Inhibitors of RNA helicase DHX9 and uses thereof

Abstract

Provided are compounds of the Formula (I): or pharmaceutically acceptable salts thereof, which are useful for the inhibition of DHX9 and in the treatment of a variety of DHX9 mediated conditions or diseases, such as cancer.

Description

[0001] INHIBITORS OF RNA HELICASE DHX9 AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 532,210, filed on August 11, 2023. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0004] FIELD OF THE INVENTION

[0005] The present disclosure relates to inhibitors of RNA helicase DHX9, and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, and their use in the treatment of diseases.

[0006] REFERENCE TO ELECTRONIC SEQUENCE LISTING

[0007] The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on July 19, 2024, is named “130090-01420. xml” and is 14,838 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety.

[0008] BACKGROUND OF THE INVENTION

[0009] DHX9, also known as RNA Helicase A (RHA) or Nuclear DNA Helicase II (NDH II), is a DExH-box RNA helicase, which shuttles between nucleus and cytoplasm, and can use all four NTPs to power cycles of directional movement from 3’ to 5’. Functionally, DHX9 can bind to and unwind or resolve dsDNA / RNA, ssDNA / RNA, DNA:RNA hybrids (such as R-loops), circular RNA, and DNA / RNA G quadruplexes. As such, DHX9 has regulatory roles in various RNA and DNA related cellular processes, such as transcription, translation, RNA splicing, editing, RNA transport and processing, microRNA genesis, and maintenance of genomic stability (Pan et al., 2021, Current Protein & Peptide Science (22), 29-40).

[0010] Due to its regulatory role in processes such as transcription and maintenance of genomic stability, DHX9 has shown to be a key regulator in a variety of cancer types (Gulliver et al., 2020, Future Science OA (2), FSO650). DHX9 has been shown to be involved in the regulation of genes associated with sustained proliferative signaling, evasion of growth suppressors, evasion of apoptosis, angiogenesis, and metastasis, all of which are hallmarks of cancer. Specifically, micro satellite instable cancers, such as Micro satellite Instable (MSI) colorectal cancer, and tumors with defective MisMatch Repair (MMR) exhibit a strong dependence on DHX9.

[0011] In addition to its role in cancer, DHX9 has been implicated in other diseases involving gene replication, translation or regulation. These diseases include viral infections and autoimmune disease.

[0012] Thus, there is a need for DHX9 inhibitors as potential therapeutic agents for treating diseases or disorders that are responsive to DHX9 inhibition.

[0013] SUMMARY OF THE INVENTION

[0014] The present disclosure provides compounds that are DHX9 inhibitors. In a first embodiment, the present disclosure relates to compounds having the Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0015] J is N or CH;

[0016] J1is N or CX1;

[0017] X1and X2are each independently H, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, CN, or C(O)RX;

[0018] Rxis H, -OH, -OC1-4alkyl, or C1-4alkyl;

[0019] Z is N or CRZ;

[0020] Rzis H, halo, cyano, C1-4alkyl, Cwhaloalkyl, OR3a, or C(O)NR3bR3c; one of T1and T2is O and the other is -CRT1R12-;

[0021] RT1and RT2are each independently H, D, halo, or C1-4alkyl;

[0022] R1is C1-4alkyl or C3-6cycloalkyl; wherein the Cwalkyl or C3-6cycloalkyl are each optionally and independently substituted with 1 to 3 halo or OH;

[0023] Ring A is 5 to 6-membered monocyclic heteroaryl; Ring B is phenyl, 6-membered monocyclic heteroaryl, 9-membered bicyclic heterocyclyl, or 9-membered bicyclic heteroaryl; m is 0 to 3; n is 1 to 3; each R2is independently selected from C1-4alkyl, C3-6cycloalkyl, halo, OR2a, cyano, - NR2bR2c, -SO2R2a, -C(O)R2d, and -C(O)NR2bR2c, wherein the Cwalkyl and C3-6cycloalkyl are optionally substituted with 1 to 4 R2e;

[0024] R2ais H, C1-4alkyl, C1-4haloalkyl or C1-4alkoxyC1-4alkyl;

[0025] R2dis H, C1-4alkyl, C3-6cycloalkyl, OR2a, phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the Cwalkyl is optionally substituted with 1 to 3 halo;

[0026] R2band R2care each independently selected from H, C1-4alkyl, C3-6cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R2band R2c, together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R2d; each R2eis independently selected from halo, cyano, NR2bR2c, OR2a, phenyl, and 4 to 6 membered monocyclic heterocyclyl;

[0027] R3is halo, cyano, C1-4alkyl, Cwhaloalkyl, OR3a, - NR3bR3c, -C(O)R3a, -C(O)OR3a, C(O)NR3bR3c, C3-6cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C1- 4alkyl, C3-6cycloalkyl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R5;

[0028] R3ais H, C1-6alkyl, or 4 to 6-membered monocyclic heterocyclyl, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH and the 4 to 6-membered monocyclic heterocyclyl is optionally substituted with one or more C1-4alkyl,

[0029] R3band R3care each independently selected from H, C1-4alkyl, and Cwhaloalkyl, or R3band R3c, together with the atom to which they are attached form 4 to 6-membered monocyclic heterocyclyl optionally substituted with one or more substituents selected from halo, C1-4alkyl, C1-4haloalkyl, and Cwalkoxy; each R4is independently selected from C1-4alkyl, Cwhaloalkyl, halo, OR4a, cyano, - NR4bR4c, -C(O)R4a, -C(O)OR4a, -C(O)NR4bR4c, -NR4bC(O)R4a-NR4bC(O)OR4a, -SR4a, - S(O)R4a, -NR4bSO2R4a, -SO2R4a, -S(O)(NR4b)R4a, -SO2NR4bR4c, or -P(O)R4bR4c; or 2 R4together with the atom to which they are attached, form oxo;

[0030] R4ais H, C1-4alkyl, C1-4haloalkyl, or C3-6cycloalkyl;

[0031] R4band R4care each independently selected from H, C1-4alkyl, C1-4haloalkyl, or C1- 4alkoxy, or R4band R4c, together with the atom to which they are attached form 4 to 6- membered monocyclic heterocyclyl optionally substituted with one or more substituents selected from halo, C1-4alkyl, C1-4haloalkyl, and -OR4a; each R5is independently C1-4alkyl, C1-4haloalkyl, halo, OR5a, -C(O)R5a, or 4 to 6- membered monocyclic heterocyclyl, wherein the 4 to 6-membered monocyclic heterocyclyl is optionally substituted with one or more C1-4alkyl;

[0032] R5ais H, C1-4alkyl, or C1-4haloalkyl; provided that: when ring B is phenyl:

[0033] (i) n is 2 or 3; or

[0034] (ii) at least one R4is -SO2R4aor -P(O)R4bR4c; and

[0035] Another aspect of the disclosure relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier.

[0036] In yet another aspect, the present disclosure provides a method of treating a disease or disorder that is responsive to inhibition of DHX9 in a subject comprising administering to said subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for the treatment of cancer. Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibition of DHX9. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder responsive to inhibition of DHX9.

[0037] DETAILED DESCRIPTION OF THE INVENTION

[0038] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in the treatment of diseases or disorders through mediation of DHX9 function / activity. In some embodiments, the compounds of present disclosure are DHX9 inhibitors.

[0039] COMPOUNDSAND COMPOSITIONS

[0040] In a first embodiment, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (I) are as defined above.

[0041] In a second embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, X2is H; and the remaining variables are as described in the first embodiment.

[0042] In a third embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, X1is H or halo; and the remaining variables are as described in the first or second embodiment.

[0043] In a fourth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, X1is H, -F, or -Cl; and the remaining variables are as described in the first or second embodiment. In a fifth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, X1is -Cl; and the remaining variables are as described in the first or second embodiment.

[0044] In a sixth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, T1is O and T2is -CR1 1R12-; and the remaining variables are as described in the first, second, third, fourth, or fifth embodiment.

[0045] In a seventh embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, RT1is H and R12is H or -CH3; and the remaining variables are as described in the first, second, third, fourth, fifth, or sixth embodiment.

[0046] In an eighth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, Z is N; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0047] In a ninth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, J is CH and J1is CX1; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0048] In a tenth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, m is 1, 2, or 3; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0049] In an eleventh embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, n is 1; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0050] In a twelfth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, n is 2 or 3; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0051] In a thirteenth embodiment, the compound of the present disclosure is represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein X1is H, halo, C1-4alkyl, C1- 4haloalkyl, Cwalkoxy, or CN, and R12is H or C1-4alkyl; and the remaining variables are as described in the first embodiment.

[0052] In a fourteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring A is thiophenyl, pyrrolyl, pyrazolyl, or isothiazolyl, each of which is optionally substituted by 1 or 2 R2; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0053] In a fifteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring A is represent by the formula: optionally substituted by 1 or 2 R2; wherein represents the connection to the amide and represents the connection to the adjacent ring; and the remaining variables are as described in the fourteenth embodiment.

[0054] In a sixteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring A is represent by the formula: connection to the adjacent ring; and the remaining variables are as described in the fifteenth embodiment.

[0055] In a seventeenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R2is independently selected from C1-4alkyl, C3-4cycloalkyl, halo, OR2a, cyano, wherein the C1-4alkyl is optionally substituted with 1 to 3 R2e; R2ais H or C1-4alkyl, each R2eis independently selected from halo and OR2a; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0056] In an eighteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R2is independently selected from -CH3, - CH2CH3, -CH2CF3, -CH2OH, -CH(OH)CH3, -CH2CH2OH, -OCH3, -Cl, -CN, and cyclopropyl; and the remaining variables are as described in the seventeenth embodiment.

[0057] In a nineteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R2is Cwalkyl optionally substituted with 1 to 3 halo or OH; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0058] In a twentieth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R2is -CH3, -CH2CF3, or -CH2OH; and the remaining variables are as described in the nineteenth embodiment.

[0059] In a twenty-first embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring B is phenyl, pyridinyl, pyridinoyl, benzoxazoyl, or isoindolin-1-onyl, each of which is optionally substituted by 1 to 3 R4; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0060] In a twenty- second embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring B is represented by the formula: each of which is optionally substituted by 1 to 3 R4; and the remaining variables are as described in the twenty-first embodiment.

[0061] In a twenty-third embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring B is represented by the formula:

[0062] remaining variables are as described in the twenty-second embodiment.

[0063] In a twenty-fourth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring B is phenyl or pyridinyl, each of which is optionally substituted by 1 to 2 R4; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0064] In a twenty-fifth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring B is represented by the formula: or , each of which is optionally substituted by 1 to 2 R4; and the remaining variables are as described in the twenty-fourth embodiment.

[0065] In a twenty- sixth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, ring B is represented by the formula: or and the remaining variables are as described in the twenty-fifth embodiment.

[0066] In a twenty- seventh embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is halo, C1-4alkyl, C1-4haloalkyl, -OR3a, cyano, C3-6cycloalkyl, or 4- to 6-membered heterocyclyl, wherein the C1-4alkyl, C3-6cycloalkyl, and the 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 R5; R3ais H, C1- 6alkyl, or 4 to 6-membered monocyclic heterocyclyl, wherein the C1-6alkyl is optionally substituted with 1 to 2 -OH and the 4 to 6-membered monocyclic heterocyclyl is optionally substituted with one or more C1-4alkyl; each R5is independently C1-4alkyl, Cwhaloalkyl, C1- 4alkoxy, halo, OH, -C(O)R5a, or 4 to 6-membered monocyclic heterocyclyl, wherein the 4 to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 2 C1-4alkyl; R5ais C1- 4alkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty- third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment. In some embodiments, the 4 to 6-membered moncyclic heterocyclyl represented by R3, R3aand / or R5is azetidinyl, oxatanyl or tetrahydropyranyl.

[0067] In a twenty-eighth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is -F, -CH3, -CF3, -CH2OCH3, -OCH3, - OCH(CH3)2, -OC(CH3)3, -OCH2C(CH3)2OH, or -CN, or R3is represented by the formula: and the remaining variables are as described in the twentyseventh embodiment. in a twenty-ninth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is halo or C1-4haloalkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, or twenty- sixth embodiment.

[0068] In a thirtieth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is -F or -CF3; and the remaining variables are as described in the twenty-ninth embodiment.

[0069] In a thirty-first embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, Rzis halo or C1-4haloalkyl, preferably wherein Rzis -F or -CF3; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty- third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment.

[0070] In a thirty- second embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R4is independently selected from halo, C1-4alkyl, Cwhaloalkyl, OR4a, cyano, -NR4bR4c, -C(O)NR4bR4c, -C(O)OH, -SR4a, -S(O)R4a, - NR4bSO2R4a, -SO2R4a, -S(O)(NR4b)R4a, -SO2NR4bR4c, or -P(O)R4bR4c; or 2 R4, together with the atoms to which they are attached, form oxo; R4ais H, C1-4alkyl, or Cwhaloalkyl; R4band R4Care each independently selected from H, C1-4alkyl, and Cwalkoxy; or R4band R4c, together with the atom to which they are attached form 4 to 6-membered monocyclic heterocyclyl optionally substituted with 1 to 3 halo; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twentysixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment.

[0071] In a thirty-third embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R4is independently -F, -Cl, -CH3, - C(CH3)2OH, -CHF2, -CF3, -OH, -OCHF2, -OCF3, -CN, -C(O)NH2, -C(O)OH, -SCH3, - S(O)CH3, -SO2CH3, -SO2CF3, -SO2CH2CH3, -SO2CH2CH2OH, -S(O)(NH)CH3, - S(O)(NCH3)CH3, -P(O)(CH3)2, -P(O)(CH3)CH2CH3, -P(O)(CH2CH3)2, -P(O)(OCH3)2, or and the remaining variables are as described in the thirty-second embodiment.

[0072] In a thirty-fourth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R4is independently halo, C1-4haloalkyl, cyano, -SO2R4a, -S(O)(NR4b)R4a, or -P(O)R4bR4c; R4ais C1-4alkyl, R4band R4care each independently selected from H and C1-4alkyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twentyseventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment.

[0073] In a thirty-fifth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R4is independently -F, -CF3, -CN, -SO2CH3, - S(O)(NH)CH3, -S(O)(NCH3)CH3, or -P(O)(CH3)2; and the remaining variables are as described in the thirty-fourth embodiment. In a thirty- sixth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R1is Cwalkyl optionally substituted with -OH; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment.

[0074] In a thirty- seventh embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R1is -CH3, -CH2CH3or -CH2CH2OH; and the remaining variables are as described in the thirty-sixth embodiment. In some embodiments, R1is -CH3.

