Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c

TITLE OF THE APPLICATION

0002TETRACYCLIC HETEROCYCLE COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF HEPATITIS C FIELD OF THE INVENTION

0003The present disclosure relates to antiviral compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS5B (non-structural protein 5B) polymerase, compositions comprising such compounds, the use of such compounds for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, methods for inhibiting the function of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.

BACKGROUND OF THE INVENTION

0005Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. Current treatments for HCV infection include immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin.

0006Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3, amino acid residues 1-180), a helicase (NS3, full length), an NS3 protease cofactor (NS4A), a membrane protein (NS4B), a zinc metalloprotein (NS5A) and an RNA-dependent RNA polymerase (NS5B).

0007One identified target for therapeutic intervention is HCV NS5B polymerase. Sven-Erik Behrens et ah, Identification and properties of the RNA-dependent RNA polymerase of heptatitis C virus, 15(1) EMBO J. 12-22 (1996). Antagonists of NS5B activity are inhibitors of HCV replication. Steven S. Carroll et al, Inhibition of Hepatitis C Virus RNA Replication by 2'- Modified Nucleoside Analogs, 278(14) J. BIOL. CHEM. 1 1979-84 (2003).

0008There is a clear and long-felt need to develop effective therapeutics for treatment of HCV infection. Specifically, there is a need to develop compounds that selectively inhibit HCV viral replication and that would be useful for treating HCV-infected patients. SUMMARY OF THE INVENTION

0009The present disclosure relates to novel compounds of formula I and/or pharmaceutically acceptable salts thereof. These compounds are useful, either as compounds or their pharmaceutically acceptable salts (when appropriate), in the inhibition of HCV (hepatitis C virus) NS5B (non-structural 5B) polymerase, the prevention or treatment of one or more of the symptoms of HCV infection, the inhibition of HCV viral replication and/or HCV viral production, and/or as pharmaceutical composition ingredients. As pharmaceutical composition ingredients, these compounds and their salts may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to other HCV antivirals, anti-infectives, immunomodulators, antibiotics or vaccines, as well as the present Standard of Care treatment options for HCV.

0010In one aspect, the present invention relates to a compound of formula I:

0011<img file="WO2014123795A2_D0001.tif" />

0012or a pharmaceutically acceptable salt thereof,

0013wherein:

0014Zi, Z₂ and Z₃ are independently CH or N;

0015Z₄ is CH or N;

0016A is C3-C6 cycloalkyl, C2-C₄ alkenyl, C3-C6 cycloalkenyl, 4- to 6-membered monocyclic heterocycloalkyl, 4- to 6-membered monocyclic heterocycloalkenyl, -C(=0)NR^aR^b, -C(=0)-(4- to 6-membered monocyclic heterocycloalkyl), -C(R^c)=NOR^d, or HetA, wherein cycloalkyl is optionally substituted by 1 or 2 substituents selected from C1-C6 alkyl and halo, wherein HetA is optionally substituted by 1 or 2 ring substituents R¹, and wherein the 4- to 6- membered monocyclic heterocycloalkyl is optionally substituted with oxo;

0017HetA is a 5- or 6- membered aromatic monocyclic ring with 1, 2 or 3 heteroatom ring atoms independently selected from N, O and S;

0018R^a, R^b, R^c, R^d are independently selected from H and C1-C6 alkyl; each occurrence of R¹ is independently selected from halo, -OH, Ci-Ce alkyl, Ci- Ce alkoxy, Ci-Ce haloalkyl, -0-(Ci-C6 alkyl), -0-(Ci-C6 haloalkyl), oxo, cyano, and

0019-O-phenyl-F;

0020R² is hydrogen, Ci-C₆ alkyl or -0(Ci-C₆ alkyl);

0021R³ is hydrogen or Ci-Ce alkyl;

0022R⁴ is Ci-Ce alkyl or -0(Ci-C₆ alkyl);

0023R⁵ is hydrogen or C1-C6 hydroxyalkyl; and

0024R⁶ and R⁷ are independently hydrogen, halo, cyano or C1-C4 alkyl. The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of treating or reducing the likelihood or severity of HCV infection, methods for inhibiting the activity of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.

0025Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

0027The present invention includes compounds of formula I above, and pharmaceutically acceptable salts thereof. The compounds of formula I are HCV NS5B polymerase inhibitors.

0028In an aspect of the invention, at least one of Zi, Z2 and Z3 is N.

0029In a first embodiment of the invention, R² and R⁴ are independently Ci-Ce alkyl. In this embodiment, all other groups are as provided in the general formula above or as in the first aspect.

0030In a second embodiment of the invention, R², R³ and R⁴ are methyl. In this embodiment, all other groups are as provided in the general formula above, as in the first aspect as in the first embodiment.

0031In a third embodiment of the invention, no more than one of R⁶ and R⁷ are halo. In all aspects of this embodiment, all other groups are as provided in the general formula above, as in the first aspect or as in the first or second embodiments. In a fourth embodiment of the invention, each halo is F. In this embodiment, all other groups are as provided in the general formula above, as in the first aspect or as in the first through third embodiments.

0032In a fifth embodiment of the invention, R⁵ is hydrogen or -CH2OH. In this embodiment, all other groups are as provided in the general formula above, as in the first aspect or as in the first through fourth embodiments.

0033In a sixth embodiment of the invention, the compound of the invention has the formula:

0034<img file="WO2014123795A2_D0002.tif" />

0035In this embodiment, all other groups are as provided in the general formula above, as in the first aspect or as in the first through fifth embodiments.

0036In a seventh embodiment of the invention, A is C3-C6 cycloalkyl, C2-C4 alkenyl, C3-C6 cycloalkeny, 4- to 6-membered monocyclic heterocycloalkyl, 4- to 6-membered monocyclic heterocycloalkenyl (optionally substituted with 1 or 2 substituents independently selected from Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, oxo, halo, and -O-C1-C6 haloalkyl), 5-6 membered aromatic monocyclic ring with 1, 2 or 3 heteroatom ring atoms selected from N, O, and S (optionally substituted with 1 or 2 substituents independently selected from Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, oxo, halo, -O-4-F-phenyl, and -0-Q-C₆ haloalkyl). In an aspect of this seventh embodiment, A is

0037cyclopropyl, <img file="WO2014123795A2_D0003.tif" />

0038wherein R^la is F, methyl, ethyl, methoxy, ethoxy, -O-isopropyl, -OCHF₂,

0039OCH₂CF₃, -C !HHFF₂₂,, oorr --CCFF₃₃,, RR^llbb iiss hhyyddrrooggeenn oorr mmeetthhyyll,, RR^llcc iiss methyl, ethyl, or isopropyl, and R¹ is methyl or ethyl. In another aspect of this embodiment, A is

0040<img file="WO2014123795A2_D0004.tif" />

0041In all aspects of this embodiment, all other groups are as provided in the general formula above, as in the first aspect or as in the first through sixth embodiments.

0042In another embodiment of the invention, the compound of the invention is selected from the exemplary species depicted in Examples 1-7, 9-27, 30-32 and 34-59 shown below, and pharmaceutically acceptable salts thereof.

0043In another embodiment of the invention, the compound of the invention is selected from the exemplary species depicted in Examples 2, 4, 7, 1 1, 14, 25, 35, 37, 38 and 59 shown below, and pharmaceutically acceptable salts thereof.

0044Other embodiments of the present invention include the following:

0045(a) A pharmaceutical composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.

0046(b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents,

0047immunomodulators, and anti-infective agents.

0048(c) The pharmaceutical composition of (b), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.

0049(d) A pharmaceutical combination that is (i) a compound of formula I and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of formula I and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV NS5B activity, or for inhibiting HCV viral replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.

0050(e) The combination of (d), wherein the HCV antiviral agents are one or more antiviral agents selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.

0051(f) A use of a compound of formula I in the preparation of a medicament for inhibiting HCV NS5B activity in a subject in need thereof.

0052(g) A use of a compound of formula I in the preparation of a medicament for preventing and/or treating infection by HCV in a subject in need thereof.

0053(h) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula I.

0054(i) The method of (h), wherein the compound of formula I is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

0055(j) The method of (i), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.

0056(k) A method of inhibiting HCV viral replication and/or HCV viral production in a cell-based system, which comprises administering to the subject an effective amount of a compound of formula I in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents,

0057immunomodulators, and anti-infective agents.

0058(1) The method of (k), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.

0059(m) A method of inhibiting HCV NS5B activity in a subject in need thereof, which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).

0060(n) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof, which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).

0061In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (n) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.

0062Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods set forth in (a) through (n) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.

0063The present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV NS5B activity, or (b) inhibiting HCV viral replication, or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, or (d) use in medicine. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.

0064Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, the structure is understood to predominate.

0065As used herein, the term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention mean providing the compound to the individual in need of treatment. When a compound of the invention is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating HCV infection), "administration" and its variants are each understood to include concurrent and sequential provision of the compound or salt and other agents.

0066As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl and decenyl. An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, -NH(alkyl), - N(alkyl)₂, -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and - C(0)0-alkyl. The term "C2-C6 alkenyl" refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.

0067As used herein, the term "alkoxy" refers to an "alkyl-O-" group. Alkoxy groups may be substituted as indicated.

0068The term "alkyl" refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C1-C6 alkyl) or from about 1 to about 3 carbon atoms (C1-C3 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. An alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, - NH(alkyl), -N(alkyl)₂, -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, - C(0)OH and -C(0)0-alkyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.

0069The term "alkynyl," as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond. An alkynyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. An alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, - O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, -NH(alkyl), -N(alkyl)₂, -NH(cycloalkyl), -O-C(O)- alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl. The term "C₂-C₆ alkynyl" refers to an alkynyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.

0070The term "aryl" (or "aryl ring system") refers to aromatic mono- and poly- carbocyclic ring systems wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. As used herein, the term aryl includes aromatic mono- and poly-carbocyclic ring systems that include from 0 to 4 heteroatoms (non-carbon atoms) that are independently chosen from N, O and S. Suitable aryl groups include phenyl, naphthyl, biphenylenyl, pyridinyl, pyrimidinyl and pyrrolyl, as well as those discussed below. Aryl groups may be substituted as indicated. Aryl ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the aryl ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.

0071The term "carbocycle" (and variations thereof such as "carbocyclic") as used herein, unless otherwise indicated, refers to (i) a C5 to C7 monocyclic, saturated or unsaturated ring, or (ii) a Cs to C₁₀ bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. Carbocycle groups may be substituted as indicated. When the carbocycles contain one or more heteroatoms independently chosen from N, O and S, the carbocycles may also be referred to as

0072"heterocycles," as defined below. The carbocycle may be attached to the rest of the molecule at any carbon or nitrogen atom that results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle" generally refers to a Cs to Cio bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which both rings are saturated is a saturated bicyclic ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. A fused bicyclic carbocycle in which one or both rings are unsaturated is an unsaturated bicyclic ring system.

0073Carbocycle ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.

0074The term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.

0075The term "compound" is intended to encompass chemical agents described by generic formula I in all forms, including hydrates and solvates of such chemical agents.

0076The term "cycloalkenyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 4 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains from about 4 to about 7 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms. Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-l,3-dienyl, and the like. A cycloalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. In one embodiment, a cycloalkenyl group is cyclopentenyl. In another embodiment, a cycloalkenyl group is cyclohexenyl. The term "4 to 7-membered cycloalkenyl" refers to a cycloalkenyl group having from 4 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkenyl group is unsubstituted.

0077The term "cycloalkyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms. The term "cycloalkyl" also encompasses a cycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl, bicyclo[3.1.0]hexyl and adamantyl. A cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, a cycloalkyl group is unsubstituted. The term "3 to 7-membered cycloalkyl" refers to a cycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkyl group is unsubstituted. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl group (also referred to herein as a "cycloalkanoyl" group) includes, but is not limited to, cyclobutanoyl:

0078<img file="WO2014123795A2_D0005.tif" />

0079The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for reduction of the severity or likelihood of one or more symptoms of the disease or condition. In another embodiment, the effective amount is a "therapeutically effective amount" for inhibition of HCV viral replication and/or HCV viral production. The term also includes herein the amount of active compound sufficient to inhibit HCV NS5B activity and thereby elicit the response being sought (i.e., an "inhibition effective amount"). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.

0080The term "haloalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms. Non-limiting examples of haloalkyl groups include -CH₂F, -CHF₂, -CF₃, -CH₂C1 and -CC1₃. The term "Ci-C₆ haloalkyl" refers to a haloalkyl group having from 1 to 6 carbon atoms.

0081The term "halogen" (or "halo") refers to atoms of fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

0082The term "heterocycloalkenyl," as used herein, refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 4 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond. A heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom. In one embodiment, a heterocycloalkenyl group has from 4 to 7 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heterocycloalkenyl group is bicyclic. A heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of heterocycloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluoro-substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like and the like. A ring carbon atom of a heterocycloalkenyl group may be functionalized as a carbonyl group. In one embodiment, a heterocycloalkenyl group is a 5-membered heterocycloalkenyl. In another embodiment, a heterocycloalkenyl group is a 6-membered heterocycloalkenyl. The term "4 to 7-membered heterocycloalkenyl" refers to a heterocycloalkenyl group having from 4 to 7 ring atoms. Unless otherwise indicated, a heterocycloalkenyl group is unsubstituted.

0083The term "heteroaryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic and has 9 or 10 ring atoms. A heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring. The term "heteroaryl" also encompasses any fused polycyclic ring system containing at least one ring heteroatom selected from N, O and S, wherein at least one ring of the fused polycyclic ring system is aromatic. For example, the term "9 to 10-membered bicyclic heteroaryl" encompasses a non-aromatic 5 membered heterocyclic ring that is fused to a benzene or pyridyl ring. Non- limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2, l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6- membered heteroaryl. In another embodiment, a heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.

0084As used herein, the term "heterocycle" (and variations thereof such as

0085"heterocyclic" or "heterocyclyl") broadly refers to (i) a stable 5- to 7-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 8- to 10-membered bicyclic ring system, wherein each ring in (ii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) independently selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the bicyclic ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized. Unless otherwise specified, the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. Heterocycle groups may be substituted as indicated, and unless otherwise specified, the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).

0086The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 1 1 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, or N, and the remainder of the ring atoms are carbon atoms. A heterocycloalkyl group can be joined via a ring carbon or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 5 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention. The term "heterocycloalkyl" also encompasses a heterocycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring. A heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone, and the like, and all isomers thereof.

0087A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. Illustrative example of such heterocycloalkyl groups, include:

0088<img file="WO2014123795A2_D0006.tif" />

0089In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered

0090monocyclic heterocycloalkyl. The term "3 to 7-membered monocyclic cycloalkyl" refers to a monocyclic heterocycloalkyl group having from 3 to 7 ring atoms. The term "4 to 7-membered monocyclic cycloalkyl" refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms. The term "5 to 7-membered monocyclic cycloalkyl" refers to a monocyclic

0091heterocycloalkyl group having from 5 to 7 ring atoms. The term "7 to 1 1-membered bicyclic heterocycloalkyl" refers to a bicyclic heterocycloalkyl group having from 7 to 1 1 ring atoms. Unless otherwise indicated, an heterocycloalkyl group is unsubstituted.

0092The term "hydroxyalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an -OH group. In one embodiment, a hydroxyalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH and - CH₂CH(OH)CH3. The term "Ci-Ce hydroxyalkyl" refers to a hydroxyalkyl group having from 1 to 6 carbon atoms.

0093As used herein, the term "oxo" or "=0" forms a carbonyl moiety with the carbon atom to which it is attached.

0094By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

0095The term "preventing," as used herein with respect to an HCV viral infection or HCV-virus related disorder, refers to reducing the likelihood of HCV infection.

0096The term "ring system substituent," as used herein, refers to a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, - alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene- heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O- alkylene-aryl, acyl, -C(0)-aryl, halo, -N0₂, -CN, -SF₅, -C(0)OH, -C(0)0-alkyl, -C(0)0-aryl, - C(0)0-alkylene-aryl, -S(0)-alkyl, -S(0)₂-alkyl, -S(0)-aryl, -S(0)₂-aryl, -S(0)-heteroaryl, - S(0)₂-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, - S(0)₂-alkylene-aryl, -S(0)₂-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -0-C(0)-alkyl, - 0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(=N-CN)-NH₂, -C(=NH)-NH₂, -C(=NH)-NH(alkyl), - N(Yi)(Y₂), -alkylene-N(Yi)(Y₂), -C(0)N(Yi)(Y₂) and -S(0)₂N(Yi)(Y₂), wherein Y_l and Y₂ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylenedioxy, ethylenedioxy, -C(C¾)₂- and the like which form moieties such as, for example: <img file="WO2014123795A2_D0007.tif" />

0097The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human.

0098The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

0099In the compounds of formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of formula I. For example, different isotopic forms of hydrogen (H) include protium (^lK) and deuterium (²H or D). Protium is the

0100predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.

0101Isotopically-enriched compounds within formula I can be prepared without undue

0102experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

0103Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaryl ring described as containing from "0 to 3 heteroatoms" means the ring can contain 0, 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N and S are also included within the scope of the present invention. When any variable (for example, R¹ or R³) occurs more than one time in any constituent or in formula I or in any other formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

0104Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom provided such substitution is chemically allowed and results in a stable compound. A "stable" compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

0105Certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.

0106Certain of the compounds of the present invention can exist as tautomers. For the purposes of the present invention a reference to a compound of formula I is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.

0107The compounds of the present inventions are useful in the inhibition of HCV replication (e.g., HCV NS5B activity), the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection. For example, the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.

0108The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5B, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to the HCV replicase.

0109The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that possesses the effectiveness of the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Many of the compounds of the invention carry an acidic moiety, in which case suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

0110Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates ("mesylates"), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)

011166(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food &amp; Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

0112Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. For the purposes of inhibiting HCV NS5B polymerase, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection and inhibiting HCV viral replication and/or HCV viral production, the compounds of the present invention, optionally in the form of a salt, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by one or more conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered by one or more of the following: orally, parenterally

0113(including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation (such as in a spray form), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18^th edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).

0114The compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, HCV viral genotype, viral resistance, and the host undergoing therapy.

0115As noted above, the present invention also relates to a method of inhibiting HCV NS5B activity, inhibiting HCV viral replication and/or HCV viral production, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an

0116immuno modulator, and an anti-infective agent. Such therapeutic agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1 , R7025 (an enhanced interferon (Roche)), interferon-β, interferon-a, pegylated interferon-a (peginterferon- a), a combination of interferon-α and ribavirin, a combination of peginterferon-a and ribavirin, a combination of interferon-α and levovirin, and a combination of peginterferon-a and levovirin. Interferon-α includes, but is not limited to, recombinant interferon-a2a (such as ROFERON interferon available from Hoffmann-LaRoche, Nutley, NJ), pegylated interferon-a2a (PEGASYS), interferon-a2b (such as INTRON-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon-a2b (PEGINTRON), a recombinant consensus interferon (such as interferon alphacon-1), albuferon (interferon-α bound to human serum albumin (Human Genome

0117Sciences)), and a purified interferon-α product. Amgen's recombinant consensus interferon has the brand name INFERGEN. Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin. Viramidine represents an analog of ribavirin disclosed in International Patent Application Publication WO 01/60379. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. For the treatment of HCV infection, the compounds of the invention may also be administered in combination with the antiviral agent NS5B polymerase inhibitor R7128 (Roche). The compounds of the present invention also may be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in Rogers E. Harry-O'Kuru et ah, A Short, Flexible Route toward 2'-C-Branched Ribonucleosides, 62 J. ORG. CHEM. 1754-59 (1997); Michael S. Wolfe &amp; Rogers E. Harry-O'Kuru, A Concise Synthesis of2'-C- Methylribonucleosides, 36(42) TETRAHEDRON LETTERS 761 1-14 (1995); U.S. Patent

0118No. 3,480,613; and International Patent Application Publications WO 01/90121, WO 01/92282, WO 02/32920, WO 04/002999, WO 04/003000 and WO 04/002422; the entire contents of each of which are incorporated by reference. Such 2'-C-branched ribonucleosides include, but are not limited to, 2'-C-methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine, 2'-C-methyl- guanosine, and 9-(2-C-methyl- -D-ribofuranosyl)-2,6-diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3 ', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3 -propanediol esters of the 5 '-phosphate derivatives.

0119For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease. HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication. Exemplary substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Patent Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116, WO 02/48172, WO 2008/057208 and WO 2008/057209, in British Patent No. GB 2 337 262, and in U.S. Patent Nos. 6,323,180 and 7,470,664.

