 HG G3 ~KN~.N< HN ~N< 8 9 Further functionalization of 7 can be readily accomplished by those skilled in the art. For example, ester hydrolysis using a suitable base (for example potassium hydroxide) in a 15 suitable polar protic solvent combination (for example THF/Water or THF/MeOH/Water) followed by amidation using a suitable coupling reagent (for example EDCI or HATU), amine (for example methyl amine), base (for example Hunig's base) and solvent (for example DCM or HATU) will afford amides with general formula 8 wherein G4 is C 1

.

8 alkyl or C 3

.

6 cycloalkyl. Removal of P 1 can be readily accomplished by treatment with an acid (for example TFA) in 20 solvent (for example DCM) to afford sulfonamides of general formula 9. 14 WO 2012/067664 PCT/US2011/024825 G4 G4 HN HN 0 0 X1L G I - G 6 G 6 G N\ X N'NG Xs_' Ge HO, O -- O0 HO, O= -- O G OH O 10 11 12 Further functionalization of 9 can be accomplished via a number of processes. For example alkylation of 9 with an activated alkylating agent such as 10 (where, for example, X is a carbon chain between 1-2 atoms in length, G 5 is a suitable halide, for example a 5 bromide, or a boronic acid, and G 6 is a halide, proton or ester, and Ll is a suitable leaving group, for example bromide) using a suitable base (for example potassium carbonate) and solvent (for example DMF) can afford functionalized boronic acids of the type 11. When G 5 is a halide (preferably bromide) conversion to the corresponding boronic acid can be readily accomplished by those skilled in the art using a suitable boron source (for example bis 10 pinacolatodiboron), catalyst (for example PdCl 2 (dppf), weak base (for example KOAc) and solvent (for example 1,4-dioxane) under an inert atmosphere. Further, where G 6 is a reducible functionality (preferably an ester in a position ortho to G 5 ) treatment of 11 with a suitable reducing reagent (for example LiBH 4 ) in a suitable solvent combination (for example THF/MeOH) affords functionalized boronates of the type 12. pi HN

G

5

G

6 HO-BX N 0 6 0 G G

G

6 13 14 15 Using chemistry similar to that described for 11 and 12 above, functionalized alkylating agents of the type 13 (where P 1 is a suitable protecting group, for example -MOM) can be combined with 9 using a suitable base (for example potassium carbonate) and solvent (for example DMF). For substrates where G 5 is a halide (preferably bromide) 20 conversion to the corresponding boronic acid can be accomplished in an analogous manner to that described above. Further, deprotection of P 1 (for example when P 1 = MOM) can be accomplished with strong acid (for example 6N HCI) in a suitable solvent (for example THF or 1,4-dioxane) to afford structures of the general formula 14. 15 WO 2012/067664 PCT/US2011/024825 The invention also extends to novel intermediates disclosed herein, used in the preparation of compounds of formula (1) and (la) or salts thereof. Further details for the preparation of compounds of formula (1) and (la) are found in the examples section hereinafter. 5 Those skilled in the art will appreciate that in the preparation of compounds of formula (1) and (la) and/or salts thereof it may be necessary and/or desirable to protect one or more sensitive groups in the molecule or the appropriate intermediate to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for 10 example, "Protective groups in organic synthesis" by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9 15 fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl or aralkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl). The invention also includes a pharmaceutical composition comprising a compound of formula (1) or (la) or pharmaceutically acceptable salt thereof together with at least one 20 pharmaceutically acceptable excipient. The term "excipient" refers to a compound that is useful in preparing a pharmaceutical composition, e.g. diluent, carrier. The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may 25 involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The dosage forms and procedures may involve amporphous dispersions, molecular dispersions, hot melt extrusion, particle size reduction through micronization or wet bead milling (nanomilling), self emulsifying systems, or complexation, for example cyclodextrin. 30 The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical, intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal or transmucosal administration. For oral administration, the compounds can be formulated into any suitable dosage 35 form, for example, tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile solutions or suspensions, syrups, elixirs and concentrated drops. 16 WO 2012/067664 PCT/US2011/024825 Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example 5 magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example a hard gelatin capsule shell or a soft gelatin capsule shell. Where the composition is in the 10 form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other 15 suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters 20 such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. 25 For injection (parenteral administration) e.g. intramuscular, intravenous, intraperitoneal, subcutaneous, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water, saline solution, Hank's solution or Ringer's solution. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved in water 30 for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. In addition, the compounds of the invention may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for 35 example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, 17 WO 2012/067664 PCT/US2011/024825 and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories. A typical suppository formulation comprises a compound of formula (1) or (Ia) 5 or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional non-CFC propellant such 10 as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The topical formulations of the present invention may be presented as, for instance, ointments, creams, gels, salves or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. 15 The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Preparations may be suitably formulated to give controlled/extended release of the active compound. The amounts of various compounds to be administered can be determined by 20 standard procedures taking into account factors such as the compound (IC50) potency, (EC 50 ) efficacy, and the biological half-life (of the compound), the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art. Amounts administered also depend on the routes of administration and the degree of 25 oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of administration of the present compounds. Preferably the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be 30 administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose. Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/kg, and preferably from 0.1 to 50 mg/kg, of a compound of formula (1) or (Ia) or a 35 pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/kg, of a compound of formula (1) or (Ia). A topical formulation contains 18 WO 2012/067664 PCT/US2011/024825 suitably 0.01 to 5.0% of a compound of formula (1) or (Ia). The active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art. In some cases the desired dose may be given on alternate days or other appropriate schedule, for example, weekly or monthly. 5 These doses may be administered in unit dosage forms, for example, containing 0.5 - 100 mg, 5 to 1000 mg or 50 to 500 mg, or 20 to 500 mg, or 50 to 400 mg of active ingredient per unit dosage form. It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and 10 extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using 15 conventional course of treatment determination tests. The compounds of formula (1) or (Ia) or pharmaceutically acceptable salt(s) thereof may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (1) or (Ia) or pharmaceutically acceptable salt thereof together with one or more further therapeutic 20 agent(s). Compounds of the invention may be administered in combination with other therapeutic agents, for example immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), 25 mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy. 30 Compounds of the invention may be administered in combination with other therapeutic anti-viral agents selected from the list: interferon, pegylated interferon, ribavirin, protease inhibitors, for example, filibuvir, polymerase inhibitors, for example, boceprevir, telaprevir, or compounds disclosed in PCT/US2010/046782, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, 35 immunoglobulines, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. For example, combination therapy may comprise providing a compound for formula (1) or (Ia) or pharmaceutically acceptable salt 19 WO 2012/067664 PCT/US2011/024825 thereof with other anti-viral agents, such as acyclovir, famciclovir, valganciclovir and related compounds, ribavirin and related compounds, amantadine and related compounds, various interferons such as, interferon-alpha, interferon-beta, interferon-gamma and the like as well as alternative forms of interferons such as pegylated interferons. 5 When a compound of formula (1) or (Ia) or pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the 10 age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with at least one pharmaceutically acceptable carrier 15 and/or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions by any convenient route. When administration is sequential, either the HCV inhibitor or the second therapeutic 20 agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient 25 formulation, conveniently in such manner as are known for such compounds in the art. The following non-limiting examples illustrate the present invention. EXAMPLES It will be appreciated by those skilled in the art that when solvents are used in 30 reactions it is desirable to use anhydrous solvents. It is further desirable to conduct reactions under an inert atmosphere, for example under nitrogen or argon, where appropriate. Abbreviations DMSO Dimethylsulfoxide 35 HATU O-(7-azabenzotriazol-1 -yl)-N,N, N', N'-tetramethyl uroni um hexafluorophosphate ISCO Companion T M Automated flash chromatography equipment with fraction analysis by UV absorption available from Presearch and manufactured by Teledyne Isco Inc. 20 WO 2012/067664 PCT/US2011/024825 THF Tetrahydrofuran Example 1: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 alpyridin-6-vl)methylsulfonamido)methyl)-2-fluorophenvlboronic acid HN 0 MeO 2 S'' ,N N F F - .OH /B,0 5 OH Step 1: N-(4-bromo-3-fluorobenzyl)-N-(4-cyclopropylpyridin-3-yl)methanesulfonamide To a solution of N-(4-cyclopropylpyridin-3-yl)methanesulfonamide (2.3 g, 10.8 mmol) in DMF (30 mL) was added 1-bromo-4-(bromomethyl)-2-fluorobenzene (3.2 g, 11.9 mmol) 10 and K 2

CO

3 (2.2 g, 16.25 mmol) at rt under nitrogen atmosphere. Then, the reaction mixture was stirred at 80 'C for 2 hr. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL) and birne (100 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford N-(4-bromo-3-fluorobenzyl)-N-(4 15 cyclopropylpyridin-3-yl)methanesulfonamide (2.3 g, 53 % ) as a white solid. Step 2: 1-amino-3-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-4 cyclopropylpyridinium A solution of O-(mesitylsulfonyl)hydroxylamine (45 mL, 0.207 mmol/L in DCM, 9.2 mmol) was added N-(4-bromo-3-fluorobenzyl)-N-(4-cyclopropylpyridin-3 20 yl)methanesulfonamide (2.3 g, 5.8 mmol) at rt under nitrogen atmosphere. Then, the reaction mixture was stirred at rt for 72 hr. The mixture was diluted with Et 2 O (40 mL) and filtered. The filtrate was dried in vacuo to afford 1-amino-3-(N-(4-bromo-3 fluorobenzyl)methylsulfonamido)-4-cyclopropylpyridinium (2.8 g, 80 %) as a white solid. Step 3: ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 25 fluorophenyl)pyrazolo[1,5-alpyridine-3-carboxylate A solution of 1-amino-3-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-4 cyclopropylpyridinium (1.3 g, 2.1 mmol), ethyl 3-(4-fluorophenyl)propiolate (0.6 g, 3.1 mmol) and K 2

CO

3 (0.43 g, 3.1 mmol) in DMF (20 mL) was stirred at 100 'C for 2 hr under nitrogen atmosphere. The reaction solution was cooled to rt and quenched with water (50 mL). The 30 mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with water (100 mL) and birne (100 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford ethyl 6-(N-(4-bromo 21 WO 2012/067664 PCT/US2011/024825 3-fl uorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fl uorophenyl)pyrazolo[ 1, 5-a]pyridi ne-3 carboxylate (0.62 g, 42 %) as a brown solid. Step 4: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-alpyridine-3-carboxylic acid 5 A solution of ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 (4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.62 g, 1.3 mmol) and KOH (0.87 g, 15.4 mmol) in EtOH/H 2 0 (22.5 mL, 2 : 1) was heated at 85 'C for 1 hr. The reaction solution was cooled down to rt and concentrated in vacuo. Water (20 mL) was added and aq. HCI (1 N, 20 mL) was added and the formed precipitated was filtered off and dried in vacuo to give 10 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.5 g, 84 %) as a brown solid. Step 5: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide To a solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 15 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.5 g, 0.87 mmol) in dry DMF (15 mL) was added DIPEA (0.246 g, 1.91 mmol) and then HATU (0.456 g, 1.04 mmol) at 21 'C under nitrogen atmosphere. After 15 min, MeNH 2 in THF (1.74 mL, 3.48 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 20 mL) and brine (50 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-3 fluorobenzyl)methylsu lfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1,5 a]pyridine-3-carboxamide (0.26 g, 51 %) as a white solid. Step 6: 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2 25 yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylpyrazolo[1, 5-alpyridine-3 carboxamide A solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (260 mg, 0.44 mmol), bis(pinacolato)diboron (216 mg, 0.88 mmol), potassium acetate (130 mg, 1.33 mmol) and 30 PdCl 2 (dppf)-CH 2

CI

2 (57 mg, 0.05 mmol) in dioxane (1 5mL) was degassed and refilled with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N 35 methylpyrazolo[1,5-a]pyridine-3-carboxamide (230 mg, 82%) as a yellow solid. Step7: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid 22 WO 2012/067664 PCT/US2011/024825 A solution of 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3 carboxamide (230mg, 0.36 mmol ) in THF (10 mL) was added PS-BBA (0.7 g, 1.8 mmol) and aqueous HCI (5N, 0.54 mL, 2.52 mmol) at rt. After the addition, the reaction mixture was 5 stirred at rt overnight. Then, the mixture was filtered and concentrated in vacuo. The residue was purified with pre-HPLC to afford 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2 fluorophenylboronic acid (65mg, 33 %) as a white solid. 1 H NMR (300MHz, METHANOL-d4) 6= 8.59 (s, 1 H), 7.76 - 7.71 (m, 2H), 7.35 - 7.04 (m, 6H), 4.94 (s, 2H), 3.30 (s, 3H), 2.82 (s, 10 3H), 2.22 - 2.17 (m, 1H), 1.17 - 0.91 (m, 3H), 0.57-0.49 (m, 1H). LCMS (m/z, ES*)= 555.0 (M+1). Example 2: 6-(N-((7-chloro-1-hydroxv-1,3-dihydrobenzo[c1[1,21oxaborol-5 vl)methvl)methylsulfonamido)-5-cyclopropvl-2-(4-fluorophenvl)-N-methvlpDvrazolo[1,5 alpvridine-3-carboxamide NH 0F N -CI B-OH 15 0 Step 1: methyl 2-bromo-3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 (methylcarbamoyl)pyrazolo[1, 5-alpyridin-6-yl)methylsulfonamido)methyl)benzoate A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (500 mg, 1.24 mmol), 5 20 (bromomethyl)-7-chlorobenzo[c][1,2]oxaborol-1 (3H)-ol (508 mg, 1.49 mmol), potassium carbonate (513 mg, 3.72 mmol) and potassium iodide (206 mg, 1.24 mmol) in DMF 20 mL) was heated at 50 'C for 30min. The reaction solution was cooled down to room temperature and diluted with water (20 mL) and extracted with ethyl acetate (30mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue 25 was purified with column chromatography to afford methyl 2-bromo-3-chloro-5-((N-(5 cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)benzoate (512 mg, 62 % yield) as a white solid. LCMS (m/z, ES*) = 663 (M+H) Step 2: methyl 3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 30 (methylcarbamoyl)pyrazolo[1, 5-alpyridin-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5 tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoate 23 WO 2012/067664 PCT/US2011/024825 A solution of 2-bromo-3-ch loro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)benzoate (510 mg, 0.77 mmol), potassium carbonate (319 mg, 2.31 mmol), bis(pinacolato)diboron (1.96 g, 7.7 mmol) and PdCl 2 (dppf)-CH 2