[0075] In a thirty-eighth embodiment, the compound of the present disclosure is represented by Formula (III): or a pharmaceutically acceptable salt thereof, wherein:

[0076] X1is H or halo;

[0077] R1is C1-3alkyl;

[0078] R2is C1-3alkyl or C1-3haloalkyl;

[0079] R3is halo or C1-3haloalkyl;

[0080] R4is halo, C1-3haloalkyl, -P(O)R4bR4c, or -SO2R4a;

[0081] R4a, R4b, and R4care each C1-3alkyl; and the remaining variables are as described in the first embodiment.

[0082] In a thirty-ninth embodiment, for the compounds of Formula (III), or a pharmaceutically acceptable salt thereof, Q is N; and the remaining variables are as described in the thirty-eighth embodiment.

[0083] In a fortieth embodiment, for the compounds of Formula (III), or a pharmaceutically acceptable salt thereof, Q is CR4; and the remaining variables are as described in the thirtyeighth embodiment. In a forty-first embodiment, for the compounds of Formula (III), or a pharmaceutically acceptable salt thereof, X1is H or Cl; R1is CH3; R2is -CH3or -CH2CF3; R3is -F or -CF3; R4is -F, -CH3, -SO2CH3, or -P(O)(CH3)2; and the remaining variables are as described in the thirty-eighth, thirty-ninth, or fortieth embodiment.

[0084] In a forty-second embodiment, the compound of the present disclosure is represented by Formula (IVA) or (IVB): or a pharmaceutically acceptable salt thereof, wherein:

[0085] X1is H or halo;

[0086] Q is N or CR4;

[0087] R1is C1-4alkyl;

[0088] R2is C1-4alkyl optionally substituted with 1 or 2 R4e;

[0089] R4eis OH;

[0090] R3is halo; each R4is independently selected from halo, C1-3haloalkyl, cyano, -P(O)R4bR4c, - SO2R4a, or -S(O)(NR4b)R4a;

[0091] R4aand R4care each C1-3alkyl;

[0092] R4bis H or C1-3alkyl; and the remaining variables are as described in the first embodiment.

[0093] In a forty-third embodiment, for the compounds of Formula (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, Q is N; and the remaining variables are as described in the forty- second embodiment.

[0094] In a forty-fourth embodiment, for the compounds of Formula (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, Q is CR4; and the remaining variables are as described in the forty-second embodiment.

[0095] In a forty-fifth embodiment, for the compounds of Formula (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, X1is H or Cl; R1is CH3; R2is -CH3or -CH2OH; R3is -F; R4is -F, -CH3, -CN, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -SO2CH3, or -P(O)(CH3)2; and the remaining variables are as described in the forty-second, forty-third, or forty-fourth embodiment.

[0096] In a forty-sixth embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1 to 189), or a pharmaceutically acceptable salt thereof.

[0097] Alternatively, as part of the forty-sixth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0098] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((3-fluoro-5- (trifluoromethyl)benzyl)oxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0099] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((2-chloro-5-fluorobenzyl)oxy)-5- fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0100] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5- fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0101] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((5-chloropyridin-3-yl)methoxy)-5- fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0102] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-((3,5- difluorobenzyl)oxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0103] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-fluoro-5- (methylsulfonyl)benzyl)oxy)-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2- carboxamide;

[0104] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- (trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0105] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-5-(5-fluoro-3-((5-fluoropyridin- 3-yl)methoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0106] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((3- (difluoromethyl)-5-fluorobenzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0107] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((6-(2-hydroxypropan-2- yl)pyridin-2-yl)methoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0108] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5- (trifluoromethoxy)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0109] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(dimethylphosphoryl)-5- fluorobenzyl)oxy)-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0110] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(difluoromethoxy)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide; N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(dimethylphosphoryl)-5- fluorobenzyl)oxy)-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2- carboxamide;

[0111] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((5-fluoro-2-methyl-3- (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0112] 4-(3-((3,5-difluorobenzyl)oxy)-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5- methyl-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0113] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-(ethyl(methyl)phosphoryl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0114] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(diethylphosphoryl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0115] 4-(3-((5-fluoropyridin-3-yl)methoxy)-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2- yl)-5-methyl-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0116] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5- (methylsulfinyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0117] 4-(3-((3,5-difluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methyl-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0118] 3-(((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophen-3- yl)-5-fluoropyridin-3-yl)oxy)methyl)-5-fluoropyridine 1-oxide;

[0119] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(ethyl(methyl)phosphoryl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0120] 3-fluoro-5-(((5-fluoro-2-(2-methyl-5-((3- (methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)pyridin-3-yl)oxy)methyl)pyridine 1- oxide;

[0121] 4-(3-((3,5-difluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methyl-N-(3-methyl-5- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0122] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5-(2- hydroxypropan-2-yl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0123] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- ( trifluoromethyl )pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0124] 4-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-N-(3-fluoro-5- (methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0125] 4-(3-((3,5-difluorobenzyl)oxy)-5-fluoropyridin-2-yl)-N-(3-methoxy-5- (methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide; N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-lH-pyrrole-3-carboxamide;

[0126] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(ethylsulfonyl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0127] 5-(5-fluoro-3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-N-(3-

[0128] (methylsulfonamido)phenyl)-1-(2,2,2-trifluoroethyl)-lH-pyrrole-3-carboxamide;

[0129] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((3,5- difluorobenzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0130] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0131] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-chloro-5-fluorobenzyl)oxy)-5- fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0132] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0133] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5- fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0134] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-((3-

[0135] (difluoromethoxy)-5-fluorobenzyl)oxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0136] 4-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methyl-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0137] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-(diethylphosphoryl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0138] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-((3-fluoro-5- (trifluoromethoxy)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0139] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((l-methyl-2-oxo-1,2- dihydropyridin-4-yl)methoxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0140] 4-(5-cyano-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methyl-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0141] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-((3-(difluoromethoxy)-5- fluorobenzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0142] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((l-methyl-2-oxo-1,2- dihydropyridin-3-yl)methoxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0143] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((5-

[0144] (methylsulfonyl)pyridin-3-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide; N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((3- (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-1-methyl- lH-pyrrole-3-carboxamide;

[0145] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((6-(2-hydroxypropan-2- yl)pyridin-2-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0146] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-

[0147] (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0148] 4-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methyl-N-(5-

[0149] (methylsulfonamido)pyridin-3-yl)thiophene-2-carboxamide;

[0150] 4-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methyl-N-(3- methyl-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0151] 5-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-1-methyl-N-(3- methyl-5-(methylsulfonamido)phenyl)-lH-pyrrole-3-carboxamide;

[0152] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5-

[0153] (trifluoromethyl)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0154] 4-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-N-(3-((2- hydroxyethyl)sulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0155] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5-

[0156] (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0157] 5-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-1-methyl-N-(3-

[0158] (methylsulfonamido)-5-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxamide;

[0159] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-cyano-5-fluorobenzyl)oxy)-5- fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0160] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide; dimethyl (3-(((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2- methylthiophen-3-yl)-5-fluoropyridin-3-yl)oxy)methyl)-5-fluorophenyl)phosphonate;

[0161] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-(dimethylphosphoryl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0162] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((2-chloro-5-fluoropyridin-3- yl)methoxy)-5-fluoropyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0163] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-fluoro-5-

[0164] (trifluoromethoxy)benzyl)oxy)-5-(l-hydroxycyclobutyl)pyridin-2-yl)-5-methylthiophene-2- carboxamide; N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-cyano-3-((3,5- difluorobenzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0165] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((3-fluoro-5-

[0166] (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-4-methylthiophene-2-carboxamide;

[0167] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-(dimethylphosphoryl)-5-fluoro- 2-methylbenzyl)oxy)-5-fluoropyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0168] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((5-fluoro-2-(2- hydroxypropan-2-yl)pyridin-3-yl)methoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3- carboxamide;

[0169] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-((3-(dimethylphosphoryl)- 5-fluorobenzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0170] 5-(3-((3,5-difluorobenzyl)oxy)-5-fluoropyridin-2-yl)-1-methyl-N-(5-

[0171] (methylsulfonamido)pyridin-3-yl)-lH-pyrrole-3-carboxamide;

[0172] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5- ((trifluoromethyl)sulfonyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0173] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((2,5-difluoro-3-

[0174] (methylsulfonyl)benzyl)oxy)-5-fluoropyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0175] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5-

[0176] (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0177] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0178] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((5-chloropyridin-3-yl)methoxy)-5- fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0179] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((5-fluoropyridin-3-yl)methoxy)-5- (trifluoromethyl)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0180] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0181] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0182] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-chloro-5-fluorobenzyl)oxy)-5- fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0183] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide; N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5-

[0184] (trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0185] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- isopropoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0186] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5- isopropoxypyridin-2-yl)-1-methyl- lH-pyrrole-3-carboxamide;

[0187] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(dimethylphosphoryl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0188] 4-(3-((3-carbamoyl-5-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-N-(3-chloro-5- (methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0189] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(dimethylphosphoryl)-5- fluorobenzyl)oxy)-5-isopropoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0190] 4-(3-((3-(dimethylphosphoryl)-5-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methyl- N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0191] 4-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0192] 4-(5-fluoro-3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methyl-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0193] 5-(5-fluoro-3-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-1-methyl-N-(3- (methylsulfonamido)phenyl)-lH-pyrrole-3-carboxamide;

[0194] 5-(5-(l-acetylazetidin-3-yl)-3-((3,5-difluorobenzyl)oxy)pyridin-2-yl)-N-(3-chloro-5- (methylsulfonamido)phenyl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0195] 5-(3-((3-(dimethylphosphoryl)-5-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-1-methyl- N-(3-(methylsulfonamido)phenyl)-lH-pyrrole-3-carboxamide;

[0196] 4-(3-((3-(dimethylphosphoryl)-5-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0197] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((3-fluoro-5-(2- hydroxypropan-2-yl)benzyl)oxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0198] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(((5-fluoropyridin-3- yl)oxy)methyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0199] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5- (methylsulfonyl)phenoxy)methyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0200] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5- methoxypyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide; (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(1-(3-fluoro-5-

[0201] (methylsulfonyl)phenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0202] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(1-(3-fluoro-5-

[0203] (methylsulfonyl)phenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0204] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-(1-(3-fluoro-5-

[0205] (methylsulfonyl)phenyl)ethoxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0206] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-(1-(3-fluoro-5-

[0207] (methylsulfonyl)phenyl)ethoxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0208] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(1-(3-fluoro-5-

[0209] (methylsulfonyl)phenyl)ethoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0210] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(1-(3-fluoro-5-

[0211] (methylsulfonyl)phenyl)ethoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0212] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(1-(5-fluoropyridin-3- yl)ethoxy)pyridin-2-yl)- 1 -methyl- 1 H-pyrrole-3-carboxamide;

[0213] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(1-(5-fluoropyridin-3- yl)ethoxy)pyridin-2-yl)- 1 -methyl- 1 H-pyrrole-3-carboxamide;

[0214] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(1-(5-fluoropyridin-3- yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0215] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(1-(5-fluoropyridin-3- yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0216] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3-(dimethylphosphoryl)-5- fluorophenyl)ethoxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0217] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3-(dimethylphosphoryl)-5- fluorophenyl)ethoxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0218] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)- 5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0219] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)- 5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0220] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-(l-

[0221] (3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0222] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-(l-

[0223] (3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0224] (R)-3-(1-((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2- methylthiophen-3-yl)-5-fluoropyridin-3-yl)oxy)ethyl)-5-fluoropyridine 1 -oxide; (S)-3-(1-((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2- methylthiophen-3-yl)-5-fluoropyridin-3-yl)oxy)ethyl)-5-fluoropyridine 1 -oxide;

[0225] 3-(((2-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1-methyl-lH-pyrrol-2- yl)-5-fluoropyridin-3-yl)oxy)methyl)-5-fluorobenzoic acid;

[0226] N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-((5- fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0227] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-((5- fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0228] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((3,5- difluorobenzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0229] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1- yl)-3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0230] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0231] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((5- fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0232] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0233] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0234] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-cyano-5-fluorobenzyl)oxy)-5-

[0235] (3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0236] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-((5- fluoropyridin-3-yl)methoxy)pyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0237] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-((3,5- difluorobenzyl)oxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0238] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0239] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2,4-difluoro-6-((5-fluoropyridin-3- yl)methoxy)phenyl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0240] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5-

[0241] ( trifluoromethyl )pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0242] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)-lH-pyrrole-3-carboxamide; N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5- (trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-(hydroxymethyl)thiophene-2-carboxamide;

[0243] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5- (trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-(l-hydroxyethyl)thiophene-2-carboxamide;

[0244] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5- (trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-(l-hydroxyethyl)thiophene-2-carboxamide;

[0245] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-((3-fluoro-5- (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0246] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0247] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-((3-fluoro-5- (trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-methyl-lH-pyrrole-3-carboxamide;

[0248] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-(3,3-difluoroazetidin-1-yl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)- 1 -methyl- lH-pyrrole-3-carboxamide;

[0249] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(3,3-difluoroazetidin-1-yl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0250] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((3-fluoro-5- (methylthio)benzyl)oxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0251] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((3-fluoro-5- (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-1-methyl- lH-pyrrole-3-carboxamide;

[0252] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5-((2- hydroxyethyl)sulfonyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0253] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-cyano-5-fluorobenzyl)oxy)-5- (3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0254] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5-(hydroxymethyl)thiophene-2- carboxamide;

[0255] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(5-fluoro-3-((3-fluoro-5- (methylsulfonyl)benzyl)oxy)pyridin-2-yl)isothiazole-5-carboxamide;

[0256] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((6-fluoro-2- methylbenzo[d]oxazol-4-yl)methoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0257] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((6-fluoro-3,3-dimethyl-1- oxoisoindolin-4-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide; 5-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-((5-fluoropyridin-

[0258] 3-yl)methoxy)pyridin-2-yl)-lH-pyrrole-3-carboxamide;

[0259] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-fluoro-2-((3-fluoro-5-

[0260] (methylsulfonyl)benzyl)oxy)-6-methylphenyl)-lH-pyrazole-4-carboxamide;

[0261] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyano-4-(5-fluoro-3-((5-fluoropyridin- 3-yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0262] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(5-fluoro-3-((3-fluoro-5-

[0263] (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-lH-pyrazole-5-carboxamide;

[0264] 4-(5-cyano-3-((3,5-difluorobenzyl)oxy)pyridin-2-yl)-5-methyl-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0265] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((5-(2-hydroxypropan-2- yl)pyridin-3-yl)methoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0266] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(((5-fluoropyridin-3- yl)oxy)methyl)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0267] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0268] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-(((5- fluoropyridin-3-yl)oxy)methyl)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0269] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0270] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5-((l- methylazetidin-3-yl)oxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0271] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5-((l- methylazetidin-3-yl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0272] 4-(5-(azetidin-3-yloxy)-3-((3,5-difluorobenzyl)oxy)pyridin-2-yl)-N-(3-chloro-5- (methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0273] 5-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((5-fluoropyridin- 3-yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0274] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- fluoropyridin-2-yl)-5-methoxythiophene-2-carboxamide;