0120The compounds of the present invention may also be combined for the treatment of HCV infection with nucleosides having anti-HCV properties, such as those disclosed in International Patent Application Publications WO 02/51425, WO 01/79246, WO 02/32920, WO 02/48165 and WO 2005/003147 (including R1656, (2'R)-2'-deoxy-2'-fluoro-2'-C- methylcytidine, shown as compounds 3^6 on page 77); WO 01/68663; WO 99/43691 ;

0121WO 02/18404 and WO 2006/021341, and U.S. Patent Application Publication

0122US 2005/0038240, including 4'-azido nucleosides such as R1626, 4'-azidocytidine; U.S. Patent Application Publications US 2002/0019363, US 2003/0236216, US 2004/0006007,

0123US 2004/0063658 and US 2004/01 10717; U.S. Patent Nos. 7, 105,499, 7, 125,855, 7,202,224; and International Patent Application Publications WO 02/100415, WO 03/026589, WO 03/026675, WO 03/093290, WO 04/011478, WO 04/013300 and WO 04/028481 ; the content of each is incorporated herein by reference in its entirety.

0124For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase. Such HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in International Patent Application Publications

0125WO 02/057287, WO 02/057425, WO 03/068244, WO 2004/000858, WO 04/003138 and WO 2004/007512; U.S. Patent Nos. 6,777,392, 7, 105,499, 7, 125,855, 7,202,224 and U.S. Patent Application Publications US 2004/0067901 and US 2004/01 10717; the content of each is incorporated herein by reference in its entirety. Other such HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2'-F-2'-beta-methylcytidine (see also WO 2005/003147).

0126In one embodiment, additional nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl- -D-arabinofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 4- amino-7-(2-C-methyl- -D-ribofuranosyl)-7H-pyrrolo[2,3-if|pyrimidine; 4-methylamino-7-(2-C- methyl- -D-ribofuranosyl)-7H-pyrrolo[2,3-if|pyrimidine; 4-dimethylamino-7-(2-C-methyl- -D- ribofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 4-cyclopropylamino-7-(2-C-methyl- -D- ribofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C-vinyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C-hydroxymethyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C-fluoromethyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-5-methyl-7-(2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine-5-carboxylic acid; 4-amino-5-bromo-7-(2-C-methyl- -D- ribofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 4-amino-5-chloro-7-(2-C-methyl- -D- ribofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 4-amino-5-fluoro-7-(2-C-methyl- -D- ribofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 2,4-diamino-7-(2-C-methyl- -D-ribofuranosyl)- 7H-pyrrolo[2,3-i/]pyrimidine; 2-amino-7-(2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 2-amino-4-cyclopropylamino-7-(2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 2-amino-7-(2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidin-4(3H)-one; 4-amino-7-(2-C-ethyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C,2-0-dimethyl-p-D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 7-(2-C-methyl- -D-ribomranosyl)-7H-pyrrolo[2,3-( Jpyrimidin-4(3H)- one; 2-amino-5-methyl-7-(2-C, 2-0-dimethyl- -D-ribofuranosyl)-7H-pyrrolo[2,3-if|pyrimidin- 4(3H)-one; 4-amino-7-(3-deoxy-2-C-methyl- -D-ribofuranosyl)-7H-pyrrolo[2,3-&lt; Jpyrimidine; 4-amino-7-(3-deoxy-2-C-methyl- -D-arabinofuranosyl)-7H^yrrolo[2,3-(i]pyrimidine; 4-amino- 2-fluoro-7-(2-C-methyl- -D-ribofuranosyl)-7H-pyrrolo[2,3-(i]pyrimidine; 4-amino-7-(3-C- methyl- -D-ribofuranosyl)-7H-pyrrolo[2,3-if|pyrimidine; 4-amino-7-(3-C-methyl-p-D- xylofuranosyl)-7H-pyrrolo[2,3-( Jpyrimidine; 4-amino-7-(2,4-di-C-methyl-p-D-ribofuranosyl)- 7H-pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(3-deoxy-3-fluoro-2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; and the corresponding 5'-triphosphates; or a pharmaceutically acceptable salt thereof.

0127The compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in U.S. Patent Applciation Publications US 2006/0100262 and US 2009/0048239; International Patent Application Publications WO 01/77091, WO 01/47883, WO 02/04425, WO 02/06246, WO 02/20497, WO 2005/016927 (in particular JTK003), WO 2004/041201, WO 2006/066079, WO 2006/066080, WO 2008/075103, WO 2009/010783 and WO 2009/010785; the content of each is incorporated herein by reference in its entirety.

0128In one embodiment, additional non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8- tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2-morpholin- 4-ylethyl)-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14- cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2, l-a]

0129[2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8- tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; methyl ({[(14-cyclohexyl-3- methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocin-l 1- yl)carbonyl]amino}sulfonyl)acetate; ( {[(14-cyclohexyl-3-methoxy-6-methyl-5, 6,7,8- tetrahydroindolo[2,l-a][2,5]benzodiazocin-l l-yl)carbonyl] amino }sulfonyl)acetic acid; 14- cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l l-carboxamide; 3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7- oxo-5, 6,7, 8-tetrahydroindolo[2, l-a][2,5]benzodiazocine 11 -carboxylic acid; N-(l l-carboxy-14- cyclohexyl-7,8-dihydro-6H-indolo[ 1 ,2-e] [ 1 ,5]benzoxazocin-7-yl)-N,N-dimethylethane- 1 ,2- diaminium bis(trifluoroacetate); 14-cyclohexyl-7,8-dihydro-6H-indolo[l,2-e][l,5]

0130benzoxazocine-1 1-carboxylic acid; 14-cyclohexyl-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo [2, 1 -a] [2, 5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-3-methoxy-6-methyl-7-oxo- 5, 6,7, 8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2- (dimethylamino)ethyl]-3-methoxy-7-oxo-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine- 1 1-carboxylic acid; 14-cyclohexyl-6-[3-(dimethylamino)propyl]-7-oxo-5,6,7,8-tetrahydroindolo [2, 1 -a] [2, 5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-7-oxo-6-(2-piperidin-l-ylethyl)- 5, 6,7, 8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2- morpholin-4-ylethyl)-7-oxo-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2-(diethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2, l-a]

0131[2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(l-methylpiperidin-4-yl)-7-oxo-

01325.6.7.8- tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-N- [(dimethylamino)sulfonyl]-7-oxo-6-(2-piperidin-l-ylethyl)-5,6,7,8-tetrahydroindolo[2, l-a] [2,5]benzodiazocine-l 1 -carboxamide; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-N-

0133[(dimethylamino)sulfonyl]-7-oxo-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l l- carboxamide; 14-cyclopentyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2, l-a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-5,6,7,8-tetrahydroindolo[2, l-a]

0134[2,5]benzodiazocine-l 1-carboxylic acid; 6-allyl-14-cyclohexyl-3-methoxy-5,6,7,8- tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclopentyl-6-[2-

0135(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine- 1 1-carboxylic acid; 13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][l,4]diazocino[l,8- a] indole- 10-carboxylic acid; 15-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-6,7,8,9- tetrahydro-5H-indolo[2, l-a][2,6]benzodiazonine-12-carboxylic acid; 15-cyclohexyl-8-oxo-

01366.7.8.9- tetrahydro-5H-indolo[2, l-a][2,5]benzodiazonine-12-carboxylic acid; 13-cyclohexyl-6- oxo-6,7-dihydro-5H-indolo[l,2-( J[l,4]benzodiazepine- 10-carboxylic acid; and pharmaceutically acceptable salts thereof.

0137In another embodiment, the present HCV NS5B polymerase inhibitors are used in combination with non-nucleoside HCV NS5A inhibitors and pharmaceutically acceptable salts thereof. The HCV NS5B inhibitory activity of the present compounds may be tested using assays known in the art. The HCV NS5B polymerase inhibitors described herein have activities in a genotype lb replicon assay as described in the Examples. The assay is performed by incubating a replicon harboring cell-line in the presence of inhibitor for a set period of time and measuring the effect of the inhibitor on HCV replicon replication either directly by quantifying replicon RNA level, or indirectly by measuring enzymatic activity of a co-encoded reporter enzyme such as luciferase or β-lactamase. By performing a series of such measurements at different inhibitor concentrations, the effective inhibitory concentration of the inhibitor (EC₅₀ or EC₉₀) is determined. See Jan M. Vrolijk et ah, A replicons-based bioassay for the measurement of interferons in patients with chronic hepatitis C, 110 J. ViROLOGiCAL METHODS 201 (2003). Such assays may also be run in an automated format for high through-put screening. See Paul Zuck et ah, A cell-based β-lactamase reporter gene assay for the identification of inhibitors of hepatitis C virus replication, 334 ANALYTICAL BIOCHEMISTRY 344 (2004).

0138The present invention also includes processes for making compounds of formula I. The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples serve only to illustrate the invention and its practice. General Schemes

0139The Compounds of Formula (I) may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis.

0140Methods useful for making the Compounds of Formula (I) are set forth in the Examples below and generalized in Schemes 1 -4 below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. All stereoisomers and tautomeric forms of the compounds are contemplated. Some commercially available starting materials and intermediates used for the synthesis of the Compounds of Formula (I) are available. These starting materials and intermediates are available from commercial suppliers such as Sigma-Aldrich (St. Louis, MO) and Acros Organics Co. (Fair Lawn, NJ). Such starting materials and intermediates compounds are used as received.

0141Scheme 1 shows methods useful for making the intermediates of formula C and D, which can be converted to Compounds of Formula (I).

0142Scheme 1

0143<img file="WO2014123795A2_D0008.tif" />

0144Scheme 2 shows a method useful for converting intermediate of formula C to Compounds of formula (I).

0145<img file="WO2014123795A2_D0009.tif" /> Alternatively, Scheme 3 shows a method useful for converting intermediate of formula D to Compounds of formula (I). Moiety A was introduced by either Suzuki coupling reaction or C-N coupling reaction or carbonylation reaction (followed by further

0146transformations).

0147Scheme 3

0148<img file="WO2014123795A2_D0010.tif" />

0149Alternatively, Scheme 4 shows a method useful for synthesizing Compound of formula (I) by Stille coupling reaction.

0150Scheme 4

0151<img file="WO2014123795A2_D0011.tif" />

0152List of Abbreviations

0153a.q. Aqueous

0154Ar₂ Argon gas

0155Boc t-butyloxycarbonyl

0156Boc₂0 Di-tert-butyl-dicarbonate

0157B(OMe)₃ Trimethoxyborane

0158Br₂ Bromine

0159n-BuLi n-butyllithium

0160cone. concentrated

0161CDCI3 Trichloro(²H)methane or deuterio-trichloromethane CHCI₃ Chloroform

0162CH₃COOK Potassium acetate

0163CH₂I₂ Methylene iodide

0164CO Carbon monoxide

0165CS₂CO₃ Cesium carbonate

0166DAST Diethylaminosulfur trifluoride

0167DCM, CH₂CI₂ Dichloromethane

0168DDQ Dichlorodicyanoquinone

0169DMAP 4-dimethylaminopyridine

0170DMF Dimethylformamide

0171DMSO Dimethylsulfoxide

0172EDCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide (also EDC)

0173Et Ethyl

0174EtiN Triethylamine

0175Et₂0 Diethylether

0176EtOAc, EA Ethyl acetate

0177EtOH, CH₃CH₂OH Ethanol

0178F₂ClCCOONa Sodium chlorodifluoroacetate

0179Fe Iron

0180FeCl Iron chloride

0181HBF₄ Fluoroboric acid

0182HBr Hydrogen bromide

0183HC1 Hydrochloric acid

0184H₂ Hydrogen gas or atmosphere

0185HNO₃ Nitric acid

0186H₂0 Water

0187H2SO4 Sulfuric acid

0188HOAc Acetic acid

0189HOBT 1 -Hydroxy benzotriazole

0190^-NMR Proton Nuclear Magnetic Resonance

0191HPLC High Performance Liquid Chromatography

0192IPA Isopropyl alcohol K₂C0₃ Potassium carbonate

0193OAc Potassium acetate

0194K₂HP0₄ Dipotassium phosphate

0195K₃P0₄ Potassium Phosphate

0196LDA Lithium diisopropylamide

0197LiCl Lithium chloride

0198LiOH Lithium hydroxide

0199MeNH₂, CH3NH2 Methanamine

0200MeCN, CH₃CN Acetonitrile

0201Mel, CH3I Methyl iodide

0202MeOD Methan(²H)ol

0203MeOH, CH,OH Methanol

0204(Me₃Sn)₂ Hexamethylditin

0205MS Mass spectroscopy

0206Ms Methanesulfonyl (or mesyl) group

0207MsCl Methanesulfonyl chloride

0208N₂ Nitrogen gas or atmosphere

0209NaBH₄ Sodium borohydride

0210Na₂C0₃ Sodium carbonate

0211NaF Sodium fluoride

0212NaHC0₃ Sodium bicarbonate

0213Nal Sodium iodide

0214Na₂S0₄ Sodium sulfate (anhydrous)

0215NH₄C1 Ammonium chloride

0216S N-iodosuccinimide

0217OPPI13 Triphenyl phosphine

0218Pd Palladium

0219Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)

0220Pd(dppf)Cl₂ 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride

0221Pd(dtbpf)Cl₂ 1 , 1 '-bis(di-?eri-butylphosphino)ferrocene-dichloropalladium(II)

0222Pd(OAc)₂ Palladium(II)acetate

0223Pd(PPh₃)₂Cl₂ 1 , 1 '-bis(tetrakis(triphenylphosphine))palladium(II)dichloride PE Petroleum ether

0224Ph Phenyl

0225PPA Polyphosphoric acid

0226RT Room temperature, approximately 25°C

0227sat saturated

0228SFC Supercritical fluid chromatography

0229p-TsCl p-toluenesulfonyl chloride

0230TEA Triethylamine

0231TFA Trifluoroacetic acid

0232THF Tetrahydrofuran

0233TLC Thin layer chromatography

0234ZnEt2 Diethylzinc

EXAMPLES

0236Example 1

0237<img file="WO2014123795A2_D0012.tif" />

0238Step 1 - Synthesis of ethyl 5-bromobenzofuran-3-carboxylate <img file="WO2014123795A2_D0013.tif" />

0239HBF₄-Et₂0 (16.2 g, 99.5 mmol) was added to a solution of 5-bromo-2- hydroxybenzaldehyde (200 g, 995 mmol) in CH2CI2 (500 mL), and then a solution of ethyl diazoacetate (180 g, 1.42 mol) in CH2CI2 (500 mL) was introduced as evolution of 2 gas while the reaction was not allowed over 38 °C. Once gas evolution ceased, the reaction mixture was concentrated by rotary evaporator and cone. H₂S0₄ (129 g, 1.29 mol, 98%) was added to the mixture while stirring. After 20 minutes, the acidic mixture was neutralized with a₂C0₃ (a.q.). After the mixture was stored and crystallized overnight, ethyl 5-bromobenzofuran-3-carboxylate (100 g, yield: 75%) was obtained by filtration. ¾-NMR (400 MHz, CDC1₃) δ 8.25 (s, 1H), 8.15-8.21 (m, IH), 7.44-7.50 (m, IH), 7.37-7.42 (m, IH), 4.41 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H).

0240Step 2 - Synthesis of ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate

0241<img file="WO2014123795A2_D0014.tif" />

0242To a solution of ethyl 5-bromobenzofuran-3-carboxylate (95 g, 353 mmol) in

0243CHC1₃ (1000 mL), fuming H 0₃ (192 mL, 95%) was added dropwise at -20 °C over 90 min and stirred at 0 °C for 1 hour. The reaction mixture was added to ice water and extracted with CH₂CI₂. The organic layer was washed with aHC0₃ and brine. The solvent was removed by distillation to provide the crude product of ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, yield: 85%). It was used for the next step without further purification.

0244Step 3 - Synthesis of ethyl 6-amino-5-bromobenzofuran-3-carboxylate

0245<img file="WO2014123795A2_D0015.tif" />

0246A mixture of crude compound ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH₄C1 (97 g, 1.82 mol) in MeOH-THF- H₂O (2 : 2 : 1, 1000 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE : EA from 20 : 1 to 10 : 1) to furnish ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.00 g, yield: 68%). ^XH- NMR (400 MHz, DMSO-i¾) δ 8.46 (s, IH), 7.85 (s, IH), 7.03 (s, IH), 5.55 (br s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H).

0247Step 4 - Synthesis of -amino-5-bromobenzofuran-3-carboxylic acid

0248<img file="WO2014123795A2_D0016.tif" />

0249To a solution of the compound ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58 g, 204 mmol) in 1,4-dioxane and H₂0 (850 mL and 150 mL) was added LiOH-H₂0 (42.8 g, 1.02 mol). The reaction mixture was refluxed for 2 hours, and then 400 mL ¾0 was added to the reaction mixture. After acidifying to pH 4~5 with HC1, the resulting solid was filtered to give 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, yield: 97%). ^XH-NMR (400 MHz, DMSO-i¾) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.02 (s, 1H), 5.51 (br s, 2H).

0250Step 5 - Synthesis of 6-amino-5-bromo-N-methyibenzofuran-3-carboxamide

0251<img file="WO2014123795A2_D0017.tif" />

0252To a solution of 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, 199 mmol) in dry DMF (500 mL) were add EDCI (53.1 g, 298.77 mmol) and HOBT (40.4 g, 299 mmol). The reaction mixture was stirred at room temperature for 2 h, and then Ets (60.5 g, 598 mmol) and Me H₂ -HCl (40.3 g, 598 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and 300 mL a₂C0₃ (a.q.) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (DCM : MeOH = 30 : 1 ) to give 6-amino-5-bromo-N- methylbenzofuran-3-carboxamide (38 g, yield: 71%). ^XH-NMR (400 MHz, DMSO-i¾) δ

02538.19-8.21 (m, 2H), 7.98 (s, 1H), 6.97 (s, 1H), 5.46 (br s, 2H), 2.75 (d, J= 4.4 Hz, 3H).

0254Step 6 - Synthesis of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid <img file="WO2014123795A2_D0018.tif" />

0255To a solution of LDA in THF (62.5 mmol, 70 mL, freshly prepared), 6-amino-5-bromo- N-methylbenzofuran-3-carboxamide (4 g, 14.86 mmol) in THF (60 mL) was added dropwise at - 78 °C under N₂. After the mixture was stirred for 1 hour, trimethyl borate (6.18 g, 59.5 mmol) was added dropwise at -78 °C. After the mixture was stirred for 1 hour, NH₄C1 (a.q.) was added, and the mixture was extracted with EtOAc (100 mLx3), dried over a2S0₄, filtrated and concentrated to give (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (3.3 g, yield: 70%). ^XH-NMR (DMSO-i¾, 400 MHz) δ 9.56 (s, 2H), 8.46 (d, J = 4.8 Hz, 1H), 8.00 (s, 1H), 6.95 (s, 1H), 5.20-5.82 (br s, 2H), 2.87 (d, J = 4.8 Hz, 3H). MS (M+H)⁺: 313 / 315.

0256Step 7 - Synthesis of 6-amino-5-bromo-2-iodo-N-methylbenzofuran-3-carboxamide <img file="WO2014123795A2_D0019.tif" />

0257To a solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (2 g, 6.4 mmol) in MeCN (20 mL) was added NIS (1.44 g, 6.4 mmol) at 0 °C, and then the mixture was stirred at 25 °C overnight. After being concentrated in vacuum, the residue was purified by column chromatography (DCM : EtOAc = 10 : 1) to give to give pure 6-amino-5-bromo-2-iodo- N-methylbenzofuran-3-carboxamide (2 g, yield: 80%). ^XH-NMR (CDC1₃, 400 MHz) δ 7.84 (s, 1H), 6.80 (s, 1H), 6.45 (s, 1H), 2.92 (s, 3H). MS (M+H)⁺: 395 / 397.

0258Step 8 - Synthesis of 5-bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide <img file="WO2014123795A2_D0020.tif" />

0259To a solution of 6-amino-5-bromo-2-iodo-N-methylbenzofuran-3-carboxamide (1 g, 2.53 mmol) in pyridine, MsCl (580 mg, 5.06 mmol) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature and stirred for 1.5 h. After the solvent was removed, the reaction mixture was adjusted to pH = 5-6 with 1 N HC1. After filtration, the solid was dissolved in THF : H₂0 = 5 : 1 (15 mL) and then LiOH-H₂0 (800 mg, 20 mmol) was added. The mixture was stirred for 30 minutes at room temperature. After the solvent was removed, the reaction mixture was adjusted to pH = 5-6 with 1 N HC1. Finally the precipitate was collected to give 5- bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (800 mg, 90% purity by HPLC, yield: 60%), which was used for the next step without further purification. ^XH-NMR (CDC1₃, 400 MHz) δ 8.37 (s, 1H), 7.84 (s, 1H), 6.86 (s, 1H), 6.29 (s, 1H), 3.07 (d, J = 4.8 Hz, 3H), 2.99 (s, 3H). MS (M+H)⁺: 473 / 475.