CI

2 adduct (29 mg, 0.039 mmol) in 1,4-dioxane (40 mL) was 5 degassed and refilled with nitrogen and heated at 100 'C overnight. After the reaction solution was cooled down to rt, water (40 mL) was added and the solution was extracted with EtOAc (3 x 30 mL ). The combined organic layers were dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified by pre-HPLC to afford 3-chloro-5-((N-(5 cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 10 yl)methylsulfonamido)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (160 mg, 29% yield) as a white solid. LCMS (m/z, ES*) = 711 (M+H). Step 3: 6-(N-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5 yl)methyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1, 5 alpyridine-3-carboxamide 15 A solution of 3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (160 mg, 0.23 mmol) and LiBH4 (0.34 mL, 0.68 mmol, 2 M) in THF (50mL) was stirred at 0 C for 1 hr. Water (20 mL) was added and the organic layer was separated, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the 20 residue was purified by pre-HPLC to afford 6-(N-((7-chloro-1-hydroxy-1,3 dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (70 mg, 50% yield) as a white solid. 1 H NMR (METHANOL-d 4 ) 6: 8.64 (s, 1H), 7.75 (t, 2H), 7.28 (m, 5H), 4.96 (m, 4H), 3.30 (s, 3H), 2.82 (s, 3H), 2.20 (m, 1H), 1.10 (m, 1H), 0.97 (m, 2H), 0.51 (m, 1H). LCMS (m/z, 25 ES*) = 583 (M+1). Example 3: 4-((N-(5-cyclopropyl-2-(4-fluorophenvl)-3-(methylcarbamovl)pyrazolo[1,5 a]pyridin-6-vl)methylsulfonamido)methyl)-2-(trifluoromethoxv)phenvlboronic acid NH 0 F MeO 2 S NF - OH

OCF

3 OH Step 1: N-(4-bromo-3-(trifluoromethoxy)benzyl)-N-(4-cyclopropylpyridin-3 30 yl)methanesulfonamide 24 WO 2012/067664 PCT/US2011/024825 To a solution of N-(4-cyclopropylpyridin-3-yl)methanesulfonamide (2.3 g, 10.8 mmol) in DMF (30 mL) was added 1-bromo-4-(bromomethyl)-2-(trifluoromethoxy)benzene (3.97 g, 11.9 mmol) and K 2

CO

3 (2.2 g, 16.25 mmol) at rt under nitrogen atmosphere. Then, the reaction mixture was stirred at 80 'C for 2 hr. The mixture was diluted with water (50 mL) 5 and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL) and birne (100 mL) and then dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford N-(4-bromo-3 (trifluoromethoxy)benzyl)-N-(4-cyclopropylpyridin-3-yl)methanesulfonamide (2.8 g, 56 %) as a white solid. 10 Step 2: 1-amino-3-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-4 cyclopropylpyridinium To a solution of O-(mesitylsulfonyl)hydroxylamine (46.5 mL, 0.207 mmol/L in DCM, 9.6 mmol) was added N-(4-bromo-3-(trifluoromethoxy)benzyl)-N-(4-cyclopropylpyridin-3 yl)methanesulfonamide (2.8 g, 6 mmol) at rt under nitrogen atmosphere. Then, the reaction 15 mixture was stirred at rt for 72 hr. The mixture was diluted with Et 2 O (40 mL) and filtered. The filtrate was dried in vacuo to afford 1-amino-3-(N-(4-bromo-3 (trifluoromethoxy)benzyl)methylsulfonamido)-4-cyclopropylpyridinium (1.8 g, 45 %) as a white solid. Step 3: ethyl 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5 20 cyclopropyl-2-(4-fluorophenyl)pyrazolo[1, 5-alpyridine-3-carboxylate A solution of 1-amino-3-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido) 4-cyclopropylpyridinium (1.8 g, 2.6 mmol), ethyl 3-(4-fluorophenyl)propiolate (0.76 g, 4 mmol) and K 2

CO

3 (0.55 g, 4 mmol) in DMF (20 mL) was stirred at 100 'C for 2 hr under atmosphere. The reaction solution was cooled down to rt and quenched with water (50 mL). The mixture 25 was extracted with EA (50 mL x 3). The combined organic layers were washed with water (100 mL) and birne (100 mL) and then dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford ethyl 6-(N-(4-bromo 3-(trifluoromethoxy)benzyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5 a]pyridine-3-carboxylate (1.4 g, 79 %) as a brown solid. 30 Step 4: 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5-cyclopropyl 2-(4-fluorophenyl)pyrazolo[1,5-alpyridine-3-carboxylic acid A solution of ethyl 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5 cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (505 mg, 0.75 mmol) and KOH (0.63 g, 11.25 mmol) in EtOH/H 2 0 (22.5 mL, 2 : 1) was heated at 85 'C for 1 hr. The 35 reaction solution was cooled to rt and concentrated in vacuo. Water (20 mL) was added and aq. HCI (1 N, 20 mL) was added. The formed precipitated was filtered off and dried in vacuo 25 WO 2012/067664 PCT/US2011/024825 to give 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.47 g, 97 %) as a white solid. Step 5: 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5-cyclopropyl 2-(4-fluorophenyl)-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide 5 To a solution of 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5 cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.47g, 0.73 mmol) in dry DMF (20 mL) was added DIPEA (0.208 g, 1.61 mmol) and then HATU (0.33 g, 0.87 mmol) at 21 'C under nitrogen atmosphere. After 15 min, MeNH 2 in THF (1.46 mL, 2.92 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was diluted with 10 water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL) and then dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (0.4 g, 85 %) as a white solid. 15 Step 6: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl- 1,3,2 dioxaborolan-2-yl)-3-(trifluoromethoxy)benzyl)methylsulfonamido)pyrazolo[1, 5-alpyridine-3 carboxamide A solution of 6-(N-(4-bromo-3-(trifluoromethoxy)benzyl)methylsulfonamido)-5 cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (400 mg, 0.61 20 mmol), bis(pinacolato)diboron (310 mg, 1.22 mmol), potassium acetate (179 mg, 1.83 mmol) and PdCl 2 (dppf)-CH 2

CI

2 (70 mg, 0.06 mmol) in dioxane (20mL) was degassed and refilled with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N 25 (4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2-yl)-3 (trifluoromethoxy)benzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (405 mg, 94%) as a yellow solid. Step7: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-(trifluoromethoxy)phenylboronic acid 30 To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5 tetramethyl- 1, 3,2-d ioxaborolan-2-yl)-3 (trifluoromethoxy)benzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (405mg, 0.58 mmol ) in THF (20 mL) was added PS-BBA (1.12 g, 2.9 mmol) and aq. HCI (5N, 0.81 mL, 4.06 mmol) at rt. After the addition, the reaction mixture was stirred at rt for overnight. 35 Then, the mixture was filtered and concentrated in vacuo. The residue was purified with pre HPLC to afford 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-(trifluoromethoxy)phenylboronic acid (159mg, 44 26 WO 2012/067664 PCT/US2011/024825 %) as a white solid. 'H NMR (300MHz, METHANOL-d4) o= 8.58 (s, 1 H), 7.76 - 7.71 (m, 2H), 7.39 - 7.18 (m, 6H), 4.94 (s, 2H), 3.23 (s, 3H), 2.82 (s, 3H), 2.18 - 2.06 (m, 1H), 1.13 - 0.85 (m, 3H), 0.57-0.49 (m, 1H). LCMS (m/z, ES*)= 621.0 (M+1). Example 4: 4-((N-(3-carbamovl-5-cyclopropyl-2-(4-fluorophenvl)pyrazolo[1,5-alpyridin-6 5 vl)methylsulfonamido)methyl)-2-fluorophenvlboronic acid 0

NH

2 F MeO 2 Ss N N'N 0H F OH Step 1: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-alpyridine-3-carboxylic acid A solution of ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 10 (4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (770mg, 1.28 mmol) in MeOH (40 mL) was treated with 5 N KOH (10 mL) and heated under reflux for 2 hr. The solution was concentrated in vacuo and water (30 mL) was added. The aqueous solution was adjusted to pH 1 with 2N HCI (aq). The solid was collected and dried in vacuo to afford 6-(N-(4-bromo-3 fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3 15 carboxylic acid (710 mg, 96% yield) as white solid. LCMS (m/z, ES*) = 575 (M+1). Step 2: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-alpyridine-3-carboxamide A solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (700 mg, 1.22 mmol), HATU (555 mg, 20 1.46 mmol) and DIPEA (346 mg, 2.68 mmol) in DMF (30 mL) was stirred under NH 3 atmosphere at rt for 0.5h. Water (30 mL) was added and the solution was extracted with EtOAc (40 mL x 3). The combined orgnic layers were washen with brine (50 mL), dried over anhydrous Na2SO4. After the removal of solvent, the residue was purified by column chromatography (gradually, from PE to PE:EA=2:1) to afford 6-(N-(4-bromo-3 25 fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3 carboxamide (613 mg, 88 %) as a white solid. LCMS (m/z, ES*) = 574 (M+1). Step 3: 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-alpyridine-3-carboxamide A solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 30 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (600 mg, 1.05 mmol), potassium acetate (309 mg, 3.2 mmol), bis(pinacolato)diboron (531 mg, 2.1 mmol) and PdCl 2 (dppf)-CH 2

CI

2 adduct (768 mg, 1.05 mmol) in 1,4-dioxane (60 mL) was degassed and refilled with nitrogen 27 WO 2012/067664 PCT/US2011/024825 and heated at 100 C overnight. After the reaction solution was cooled down to rt, water (60 mL) was added and the solution was extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified by column chromatography to afford 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5 5 tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-2-(4 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (577 mg, 88%) as a white solid. LCMS (m/z, ES*) = 623 (M+1). Step 4: 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-alpyridin-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid 10 A solution of 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (570 mg, crude, 0.92 mmol), PS-BBA (3.5 g, 9.2 mmol) and HCI (5N aq., 8 mL) in THF (60 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified with pre-HPLC to afford 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4 15 fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid (210 mg, 42%) as a white solid. 'H NMR (METHANOL-d 4 ) 6: 8.63 (s, 1H), 7.80 (q, 2H), 7.41 (m, 2H), 7.28 (m, 2H), 7.15 (m, 2H), 4.94 ( t, 2H), 3.26 (s, 3H), 2.06 (m, 1H), 0.89 (m, 3H), 0.59 (m, 1 H). L CMS (m/z, ES*) = 541 (M+1). Example 5: 4-((N-(5-cycloPropyl-3-(methylcarbamoyl)-2-(pyrid in-3-yl)pyrazolo[1, 5-alpyrid in-6 20 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid O H N MeO 2 S, N N'N N B OH F OH Step 1: ethyl 3-oxo-3-(pyridin-3-yl)propanoate A solution of nicotinic acid (15.0 g, 0.134 mol, Sinopharm) in DCM (75 mL) was added oxalyl chloride (12 mL, 0.134 mol) and then DMF (0.1 mL) was added drop wise. The 25 reaction mixture was refluxed for 1.5 hr. The resulting solution was concentrated in vacuo. The carbonyl chloride was obtained as a brown solid. A solution of ethyl potassium malonate (26g, 0.152 mol) in MeCN (340 mL) was added TEA (43 mL) and cooled in an ice-salt bath and MgCl 2 (17.5 g, 0.183 mol) was added and the resulting mixture was stirred at same temperature for 2 hr. The carbonyl chloride prepared above was added dropwise and the 30 reaction mixture was warmed to rt and stirred overnight. After the reaction was completed (monitored by TLC), the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2N HCI (240 mL). This mixture was stirred in the ice 28 WO 2012/067664 PCT/US2011/024825 bath for 1.5 hr and then transferred to a separating funnel and extracted with EA (300 mL x 3). The combined organic layers were washed with sat. NaHCO 3 (250 mL), brine (250 mL), dried over anhydrous Na 2

SO

4 . After the removal of the solvent, it afforded the crude product ethyl 3-oxo-3-(pyridin-3-yl)propanoate (13.84 g, 53.6%) as a red brown oil. 5 Step 2: ethyl 3-(pyridin-3-yl)propiolate To a soluton of Ph 3 PO (39.86 g, 71.7 mmol) in dry DCE (220 mL) was added Tf 2 O (15.06 g, 71.7 mmol) at 0 C under nitrogen atmosphere and the mixture was stirred at the same temperature for 15 min. Ethyl 3-oxo-3-(pyridin-3-yl)propanoate (13.84 g, 71.7 mmol) and TEA (7.25 g, 143.4 mmol) was added and the mixture was heated at 85'C for 2 hr. The 10 resulting mixture was cooled to rt and washed with brine (3*50 mL). After the removal of solvent, the crude product was purified with column chromatography (gradually from PE:EA =10:1 to PE/EA = 5:1) to afford ethyl 3-(pyridin-3-yl)propiolate (3.4 g, 27%) as a yellow oil. Step 3: ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 (pyridin-3-yl)pyrazolo[1, 5-a]pyridine-3-carboxylate 15 A solution of 1-amino-3-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-4 cyclopropylpyridinium 2,4,6-trimethylbenzenesulfonate (2 g, 3.255 mmol, U25277/192/1), ethyl 3-(pyridin-3-yl)propiolate (0.855 g, 4.883 mmol) and K 2