[0275] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(5-fluoro-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0276] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)-5- (methoxymethyl)pyridin-2-yl)-lH-pyrazole-4-carboxamide; N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-((3- fluoro-5-(methylsulfonyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0277] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5- fluoropyridin-2-yl)-5-(2-hydroxyethyl)thiophene-2-carboxamide;

[0278] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((3-fluoro-5-(S- methylsulfonimidoyl)benzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0279] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-(N,S-dimethylsulfonimidoyl)-5- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0280] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-cyano-5-fluorobenzyl)oxy)-5- fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0281] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((5-fluoro-2-methylpyridin-

[0282] 3-yl)methoxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0283] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3-

[0284] (dimethylphosphoryl)benzyl)oxy)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0285] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3-

[0286] (dimethylphosphoryl)benzyl)oxy)-5-fluoropyridin-2-yl)-1-methyl-lH-pyrrole-3- carboxamide;

[0287] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-difluorobenzyl)oxy)-5- fluoropyridin-2-yl)-lH-pyrrole-3-carboxamide;

[0288] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((3-fluoro-5-

[0289] (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-lH-pyrrole-3-carboxamide;

[0290] 4-(5-(tert-butoxy)-3-((3,5-difluorobenzyl)oxy)pyridin-2-yl)-N-(3-chloro-5-

[0291] (methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0292] 4-(5-(tert-butoxy)-3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-

[0293] (methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0294] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-fluoro-2-((3-fluoro-5-

[0295] (methylsulfonyl)benzyl)oxy)phenyl)-lH-pyrazole-4-carboxamide;

[0296] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-((3-fluoro-5-

[0297] (methylsulfonyl)benzyl)oxy)pyridin-2-yl)-lH-pyrazole-4-carboxamide;

[0298] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-4-(5-fluoro-3-((5- fluoropyridin-3-yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0299] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-4-(3-((3,5- difluorobenzyl)oxy)-5-fluoropyridin-2-yl)thiophene-2-carboxamide; N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)-5- methoxypyridin-2-yl)-lH-pyrazole-4-carboxamide;

[0300] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)-5- ((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-lH-pyrazole-4-carboxamide;

[0301] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)-5-(oxetan- 3-yloxy)pyridin-2-yl)-lH-pyrazole-4-carboxamide;

[0302] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)-5-(2- hydroxy-2-methylpropoxy)pyridin-2-yl)-lH-pyrazole-4-carboxamide;

[0303] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-cyano-3-((3,5- difluorobenzyl)oxy)pyridin-2-yl)-1-methyl-lH-pyrrole-3-carboxamide;

[0304] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-((3,5- difluorobenzyl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0305] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-cyano-3-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)- 1-methyl- lH-pyrrole-3-carboxamide;

[0306] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(1-((5-fluoropyridin-3- yl)oxy)ethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0307] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(1-((5-fluoropyridin-3- yl)oxy)ethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0308] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5-(l- hydroxy-1-(l-methylazetidin-3-yl)ethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide; and

[0309] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorobenzyl)oxy)-5-(3- hydroxy-1-methylazetidin-3-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide; or a pharmaceutically acceptable salt thereof.

[0310] The compounds and intermediates described herein may be isolated and used as the compound per se. Alternatively, when a moiety is present that is capable of forming a salt, the compound or intermediate may be isolated and used as its corresponding salt. As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound described herein. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfomate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

[0311] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0312] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0313] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0314] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0315] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0316] The salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0317] Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed. In one embodiment, the present disclosure provides deuterated compounds described herein or a pharmaceutically acceptable salt thereof.

[0318] Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, de-DMSO.

[0319] It will be recognized by those skilled in the art that the compounds of the present disclosure may contain chiral centers and as such may exist in different stereoisomeric forms. As used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound.

[0320] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “racemic” or “rac” is used to designate a racemic mixture where appropriate. When designating the stereochemistry for the compounds of the present disclosure, a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)). “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R- S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times for the corresponding enantiomers / diastereomers via chiral HPLC. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0321] Unless specified otherwise, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAKR™ and CHIRALCELR™ available from DAICEL Corp, using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0322] The present disclosure also provides a pharmaceutical composition comprising a compound described herein (e.g., a compound according to any one of the preceding embodiments), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0323] METHODS OF USE

[0324] The compounds described herein have DHX9 inhibitory activity. As used herein, "DHX9 inhibitory activity" refers to the ability of a compound or composition to induce a detectable decrease in DHX9 activity in vivo or in vitro (e.g., at least 10% decrease in DHX9 activity as measured by a given assay such as the bioassay described in the examples and known in the art).

[0325] In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of DHX9 activity (referred herein as “DHX9 mediated disease or disorder”) in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to forty- sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0326] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to forty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a DHX9 mediated disorder or disease in a subject in need of the treatment.

[0327] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of a DHX9 mediated disorder or disease in a subject in need of the treatment.

[0328] In certain embodiments, the DHX9 mediated disease or disorder is selected from cancer, viral infections, and autoimmune disease.

[0329] In some embodiments, the present disclosure provides a method of treating cancer. In some embodiments, the cancer is selected from colorectal, endometrial, ovarian, gastric, hematopoietic, breast, brain, skin, lung, blood, prostate, head and neck, pancreatic, bladder, bone, soft-tissue, kidney, and liver cancer. In some embodiments the cancer is selected from colorectal, endometrial, ovarian, hematopoietic, and gastric cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is Ewing’s Sarcoma.

[0330] In some embodiments, the cancer is a microsatellite instable (MSI) cancer. In some embodiments, the cancer is MSI-high cancer. In other embodiments, the cancer is MSI-low cancer. MSI is determined by PCR analysis of 5 different nucleotide repeats, which is dependent on the cancer type. MSI-low cancers are characterized by instability at only 1 of the 5 sites; while MSI-high cancers are characterized by instability at 2 or more of the 5 sites (G. Yang et al. Correlations between micro satellite instability and the biological behavior of tumors. Journal of Cancer Research and. Clinical Oncology, 2019) .

[0331] MSI-high cancer is additionally characterized by defective mismatch repair (dMMR) (M. Lorenzi, et al. Epidemiology of Micro satellite Instability High (MSLH) and Deficient Mismatch Repair (dMMR) in Solid Tumors: A Structured Literature Review. Journal of Oncology, Volume 2020, Article ID 1897929). For example, dMMR in colorectal cancer can be determined by MLH1 promoter hypermethylation, rendering MLH1 inactive, which comprises about 80-90% of MSI-high colorectal cancers. MSI-high colorectal cancer with inactivated MLH1 is also named sporadic MSI-high colorectal cancer. Alternatively, dMMR can be determined by immunohistochemistry mutation status of MLH1, MSH2, MSH6, MSH3, PMS1 and / or PMS2 mismatch repair (MMR) proteins. In MSI-high colorectal cancer, MLH1 and MSH2 are the 2 predominantly mutated MMR proteins. They are mutated in about 10-20% of MSI-high colorectal cancers. MSI-high colorectal cancers with these mutations are also known as Lynch Syndrome cancers. In some embodiments, the cancer is a MSI cancer and / or has mutations or defects in DNA mis-match repair (MMR), and / or mutations or defects in RNA splicing and the kinetochore complex.

[0332] The compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease the expression or activity of DHX9, or to otherwise affect the properties and / or behavior of DHX9 in a cell.

[0333] One embodiment of the present disclosure includes a method of decreasing the expression or activity of DHX9, or to otherwise affect the properties and / or behavior of DHX9 in a subject comprising administering to said subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0334] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a mammal.

[0335] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a primate.

[0336] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a human.

[0337] As used herein, an “effective amount” and a “therapeutically effective amount” can used interchangeably. It means an amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited herein. In some embodiments, the effective dose can be between 10 pg and 500 mg.

[0338] The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions recited above.

[0339] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered parenterally.

[0340] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically or intranasally.

[0341] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered systemically.

[0342] The compounds of the present disclosure are typically used as a pharmaceutical composition (e.g., a compound of the present disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term “pharmaceutically acceptable carrier” includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered pharmaceutical compositions comprising a compound of the present disclosure and a solvent (i.e., solvate) or water (i.e., hydrate).

[0343] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present disclosure or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

[0344] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0345] The pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration or alternatively suppositories.

[0346] For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0347] Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavors and sweeteners.

[0348] Tablets may be either film coated or enteric coated according to methods known in the art.

[0349] Suitable compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0350] The parenteral compositions (e.g, intravenous (IV) formulation) are aqueous isotonic solutions or suspensions. The parenteral compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1- 75%, or contain about 1-50%, of the active ingredient.

[0351] The compound of the present disclosure or pharmaceutical composition thereof for use in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose. When administered intravenously via infusion, the dosage may depend upon the infusion rate at which an IV formulation is administered. In general, the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

[0352] The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10'3molar and 10'9molar concentrations.

[0353] DEFINITIONS

[0354] As used herein, a “patient,” “subject” or “individual” are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human. As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0355] As used herein, the term “treat”, “treating” or “treatment” of any disease, condition or disorder, refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present disclosure to obtaining desired pharmacological and / or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, condition or disorder; ameliorating or improving a clinical symptom, complications or indicator associated with the disease, condition or disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or disorder; or eliminating the disease, condition or disorder. In certain embodiments, the effect can be to prevent the onset of the symptoms or complications of the disease, condition or disorder.

[0356] As used herein the term “cancer” has the meaning normally accepted in the art. The term can broadly refer to abnormal cell growth.

[0357] As used herein, a subject is “in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (in some embodiments, a human).

[0358] As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general the term “optionally substituted” refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.

[0359] As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. The term “C1-4alkyl” refers to an alkyl having 1 to 4 carbon atoms. The terms “C1-3alkyl” and “C1-2alkyl” are to be construed accordingly. Representative examples of “C1-4alkyl” include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy have the same definition as above. When indicated as being “optionally substituted”, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).

[0360] As used herein, the term “alkylene” refers to a fully saturated branched or unbranched divalent hydrocarbon radical. The term “C1-4alkylene” refers to an alkylene having 1 to 4 carbon atoms. The terms “ C1-3alkylene” and “Cl-2alkylene” are to be construed accordingly. Representative examples of “C1-4alkylene” include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, and tert-butylene.

[0361] As used herein, the term “alkoxy” refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a — O— C1-4alkyl group wherein C1-4alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like. In some embodiments, alkoxy groups have about 1-4 carbons, and in some embodiments about 1-2 carbons. The term “ C1-2alkoxy” is to be construed accordingly.

[0362] As used herein, the term “C1-4alkoxyC1-4alkyl” refers to a C1-4allkyl group as defined herein, wherein at least of the hydrogen atoms is replaced by an C1-4alkoxy. The C1- 4alkoxyC1-4alkyl group is connected through the rest of the molecule described herein through the alkyl group.

[0363] The number of carbon atoms in a group is specified herein by the prefix “Cx-xx”, wherein x and xx are integers. For example, “C1-3alkyl” is an alkyl group which has from 1 to 3 carbon atoms.

[0364] “Halogen” or “halo” may be fluorine, chlorine, bromine or iodine.

[0365] As used herein, the term “halo-substituted-C1-4alkyl” or “ Cwhaloalkyl” refers to a C1-4alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The C1-4haloalkyl group can be monohalo-C1-4alkyl, dihalo-C1-4alkyl or polyhalo- C1-4alkyl including perhalo-C1-4alkyl. A monohalo-C1-4alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihalo-C1-4alkyl and polyhalo-C1-4alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhalo-C1-4alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of C1-4haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhalo-C1-4alkyl group refers to a Cwalkyl group having all hydrogen atoms replaced with halo atoms. The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl.

[0366] The term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, indazoyl, benzofuranyl, benzoxazole, benzimidazolyl, and imidazo[l,2- a]pyridine. The term “heteroaryl” also includes N-oxides of heteroaryl groups, for example pyridine-N-oxide. The term “heteroaryl” also includes tautomeric forms of heteroaryl rings. For example, pyridin-2-( 1 H) -one, as a tautomeric form of pyridine-2-ol (see below) is defined as a “heteroaryl” in this application. pyridin-2-ol pyridin-2(1 / - / )-one

[0367] The term “carbocyclic ring” or “carbocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a single ring, bicyclic ring (including fused , spiro or bridged carbocyclic rings) or a spiro ring. Bi-cyclic carbocyclyl groups include, e.g., unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, cycloalkyl, or aryl, such as, for example, cyclohexyl, cyclohexenyl, 2,3- dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless specified otherwise, the carbocyclic ring generally contains 4- to 10- ring members.

[0368] The term “C3-6cycloalkyl” refers to a carbocyclic ring which is fully saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0369] The term “heterocycle” or “heterocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, piperdinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as, for example, isoindolin-1-onyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 1, 4,5,6- tetrahydrocyclopenta[c]pyrazolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H- cyclopenta[b] thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclyl group is a 4 to 6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 8 to 10 membered bicyclic heterocyclyl group.

[0370] As used herein the term “spiro” ring means a two-ring system wherein both rings share one common atom. Examples of spiro rings include 5-oxaspiro[2.3]hexane, oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptane, 4- oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetan]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'- cyclobutan]-7-yl, 2,6-diazaspiro[3.3]heptanyl, -oxa-6-azaspiro[3.3]heptane, 2,2,6- diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7- azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 8-azaspiro[4.5]decane, 1,6- diazaspiro[3.3]heptane, 5-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 5-oxa-2- azaspiro[3.4]octane, 6-oxa-1-azaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9- diazaspiro[5.5]undecanyl, and the like.

[0371] The term “fused” ring refers to two ring systems share two adjacent ring atoms. Fused heterocycles have at least one the ring systems contain a ring atom that is a heteroatom selected from O, N and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0372] As used herein the term “bridged” refers to a 5 to 10 membered cyclic moiety connected at two non-adjacent ring atoms (e.g. bicyclo[l.l.l]pentane, bicyclo [2.2.1] heptane and bicyclo [3.2.1] octane).

[0373] The phrase “pharmaceutically acceptable” indicates that the substance, composition or dosage form must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0374] Unless specified otherwise, the term “compounds of the present disclosure” refers to compounds of Formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). When a moiety is present that is capable of forming a salt, then salts are included as well, in particular pharmaceutically acceptable salts. As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

[0375] It is also possible that the intermediates and compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0376] In one embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in free form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in salt form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in acid addition salt form. In a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable salt form. In yet a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in free form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable salt form. In still another embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable acid addition salt form.