0260Step 9 - Synthesis of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide

0261<img file="WO2014123795A2_D0021.tif" /> To a suspension of 5-bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (177 mg, 90% purity, 0.34 mmol) and K₂C0₃ (140 mg, 1.01 mmol) in DMF (3 mL) was added dropwise CH₃I (79 mg, 0.68 mol) at 0 °C under N₂, and then the mixture was stirred at 80 °C for 1 hour. After concentrated in vacuum, the residue was suspended in H₂0 and extracted with DCM. The residue was purified by column chromatography (eluted with DCM : EtOAc from 10 : 1 to 2 : 1) to give 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido) benzofuran-3 -carboxamide (150 mg, yield: 90%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.38 (s, 1H), 7.66 (s, 1H), 6.27 (s, 1H), 3.32 (s, 3H), 3.08 (d, J = 4.8 Hz, 3H), 2.89 (s, 3H). MS (M+H)⁺: 487 / 489.

0262Step 10 - Synthesis of 5-bromo-2-(2-methoxypyridin-4-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide

0263<img file="WO2014123795A2_D0022.tif" />

0264To a 2 degassed solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido) benzofuran-3 -carboxamide (300 mg, 0.3 mmol), (2-methoxypyridin-4-yl)boronic acid (94 mg, 0.3 mmol) and K₂C0₃ (195 mg, 0.9 mmol) in DMF (4 mL) was added Pd(dppf)Cl₂ (5 mg) under N₂. The mixture was stirred at 100 °C for 1 h. After the solvent was removed, the residue was purified by prep-TLC (DCM : EtOAc = 5 : 1) to give the product of compound 2 (150 mg, yield: 52%). ¾-NMR (CDCI₃, 400 MHz) δ 8.29 (d, J= 5.6 Hz, 1H), 8.10 (s, 1H), 7.71 (s, 1H), 7.32-7.34 (m, 1H), 7.22 (s, 1H), 5.96 (s, 1H), 3.98 (s, 3H), 3.33 (s, 3H), 3.09 (s, 3H), 3.02 (d, J= 4.8 Hz, 3H). MS (M+H)⁺: 468 / 470.

0265Step 11 - Synthesis of2-(2-methoxypyridin-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5- ( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)benzofuran-3-carboxamide

0266<img file="WO2014123795A2_D0023.tif" />

0267To a ₂ degassed solution of 5-bromo-2-(2-methoxypyridin-4-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.3 mmol), KOAc (94 mg, 0.9 mmol) and bis(pinacolato)diboron (41 1 mg, 1.6 mmol) in dioxane (5 mL) and ¾0 (0.1 mL) was added Pd(dppf)Cl₂ (3 mg) under N₂, and the mixture was stirred at 130 °C for 3 hours. After the solvent was removed, the residue was purified by prep-TLC (DCM : EtOAc = 5 : 1) to give the product of 2-(2-methoxypyridin-4-yl)-N-methyl-6-( -methylmethylsulfonamido)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (120 mg, yield: 72%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.26 (d, J= 5.6 Hz, 1H), 8.20 (s, 1H), 7.59 (s, 1H), 7.38-7.41 (m, 1 H), 7.29 (s, 1H), 6.04 (s, 1H), 3.97 (s, 3H), 3.36 (s, 3H), 3.06 (d, J= 4.8 Hz, 3H), 2.95 (s, 3H), 1.36 (s, 12H). MS (M+H)⁺: 516.

0268Step 12 - Synthesis of tert-butyl 4-fluoro-lH-indole-l-carboxylate <img file="WO2014123795A2_D0024.tif" />

0269To a solution of 4-fluoro-lH-indole (150 g, 1.11 mol) and DMAP (4.5 g, 3%Wt) in THF (2.5 L) was added (Boc)20 (255 g, 1.16 mol) dropwise. The mixture was stirred at room temperature overnight. The organic solvent was removed in vacuum, and the residue was purified by column chromatography (PE) to give tert-butyl 4-fluoro-lH-indole-l-carboxylate (250 g, yield: 96%). ¾-NMR (CDC1₃, 400 MHz) δ 7.92 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 3.6 Hz, 1H), 7.23 (m, 1H), 6.90 (m, 1H), 6.66 (d, J= 3.6 Hz, 1H), 1.67 (s, 9H). MS (M+H)⁺: 236.

0270Step 13 - Synthesis of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid <img file="WO2014123795A2_D0025.tif" />

0271To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0 °C was added n-BuLi (500 mL, 1.25 mol) dropwise. The mixture was stirred at 0 °C for 40 min. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-lH-indole-l-carboxylate (1 18 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at -78 °C for another 40 min. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with NH₄CI (sat. 500 mL). Then the mixture was adjusted to pH = 6 with 1 N HC1. Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na₂S0₄, filtered and concentrated. The obtained solid was recrystallized with EtOAc and PE to give (l-(tert- butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (93 g, yield: 64%, store in fridge). ^XH- NMR (CDCI₃, 400 MHz) δ 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)⁺: 280. Step 14 - Synthesis of 4-fluoro-lH-indol-2-ylboronic acid <img file="WO2014123795A2_D0026.tif" />

0272TFA (60 niL) was added l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-ylboronic acid (10 g, 35.83 mmol) in portions at 0 °C and then the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water, stirred for 10 minutes and filtered through a pad to give the crude 4-fluoro-lH-indol-2-ylboronic acid (6.0 g, yield: 94%) without further purification. ^XH-NMR (DMSO-i/₆, 400 MHz) δ 1 1.09 (s, 1H), 8.35 (br s, 2H), 7.22 (d, J= 8.00 Hz, 1H), 7.02-7.07 (m, 2H), 6.68-6.72 (m, 1H). MS (M+H)⁺: 180.

0273Step 15 - Synthesis of 6-chior -2-iodopyridin-3-oi <img file="WO2014123795A2_D0027.tif" />

02746-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an ₂ atmosphere. a₂C03 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M a₂S₂03 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂S0₄ and concentrated to give the product of 6-chloro-2-iodopyridin-3- ol (7.0 g, yield: 70.9%). ^XH-NMR (CDC1₃, 400 MHz) δ 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H). MS (M+H)⁺: 256 / 258.

0275Step 16 - Synthesis of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol

0276<img file="WO2014123795A2_D0028.tif" />

0277A mixture of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (5 g, 18.0 mmol), 6-chloro-2-iodopyridin-3-ol (3.82 g, 15.0 mol) and NaHC0₃ (3.78 g, 45.0 mol) in 1, 4- dioxane (76 mL) and water (7 mL) was stirred at room temperature for 15 min. Then

0278Pd(PPh₃)₂Cl₂ (527 mg, 0.75 mmol) was added under nitrogen atmosphere, and the mixture was heated at 100 °C under N₂ for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered and concentrated. The residue was diluted with H₂0 (60 mL) and EtOAc (30 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*30 niL). The combined organic layers were washed with brine (50 mL), dried over a₂S0₄, filtered and concentrated. The residue was purified by column chromatography (PE / EtOAc = 20 / 1 ~ 3 / 1) to give 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (3 g, yield: 76.5%). ^XH-NMR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23-7.27 (m, 2H), 7.03-7.11 (m, 2H), 6.63-6.68 (m, 1H). MS (M+H)⁺: 263 / 265.

0279Step 17 - Synthesis of -chloro-ll-fluoro- -pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole <img file="WO2014123795A2_D0029.tif" />

0280A solution of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (2 g, 7.6 mmol) and Cs₂C0₃ (7.46 g, 22.89 mmol) in DMF (100 mL) was stirred at 100 °C (internal temperature) for 15 min, and then chloroiodomethane (2.85 g, 15.3 mmol) in DMF (2 mL) was added dropwise. After the reaction was completed, the mixture was filtered and concentrated. The residue was diluted with water (50 mL) and extracted with EA (30 mL*3). The organic layer was washed with brine, dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography (PE:EA=10: 1) to afford 2-chloro- 11 -fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (1.8 g, yield: 86.1%). ¾-NMR (DMSO-ifc, 400 MHz) δ 7.64 (d, J= 8.8 Hz, 1H), 7.39-7.46 (m, 2H), 7.21-7.25 (m, 1H), 7.06 (s, 1H), 6.88-6.92 (m, 1H), 6.18 (s, 2H). MS (M+H)⁺: 275 / 277.

0281methoxypyridin-4-yl)-N-methyl-6-(N-methylmethylsulfonam

0282(Example 1)

0283<img file="WO2014123795A2_D0030.tif" />

0284To a degassed solution of 2-(2-methoxypyridin-4-yl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (60 mg, 0.12 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- ajindole (35 mg, 0.13 mmol) and a₂C03 (25 mg, 0.23 mmol) in dioxane (1.5 mL) and H₂0 (0.1 niL) was added Pd2(dba)₃ (3 mg) and X-Phos (3 mg) under N₂. Then the mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H₂0 and dried over Na₂S0₄. After concentrated, the residue was purified by prep-HPLC to give the product of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(2- methoxypyridin-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3 -carboxamide (35 mg, yield: 48%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.29 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.69 (s, 2H), 7.40-7.49 (m, 1H), 7.30 (s, 1H), 7.19-7.24 (m, 2H), 7.10-7.18 (m, 1H), 6.82-6.87 (m, 1H), 6.11 (s, 1H), 5.99 (s, 2H), 3.99 (s, 3H), 3.36 (s, 3H), 3.04 (d, J = 4.8 Hz, 3H), 2.75 (s, 3H). MS (M+H)⁺: 628.

0285Examples 2 -16

0286Examples 2-16, depicted in the table below, were prepared in accordance with the method described in Example 1.

0287<img file="WO2014123795A2_D0031.tif" />

0288<img file="WO2014123795A2_D0032.tif" /><img file="WO2014123795A2_D0033.tif" />

0289<img file="WO2014123795A2_D0034.tif" /> Ή-NMR (CDCI₃, 400 MHz) δ 8.31

0290(s, 1H), 7.71 (s, 1H), 7.51 (s, 2H),

02917.20-7.23 (m, 2H), 7.13 (d, J = 8.4

0292Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H),

02936.56 (s, 1H), 6.02 (s, 2H), 5.95 (br s,

02941H), 3.98 (s, 3H), 3.41 (s, 3H), 2.96

0295<img file="WO2014123795A2_D0035.tif" />

0296(d, J = 4.8 Hz, 3H), 2.71 (s, 3H),

02972.37 (s, 3H).

0298Example 17; 5-(ll-nuoro-6H-pyrido[2',3';5,61[l,31oxazino[3,4-alindol-2-vn-2-(2- hvdroxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

0299<img file="WO2014123795A2_D0036.tif" />

0300Step 1 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3 ':5, 6] ^' [ 1,31 oxazino[3 A-alindol-2-yl)-2-(2- hydroxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)ben^

0301<img file="WO2014123795A2_D0037.tif" />

0302A mixture of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2- (2-methoxypyridin-3-yl)-N-methyl-6-(TSi-methylmethylsulfonamido)benzofuran-3-carboxamide (45 mg, 0.07 mmol) and Nal (54 mg, 0.36 mmol) in HO Ac (1 mL) was stirred at 100 °C under 2 for 5 h. After the reaction, it was extracted with EtOAc (10 mL x3) and a₂C03 (a.q., 5mL). The organic layer was washed with brine (5 mL x3), dried over aq. Na₂S0₄ and concentrated. The residue was purified by prep-HPLC to give 5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(2-hydroxypyridin-3-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (10 mg, yield: 23%). ^XH-NMR (CDCI₃, 400 MHz) δ 8.20 (s, 1H), 8.1 1 (s, 1H), 7.97 (d, J= 5.2 Hz, 1H), 7.96 (s, 1H), 7.66 (d, J= 1.2 Hz, 1H), 7.55 (m, 2H), 7.23 (s, 2H), 7.14 (d, J= 8.4 Hz, 1H), 6.85 (s, 1H), 6.60 (t, J= 6.8 Hz, 1H), 6.01 (s, 2H), 5.30 (s, 1H), 3.41 (s, 3H), 2.96 (d, J= 4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)⁺: 614. Example 18; 5-(ll-nuoro-6H-pyrido[2',3';5,6Ul,31oxazino[3,4-alindol-2-vn-2-(2- methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide

0303<img file="WO2014123795A2_D0038.tif" />

0304Step 1 - Synthesis of 5-( Ί l-fluoro-6H-pyrido [2',3 ': 5 6] ^' 17,3/ 'oxazino[3 ,4-ai^' 'indol-2-yl)-N-methyl- 6-fN-methyimethyisuifonamido)-2-f2-oxo-l -dihydropyridin-4-yi)benzo

0305<img file="WO2014123795A2_D0039.tif" />

0306To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(2-methoxypyridin-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (30 mg, 0.05 mmol) in HOAc (1 mL) was added HBr-HOAc (1 mL) at 0 °C. Then the mixture was stirred at 80 °C for 2 hours. The solvent was removed by vacuum and aHC03 (a.q.) was added. The mixture was extracted with DCM, and the organic phase was dried over Na₂S0₄. After concentrated in vacuo, the residue was purified by prep-HPLC to give the product of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)-2-(2-oxo- 1 ,2-dihydropyridin-4-yl)benzofuran-3-carboxamide (15 mg, yield: 52%). ^XH-NMR (DMSO-i¾, 400 MHz) δ 8.73-8.75 (m, 1H), 8.1 1 (s, 1H), 7.85 (s, 1H), 7.73 (q, J = 8.8 Hz, 1H), 7.59-7.62 (m, 2H), 7.51-7.61 (m, 2H), 7.25-7.27 (m, 1H), 7.1 1 (s, 1H), 6.88-6.96 (m, 1H), 6.65 (d, J = 2.8 Hz, 1H), 6.27 (s, 2H), 3.31 (s, 3H), 2.97 (s, 3H), 2.85 (d, J = 4.0 Hz, 3H). MS (M+H)⁺: 614.

0307Step 2 - Synthesis of 5-(ll-fluoro-6H-pyridof2',3 ':5, 61 fl,31oxazinof3,4- lindol-2-yl)-2-(2- methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofura

0308<img file="WO2014123795A2_D0040.tif" />

0309To a suspension of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2- yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(2-oxo-l,2-dihydropyridin-4-yl)benzofuran-3- carboxamide (20 mg, 0.03 mmol) and K2CO₃ (10 mg, 0.06 mmol) in DMF (1 niL) was added CH₃I (5 mg, 0.03 mol) at 0 °C under N₂, and then the mixture was stirred for 12 hours at room temperature. After being concentrated in vacuo, the resulting residue was suspended in H₂0 and extracted with DCM. The combined organic layer was washed with H₂O and dried over a₂S0₄. After concentration, the residue was purified by prep-HP LC to give the product of 5-(l 1-fluoro- 6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-2-(l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-( -methylmethylsulfonamido)benzofuran-3 -carboxamide (10 mg, yield: 49%). ¾-NMR (DMSO-i¾, 400 MHz) δ 8.72-8.74 (m, 1H), 8.10 (s, 1H), 7.84-7.86 (m, 2H), 7.70-7.72 (m, 1H), 7.59-7.62 (m, 1H), 7.50-7.53 (m, 1H), 7.24-7.28 (m, 1H), 7.23 (s, 1H), 6.96-7.09 (m, 2H), 6.67-6.91 (m, 1H), 6.27 (s, 2H), 3.48 (s, 3H), 3.31 (s, 3H), 2.97 (s, 3H), 2.85 (d, J = 4.4 Hz, 3H). MS (M+H)⁺: 628.

0310Examples 19 and 20

0311<img file="WO2014123795A2_D0041.tif" />

031219 20

0313Step 1 - Synthesis of methyl 3-hydroxypicolinate <img file="WO2014123795A2_D0042.tif" />

0314A solution of 3-hydroxypicolinic acid (30 g, 0.22 mol) in CH₃OH (300 mL) was stirred at RT and cone. H₂S0₄ (30 mL) was added dropwise. The resulting mixture was stirred at 80 °C overnight. After the pH was adjusted to 7 with solid a₂C0₃, the mixture was filtrated and the precipitate was thoroughly washed with EtOAc several times. The filtrate was concentrated to give crude methyl 3-hydroxypicolinate (27 g, yield: 82.8 %). ^XH-NMR (CDCI_3, 400 MHz) δ 10.57 (s, 1H), 8.22-8.20 (m, 1H), 7.32-7.29 (m, 1H), 3.93 (s, 3H). MS (M+H)⁺: 154.

0315Step 2 - Synthesis of methyl 6-bromo-3-hydroxypicolinate <img file="WO2014123795A2_D0043.tif" /> A solution of methyl 3-hydroxypicolinate (5 g, 32.65 mmol) in 60 mL of Ι¾0 was stirred at RT and Br₂ (5.22 g, 32.65 mmol) was added dropwise. The mixture was stirred at RT overnight, and the resulting solid was collected and washed with water to afford methyl 6- bromo-3-hydroxypicolinate. Then the filtrate was basified with a₂C0₃ until pH reached 7, and after extracted with EtOAc, the organic layer was concentrated to give the 2^nd part of methyl 6- bromo-3-hydroxypicolinate (6.1 g total, yield: 80.7%). ^XH-NMR (CDC1₃ , 400 MHz) δ 10.67 (s, 1H), 7.54 (t, J= 8.0 Hz, 1H), 7.24 (d, J= 4.0 Hz, 1H), 4.02 (s, 3H). MS (M+H)⁺: 232 / 234. Step 3 - Synthesis of methyl -bromo-3-methoxypicolinate <img file="WO2014123795A2_D0044.tif" />

0316A mixture of methyl 6-bromo-3-hydroxypicolinate (4 g, 17.2 mmol), CH₃I (7.15 g, 34.5 mmol) and K2CO₃ (4.76 g, 34.5 mmol) in DMF (50 mL) was stirred at RT for 3 hours. After concentrated, the mixture was diluted with ¾0 and extracted with EtOAc (50 mL * 3). The organic layer was dried over a₂S0₄ and concentrated to give crude methyl 6-bromo-3- methoxypicolinate (4 g, yield: 90%). ¾-NMR (CDC1₃ , 400 MHz) δ 7.56 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)⁺: 256 / 258.

0317Step 4 - Synthesis of 6-bromo- -methoxypicoiinic acid <img file="WO2014123795A2_D0045.tif" />

0318A mixture of methyl 6-bromo-3-methoxypicolinate (4 g, 18.4 mmol) and LiOH-

0319H2O (1.6 g, 36.9 mmol) in dioxane / ¾0 (5 / 1, 40 mL) was stirred at RT overnight. After pH was adjusted to 7, the mixture was filtered to provide crude 6-bromo-3-methoxypicolinic acid (3.1 g, yield: 81 %). ¾-NMR (CDC1₃ , 400 MHz) δ 10.71 (m, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 4.01 (s, 3H). MS (M+H)⁺: 232 / 234.

0320Step 5 - Synthesis of 2-(6-bromo-3-methoxypyridin-2-yl)-4-fluoro-lH-benzofdl imidazole and 6-

0321<img file="WO2014123795A2_D0046.tif" /> A mixture of 6-bromo-3-methoxypicolinic acid (1.84 g, 7.93 mmol) and 3- fluorobenzene-l,2-diamine (1.0 g, 7.93 mmol) was stirred in PPA (3 mL) on a pre-heated oil- bath at 120 °C for 14 h. The mixture was poured to ice-water and basified to pH = 8 with a₂C0₃. Then the mixture was filtrated to collect the brown solid as 6-bromo-2-(4-fluoro-lH- benzo[d]imidazol-2-yl)pyridin-3-ol (900 mg, yield: 37%). The filtrated was extracted with ethyl acetate, and the organic layer was washed with brine and dried over a₂S0₄. After concentrated, the residue was purified by column chromatography to give the product of 2-(6-bromo-3- methoxypyridin-2-yl)-4-fluoro-lH-benzo[d]imidazole (350 mg, yield: 14%). ^XH-NMR (CDC1₃, 400 MHz) δ 10.43-10.56 (m, 1H), 7.46 (d, J= 8.8 Hz, 1H), 7.33 (d, J= 8.8 Hz, 1H), 7.21-7.30 (m, 2H), 6.90-6.98 (m, 1H), 4.05 (s, 3H). MS (M+H) : 322 / 324.