CO

3 (0.674 g, 4.883 mmol) in DMF (15 mL) was heated at 80'C overnight under nitrogen atmosphere. The reaction mixture was cooled to rt and quenched with water (50 mL). The mixture was extracted with 20 EtOAc (50 mL x 3) and the combined organic layers were dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography (gradually from PE:EA =10:1 to PE/EA =1:1) to afford ethyl 6-(N-(4-bromo-3 fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3 carboxylate (1.01 g, 53%) as a white solid. 25 Step 4: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(pyridin-3 yl)pyrazolo[1,5-alpyridine-3-carboxylic acid A solution of ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 (pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.01 g, 1.72 mmol) and KOH (1.44 g, 25.8 mmol) in EtOH/H 2 0 (15 mL, 2:1) was heated at 85'C for 1.5 hr under nitrogen atmosphere. 30 The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in water (100 mL) and acidified with aq. HCI (1 N, 50 ml) to pH 1. The mixture was filtered and the solid was dried in vacuo to afford 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido) 5-cyclopropyl-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.919 g, 95%) as a white solid. 35 Step 5: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2 (pyridin-3-yl)pyrazolo[1, 5-alpyridine-3-carboxamide 29 WO 2012/067664 PCT/US2011/024825 To a solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 (pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.919 g, 1.643 mmol) and TEA (0.366 g, 3.615 mmol) in dry DMF (15 mL) was added HATU (0.753 g, 1.971 mmol) at 21'C under nitrogen atmosphere. After the mixture was stirred at rt for 15 min, MeNH 2 in THF (2 M, 3.29 5 mL, 6.572 mmol) was added and the mixture was stirred at rt for 1 h. The reaction was quenched with water (50 mL) and filtered off. The solid was dissolved in EtOAc (200 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified by column chromatography (EtOAc) to afford 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido) 5-cyclopropyl-N-methyl-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.669 g, 71%) 10 as a brown solid. Step 6: 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-N-methyl-2-(pyridin-3-yl)pyrazolo[1, 5-alpyridine-3-carboxamide A solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-N methyl-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.669 g, 1.17 mmol), KOAc 15 (0.344 g, 3.5 mmol), (BPIN) 2 (0.445 g, 1.75 mmol) and Pd(dppf)C1 2 (0.135 g, 0.12 mmol) in dry dioxane (20 mL) was degassed and refilled with nitrogen three times and then heated at 98'C for 3.5 hr. After the mixture was cooled down to rt and concentrated in vacuo, the residue was purified by column chromatography (gradually from PE:EA =5:1 to EA) to afford 5-cyclopropyl-6-(N-(3-fl uoro-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2 20 yl)benzyl)methylsulfonamido)-N-methyl-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.65 g, 89%) as a brown solid. Step 7: 4-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(pyridin-3-yl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid A solution of 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2 25 yl)benzyl)methylsulfonamido)-N-methyl-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.65 g, 1.05 mmol), PS-BBA (1.8 g, 5.25 mmol) and aq. HCI (5 N, 1.53 mL, 7.35 mmol) in THF(1 5 mL) was stirred at rt for 4 hr. The mixture was filtered and concentrated in vacuo. The crude product was purified by pre-HPLC to afford 4-((N-(5-cyclopropyl-3 (methylcarbamoyl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2 30 fluorophenylboronic acid (0.15 g, 26%). 1 H NMR (300MHz, METHANOL-d4) 6= 8.92 (s, 1 H), 8.71 (s, 1 H), 8.62 - 8.60 (m, 1 H), 8.23 - 8.19 (m, 1 H), 7.59 - 7.54 (m, 1 H), 7.35 - 7.33 (m, 1 H), 7.25 (s, 1 H), 7.15 - 7.07 (m, 2 H), 4.94 - 4.88 (m, 2 H), 3.26 (s, 3 H), 2.87 (s, 3 H), 2.21 (m, 1 H), 1.19 - 1.06 (m, 1 H), 1.00 - 0.96 (m, 2 H), 0.65 (m, 1 H). LCMS (m/z, ES*)= 538 (M+1). 35 Example 6: 4-((N-(5-cycloprovl-3-(methylcarbamovl)-2-(pvrid in-4-vl')pvrazolo[1, 5-alpyrid in-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid 30 WO 2012/067664 PCT/US2011/024825 O H N MeO 2 S' N N'N N B OH F OH Step 1: ethyl 3-oxo-3-(pyridin-4-yl)propanoate To a solution of isonicotinic acid (12.0 g, 0.097mol, Sinopharm) in DCM (90 mL) was added oxalyl chloride (9.6 mL, 0.107mol) and then, DMF (O.1mL) was added drop wise. The 5 reaction mixture was heated under refluxed for 1.5 hr. The resulting solution was concentrated in vacuo. The acid chloride was obtained as a brown solid. To a solution of ethyl potassium malonate (20.8g, 0.122 mol) in MeCN (272 mL) was added TEA (34.4 mL) and cooled in an ice-salt bath. MgCl 2 (14 g, 0.146 mol) was added and the resulting mixture was stirred at the same temperature for 2 hr. The acid chloride prepared above was added 10 and the reaction mixture was warmed to rt and stirred overnight. After the reaction was completed, the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2N HCI (250 mL). This mixture was stirred in the ice bath for 1.5 hr and then transferred to a separating funnel and extracted with EtOac (200 mL x 3). The combined organic layers were washed with sat. NaHCO3 (250 mL), brine (300mL x 3) and 15 dried over anhydrous sodium sulfate. After the removal of solvent, it afforded the crude ethyl 3-oxo-3-(pyridin-4-yl)propanoate (11 g, 58%) as a white solid. Step 2: ethyl 3-(pyridin-4-yl)propiolate To a solution of Ph 3 PO (31.68 g, 68 mmol) in dry DCE (176 mL) was added Tf 2 O (11.97 g, 68 mmol) at 0 C under nitrogen atmosphere and the mixture was stirred at 0 C for 20 15min. To this solution was added ethyl 3-oxo-3-(pyridin-4-yl)propanoate (11 g, 57 mmol) and TEA (5.76 g, 142 mmol) and the mixture was heated at 85'C for 2 hr. The resulting solution was cooled down to rt and washed with brine (50 mL x 3). After the removal of solvent, the crude residue was purified with column chromatography (from PE:EA =10:1 to PE:EA = 5:1) to afford ethyl 3-(pyridin-4-yl)propiolate (2 g, 27%) as a red oil. 25 Step 3: ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 (pyridin-4-yl)pyrazolo[1, 5-a]pyridine-3-carboxylate A solution of 1-amino-3-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-4 cyclopropylpyridinium 2,4,6-trimethylbenzenesulfonate (2 g, 3.255 mmol, U25277/192/1), ethyl 3-(pyridin-4-yl)propiolate (0.855 g, 4.883 mmol) and K 2

CO

3 (0.674 g, 4.883 mmol) in 30 DMF (15 mL) was heated at 80'C overnight under nitrogen atmosphere. The reaction mixture was cooled to rt and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL x 3) and the combined layers were dried over anhydrous Na 2

SO

4 . After the 31 WO 2012/067664 PCT/US2011/024825 removal of solvent, the residue was purified with column chromatography (from PE:EA =5:1 to PE/EA = 1:1) to afford ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5 cyclopropyl-2-(pyrid in-4-yl)pyrazolo[ 1, 5-a]pyrid ine-3-carboxylate (1.05 g, 55%) as a white solid. 5 Step 4: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(pyridin-4 yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid A solution of ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 (pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.05 g, 1.78 mmol) and KOH (1.5 g, 26.8 mmol) in EtOH/H 2 0 (15 mL, 2:1) was heated at 85'C for 1.5 hr under nitrogen atmosphere. 10 The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in water (100 mL) and acidified with HCI (1N, 50 ml) to pH 1. The precipitated was filtered off and the solid was dried in vacuo to afford 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido) 5-cyclopropyl-2-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.9 g, 90%) as a brown solid. 15 Step 5: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2 (pyridin-4-yI)pyrazolo[1, 5-alpyridine-3-carboxamide To a solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2 (pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.956 g, 1.71 mmol) and TEA (0.382 g, 3.762 mmol) in dry DMF (15 mL) was added HATU (0.784 g, 2.05 mmol) at 21'C under 20 nitrogen atmosphere. After the mixture was stirred for 15 min, MeNH 2 in THF (2 M, 3.5 mL, 6.84 mmol) was added and the mixture was stirred at rt for 1 h. The reaction was quenched with water (50 mL) and filtered off. The solid was dissolved in EtOAc (200 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude solid was purified by column chromatography (gradually from PE:EA =1:1 to EA) to afford 6-(N-(4-bromo-3 25 fluorobenzyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(pyridin-4-yl)pyrazolo[1,5 a]pyridine-3-carboxamide (0.82 g, 83%) as a brown solid. Step 6: 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-N-methyl-2-(pyridin-4-yl)pyrazolo[1, 5-alpyridine-3-carboxamide A solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-N 30 methyl-2-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.533 g, 0.932 mmol), KOAc (0.274 g, 2.8 mmol), (BPIN) 2 (0.355 g, 1.4 mmol) and Pd(dppf)C1 2 (0.108 g, 0.09 mmol) in dry dioxane (20 mL) was degassed and refilled with nitrogen three times and then heated at 98'C for 3 hr. After the reaction mixture was cooled to rt and concentrated in vacuo, the crude residue was purified by column chromatography ( EtOAc ) to afford 5-cyclopropyl-6-(N 35 (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-N-methyl 2-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.55 g, 95%) as a brown solid. 32 WO 2012/067664 PCT/US2011/024825 Step 7: 4-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(pyridin-4-yl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid A solution of 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-N-methyl-2-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide 5 (0.6 g, 0.97 mmol), PS-BBA (1.66 g, 4.85 mmol) and aqueous HCI (5N, 1.35 mL, 6.78 mmol) in THF(15 mL) was stirred at rt for 4 h. The mixture was filtered off and concentrated in vacuo. The crude product was purified by pre-HPLC to afford 4-((N-(5-cyclopropyl-3 (methylcarbamoyl)-2-(pyridin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2 fluorophenylboronic acid (0.16 g, 31%). 1 H NMR (300MHz, METHANOL-d4) 6: 8.69 (s, 1 H), 10 8.64 - 8.62 (d, 2 H), 8.08 (s, 1 H), 7.83 - 7.81 (d, 2 H), 7.20 (m, 1 H), 7.13 - 7.05 (m, 2 H), 4.92 - 4.85 (d, 2 H), 3.24 (s, 3 H), 2.87 (s, 3 H), 2.19 (m, 1 H), 1.11 (m, 1 H), 0.96 - 0.94 (m, 2 H), 0.48 (m, 1 H). LCMS (m/z, ES*) = 538 (M+1). Example 7: 4-((N-(3-carbamovl-2-(4-chlorophenvl)-5-cycloprovlpvrazolo[1,5-alpvridin-6 vl)methylsulfonamido)methyl)-2-fluorophenvlboronic acid 0

NH

2 MeO 2 S, N N- \/ CI B OH 15 F OH Step 1: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 cyclopropylpyrazolo[1, 5-alpyridine-3-carboxamide To a solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl) 5-cyclopropylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.4 g, 0.6745 mmol) and TEA (0.15 g, 20 1.484 mmol) in dry DMF (8 mL) was added HATU (0.309 g, 0.8094 mmol) at 21'C under nitrogen atmosphere. After the mixture was stirred for 15 min, NH 3 in THF (1.35 mL, 2.7 mmol) was added and the mixture was stirred at rt for 0.5 hr. The reaction was quenched with water (30 mL) and filtered off. The solid was dissolved in EtOAc (100 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude solid was purified by column 25 chromatography to afford 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4 chlorophenyl)-5-cyclopropylpyrazolo[1,5-a]pyridine-3-carboxamide (0.39 g, 97%) as a brown solid. Step 2: 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzyl)methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxamide 30 A solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 cyclopropylpyrazolo[1,5-a]pyridine-3-carboxamide (0.39 g, 0.66 mmol), KOAc (0.194 g, 1.977 mmol), (BPIN) 2 (0.251 g, 0.988 mmol) and Pd(dppf)C1 2 (0.076 g, 0.066 mmol) in dry dioxane 33 WO 2012/067664 PCT/US2011/024825 (15 mL) was degassed and refilled with nitrogen three times and then it was heated at 980C overnight. After the mixture was cooled down to rt and concentrated in vacuo, the crude residue was purified by column chromatography (gradually from PE:EA =10:1 to PE:EA = 1:1) to afford 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fl uoro-4-(4,4,5,5-tetramethyl-1,3,2 5 dioxaborolan-2-yl)benzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (0.45 g, quantitative) as a brown oil. Step 3: 4-((N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylpyrazolo[1,5-alpyridin-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid A solution of 2-(4-ch lorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl 10 1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (0.45 g, 0.7 mmol), PS-BBA (1.2 g, 3.52 mmol) and aqueous HCI (5N, 1 mL, 4.93 mmol) in THF(1 5 mL) was stirred at rt overnight. The mixture was filtered off and concentrated in vacuo. The crude oil was purified by pre-HPLC to afford 4-((N-(3-carbamoyl-2-(4 chlorophenyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2 15 fluorophenylboronic acid (0.06 g, 15%). 'H NMR (300MHz, METHANOL-d4) 6= 8.61 (s, 1 H), 7.74 - 7.71 (d, 2 H), 7.51 - 7.48 (d, 2 H), 7.37 - 7.31 (m, 2 H), 7.13 - 7.05 (m, 2 H), 4.91 - 4.85 (d, 2 H), 3.23 (s, 3 H), 2.19 (m, 1 H), 1.11 (m, 1 H), 0.95 (m, 2 H), 0.53 (m, 1 H). LCMS (m/z, ES*)= 557.1 (M+1). Example 8: 4-((N-(2-(4-chlorophenVl)-5-cVclopropVl-3-(methVlcarbamol)H-pyrazolo[1,5 20 alpyridin-6-yl)methan-16-ylsulfonamido)methyl)-2-fluorophenylboronic acid O H N MeO 2 S, N N'N CI B OH F OH Step 1: ethyl 3-(4-chlorophenyl)-3-oxopropanoate A solution of 4-chlorobenzoic acid (20.0 g, 0.128 mol, Ouhe) in DCM (160 mL) was added oxalyl chloride (17 mL, 0.192 mol), then DMF (0.5 mL) was added drop wise and then 25 heated under refluxed for 2 h. The resulting solution was concentrated in vacuo. The carbonyl chloride was obtained as a yellow liquid. To a solution of ethyl potassium malonate (27.3g, 0.16 mol) in MeCN (360 mL) was added TEA (44.6 mL) and cooled in an ice-salt bath. MgCl 2 (18.3 g, 0.192 mol) was added and the resulting mixture was stirred at that temperature for 3 h. The carbonyl chloride prepared above was added dropwise and the 30 reaction mixture was warmed to rt and stirred overnight. After the reaction was completed (monitored by TLC), the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2N HCI (aq., 500 mL). This mixture was stirred in the 34 WO 2012/067664 PCT/US2011/024825 ice bath for 1.5 hr and then transferred to a separating funnel and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with saturated sodium hydrogen carbonate (300 mL), brine (250 mL x 2), dried over anhydrous Na 2

SO

4 . After the removal of organic solvent, it afforded ethyl 3-(4-chlorophenyl)-3-oxopropanoate (7g, 24%) as a red 5 brown oil. Step 2: ethyl 3-(4-chlorophenyl)propiolate To a soluton of Ph 3 PO (13.5 g, 24.3 mmol) in dry DCE (80 mL) was added Tf 2 O (5.1 g, 24.3 mmol) at 0 C under nitrogen atmosphere and the mixture was stirred at 0 C for 15 min. To this solution was added ethyl 3-(4-chlorophenyl)-3-oxopropanoate (5 g, 22.1 mmol) 10 and TEA (4.92 g, 48.6 mmol) and the mixture was heated at 85'C for 1.5 hr. The resulting solution was cooled to rt and washed with brine (50 mL x 3). After the removal of solvent, the crude residue was purified with column chromatography (PE) to afford ethyl 3-(4 chlorophenyl)propiolate (2.4 g, 52%) as a colorless oil. Step 3: ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 15 cyclopropylpyrazolo[1, 5-alpyridine-3-carboxylate A solution of 1-amino-3-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-4 cyclopropylpyridinium 2,4,6-trimethylbenzenesulfonate (2.47 g, 4.02 mmol), ethyl 3-(4 chlorophenyl)propiolate (1.26 g, 6.03 mmol) and K 2