[0377] Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma- Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967- 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0378] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions.

[0379] EXEMPLIFICATION

[0380] Abbreviations used :

[0381] (NH4)2CO3= Ammonium carbonate

[0382] 1,10-Phen = 1,10-Phenanthroline

[0383] AcOH = acetic acid

[0384] AIBN = azobisisobutyronitrile

[0385] Al(Me)3= AlMe3= trimethylaluminum

[0386] B(OH)3= Boric acid

[0387] B2Pin2= B2(pin)2= Bis(pinacolato)diboron

[0388] BF3-Et2O = trifluoroborane diethyl ether

[0389] BHMPO = N,N'-bis(4-hydroxyl-2,6-dimethylphenyl)oxalamide

[0390] BINAP = (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl)

[0391] BPO = Benzoyl peroxide

[0392] CAN = ceric ammonium nitrate

[0393] CCI4 = Carbontetrachloride

[0394] CDI = carbonyldiimidazole CH3I = methyl iodide

[0395] CS2CO3= caesium carbonate

[0396] Cu(acac)2= Copper(II) acetylacetonate

[0397] CU2O = Copper(I) oxide

[0398] Cui = Copper(I) iodide

[0399] DCE = dichloroethane DCM = dichloromethane

[0400] DIAD = Diisopropyl azodicarboxylate

[0401] DIBAL-H = diisobutylaluminium hydride dioxane = 1,4-dioxane

[0402] DIPEA = DIEA = diisopropylethyl amine

[0403] DMF = dimethylformamide

[0404] DMSO = dimetylsulfoxide

[0405] DPP A = Diphenylphosphoryl azide dtbpy = 4,4 '-Di-tert-butyl-2, 2 '-dipyridyl

[0406] EDO = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0407] ESI = electrospray ionisation

[0408] Et2O = diethyl ether

[0409] EtOAc = EA = ethyl acetate

[0410] EtOH = ethanol

[0411] FA = Formic acid

[0412] H2O = water

[0413] H2O2= Hydrogen peroxide

[0414] HATU = Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium

[0415] HC1 = hydrochloric acid

[0416] HPLC = high pressure liquid chromatography iPrMgCl = Isopropylmagnesium chloride

[0417] K2CO3= potassium carbonate

[0418] KO Ac = AcOK = potassium acetate

[0419] KOH = Potassium Hydroxide

[0420] LCMS = liquid chromatography mass spectrometry

[0421] LiAlH4 = lithium aluminium tetrahydride

[0422] LiOH = lithium hydroxide m-CPBA = mCPBA = m-chloroperbenzoic acid

[0423] MeCN = ACN = acetonitrile

[0424] MeOH = CH3OH = methanol

[0425] MOMBr = bromethyl methyl ether

[0426] N2= Nitrogen

[0427] Na2SO4= sodium sulfate

[0428] NaBH4= Sodium borohydride NaH = sodium hydride

[0429] NaHCO3= sodium bicarbonate

[0430] NaNO2= sodium nitrite

[0431] NaOH = Sodium Hydroxide

[0432] NBS = N-bromosuccinimide n-BuLi = n-butyllithium

[0433] NCS = N-chlorosuccinimide

[0434] NH4CI = ammonium chloride NH4HCO3= Ammonium Bicarbonate

[0435] Ni(OAc)2= Nickel(II) acetate

[0436] NMI = 1 -Methylimidazole

[0437] NMP = N-Methyl-2-pyrrolidone

[0438] Pd(dppf)Cl2= [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0439] Pd(dppf)Cl2DCM = [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane

[0440] Pd(OAc)2= Palladium (II) Acetate

[0441] Pd(PPh3)4= Tetrakis(triphenylphosphine)palladium(0)

[0442] Pd(PPh3)Cl2= Bis(triphenylphosphine)palladium(II) dichloride

[0443] Pd / C = Palladium on Carbon

[0444] Pd2(dba)3= tris-(dibenzylideneacetone)dipalladium(0)

[0445] PE = petroleum ether

[0446] PhI(AcO)2= [bis(acetoxy)iodo]benzene

[0447] PhMe = toluene PPh3= triphenylphosphine

[0448] Prep-SFC = preparatory supercritical fluid chromatography

[0449] RT = room temperature

[0450] RuPhos-Pd-G3= (2-dicyclohexylphosphino-2,6-diisopropoxy-l,l-biphenyl)[2-(2- amino- 1 , 1 -biphenyl)]palladium(II) methanesulfonate

[0451] SEM-BF3K = Potassium (2-trimethylsilyl)-ethoxymethyl trifluoroborate

[0452] SEMC1 = trimethylsilylmethoxymethyl chloride

[0453] SnCl2= tin(ll) chloride

[0454] SOCl2= thionyl chloride

[0455] STAB = Sodium triacetoxyborohydride

[0456] TBAF = tetrabutyl ammonium fluoride TBSC1 = tert-butyldimethylsilyl chloride tBuBrettPhos = 2-(Di-tert-butylphosphino)-2',4',6'- triisopropyl-3,6-dimethoxy-1,1'- biphenyl t-BuOH = tert-butanol t-BuOK = potassium tert-butoxide

[0457] TCFH = N '-tetramethylformamidinium hexafluorophosphate

[0458] TEA = triethylamine

[0459] TFA = trifluoroacetic acid

[0460] TFAA = trifluoroacetic anhydride

[0461] TfOH = trifluoromethanesulfonic acid

[0462] THF = tetrahydrofuran

[0463] TEC = Thin Eayer Chromatography

[0464] TMSCHN2 = (Trimethylsilyl)diazomethane

[0465] Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0466] XantPhosPdG3 = [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-

[0467] 1 , 1 '-biphenyl)]palladium(II) methanesulfonate

[0468] XPhos Pd G3 = (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'- amino- 1 , 1 '-biphenyl)]palladium(II) methanesulfonate

[0469] Zn(CN)2= zinc(II) cyanide

[0470] GENERAL METHODS

[0471] 1. NMR spectra were recorded on :

[0472] NMR10 Bruker AVANCE III HD 300MHz

[0473] NMR16 Bruker AVANCE III HD 300MHz

[0474] NMR19 Bruker AVANCE III HD 400MHz

[0475] NMR24 Bruker AVANCE NEO 400MHz

[0476] NMR30 Bruker AVANCE NEO 400MHz

[0477] 2. LCMS measurement was run on SHIMADZU LCMS-2020 using the follow conditions: Method A: Mobile Phase: A: Water (0.05%TFA) B: Acetonitrile (0.05%TFA); Gradient Phase: 5%B to 100%B within 2.0 min, 100%B with 0.7 min (total runtime: 2.8 min); Flow Rate: 1.5 mL / min; Column: HALO C18, 3.0*30mm, 2.0|am; Column Temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0478] Method B: Mobile Phase: A: Water (0.1%FA) B: Acetonitrile (0.1%FA); Gradient Phase: 5%B to 100%B within 2.0 min, 100%B with 0.7 min (total runtime: 2.8 min); Flow Rate: 1.5 mL / min; Column: HALO C18, 3.0*30mm, 2.0μm; Column Temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0479] Method C: Mobile Phase: A: Water (5mM NH4HCO3) B: Acetonitrile; Gradient Phase: 10%B to 95%B within 2.0 min, 100%B with 0.6 min (total runtime: 2.8 min); Flow Rate: 1.5 mL / min; Column: Poroshell HPH-C18, 3.0*50mm, 4.0pm; Column Temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0480] Method D: Mobile Phase: A: Water (0.05%TFA) B: Acetonitrile (0.05%TFA); Gradient Phase: 5%B to 100%B within 1.2 min, 100%B with 0.6 min (total runtime: 2.0 min); Flow Rate: 1.5 mL / min; Column: Express C18, 3.0*30mm, 2.7pm; Column Temperature: 40 °C. Detectors: ELSD, PDA (220 nm and 254 nm), ESI.

[0481] Method E: Mobile Phase: A: Water (0.1%FA) B: Acetonitrile (0.07%FA); Gradient Phase: 5%B to 100%B within 1.2 min, 100%B with 0.6 min (total runtime: 2.0 min); Flow Rate: 1.5 mL / min; Column: Express C18, 3.0*30mm, 2.7pm; Column Temperature: 40 °C. Detectors: ELSD, PDA (220 nm and 254 nm), ESI.

[0482] Method F: Mobile Phase: A: Water (5mM NH4HCO3) B: Acetonitrile; Gradient Phase: 10%B to 95%B within 1.2 min, 95%B with 0.6 min (total runtime: 2.0 min); Flow Rate: 1.2 mL / min; Column: Poroshell HPH-C18, 3.0*50mm, 2.7μm; Column Temperature: 40 °C. Detectors: ELSD, PDA (220 nm and 254 nm), ESI.

[0483] PREPARATION OF INTERMEDIATES The compounds claimed herein were prepared following the procedures outlined in the following schemes. Compound names were generated using the software built into ChemDraw. To the extent that there are discrepancies between the name of a compound and its depicted structure, the depicted chemical structure is to be taken as the appropriate compound.

[0484] Intermediate A: N-(3-amino-5-chlorophenyl)methanesulfonamide

[0485] Step 1: To a stirred mixture of l-chloro-3-fluoro-5-nitrobenzene (45 g, 256.35 mmol, 1.00 equiv) and methane sulfonamide (24.38 g, 256.35 mmol, 1.00 equiv), Cs2CO3(250.57 g, 769.05 mmol, 3.00 equiv) in 500 mL of DMSO, the resulted solution was stirred for 2h at 60 °C. The mixture was cooled then quenched with 1000 mL of water and extracted with 3 x 1000 mL of ethyl acetate and dried over anhydrous Na2SO4and concentrated and the residue was purified onto silica gel column eluted with 50% of ethyl acetate in petroleum ether to afford N-(3-chloro-5-nitrophenyl) methane sulfonamide (41 g, 63.81%) as a light yellow solid.

[0486] LCMS (ESI) [M + H]+: 249.9

[0487] Step 2: To a stirred solution of N-(3-chloro-5-nitrophenyl) methanesulfonamide (41.00 g, 163.57 mmol, 1.00 equiv) and Fe (91.35 g, 1635.75 mmol, 10.00 equiv), NH4CI (87.50 g, 1635.75 mmol, 10.00 equiv) in 500 mL of ethanol and 300 mL of water, this was stirred for 2h at 90 °C. The resulting mixture was filtered, the filter cake was washed with 6 x 50 mL of methanol. The filtrate was concentrated under reduced pressure. The residue was purified onto silica gel column eluted with 50% of ethyl acetate in petroleum ether to afford N-(3- amino-5-chlorophenyl) methanesulfonamide (25.3 g, 70.1%) as a light yellow solid.

[0488] LCMS (ESI) [M + H]+: 220.01

[0489] NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 6.41 - 6.31 (m, 3H), 5.54 (s, 2H), 2.98 (s, 3H)

[0490] Intermediate B: N-(3-amino-5-chlorophenyl)propane-l -sulfonamide

[0491] A solution of 3-bromo-5-chloroaniline (1 g, 4.843 mmol, 1 equiv), propane- 1 -sulfonamide (1.19 g, 9.686 mmol, 2 equiv), ( 1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (2.07 g, 14.529 mmol, 3 equiv), Cui (2.77 g, 14.529 mmol, 3 equiv) and K2CO3(2.01 g, 14.529 mmol, 3 equiv) in ACN (10 mL) was stirred for 2 hours at 110°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-(3-amino-5- chlorophenyl)propane-1- sulfonamide (540 mg, 44.83% yield) as a yellow solid.

[0492] LCMS (ESI) [M + H]+: 249 The following intermediates were prepared using experimental procedures similar for intermediates A or B:

[0493] Intermediate H: 5 -methyl-4-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl )thiophene-2- carboxylate

[0494] Step 1: A mixture of 5-methylthiophene-2-carboxylic acid (100 g, 703.383 mmol, 1 equiv) and Br2(123.65 g, 773.721 mmol, 1.1 equiv) in AcOH (1 L) was stirred for 2 hours at 60°C. The product was precipitated by the addition of water (500 mL) at 0°C. The precipitated solids were collected by filtration and washed with water to afford 4-bromo-5- methylthiophene-2-carboxylic acid (130 g, 83.60%) as a yellow solid.

[0495] LCMS (ESI) [M+H]+: 221

[0496] Step 2: A mixture of 4-bromo-5-methylthiophene-2-carboxylic acid (100 g, 452.345 mmol, 1 equiv) and H2SO4(100 mL, 1876.211 mmol, 4.15 equiv) in MeOH (1 L) was stirred for overnight at 50°C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (3x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford methyl 4-bromo-5-methylthiophene-2- carboxylate (80 g, 74.47%) as a light yellow solid.

[0497] GCMS: 234.

[0498] NMR (300 MHz, DMSO-d6) δ 7.70 (s, 1H), 3.82 (s, 3H), 2.43 (s, 3H).

[0499] Step 3: A mixture of methyl 4-bromo-5-methylthiophene-2-carboxylate (80 g, 340.281 mmol, 1 equiv), bis(pinacolato)diboron (172.82 g, 680.562 mmol, 2 equiv) Pdldppf)Cl2(12.45 g, 17.014 mmol, 0.05 equiv) and KOAc (100.19 g, 1020.843 mmol, 3 equiv) in 1,4-dioxane (800 mL) was stirred for overnight at 80°C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (15:1) to afford methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)thiophene-2-carboxylate (90 g, crude). The crude product was re-crystallized from hexane to afford methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)thiophene-2-carboxylate (35 g, 36.41%) as a white solid.

[0500] LCMS (ESI) [M+H]+: 283.

[0501] NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 3.79 (s, 3H), 2.65 (s, 3H), 1.28 (s, 12H) The following intermediates were prepared using experimental procedures similar for intermediate H:

[0502] Intermediate J: methyl 5-methyl-lH-pyrrole-3-carboxylate

[0503] Step 1: Tosyl methylisocyanide (200g, 1.03 mol, 1 equiv) was dissolved in dichloromethane 1.5 L and cooled to 0 °C. Benzyltriethylammonium chloride (46.62 g, 2.05 mol, 2 equiv.), methyl iodide 126.3mL (2.05 mol, 2 equiv) and 1.5 L of 30% aqueous sodium hydroxide solution were added. The mixture was stirred for 3 hours at 0°C. Water (4 L) was added to the reaction mixture, extracted with dichloromethane (1.5 L x 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 1-((1- isocyanoethyl)sulfonyl)-4-methylbenzene(167g, 78.0% yield) as a brown oil. Step 2: A solution of methyl acrylate (138.2 mL, 1.55 mol, 0.97 equiv) and 1-(1- isocyanoethylsulfonyl)-4-methylbenzene (335 g, 1.60 mol, 1 equiv) in diethyl ether (3 L) and DMSO (1.5L) were added dropwise to a stirred suspension of sodium hydride (60% purity) (99.7 g, 2.49 mol, 1.55 equiv) in diethyl ether (4L) under nitrogen. The resulting suspension was stirred at room temperature for 4 hours. The reaction mixture was poured into sodium chloride solution (5 L), layers separated and the aqueous extracted with EA (3 x 5 L), the organic layers were combined and washed with water (5 L), dried over Na2SO4, filtered and evaporated to afford beige solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate to afford methyl 5-methyl-lH- pyrrole-3-carboxylate (105.6g, 47.4% yield) as a white solid.