0322<img file="WO2014123795A2_D0047.tif" />

0323To a solution of 2-(6-bromo-3-methoxypyridin-2-yl)-4-fluoro-lH- benzo[d]imidazole (350 mg, 1.12 mmol) in DMF (10 mL) was added LiCl (650 mg, 15.5 mmol) under ₂ protection. The mixture was stirred on a pre-heated oil-bath at 100 °C overnight. After extracted with EtOAc, the organic phase was dried over a2S0₄ and concentrated. The residue was purified by prep-TLC (PE: EA = 5: 1) to give the product of 6-bromo-2-(4-fluoro-lH- benzo[d]imidazol-2-yl)pyridin-3-ol (200 mg, yield: 60%). ^XH-NMR (DMSO-i¾, 400 MHz) δ 13.75 (s, 1H), 12.70 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 7.12 (s, 1H). MS (M+H)⁺: 308 / 310.

0324Step 7 - Synthesis of 2-bromo-ll-fluoro-6H-benzo[4,5]imidazo[l,2-c]pyrido[2,3-e] ' [l,3]oxazine and 2-bromo- -fluoro-6H-benzof 4, 51imidazof 1, 2-clpyridof2, 3-eJf UJoxazine

0325<img file="WO2014123795A2_D0048.tif" />

0326To a mixture of compound 7 (540 mg, 1.75 mmol) and CS2CO₃ (1.15 g, 3.50 mmol) in DMF (27 mL) was added chloroiodomethane (0.14 mL) in DMF (5.4 mL) under ₂ protection. The mixture was stirred at 90 °C overnight, and after concentrated, the mixture was diluted with water and extract with EtOAc. The organic layer was dried over a₂S0₄ and concentrated, the resulting yellow solid was obtained as a mixture of 2-bromo- 11 -fluoro-6H- benzo[4,5]imidazo[l,2-c]pyrido[2,3-e][l,3]oxazine and 2-bromo-8-fluoro-6H- benzo[4,5]imidazo[l,2-c]pyrido[2,3-e][l,3]oxazine (360 mg total, ~1 : 1, yield: -35% each), which couldn't be separated with column and was used for the next step without further purification. A sample of pure 2-bromo-8-fluoro-6H-benzo[4,5]imidazo[l,2-c]pyrido[2,3- e][l,3]oxazine was obtained by prep-TLC and identified with 2D NMR. ^XH-NMR (DMSO-fifc, 400 MHz) δ 7.73 (d, J= 8.8 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.31-7.36 (m, 1H), 7.10-7.15 (m, 1H), 6.37 (s, 2H). MS (M+H)⁺: 320 / 322.

0327Step 8 - Synthesis of 5-(8-fluoro-6H-benzo[4,5Jimidazo[l,2-cJpyrido[2,3-eJ[l,3Joxazin-2-yl)-2- (6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)be

0328(Example 19) and 5-(ll-fluoro-6H-benzof4,51imidazofl,2-clpyridof2,3-el fl,31oxazin-2-yl)-2- (6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Example 2

0329<img file="WO2014123795A2_D0049.tif" />

033019 20

0331a stirring mixture of 2-(6-methoxypyridin-3-yl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (160 mg, 0.32 mmol), 2-bromo-l l-fluoro-6H-benzo[4,5]imidazo[l,2-c]pyrido[2,3- e][l,3]oxazine and 2-bromo-8-fluoro-6H-benzo[4,5]imidazo[l,2-c]pyrido[2,3-e][l,3]oxazine (100 mg, -1 : 1 mixture, 0.32 mmol total) and K2CO₃ (86 mg, 0.64 mmol) in dioxane/H₂0 (2.0 mL / 0.2 mL) was added Pd(dppf)Cl₂ (32 mg) under ₂ protection. The mixture was stirred at 90 °C for 10 h. The mixture was concentrated and the residue was extract with EtOAc. The residue was washed with H₂0, brine, dried over Na₂S0₄. After being concentrated, the crude product was purified by prep-HPLC to give two individual regio-isomers.

03325-(8-fluoro-6H-benzo[4,5]imidazo[l,2-c]pyrido[2,3-e][l,3]oxazin-2-yl)-2-(6- methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3 -carboxamide (80 mg, yield: 70%, based on the content of corresponding bromide). 1H-NMR (CDCI₃, 400 MHz) δ 8.76 (d, J= 2.4 Hz, 1H), 8.22 (d, J= 8.8 Hz, 1H), 8.03 (s, 1H), 7.77 (d, J= 4.8 Hz, 1H), 7.56-7.63 (m, 3H), 7.20-7.23 (m, 1H), 7.03-7.07 (m, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.41 (s, 1H), 6.30 (s, 2H), 4.00 (s, 3H), 3.20 (s, 3H), 3.02 (d, J= 5.2 Hz, 3H), 2.97 (s, 3H). MS (M+H)⁺: 629.

03335-(l l-fluoro-6H-benzo[4,5]imidazo[l,2-c]pyrido[2,3-e][l,3]oxazin-2-yl)-2-(6- methoxypyridin-3 -yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3 -carboxamide (70 mg, yield: 65%, based on the content of corresponding bromide). ^XH-NMR (CDCI₃, 400 MHz) δ 8.70 (d, J= 2.4 Hz, 1H), 8.16-8.19 (m, 1H), 7.99 (s, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.23-7.26 (m, 1H), 7.10 (d, J= 8.0 Hz, 1H), 6.93-6.97 (m, 1H), 6.77 (d, J= 8.8 Hz, 1H), 6.59 (s, 1H), 6.08 (s, 2H), 3.94 (s, 3H), 3.14 (s, 3H), 2.99 (d, J= 4.8 Hz, 3H), 2.95 (s, 3H). MS (M+H)⁺: 629.

0334Example 21 ; (S or R)-5- il-fluoro-6- hvdroxymethyl)-6H-pyrido[2',3';5,6Ul,31oxazino[3,4- alindol-2-yl)-2- 6-methoxypyridin-3-yl)-N-methyl-6- N-methylmethylsulfonamido) benzofuran-3-carboxamide

0335<img file="WO2014123795A2_D0050.tif" />

0336A mixture of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (10 g, 38 mmol) and metal Sn (23 g, 190 mmol) in CH₃CH₂OH / concentrated HC1 (60 mL / 40 mL) was stirred under reflux for 3 h. The mixture was cooled to room temperature and adjusted to pH = 7 by saturated NaOH and filtered though a Celite pad. The filtrate was extracted with EtOAc, washed by brine, dried over Na₂S0₄ and concentrated. The residue was purified by silica gel chromatography (PE : EtOAc = 10 : 1 ) to get 6-chloro-2-(4-fluoroindolin-2-yl) pyridin-3-ol (8 g, yield: 80%). ¾-NMR (CDC1₃, 400 MHz) δ 9.86 (s, 1H), 7.10-7.20 (m, 3H), 6.33-6.91 (m, 2H), 5.15-5.21 (m, 1H), 4.61 (s, 1H), 3.65-3.71 (m, 1H), 3.04-3.11 (m, 1H). MS (M+H)⁺: 265. Step 2 - Synthesis of ethyl 2-chloro-ll-fluoro-12J2a-dihvdro-6H- pyrido[2',3':5, 6] [1 ,3] oxazino[3,4-a] indole-6-carboxylate

0337<img file="WO2014123795A2_D0051.tif" />

0338To a solution of 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8.53 g, 32.31 mmol) and glyoxylic acid ethyl ester (6.59 g, 64.59 mmol) in THF (80 mL), MsOH (0.3 lg, 3.23mmol) was added. The mixture was stirred at 50 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (30 mL), dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography (PE : EtOAc = 10 : 1) to afford ethyl 2-chloro-l l-fluoro-12,12a-dihydro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole -6-carboxylate (10.2 g, yield: 90.3%). ^XH-NMR (CDC1₃, 400 MHz) δ 7.04-7.13 (m, 3H), 6.63 (d, J= 8.0Hz, 1H), 6.55 (t, J= 8.4Hz, 1H), 6.03 (s, 1H), 5.09 (d, J= 8.8Hz, 1H), 4.22-4.34 (m, 2H), 3.73 (d, J= 16.4Hz, 1H), 3.44-3.51 (m, 1H), 1.29 (d, J= 7.2Hz, 3H). MS (M+H)⁺: 349.

0339Step 3 - Synthesis of ethyl 2-chloro-ll-fluoro-6H-pyrido[2',3':5,6] ^' [l,3]oxazino[3,4-a]indole-6- carboxylate

0340<img file="WO2014123795A2_D0052.tif" />

0341To a solution of ethyl 2-chloro- 11 -fluoro- 12, 12a-dihydro-6H-pyrido

0342[2',3':5,6][l,3]oxazino[3,4-a]indole-6-carboxylate (10.22 g, 29.36 mmol) and DDQ (8.67 g, 38.17 mmol) in toluene (80 mL) was stirred at 80 °C for 2 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mL* 3). The organic layer was washed with brine (30 mL), dried over a2S0₄ and concentrated. The residue was purified by column chromatography (PE : EtOAc = 20 : 1) to afford ethyl 2-chloro- 11 -fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole- 6-carboxylate (8.64 g, yield: 85%), which was also prepared from 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol and methyl 2,2-dibromoacetate in the presence of base, such as DBU etc. ^XH-NMR (CDC1_3, 400 MHz) δ 7.33 (d, J= 8.4 Hz, 1H), 7.30 (s, 1H), 7.09-7.18 (m, 3H), 6.78-6.83 (m, 1H), 6.52 (s, 1H), 3.96-4.09 (m, 2H), 1.02 (t, J= 7.2 Hz, 3H). MS (M+H)⁺: 347.

0343Step 4 - Synthesis of (2-chloro-l l-fluoro-6H-pyrido[2', 3 ': 5, 6] ' [l,3]oxazino [3,4-a]indol-6- vDmethanol

0344<img file="WO2014123795A2_D0053.tif" />

0345(Enantiomer 1, peak 1 on SFC, or S) (Enantiomer 2, peak 2 on SFC, S or R) To a solution of ethyl 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4- a]indole-6-carboxylate (3 g, 8.73 mmol) and NaBH₄ (1.58 g, 43.67 mmol) in CH₃OH /DCM (30 mL / 10 mL) was stirred at room temperature for 2 hours. The mixture was poured to ¾0 and extracted with ethyl acetate. The organic layer was washed with brine, dried over a2S0₄ and concentrated in vacuum to give (2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-6-yl) methanol (2.54 g, yield: 95.5%).

0346The product was purified by SFC to give two single enantiomers.

0347(R or 5)-(2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6- yl)methanol (enantiomer 1, peak 1 on SFC, AD-3_5_5_40_2,4ML, HPLC_RT= 1.522 min).

0348(5^, or R)-(2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6- yl)methanol (enantiomer 1, peak 2 on SFC, AD-3_5_5_40_2,4ML, HPLC_RT= 1.731 min). Step 5 - Synthesis of (S or R)-5-(ll-fluoro-6-(hvdroxymethyl)-6H- pyridof2',3 ':5, 61 'fl ,3) Oxazino[3,4-ai ¹indol-2-yl)-2-(6-methoxypyridin-3-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide

0349<img file="WO2014123795A2_D0054.tif" />

0350To a solution of (S or R)-(2-chloro- 11 -fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6-yl)methanol (35 mg, 0.1 15 mmol), 2-(6- methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzofuran-3-carboxamide (50 mg, 0.097 mmol) and sodium carbonate (20 mg, 0.188 mmol) in 2 mL of 1,4-dioxane and 0.2 mL of water was added Pd₂(dba)₃ (10 mg) and X-Phos (10 mg) under nitrogen. The reaction mixture was heated at 70 °C for 16 hours and concentrated in vacuo to remove 1,4-dioxane. And then the residue was suspended in water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂S0₄ and concentrated. The residue was purified by prep-HPLC to give the product of (S or R)-5-(l 1- fluoro-6-(hydroxymethyl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(6- methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 47%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.72 (d, J= 2.4 Hz, 1H), 8.14-8.17 (m, 1H), 7.99 (s, 1H), 7.64 (s, 1H), 7.43-7.48 (m, 2H), 7.14-7.23 (m, 3H), 6.81-6.86 (m, 2H), 6.42-6.45 (m , 1H), 6.06 (brs, 1H), 4.01 (s, 3H), 3.98-4.00 (m, 1H), 3.85-3.88 (m, 1H), 3.37 (s, 3H), 2.96 (d, J= 4.8 Hz, 3H), 2.72 (s, 3H), 2.27 (s, 1H). MS (M+H)⁺: 658.

0351Examples 22 - 24

0352Examples 22-24, depicted in the table below, were prepared in accordance with the method described in Example 21. <img file="WO2014123795A2_D0055.tif" /><img file="WO2014123795A2_D0056.tif" />

0353Examples 25 and 26 <img file="WO2014123795A2_D0057.tif" />

0354Step 1 - Synthesis of 5-( Ί l-fluoro-6H-pyrido [2',3 ': 5 ,61 I 1,3) 'oxazino[3 ,4-ai^{' ,}indol-2-yl)-N-methyl- 6-(N-methylmethylsulfonamido)-2-(6-oxo-l,6-dihydropyridin-3-yl)benzofuran-3-carboxamide

0355<img file="WO2014123795A2_D0058.tif" />

0356To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-

03572-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (40 mg, 0.64 mmol) in HOAc (4 mL) was added HBr-HOAc (4 ml) at 0 °C. Then the mixture was stirred at 80 °C for 2 hours. After the solvent was removed by vacuum, the residue was washed with a₂C0₃ (a.q.), extracted with DCM, dried over Na₂S0₄, filtrated and concentrated in vacuo. The residue was purified by prep-HPLC to give the product 5-(l 1-fluoro- 6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(TSi-methylmethylsulfonamido)-2- (6-oxo-l, 6-dihydropyridin-3-yl)benzofuran-3 -carboxamide (20 mg, yield: 50%). ^- MR (MeOD, 400 MHz) δ 8.33 (s, IH), 7.96 (q, J =9.6 Hz, IH), 7.84 (s, IH), 7.88 (s, IH), 7.55 (d, J =9.6 Hz, 2H), 7.28 (d, J = 9.6 Hz, IH), 7.15-7.21 (m, 2H), 6.87 (q, J =9.6 Hz, IH), 6.53 (t, J =9.6 Hz, IH), 6.06 (s, 2H), , 3.31 (s, 3H), 2.95 (d, J =9.6 Hz, 3H), 2.85 (s, 3H). MS (M+H)⁺: 614.

0358Step 2 - Synthesis of 2-(6-(difluoromethoxy)pyridin-3-yl)-5-(ll-fluoro-6H- pyridof2',3 ':5, 61 fl ,31 oxazinof3,4-al indol-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 25) &amp; 2-(l-(difluoromethyl)- 6-oxo-l, 6-dihydropyridin-3-yl)-5-(ll-fluoro-6H-pyridof2 ', 3 ':5, 61[l,31oxazino[3,4-alindol-2-yl)- N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide ( Compound 26)

0359<img file="WO2014123795A2_D0059.tif" />

036025 26

0361To a suspension of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2- yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(6-oxo- 1 ,6-dihydropyridin-3 -yl)benzofuran-3- carboxamide (40 mg, 0.06 mmol) in MeCN (5 mL) was added F₂ClCCOONa (20 mg, 0.13 mol) under N₂, and then the mixture was stirred at 100 °C for 12 hours. After concentrated in vacuo, the resulting residue was suspended in H₂0 and extracted with DCM. The combined organic layer was washed with H₂0, brine, dried over Na₂S0₄, filtrated and concentrated in vacuo. The residue was purified by prep-HP LC to give the product of 2-(6-(difluoromethoxy)pyridin-3-yl)- 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide and 2-(l-(difluoromethyl)-6-oxo-l,6- dihydropyridin-3-yl)-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl- 6-( -methylmethylsulfonamido)benzofuran-3-carboxamide.

03622-(6-(difluoromethoxy)pyridin-3-yl)-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol- 2-yl)-N-methyl-6-( -methylmethylsulfonamido)benzofuran-3 -carboxamide (20 mg, yield: 47%). ¾-NMR (CDC1₃, 400 MHz) δ 8.84 (d, J= 2.0 Hz, 1H), 8.43-8.47 (m, 1H), 7.96 (s, 1H), 7.73 (s, 0.25H), 7.69 (s, 1H), 7.55 (s, 0.5H), 7.50-7.52 (m, 2H), 7.37 (s, 0.25H), 7.20-7.24 (m, 2H), 7.13 (d, J= 4.4 Hz, 1H), 7.04 (d, J= 4.2 Hz, 1H), 6.84-6.87 (m, 1H), 6.07 (s, 1H), 5.99 (s, 2H), 3.35 (s, 3H), 3.05 (d, J = 4.8 Hz, 3H), 2.78 (s, 3H). MS (M+H)⁺: 664.

03632-( 1 -(difluoromethyl)-6-oxo- 1 ,6-dihydropyridin-3 -yl)-5-( 11 -fluoro-6H- pyrido[2',3 ': 5 ,6] [1,3] oxazino [3 ,4-a] indol-2-yl)-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (10 mg, yield: 23%). ^XH-NMR (CDCI₃, 400 MHz) δ 8.67 (d, J = 2.0 Hz, 1H), 8.12-8.15 (m, 1H), 7.92 (s, 1H), 7.76 (s, 0.25H), 7.69 (s, 0.5H), 7.61 (s, 0.25H), 7.51-7.53 (m, 2H), 7.50 (s, 1H), 7.21-7.24 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.84-6.89 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 6.02 (s, 2H), 3.35 (s, 3H), 3.08 (d, J = 4.8 Hz, 3H), 2.81 (s, 3H). MS (M+H)⁺: 664.

0364Example 27; 5-(ll-nuoro-6H-pyrido[2',3';5,61 [l,31oxazino[3,4-alindol-2-vn-2-(6-(4- fluorophenoxy)pyridin-3-yl)-N-methyl-6- N-methylmethylsulfonamido)benzofuran-3- carboxamide

0365<img file="WO2014123795A2_D0060.tif" />

0366Step 1 - Synthesis of 6-amino-5-bromo-2- 6-fluoropyridin-3-yl)-N-methylbenzofuran-3- carboxamide <img file="WO2014123795A2_D0061.tif" />

0367To a solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (500 mg, 1.61 mmol) in dioxane/H₂0 (5 mL / 0.5 mL) was added 5-bromo-2-fluoropyridine (420 mg, 2.42 mmol), Pd(dppf)Cl₂ (10 mg) and Κ₃Ρ0₄·3Η₂0 (855 mg, 3.21 mmol). The mixture was stirred at 50 °C for 10 h. The mixture was evaporated and washed with MeOH to obtain the yellow solid as the product of 6-amino-5-bromo-2-(6-fluoropyridin-3-yl)-N-methylbenzofuran-3- carboxamide (300 mg, yield: S l^o^H- MR (DMSO-d6, 400 MHz) δ 8.76 (s, 1H), 8.44-8.51 (m, 2H), 7.75 (s, 1H), 7.39-7.42 (m, 1H), 7.09 (s, 1H), 5.71 (s, 2H), 2.88 (d, J= 8.4 Hz, 3H). (M+H)⁺: 364 / 366.

0368Step 2 - Synthesis of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methylbenzofuran- 3-carboxamide

0369<img file="WO2014123795A2_D0062.tif" />

0370To a degassed solution of 6-amino-5-bromo-2-(6-fluoropyridin-3-yl)-N- methylbenzofuran-3-carboxamide (500 mg, 1.41 mmol) and 4-fluorophenol (460 mg, 5.21 mmol) in DMF/THF (1 mL/7 mL) was added K₂C0₃ (260 mg, 5.62 mmol) under N₂. The mixture was heated at 90 °C for 8 h. The reaction mixture was concentrated in vacuo and it was extracted with EtOAc. It was washed with H₂0, brine and dried over Na₂S0₄. After being concentrated, the residue was purified by column chromatography (PE : EA = 4 : 1) to give the product of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methylbenzofuran-3- carboxamide (380 mg, yield: 61%). ^χΗ-ΝΜΡν (CDC1₃, 400 MHz) δ 8.61 (d, J= 2.4 Hz, 1H), 8.23-8.25 (m, 1H), 7.74 (s, 1H), 7.02-7.09 (m, 4H), 6.91 (d, J= 8.8 Hz, 1H), 8.85 (d, J= 4.8 Hz, 1H), 5.76 (s, 1H), 4.20 (s, 2H), 2.95 (d, J= 5.2 Hz, 3H). (M+H)⁺: 456 / 458.