CO

3 (1.11 g, 8.04 mmol) in DMF (20 mL) was heated at 80'C for 3 hr under nitrogen atmosphere. The reaction solution was cooled to 20 rt and quenched with water (50 mL). The mixture was extracted with EA (50 mL x 3) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography (gradually from PE:EA =10:1 to PE:EA = 5:1) to afford ethyl 6-(N-(4 bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylpyrazolo[1,5 a]pyridine-3-carboxylate (1.27 g, 51%) as a brown solid. 25 Step 4: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 cyclopropylpyrazolo[1,5-alpyridine-3-carboxylic acid A solution of ethyl 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4 chlorophenyl)-5-cyclopropylpyrazolo[1,5-a]pyridine-3-carboxylate (1.27 g, 2.04 mmol) and KOH (1.72 g, 30.68 mmol) in EtOH/H 2 0 (30 mL, 2:1) was heated to 85'C for 2 hs under 30 nitrogen atmosphere. The reaction solution was cooled to rt and concentrated in vacuo. The crude residue was dissolved in water (150 mL) and acidified with HCI (2N aq., 30 ml) to pH 1. The mixture was filtered off and the solid was dried in vacuo to afford 6-(N-(4-bromo-3 fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylpyrazolo[1,5-a]pyridine-3 carboxylic acid (1.2 g, 99%) as a white solid. 35 Step 5: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 cyclopropyl-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide 35 WO 2012/067664 PCT/US2011/024825 To a solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl) 5-cyclopropylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.4 g, 0.6745 mmol) and TEA (0.15 g, 1.484 mmol) in dry DMF (8 mL) was added HATU (0.309 g, 0.8094 mmol) at 210C under nitrogen atmosphere. After the mixture was stirred for 15 min, MeNH 2 in THF (1.35 mL, 2.7 5 mmol) was added and the mixture was stirred at rt for 1 h. The reaction was quenched with water (30 mL) and filtered. The crude solid was dissolved in EtOAc (100 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified by column chromatography to afford 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4 chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (0.39 g, 95%) as 10 a brown solid. Step 6: 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzyl)methylsulfonamido)-N-methylpyrazolo[1, 5-alpyridine-3 carboxamide A solution of 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 15 cyclopropyl-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (0.39 g, 0.643 mmol), KOAc (0.189 g, 1.931 mmol), (BPIN) 2 (0.245 g, 0.965 mmol) and Pd(dppf)C1 2 (0.074 g, 0.064 mmol) in dry dioxane (20 mL) was degassed and refilled with nitrogen three times and then heated to 98'C for 16 hr under nitrogen atmosphere. After the mixture was cooled down to rt and concentrated in vacuo, the residue was purified by column chromatography (gradually from 20 PE:EA=10:1 to PE:EA = 1:1) to afford 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-N methylpyrazolo[1,5-a]pyridine-3-carboxamide (0.4 g, 95%) as a brown oil. Step 7: 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid 25 A solution of 2-(4-ch lorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-N-methylpyrazolo[1,5-a]pyridine-3 carboxamide (0.4 g, 0.612 mmol), PS-BBA (1.04 g, 3.06 mmol) and aqueous HCI (5N, 0.9 mL, 4.29 mmol) in THF(15 mL) was stirred at rt overnight. The mixture was filtered off and concentrated in vacuo. The crude oil was purified by pre-HPLC to afford 4-((N-(2-(4 30 chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid (0.1 g, 28.5%). 1 H NMR (300MHz, METHANOL-d4) 6= 8.60 (s, 1 H), 7.71 - 7.69 (m, 2 H), 7.58 (m, 1 H), 7.49 - 7.46 (m, 1 H), 7.32 -7.23 (m, 2 H), 7.12 - 7.05 (m, 2 H), 4.91 - 4.85 (d, 2 H), 3.21 (s, 3 H), 2.83 (s, 3 H), 2.18 (m, 1 H), 1.10 (m, 1 H), 0.94 (m, 2 H), 0.51 (m, 1 H). LCMS (m/z, ES*) = 570.9 (M+1). 35 Example 9: 4-((N-(3-carbamovl-5-cyclopropvl-2-(4-fluorophenvl )pvrazolo[1,5-alpvridin-6 yl)methylsulfonamido)methyl)-2-chlorophenylboronic acid 36 WO 2012/067664 PCT/US2011/024825 0

NH

2 MeO 2 SN N-/ F -OH CI OH Step 1: ethyl 4-bromo-3-chlorobenzoate A solution of 4-bromo-3-chlorobenzoic acid (5 g, 21.23 mmol) and H 2

SO

4 (5 mL) in EtOH (50 mL) was heated under reflux for 4 hr under nitrogen atmosphere. The mixture was 5 cooled down to rt and quenched with water (100 mL). The solution was extracted with EA (150 mL x 3), washed with saturated NaHCO 3 (500 mL x 3), dried over anhydrous Na 2

SO

4 and concentrated in vacuo to afford ethyl 4-bromo-3-chlorobenzoate (5.39 g, 96%) as a colorless oil. Step 2: (4-bromo-3-chlorophenyl)methanol 10 To a solution of LAH (0.672 g, 17.6 mmol) in dry THF (80 mL) was added ethyl 4 bromo-3-chlorobenzoate (4.2 g, 16 mmol) in THF (20 mL) at -15'C under nitrogen atmosphere and the mixture was stirred at 0 C for 2 hr. The reaction was quenched with sat.

NH

4 CI (50 mL), extracted with EA (100 mL x 3), dried over anhydours Na 2

SO

4 . After the removal of solvent, the crude residue was purified by column chromatography to afford (4 15 bromo-3-chlorophenyl)methanol (2.57 g, 72%) as a colorless oil. Step 3: 1-bromo-4-(bromomethyl)-2-chlorobenzene To a solution of (4-bromo-3-chlorophenyl)methano (2.57 g, 11.6 mmol) and Ph 3 P (5.14 g, 23.2 mmol) in dry DCM (25 mL) was added NBS (3.667 g, 24.4 mmol) at -10 C under nitrogen atmosphere and the mixture was stirred at rt for 0.5 hr. The reaction solution 20 was conentrated in vacuo and the residue was purified by column chromatography (PE) to afford 1-bromo-4-(bromomethyl)-2-chlorobenzene (2.64 g, 80%) as a colorless oil. Step 4: 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluoropheny)pyrazolo[1,5-alpyridine-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5 25 a]pyridine-3-carboxamide (300 mg, 0.773 mmol, U25661/43/1), KI (128 mg, 0.773 mmol),

K

2

CO

3 (320 mg, 2.32 mmol) and 1-bromo-4-(bromomethyl)-2-chlorobenzene (264 mg, 0.928 mmol) in dry DMF (10 mL) was stirred at rt for 1 hr under nitrogen atmosphere. The reaction solution was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and then, dried 30 over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-5 37 WO 2012/067664 PCT/US2011/024825 cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (500 mg, quantitative) as a colorless oil. Step 5: 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-alpyridine-3 5 carboxamide A solution of 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.458 g, 0.772 mmol), KOAc (0.227 g, 2.32 mmol), (BPIN) 2 (0.294 g, 1.16 mmol) and Pd(dppf)C1 2 (0.089 g, 0.077 mmol) in dry dioxane (15 mL) was degassed and refilled with nitrogen three times and then heated at 10 98'C overnight. After the mixture was cooled down to rt and concentrated in vacuo, the crude residue was purified by column chromatography to afford 6-(N-(3-chloro-4-(4,4,5,5 tetramethyl- 1, 3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.537 g, quantitative) as a brown solid. Step 6: 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-alpyridin-6 15 yl)methylsulfonamido)methyl)-2-chlorophenylboronic acid A solution of 6-(N-(3-ch loro-4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3 carboxamide (0.537 g, 0.77 mmol), PS-BBA (1.3 g, 3.6 mmol) and aqueous HCI (5N, 1 mL, 4.93 mmol) in THF(15 mL) was stirred at rt overnight. The mixture was filtered off and the 20 filtrate was concentrated in vacuo. The crude oil was purified by pre-HPLC to afford 4-((N-(3 carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-chlorophenylboronic acid (0.075 g, 17.5%). 1H NMR (300MHz, METHANOL-d4) 6= 8.65 (s, 1 H), 7.80 - 7.75 (m, 2 H), 7.40 - 7.39 (m, 2 H), 7.29 7.22 (m, 4 H), 4.92 - 4.87 (m, 2 H), 3.25 (s, 3 H), 2.23 - 2.18 (m, 1 H), 1.12 (m, 1 H), 0.98 25 0.95 (m, 2 H), 0.53 - 0.51 (m, 1 H). LCMS (m/z, ES*)= 558 (M+1). Example 10: 2-chloro-4-((N-(5-cyclopropyl-2-(4-fluorophenvl)-3 (methylcarbamovl)pyrazolo[1, 5-a pyridin-6-l)methylsulfonamido)methyl)phenvlboronic acid O H N MeO 2 S, N N-' F - OH CI OH Step 1: 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 30 fluorophenyl)-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (400 mg, 0.995 mmol), KI (165 38 WO 2012/067664 PCT/US2011/024825 mg, 0.995 mmol), K 2

CO

3 (412 mg, 2.985 mmol) and 1-bromo-4-(bromomethyl)-2 chlorobenzene (340 mg, 1.19 mmol) in dry DMF (10 mL) was stirred at rt for 1 hr under nitrogen atmosphere. The reaction solution was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and 5 brine (50 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography (gradually from PE:EA=10:1 to PE:EA = 1:1) to afford 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (396 mg, 65%) as a white solid. 10 Step 2: 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1, 5 alpyridine-3-carboxamide A solution of 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (396 mg, 0.653 mmol), KOAc 15 (0.192 g, 1.961 mmol), (BPIN) 2 (0.25 g, 0.98 mmol) and Pd(dppf)C1 2 (0.075 g, 0.065 mmol) in dry dioxane (15 mL) was degassed and refilled with nitrogen three times and then heated to 98'C overnight. After the mixture was concentrated in vacuo, the crude residue was purified by column chromatography to afford 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N 20 methylpyrazolo[1,5-a]pyridine-3-carboxamide (0.51 g, quantitative) as a brown oil. Step 3: 2-chloro-4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)phenylboronic acid A solution of 6-(N-(3-ch loro-4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1,5 25 a]pyridine-3-carboxamide (0.51 g, 0.65 mmol), PS-BBA (1.1 g, 3.4 mmol) and HCI (5N aq., 0.9 mL, 4.6 mmol) in THF(15 mL) was stirred at rt overnight. The mixture was filtered and concentrated in vacuo. The residue was purified by pre-HPLC to afford 2-chloro-4-((N-(5 cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)phenylboronic acid (0.11 g, 29%). 1 H NMR (300MHz, 30 METHANOL-d4) 6: 8.64 (s, 1 H), 7.78 - 7.74 (m, 2 H), 7.39 (s, 1 H), 7.29 - 7.21 (m, 5 H), 4.92 - 4.87 (m, 2 H), 3.25 (s, 3 H), 2.84 (s, 3 H), 2.22 - 2.18 (m, 1 H), 1.12 (m, 1 H), 0.97 - 0.95 (m, 2 H), 0.50 (m, 1 H). LCMS (m/z, ES*) = 572 (M+1). Example 11: 4-((N-(3-carbamovl-5-cyclopropvl-2-(4-fluorophenvl)pvrazolo[1,5-alpyridin-6 vl)methylsulfonamido)methyl)-2-methylphenvlboronic acid 35 39 WO 2012/067664 PCT/US2011/024825

H

2 N MeO 2 S, N N_ F B OH OH Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxamide 5 To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (3.5 g, 6.9 mmol) in dry DMF (50 mL) added DIPEA (1.69 g, 15.2 mmol) and then HATU (3.15 g, 8.3 mmol) at 21 'C under nitrogen atmosphere. After 15 min, the mixture was stirred under NH 3 atmosphere for 30 min. The mixture was diluted with water (150 mL) and extracted with 10 EtOAc (150 mL x 3). The combined organic layers were washed with water (200 mL) and brine (200 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl) 6-(N-(4-methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (3.27 g, 93 %) as a white solid. LCMS (m/z, ES*)= 509.0 (M+1). 15 Step 2: 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5 alpyridine-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (3.27 g, 6.4 mmol) in TFA (20 mL) was heated under reflux for 1hr. The mixture was poured into ice-water (100 20 mL) and the formed precipitated was filtered off and then dissolved in EtOAc (2 L). The organic solution was washed with water (1 L) and Na 2

CO

3 (10% aq. 1 L) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, it afforded the crude 5-cyclopropyl-2-(4 fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (2.2 g, 88 %) as a white solid. LCMS (m/z, ES*)= 389.2 (M+1). 25 Step 3: 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluoropheny)pyrazolo[1,5-alpyridine-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5 a]pyridine-3-carboxamide (320 mg, 0.85 mmol), 1-bromo-4-(bromomethyl)-2-methylbenzene (328 mg, 1.25 mmol), KI (137 mg, 0.83 mmol) and K 2

CO

3 (345 mg, 2.49 mmol) in dry DMF 30 (25 mL) was stirred at rt for 0.5 hr under nitrogen atmosphere. The reaction mixture was diluted with water (70 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then, dried over anhydrous 40 WO 2012/067664 PCT/US2011/024825 Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (460 mg, 97 %) as a white solid. LCMS (m/z, ES*)= 571.1 (M+1). 5 Step 4: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-methy-4-(4,4,5,5-tetramethyl- 1,3,2 dioxaborolan-2-yl)benzyl)methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxamide A solution of 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (460 mg, 0.8 mmol), bis(pinacolato)diboron (406 mg, 1.6 mmol), potassium acetate (235 mg, 2.4 mmol) and 10 PdCl 2 (dppf)-CH 2

CI

2 (92 mg, 0.08 mmol) in dioxane (30 mL) was degassed and refilled with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)pyrazolo[1,5 15 a]pyridine-3-carboxamide (495 mg, 99 %) as a yellow solid. LCMS (m/z, ES*)= 619.2 (M+1). Step 5: 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-alpyridin-6 yl)methylsulfonamido)methyl)-2-methylphenylboronic acid To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-methyl-4-(4,4,5,5 tetramethyl- 1, 3,2-dioxaborolan-2-yl)benzyl)methylsulfonam ido)pyrazolo[ 1, 5-a]pyridi ne-3 20 carboxamide (495 mg, 0.8 mmol ) in THF (20 mL) was added PS-BBA (1.5 g, 4 mmol) and aq. HCI (5N, 1.12 mL, 5.6 mmol) at rt. After the addition, the reaction mixture was stirred at rt overnight. Then, the mixture was filtered and concentrated in vacuo, the residue was purified with pre-HPLC to afford 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-methylphenylboronic acid (92mg, 20 %) as a 25 white solid. 1 H NMR (300MHz, METHANOL-d4) 6= 8.54 (s, 1H), 7.78 - 7.74 (m, 2H), 7.41 7.08 (m, 6H), 4.94 - 4.81 (m, 2H), 3.23 (s, 3H), 2.28 (s, 3H), 2.27 - 2.18 (m, 1H), 1.14 - 0.92 (m, 3H), 0.62 - 0.53 (m, 1 H). LCMS( m/z, ES*)= 537.2 (M+1). Example 12: 4-((N-(5-cyclopropyl-2-(4-fluorophenvl)-3-(methylcarbamovl)pyrazolo[1,5 alpyridin-6-vl)methylsulfonamido)methyl)-2-methylphenvlboronic acid HN 0 MeO 2 S. NN- ~ N 30 OH Step 1: 4-cyclopropyl-3-nitropyridine 41 WO 2012/067664 PCT/US2011/024825 To a solution of 4-chloro-3-nitropyridine (150 g, 0.94mol, Alfa) in toluene (3 L) and water (68 mL) was added cyclopropylboronic acid (122 g, 1.42 mol, Alfa), KF (192 g, 3.3 mol), NaBr (102 g, 0.99 mol) and Pa(PPh 3

)