[0504] LCMS (ESI) [M+H]+: 140.

[0505] 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 7.24 (dd, J = 3.0, 1.7 Hz, 1H), 6.10 (dt, J = 2.7, 1.4 Hz, 1H), 3.66 (s, 3H), 2.15 (d, J = 1.0 Hz, 3H).

[0506] Intermediate K: l-methyl-5- 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrole-3- carboxylate

[0507] Step 1: To a stirred solution of methyl lH-pyrrole-3-carboxylate (100 g, 800 mmol, 1 equiv) and NaH(60%) (64 g, 1.6 mol, 2 equiv) in DMF (I L) was added CH3I (227.2 g, 1.6 mol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional 3 hours at room temperature. The reaction was quenched by the addition of water (5 L) at 0°C. The resulting mixture was extracted with EtOAc (3 x 5 L). The combined organic layers were washed with brine (3x5L), dried over anhydrous NaiSCL,. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl l-methylpyrrole-3-carboxylate (95g, 85.6%) as a white solid

[0508] LCMS (ESI) [M+H]+: 140

[0509] Step 2: A solution of methyl l-methylpyrrole-3-carboxylate (95 g, 683. 5mmol, 1 equiv), B2Pin2(138.9 g, 546.7 mmol, 0.8 equiv), Di-mu-methoxobis(l,5-cyclooctadiene)diiridium(I) (6.7g, 10.3 mmol, 0.015 equiv)and 4,4 -Di-tert-butyl-2,2 -bipyridine (5.49 g, 20.5 mmol, 0.03 equiv) in l,4-dioxane(lL) was stirred for 3 hours at 100°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford crude product. The crude product was triturated with PE for 12 hours at RT and filtered to afford l-methyl-5-(4,4,5,5- tetrameth yl-1, 3, 2-dioxaborolan-2-yl)pyrrole-3-carboxylate( 105 g, 57.8% yield) as a white solid.

[0510] LCMS (ESI) [M+H]+: 266

[0511] 1H NMR (300 MHz, Chloroform-d) δ 7.37 (d, J = 1.6 Hz, 1H), 7.21 (d, J= 1.6 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 1.31 (s, 12H).

[0512] The following intermediates were prepared using experimental procedures similar for intermediate K: Intermediate 0: 1 -(chloromethyl)-3-fluoro-5 -methane sulfonylbenzene

[0513] Step 1: To a stirred solution of 3-bromo-5-fluorobenzaldehyde (5 g, 24.6 mmol), (methylsulfanyl) sodium (3.44 g, 49.2 mmol), XantPhos (4.25 g, 7.37 mmol), Pd2(dba)3(3.37 g, 3.68 mmol) and Cs2CO3(24.0 g, 73.8 mmol) in PhMe (50 mL). Then the mixture was stirred overnight at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-50%) to afford 3-fluoro-5- (methylsulfanyl)benzaldehyde (1.50 g, 8.81 mmol).

[0514] LCMS [M+H]+: 171

[0515] Step 2: To a solution of 3-fluoro-5-(methylsulfanyl)benzaldehyde (1.5 g, 8.81 mmol) in MeOH (13 mL) was slowly added NaBPL (756 mg, 20.0 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-50%) to afford [3-fluoro-5- (methylsulfanyl)phenyl] methanol (1.30 g, 7.54 mmol) as a white solid.

[0516] LCMS [M+H]+: 173

[0517] Step 3: To a stirred solution of [3-fluoro-5-(methylsulfanyl)phenyl]methanol (1.3 g, 7.54 mmol) in DCM (12 mL) was slowly added SOCl2(8.95 g, 75.3 mmol) at 0 °C. Then the mixture was stirred for 1 hour at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography eluting with ACN / H2O (5-95%, acidic system) to afford 1- (chloromethyl)-3-fluoro-5-(methylsulfanyl)benzene (1.20 g, 6.29 mmol) as a yellow solid. LCMS [M+H]+: 191

[0518] Step 4: To a stirred solution of 1-(chloromethyl)-3-fluoro-5-(methylsulfanyl)benzene (600 mg, 3.14 mmol) in DCM (10 mL )was added mCPBA (2.69 g, 15.6 mmol) at room temperature. Then the mixture was stirred for 4 hours at room temperature. The reaction was quenched with Na2S2O3(aq) and NaHCO3(aq). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with PE / EA (1:1) to afford 1-(chloromethyl)-3-fluoro-5-methanesulfonylbenzene (481 mg, 2.16 mmol) as a yellow solid.

[0519] LCMS (ESI) [M + H]+: 222

[0520] The following intermediates were prepared using experimental procedures similar for intermediate O:

[0521] Intermediate R: l-(chloromethyl)-2,5-difluoro-3-methanesulfonylbenzene

[0522] Step 1: A mixture of (3-bromo-2,5-difluorophenyl)methanol (1.6 g, 7.17 mmol), (methylsulfanyl) sodium (1 g, 14.3 mmol), Pd2(dba)3(656 mg, 717 pmol), Xantphos (827 mg, 1.43 mmol) and Cs2CO3(4.65 g, 14.3 mmol) in PhMe (80 mL) was stirred for 2 hours at 110 °C under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (35%) to afford [2,5-difluoro-3- (methylsulfanyl)phenyl] methanol (1.30 g, 6.83 mmol) as a yellow oil.

[0523] Step 2: To a stirred solution [2,5-difluoro-3-(methylsulfanyl)phenyl]methanol (1.3 g, 6.83 mmol) in DCM (50 mL) was added mCPBA (5.88 g, 34.1 mmol) at 0 °C under N2 atmosphere. Then the mixture was stirred for 2 hours at room temperature. The residue was purified by silica gel column chromatography, eluted with EA / PE (45%) to afford (2,5- difluoro-3-methanesulfonylphenyl) methanol (650 mg, 2.92 mmol) as a yellow oil.

[0524] Step 3: To a stirred solution of (2,5-difluoro-3-methanesulfonylphenyl)methanol (650 mg, 2.92 mmol) in DCM (30 mL) was added DMF (0.2 mL) and SOCl2(1.04 g, 8.76 mmol). Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (35%) to afford 1- (chloromethyl)-2,5-difluoro-3-methanesulfonylbenzene (550 mg, 2.28 mmol) as a yellow oil. Intermediate S: 1 -(chloromethyl)- 5 -fluoro-3 -methane sulf onyl-2 -methylbenzene

[0525] Step 1: A solution of methyl 3-bromo-5-fluoro-2-methylbenzoate (5 g, 20.238 mmol, 1 equiv), (methyl sulfanyl) sodium (5.67 g, 80.952 mmol, 4 equiv), Pd2(dba)3(3.71 g, 4.048 mmol, 0.2 equiv), XantPhos (2.34 g, 4.048 mmol, 0.2 equiv) and Cs2CO3(19.78 g, 60.714 mmol, 3 equiv) in toluene (15 mL) was stirred for 2 hours at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (5 x 50 mL). The combined organic layers were washed with water (5x40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-fluoro-2- methyl-3-(methylsulfanyl)benzoate (1.1 g, 25.37% yield) as a white solid.

[0526] LCMS (ESI) [M + H]+: 215

[0527] Step 2: A solution of methyl 5-fluoro-2-methyl-3-(methylsulfanyl)benzoate (1.1 g, 5.134 mmol, 1 equiv) and LiAlH4(2.92 g, 77.010 mmol, 15 equiv) in THF (20 mL) was stirred for 1 hour at room temperature under air atmosphere. The reaction was quenched by the addition of Water (10 mL) at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford [5-fluoro-2-methyl-3- (methylsulfanyl)phenyl] methanol (540 mg, 56.47% yield) as a white solid.

[0528] LCMS (ESI) [M + H]+: 187

[0529] Step 3: A solution of [5-fluoro-2-methyl-3-(methylsulfanyl)phenyl]methanol (540 mg, 2.899 mmol, 1 equiv) and SOCl2(3449 mg, 28.990 mmol, 10 equiv) in DCM (7 mL) was stirred for 1 hour at room temperature under air atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (5 x 50 mL). The combined organic layers were washed with water (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-(chloromethyl)-5-fluoro-2- methyl-3-(methylsulfanyl)benzene (290 mg, 48.86% yield) as a white solid.

[0530] LCMS (ESI) [M + H]+: 205

[0531] Step 4: A solution of 1-(chloromethyl)-5-fluoro-2-methyl-3-(methylsulfanyl)benzene (290 mg, 1.417 mmol, 1 equiv) and mCPBA (733.4 mg, 4.251 mmol, 3 equiv) in DCM (15 mL) was stirred for 1 hour at room temperature under air atmosphere. The resulting mixture was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with water (3x60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-(chloromethyl)-5-fluoro-3-methanesulfonyl-2-methylbenzene (140 mg, 41.75% yield) as a white solid.

[0532] LCMS (ESI) [M + H]+: 237

[0533] Intermediate T: 1 -(bromomethyl)-3 -fluoro-5 -trifluoromethane sulfonylbenzene

[0534] Step 1: To a solution of l-fluoro-3-iodo-5-methylbenzene (5.1 g, 21.6 mmol) and 1,3,5- trimethylbenzene (2.59 g, 21.6 mmol), TfOH (3.24 g, 21.6 mmol) in DCM (120 mL) was slowly added m-CPBA (11.1 g, 64.8 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The residue was purified by silica gel column chromatography, eluted with EA / PE (47%) to afford (3-fluoro-5-methylphenyl)(2,4,6- trimethylphenyl)iodanium trifluoromethanesulfonate (2.80 g, 5.55 mmol) as a yellow solid.

[0535] LCMS (ESI) [M + H]+: 505

[0536] Step 2: A mixture of (3-fluoro-5-methylphenyl)(2,4,6-trimethylphenyl)iodanium trifluoromethanesulfonate (2.8 g, 5.55 mmol), sodium trifluoromethanesulfinate (1.29 g, 8.32 mmol) and Cu2O (79.4 mg, 0.555 mmol) in DMF (25 mL) was stirred for 3 hours at 70 °C. The mixture was diluted with 300 mL of water and extracted with EtOAc (3 x 150 mL). The combined organic phase was concentrated under reduced pressure and purified by flash chromatography eluting with EA / PE (0% - 20%) to afford l-fluoro-3-methyl-5- trifluoromethanesulfonylbenzene (300 mg, 1.23 mmol) as a white solid.

[0537] Step 3: A mixture of l-fluoro-3-methyl-5-trifluoromethanesulfonylbenzene (300 mg, 1.23 mmol), NBS (437 mg, 2.46 mmol) and AIBN (30.2 mg, 0.1844 mmol) in DCE (8 mL) was stirred for 2 h at 80 °C. The mixture was concentrated and purified by flash chromatography eluting with EA / PE (0% - 20%) to afford 1-(bromomethyl)-3-fluoro-5- trifluoromethanesulfonylbenzene (375 mg, 1.16 mmol) as a yellow solid.

[0538] Intermediate U: l-(chloromethyl)-3-(dimethylphosphoryl)-5-fluorobenzene

[0539] Step 1: A mixture of methyl 3-bromo-5-fluorobenzoate (2 g, 8.582 mmol, 1 equiv), (methylphosphonoyl) methane (3.35 g, 42.910 mmol, 5 equiv), Pd2(dba)3(0.79 g, 0.858 mmol, 0.1 equiv), XantPhos (0.99 g, 1.716 mmol, 0.2 equiv) and K3PO4(5.47 g, 25.746 mmol, 3 equiv) in toluene (50 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford methyl 3-(dimethylphosphoryl)-5-fluorobenzoate (1.4 g, 70.87% yield) as a yellow oil. LCMS (ESI) [M + H]+: 231

[0540] Step 2: To a stirred solution of methyl 3-(dimethylphosphoryl)-5-fluorobenzoate (1.4 g, 6.082 mmol, 1 equiv) in THF (20 mL) was added LiAlH4(12.2 mL, 12.2 mmol, 2 equiv) at 0 °C under nitrogen atmosphere. The mixture was stirred for 3 hours at 0 °C under nitrogen atmosphere. The reaction was quenched with MeOH (5 mL) at 0 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford [3-(dimethylphosphoryl)-5- fluoro phenyl] methanol (710 mg, 57.74% yield) as a light yellow oil.

[0541] LCMS (ESI) [M + H]+: 203

[0542] Step 3: To a stirred solution of [3-(dimethylphosphoryl)-5-fluorophenyl]methanol (710 mg, 3.512 mmol, 1 equiv) in DCM (20 mL) was added SOCl2(627 mg, 5.268 mmol, 1.5 equiv) and DMF (0.1 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred for 3 hours at 0 °C. The reaction was quenched with MeOH at 0 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) to afford 1-(chloromethyl)-3-(dimethylphosphoryl)-5-fluorobenzene (240 mg, 30.98% yield) as a yellow oil.

[0543] LCMS (ESI) [M + H]+: 221

[0544] Intermediate V: dimethyl [3 -(chloromethyl)- 5 -fluorophenyl] phosphonate

[0545] Step 1: A mixture of 3-bromo-5-fluorobenzaldehyde (3 g, 14.7 mmol), dimethyl phosphite (1.95 g, 17.64 mmol), Pd(dppf)Cl2(1.56 g, 2.20 mmol) and K2CO3(6.08 g, 44.1 mmol) in dioxane (10 mL) was stirred for 5 hours at 100 °C under N2 atmosphere. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / H2O (5-95%, acidic system) to afford dimethyl (3-fluoro-5-formylphenyl) phosphonate (850 mg, 3.66 mmol) as a white solid.

[0546] LCMS [M+H]+: 233

[0547] Step 2: To a stirred of dimethyl (3-fluoro-5-formylphenyl)phosphonate (850 mg, 3.66 mmol) in MeOH (8 mL) was slowly added NaBH4 (138 mg, 3.66 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford dimethyl [3- fluoro-5-(hydroxymethyl) phenyl] phosphonate (620 mg, 2.64 mmol) as a white solid.