0371Step 3 - Synthesis of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide

0372<img file="WO2014123795A2_D0063.tif" />

0373To a degassed solution of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)- N-methylbenzofuran-3-carboxamide (100 mg, 0.22 mmol) and DMAP (10 mg, 0.02 mmol) in Pyridine (5 ml) under N₂ was added MsCI (32 mg, 0.38 mmol) at 0 °C. Then it was stirred at 20 °C for 15 h. The reaction mixture was concentrated and extracted with DCM. After it was washed with brine, dried over Na₂S0₄ and concentrated, the residue was purified by prep-TLC to give 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(methylsulfonamido)benzofuran- 3-carboxamide (100 mg, yield: SS^o^H- MR (CDC1₃, 400 MHz) δ 9.65 (s, 1H), 8.73 (s, 1H), 8.54 (d, J= 4.8 Hz, 1H), 8.39 (d, J= 2.8 Hz, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.33-7.38 (m, 4H), 7.28 (d, J= 8.8 Hz, 1H). (M+H)⁺: 534 / 536.

0374Step 4 - Synthesis of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide

0375<img file="WO2014123795A2_D0064.tif" />

0376To a degassed solution of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N- methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.187 mmol) and K₂C0₃ (53 mg, 0.374 mmol) in DMSO (2mL) was added Mel (27 mg, 0.187 mmol) under N₂. The mixture was heated at 20 °C for 2 h. The reaction mixture was diluted with Η₂0 and extracted with EtOAc. It was washed with H₂0, brine and dried over Na₂S0₄. After concentrated, the residue was purified by column chromatography (PE : EA = 2 : 1) to give the product of 5-bromo-2-(6- (4-fluorophenoxy)pyridin-3 -yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3 - carboxamide (20 mg, yield: 20%).¹H-NMR (CDC1₃, 400 MHz) δ 8.63 (d, J= 2.8 Hz, 1H), 8.21-8.24 (m, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.06-7.08 (m, 3H), 6.98 (d, J= 8.8 Hz, 1H), 5.77 (d, J= 8.8 Hz, 1H), 3.27 (s, 3H), 3.03 (s, 3H), 2.96 (d, J= 4.8 Hz, 3H). MS (M+H)⁺: 548 / 550. Step 5 - Synthesis of2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide

0377<img file="WO2014123795A2_D0065.tif" />

0378To a degassed solution of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N- methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.09 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (115 mg, 0.46 mmol) in 1, 4-dioxane (1 mL) was added Pd(dppf)Cl₂ (10 mg) and KOAc (27 mg, 0.27 mmol) under N₂. The mixture was heated at a pre-heated oil-bath at 100 °C for 3 h. The reaction mixture was concentrated in vacuo and it was extracted with EtOAc. The residue was washed with H₂0, brine and dried over Na₂S0₄. After being concentrated, the crude product was purified by prep-TLC (PE : EA = 1 : 1) to give 2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6- (N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (20 mg, yield: 37%). MS (M+H)⁺: 596.

0379Step 6 - Synthesis of 5-(l l-fluoro-6H-pyridof2',3 ':5 , 61 ' fl ,31oxazino[3 ,4-alindol-2-yl)-2-(6-(4- fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (Compound 27)

0380<img file="WO2014123795A2_D0066.tif" />

0381To a stirring mixture of 2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (50 mg, 0.09 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (28 mg, 0.10 mmol) and a₂C0₃ (18 mg, 0.17 mmol) in dioxane (0.8 mL) was added X- Phos (5 mg) and Pd2(dba)₃ (5 mg) under 2 protection. The mixture was stirred at a pre-heated oil-bath 100 °C for 3 h. The mixture was concentrated and the residue was extracted with EA. The residue was washed with H₂0, brine and dried over Na₂S0₄. After concentrated, the crude product was purified by prep-HPLC to give the product of 5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6- (N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 30%). ^- MR (CDCI₃, 400 MHz) δ 8.70 (d, J= 2.0 Hz, 1H), 8.31-8.34 (m, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 7.44 (s, 2H), 7.15 (s, 2H), 7.04-7.10 (m, 5H), 6.98 (d, J= 8.8 Hz, 1H), 6.76-6.81 (m, 1H), 5.94 (s, 2H), 5.90 (d, J= 8.8 Hz, 1H), 3.30 (s, 3H), 2.96 (d, J= 4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)⁺: 708.

0382Example 28 ; 2-(4-( difluoromethyl)phenyl)-5-( 1 l-fluoro-6H-pyrido [2',3 ' ; 5,61

0383[l,31oxazino[3,4-alindol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide

0384<img file="WO2014123795A2_D0067.tif" />

0385Step 1 - Synthesis of 5-bromo-2-(4-formylphenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide <img file="WO2014123795A2_D0068.tif" />

0386To a degassed solution of compound 5-bromo-2-iodo-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (400 mg, 0.82 mmol), (4- formylphenyl)boronic acid (1 10 mg, 0.74 mmol) and a₂C0₃ (174 mg, 1.6 mmol) in DMF (4 mL) was added Pd(dppf)Cl₂ (20 mg) under N₂, and the mixture was stirred at 100 °C for 2 h. After the solvent was removed, the residue was purified by column chromatography (DCM : EtOAc = 10 : 1) to give the product of compound 5-bromo-2-(4-formylphenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, yield: 52%). ^XH-NMR (CDC1_3, 400 MHz) 10.09 (s, 1H), 8.09-8.15 (m, 3H), 8.02 (s, 2H), 7.75 (s, 1H), 5.90 (s, 1H), 3.36 (s, 3H), 3.1 1 (s, 3H), 3.05 (d, J= 4.8 Hz, 3H). MS (M+H)⁺: 465 / 467.

0387Step 2 - Synthesis of 5-bromo-2-(4-(difluoromethyl)phenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide

0388<img file="WO2014123795A2_D0069.tif" />

0389To a solution of 5-bromo-2-(4-formylphenyl)-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.1 mmol) in DCM (1 mL) was added dropwise DAST (0.2 mL) at -78 °C. Then the mixture was stirred at 25 °C for 5 hours. Then MeOH (3 ml) was added, and the mixture was adjusted to pH = 7, extracted with DCM (10 ml). The organic phase was dried over Na₂S0₄. After concentrated in vacuo, the residue was purified by prep-TLC (DCM : EtOAc = 10 : 1) to give the product of compound 5-bromo-2-(4- (difluoromethyl)phenyl)-N-methyl-6-( -methylmethylsulfonamido)benzofuran-3-carboxamide (26 mg, yield: 50%). ¾-NMR (CDC1_3, 400 MHz) δ 8.16 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 6.56-6.88 (m, 1H), 5.85 (s, 1H), 3.35 (s, 3H), 3.10 (s, 3H), 3.02 (d, J = 5.2 Hz, 3H). MS (M+H)⁺: 487 / 489.

0390Step 3 - Synthesis of2-(4-(di uoromethyl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5- ( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)benzofuran-3-carboxamide <img file="WO2014123795A2_D0070.tif" />

0391To a degassed solution of 5-bromo-2-(4-(difluoromethyl)phenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.1 mmol), KOAc (30 mg, 0.3 mmol) and dis(pinacolato)diboron (130 mg, 0.5 mmol) in 1,4-dioxane (2 mL) and ¾0 (0.1 mL) was added Pd(dppf)Cl₂ (5 mg) under N₂, and the mixture was stirred at 130 °C for 3 hours. After the solvent was removed, the residue was purified by column chromatography (DCM : EtOAc = 10 : 1) to give the product of 2-(4-(difluoromethyl)phenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (30 mg, yield: 55%). ^XH-NMR (CDC1_3, 400 MHz) δ 8.16 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.66 (d, J = 80 Hz, 2H), 6.56-6.88 (m, 1H), 5.85 (br s., 1H), 3.35 (s, 3H), 3.10 (s, 3H), 3.02 (d, J = 5.2 Hz, 3H), 1.33 (s, 12H). MS (M+H)⁺: 535.

0392Step 4 - Synthesis of2-(4-(difluoromethyl)phenyl)-5-(ll-fluoro-6H-pyridof2',3 ':5, 61

0393f l,3]oxazino[3, 4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide

0394<img file="WO2014123795A2_D0071.tif" />

0395To a degassed solution of 2-(4-(difluoromethyl)phenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (100 mg, 0.18 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (50 mg, 0.20 mmol), Na₂C0₃ (39 mg, 0.37 mmol), in 1,4-dioxane (3 mL) and H₂0 (0.1 mL) were added Pd₂(dba)₃ (5 mg) and X-Phos (5 mg) under N₂. Then the mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H₂0 and dried over Na₂S0₄. After being concentrated, the residue was purified by prep- HPLC to give the product of 2-(4-(difluoromethyl)phenyl)-5-(l l-fluoro-6H-pyrido[2',3':5,6] [l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-CN-methylmethylsulfonamido)benzofuran-3- carboxamide (50 mg, yield: 41%). ^XH-NMR (CDC1_3, 400 MHz) δ 8.08 (d, J= 7.6 Hz, 2H), 8.05 (s, 1H), 7.73 (s, 1H), 7.69 (d, J= 8.0 Hz, 2H), 7.53 (s, 2H), 7.30 (s, 1H), 7.25 (d, J= 2.8 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.88-6.93 (m, 1H), 6.75 (s, 1H), 6.09 (d, J= A A Hz, 1H), 6.04 (s, 2H), 3.41 (s, 3H), 3.04 (d, J= 4.8 Hz, 3H), 2.79 (s, 3H). MS (M+H)⁺: 647. Example 29 ; 2-(4-cyanophenyl)-5-(l l-fluoro-6H-pyrido [2 ',3 ' ; 5,61 [1,31 oxazino [3,4-alindol-

03962-yl)-N-methyl-6- N-methylmethylsulfonamido)benzofuran-3-carboxamide

0397<img file="WO2014123795A2_D0072.tif" />

0398A solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (1 g, 3.19 mmol), 4-bromobenzonitrile (1.17 g, 6.39mmol), K₃P0₄^»3H₂0 (1.7 g, 6.39 mmol) and Pd(dppf)Cl₂ (40 mg) in dioxane/H₂0 (10 mlV 2 mL) was stirred at 80 °C for 4 h. The mixture was filtered to remove the solid and then the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried with a₂S0₄ and

0399concentrated. The residue was purified by column chromatography (PE : EA= 5 : 1) to give 6- amino-5-bromo-2-(4-cyanophenyl)-N-methylbenzofuran-3-carboxamide (300 mg, yield: 26%). ¾-NMR (CDC1₃ , 400MHz) δ 8.09 (d, J= 8.0 Hz, 2H), 7.72 (s, 1H), 7.65 (d, J= 8.4 Hz, 2H), 6.84 (s, 1H), 5.84 (s, 1H), 4.28 (s, 2H), 3.00(d, J= 4.4 Hz, 3H). MS (M+H)⁺: 370 / 372.

0400Step 2 - Synthesis of 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide <img file="WO2014123795A2_D0073.tif" />

0401A mixture of 6-amino-5-bromo-2-(4-cyanophenyl)-N-methylbenzofuran-3- carboxamide (300 mg, 0.80 mmol) in DCM (2 mL) and pyridine (2 mL) was stirred at room temperature and MsCI (278 mg, 2.4 mmol) was added dropwise. The reaction was stirred at room temperature for 8 h. The reaction was washed with IN HC1 and extracted with DCM, dried with a₂S0₄ and concentrated to give 5-bromo-2-(4-cyanophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (260 mg, yield: 72%). MS (M+H)⁺: 448 / 450. Step 3 - Synthesis of 5-bromo-2-(4-cvanophenyl)-N-methyl-6-(N-methylmethylsulfonamido) benzofuran-3-carboxamide

0402<img file="WO2014123795A2_D0074.tif" />

0403A solution of 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido) benzofuran-3-carboxamide (200 mg, 0.44 mmol), K2CO₃ (124 mg, 1.89 mmol) in DMF (5 mL) was stirred at RT and CH₃I (182 mg, 1.32 mmol) was added dropwise. The reaction was stirred at RT for 3 h. The reaction was concentrated, washed with H2O and filtered to give 5-bromo-2- (4-cyanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 73%). ¾-NMR (CDC1₃ , 400MHz) δ 8.09 (s, 1H), 8.07 (d, J= 8.0 Hz, 2H), 7.78 (s, 1H), 7.76 (s, 1H), 7.74( s, 1H), 5.88 (s, lH), 3.34 (s,3H), 3.10 (s,3H), 3.05 (d, J= 5.2 Hz, 3H). MS (M+H)⁺: 462 / 464.

0404Step 4 - Synthesis of2-(4-cvanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide <img file="WO2014123795A2_D0075.tif" />

0405A solution of 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.32 mmol), 4,4,5, 5-tetramethyl- 2-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (549 mg, 2.16mmol), KOAc (84 mg, 0.87 mmol) and Pd(dppf)Cl₂ (25 mg) in dioxane/H₂0 (5 mL / ImL) was stirred at 130 °C for 3 h. The reaction was filtered to remove the solid and then the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over a₂S0₄ and concentrated. The residue was purified by prep-HPLC to give 2-(4-cyanophenyl)-N-methyl- 6-(^-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (1 15 mg, yield: 52%). MS (M+H)⁺: 510.

0406Step 5 - Synthesis of2-(4-cyanophenyl)-5-(ll-fluoro-6H-pyrido[2',3 ':5,6][l,3]oxazino[3,4- a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-car^

0407<img file="WO2014123795A2_D0076.tif" />

0408To a solution of 2-(4-cyanophenyl)-N-methyl-6-( -methylmethylsulfonamido)-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (115 mg, 0.22 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (75 mg, 0.27 mmol) K₂C0₃ (60 mg, 0.44 mmol), Pd₂(dba)₃ (30 mg) and X-Phos (30 mg) in dioxane / H₂0 (3 mL / 0.6 mL) was stirred at 100 °C for 3 h. The reaction was filtered to remove the solid and then the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na₂S0₄ and concentrated. The residue was purified by prep-HPLC to get the product of 2-(4- cyanophenyl)-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 21 %).¹H-NMR (CDCI3, 400 MHz) δ 8.16 (d, J= 8.4 Hz, 2H), 7.96 (s, 1H), 7.78 (d, J= 8.4 Hz, 2H), 7.70 (s, 1H), 7.23-7.19 (m, 3H), 7.13 (d, J= 8.4 Hz, 2H), 6.87 (m, 1H), 6.14 (d, J= 4.4 Hz, 1H), 6.00 (s, 2H), 3.35 (s, 3H), 3.05 (d, J= 5.2 Hz, 3H), 2.77 (s, 3H). MS (M+H)⁺: 622. Examples 30 - 31

0409Examples 30 - 31, depicted in the table below, were prepared in accordance with the method described in Example 29.

0410<img file="WO2014123795A2_D0077.tif" /> 1H-NMR (CDC13, 500 MHz) δ

041111.01 (s, lH), 8.99 (s, 1H), 8.83 (s,

04121H), 8.38-8.22 (m, 2H), 7.77 (s,

041331 1H), 7.54-7.48 (m, 2H), 7.21-7.11 666

0414(m, 2H), 7.2 (s, 1H), 6.85-6.81 (m,

0415<img file="WO2014123795A2_D0078.tif" />

04161H), 6.01 (s, 2H), 3.42 (s, 3H), 3.08

0417(d, J= 4.8 Hz, 3H), 2.67 (s, 3H).

0418Example 32; 2-(3,6-dihvdro-2H-thiopyran-4-yl)-5-(ll-fluoro-6H- pyrido Γ2'.3':5.61 [1.31 oxazino r3.4-alindol-2-ylVN-methyl-6-iN- methylmethylsulfonamido)benzofuran-3-carboxamide

0419<img file="WO2014123795A2_D0079.tif" />

0420To a solution of 5-bromo-2-iodo-N-methyl-6-( -methylmethylsulfonamido) benzofuran-3-carboxamide (800 mg, 1.6 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl) -4,4,5,5- tetram ethyl-l,3,2-dioxaborolane (371 mg, 1.6 mmol) and CS₂CO₃ (1.07 g, 3.28 mmol) in 1,4- dioxane (20 mL) was added Pd(dppf)Cl2 (50 mg) and tri-o-tolylphosphine (50 mg) under nitrogen. The reaction mixture was heated at 100 °C for 4 h, concentrated in vacuo to remove 1,4-dioxane and purified by column chromatography (PE : EA = 3 : 1) to give the compound 5- bromo-2-(3,6-dihydro-2H-thiopyran-4-yl)-N-methyl-6-( -methylmethylsulfonamido) benzofuran-3-carboxamide (250 mg, yield: 33%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.09 (s, 1H), 7.59 (s, 1H), 6.73 (s, 1H), 6.06 (brs, 1H), 3.38 (t, J = 2.0 Hz, 2H), 3.30 (s, 3H), 3.05 (s, 3H), 3.00 (d, J = 4.8 Hz, 3H), 2.87 (t, J = 5.6 Hz, 2H), 2.70-2.76 (m, 2H). MS (M+H)⁺: 459 / 461.

0421Step 2 - Synthesis of ll-fluoro-2-(trimethylstannyl)-6H-pyridof2',3':5, 61fl,31oxazinof3,4- al indole <img file="WO2014123795A2_D0080.tif" />

0422To a degassed solution of 2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (3.0 g, 10.92 mmol) in Toluene (80 mL), (Me₃Sn)₂ (5.4 g, 16.40 mmol) and Pd(DTBPF)Ci2 (250 mg, 0.41 mmol) were added. The reaction mixture was stirred at 100 °C for 3.5 hours. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo and purified by aluminum oxide column chromatography (PE : EtOAc = 30: 1) to give 1 l-fluoro-2-(trimethylstannyl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (3.7 g, yield 84 %). ¾-NMR (CDC1₃, 400 MHz) δ 7.35-7.31 (m, 2H), 7.26-7.16 (m, 2H), 7.08 (d, J= 8.4 Hz, 1H), 6.84 (dd, J= 8.4 Hz, 1H), 5.91 (s, 2H), 0.45-0.31 (m, 9H).

0423Step 3 - Synthesis of 2-(3, 6-dihvdro-2H-thiopyran-4-yl)-5-(l l-fluoro-6H- pyridof2',3 ':5, 61 fl ,31 oxazino[3,4- l indol-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide

0424<img file="WO2014123795A2_D0081.tif" />

0425To a solution of 5-bromo-2-(3,6-dihydro-2H-thiopyran-4-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.2 mmol), l l-fluoro-2-

0426(trimethylstannyl)-6H-pyrido [2',3':5,6] [l,3]oxazino[3,4-a]indole (105 mg, 0.26 mmol) in 1,4- dioxane (5 mL) was added Pd(PPh₃)₄(10 mg) under nitrogen. The reaction mixture was heated at 100 °C overnight, concentrated in vacuo to remove 1,4-dioxane and purified by prep-TLC (PE : EA = 1 : 1) to give 2-(3,6-dihydro-2H-thiopyran-4-yl)-5-(l l-fluoro-6H- pyrido[2',3 ': 5 ,6] [1,3] oxazino [3 ,4-a] indol-2-yl)-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (15 mg, yield: 1 1%). ^XH-NMR (CDCI₃, 400 MHz) δ 7.97 (s, 1H), 7.58 (s, 1H), 7.47 (s, 2H), 7.18-7.23 (m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.80-6.86 (m, 2H), 6.05 (d, J = 4.8 Hz, 1H), 5.99 (s, 2H), 3.41 (t, J = 2.0 Hz, 2H), 3.35 (s, 3H), 3.00 (d, J = 4.8 Hz, 3H), 2.90 (t, J = 5.6 Hz, 2H), 2.80 (d, J = 3.2 Hz, 2H), 2.71 (s, 3H). MS (M+H)⁺: 619. Examples 33-35

0427Examples 33-35 depicted in the table below, were prepared in accordance with the method described in Example 35.

0428<img file="WO2014123795A2_D0082.tif" />

0429Example 36 ; 5-( 1 l-fluoro-6H-pyrido [2 ',3 '; 5,61 [1,31 oxazino [3,4-al ίηάο1-2-ν1)-2-( 1H- imidazol-l-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide <img file="WO2014123795A2_D0083.tif" />

0430Step 1 - 5-bromo-2-(lH midazol-l-yl)-N-methyl-6-(N-methylmethylsulfon

0431carboxamide

0432^ΒΓγγΙ.

0433o=s=o

0434<img file="WO2014123795A2_D0084.tif" />

0435To a degassed solution of 5-bromo-2-iodo-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.21 mmol) and K₂CO₃ (43 mg, 0.31 mmol) in DMF (1 mL) was added lH-imidazole (14 mg, 0.21 mmol) under ₂ at 0 °C. The mixture was heated at 60 °C for 10 hours. The reaction mixture was concentrated and it was extracted with EtOAc. The residue was washed with H2O, brine, dried over a2S0₄. After being concentrated, the crude product was purified by column (PE : EA = 1 : 1) to give of 5- bromo-2-(lH-imidazol-l-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (72 mg, yield: 83%). ^XH-NMR (OMSO-d₆, 400 MHz) δ 8.40 (d, J = 4.4 Hz, 1H), 8.36 (s, 1H), 8.10 (s, 2H), 7.80 (s, 1H), 7.19(s, 1H), 3.21 (s, 3H), 3.20 (s, 3H), 2.81 (d, J = 4.4 Hz, 3H). MS (M+H)⁺: 427 / 429.