4 (54 g, 0.047 mol) under nitrogen atmosphere. Then, the reaction mixture was refluxed for overnight. The mixture was filtered and diluted 5 with EtOAc (3 L), washed with water (3 L) and birne (3 L) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 4-cyclopropyl-3-nitropyridine (96.8 g, 63 % yield) as a yellow solid. LCMS (m/z, ES*) = 165.1 (M+H). Step 2: 4-cyclopropylpyridin-3-amine 10 To a solution of 4-cyclopropyl-3-nitropyridine (96.8 g, 0.59mol) in MeOH (2 L) was added Pd/C (9.68 g) under 50 psi of H 2 atmosphere. The reaction mixture was stirred at rt overnight. The mixture was filtered and concentrated to afford 4-cyclopropylpyridin-3-amine (74.9 g, 94 % yield) as a yellow solid. LCMS (m/z, ES*)=135.1 (M+H). Step 3: N-(4-cyclopropylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide 15 To a solution of 4-cyclopropylpyridin-3-amine (61.9 g, 0.46mol) in DCM (1 L) was added TEA (116 g, 1.15mol) under nitrogen atmosphere. Then Ms-Cl (115 g, 1.01mol) was added drop wise. The mixture was diluted with DCM (1 L) and washed with water (2 x 1.5 L) and brine (1.5 L) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford N-(4-cyclopropylpyridin-3-yl)-N 20 (methylsulfonyl)methanesulfonamide (81.2 g, 61 % yield) as a white solid. Step 4: N-(4-cyclopropylpyridin-3-yl)methanesulfonamide To a solution of N-(4-cyclopropylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (81.2 g, 0.31 mol) in THF (1 L) was added TBAF (121.5 g, 0.46 mol) at rt. Then, the reaction mixture was stirred at 40 'C overnight. The mixture was concentrated under reduce 25 pressure, the crude product was purified with column chromatography to afford N-(4 cyclopropylpyridin-3-yl)methanesulfonamide (42.8 g, 66 % yield) as a white solid. Step 5: N-(4-cyclopropylpyridin-3-yl)-N-(4-methoxybenzyl)methanesulfonamide To a solution of N-(4-cyclopropylpyridin-3-yl)methanesulfonamide (40.8 g, 0.19 mol) in DMF (350 mL) was added 1-(chloromethyl)-4-methoxybenzene (31.6 g, 0.2 mol) and 30 K 2

CO

3 (78.6 g, 0.57 mol) at rt under nitrogen atmosphere. The reaction mixture was stirred at 80 'C for 30 mins. The mixture was diluted with water (1 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were washed with water (1 L) and brine (1 L) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford N-(4-cyclopropylpyridin-3-yl)-N-(4 35 methoxybenzyl)methanesulfonamide (27.4 g, 44 % yield) as a white solid. Step 6: tert-butyl mesitylsulfonyloxycarbamate 42 WO 2012/067664 PCT/US2011/024825 To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (120 g, 0.55 mol, Beiou) and tert-butyl hydroxycarbamate (73 g, 0.55 mol, Beiou) in Et 2 O (1 L) was added TEA (58.3 g, 0.57 mol) drop wise at 0 OC under nitrogen atmosphere. Then, the reaction mixture was stirred at rt for overnight. The mixture was filtered and organic layer was concentrated, the 5 crude product was washed with PE (0.5 L) to afford tert-butyl mesitylsulfonyloxycarbamate (151.5 g, 0.48mol, 87 % yield) as a white solid. Step 7: 0-(mesitylsulfonyl)hydroxylamine tert-Butyl mesitylsulfonyloxycarbamate (104.2 g, 0.33 mol) was added portionwise to TFA (300 mL) at 0 OC under nitrogen atmosphere. Then, the reaction mixture was stirred at 0 10 OC for 3 h. The mixture was poured into ice-water (800 mL) and the formed precipitate was filtered and washed with cold water until PH>6. The solid was dissolved in DCM (600 mL) and dried over anhydrous Na 2

SO

4 . After filtration, the filtrate, o (mesitylsulfonyl)hydroxylamine (0.3mol/L in DCM, 600 mL), was directly used in next step. Step 8: 1-amino-4-cyclopropyl-3-(N-(4-methoxybenzyl)methylsulfonamido)pyridinium 15 A solution of O-(mesitylsulfonyl)hydroxylamine (440 mL, 0.3 mmol/L in DCM, 132 mmol) and N-(4-cyclopropylpyridin-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (27.4 g, 82.5 mmol) was stirred at rt for 48 hr under nitrogen atmosphere. The mixture was diluted withEt 2 O (400 mL) and filtered. After drying in vacuo, it afforded 1-amino-4-cyclopropyl-3-(N (4-methoxybenzyl)methylsulfonamido)pyridinium (36.2 g, 78 % yield) as a white solid. 20 Step 9: ethyl 3-(4-fluorophenyl)-3-oxopropanoate To a solution of 4-fluorobenzoic acid (200 g, 1.428 mol, Ouhe) and oxalyl chloride (184 mL, 2.16 mol) in DCM (2 L) was added drop wise DMF (1 mL). The reaction mixture was refluxed for 1.5 h. The resulting solution was concentrated under the reduce pressure. The acid chloride was obtained as a brown solid. A solution of ethyl potassium malonate 25 (300 g, 1.428 mol) in MeCN (4 L) was added TEA (500 mL, 3.587 mol) and cooled in an ice salt bath, MgCl 2 (204 g, 2.147 mol) was added and the resulting mixture was stirred at that temperature for 2 h. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. After the reaction was completed (monitored by TLC), the mixture was cooled in an ice bath and the intermediate was 30 decarboxylated by careful addition of 2N HCI (2.6 L). This mixture was stirred in the ice bath for 1.5 h then transferred to a separate funnel and then, extracted with EA (3 x 1 L). The combined organic layers were washed with saturated sodium hydrogen carbonate (2 L), brine (2 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure to afford the crude product ethyl 3-(4-fluorophenyl)-3-oxopropanoate (296 g, 96%) 35 as a red brown solid. Step 10: ethyl 3-(4-fluorophenyl)propiolate 43 WO 2012/067664 PCT/US2011/024825 To a solution of Ph 3 PO (71.3 g, 0.13 mol) in dry DCE (200 mL) was added Tf 2 O (27.3 g, 0.13 mol) at 0 OC under N 2 atmosphere and the mixture was stirred at the same temperature for 15 Min. Ethyl 3-(4-fluorophenyl)-3-oxopropanoate (28 g, 0.13 mol) and TEA (26.3 g, 0.26 mol) was added and the mixture was heated to 85 for 2 h. The resulting 5 solution was cooled to RT and washed with brine (500 mL). After the removal of solvent, the crude residue was purified with column chromatography to afford ethyl 3-(4 fluorophenyl)propiolate (17.1 g, 67%) as a white solid. Step 11: ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxylate 10 A solution of 1-amino-4-cyclopropyl-3-(N-(4 methoxybenzyl)methylsulfonamido)pyridinium (20.2 g, 36.9 mmol), ethyl 3-(4 fluorophenyl)propiolate (10.6 g, 50.5 mmol) and K 2

CO

3 (10.2 g, 79.3 mmol) in DMF (200 mL) was stirred at 100 OC for overnight under atmosphere. The reaction solution was cooled to rt and quenched with water (500 mL). The mixture was extracted with EA (3 x 500 mL). The 15 combined organic layers were washed with water (1 L) and birne (1 L) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (14.8 g, 74%) as a brown solid. LCMS (m/z, ES*) = 538.1 (M+H) 20 Step 12: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-alpyridine-3-carboxylic acid A solution of ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (14.8 g, 27.6 mmol) and KOH (23.18 g, 414 mmol) in EtOH/H 2 0 (150 mL, 2 : 1) was heated at 85 OC for 1 h. The 25 reaction solution was cooled to rt and diluted with water (200 mL), filtered and the liquid was added 1 N HCI to PH=2, extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (11.4 g, 81 % 30 yield) as a yellow solid. The compound was used in next step without purification. LCMS (m/z, ES*) = 510.0 (M+H) Step 13: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-methoxybenzyl)methylsulfonamido) N-methylpyrazolo[1,5-alpyridine-3-carboxamide To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 35 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (7.5 g, 14.7 mmol) in dry DMF (100 mL) was added DIPEA (4.16 g, 32.3 mmol) and HATU (6.6 g, 17.6 mmol) at 21 OC under N 2 atmosphere. After the mixture was stirred for 15 mins, MeNH 2 in 44 WO 2012/067664 PCT/US2011/024825 THF (29.4 mL, 58.8 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with 5 column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (7.2 g, 93 % yield) as a white solid. LCMS (m/z, ES*) = 523.0 (M+H) Step 14: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6 (methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxamide 10 A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (7.6 g, 14.5 mmol) in TFA (40 mL) was heated under refluxed for 1h. The mixture was poured into ice-water (200 mL) and the solid was filtered and dissolved in EtOAc (2 L). The combined organic layers were washed with water (1 L) and Na 2

CO

3 (10% aq. 1 L) and dried over 15 anhydrous Na 2

SO

4 . After the removal of solvent, it afforded the crude 5-cyclopropyl-2-(4 fluorophenyl)-N-methyl-6-(methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (5.4 g, 92 % yield) as a white solid. LCMS (m/z, ES*) = 403.1 (M+H) Step 15: (4-bromo-3-methylphenyl)methanol To a solution of methyl 4-bromo-3-methylbenzoate (5.0 g, 21.8 mmol, Alfa) in dry THF 20 (50 mL) was added LiAIH 4 (1.66 g, 43.6 mmol) at -15 'C. The reaction mixture was stirred at -15 C for 15 mins. Then added 1.66 g H 2 0 to the reaction mixture, filtered and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford (4-bromo-3-methylphenyl)methanol (5.15 g, 25.6 mmol, 117 % yield) as a yellow oil. 1 H NMR (300MHz, CHLOROFORM-d) 6: 7.51 - 7.48 (d, 1 H), 7.22 (s, 25 1 H), 7.04 - 7.01 (m, 1 H), 4.61 (s, 2H), 2.39 (s, 3H). Step 16: 1-bromo-4-(bromomethyl)-2-methylbenzene To a solution of (4-bromo-3-methylphenyl)methano (5.15 g, 25.6 mmol) and NBS (9.07 g, 51.2 mmol) in DCM (1OOmL) was added drop wise PPh 3 (13.36 g, 51.2 mmol) in DCM (50 mL) at rt and the reaction mixture was stirred for 15 mins at rt. Then, water (50 mL) 30 was added and the organic layers were washed with water (100 mL x 2) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford 1-bromo-4-(bromomethyl)-2-methylbenzene (4.15 g, 65 % yield) as a colorless oil. 1 H NMR (300MHz, CHLOROFORM-d) 6: 7.50 - 7.48 (d, 1H), 7.26 (s, 1H), 7.08 - 7.05 (m, 1H), 4.41 (s, 2H), 2.39 (s, 3H),. 35 Step 17: 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide 45 WO 2012/067664 PCT/US2011/024825 A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (400 mg, 1.49mmol), 1-bromo-4 (bromomethyl)-2-methylbenzene (394 mg, 1.5 mmol), KI (166 mg, 1.0 mmol) and K 2

CO

3 (400 mg, 3.0 mmol) in dry DMF (20 mL) was stirred at rt for 0.5 h under nitrogen. The reaction 5 mixture was diluted with water (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl 2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (364 mg, 62 % yield) as a 10 white solid. LCMS (m/z, ES*) = 584.9 (M+H) Step 18: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)pyrazolo[1,5-alpyridine-3 carboxamide A solution of methyl 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl 15 2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (364 mg, 0.62 mmol), bis(pinacolato)diboron (315 mg, 1.24 mmol), potassium acetate (182 mg, 1.86 mmol) and PdCl 2 (dppf)-CH 2

CI

2 (72 mg, 0.06 mmol) in dioxane (30 mL) was degassed and refilled with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was 20 purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N (3-methyl-4-(4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (382 mg, 0.6 mmol, 97 % yield) as a yellow solid. LCMS (m/z, ES*) = 633.4 (M+H) Step19: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 25 a]pyridin-6-yl)methylsulfonamido)methyl)-2-methylphenylboronic acid To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3 carboxamide (282 mg, 0.6 mmol ) in THF (15 mL) was added PS-BBA (1.15 g, 3.0 mmol) and aqueous HCI (5N, 0.84 mL, 4.2 mmol) at rt. After the addition, the reaction mixture was 30 stirred at rt for overnight. Then, the mixture was filtered and concentrated in vacuo, the residue was purified with pre-HPLC to afford 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2 methylphenylboronic acid (114 mg, 35 % yield) as a white solid. 1 H NMR (300MHz, METHANOL-d4) 6: 8.52 (s, 1 H), 7.76 - 7.71 (m, 2H), 7.26 - 7.08 (m, 6H), 4.94-4.81 (m, 2H), 35 3.22 (s, 3H), 2.84 (s, 3H), 2.27 (s, 3H), 2.24 - 2.18 (m, 1H), 1.13 - 0.93 (m, 3H), 0.57-0.49 (m, 1H). LCMS( m/z, ES*) = 551.1 (M+1) 46 WO 2012/067664 PCT/US2011/024825 Example 13: 4-((N-(5-cycloPropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1, 5 alpyridin-6-l)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid HN 0 MeO 2 S,, N'-. / N F F BOH F OH 5 Step 1: (4-bromo-2,3-difluorophenyl)methanol A solution of 4-bromo-2,3-difluorobenzoic acid (2.0 g, 8.4 mmol, Alfa) in dry THF (25 mL) added BH 3 (29.2mL, 1 mol/L in THF) at rt under nitrogen atmosphere. The reaction mixture was stirred at rt overnight. The reaction mixture was cooled down to 0 'C and quenched whit aq. HCI (2N, 20 mL) and extracted with EtOAc (50 mL x 3). The combined 10 organic layers were washed with 10% NaHCO 3 (100 mL), water (100 mL) and brine (100 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent to afford (4-bromo-2,3 difluorophenyl)methanol (.1.91 g, quantitative) as a yellow solid. 1 H NMR (300MHz, CDC13) 6= 7.34 - 7.29 (m, 1H), 7.15 - 7.09 (m, 1H), 4.75 (s, 2H), 1.90 (brs, 1H). Step 2: 1-bromo-4-(bromomethyl)-2,3-difluorobenzene 15 To a solution of (4-bromo-2,3-difluorophenyl)methano (1.91 g, 8.5 mmol) and NBS (3.03 g, 17.0 mmol) in DCM (40mL) was added drop wise PPh 3 (4.45 g, 17.0 mmol) in DCM (20 mL) at rt and the mixture was stirred for 15 mins at rt. Then, water (30 mL) was added and the organic layers were washed with water (40 mL) and brine (40 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column 20 chromatography to afford 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (1.98 g, 81 %) as colorless oil. 1 H NMR (300MHz, CDC13) 6= 7.33 - 7.28 (m, 1H), 7.09 - 7.04 (m, 1H), 4.46 (s, 2H). Step 3: 6-(N-(4-bromo-2,3-difluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide 25 A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (350 mg, 0.87mmol), 1-bromo-4 (bromomethyl)-2,3-difluorobenzene (375 mg, 1.31 mmol), KI (144 mg, 0.87mmol) and K 2 CO3 (360 mg, 2.61 mmol) in dry DMF (15 mL) was stirred at rt for 0.5 hr under nitrogen atmosphere. The reaction mixture was diluted with water (45 mL) and extracted with EtOAc 30 (40 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product 47 WO 2012/067664 PCT/US2011/024825 was purified with column chromatography to afford 6-(N-(4-bromo-2,3 difluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1,5 a]pyridine-3-carboxamide (378 mg, 71 %) as a light yellow solid. LCMS (m/z, ES*)= 607.1 (M+1). 5 Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid A solution of methyl 6-(N-(4-bromo-2,3-difluorobenzyl)methylsulfonamido)-5 cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (378 mg, 0.62 mmol), bis(pinacolato)diboron (314 mg, 1.24 mmol), potassium acetate (182 mg, 1.86 mmol) 10 and PdCl 2 (dppf)-CH 2