[0548] LCMS [M+H]+: 235

[0549] Step 3: To a stirred solution of dimethyl [3-fluoro-5- (hydroxymethyl)phenyl]phosphonate (620 mg, 2.64 mmol) in DCM (30 mL) was slowly added SOCl2(3.11 g, 26.4 mmol) and DMF (0.01 mL) at 0 °C. Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (0-100%) to afford dimethyl [3- (chloromethyl)-5-fluorophenyl]phosphonate (540 mg, 2.13 mmol) as a white solid.

[0550] LCMS [M+H]+: 253 The following intermediates were prepared using experimental procedures similar for intermediate V :

[0551] Intermediate X: l-(chloromethyl)-3-[ethyl(methyl)phosphoryl]- 5 -fluorobenzene

[0552] Step 1: A solution of (3-bromo-5-fluorophenyl)methanol (1.5 g, 7.31 mmol, 1 equiv), TBSC1 (1.65 g, 10.97 mmol, 1.5 equiv) and Imidazole (1.49 g, 21.94 mmol, 3 equiv) in DMF (15 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was washed with 10 mL of H2O. The aqueous layer was extracted with EtOAc (3x40 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford [(3-bromo-5- fluorophcnyl)methoxy] (tert-butyl)dimethyl silane (1.2 g, 51.3% yield) as a white solid. LCMS (ESI) [M+H]+: 319.00

[0553] Step 2: A solution of [(3-bromo-5-fluorophenyl)methoxy](tert-butyl)dimethylsilane (1.2 g, 3.75 mmol, 1 equiv), ethyl methylphosphinate (0.49 g, 4.51 mmol, 1.2 equiv), Pd2(dba)3(0.34 g, 0.37 mmol, 0.1 equiv), XantPhos (0.43 g, 0.75 mmol, 0.2 equiv) and K3PO4(2.39 g, 11.27 mmol, 3 equiv) in PhCH3(12 mL) was stirred for 1 hour at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford ethyl 3- {[(tert-butyldimethylsilyl)oxy]methyl}-5-fluorophenyl(methyl)phosphinate (900 mg, 69.1% yield) as a white solid. LCMS (ESI) [M+H]+: 347.00

[0554] Step 3: A solution of ethyl 3-{[(tert-butyldimethylsilyl)oxy]methyl}-5- fluorophenyl(methyl)phosphinate (900 mg, 2.59 mmol, 1 equiv) and ethylmagnesium bromide (1038 mg, 7.79 mmol, 3 equiv) in THF (10 mL) was stirred for 1 hour at 60 °C under nitrogen atmosphere. The reaction was quenched with Water at 0 °C. The aqueous layer was extracted with EtOAc (3x30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl( {3- [cthyl( methyl )phosphoryl ] -5- fluorophenyl}methoxy)dimethylsilane (750 mg, 87.4% yield) as a white solid.

[0555] LCMS (ESI) [M+H]+: 331.00

[0556] Step 4: A solution of tert-butyl({3-[ethyl(methyl)phosphoryl]-5- fluorophenyl}methoxy)dimethylsilane (750 mg, 1.69 mmol, 1 equiv) and HC1 (gas) in 1,4- dioxane (6 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford {3- [ethyl(methyl)phosphoryl]-5- fluorophenyl} methanol (450 mg, 91.6% yield) as a white solid. LCMS (ESI) [M+H]+: 217.00

[0557] Step 5: A solution of { 3- [ethyl(methyl)phosphoryl]- 5 -fluorophenyl} methanol (450 mg, 2.08 mmol, 1 equiv) and SOCl2(742 mg, 6.24 mmol, 3 equiv) in DCM (5 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 1-(chloromethyl)-3-[ethyl(methyl)phosphoryl]- 5 -fluorobenzene (250 mg, 51.1% yield) as a white solid.

[0558] LCMS (ESI) [M+H]+: 235.00

[0559] Intermediate Y: 3-(l -chloroethyl )-5-fluoropyridin-l -ium-1 -olate

[0560] Step 1: To a solution of 5-fluoropyridine-3-carbaldehyde (1 g, 7.99 mmol) and Et2O (30 mL) at room temperature. To the above mixture was added bromo(methyl)magnesium (20 mL, 15.9 mmol) in portions over 5 minutes at 0 °C. The resulting mixture was stirred for an additional 2 hours at 0 °C. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (72%) to afford 1-(5-fluoropyridin-3- yl)ethan-1-ol (650 mg, 4.60 mmol) as a white solid.

[0561] LCMS (ESI) [M + H]+: 142

[0562] Step 2: To a stirred solution of 1-(5-fluoropyridin-3-yl)ethan-1-ol (650 mg, 4.60 mmol) in DMF (0.1 mL) and DCM (10 mL) at room temperature. To the above mixture was added SOCl2(5 mL, 13.7 mmol) in portions over 3 minutes at 0 °C. The resulting mixture was stirred for an additional 2 hours at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (20%) to afford 3-(l- chloroethyl)-5-fluoropyridine (500 mg, 3.13 mmol) as a white liquid.

[0563] LCMS (ESI) [M + H]+: 160

[0564] Step 3: To a stirred solution of 3-(l-chloroethyl)-5-fluoropyridine (500 mg, 3.13 mmol), mCPBA (1.61 g, 9.38 mmol) in DCM (10 mL).Then the mixture was stirred for 2 hours at 40 °C under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (35%) to afford 3-(l-chloroethyl)-5- fluoropyridin-1-ium-1-olate (180 mg, 1.02 mmol) as a yellow solid.

[0565] LCMS (ESI) [M + H]+: 176

[0566] Intermediate Z: Methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)-1-methylpyrrole-3-carboxylate

[0567] Step 1: A solution of 2-chloro-5-fluoropyridin-3-ol (2 g, 13.55 mmol, 1 equiv), methane, bromomethoxy- (2.54 g, 20.33 mmol, 1.5 equiv) and K2CO3(5.62 g, 40.67 mmol, 3 equiv) in DMF (20 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was washed with H2O. The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-chloro- 5-fluoro-3-(methoxymethoxy)pyridine (2.03 g, 78.1% yield) as a white solid. CMS (ESI) [M+H]+: 192.00.

[0568] Step 2: A solution of 2-chloro-5-fluoro-3-(methoxymethoxy)pyridine (2.03 g, 10.59 mmol, 1 equiv), methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3- carboxylate (3.37 g, 12.71 mmol, 1.2 equiv), Pd(dppf)Cl2(0.78 g, 1.06 mmol, 0.1 equiv) and K2CO3(4.39 g, 31.78 mmol, 3 equiv) in dioxane (20 mL) and H2O (2 mL) was stirred for 1 hour at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 5-[5-fluoro-3-(methoxymethoxy)pyridin-2-yl]-1- methylpyrrole-3- carboxylate (2.1 g , 67.3% yield) as a white solid.

[0569] LCMS (ESI) [M+H]+: 295.00.

[0570] Step 3: A solution of methyl 5- [5-fluoro-3 -(methoxymethoxy)pyridin-2-yl]-1-methyip yrrole- 3-carboxylate (2 g, 6.79 mmol, 1 equiv) and HC1 in 1,4-dioxane (20 mL, 4 M) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. This resulted in methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)-1- methylpyrrole-3-carboxylate (1.62 g, 95.1% yield) as a white solid.

[0571] LCMS (ESI) [M+H]+: 251.00.

[0572] The following intermediates were prepared using experimental procedures similar for intermediate Z: Intermediate AD: Methyl 5-[5-(3,3-difluoroazetidin-1-yi)-3-hydroxypyridin-2-yl]-1- methylpyrrole-3 -carboxylate

[0573] Step 1: A solution of 5-bromo-2-iodopyridin-3-ol (2 g, 6.669 mmol, 1 equiv), bromo(methoxy)methane (1.25 g, 10.003 mmol, 1.5 equiv) and K2CO3(2.77 g, 20.007 mmol,

[0574] 3 equiv) in DMSO (30 mL) was stirred for 1 h at room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-bromo-2-iodo-3- (methoxymethoxy) pyridine (1.8 g, 78.47% yield) as a white solid.

[0575] LCMS (ESI) [M + H]+: 343.87.

[0576] Step 2: A solution of 5-bromo-2-iodo-3-(methoxymethoxy)pyridine (1.8 g, 5.233 mmol, 1 equiv), methyll-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate (1.39 g, 5.233 mmol, 1 equiv), Pd(dppf)Cl2(0.38 g, 0.523 mmol, 0.1 equiv) and K2CO3(2.17 g, 15.699 mmol, 3 equiv) in 1,4-dioxane (30 mL) and H2O (6 mL) was stirred for 1 hour at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-[5-bromo-3-(methoxymethoxy)pyridin-2-yl]-1-methylpyrrole-3-carboxylate (1.2 g, 64.56% yield) as a white solid.

[0577] LCMS (ESI) [M + H]+: 355.02.

[0578] Step 3: A solution of methyl 5-[5-bromo-3-(methoxymethoxy)pyridin-2-yl]-1-methylpyrrole- 3-carboxylate (1.2 g, 3.378 mmol, 1 equiv), 3,3-difluoroazetidine (0.47 g, 5.067 mmol, 1.5 equiv), Pd(OAc)2(80 mg, 0.338 mmol, 0.1 equiv), BINAP (420 mg, 0.676 mmol, 0.2 equiv) and C.S2CO3(3.30 g, 10.134 mmol, 3 equiv) in toluene (30 mL) was stirred for 2 hours at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-[5-(3,3-difluoroazetidin-1-yl)-3-(methoxymethoxy)pyridin-2-yl]-1-methylpyn’ole-3- carboxylate (850 mg, 68.49% yield) as a white solid.

[0579] LCMS (ESI) [M + H]+: 368.13.

[0580] Step 4: A solution of methyl 5-[5-(3,3-difluoroazetidin-1-yl)-3-(methoxymethoxy)pyridin-2- yl]-1-methyl pyrrole-3-carboxylate (850 mg, 2.314 mmol, 1 equiv) in HC1 / 1 ,4-dioxane (10 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5:1) to afford methyl 5-[5-(3,3-difhioroazetidin-1-yl)-3- hydroxypyridin-2-yl]-1-methylpyrrole-3-carboxylate (700 mg, 93.57% yield) as a white solid.

[0581] LCMS (ESI) [M + H]+: 324.11.

[0582] The following intermediates were prepared using experimental procedures similar for intermediate AD:

[0583] Intermediate AG: Methyl 4-[3-hydroxy-5-(trifluoromethyl)pyridin-2-yl]-5-methylthiophene - 2-carboxylate

[0584]

[0585] Step 1: To a stirred solution of 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (1.5 g, 5.75 mmol), methyl 5-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)thiophene-2- carboxylate (1.78 g, 6.32 mmol) and K3PO4(3.65 g, 17.2 mmol), Pd(dppf)Cl2(417 mg, 0.575 mmol) and H2O (1.5 mL) in dioxane (15 mL). Then the mixture was stirred for 2 hours at 80 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (45%) to afford methyl 4-[3-chloro-5- (trifluoromethyl)pyridin-2-yl]-5-methylthiophene-2-carboxylate (1.30 g, 3.87 mmol) as a yellow solid.

[0586] LCMS (ESI) [M + H]+: 336

[0587] Step 2: To a stirred solution of methyl 4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-5- methylthiophene-2-carboxylate (1.3 g, 3.87 mmol), B2(Pin)2(4.90 g, 19.3 mmol), AcOK (1.13 g, 11.6 mmol) and Pd(dppf)Cl2(420 mg, 0.580 mmol) in dioxane (15 mL). Then the mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (40%) to afford methyl 5- methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2- yl]thiophene-2-carboxylate (5.00 g, 11.7 mmol) as a white solid.

[0588] LCMS (ESI) [M + H]+: 428

[0589] Step 3: To a stirred solution of methyl 5-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-yl]thiophene-2-carboxylate (5 g, 11.7 mmol), H2O2 (448 mg, 13.2 mmol) and H2O (4 mL) in acetone (20 mL). Then the mixture was stirred for 2 hours at 25 °C under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography eluted with PE / EA (70%) to afford methyl 4-[3- hydroxy-5-(trifluoromethyl)pyridin-2-yl]-5-methylthiophene -2-carboxylate (1.20 g, 3.78 mmol) as a white solid.

[0590] LCMS (ESI) [M + H]+: 318 Intermediate AH: Methyl 4-(5-cyano-3-hydroxypyridin-2-yl)-5-methylthio phene-2-

[0591] Step 1: To a solution of 5-bromo-2-iodopyridin-3-ol (8 g, 26.6 mmol) and Cs2CO3(26.0 g, 79.8 mmol) in DMF (80 mL) was slowly added bromo(methoxy)methane (3.98 g, 31.9 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0-100%) to afford 5-bromo-2-iodo-3- (methoxymethoxy)pyridine (6.50 g, 18.8 mmol) as white solid.

[0592] LCMS [M+H]+: 344

[0593] Step 2: A solution of 5-bromo-2-iodo-3-(methoxymethoxy)pyridine (6.5 g, 18.8 mmol), methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2- carboxylate (5.81 g, 20.6 mmol), Pd(dppf)Cl2(958 mg, 1.31 mmol) and K3PO4(11.9 g, 56.4 mmol) in dioxane (60 mL) and H2O (6 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford methyl 4-[5-bromo-3-(methoxymethoxy)pyridin-2-yl]-5-methylthiophene-2-carboxylate (4.30 g, 11.5 mmol) as a white solid.

[0594] LCMS [M+H]+: 372

[0595] Step 3: A solution of methyl 4-[5-bromo-3-(methoxymethoxy)pyridin-2-yl]-5- methylthiophene-2-carboxylate (4.3 g, 11.5 mmol), Zn(CN)2(1.08 g, 9.20 mmol) and Pd(PPh3)4 (1.32 g, 1.15 mmol) in NMP (40 mL) was stirred for 4 hours at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0-100%) to afford methyl 4-[5- cyano-3-(methoxymethoxy)pyridin-2-yl]-5-methylthiophene-2-carboxylate (3.20 g, 10.0 mmol) as yellow solid.

[0596] LCMS [M+H]+:319

[0597] Step 4: To a stirred solution of methyl 4-[5-cyano-3-(methoxymethoxy)pyridin-2-yl]-5- methylthiophene-2-carboxylate (3.2 g, 10.0 mmol) in HCl / dioxane (20 mL) at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (0- 100%) to afford methyl 4-(5-cyano-3-hydroxypyridin-2-yl)-5-methylthio phene-2- carboxylate (2.10 g, 7.65 mmol) as a white solid.