0436Step 2 - 2-(lH-imidazoI-l-vI)-N-methvI-6-(N-methvImethvIsuIfonam^

04371, 3, 2-dioxaborolan-2-yl)benzofuran-3-carboxamide <img file="WO2014123795A2_D0085.tif" />

0438To a degassed solution of 5-bromo-2-(lH-imidazol-l-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 0.12 mmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (220 mg, 0.60 mmol) in 1, 4-dioxane (2 mL) were added Pd(dppf)Ci₂ (10 mg) and KOAc (40 mg, 0.35 mmol) under N₂. The mixture was heated at a pre-heated oil-bath at 130 °C for 3 h. The reaction mixture was concentrated in vacuo and it was extracted with EtOAc. The residue was washed with H₂0, brine, dried over Na₂S0₄. After concentrated, the crude product was purified by prep- TLC (PE : EA = 1 : 1) to give of 2-(lH-imidazol-l-yl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (30 mg, yield: 53%). ^XH-NMR (OMSO-d₆, 400 MHz) δ 8.18 (s, 1H), 7.69 (s, 1H), 7.46 (d, J = 6.4 Hz, 2H), 7.21 (s, 1H), 5.92 (s, 1H), 3.36 (s, 3H), 3.04 (d, J = 4.48 Hz, 3H), 2.95 (s, 3H), 1.37 (s, 12H). MS (M+H)⁺: 475.

0439Step 3 - Synthesis of 5-(ll-fluoro-6H-pyridof2',3 ':5, 61 ^' il,31oxazino[3A- lindol-2-yl)-2-(lH- imidazol-l- -N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

0440<img file="WO2014123795A2_D0086.tif" />

0441To a solution of 2-(lH-imidazol-l-yl)-N-methyl-6-( - methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (60 mg, 0.13 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- ajindole (42 mg, 0.15 mmol) and K2CO₃ (26 mg, 0.19 mmol) in 1, 4-dioxane (1 mL) and water (0.01 mL) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under nitrogen. The mixture was heated at 1 10 °C for 3 hours and filtered through the celite pad. The filtrate was extracted with EtOAc and the combined organic phase was washed with brine, dried over a2S0₄ and concentrated in vacuo. The crude product was purified by prep-HPLC to give 5-(l l-fluoro-6H- pyrido[2;3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(lH-imidazol-l-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 40%). ^XH-NMR (400 MHz, CDCI₃) δ 8.36 (s, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.52 (s, 2H), 7.20-7.25 (m, 3H), 7.12 (d, J= 8.4 Hz, 1H), 6.84-6.88 (m, 1H), 6.02 (s, 2H), 5.93 (d, J= 4.8 Hz, 1H), 3.35 (s, 3H), 3.02 (d, J= 4.8 Hz, 3H), 2.78 (s, 3H). MS (M+H)⁺: 587.

0442Examples 37-41

0443Examples 37-41, depicted in the table below, were prepared in accordance with the method described in Example 39. <img file="WO2014123795A2_D0087.tif" /><img file="WO2014123795A2_D0088.tif" />

0444Example 42 ; 5-( 1 l-fluoro-6H-pyrido [2 ',3 '; 5,61 [1,31 oxazino [3,4-al indol-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)-2-morpholinobenzofuran-3-carboxamide

0445<img file="WO2014123795A2_D0089.tif" />

0446Step 1 - 5-bromo-N-methyl-6-(N-methylmethylsulfonamido)-2-morphotinob

0447carboxamide

0448<img file="WO2014123795A2_D0090.tif" />

0449To a suspension of compound 5-bromo-2-iodo-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.1 mmol) in pyridine (3 mL) was added morpholine (18 mg, 0.2 mol) under N₂, and then the mixture was stirred at 60 °C for 3 hours. After concentration in vacuo, DCM was added and the resulting residue was washed with 10% HC1 (a.q., 3 mL) and dried over Na₂S0₄. After concentration, the residue was purified by prep-TLC (DCM : MeOH = 20 : 1) to give the product of 5-bromo-N-methyl-6-(N- methylmethylsulfonamido)-2-morpholinobenzofuran-3 -carboxamide (20 mg, yield: 44%). ^XH- NMR (CDCI3, 400 MHz) δ 8.05 (s, 1H), 7.47 (s, 1H), 6.48 (s, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.46 (t, J = 6.4 Hz, 4H), 3.28 (s, 3H), 3.04 (s, 3H), 2.99 (d, J = 4.8 Hz, 3H). MS (M+H)⁺: 446 / 448. Step 2 - Synthesis ofN-methyl-6-(N-methylmethylsulfonamido)-2-morphoUno-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide <img file="WO2014123795A2_D0091.tif" />

0450To a ₂ degassed solution of compound 5-bromo-N-methyl-6-(N- methylmethylsulfonamido)-2-morpholinobenzofuran-3-carboxamide (100 mg, 0.22 mmol), KOAc (66 mg, 0.67 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (284 mg, 1.12 mmol) in dioxane (5 mL) and H₂0 (0.1 mL) was added Pd(dppf)Ci2 (5 mg) under N₂, and the mixture was stirred at 130 °C for 3 hours. After concentration, the residue was purified by prep-TLC (DCM : MeOH = 20 : 1) to give the product of compound N-methyl-6-(N- methylmethylsulfonamido)-2-morpholino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3-carboxamide (50 mg, yield: 45%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.05 (s, 1H), 7.47 (s, 1H), 6.48 (s, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.46 (t, J = 6.4 Hz, 4H), 3.28 (s, 3H), 3.04 (s, 3H), 2.99 (d, J = 4.8 Hz, 3H), 1.34 (s, 12H). MS (M+H)⁺: 494.

0451Step 3 - Synthesis of 5-(ll-fluoro-6H-pyridof2',3 ':5,61 fl,31oxazino[3,4- lindol-2-yl)-N-methyl- 6-(N-methylmethylsulfonamido)-2-morphotinobenzofuran-3-carboxamide

0452<img file="WO2014123795A2_D0092.tif" />

0453To a degassed solution of N-methyl-6-( -methylmethylsulfonamido)-2- moφholino-5-(4,4,5,5 etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (80 mg, 0.16 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (47 mg, 0.17 mmol), a₂C0₃ (34 mg, 0.32 mmol) in dioxane (1.5 mL) and H₂0 (0.1 mL) was added

0454Pd(dppf)Cl₂ (3 mg) under N₂. Then the mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with ¾0 and dried over

0455Na₂S0₄. After concentration, the residue was purified by prep-HPLC to give the product of 5- (l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-( - methylmethylsulfonamido)-2-morpholinobenzofuran-3-carboxamide (10 mg, yield: 10%). ^XH- NMR (CDC1₃, 400 MHz) δ 8.01 (s, 1H), 7.45-7.47 (m, 3H), 7.18-7.21 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.82-6.87 (m, 1H), 6.64 (s, 1H), 5.99 (s, 2H), 3.89 (t, J = 4.4 Hz, 4H), 3.51 (t, J = 6.4 Hz, 4H), 3.36 (s, 3H), 3.01 (d, J = 4.8 Hz, 3H), 2.68 (s, 3H). MS (M+H)⁺: 606. Example 43

0456Example 43 depicted in the table below, was prepared in accordance with the method described in Example 42.

0457<img file="WO2014123795A2_D0093.tif" />

0458Example 44; 2-(cvclopent-l-en-l-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- Pyrido[2',3';5,61 [l,31oxazino[3,4-alindol-2-yl)benzofuran-3-carboxamide

0459<img file="WO2014123795A2_D0094.tif" />

0460Step 1 - Synthesis of ethyl 6-amino-5-bromo-2-(l-hydroxycyclopentyl)benzofuran-3-carboxylate <img file="WO2014123795A2_D0095.tif" />

0461To a solution of LDA (6.32 g, 59.0 mmol) in THF (60 mL) was added dropwise ethyl 6-amino-5-bromobenzofuran-3-carboxylate (5 g, 17.6 mmol) at -78 °C under N₂. After the mixture was stirred for 1 hour, cyclopentanone (4.44 g, 52.8 mmol) in THF (40 mL) was added dropwise at -78 °C. After the mixture was stirred for 1 h, NH₄C1 (a.q.) was added, then the mixture was extracted with EtOAc (100 mL * 3) and dried over a₂S0_4. After concentration, the residue was purified by column chromatography (PE : EtOAc = 10 : 1) to give the product of ethyl 6-amino-5-bromo-2-(l-hydroxycyclopentyl) benzofuran-3-carboxylate (2.9 g, yield: 44%). ^XH-NMR (CDCI₃, 400 MHz) δ 7.94 (s, 1H), 6.86 (s, 1H), 6.07 (s, 1H), 4.46 (q, J= 7.2 Hz, 2H), 4.20 (s, 1H), 2.12-2.17 (m, 4H), 1.99 (t, J= 5.6 Hz, 2H), 1.79 (t, J= 3.2 Hz, 2H), 1.50 (t, J= 7.2 Hz, 3H). MS (M+H)⁺: 368 / 370.

0462Step 2 - Synthesis of ethyl -amino-5-bromo-2-(cyclopent-l-en-l-yl)benzofuran-3-carboxylate <img file="WO2014123795A2_D0096.tif" />

0463TFA (1.5 niL) was added into a solution of ethyl 6-amino-5-bromo-2-(l- hydroxycyclopentyl)benzofuran-3-carboxylate (2.9 g, 7.89 mmol) in DCM (30 mL), then the mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into ice water, adjusted to pH = 7 with aHC0₃ (a.q.), then the residue was extracted with DCM (50 mL*3), dried over Na₂S0₄, and concentrated to give the product of ethyl 6-amino-5-bromo-2-(cyclopent- l-en-l-yl)benzofuran-3-carboxylate (2.6 g, yield: 94%). ^XH-NMR (CDC1₃, 400 MHz) δ 7.99 (s, 1H), 7.1 1 (t, J= 7.2 Hz, 1H), 6.83 (s, 1H), 4.43 (q, J= 7.2 Hz, 2H), 2.86-2.91 (m, 2H),

04642.59-2.63 (m, 2H), 2.01 (t, J= 8.0 Hz, 2H), 1.46 (t, J= 3.2 Hz, 3H). MS (M+H)⁺: 350 / 352. Step 3 - Synthesis of ethyl 5-bromo-2-(cyclopent-l-en-l-yl)-6-(methylsulfonamido)benzofuran-3- carboxylate

0465<img file="WO2014123795A2_D0097.tif" />

0466To a solution of ethyl 6-amino-5-bromo-2-(cyclopent-l-en-l-yl)benzofuran-3- carboxylate (3.63 g, 10.37 mmol) and pyridine (2.46 g, 31.1 mmol) in DCM (30 mL) was added dropwise methanesulfonyl chloride (2.37 g, 20.7 mmol) at 0 °C, then the mixture was stirred at

046725 °C overnight. 10% HC1 (a.q.) was added, then the mixture was extracted with DCM (50 mL*3), dried over Na₂S0₄, and concentrated to give the product of ethyl 5-bromo-2-(cyclopent- l-en-l-yl)-6-(methylsulfonamido)benzofuran-3-carboxylate (4.3 g, yield: 96%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.19 (s, 1H), 7.80 (s, 1H), 7.22 (t, J= 2.0 Hz, 1H), 6.84 (s, 1H), 4.45 (q, J = 12 Hz, 2H), 2.99 (s, 3H), 2.89-2.94 (m, 2H), 2.62-2.67 (m, 2H), 2.06 (t, J= 7.6 Hz, 2H), 1.47 (t, J= 7.2 Hz, 3H). MS (M+H)⁺: 428 / 430.

0468Step 4 - Synthesis of ethyl 5-bromo-2-(cyclopent-l-en-l-yl)-6-(N-methylmethylsulfonamido) benzofuran-3-carboxylate <img file="WO2014123795A2_D0098.tif" />

0469To a solution of ethyl 5-bromo-2-(cyclopent-l-en-l-yl)-6-(methylsulfonamido) benzofuran-3 -carboxylate (5.3 g, 12.37 mmol), K2CO₃ (5.13 g, 37.12 mmol) in DMF (50 mL) was added Mel (30 g, 23.5 mmol), then the mixture was stirred at 80°C. After 3 hours, the solvent was removed by vacuum, the mixture was washed with H₂0 (100 mL) and extracted with DCM (100 mL*3), dried over Na₂S0₄ and concentrated to give the desired product of ethyl 5- bromo-2-(cyclopent- 1 -en- 1 -yl)-6-(N-methylmethylsulfonamido)benzofuran-3 -carboxylate (5 g, yield: 91%). ¾-NMR (CDC1₃, 400 MHz) δ 8.22 (s, 1H), 7.61 (s, 1H), 7.23 (t, J= 2.0 Hz, 1H), 4.42 (q, J= 12 Hz, 2H), 3.31 (s, 3H), 3.06 (s, 3H), 2.63-2.64 (m, 2H), 1.99-2.03 (m, 2H), 2.01 (t, J= 7.6 Hz, 2H), 1.46 (t, J= 7.2 Hz, 3H). MS (M+H)⁺: 442 / 444.

0470Step 5 - 5-bromo-2-(cvclopent-l-en-l-yl)-6-(N-methylmethylsulfonamido)benzofuran-3- carboxylic acid

0471<img file="WO2014123795A2_D0099.tif" />

0472To a solution of ethyl 5-bromo-2-(cyclopent-l-en-l-yl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxylate (4.4 g, 9.94 mmol) in 1,4-Dioxane (40 mL) and H₂O (4 mL) was added LiOH (1.2 g, 49.72 mmol), then the mixture was stirred at 1 10°C. After 3 hours, the solvent was removed by vacuum, 10% HC1 (aq) was added, and the mixture was adjusted to pH = 4-5. Then the residue was dissolved in EtOAc (200 mL), dried over Na₂S0₄ and concentrated to give the desired product of 5-bromo-2-(cyclopent-l-en-l-yl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxylic acid (3.5 g, yield: 84 %). ^XH-NMR (CDCI3, 400 MHz) δ 8.35 (s, 1H), 7.66 (s, 1H), 7.32 (t, J= 2.0 Hz, 1H), 3.36 (s, 3H), 3.09 (s, 3H), 2.90-2.95 (m, 2H), 2.67-2.71 (m, 2H), 2.08 (t, J= 8.0 Hz, 2H). MS (M+H)⁺: 414 / 416.

0473Step 6 - Synthesis of 5-bromo-2-(cvclopent-l-en-l-yl)-N-methyl-6-(N-methylmethylsulfonamido) benzofuran-3-carboxamide <img file="WO2014123795A2_D0100.tif" />

0474A solution of 5-bromo-2-(cyclopent- 1 -en- 1 -yl)-6-( -methylmethylsulfonamido) benzofuran-3-carboxylic acid (3.5 g, 7.70 mmol), HOBT (1.6 g, 1 1.55 mmol) and EDCI (2.2 g, 1 1.55 mmol) in dry DMF (40 mL) was stirred at 25 °C. After 2 hours, Et₃N (2.4 g, 23.11 mmol) and Me H₂ (1.6 g, 23.1 1 mmol) were added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H₂0 (50 mL) and extracted with EtOAc (50 mL*3), and dried over Na₂S0₄. After concentration, the residue was purified by column chromatography (DCM) to give the product of 5-bromo-2-(cyclopent-l-en-l-yl)-N- methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (2 g, yield: 56%). ^χΗ-ΝΜΡν (CDC1₃, 400 MHz) δ 8.00 (s, IH), 7.59 (s, IH), 6.70 (t, J= 3.2 Hz, IH), 5.95 (s, IH), 3.31 (s, 3H), 3.30 (s, 3H), 3.06 (s, 3H), 2.76-2.81 (m, 2H), 2.58-2.62 (m, 2H), 2.07 (t, J= 7.6 Hz, 2H). MS (M+H)⁺: 427 / 429.

0475Step 7 - Synthesis of2-(cyclopent-l-en-l-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5- ( 4, 4, 5, 5-tetramethyl-l, -dioxaborolan-2-yl)benzofuran-3-carboxamide

0476<img file="WO2014123795A2_D0101.tif" />

0477To a degassed solution of 5-bromo-2-(cyclopent-l-en-l-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (1 g, 2.34 mmol), bis(pinacolato)diboron (3 g, 1 1.70 mmol), CH₃COOK (689 mg, 7.02 mmol) in 1,4-Dioxane (10 mL) and H₂0 (1 mL) was added Pd(dppf)Cl₂ (10 mg), then the mixture was stirred at 130 °C. After 3 hours, the solvent was removed by vacuum, and the mixture was washed with H₂0 (60 mL), extracted with DCM (50 mL*3), and dried over Na₂S0₄. After concentration, the residue was purified by column chromatography (PE : EtOAc = 2 : 1) to give the product of 2-(cyclopent-l-en-l-yl)-N- methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3-carboxamide (400 mg, yield: 36%). ¾-NMR (CDC1₃, 400 MHz) δ 8.06 (s, IH), 7.45 (s, IH), 6.66 (s, IH), 6.62 (s, IH), 3.32 (s, 3H), 3.02 (s, 3H), 2.92 (s, 3H), 2.76-2.79 (m, 2H), 2.53-2.57 (m, 2H), 2.01 (t, J= 7.6 Hz, 2H), 1.34 (s, 12H),. MS (M+H)⁺: 475. Step 8 - Synthesis of2-(cyclopent-l-en-l-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- pyridof2',3 ':5, 61 fl ,31 oxazino[3,4- l indol-2-yl)benzofuran-3-carboxamide

0478<img file="WO2014123795A2_D0102.tif" />

0479To a degassed solution of 2-(cyclopent-l-en-l-yl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5 etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (1 10 mg, 0.23 mmol), 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (70 mg, 0.27 mmol), K₃P0₄ (123 mg, 0.46 mmol) in 1,4-Dioxane (5 mL) and ¾0 (0.5 ml) was added Pd(dba)₃ (5 mg) and X-Phos (5 mg) under N₂, then the mixture was stirred at 1 10°C for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with ¾0, brine, extract with DCM, and dried over Na₂S0₄. After concentration, the residue was purified by prep-HPLC to give the product of 2-(cyclopent-l-en-l-yl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(6H^yrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)benzofuran-3- carboxamide (30 mg, yield: 23%). ^XH-NMR (CDC1₃, 400 MHz) δ 7.88 (s, IH), 7.69 (d, J= 7.6 Hz, IH), 7.56 (s, IH), 7.47 (s, 2H), 7.27-7.33 (m, 2H), 7.14-7.20 (m, 2H), 6.74 (s, IH), 6.10 (s, IH), 5.99 (s, 2H), 3.32 (s, 3H), 3.01 (d, J= 4.8 Hz, 3H), 2.83 (d, J= 6.8 Hz, 2H), 2.73 (s, 3H), 2.62 (t, J= 6.8 Hz, 2H), 2.00-2.08 (m, 2H). MS (M+H)⁺: 569.

0480Examples 45-47

0481Examples 45-47, depicted in the table below, were prepared in accordance with the method described in Example 47. <img file="WO2014123795A2_D0103.tif" /> Ή-NMR (CDC1₃, 400 MHz) δ 7.91

0482(s, 1H), 7.58 (s, 1H), 7.50 (s, 2H),

04837.19-7.24 (m, 1H), 7.12 (d, J = 8.0

0484Hz, 1H), 6.87 (t, J= 7.6 Hz, 1H),

048545 6.76 (s, 1H), 6.10 (t, J= 3.6 Hz, 1H), 587

04866.00 (s, 2H), 3.35 (s, 3H), 3.04 (d, J

0487F °=†= ° = 4.8 Hz, 3H), 2.83-2.88 (m, 2H),

04882.76 (s, 3H), 2.60-2.64 (m, 2H),

04892.02-2.10 (m, 2H).

0490¾-NMR (CDCI₃, 400 MHz) δ 8.65 (s, 1H), 8.18 (s, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.61 (s, 1H), 7.37-7.42 (m, 2H), 7.33-7.36 (m, 2H), 6.80 (s,

049146 1H), 6.18-6.21 (m, 1H), 6.07 (s, 570

04922H), 3.48 (s, 3H), 3.03 (d, J= 4.8

0493o=s=o

04941 Hz, 3H), 2.80-2.87 (m, 2H), 2.64 (s,

04953H), 2.58 (t, J = 4.8 Hz, 2H),

04961.98-2.01 (m, 2H).