CI

2 (50 mg, 0.06 mmol) in dioxane (15 mL) was degassed and refilled with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with pre-HPLC to afford 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2,3 15 difluorophenylboronic acid (75 mg, 21 %) as a white solid. 1 H NMR (300MHz, METHANOL d4) 6= 8.64 (s, 1H), 7.76 - 7.72 (m, 2H), 7.25 - 7.13 (m, 5H), 5.09 - 4.09 (m, 2H), 3.24 (s, 3H), 2.21 - 2.16 (m, 1 H), 1.11 - 0.91 (m, 3H), 0.55 - 0.43 (m, 1 H). LCMS(m/z, ES*)= 573.0 (M+1). Example 14: 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-alpyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid

H

2 N O N F MeO 2 SI NF F BOH 20 F OH Step 1: 6-(N-(4-bromo-2,3-difluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4 fluorophenyl)pyrazolo[1,5-alpyridine-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5 a]pyridine-3-carboxamide (300 mg, 0.77mmol), 1-bromo-4-(bromomethyl)-2,3 25 difluorobenzene (330 mg, 1.16 mmol), KI (127 mg, 0.77mmol) and K 2

CO

3 (318 mg, 2.13 mmol) in dry DMF (15 mL) was stirred at rt for 0.5 hr under nitrogen atmosphere. The reaction mixture was diluted with water (45 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified 30 with column chromatography to afford 6-(N-(4-bromo-2,3-difluorobenzyl)methylsulfonamido) 5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (436 mg, 95 %) as white solid. LCMS (m/z, ES*)= 615.0 (M+1). 48 WO 2012/067664 PCT/US2011/024825 Step2: 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-alpyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid A solution of methyl 6-(N-(4-bromo-2,3-difluorobenzyl)methylsulfonamido)-5 cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (436 mg, 0.73 mmol), 5 bis(pinacolato)diboron (370 mg, 1.46 mmol), potassium acetate (214 mg, 2.19 mmol) and PdCl 2 (dppf)-CH 2

CI

2 (60 mg, 0.07 mmol) in dioxane (15 mL) was degassed and refilled with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with pre-HPLC to afford 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4 10 fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid (75 mg, 21 %) as a white solid. 1 H NMR (300MHz, METHANOL-d4) 6= 8.66 (s, 1 H), 7.79 - 7.74 (m, 2H), 7.39 - 7.13 (5, 6H), 5.08 - 4.92 (m, 2H), 3.24 (s, 3H), 2.24 - 2.17 (m, 1 H), 1.16 - 0.94 (m, 3H), 0.53 - 0.45 (m, 1H). LCMS(m/z, ES*)= 558.9 (M+1). Example 15: 2-chloro-4-((N-(2-(4-chlorophenvl)-5-cyclopropvl-3 15 (methvlcarbamovl)pvrazolo[1, 5-alpyridin-6-vl)methylsulfonamido)methvl)phenvlboronic acid NH MeO 2 S N C Z OH CI OH Step 1: ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(4 20 methoxybenzyl)methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxylate A solution of 1-amino-4-cyclopropyl-3-(N-(4 methoxybenzyl)methylsulfonamido)pyridinium (13.3 g, 23 mmol), ethyl 3-(4 chlorophenyl)propiolate (7.28 g, 35 mmol) and K 2

CO

3 (6.35 g, 46 mmol) in DMF (100 mL) was stirred at 100 'C for 48 hr under nitrogen atmosphere. The reaction solution was cooled 25 down to rt and quenched with water (300 mL). The mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (300 mL) and birne (300 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford ethyl 2-(4-ch lorophenyl)-5-cyclopropyl-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (9.03 g, 71%) as a 30 brown solid. LCMS (m/z, ES*) = 553.8 (M+1). Step 2: 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-alpyridine-3-carboxylic acid 49 WO 2012/067664 PCT/US2011/024825 A solution of ethyl ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (9.03 g, 16.3 mmol) and KOH (13.72 g, 244.5 mmol) in EtOH/H 2 0 (90 mL, 2:1) was heated at 85 OC for 1 hr. The reaction solution was cooled down to rt and diluted with water (200 mL). After the filtration, 5 the filtrate was acidified with 1 N HCI (aq) to pH 2 and then extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent to afford 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (6.1 g, 71 %) as a white solid. LCMS (m/z, ES*)= 525.9 (M+1). 10 Step 3: 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(4-methoxybenzyl)methylsulfonamido) N-methylpyrazolo[1,5-alpyridine-3-carboxamide To a solution of 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (6.1 g, 11.6 mmol) in dry DMF (60 mL) was added DIPEA (3.29 g, 25.5 mmol) and then HATU (5.28 g, 15 13.9 mmol) at 21 OC under nitrogen atmosphere. After 15 min, MeNH 2 in THF (23.2 mL, 46.4 mmol) was added and the mixture was stirred at rt for 30 mins. The mixture was diluted with water (180 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (300 mL) and brine (300 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 2 20 (4-chlorophenyl)-5-cyclopropyl-6-(N-(4-methoxybenzyl)methylsulfonamido)-N methylpyrazolo[1,5-a]pyridine-3-carboxamide (5.38 g, 86 %) as a white solid. LCMS (m/z, ES*)= 539.0 (M+1). Step 4: 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6 (methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxamide 25 A solution of 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(4 methoxybenzyl)methylsulfonamido)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (5.38 g, 10 mmol) in TFA (40 mL) was heated under reflux for 1 hr. The mixture was poured into ice water (200 mL) and the solid was filtered off. The collected solid was dissolved in EtOAc (600 mL). The organic solution was washed with water (600 mL) and Na 2

CO

3 (10% aq., 600 30 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, it afforded the crude 2 (4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)pyrazolo[1,5-a]pyridine-3 carboxamide (3.1 g, 74 %) as a white solid. LCMS (m/z, ES*)= 419.1 (M+1). Step 5: 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 cyclopropyl-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide 35 A solution of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (350 mg, 0.84mmol), 1-bromo-4 (bromomethyl)-2-chlorobenzene (357 mg, 1.26 mmol), KI (140 mg, 0.84 mmol) and K 2 CO3 50 WO 2012/067664 PCT/US2011/024825 (350 mg, 2.52 mmol) in dry DMF (25 mL) was stirred at rt for 0.5 hr under nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product 5 was purified with column chromatography to afford 6-(N-(4-bromo-3 chlorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5 a]pyridine-3-carboxamide (310 mg, 59 %) as a yellow solid. LCMS (m/z, ES*)= 620.9 (M+1). Step 6: 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5 10 alpyridine-3-carboxamide A solution of methyl 6-(N-(4-bromo-3-chlorobenzyl)methylsulfonamido)-2-(4 chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (310 mg, 0.5 mmol), bis(pinacolato)diboron (254 mg, 1 mmol), potassium acetate (147 mg, 1.5 mmol) and PdCl 2 (dppf)-CH 2

CI

2 (41 mg, 0.05 mmol) in dioxane (15 mL) was degassed and refilled with 15 nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N methylpyrazolo[1,5-a]pyridine-3-carboxamide (305 mg, 91 %) as a yellow solid. LCMS (m/z, 20 ES*)= 669.1 (M+1). Step 7: 2-chloro-4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)phenylboronic acid To a solution of 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5 25 a]pyridine-3-carboxamide (305 mg, 0.45 mmol ) in THF (15 mL) was added PS-BBA (0.87 g, 2.25 mmol) and aq. HCI (5N, 0.63 mL, 3.15 mmol) at rt. After the addition, the reaction mixture was stirred at rt overnight. Then, the mixture was filtered and concentrated in vacuo and the residue was purified with pre-HPLC to afford 2-chloro-4-((N-(2-(4-chlorophenyl)-5 cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 30 yl)methylsulfonamido)methyl)phenylboronic acid (78 mg, 29 %) as a white solid. 1 H NMR (300MHz, METHANOL-d4) 6= 8.64 (s, 1 H), 7.74-7.71 (d, 2H), 7.54 - 7.22 (m, 6H), 4.96 - 4.90 (m, 2H), 3.25 (s, 3H), 2.85 (s, 3H), 2.22 - 2.18 (m, 1 H), 1.15 - 0.92 (m, 3H), 0.53 - 0.47 (m, 1H). LCMS (m/z, ES*)= 586.8 (M+1). Example 16: 4-((N-(2-(4-chlorophenvl)-5-cyclopropvl-3-(methvlcarbamovl)pvrazolo[1,5 35 alpvridin-6-vl)methylsulfonamido)methyl)-2,3-difluorophenvlboronic acid 51 WO 2012/067664 PCT/US2011/024825 NH MeO 2 S N CI F BOH F OH Step 1: 6-(N-(4-bromo-2,3-difluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5 cyclopropyl-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide A solution of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6 5 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (400 mg, 0.96mmol), 1-bromo-4 (bromomethyl)-2,3-difluorobenzene (411 mg, 1.44 mmol), KI (159 mg, 0.96 mmol) and K 2 CO3 (397 mg, 2.88 mmol) in dry DMF (30 mL) was stirred at rt for 0.5 h under nitrogen atmosphere. The reaction mixture was diluted with water (90 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (150 mL) and brine (150 10 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-2,3 difluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5 a]pyridine-3-carboxamide (330 mg, 55 %) as a yellow solid. LCMS ( m/z, ES*)= 622.9 (M+1). Step 2: 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5 15 a]pyridin-6-yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid A solution of methyl 6-(N-(4-bromo-2,3-difluorobenzyl)methylsulfonamido)-2-(4 chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (330 mg, 0.53 mmol), bis(pinacolato)diboron (269 mg, 1.06 mmol), potassium acetate (155 mg, 1.59 mmol) and PdCl 2 (dppf)-CH 2

CI

2 (43 mg, 0.053 mmol) in dioxane (15 mL) was degassed and refilled 20 with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with pre-HPLC to afford 4-((N-(2-(4-ch lorophenyl)-5-cyclopropyl-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)-2,3 difluorophenylboronic acid (42 mg, 13.5 %) as a white solid. 1 H NMR (300MHz, 25 METHANOL-d4) 6= 8.67 (s, 1H), 7.74 - 7.72 (d, 2H), 7.52 - 7.49 (d, 2H), 7.26 - 7.12 (m, 3H), 5.05 - 5.04 (m, 2H), 3.26 (s, 3H), 2.86 (s, 3H), 2.22 - 2.15 (m, 1 H), 1.16 - 0.92 (m, 3H), 0.53 0.45 (m, 1H). LCMS (m/z, ES*)= 588.7 (M+1). Example 17: 2-fluoro-4-((N-(2-(4-fluorophenvl)-5-(furan-3-vl)-3 (methylcarbamovl)pyrazolo[1, 5-a pyridin-6-l)methylsulfonamido)methyl)phenvlboronic acid 52 WO 2012/067664 PCT/US2011/024825 O HN MeO 2 SIN ~N' F F ..- OH OH Step 1: 4-methoxypyridin-3-amine A solution of 4-methoxy -3-nitropyridine (100 g, 0.65 mol, Ouhe) and 10% Pd/C (10 g) in MeOH (2 L) was stirred under 50 psi of hydrogen. The reaction mixture was stirred at rt 5 overnight. The mixture was filtered and concentrated in vacuo to afford 4-methoxypyridin-3 amine (82.1 g, quantitative) as a yellow solid. Step 2: N-(4-methoxypyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide To a solution of 4-methoxypyridin-3-amine (77.1 g, 0.62mol) and DIPEA (200.7 g, 1.55 mol) in DCM (0.75 L) was added drop wise MsCI (145 g, 3.17 mol) and the reaction 10 mixture was heated under reflux under nitrogen atmosphere. The mixture was diluted with DCM (1 L) and washed with water (1.5 L x 2) and brine (1.5 L) and then dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford N-(4-cyclopropylpyridin-3-yl)-N (methylsulfonyl)methanesulfonamide (118 g, 67 %) as a white solid. 15 Step 3: N-(4-methoxypyridin-3-yl)methanesulfonamide To a solution of N-(4-cyclopropylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (118 g, 0.42 mol) in THF (0.8 L) was added TBAF (110 g, 0.42 mol). Then, the reaction mixture was stirred at 40 'C overnight. The mixture was concentrated in vacuo and the residue was purified with column chromatography to afford N-(4-methoxypyridin-3 20 yl)methanesulfonamide (45 g, 53%) as a white solid. Step 4: N-benzyl-N-(4-methoxypyridin-3-yl)methanesulfonamide To a solution of N-(4-methoxypyridin-3-yl)methanesulfonamide (45 g, 0.22 mol) in DMF (200 mL) was added (chloromethyl)benzene (28.2 g, 0.22 mol) and K 2

CO

3 (85.4 g, 0.66 mol) at rt under nitrogen atmosphere. Then, the reaction mixture was stirred at 80 'C for 30 25 min. The mixture was diluted with water (1 L) and extracted with EtOAc (1 L x 3). The combined organic layers were washed with water (1 L) and brine (1 L) and then dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford N-benzyl-N-(4-methoxypyridin-3-yl)methanesulfonamide (23.15 g, 35 %) as a white solid. 30 Step 5: tert-butyl mesitylsulfonyloxycarbamate 53 WO 2012/067664 PCT/US2011/024825 To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (48.4 g, 0.22 mol, Beiou) and tert-butyl hydroxycarbamate (29.6 g, 0.22 mol, Beiou) in Et 2 O (0.4 L) was added drop wise TEA (24.6 g, 0.24 mol) at 0 'C under nitrogen atmosphere. Then, the reaction mixture was stirred at rt overnight. The mixture was filtered and the filtrate was concentrated in 5 vacuo. The residue was washed with PE (0.5 L) to afford tert-butyl mesitylsulfonyloxycarbamate (61 g, 87 %) as a white solid. Step 6: 0-(mesitylsulfonyl)hydroxylamine Tert-butyl mesitylsulfonyloxycarbamate (37.38 g, 0.12 mol) was added to TFA (77.5 mL) in portions at 0 'C under nitrogen atmosphere. After the addition, the reaction mixture 10 was stirred at 0 'C for 3 hr. Then, the mixture was poured into ice-water (500 mL). The formed precipitate was filtered off and washed with cold water until the filtrate was with pH>6. The collected solid was dissolved in DCM (300 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, it afforded O-(mesitylsulfonyl)hydroxylamine (0.26 mol/L in DCM, 300 mL). 15 Step 7: 1-amino-3-(N-benzylmethylsulfonamido)-4-methoxypyridinium 2,4,6 trimethylbenzenesulfonate To a solution of O-(mesitylsulfonyl)hydroxylamine (300 mL, 0.26 mmol/L in DCM, 79 mmol) was added N-benzyl-N-(4-methoxypyridin-3-yl)methanesulfonamide (23.15 g, 79 mmol) at rt under nitrogen atmosphere. Then, the reaction mixture was stirred at rt for 72 hr. 20 The mixture was diluted with Et 2 O (200 mL) and filtered off. The solid was dried in vacuo to afford 1-amino-3-(N-benzylmethylsulfonamido)-4-methoxypyridinium 2,4,6 trimethylbenzenesulfonate (34.3 g, 85 %) as a white solid. Step 8: ethyl 6-(N-benzylmethylsulfonamido)-2-(4-fluorophenyl)-5 methoxypyrazolo[1, 5-alpyridine-3-carboxylate 25 A solution of 1-amino-3-(N-benzylmethylsulfonamido)-4-methoxypyridinium 2,4,6 trimethylbenzenesulfonate(34.3g, 67.5 mmol), ethyl 3-(4-fluorophenyl)propiolate (15.1 g, 101.2 mmol) and K 2