[0598] LCMS [M+H]+: 275

[0599] Intermediate Al: Methyl 4-[3-hydroxy-5-(l-hydroxycyclobutyl)pyridin-2-yl]-5-

[0600] Step 1: To a stirred solution of 5-bromo-2-chloropyridin-3-ol (1 g, 4.79 mmol) and Cs2CO3(4.65 g, 14.3 mmol) in DMF (20 mL) was added bromo(methoxy)methane (717 mg, 5.74 mmol). Then the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (35%) to afford 5-bromo-2-chloro-3-(methoxymethoxy)pyridine (1.10 g, 4.35 mmol) as a white solid.

[0601] LCMS [M+H]+:252

[0602] Step 2: In a 500-mL round bottom flask, to a solution of 5-bromo-2-chloro-3- (methoxymethoxy)pyridine (1 g, 3.96 mmol) in THF (35 mL) was added dropwise n-BuLi (379 mg, 5.93 mmol) solution at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 30 minutes. Then a solution of cyclobutanone (415 mg, 5.93 mmol) in THF (35 mL) was added dropwise and the mixture was stirred for another 3 hours. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (50%, acidic system) to afford 1-[6-chloro-5-(methoxymethoxy)pyridin-3- yl]cyclobutan-1-ol (640 mg, 2.62 mmol) as a white solid.

[0603] LCMS [M+H]+:244

[0604] Step 3: To a mixture of 1-[6-chloro-5-(methoxymethoxy)pyridin-3-yl]cyclobutan-1-ol (640 mg, 2.62 mmol) , methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene- 2-carboxylate (885 mg, 3.14 mmol), Pd(dppf)Cl2(320 mg, 393 pmol), K3PO4(1.66 g, 7.86 mmol) in dioxane (15 mL) and H2O (2 mL). The resulting mixture was stirred for 2 hours at 80 °C under N2 atmosphere. The residue was purified by silica gel column chromatography, eluted with EA / PE (45%) to afford methyl 4-[5-(l-hydroxycyclobutyl)-3- (methoxymethoxy)pyridin-2-yl]-5-methylthiophene-2-carboxylate (480 mg, 1.32 mmol) as a yellow solid.

[0605] LCMS [M+H]+: 364

[0606] Step 4: To a stirred solution of methyl 4-[5-(l-hydroxycyclobutyl)-3- (methoxymethoxy)pyridin-2-yl]-5-methylthiophene-2-carboxylate (480 mg, 1.321 mmol) was added HC1 / dioxane (5 mL, 2.5 M). Then the mixture was stirred for 1 hour at 0 °C. The residue was purified by silica gel column chromatography, eluted with PE / EA (60%) to afford methyl 4- [3-hydroxy-5 -( 1 -hydroxycyclobutyl)pyridin-2-yl] -5 -methyl thiophene-2- carboxylate (400 mg, 1.25 mmol) as a white solid.

[0607] LCMS [M+H]+: 320

[0608] GENERAL SCHEMES

[0609] Compounds described below can be prepared through the following general schemes:

[0610] General Scheme A: An aryl alcohol, either commercially available or prepared through various means as described herein or known to those skilled in the art, is alkylated with an appropriate substituted alkyl halide (either commercially available or synthesized through various means, including those described herein and similar). The product ester is then coupled with an appropriate aniline, either through hydrolysis (e.g. with lithium hydroxide) followed by coupling (with various reagents, such as HATU, CDI, TCFH, T3P or various others), or by direct reaction of the ester with an aniline under appropriate reagents (e.g. trimethylaluminum) to provide the desired product.

[0611] General Scheme B:

[0612] An aryl alcohol, either commercially available or prepared through various means as described above or known to those skilled in the art, is alkylated with an appropriate substituted alkyl halide (either commercially available or synthesized through various means, including those described herein and similar). The product aryl halide is then coupled with an appropriately functionalized aryl ring prepared as described herein or via similar means under metal-catalyzed coupling conditions (e.g. copper, palladium or similar) with an appropriate ligand (e.g. Xantphos, BINAP, or similar). The product ester is then coupled with an appropriate aniline, either through hydrolysis (e.g. with lithium hydroxide) followed by coupling (with various reagents, such as HATU, CDI, TCFH, T3P or various others), or by direct reaction of the ester with an aniline under appropriate reagents (e.g. trimethylaluminum) to provide the desired product. General Scheme C:

[0613] An aryl alcohol, either commercially available or prepared through various means as described above or known to those skilled in the art, is alkylated with an appropriate substituted alkyl halide (either commercially available or synthesized through various means, including those described herein and similar). The product aryl halide is then coupled with an appropriately functionalized aryl ring prepared as described herein or via similar means under metal-catalyzed coupling conditions (e.g. copper, palladium or similar) with an appropriate ligand (e.g. Xantphos, BINAP, or similar). The product ester is then coupled with an appropriate nucleophile (e.g. an amine, alcohol, boron or carbon nucleophile) using metal- catalyzed coupling conditions (e.g. copper, palladium or similar) with an appropriate ligand (e.g. Xantphos, BINAP, or similar). The product ester is then coupled with an appropriate aniline, either through hydrolysis (e.g. with lithium hydroxide) followed by coupling (with various reagents, such as HATU, CDI, TCFH, T3P or various others), or by direct reaction of the ester with an aniline under appropriate reagents (e.g. trimethylaluminum) to provide the desired product.

[0614] General Scheme D:

[0615]

[0616] A methyl-substituted aryl group, either commercially available or prepared through various means, is treated with a halogenation reagent (e.g. NBS, NCS or similar). The resulting product is then alkylated with an alcohol, either commercially available or prepared through means known to those skilled in the art. The product aryl halide is then coupled with an appropriately functionalized aryl ring prepared as described herein or via similar means under metal-catalyzed coupling conditions (e.g. copper, palladium or similar) with an appropriate ligand (e.g. Xantphos, BINAP, or similar). The product ester is then coupled with an appropriate aniline, either through hydrolysis (e.g. with lithium hydroxide) followed by coupling (with various reagents, such as HATU, CDI, TCFH, T3P or various others), or by direct reaction of the ester with an aniline under appropriate reagents (e.g. trimethylaluminum) to provide the desired product. General Scheme E:

[0617]

[0618] A methyl-substituted aryl group, either commercially available or prepared through various means, is treated with a halogenation reagent (e.g. NBS, NCS or similar). The resulting product is then alkylated with an alcohol, either commercially available or prepared through means known to those skilled in the art. The product aryl halide is then coupled with an appropriately functionalized aryl ring prepared as described herein or via similar means under metal-catalyzed coupling conditions (e.g. copper, palladium or similar) with an appropriate ligand (e.g. Xantphos, BINAP, or similar). The product ester is then coupled with an appropriate nucleophile (e.g. an amine, alcohol, boron or carbon nucleophile) using metal- catalyzed coupling conditions (e.g. copper, palladium or similar) with an appropriate ligand (e.g. Xantphos, BINAP, or similar). The product ester is then coupled with an appropriate aniline, either through hydrolysis (e.g. with lithium hydroxide) followed by coupling (with various reagents, such as HATU, CDI, TCFH, T3P or various others), or by direct reaction of the ester with an aniline under appropriate reagents (e.g. trimethylaluminum) to provide the desired product.

[0619] In all cases, additional functional group manipulations (including deprotections, halogenation, cross-coupling, amide coupling, etc.) are possible at any intermediate step of these methods, as demonstrated by the examples below. EXAMPLES

[0620] Example 1: N-(3-chloro-5-methanesulfonamidophenyl)-5-{3-[(3,5- difluorophenyl)methoxy]-5-fluoropyridin-2-yl}-1-methylpyrrole-3-carboxamide

[0621] Step 1: A mixture of methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)-1-methylpyrrole-3- carboxylate (310 mg, 1.239 mmol, 1 equiv) and 1-(chloromethyl)-3,5-difluorobenzene (241.6 mg, 1.487 mmol, 1.2 equiv) and Cs2CO3(605.5 mg, 1.859 mmol, 1.5 equiv) in DMSO (10 mL) was stirred for 2 hours at 80 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-{3-[(3,5-difluorophenyl)methoxy]-5-fluoropyridin-2-yl}-1- methylpyrrole-3-carboxylate (240 mg, 51.48%) as a white solid.

[0622] LCMS (ESI) [M + H]+: 377

[0623] Step 2: A solution of methyl 5-{3-[(3,5-difluorophenyl)methoxy]-5-fluoropyridin-2-yl}-1- methylpyrrole-3-carboxylate (240 mg, 0.638 mmol, 1 equiv) and LiOH (76.4 mg, 3.190 mmol, 5 equiv) in EtOH (9 mL) and H2O (3 mL) was stirred for 2 hours at 60 °C. The mixture was acidified pH to 6 with HC1 (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 5- { 3- [(3 ,5-difluorophenyl)methoxy] -5 -fluoropyridin-2-yl } - 1 -methylpyrrole-3- carboxylic acid (150 mg, 64.92%) as a white solid. LCMS (ESI) [M + H]+: 363

[0624] Step 3: A solution of 5-{3-[(3,5-difluorophenyl)methoxy]-5-fluoropyridin-2-yl}-1- methylpyrrole-3-carboxylic acid (150 mg, 0.414 mmol, 1 equiv), N-(3-amino-5- chlorophenyl)methanesulfonamide (109.6 mg, 0.497 mmol, 1.2 equiv), TCFH (174.2 mg, 0.621 mmol, 1.5 equiv) and NMI (101.9 mg, 1.242 mmol, 3 equiv) in MeCN (10 mF) was stirred for 2 hours at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-(3-chloro-5-methanesulfonamidophenyl)-5-{3-[(3,5-difluorophenyl)methoxy]-5- fluoropyridin-2-yl}-1-methylpyrrole-3-carboxamide (45.6 mg, 19.50%) as a white solid.

[0625] LCMS (ESI) [M + H]+: 564.90

[0626] 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.81 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.72 - 7.64 (m, 3H), 7.62 (s, 1H), 7.28 - 7.06 (m, 4H), 6.89 (d, J= 2.0 Hz, 1H), 5.31 (s, 2H), 3.75 (s, 3H), 3.05 (s, 3H).

[0627] Examples 2-9, 11-13, 15-26, and 28-35

[0628] The compounds listed in the following table were prepared using a procedure similar to that described for example 1 : Example 14: N-( 3-chloro-5-methanesulfon amidophenyl)-4-{3-[(3,5- difluorophenyl)methoxy]-5-(3-hydroxy-1-methylazetidin-3-yl)pyridin-2-yl}-5- methylthiophene-2-carboxamide

[0629] Step 1: A solution of 5-bromo-2-chloropyridin-3-ol (4 g, 19.190 mmol, 1 equiv) and methane, bromomethoxy- (4.80 g, 38.380 mmol, 2 equiv) and Cs2CO3(9.38 g, 28.785 mmol, 1.5 equiv) in DMF (50 mL) was stirred for 1 hour at

[0630] 0 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-bromo-2-chloro-3-(methoxymethoxy)pyridine (4.6 g, 94.94% yield) as a white solid.

[0631] LCMS (ESI) [M + H]+: 252 Step 2: A solution of 5-bromo-2-chloro-3-(methoxymethoxy)pyridine (2.8 g, 11.090 mmol, 1 equiv) and tert-butyl 3-oxoazetidine-1-carboxylate (2.28 g, 13.308 mmol, 1.2 equiv) and n- BuLi (1.07 g, 16.635 mmol, 1.5 equiv) in THF (30 mL) was stirred for 1 hour at - 78 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (15 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford tert-butyl 3-[6-chloro-5-(methoxymethoxy)pyridin-3-yl]-3-hydroxyazetidine-1- carboxylate (1.35 g, 22.95% yield) as a white solid.

[0632] LCMS (ESI) [M + H]+: 345

[0633] Step 3: A solution of tert-butyl 3-[6-chloro-5-(methoxymethoxy)pyridin-3-yl]-3- hydroxyazetidine-1 -carboxy late (1.35 g, 2.545 mmol, 1 equiv, 65%) and methyl 5-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiophene-2-carboxylate (0.86 g, 3.054 mmol, 1.2 equiv) and Pd(dppf)Cl2(0.19 g, 0.255 mmol, 0.1 equiv) and K3PO4(1.62 g, 7.635 mmol, 3 equiv) in dioxane (20 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na2SO4.

[0634] After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3- hydroxy-3-{6-[5-(methoxycarbonyl)-2-methylthiophen-3-yl]-5-(methoxymethoxy)pyridin-3- yl } azetidine- 1 -carboxylate (640 mg, 54.13% yield) as a light brown solid.

[0635] LCMS (ESI) [M + H]+: 465

[0636] Step 4: A solution of tert-butyl 3-hydroxy-3-{6-[5-(methoxycarbonyl)-2-methylthiophen-3- yl]-5-(methoxyme thoxy) pyridin-3-yl} azetidine- 1 -carboxylate (640 mg, 1.378 mmol, 1 equiv) and TFA (471 mg, 4.134 mmol, 3 equiv) in DCM (10 mL) was stirred for 2 hours at room temperature under air atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-[3-hydroxy-5-(3- hydroxyazetidin-3-yl)pyridin-2-yl]-5-methylthiophene-2-carboxylate (315 mg, 71.37% yield) as a dark green solid.

[0637] LCMS (ESI) [M + H]+: 321

[0638] Step 5: A solution of methyl 4-[3-hydroxy-5-(3-hydroxyazetidin-3-yl)pyridin-2-yl]-5- methylthiophene-2-carboxylate (315 mg, 0.983 mmol, 1 equiv) and formaldehyde (59 mg, 1.966 mmol, 2 equiv) and STAB (625 mg, 2.949 mmol, 3 equiv) in MeOH (5 mL) was stirred for 2 hours at room temperature under air atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-[3-hydroxy-5-(3- hydroxy-1-methylazetidin-3-yl)pyridin-2-yl]-5-methylthiophene-2-carboxylate (190 mg, 57.7 9% yield) as an off-white solid.

[0639] LCMS (ESI) [M + H]+: 335 Step 6: A solution of methyl 4-[3-hydroxy-5-(3-hydroxy-1-methylazetidin-3-yl)pyridin-2-yl]- 5-methylthiophe ne-2-carboxylate (190 mg, 0.568 mmol, 1 equiv) and 1-(bromomethyl)-3,5- difluorobenzene (141 mg, 0.682 mmol, 1.2 equiv) and Cs2CO3(278mg, 0.852 mmol, 1.5 equiv) in DMSO (10 mL) was stirred for 1 hour at 80 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford methyl 4-{3-[(3,5- difluorophenyl)methoxy]-5-(3-hydroxy-1-methylazetidin-3-yl)pyridin-2-yl}-5- methylthiophene-2-carboxy late (165 mg, 63.06% yield) as a white solid.