0497Ή-NMR (CDCI₃, 400 MHz) δ 8.62 (s, 1H), 8.14 (s, 1H), 7.79 (d, J= 8.8 Hz, 1H), 7.32-7.45 (m, 2H),

04987.30-7.35 (m, 2H), 6.75 (s, 1H),

049947 6.15-6.19 (m, 1H), 6.06 (s, 2H), 588

05003.49 (s, 3H), 3.06 (d, J= 4.8 Hz,

0501F ⁰⁼ ° 3H), 2.82-2.88 (m, 2H), 2.66 (s,

05023H), 2.60 (t, J = 4.8 Hz, 2H),

05031.99-2.06 (m, 2H)

0504Example 48; -rbicvclofS.l.Olhexan-l-vn-S-dl-nuoro-eH-pyridof '^'iS^l [1,31 oxazino[3,4-alindol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide

0505<img file="WO2014123795A2_D0104.tif" /> Step 1 - 2- bicvclof3 ^Jhexan-l-yl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido) benzofuran-3-carboxamide <img file="WO2014123795A2_D0105.tif" />

0506To a solution of 5-bromo-2-(cyclopent-l-en-l-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, 1.40 mmol) and ZnEt₂ (15 mL,

050714.04 mmol) in DCM (10 mL) was added dropwise CH₂I₂ (1.2 mL, 14.04 mmol) at 0 °C, and then the mixture was stirred at 25 °C. After 3 hours, 10 mL NH₄C1 (a.q.) was added, and the mixture was extracted with DCM (30 mL*3), and dried over a₂S0₄. After concentration, the residue was purified by column chromatography (DCM : EtOAc = 3 : 1) to give the product of 2- (bicyclo[3.1.0]hexan-l-yl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (300 mg, yield: 48%). ^XH-NMR (CDC1₃, 400 MHz) δ 8.30 (s, 1H), 7.60 (s, 1H),

05086.16 (d, J= 2.0 Hz, 1H), 3.34 (s, 3H), 3.12 (d, J= 4.8 Hz, 3H), 3.07 (s, 3H), 2.10-2.21 (m, 2H),

05092.01-2.09 (m, 2H), 1.86-1.99 (m, 2H), 1.38-1.46 (m, 1H), 1.37 (d, J= 4.0 Hz, 2H). MS

0510(M+H)⁺: 441 / 443.

0511Step 2 - 2-(bicvcloi3A.01hexan-l-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4A,5,5-

0512<img file="WO2014123795A2_D0106.tif" />

0513To a degassed solution of 2-(bicyclo[3.1.0]hexan-l-yl)-5-bromo-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (220 mg, 0.50 mmol),

0514bis(pinacolato)diboron (633 mg, 2.49 mmol), CH₃COOK (147 mg, 1.50 mmol) in 1,4-Dioxane (8 mL) and H₂0 (1 mL) was added Pd(dppf)Cl₂ (10 mg), then the mixture was stirred at 130°C. After 3 hours, the solvent was removed by vacuum, and the mixture was washed with H₂0 (50 mL), extract with DCM (30 mL*3), and dried over a2S0₄. After concentrated, the residue was purified by prep-TLC (PE : EtOAc = 1 : 1) to give the product of 2-(bicyclo[3.1.0]hexan-l-yl)- N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3-carboxamide (121 mg, yield: 50%). ¾-NMR (CDC1₃, 400 MHz) 8.27 (s, 1H), 7.43 (s, 1H), 6.20 (d, J= 4.0 Hz, 1H), 3.30 (s, 3H), 3.03 (d, J= 4.8 Hz, 3H), 2.91 (s, 3H), 2.17-2.21 (m, 2H), 2.1 1-2.16 (m, 2H), 2.01-2.09 (m, 2H), 1.91-1.98 (m, 1H), 1.75 (d, J= 4.0 Hz, 2H), 1.06 (s, 12H). MS (M+H)⁺: 489.

0515Step 3 - Synthesis of2-(bicyclof3.1.01hexan-l-yl)-5-(ll-fluoro-6H-pyridof2',3':5, 61fl,31

0516<img file="WO2014123795A2_D0107.tif" />

0517To a degassed solution of 2-(bicyclo[3.1.0]hexan-l-yl)-N-methyl-6-( - methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (100 mg, 0.20 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (67 mg, 0.24 mmol), K₃P0₄ (109 mg, 0.41 mmol) in 1,4-Dioxane (5 mL) and H₂0 (0.5 ml) was added Pd(dba)₃ (5 mg), X-Phos (5 mg) under N₂, then the mixture was stirred at 1 10°C for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H₂0, brine, extracted with DCM, and dried over Na₂S0₄. After concentration, the residue was purified by prep-HPLC to give the product of 2-(bicyclo[3.1.0]hexan-l-yl)-5-(l l-fluoro-6H- pyrido[2',3 ': 5 ,6] [1,3] oxazino [3 ,4-a] indol-2-yl)-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 16%). ^XH-NMR (CDCI₃, 400 MHz) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.46 (s, 2H), 7.21 (s, 2H), 7.12 (d, J= 8.0 Hz, 1H), 6.86 (q, J= 8.0 Hz, 1H), 6.17 (d, J= 4.0 Hz, 1H), 5.60 (s, 2H), 3.38 (s, 3H), 3.05 (d, J= 4.8 Hz, 3H), 2.67 (s, 3H), 2.14-2.22 (m, 2H), 2.1 1-2.16 (m, 2H), 2.01-2.09 (m, 2H), 1.91-1.98 (m, 1H), 1.84 (d, J= 4.0 Hz, 2H). MS (M+H)⁺: 601.

0518Example 49

0519Example 49, depicted in the table below, was prepared in accordance with the method described in Example 48. <img file="WO2014123795A2_D0108.tif" /> Ή-NMR (CDC1₃, 400 MHz) δ 8.06

0520(s, 1H), 7.55 (s, 1H), 7.44-7.52 (m,

05212H), 7.15-7.24 (m, 2H), 7.11 (d, J =

05228.0Hz, 1H), 6.84 (dd, J= 9.6, 8.0Hz,

05231H), 6.10 (d, J = 4.4Hz, 1H), 5.99 (s,

052449 589

05252H), 3.35 (s, 3H), 3.04 (d, J= 4.8Hz, o=s=o 3H), 2.71 (s, 3H), 2.35 (dd, J = 8.0,

05261

05276.0Hz, 1H), 1.42 (t, J= 5.2Hz, 1H),

05281.35 (s, 3H), 1.16 (dd, .7= 8.4,

05294.8Hz, 1H), 1.07 (s, 3H).

0530Example 50; 2- 2,2-difluorocvclopropyl)-5- il-fluoro-6H-pyrido[2',3';5,61[l,31 oxazino

0531[3,4-alindol-2-yl)-N-methyl-6- N-methylmethylsulfonamido)benzofuran-3-carboxamide

0532<img file="WO2014123795A2_D0109.tif" />

0533Step 1 - 5-bromo-2-(2,2-difluorocyclopropyl)-N-methyl-6-(N-methy

0534<img file="WO2014123795A2_D0110.tif" />

0535A solution of trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (31 mg, 0.12 mmol) in toluene (0.5 mL) was added dropwise to a solution of 5-bromo-N-methyl-6-(N- methylmethylsulfonamido)-2-vinylbenzofuran-3-carboxamide (30 mg, 0.07 mmol) and NaF (1 mg, 0.02 mmol) in diglyme (1 mL) at 120 °C over 15 min. The mixture was then stirred at 120 °C for 2 h. The mixture was concentrated in vacuum and the residue was purified by prep-TLC (PE : EA = 1 : 1) to give the product of 5-bromo-2-(2,2-difluorocyclopropyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (7 mg, yield: 22%). ^- MR (DMSO-ί/ή, 400 MHz) δ 8.13 (s, 1H), 8.02 (s, 1H), 3.74-3.66 (m, 1H), 3.19 (s, 3H), 3.18 (s, 3H), 2.84 (s, 3H), 2.38-2.39 (m, 1H), 2.21-2.17 (m, 1H). MS (M+H)⁺: 437 / 439.

0536Step 2 - 2-(2,2-di uorocvclopropyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4A,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide <img file="WO2014123795A2_D0111.tif" />

0537A mixture of 5-bromo-2-(2,2-difluorocyclopropyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, 0.07 mmol),

0538bis(pinacolato)diboron (87 mg, 0.34 mmol), Pd(dppf)Cl₂ (10 mg, 0.01 mmol) and KOAc (60 mg, 0.2 mmol) in DMF (2 mL) was stirred at 110 °C for 6 h. Water was added and the mixture was extracted with EtOAc. After concentrated, the residue was purified by prep-TLC (PE : EA = 1 : 1) to give the crude product of 2-(2,2-difluorocyclopropyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (7 mg, yield: 20%). MS (M+H)⁺: 485.

0539Step 3 - Synthesis of 2-(2,2-difluorocyclopropyl)-5-(l l-fluoro-6H-pyrido[2',3':5, 6] [1,3] oxazino f3A- lindol- -yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3

0540<img file="WO2014123795A2_D0112.tif" />

0541A mixture of 2-(2,2-difluorocyclopropyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (20 mg, 0.04 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (11 mg, 0.04 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol), X-Phos (10 mg, 0.02 mmol) and K₃PO₄ (60 mg, 0.12 mmol) in DMF (2 mL) was stirred at 100 °C for 6 h. Water was added and the mixture was extracted with EtOAc. After concentration, the residue was purified by prep- TLC (PE : EA = 1 : 3) to give the product of 2-(2,2-difluorocyclopropyl)-5-(l l-fluoro-6H- pyrido[2',3 ': 5 ,6] [1,3] oxazino [3 ,4-a] indol-2-yl)-N-methyl-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (2 mg, yield: 8%). ^- MR (MeOD, 400 MHz) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.60 (s, 2H), 7.32 (d, J= 8.4 Hz, 1H), 7.26-7.20 (m, 2H), 6.93 (dd, J= 8.0, 10.4 Hz, 1H), 6.11 (s, 2H), 3.64-3.56 (m, 1H), 3.34 (s, 3H), 2.99 (s, 3H), 2.98 (s, 3H), 2.26-2.17 (m, 2H). MS (M+H)⁺: 597. Example 51; (R or S)-2-cvclopropyl-5-(ll-fluoro-6-(hvdroxymethyl)-6H- pyrido[2',3';5,6Ul,31 oxazino[3,4-alindol-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide

0542<img file="WO2014123795A2_D0113.tif" />

0543(?-BuO)₂ (94 g, 640 mol) was added to a solution of ethyl 3-cyclopropyl-3- oxopropanoate (50 g, 320 mmol), 4-bromophenol (166 g, 9.6 mol) and FeCP6H20 (5.8 g, 32 mmol) in Di-chlorine Ethane (316 g, 3.2 mol) under ₂ gas at 25 °C. The mixture was stirred at 80 °C for 6 hours. The solvent was removed and the residue was purified by column chromatography (eluted with PE : EA from 20 : 1 to 10 : 1) to furnish the pure product of ethyl 5-bromo-2-cyclopropylbenzofuran-3-carboxylate (20.0 g, yield: 21%). ^- MR (400 MHz, CDCI3) δ 8.02 (s, 1H), 7.30 (d, J= 7.2 Hz, 1H), 7.18 (d, J= 7.2 Hz, 1H), 4.42 (q, J= 7.2 Hz, 2H), 3.01-3.05 (m, 1H), 1.44 (t, J= 7.2 Hz, 3H), 1.24-1.26 (m, 2H), 1.16-1.19 (m, 2H). MS (M+H)⁺: 309 / 311.

0544Step 2 - Synthesis of ethyl 5-bromo-2-cyclopropyl-6-nitrobenzofuran-3-carboxylate <img file="WO2014123795A2_D0114.tif" />

0545To a solution of compound ethyl 5-bromo-2-cyclopropylbenzofuran-3- carboxylate (10 g, 34 mmol) in CHC1₃ (60 mL), fuming H 0₃ (12 mL, 95%) was added dropwise at -20 °C over 90 min and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was added to ice water and extracted with CH₂CI₂. The organic layer was washed with aHC03 (aq.) and brine. The solvent was removed by distillation to provide the crude product of ethyl 5 -bromo-2-cyclopropyl-6-nitrobenzofuran-3 -carboxylate (4.5 g, yield: 40%). ^XH-NMR (400 MHz, CDCI₃) δ 8.26 (s, 1H), 7.95 (s, 1H), 4.46 (q, J= 7.2 Hz, 2H), 3.06-3.10 (m, 1H), 1.46 (t, J= 12 Hz, 3H), 1.34-1.36 (m, 2H), 1.28-1.32 (m, 2H). MS (M+H)⁺: 354 / 356. Step 3 - Synthesis of ethyl 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylate <img file="WO2014123795A2_D0115.tif" />

0546A mixture of crude compound ethyl 5-bromo-2-cyclopropyl-6-nitrobenzofuran-3- carboxylate (8.5 g, 25 mmol), iron filings (4.1 g, 75 mmol) and H₄Cl (8 g, 150 mmol) in MeOH-THF-H^O (2 : 2 : 1, 100 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE : EA from 20 : 1 to 10 : 1) to furnish the pure product of ethyl 6-amino-5-bromo-2- cyclopropylbenzofuran-3-carboxylate (7.00 g, yield: 91%). ¾-NMR (400 MHz, CDC1₃) δ 7.93 (s, 1H), 6.75 (s, 1H), 4.40 (q, J= 7.2 Hz, 2H), 4.11 (s, 2H), 2.94-2.99 (m, 1H), 1.43 (t, J= 7.2 Hz, 3H), 1.19-1.21 (m, 2H), 1.12-1.15 (m, 2H). MS (M+H)⁺: 324 / 326.

0547Step 4 - Synthesis of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid <img file="WO2014123795A2_D0116.tif" />

0548To a solution of ethyl 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylate (7 g, 22.5 mmol) in 1,4-dioxane and H₂0 (50 mL and 50 mL) was added LiOH-H₂0 (4.6 g, 1 12 mmol). The reaction mixture was refluxed for 2 hours, and then 400 mL ¾0 was added to the reaction mixture. After acidifying to pH 4-5 with HC1, the resulting solid were filtered to give the product of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid (6.5 g, yield: 97%). ^XH-NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 6.85 (s, 1H), 4.31 (s, 2H), 2.93-3.00 (m, 1H), 1.19-1.22 (m, 2H), 1.13-1.16 (m, 2H). MS (M+H)⁺: 296 / 298.

0549Step 5 - Synthesis of 6-amino-5-bromo-2-cyclopropyl-N-methylbenzofuran-3-carboxamide <img file="WO2014123795A2_D0117.tif" />

0550To a solution of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid (6.5 g, 22 mmol) in dry DMF (500 mL) were added EDCI (2.98 g, 2.4 mmol) and HOBT (6.33 g, 3.6 mmol). The reaction mixture was stirred at room temperature for 2 h, and then Et₃ (20 mL) and Me H₂ -HCl (7.3 g, 1 10 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and a₂C0₃ (a.q., 300 mL) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (DCM : MeOH = 30 : 1) to give the product of 6-amino-5- bromo-2-cyclopropyl-N-methylbenzofuran-3-carboxamide (5.3 g, yield: 78%). ^XH-NMR (400 MHz, CDC1₃) δ 7.69 (s, 1H), 6.77 (s, 1H), 5.88 (s, 1H), 4.1 1 (s, 2H), 3.04 (d, J = 4.8 Hz, 3H), 2.69-2.73 (m, 1H), 1.10-1.16 (m, 2H), 1.07-1.09 (m, 2H). MS (M+H)⁺: 309 / 31 1.

0551Step 6 - Synthesis of 5-bromo-2-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide

0552<img file="WO2014123795A2_D0118.tif" />

0553To a degassed solution of 6-amino-5-bromo-2-cyclopropyl-N-methylbenzofuran- 3-carboxamide (4.0 g, 13 mmol) in DCM / Pyridine (80 mL / 10 mL) was added MsCl (4.5 g, 39 mmol) under ₂ at 0 °C over a period of 30 min. The reaction mixture was stirred at 25 °C for 8 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine and dried over a2S0₄. After concentration, the residue was purified by column chromatography (PE) to give crude product of 5-bromo-2-cyclopropyl-N- methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (4.5 g, yield: 90%). ^XH-NMR (400 MHz, CDCI₃) δ 7.98 (s, 1H), 7.71 (s, 1H), 6.79 (s, 1H), 5.93 (s, 1H), 3.06 (d, J = 4.8 Hz, 3H), 2.96 (s, 3H), 2.59-2.61 (m, 1H), 1.13-1.14 (m, 2H), 1.16-1.20 (m, 2H). MS (M+H)⁺: 387 / 389. Step 7 - Synthesis of 5-bromo-2-cvclopropyl-N-methyl-6-(N-methylmethylsulfonamido) benzofuran-3-carboxami

0554o

0555<img file="WO2014123795A2_D0119.tif" />

0556To a suspension of compound 5-bromo-2-cyclopropyl-N-methyl-6-

0557(methylsulfonamido)benzofuran-3-carboxamide (1.5 g, 3.9 mmol) and K₂CO₃ (1.6 mg, 7.8 mmol) in DMF (15 mL) was added dropwise CH3I (1.1 mg, 7.8 mmol) at 0 °C under N₂, and then the mixture was stirred at 80 °C for 2 hours. After concentration in vacuum, the residue was suspended in H₂0 and extracted with DCM. The combined organic layer was washed with H₂0, brine and dried over Na₂S0₄. The mixture was filtered and concentrated to give the product of compound 5-bromo-2-cyclopropyl-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (1 g, yield: 65%). ^XH-NMR (400 MHz, CDC1₃) δ 7.70 (s, 1H), 6.98 (s, 1H), 5.63 (s, 1H), 3.05 (s, 3H), 2.79 (s, 6H), 2.39-2.43 (m, 1H), 0.95-0.97 (m, 2H), 0.89-0.91 (m, 2H). MS (M+H)⁺: 401 / 403.

0558Step 8 - Synthesis of2-cyclopropyl-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide

0559<img file="WO2014123795A2_D0120.tif" />

0560To a 2 degassed solution of 5-bromo-2-cyclopropyl-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (2.0 g, 5.0 mmol), KOAc (1.5 g, 15 mmol) and bis(pinacolato)diboron (6.3 g, 25 mmol) in dioxane (20 mL) was added Pd(dppf)Ci2 (650 mg, 1.0 mmol). The reaction mixture was stirred at 100 °C for 3 hours, and then filtered through a celite pad. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (PE : EA = 1 : 1) to give the product of compound 2-cyclopropyl-N- methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3 -carboxamide (800 mg, yield: 37%). ¾-NMR (400 MHz, CDC1₃) δ 8.02 (s, 1H), 7.41 (s, 1H), 6.14 (s, 1H), 3.32 (s, 3H), 3.06 (d, J = 4.8 Hz, 3H), 2.93 (s, 3H), 2.81-2.87 (m, 1H), 1.20 (s, 12H) 1.13-1.16 (m, 2H), 1.10-1.13 (m, 2H). MS (M+H)⁺: 449.

0561Step 9 - Synthesis of2-cyclopropyl-5-(ll-fluoro-6-(hydroxymethyl)-6H-pyridof2',3 ':5, 61fl,31 oxazinof3 - lindol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

0562<img file="WO2014123795A2_D0121.tif" />

0563To a degassed solution of 2-cyclopropyl-5-(l l-fluoro-6-(hydroxymethyl)-6H- pyrido[2 3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(TSi-methylmethylsulfonamido) benzofuran-3 -carboxamide (74 mg, 0.16 mmol), (2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4-a]indol-6-yl)methanol (50 mg, 0.16 mmol) and Κ₃Ρ0₄·3Η₂θ (131 mg, 0.49 mmol) in 1,4-dioxane (4 mL) was added Pd2(dba)3 (16 mg, 0.016 mmol) and X-Phos (16 mg, 0.03 mmol) under 2 protection. The reaction mixture was heated to 100 °C and stirred for 3 hours, and then filtered through a celite pad. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (PE : EA = 1 : 1) to give the product of 2-cyclopropyl- 5-(l l-fluoro-6-(hydroxymethyl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6- (N-methylmethylsulfonamido)benzofuran-3-carboxamide (41 mg, yield: 43%). ^XH-NMR (400 MHz, CDCI3) δ 7.85 (s, 1H), 7.43-7.48 (m, 3H), 7.13-7.22 (m, 3H), 6.81-6.85 (m, 1H), 6.42-6.44 (m, 1H), 6.02-6.04 (m, 1H), 3.96-3.98 (m, 1H), 3.84-3.87 (m, 1H), 3.33 (s, 3H), 3.02 (d, J = 4.8 Hz, 3H), 2.79-2.80 (m, 1H), 2.59 (s, 3H), 1.24 -1.27 (m, 2H), 1.16-1.19 (m, 2H). MS (M+H)⁺: 591.