CO

3 (14 g, 101.4 mmol) in DMF (80 mL) was stirred at 80 C overnight under atmosphere. The reaction solution was cooled to rt and quenched with water (400 mL). The mixture was extracted with EtOAc (500 mL x 3). The combined organic layers 30 were washed with water (1 L) and birne (1 L) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford ethyl 5 cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-methoxybenzyl)methylsulfonamido)pyrazolo[1,5 a]pyridine-3-carboxylate (14 g, 42%) as a brown solid. Step 9: 6-(N-benzylmethylsulfonamido)-2-(4-fluorophenyl)-5-methoxypyrazolo[1,5 35 alpyridine-3-carboxylic acid A solution of ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4 methoxybenzyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (14 g, 28.1 mmol) 54 WO 2012/067664 PCT/US2011/024825 and KOH (23.6 g, 422 mmol) in EtOH/H 2 0 (195 mL, 2:1) was heated at 80 C for 2 hr. The reaction solution was cooled to rt and diluted with water (200 mL). After the filtration, the filtrate was acidified with aq. HCI (1 N) to pH 2 and then extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (500 mL) and dried over anhydrous 5 Na 2

SO

4 . After the removal of solvent, it afforded 6-(N-benzylmethylsulfonamido)-2-(4 fluorophenyl)-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (13.4 g, quantitative) as a white solid. Step 10: 6-(N-benzylmethylsulfonamido)-2-(4-fluorophenyl)-5-methoxy-N methylpyrazolo[1,5-alpyridine-3-carboxamide 10 To a solution of 6-(N-benzylmethylsulfonamido)-2-(4-fluorophenyl)-5 methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (13.4 g, 28.56 mmol) in dry DMF (60 mL) was added TEA (6.36 g, 62.8 mmol) and then HATU (13.1 g, 34.27 mmol) at 21 OC under nitrogen atmosphere. After 15 min, MeNH 2 in THF (57.1 mL, 115.2 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was diluted with water (300 mL) and 15 extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (500 mL) and brine (500 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford 6-(N benzylmethylsu lfonamido)-2-(4-fluorophenyl)-5-methoxy-N-methylpyrazolo[1, 5-a]pyrid ine-3 carboxamide (12.9 g, 93 %) as a white solid. 20 Step 11: 2-(4-fluorophenyl)-5-hydroxy-N-methyl-6-(methylsulfonamido)pyrazolo[1,5 a]pyridine-3-carboxamide To a solution of 6-(N-benzylmethylsulfonamido)-2-(4-fluorophenyl)-5-methoxy-N methylpyrazolo[1,5-a]pyridine-3-carboxamide (12.9 g, 26.73 mmol) in dry toluene (400 mL) was added drop wise BBr 3 at rt and the mixture was heated at 700C overnight under nitrogen 25 atmosphere. The mixture was cooled down to rt and poured into ice-water (800 mL). The formed precipitate was washed with EtOAc (20 mL). The collected brown solid was dried in vacuo to afford 2-(4-fluorophenyl)-5-hydroxy-N-methyl-6-(methylsulfonamido)pyrazolo[1,5 a]pyridine-3-carboxamide (9.15 g, 90 %). Step 12: 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(methylsulfonamido)pyrazolo[1,5 30 alpyridin-5-yl trifluoromethanesulfonate To a solution of 2-(4-fluorophenyl)-5-hydroxy-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (9.15 g, 24.2 mmol), TEA (1.2 g, 119 mmol) and DMAP (0.16 g, 1.32 mmol) in dry DCM (1000 mL) was added drop wise Tf 2 O (11.2 g, 39.7 mmol) at -100C under nitrogen atmosphere over 15 min and the mixture was 35 stirred at the same temperature for 2 hr. The reaction was quenched with sat. NH 4 CI (200 mL) and washed with brine (500 mL x 3) and then dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford 2-(4 55 WO 2012/067664 PCT/US2011/024825 fluorophenyl)-3-(methylcarbamoyl)-6-(methylsu lfonamido)pyrazolo[1, 5-a]pyrid in-5-yl trifluoromethanesulfonate (5.27 g, 78 %) as a brown solid. Step 13: 2-(4-fluorophenyl)-5-(furan-3-yl)-N-methyl-6 (methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxamide 5 A solution of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6 (methylsulfonamido)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (250 mg, 0.49 mmol), furan-3-ylboronic acid (82 mg, 0.735 mmol), potassium acetate (135 mg, 0.98 mmol) and Pd (Ph 3 P) 4 (56.5 mg, 0.049 mmol) in dioxane (15 mL) and water (1.5 mL) was degassed and refilled with nitrogen three times and then heated at 85 'C for 2 hr. After cooling down to 10 rt, the reaction mixture was concentrated under reduced pressure and then the residue was purified by column chromatography to afford 2-(4-fluorophenyl)-5-(furan-3-yl)-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (100 mg, 47%) as a brown oil. Step 14: 2-fluoro-4-((N-(2-(4-fluorophenyl)-5-(furan-3-yl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)phenylboronic acid 15 A solution of 2-(4-fluorophenyl)-5-(furan-3-yl)-N-methyl-6 (methylsulfonamido)pyrazolo[1, 5-alpyridine-3-carboxamide (100 mg, 0.234 m mol), 4 (bromomethyl)-2-fluorophenylboronic acid (60 mg, 0.235 mmol), KI (38 mg, 0.233 mmol) and

K

2

CO

3 (96 mg, 0.70 mmol) in dry DMF (8 mL) was heated at 60'C for 1 hr under nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc 20 (30 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with pre-HPLC to afford 2-fluoro-4-((N-(2-(4-fluorophenyl)-5-(furan-3-yl)-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)methyl)phenylboronic acid (78 mg, 57 %) as a white solid. 1 H NMR (300MHz, METHANOL-d4) 6= 8.75 (s, 1 H), 7.88 25 7.77 (m, 4 H), 7.55 (s, 1 H), 7.25 - 7.19 (m, 3 H), 6.93 - 6.76 (m, 3 H), 4.86 - 4.71 (m, 2 H), 3.24 (s, 3 H), 2.86 (s, 3 H). LCMS (m/z, ES*)= 580.7 (M+1). Example 18: 4-((N-(2-(4-chlorophenvl)-5-cyclopropyl-3-(methylcarbamovl)pyrazolo[1,5 alpyridin-6-vl)methylsulfonamido)methyl)-2-fluoro-3-(trifluoromethyl)phenvlboronic acid H -N 0 MeO 2 s N CI F3C B OH F OH 30 Step 1: 6-(N-(4-bromo-3-fluoro-2-(trifluoromethyl)benzyl)methylsulfonamido)-2-(4 chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5-alpyridine-3-carboxamide 56 WO 2012/067664 PCT/US2011/024825 A solution of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (365mg, 0.872 mmol), 1-bromo 4-(bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene (436.7 mg, 1.3mmol), KI (144.8 mg , 0.872 mmol) and K 2

CO

3 (359.3 mg, 2.6 mmol) in dry DMF (20 mL) was stirred at rt for 1 hr 5 under nitrogen. The reaction mixture was diluted with water (45 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-3-fluoro-2 (trifluoromethyl)benzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N 10 methylpyrazolo[1,5-a]pyridine-3-carboxamide (360 mg, 79 % yield) as a yellow solid. Step2: 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluoro-3-(trifluoromethyl)phenylboronic acid A solution of 6-(N-(4-bromo-3-fluoro-2-(trifluoromethyl)benzyl)methylsulfonamido)-2 (4-chlorophenyl)-5-cyclopropyl-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (360 mg, 15 0.54 mmol), bis(pinacolato)diboron (274.3 mg, 1.08 mmol), potassium acetate (158.8 mg, 1.62 mmol) and PdCl 2 (dppf)-CH 2

CI

2 (44 mg, 0.054 mmol) in dixoane (25 mL) was degassed and refilled with nitrogen three times and then heated at 1000C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with pre-HPLC to afford 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3 20 (methylcarbamoyl)pyrazolo[1, 5-a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluoro-3 (trifluoromethyl)phenylboronic acid (52 mg, 17 % yield) as a white solid. 1 H NMR (300MHz, METHANOL-d4) 6: 8.67 (s, 1 H), 7.78 - 7.58 (d, 2H), 7.74 - 7.65(d, 2H), 7.26 -7.21 (m, 3H), 5.23 (s, 2H), 3.26 (s, 3H), 2.84 (s, 3H), 2.18 (m, 1H), 1.16 - 0.92 25 (m,3H), 0.53 - 0.45 (m, 1 H). LCMS (m/z, ES*) =640 (M+1). Example 19: 5-cyclopropyl-2-(4-fluorophenvl)-6-(N-((1-hydroxv-7-(trifluoromethyl)-1,3 dihydrobenzo[c1[1,21oxaborol-5-vl)methyl)methylsulfonamido)-N-methylbenzofuran-3 carboxamide N MeO 2 s F

F

3 C BOH F OH 30 Step 1: 4-bromo-2-fluoro-3-(trifluoromethyl)analine 57 WO 2012/067664 PCT/US2011/024825 To a solution of 2-fluoro-3-(trifluoromethyl)benzenamine (10 g, 55.8 mmol) in DMF (100 mL) was added NBS (9.93g, 55.8 mmol) in portions at 150C under nitrogen atmosphere. Then, the reaction mixture was stirred at rt for 1 h. The mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 5 water (2 x 150 mL) and Na 2

CO

3 (10% aq. 150 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 4-bromo-2-fluoro-3-(trifluoromethyl)analine (14 g, 97% yield) as a red liquid. Step 2: methyl 4-amino-3-fluoro-2-(trifluoromethyl)benzoate A solution of 4-bromo-2-fluoro-3-(trifluoromethyl)benzenamine (11 g, 42.6 mmol), 10 Pd(OAc) 2 (1.95 g, 8.52 mmol), dppf (7.2 g, 12.8 mmol) and EtN 3 (4.8 g, 46.9 mmol) in DMSO (40 mL) and MeOH (40 mL) was heated at 80 'C for 16h under 5.0 MPa of carbon monoxide. The reaction mixture was cooled down to room temperature and filtered. The filtrate was diluted with EtOAc (100 mL), washed with water (3 x 100 mL) and brine (300 mL) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with 15 column chromatography to afford methyl 4-amino-3-fluoro-2-(trifluoromethyl)benzoate (8.6 g, 85% yield) as a purple liquid. Step 3: methyl 4-bromo-3-fluoro-2-(trifluoromethyl)benzoate To a solution of methyl 4-amino-3-fluoro-2-(trifluoromethyl)benzoate (8.6 g, 36.3 mmol) in MeCN (40mL) was added HBr (47% aq. 61mL) drop wise at 0 'C over 10 mins. 20 Then, NaNO 2 (2.75 g, 39.9 mmol) in water (10 mL) was added drop wise over 1 h at 0 'C. After the addition, the solution was stirred for 5 min at 0 'C followed by the addition of CuBr (6.0 g, 41.75mmol) in portions over 30 mins. The mixture was heated at 70 'C for 1 h. After cooling down to 0 'C, H20 (40 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with cold water (100 mL) and dried 25 over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford methyl 4-bromo-3-fluoro-2-(trifluoromethyl)benzoate (8.3 g, 76 % yield) as a yellow oil. Step 4: (4-bromo-3-fluoro-2-(trifluoromethyl)phenyl)methanol To a solution of methyl 4-bromo-3-fluoro-2-(trifluoromethyl)benzoate (8.6 g, 30 28.6mmol) in anhydrous toluene (60 mL) at -78'C was added DIBAL-H (21.5 g, 71.4 mmol) and stirred for 30 min. The mixture was allowed to be stirred at 0 C for 30 min. Then, the reaction mixture was quenched by MeOH (40mL) at -78'C. The mixture was washed by brine (50mL x 3) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford (4-bromo-3-fluoro-2 35 (trifluoromethyl)phenyl)methanol (6.5 g, 83%) as a yellow oil. Step 5: 1-bromo-4-(bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene 58 WO 2012/067664 PCT/US2011/024825 To a solution of (4-bromo-3-fluoro-2-(trifluoromethyl)phenyl)methanol (3 g, 11 mmol) and NBS (3.92 g , 22mmol) in anhydrous DCM(30 mL) was added triphenylphosphine (5.76 g, 22mmol) in anhydrous DCM(10 mL). The mixture was stirred at rt for 30 min and then quenched by H20 (10 mL). The organic layer was separated and washed with brine (20 mL 5 x3) and dried over anhydrous Na 2

SO

4 . After the removal of solvent, the residue was purified with column chromatography to afford 1-bromo-4-(bromomethyl)-2-fluoro-3 (trifluoromethyl)benzene (2.7 g, 73%yield) as a colorless oil. Step 6: 6-(N-(4-bromo-3-fluoro-2-(trifluoromethyl)benzyl)methylsulfonamido)-5 cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1, 5-alpyridine-3-carboxamide 10 A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5 a]pyridine-3-carboxamide (350 mg, 0.872 mmol), 1-bromo-4-(bromomethyl)-2-fluoro-3 (trifluoromethyl)benzene (439.4 mg, 1.31 mmol), KI (144 mg , 0.872 mmol) and K 2

CO

3 (361.6 mg, 2.616 mmol) in dry DMF (20 mL) was stirred at room temperature for 1h under nitrogen. The reaction mixture was diluted with water (45 mL) and extracted with EtOAc (3 x 40 mL). 15 The combined organic layers were washed with water (50 mL) and brine (50 mL) and then, dried over anhydrous Na 2

SO

4 . After the removal of solvent, the crude product was purified with column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (387mg, 66 % yield) as a yellow solid. 20 Step 7: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)methyl)-2-fluoro-3-(trifluoromethyl)phenylboronic acid A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5 a]pyridine-3-carboxamide (371 mg, 0.56mmol), bis(pinacolato)diboron (284 mg, 1.12 mmol), potassium acetate (164 mg, 1.68mmol) and PdCl 2 (dppf)-CH 2