0564Examples 52 and 53

0565Examples 52 &amp; 53, depicted in the table below, were prepared in accordance with the method described in Example 54.

0566<img file="WO2014123795A2_D0122.tif" /> Example 54; 5-qi-fluoro-6H-pyrido[2',3';5,61 [l,31oxazino[3,4-alindol-2-vn-N2,N3- dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide

0567<img file="WO2014123795A2_D0123.tif" />

0568Step 1 - Synthesis of methyl 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido) benzofuran-2-carboxylate <img file="WO2014123795A2_D0124.tif" />

0569To a solution of 5-bromo-2-iodo-N-methyl-6-(TSi-methylmethylsulfonamido) benzofuran-3-carboxamide (4.0 g, 8.21 mmol) in MeOH (10 mL) and DMSO (35 mL) was added Pd(PPh₃)₂Cl₂ under Ar₂. The suspension was degassed under vacuum and purged with CO 4 times. The mixture was stirred under CO (50 Psi) at 50 °C for 16 h. Then 30 mL MeOH was added to the mixture. The resulting solid was filtered to give the product of compound methyl 5-bromo-3 -(methylcarbamoyl)-6-(N-methylmethylsulfonamido) benzofuran-2- carboxylate (2.90 g, yield: 84%). ¾-NMR (CDC1₃, 400 MHz) δ 9.39 (br s, 1H), 8.94 (s, 1H), 7.74 (s, 1H), 4.08 (s, 3H), 3.34 (s, 3H), 3.08 (s, 3H), 3.04 (d, J= 4.8 Hz, 3H). MS (M+H)⁺: 419 / 421.

0570Step 2 - Synthesis of methyl 3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5- tetramethyl-1.3.2-dioxaborolan-2-yl)benzofuran-2-carboxylate

0571<img file="WO2014123795A2_D0125.tif" />

0572To a mixture of methyl 5-bromo-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-2-carboxylate (1.0 g, 2.39 mmol), bis(pinacolato)diboron (908mg, 3.58 mmol), CH₃COOK (702 mg, 7.16 mmol) in 1,4-dioxane was added Pd(dtbpf)Cl₂ under N₂. The mixture was stirred at 90 for 1.5 h. Then it was concentrated in vacuo and the residue was purified by column chromatography (PE: EA = 5: 1-DCM : MeOH = 100 : 1) to give the product of compound methyl 3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate (700 mg, yield: 64%). ^XH-NMR (CDC1₃, 400 MHz) δ 9.30 (br s, 1H), 9.06 (s, 1H), 7.62 (s, 1H), 4.07 (s, 3H), 3.35 (s, 3H), 3.05 (d, J= 4.8 Hz, 3H), 2.96 (s, 3H), 1.35 (s, 12H). MS (M+H)⁺: 467.

0573Step 3 - Synthesis of 5 methyl 5-(l l-fluoro-6H-pyrido[2',3 ': 5, 6] [1 ,3] oxazino[3,4-a] indol-2-yl)-3- (methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate

0574<img file="WO2014123795A2_D0126.tif" />

0575To a mixture of compound methyl 3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2- carboxylate (700 mg, 1.50 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (536 mg, 1.95 mmol) and K₃P0₄-3H₂0 (1.20 g, 4.50 mmol) in 1,4-dioxane (25 mL), Pd₂(dba)₃/XPhos (50 mg/50 mg) was added under ₂ protection. After stirring at 100 °C for 3 h, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over a2S0₄ and concentrated. The residue was purified by prep-TLC (DCM: MeOH = 200 : 1 ) to give the product of methyl 5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-2-carboxylate (700 mg, yield: 80%). ^XH-NMR (CDCI₃, 400 MHz) δ 9.41 (br s, 1H), 8.79 (s, 1H), 7.74 (s, 1H), 7.55-7.45 (m, 2H), 7.24-7.17 (m, 2H), 7.12 (d, J= 8.0 Hz, 1H), 6.88-6.81 (m, 1H), 6.01 (s, 2H), 4.10 (s, 3H), 3.40 (s, 3H), 3.05 (d, J = 4.4 Hz, 3H), 2.69 (s, 3H). MS (M+H)⁺: 579.

0576Step 4 - Synthesis of 5-(ll-fluoro-6H-pyridof2',3 ':5, 61 fl,31oxazino[3,4-alindol-2-yl)-3- (methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxyUc acid

0577<img file="WO2014123795A2_D0127.tif" />

0578To a suspension of compound methyl 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2- carboxylate (540 mg, 0.93 mmol) in l,4-dioxane/H₂0 (6 mL/1 mL) was added LiOH-H₂0 (196 mg, 4.67 mmol). The mixture was stirred at RT overnight. Then it was concentrated in vacuo, diluted with water, acidized with HC1 (aq. 2 M) and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂S0₄ and concentrated give the product of compound 5- (1 l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-2-carboxylic acid (500 mg, yield: 95%). It was used for the next step without further purification. ^XH-NMR (DMSO-i¾, 400 MHz) δ 9.21 (br s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.54-7.58 (m, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.28-7.1 1 (m, 2H), 7.07 (s, 1H), 6.95-6.88 (m, 1H), 6.25 (s, 2H), 3.28 (s., 3H), 2.95 (s, 3H), 2.83 (d, J= 4.4 Hz, 3H). MS (M+H)⁺: 565.

0579Step 5 - Synthesis of 5-(ll-fluoro-6H-pyridof2',3 ':5, 61 fl,31oxazino[3,4- lindol-2-yl)-N2,N3- dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide

0580<img file="WO2014123795A2_D0128.tif" />

0581A mixture of compound 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (50 mg, 0.09 mmol), HOBT (24 mg, 0.17 mmol), EDCI (102 mg, 0.53 mmol), methanamine hydrochloride (42 mg, 0.62 mmol) and Ets (72 mg, 0.71 mmol) in DMF (2 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue was purified by prep-TLC (DCM : MeOH = 200 : 1) to give the product 5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N2,N3-dimethyl-6-(N-methylmethylsulfonamido) benzofuran-2,3-dicarboxamide (20 mg, yield: 39%). ¾ NMR (CDC1₃, 400 MHz) δ 10.49 (br s, 1H), 8.81 (s, 1H), 7.68 (s, 1H), 7.49 (s, 2H), 7.24-7.17 (m, 3H), 7.12 (d, J= 8.2 Hz, 1H), 6.88-6.81 (m, 1H), 6.01 (s, 2H), 3.39 (s, 3H), 3.12 (d, J= 5.2 Hz, 3H), 3.02 (d, J= 4.8 Hz, 3H), 2.65 (s, 3H). MS (M+H)⁺: 578.

0582Examples 55 - 57

0583Examples 55-57, depicted in the table below, were prepared in accordance with the method described in Example 57. <img file="WO2014123795A2_D0129.tif" />

0584Example 58; 5-(ll-nuoro-6H-pyrido[2',3';5,61[l,31oxazino[3,4-alindol-2-vn-N-methyl-2-(5- methyl-l,3,4-oxadiazol-2-yl)-6- N-methylmethylsulfonamido)benzofuran-3-carboxamide <img file="WO2014123795A2_D0130.tif" /> Step 1 - Synthesis of 5-bromo-2-(hydrazinecarbonyl)-N-methyl-6-(N- methvimethvisuifonamido)benzofuran-3-carboxamide <img file="WO2014123795A2_D0131.tif" />

0585To a suspension of compound methyl 5-bromo-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-2-carboxylate in EtOH was added hydrazine hydrate (421 mg, 7.16 mmol). The mixture was refluxed overnight. Then it was concentrated in vacuo and the resulting solid was washed with MeCN to give the compound 5-bromo-2-

0586(hydrazinecarbonyl)-N-methyl-6-( -methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, yield: 100%). It was used for the next step without further purification. ^XH-NMR (DMSO- d₆, 400 MHz) δ 10.33 (br s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 5.03 (br s, 3H), 3.22 (s, 3H), 3.20 (s, 3H), 2.87 (d, J= 4.8 Hz, 3H). MS (M+H)⁺: 419 / 421.

0587Step 2 - Synthesis of 2-(2-acetylhydrazinecarbonyl)-5-bromo-N-methyl-6-(N- methyimethyisuifonamido)benzofuran-3-carboxamide

0588<img file="WO2014123795A2_D0132.tif" />

0589A mixture of compound 5-bromo-2-(hydrazinecarbonyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (210 mg, 0.50 mmol), EDCI (384 mg, 2.0 mmol) and acetic acid (60 mg, 1.0 mmol) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue diluted with water, and the resulting solid was filtered to give the product 2-(2-acetylhydrazinecarbonyl)-5-bromo- N-methyl-6-( -methylmethylsulfonamido)benzofuran-3-carboxamide (146 mg, yield: 63%). ¾-NMR (DMSO-i/₆, 400 MHz) δ 1 1.25 (br s, 1H), 10.22 (s, 1H), 9.68 (br s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 3.20 (s, 3H), 3.17 (s, 3H), 2.83 (d, J= 4.4 Hz, 3H), 1.92 (s, 2H). MS (M+H)⁺: 461 / 463.

0590Step 3 - Synthesis of 5-bromo-N-methyl-2-(5-methyl-l,3,4-ox diazol-2-yl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide

0591<img file="WO2014123795A2_D0133.tif" /> A mixture of compound 2-(2-acetylhydrazinecarbonyl)-5-bromo-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.33 mmol), p-TsCl (124 mg, 0.66 mmol) and Et₃N (108 mg, 0.98 mmol) in CH₂C1₂ (6 mL) was refluxed for 5 h. After concentration in vacuo, the residue was purified with prep-TLC (DCM: MeOH = 100 : 1 ) to give the product 5-bromo-N-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (146 mg, yield: 63%). ^XH-NMR (CDCI₃, 400 MHz) δ 9.80 (br s, 1H), 8.96 (s, 1H), 7.77 (s, 1H), 3.36 (s, 3H), 3.13-3.06 (m, 6H), 2.75 (s, 3H). MS (M+H)⁺: 443 / 445.

0592Step 4 - Synthesis of 5-(ll-fluoro-6H-pyridof2',3 ':5,61 fl,31oxazino[3,4- lindol-2-yl)-N-methyl- 2-(5-methyl- -ox diazol-2-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

0593<img file="WO2014123795A2_D0134.tif" />

0594To a mixture of compound 5-bromo-N-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)- 6-( -methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, 0.16 mmol), 1 l-fluoro-2- (trimethylstannyl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (95 mg, 0.24 mmol) and LiCl (20 mg, 0.47 mmol) in IPA (2 mL), chloro[(tricyclohexylphosphine)-2-(2'- aminobiphenyl)]palladium(II) (50 mg) was added under 2 protection. After stirring at 100 °C overnight, the reaction mixture was concentrated in vacuo. The residue was purified by prep- TLC (DCM: MeOH = 100 : 1 ) to give the product of 5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)-6- (N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 21%). ^XH-NMR

0595(CDCI₃, 400 MHz) δ 9.81 (br s, 1H), 8.81 (s, 1H), 7.77 (s, 1H), 7.55-7.46 (m, 2H), 7.25-7.18 (m, 2H), 7.13 (s, 1H), 6.89-6.80 (m, 1H), 6.01 (s, 2H), 3.41 (s, 3H), 3.09 (d, J= 4.4 Hz, 3H), 2.76 (s, 3H), 2.68 (s, 3H). MS (M+H)⁺: 603. Example 59 ; 5-(l l-fluoro-6H-pyrido [2 ',3 '; 5,61 [1,31 oxazino [3,4-al indol-2-yl)-2-(l-

0596(methoxyimino)ethyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide

0597<img file="WO2014123795A2_D0135.tif" />

0598<img file="WO2014123795A2_D0136.tif" />

0599To a solution of diisopropylamine (3.76 g, 37.1 mmol) in THF (25 mL) was slowly added a solution of n-BuLi (2.5 mol/L in hexane) (16.5 mL, 40.5 mmol) under ₂ at -78 °C and the resulting solution was stirred at -78 °C for 30 minutes. A solution of compound 6- amino-5-bromo-N-methylbenzofuran-3-carboxamide (2 g, 7.43 mmol) in THF (50 mL) was slowly added to the fresh lithium diisopropylamide at -78 °C and stirred for another one hour. To the resulting mixture was added N-methoxy-N-methylacetamide (3.83g, 37.16 mmol) at -78 °C and stirred for another one hour. The reaction was quenched with saturated NH₄CI at -78 °C and the mixture was slowly warmed to room temperature. Water was added and the mixture extracted with EtOAc. The organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give compound 2-acetyl-6-amino-5-bromo-N-methylbenzofuran-3- carboxamide (700 mg, yield: 30%). ^XH-NMR (CDC1₃, 400 MHz) δ 10.00 (s, 1H), 8.76 (s, 1H), 6.86 (s, 1H), 4.54 (s, 2H), 3.00 (d, J= 4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)⁺: 31 1 / 313. Step 2 - Synthesis of 2-acetyl-5-bromo-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide

0600<img file="WO2014123795A2_D0137.tif" />

0601To a mixture of 2-acetyl-6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (500 mg, 1.61 mmol) and triethylamine (650 mg, 6.43 mmol) in THF (20 mL) was added MsCl (406 mg, 3.54 mmol) dropwise at 0 °C under N₂. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with ¾0 and extracted with EtOAc, and then the combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo to give the crude product. The crude product was dissolved in THF (20 mL) and then a solution of LiOH / H₂O (200 mg / 6 mL) was added. The mixture was stirred at room temperature for 1 hour, then water was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂S0_4; and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give compound 2-acetyl- 5-bromo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (280 mg, yield: 44.8 %). ¹ H-NMR (CDCI₃, 400 MHz) δ 9.83 (s, IH), 8.97 (s, 1H),.7.91 (s, IH), 7.07 (s, IH), 3.06 (s, 3H), 3.02 (d, J= 4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)⁺: 389 / 391.

0602Step 3 - Synthesis of 2-acetyl-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide

0603<img file="WO2014123795A2_D0138.tif" />

0604To a solution of 2-acetyl-5-bromo-N-methyl-6-(methylsulfonamido)benzofuran- 3-carboxamide (150 mg , 0.38 mmol) in DMF (3 mL) was added K2CO₃ (160 mg, 1.16 mmol) and Mel (164 mg, 1.16 mmol). The mixture was heated at 60 °C for 1 hour, concentrated in vacuo to remove DMF and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂S0₄, and concentrated to give crude product. The crude product was purified by column chromatography to give 2-acetyl-5-bromo-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, yield: 45%). ^XH-NMR (CDCI₃, 400 MHz) δ 9.73 (s, IH), 9.01 (s, IH), 7.78 (s, 1H),3.35 (s, 3H), 3.09 (s, 3H), 3.02 (d, J= 4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)⁺: 403 / 405.

0605Step 4 - Synthesis of2-acetyl-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzofuran-3-carboxamide

0606<img file="WO2014123795A2_D0139.tif" />

0607To a degassed solution of 2-acetyl-5-bromo-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (420 mg, 1.04 mmol), KOAc (306 mg, 3.12 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.06 g, 4.17 mmol) 1,4-dioxane (10 niL) was added Pd(dppf)Cl2 (50 mg) under 2 protection. The mixture was stirred at 90 °C for 4 hours. The mixture was filtered through a celite pad, and the residue was concentrated to give crude product. The residue was purified by column chromatography (PE : EA = 3 : 1) to give 2-acetyl-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (220 mg, yield: 47 %). ^XH-NMR (CDC1₃, 400 MHz) δ 9.74 (s, 1H), 9.15 (s, 1H), 7.66 (s, 1H), 3.36 (s, 3H), 3.03 (d, J= 4.8 Hz, 3H), 2.98 (s, 3H), 2.77 (s, 3H), 1.36 (s, 12H). MS (M+H)⁺: 451.

0608Step 5 - Synthesis of2-acetyl-5-(ll-fluoro-6H-pyridof2',3 ':5, 61fl,31oxazinof3,4- lindol-2-yl)-N- methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

0609<img file="WO2014123795A2_D0140.tif" />

0610To a solution of compound 2-acetyl-N-methyl-6-( -methylmethylsulfonamido)- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.33 mmol), 2-chloro-l l-fluoro-6H-benzo[5,6][l,3]oxazino[3,4-a]indole (91 mg, 0.33 mmol) and CS2CO₃ (215 mg, 0.66 mmol) in 1, 4-dioxane (3 mL) and water (0.01 mL) was added Pd(dtbpf)Ci₂ (20 mg) under nitrogen. The mixture was heated at 90 °C for 3 hours and filtered through the celite pad. The filtrate was extracted with EtOAc, then the combined organic phase was washed with brine, dried over a2S0₄ and concentrated in vacuo to give the compound 2-acetyl-5-(l 1-fluoro- 6H^yrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(TSi-methylmethylsulfonamido) benzofuran-3-carboxamide (50 mg, yield: 27%) by the prep-TLC (PE : EtOAc = 1 : 1). MS (M+H)⁺: 563.

0611Step 6 - Synthesis of 5-(l l-fluoro-6H-pyridof2',3 ':5 , 61 ' fl ,31oxazino[3 ,4-alindol-2-yl)-2-(l- (methoxyimino)ethyl)-N-methyl-6-(N-methylmethylsulfonam

0612<img file="WO2014123795A2_D0141.tif" />

0613To a solution compound 2-acetyl-5-(l l-fluoro-6H- pyrido[2',3 ': 5 ,6] [1,3] oxazino [3 ,4-a] indol-2-y l)-N-methy l-6-( - methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.088 mmol) in ethanol (1.5 mL) was added O-methylhydroxylamine hydrochloride (25 mg, 0.26 mmol) and 2 drops pyridine. The resulting mixture was stirred at 70 °C for 2 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the product of (E)-5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(l-(methoxyimino)ethyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 40 %). ^XH-NMR (CDCI₃, 400 MHz) δ 9.56 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J= 10 Hz, 2H), 7.18 ~ 7.23 (m, 2H), 7.10 (d, J= 8.0 Hz, 1H), 6.84 (t, J= 8.0 Hz, 1H), 5.99 (s, 2H), 4.12 (s, 3H), 3.41 (s, 3H), 2.99 (d, J= 4.8 Hz, 3H), 2.66 (s, 3H), 2.41 (s, 3H). MS (M+H)⁺: 592.

0614Example 60

0615Measuring Compound Inhibitory Potency

0616Measurement of inhibition by compounds was performed using the HCV replicon system. Several different replicons encoding different HCV genotypes or mutations were used. In addition, potency measurements were made using different formats of the replicon assay, including different ways of measurements and different plating formats. See Jan M. Vrolijk et ah, A replicons-based bioassay for the measurement of interferons in patients with chronic hepatitis C, 1 10 J. ViROLOGiCAL METHODS 201 (2003); Steven S. Carroll et al, Inhibition of Hepatitis C Virus RNA Replication by 2'-Modifled Nucleoside Analogs, 278(14) J. BIOLOGICAL CHEMISTRY 11979 (2003). However, the underlying principles are common to all of these determinations, and are outlined below.

0617Stable neomycin phosphotransferase encoding replicons-harboring cell lines were used, so all cell lines were maintained under G418 selection prior to the assay. Potency was deteremined using a cell ELISA assay with an antibody to the replicons encoded NS3/4a protease. See Caterina Trozzi et al. , In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor, 77(6) J. Virol. 3669 (2003). To initiate an assay, replicon cells were plated in the presence of a dilution series of test compound in the absence of G418. Typically, the assays were performed in a 96-well plate formate for manual operation, or a 384-well plate format for automated assay. Replicon cells and compound were incubated for 96 hours. At the end of the assay, cells were washed free of media and compound, and the cells were then lysed. RNA was quantified indirectly through detection of replicon-encoded NS3/4A protein levels, through an ELISA-based assay with an antibody specific for NS3/4A. IC5₀ determinations were calculated as a percentage of a DMSO control by fitting the data to a four-parameter fit function and the data obtained is provided in the table below.

0618Data for selected compounds of the present invention was obtained for genotypes la and lb using this method and is provided in the table below:

0619<img file="WO2014123795A2_D0142.tif" /> 25 3.0 5.0 55 4.0 6.4

062026 118 108 56 5.0 11

062127 23 34 57 232 135

062228 9.0 6.9 58 8.1 7.9

062329 13 25 59 34 13

062430 11 25

0625It will be appreciated that various of the above-discussed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.