CI

2 (45.7 mg, 0.056 mmol) in 25 dixoane (25 mL) was degassed and refilled with nitrogen three times and then heated at 100 'C overnight. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with pre-HPLC to afford 4-((N-(5 cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluoro-3-(trifluoromethyl)phenylboronic acid (76 mg, 15 % 30 yield) as a white solid. 1 H NMR (300MHz, METHANOL-d4) 6: 8.67 (s, 1 H), 7.78 - 7.58 (d, 2H), 7.74 - 7.65(d, 2H), 7.26 -7.21 (m, 3H), 5.23 (s, 2H), 3.26 (s, 3H), 2.84 (s, 3H), 2.18 (m, 1H), 1.16 - 0.92 (m,3H), 0.53 - 0.45 (m, 1 H). LCMS(m/z, ES*) =623 (M+1). Example 20: (2-(N-(2-(4-chlorophenvl)-5-cyclopropvl-3-(methvlcarbamovl)pvrazolo[1,5 35 alpyrid in-6-vl)methylsu lfonamido)ethoxv)methylboron ic acid 59 WO 2012/067664 PCT/US2011/024825 HN 0 CI N/ N Os 0 HO'BOH Step 1: 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(2-hydroxyethyl)methylsulfonamido)- N methylpyrazolo[1,5-alpyridine-3-carboxamide 5 To a solution of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6 (methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (300 mg, 0.716 mmol) and 2 bromoethanol (0.101 mL, 1.432 mmol) in N,N-Dimethylformamide (15 mL) was added K 2 CO3 (297 mg, 2.148 mmol) and KI (119 mg, 0.716 mmol) under nitrogen at room temperature. The reaction mixture was stirred at 80 'C for 6 hours, cooled to room temperature, quenched 10 with water (20mL), and extracted with ethyl acetate (3X20mL). The organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to give 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(2-hydroxyethyl)methylsulfonamido)-N methylpyrazolo[1,5-a]pyridine-3-carboxamide (260 mg, 0.505 mmol, 70.6 % yield) as light 15 yellow solid. LCMS (m/z) ES' = 463 (M+H) Step 2: ((2-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5 a]pyridin-6-yl)methylsulfonamido)ethoxy)methyl)boronic acid To a solution of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (248 mg, 1.123 mmol) and 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(2-hydroxyethyl)methylsulfonamido) 20 N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (260 mg, 0.562 mmol) in N,N Dimethylformamide (15 mL) was added K 2

CO

3 (233 mg, 1.685 mmol) and KI (93 mg, 0.562 mmol) under nitrogen at room temperature. The reaction mixture was stirred at 60 'C for 16 hours. The mixture was cooled to room temperature, quenched with water (20mL), and extracted with ethyl acetate (3X2OmL). The organic layers were combined, washed with 25 saturated brine (50 mL), dried over sodium sulfate, concentrated under reduced pressure and purified by HPLC to give ((2-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3 (methylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)methylsulfonamido)ethoxy)methyl)boronic acid (50 mg, 0.094 mmol, 16.75 % yield) as white solid. 1 H NMR (METHANOL-d 4 ) 6 8.79 (s, 1 H), 7.74 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.39 (s, 1H), 4.18 (s, 1H), 3.66 - 3.46 (m, 30 3H), 3.41 (d, J = 15.2 Hz, 1H), 3.35 (s, 2H), 3.25 (d, J = 8.0 Hz, 3H), 2.86 (s, 3H), 2.31 (s, 1H), 1.07 (dd, J = 46.2, 8.9 Hz, 3H), 0.77 (s, 1H)); LCMS (m/z) ES' = 521 (M+1). 60 WO 2012/067664 PCT/US2011/024825 Example 21: BIOLOGICAL ASSAYS Replicon Luciferase cell based assay Method 5 150pL of a 1mM stock solution in DMSO of each test compound was transferred into in the first column of a 96 well, V-bottom microplate, to give 200 times the top concentration of the required dilution series. Aliquots of 50pL were added to each well of the remaining rows containing 1 00pL of DMSO giving a 1:3 dilution series over ten points. Columns 11 and 12 contained DMSO only for the positive and negative control, respectively. 10pL of each 10 well were transferred into 90pL of DMEM medium (Invitrogen #41965-039) supplemented with 5% v/v foetal calf serum, 1% v/v non-essential amino acids solution, 100 units/ml penicillin, 100 tg/ml streptomycin and 2mM L-glutamine to give 20 times the top concentration of the required dilution series. For replicon assays, Huh-7 cells stably transfected with sub-genomic HCV NS3 15 NS5B replicons of either genotype 1b (the ET subline described by Pietschmann,T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. & Bartenschlager, R., Joumal of Virology, 2002, 76, 4008-4021), genotype 1a (subline 1.19 constructed in-house) or genotype 1b C316N (constructed in-house) linked to a firefly luciferase reporter gene were used. Monolayers nearing confluency were stripped from growth flasks with versene-trypsin 20 solution and the cells re-suspended in assay medium comprising DMEM. Alternatively, frozen cell stocks were prepared and validated to function comparably to fresh cells. Frozen cells were thawed rapidly from a liquid Nitrogen tank in a 37'C waterbath and transferred to a large conical tube where complete media was added dropwise. Cells were centrifuged for 5 mintues at 1 K rpm and resuspended in complete medium. Trypsinized cells or resuspended 25 frozen cells were counted and diluted to the approporiate concentration for assay purposes. 95pL of suspension containing either 15,000 cells (genotype 1 b luciferase replicon) or 20,000 cells (genotype 1 a luciferase replicon) were added to all wells of a 96 well plate (Perkin Elmer, #6005686), except medium controls in column 12 of the assay plate. The cell suspension was dosed with 5pL of compound solution and the plate was incubated for 48 30 hours at 37'C in a 5% CO 2 atmosphere. For toxicity the cells in one plated were treated with Cell Titer Glo (Promega, #G7573). A solution of Cell Titer Glo was prepared according to the manufacturer's instructions, and 100 pL added to each well. The plate was then read for luminescence on an Envision. 35 For potency a solution of Steady Glo (Promega, #E2550) was prepared according to the manufacturer's instructions and 1OOpL added to each well. After a 20 minute incubation the plate was then read for luminescence on an Envision. 61 WO 2012/067664 PCT/US2011/024825 Data Analysis Toxicity : The luminescence values from duplicate wells were averaged and expressed as a percentage of the mean absorbance of compound free control wells to determine comparative cell viability. Compound cytotoxicity was expressed either as the 5 lowest concentration at which a significant reduction in viability was observed or a 50% toxic concentration (CCID 50 ) was determined by plotting percentage cytotoxicity against compound concentration using ActivityBase (IDBS Software) with curve fitting done through the XC50 module. Potency: The luminescence values from all compound-free wells containing cells 10 were averaged to obtain a positive control value. The mean luminescence value from the compound-free wells that had received no cells was used to provide the negative (background) control value. The background value was subtracted from the readings from the wells at each compound concentration and all values were expressed as a percentage of the positive control signal. The quantifiable and specific reduction of luciferase signal in the 15 presence of a drug is a direct measure of replicon inhibition. BioAssay Enterprise (CamebridgeSoft) with the XC50 module for curve fitting was used to plot the curve of percentage inhibition against compound concentration and derive the 50% inhibitory concentration (IC50) for the compound. The EC50 values obtained from duplicate plates were averaged. Results are expressed in Table 1. 20 Most of the compounds tested demonstrated activity against NS5B-316N that was equal to, or close to the wildtype NS5B-316C. NS5B-316N is a polymorphic change on residue 316 that occurs in about 40% of HCV genotype 1b patients and it is therefore advantageous for a compound to exhibit activity against NS5B-316N. Table 1 25 Example No. la Wild Type (nM) lb Wild Type (nM) 1b 316N (nM) 1 ** 2 ** ** * 3 ** ** * 4 ** ** ** 5 * * * 6 * * * 7 ** ** ** 8 *** *** ** 9 ** ** ** 62 WO 2012/067664 PCT/US2011/024825 10 ** 11 * * * 12 ** ** * 13 ** ** ** 14 ** ** ** 15 *** *** ** 16 *** *** ** 17 ** ** ** 18 ** ** ** 19 ** ** ** * 200 - 5000 nM ** 10 - 200 nM <10 nM 5 ND = not determined 63

Claims (20)

1. A compound of formula (1): 0 R 2 0 R 3 ON N X R R 4 (1) wherein: R 1 is one or more substituents independently selected from the group consisting of hydrogen, halogen, C 1 . 6 alkyl, hydroxyC 1 . 6 alkyl, alkoxy, -CN, and -CF 3 ; R 2 is NR 5 R 6 R 5 is hydrogen; R 6 is hydrogen or C 16 alkyl; R 3 is C 1 . 6 alkyl, C 3 . 6 cycloalkyl, C 1 . 6 alkoxy, or heterocyclyl; R 4 is (a) aryl substituted with B(OR 7 )(OR 8 ) and additionally substituted with one or more substituents selected from the group consisting of C 1 . 6 alkyl, C 3 . 6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ; (b) Het substituted with hydroxyl on the boron atom and additionally substituted with one or more substituents selected from the group consisting of halogen and C 16 alkyl; or (c) OR 9 B(OR 7 )(OR) wherein R 9 is alkylene; R 7 and R3 are both hydrogen or C 1 . 6 alkyl or when R 7 and R3 are C 1 . 6 alkyl, R 7 and R3 together with the oxygen atoms to which they are attached form a 5 to 8-membered ring; X and Z are independently CH or N, provided that both X and Z are not N; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (1) according to claim 1 wherein: R 1 is one or more substituents independently selected from the group consisting of hydrogen, halogen, C1. 6 alkyl, hydroxyC 1 . 6 alkyl, alkoxy, -CN, and -CF 3 ; 64 WO 2012/067664 PCT/US2011/024825 R 2 is NR 5 R 6 R 5 is hydrogen; R 6 is hydrogen or C 1 . 6 alkyl; R 3 is C 1 . 6 alkyl, C 3 . 6 cycloalkyl, C 1 . 6 alkoxy, or heterocyclyl; R 4 is (a) aryl substituted with B(OR 7 )(OR) and additionally substituted with one or more substituents selected from the group consisting of C 1 . 6 alkyl, C 3 . 6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ; or (b) Het substituted with hydroxyl on the boron atom and additionally substituted with one or more substituents selected from the group consisting of halogen and C 1 . 6 alkyl; R 7 and R3 are both hydrogen or C 1 . 6 alkyl or when R 7 and R3 are C 1 . 6 alkyl, R 7 and R3 together with the oxygen atoms to which they are attached form a 5 to 8-membered ring; X and Z are independently CH or N, provided that both X and Z are not N; or a pharmaceutically acceptable salt thereof.

3. A compound of formula (1) according to claim 1 wherein: R 1 is halogen; R 2 is NR 5 R 6 R 5 is hydrogen; R 6 is hydrogen or C 1 . 6 alkyl; R 3 is C 3 - 6 cycloalkyl; R 4 is aryl substituted with B(OR 7 )(OR") and additionally substituted with one or more substituents selected from the group consisting of C 1 . 6 alkyl, C 3 . 6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ; R 7 and R 8 are both hydrogen or C 1 . 6 alkyl.; X and Z are independently CH or N, provided that both X and Z are not N; or a pharmaceutically acceptable salt thereof.

4. A compound of formula (1) according to any of claims 1 - 3 wherein X and Z are CH.

5. A compound of formula (la) 65 WO 2012/067664 PCT/US2011/024825 0 R 2 0,..s- N-R // 1 "OH R 9 B OH (la) wherein: R 1 is halogen; R 2 is NR 5 R 6 R 5 is hydrogen; R 6 is hydrogen or C 16 alkyl; R 9 is one or more substituents independently selected from the group consisting of C 1 . 6 alkyl, C 3 . 6 cycloalkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF 3 and -OCF 3 ; or a pharmaceutically acceptable salt thereof.

6. A compound of formula (la) according to claim 5 wherein R 9 is one or more halogen.

7. A compound of formula (1) according to claim 1 wherein: R 1 is halogen; R 2 is NR 5 R 6 R 5 is hydrogen; R 6 is hydrogen or C 16 alkyl; R 3 is C 3 - 6 cycloalkyl; R 4 is Het substituted with hydroxyl on the boron atom and additionally substituted with one or more substituents selected from the group consisting of halogen and C 16 alkyl; or a pharmaceutically acceptable salt thereof.

8. A compound according to any of claims 1 - 7 wherein R 1 is fluoro or chloro.

9. A compound according to any of claims 1 - 7 wherein R 6 is C 1 . 6 alkyl. 66 WO 2012/067664 PCT/US2011/024825

10. A compound of formula (1) according to claim 1 selected from the group consisting of: 4-((N-(5-cyclopropyl-2-(4-fl uorophenyl)-3-(methylcarbamoyl)pyrazolo[1, 5-a]pyrid in-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 6-(N-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)methylsulfonamido) 5-cyclopropyl-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsu lfonamido)methyl)-2-(trifluoromethoxy)phenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(pyrid in-3-yl)pyrazolo[1, 5-a]pyrid in-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(pyrid in-4-yl)pyrazolo[1, 5-a]pyrid in-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)H-pyrazolo[1,5-a]pyridin-6 yl)methan-1 6-ylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-chlorophenylboronic acid; 2-chloro-4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)phenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-methylphenylboronic acid; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-methylphenylboronic acid; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid; 4-((N-(3-carbamoyl-5-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid; 2-chloro-4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin 6-yl)methylsulfonamido)methyl)phenylboronic acid ; 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2,3-difluorophenylboronic acid; 2-fluoro-4-((N-(2-(4-fluorophenyl)-5-(furan-3-yl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)phenylboronic acid; 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-6 yl)methylsulfonamido)methyl)-2-fluoro-3-(trifluoromethyl)phenylboronic acid; 67 WO 2012/067664 PCT/US2011/024825 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((1 -hydroxy-7-(trifluoromethyl)-1,3 di hyd robenzo[c][ 1, 2]oxaborol-5-yl)methyl)methylsu lfonamido)-N-methylbenzofuran-3 carboxamide; and pharmaceutically acceptable salts thereof.

11. A pharmaceutically acceptable salt of a compound as claimed in any of claims 1 - 10.

12. A pharmaceutical composition comprising a compound according to any of claims 1 - 11 together with at least one pharmaceutically acceptable excipient.

13. A compound as claimed in any of claims 1 - 11 for use in therapy.

14. Use of a compound as claimed in any of claims 1 - 11 in the manufacture of a medicament for treating or preventing a viral infection or disease associated with such infection.

15. Use according to claim 14 wherein the viral infection is HCV infection.

16. A compound as claimed in any of claims 1 to 11 for use in treating or preventing a viral infection or disease associated with such infection.

17. A compound according to claim 16 wherein the viral infection is HCV infection.

18. A method of treatment of a viral infection or disease associated with such infection comprising administering to a human a therapeutically effective amount of compound as claimed in any one of claims 1 to 11.

19. A method according to claim 18 wherein the viral infection is HCV infection.

20. A compound as claimed in any one of claims 1 to 11 in combination with one or more active anti-viral agents. 68