[0640] LCMS (ESI) [M + H]+: 461

[0641] Step 7: A solution of methyl 4-{3-[(3,5-difluorophenyl)methoxy]-5-(3-hydroxy-1- methylazetidin-3-yl)pyridin-2-yl}-5-methylthiophene-2-carboxylate (160 mg, 0.347 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl) methanesulfonamide (92 mg, 0.416 mmol, 1.2 equiv) and AlMe3 (37 mg, 0.520 mmol, 1.5 equiv) in toluene (10 mL) was stirred for 2 hours at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of MeOH (5 mL) at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 25 min; detector, UV 254 nm. This resulted in N-(3-chloro-5-methanesulfon amidophenyl)-4-{3-[(3,5- difluorophenyl)methoxy]-5-(3-hydroxy-1-methylazetidin-3-yl)pyridin-2-yl}-5- methylthiophene-2-carboxamide (44.1 mg, 19.41% yield) as a white solid.

[0642] LCMS (ESI) [M + H]+: 649.10

[0643] 1H NMR (400 MHz, Methanol-d4) δ 8.26 (dd, J = 4.8, 1.2 Hz, 1H), 7.98 (s, 1H), 7.67 (dd, J = 8.5, 1.3 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.51 (t, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.4, 4.8 Hz, 1H), 7.01 (t, J = 1.9 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 5.19 (s, 2H), 3.84 - 3.76 (m, 2H), 3.53 (d, J= 9.1 Hz, 2H), 3.03 (s, 3H), 2.45 (s, 3H), 2.37 (s, 3H).

[0644] Example 27: \-(3-chloro-5-methanesull'onamidophenyl)-4- (5-fhioro-3-{[3-fhioro-5-(2- hydroxypropan-2-yl)phenyl]methoxy}pyridin-2-yl)-5-methylthiophene-2-carboxamide

[0645]

[0646] Step 1: To a stirred solution of 3-fluoro-5-methylbenzoic acid (500 mg, 3.24 mmol), TCFH (2.72 g, 9.72 mmol) in CH3OH (25 mL) was added NMI (1.59 g, 19.4 mmol). Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (35%) to afford methyl 3-fluoro-5-methylbenzoate (500 mg, 2.97 mmol) as a yellow solid.

[0647] Step 2: To a stirred solution of methyl 3-fluoro-5-methylbenzoate (500 mg, 2.97 mmol) in DCE (15 mL) was added AIBN (24.3 mg, 148 pmol) and NBS (687 mg, 3.86 mmol) at 0 °C under N2 atmosphere. Then the mixture was stirred for 1 hour at 80 °C. After concentration, the residue was purified by silica gel column chromatography, eluted with EA / PE (45%) to afford methyl 3-(bromomethyl)-5-fluorobenzoate (400 mg, 1.61 mmol) as a yellow oil.

[0648] Step 3: A mixture of methyl 3-(bromomethyl)-5-fluorobenzoate (400 mg, 1.61 mmol), 2- chloro-5-fluoropyridin-3-ol (284 mg, 1.93 mmol), K2CO3(667 mg, 4.83 mmol) in DMF (10 mL) was stirred for 2 hours at 60 °C under nitrogen atmosphere. The mixture was diluted with 100 mL of water and extracted with EtOAc (3 x 100 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / PE) (35%) to afford methyl 3-{[(2-chloro-5-fluoropyridin- 3-yl)oxy] methyl} -5-fluorobenzoate (380 mg, 1.21 mmol) as a white solid.

[0649] LCMS (ESI) [M + H]+: 314 Step 4: To a stirred solution methyl 3-{[(2-chloro-5-fluoropyridin-3-yl)oxy]methyl}-5- fluorobenzoate (380 mg, 1.21 mmol) in Et2O (15 mL) was added MeMgBr (2.42 mL, 2.42 mmol, 1 M in THF) dropwise at 0 °C under N2 atmosphere. Then the mixture was stirred for 1 hour at room temperature. The residue was purified by silica gel column chromatography, eluted with EA / PE (50%) to afford 2-(3-{[(2-chloro-5-fluoropyridin-3-yl)oxy]methyl}-5- fluorophenyl)propan-2-ol (250 mg, 0.796 mmol) as a white solid.

[0650] LCMS (ESI) [M + H]+: 314

[0651] Step 5: A mixture of 2-(3-{[(2-chloro-5-fluoropyridin-3-yl)oxy]methyl}-5- fluorophenyl)propan-2-ol (250 mg, 0.796 mmol), methyl 5-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (290 mg, 1.03 mmol), Pd(dppf)Cl2(65.0 mg, 0.0796 mmol), K3PO4(505 mg, 2.38 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred for 2 hours at 100 °C under N2 atmosphere. The mixture was diluted with 100 mL of water and extracted with EtOAc (3 x 100 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (45%) to afford methyl 4-(5-fluoro-3-{[3-fluoro-5-(2- hydroxypropan-2-yl)phenyl]methoxy}pyridin-2-yl)-5-methylthiophene-2-carboxylate (165 mg, 0. 380 mmol) as a white solid.

[0652] LCMS (ESI) [M + H]+: 434

[0653] Step 6: To a stirred solution of methyl 4-(5-fluoro-3-{[3-fluoro-5-(2-hydroxypropan-2- yl)phenyl] methoxy} pyridin-2-yl)-5-methylthiophene-2-carboxylate (165 mg, 0.380 mmol) and N-(3-amino-5-chlorophenyl) methanesulfonamide (100 mg, 0.455 mmol) in PhMe (10 mL) was added Al Me ? (41.0 mg, 0.570 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 2 hours at 80 °C. The mixture was concentrated and purified by flash chromatography eluted with EA / PE (80%) to afford N-(3- chloro-5-methanesulfonamidophenyl)-4- (5-fluoro-3-{ [3-fluoro-5-(2-hydroxypropan-2- yl)phenyl]methoxy}pyridin-2-yl)-5-methylthiophene-2-carboxamide (72.5 mg, 0.116 mmol) as a white solid.

[0654] LCMS (ESI) [M + H]+: 622.10

[0655] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.05 (s, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 7.78 (dd, J = 10.9, 2.4 Hz, 1H), 7.64 (dt, J = 11.5, 1.9 Hz, 2H), 7.26 (t, J= 1.5 Hz, 1H), 7.20 (dt, J = 10.5, 2.2 Hz, 1H), 7.02 (dt, J= 9.0, 2.0 Hz, 1H), 6.94 (t, J = 2.0 Hz, 1H), 5.25 (s, 2H), 5.12 (s, 1H), 3.05 (s, 3H), 2.40 (s, 3H), 1.33 (s, 6H). Example 36: 5-{3-[(3-chloro-5-fluorophenyl)methoxy]-5-fhioropyridin-2-yl}-N-( 3- chloro-5-methanesulfonamidophenyl)-1-methyl-lH-pyrrole-3-carboxamide

[0656] Step 1: A solution of l-chloro-3-(chloromethyl)-5-fluorobenzene (300 mg, 1.67 mmol), methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (417 mg, 1.67 mmol) and K2CO3(691 mg, 5.01 mmol) in DMSO (5 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was diluted with water. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:3) to afford methyl 5-{3-[(3-chloro-5-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}-1-methyl-1H- pyrrole-3-carboxylate (130 mg, 330 pmol) as a yellow oil.

[0657] LCMS (ESI) [M + H]+: 392.07

[0658] Step 2: A solution of methyl 5-{3-[(3-chloro-5-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}- l-methyl-1H-pyrrole-3-carboxylate (110 mg, 280 pmol) and N-(3-amino-5- chlorophenyl)methanesulfonamide (74 mg, 3 36 pmol) in toluene (4 mL) was stirred for 10 minutes at 0 °C under nitrogen atmosphere. To the above mixture was added Al Me ? (0.4 mL, 280 pmol) dropwise over 1 minute at 0 °C. The resulting mixture was stirred for additional 40 minutes at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product (115 mg) was purified by Prep- HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*150 mm, 5pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 44% B to 67% B in 9 min, 67% B; Wave Length: 254 / 220 nm; RTl(min): 9.33) to afford 5-{3-[(3-chloro-5-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}-A- (3-chloro-5-methanesulfonamidophenyl)-1-methyl-1H-pyrrole-3-carboxamide (91.2 mg, 56.1% yield) as a white solid.

[0659] LCMS (ESI) [M + H]+: 581.101H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.83 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 7.84 - 7.53 (m, 4H), 7.46 - 7.33 (m, 2H), 7.28 (dt, J = 9.8, 1.7 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.89 (d, J= 2.0 Hz, 1H), 5.31 (s, 2H), 3.76 (s, 3H), 3.06 (s, 3H). Examples 37-71

[0660] The compounds listed in the following table were prepared using a procedure similar to that described for example 36:

[0661] Example 72: N-(3-chloro-5-methanesulfonamidophenyl)-4-{5-fhioro-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl}thiophene-2-carboxamide

[0662] Step 1: A solution of 1-(chloromethyl)-3-fluoro-5-methanesulfonylbenzene (480 mg, 2.15 mmol), 2-bromo-5-fluoropyridin-3-ol (453 mg, 2.36 mmol) and K2CO3(891 mg, 6.45 mmol) in DMF (8 mL ) was stirred for 4 hours at room temperature under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (1:2) to afford 2-bromo-5-fluoro-3-[(3-fluoro-5-methanesulfonylphenyl)methoxy] pyridine (600 mg, 1.58 mmol) as a yellow solid.

[0663] LCMS (ESI) [M + H]+: 378

[0664] Step 2: A solution of 2-bromo-5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridine (600 mg, 1.58 mmol), methyl 5-methyl-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) thiophene-2-carboxylate (578 mg, 2.05 mmol), Pd(dppf)Cl2(129 mg, 158 pmol) and K3PO4(1 g, 4.74 mmol) in H2O (3 mL ) and 1,4-dioxane (15 mL ) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel eluting with (1:4) to afford methyl 4-{5-fluoro-3-[(3-fluoro-5-methanesulfonylphenyl) methoxy]pyridin- 2-yl}-5-methylthiophene-2-carboxylate (420 mg, 0.926 mmol) as a yellow solid.

[0665] LCMS (ESI) [M + H]+: 454

[0666] Step 3: To a stirred solution of methyl 4-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy] pyridin-2-yl}-5-methylthiophene-2-carboxylate (420 mg, 0.926 mmol) in EtOH (5 mL) and H2O (5 mL) was added LiOH (221 mg, 9.26 mmol) at room temperature. Then the mixture was stirred for 2 hours at 60 °C. The mixture was acidified to pH 5 with 1 M HC1 (aq). The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 50% gradient in 20 min; detector, UV 254 nm to afford 4-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-5-methylthiophene-2-carboxylic acid (250 mg, 0.568 mmol)l) as a white solid.

[0667] LCMS (ESI) [M + H]+: 440

[0668] Step 4: To a stirred solution of 4-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}- 5-methylthiophene-2-carboxylic acid (250 mg, 0.568 mmol), TCFH (476 mg, 1.70 mmol) and NMI (279 mg, 3.40 mmol) in ACN (10 mL) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (137 mg, 0.624 mmol) at room temperature. Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by flash chromatography eluted with PE / EA (1:2) to afford N-(3-chloro-5-methanesulfonamidophenyl)-4-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl } -5 -methylthiophene-2-carboxamide (178 mg, 0.275 mmol) as a white solid.

[0669] LCMS (ESI) [M + H]+: 642.05

[0670] ’ H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.05 (s, 1H), 8.36 (d, J= 2.3 Hz, 1H), 8.18 (s, 1H), 7.85 - 7.71 (m, 3H), 7.67 - 7.55 (m, 3H), 6.94 (t, J = 2.0 Hz, 1H), 5.39 (s, 2H), 3.21 (s, 3H), 3.06 (s, 3H), 2.41 (s, 3H).

[0671] Examples 73-89, 91, 92 and 94-96

[0672] The compounds listed in the following table were prepared using a procedure similar to that described for example 72:

[0673] Example 90: 5-[5-(l-acetylazetidin-3-yl)-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl]-2V

[0674] -(3-chloro-5-methanesulfo namidophenyl)-1-methylpyrrole-3-carboxamide

[0675]

[0676] Step 1: A solution of 5-bromo-2-iodopyridin-3-ol (1 g, 3.33 mmol, 1 equiv), 1- (bromomethyl)-3,5- difluorobenzene (0.83 g, 4.01 mmol, 1.2 equiv) and K2CO3(1.38 g, 10.01 mmol, 3 equiv) in DMSO (10 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 5- bromo-3-[(3,5-difluorophenyl)methoxy]-2-iodopyridine (850 mg, 59.8% yield) as a white solid.

[0677] LCMS (ESI) [M+H]+: 426.00.

[0678] Step 2: A solution of 5-bromo-3-[(3,5-difluorophenyl)methoxy]-2-iodopyridine (850 mg, 1.99 mmol, 1 equiv), methyl l-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrrole-3-carboxylate (634 mg, 2.39 mmol, 1.2 equiv), Pd(dppf)Cl2(292 mg, 0.39 mmol, 0.2 equiv) and K2CO3(827 mg, 5.98 mmol, 3 equiv) in H2O (0.8 mL) and 1,4-dioxane (8 mL) was stirred for 1 hour at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford methyl 5-{5-bromo-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl}-1-methylpyrrole-3- carboxylate (650 mg, 74.5% yield) as a white solid.

[0679] LCMS (ESI) [M+H]+: 437.00. Step 3: A solution of methyl 5-{5-bromo-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl}-1- methylpyrrole-3- carboxylate (650 mg, 1.48 mmol, 1 equiv), tert-butyl 3-iodoazetidine-1- carboxylate (0.63 g, 2.21 mmol, 1.5 equiv), Ni(OAc)2(0.03 g, 0.14 mmol, 0.1 equiv), dtbpy (0.04 g, 0.14 mmol, 0.1 equiv), manganese (0.16 g, 2.97 mmol, 2 equiv) and pyridine (0.12 g, 1.48 mmol, 1 equiv) in DMA (15 mL) was stirred overnight at 60 °C under nitrogen atmosphere. The resulting mixture was washed with 3x10 mL of H2O. The aqueous layer was extracted with EtOAc (3x30 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5- { 5- [ 1 -(tert-butoxycarbonyl)azetidin-3-yl] -3- [(3,5- difluorophenyl)methoxy]pyridin-2-yl}-1-methylpyrrole-3-carboxylate (235 mg, 30.7% yield) as a white solid.

[0680] LCMS (ESI) [M+H]+: 514.00.

[0681] Step 4: A solution of methyl 5-{5-[1-(tert-butoxycarbonyl)azetidin-3-yl]-3-[(3,5- difluorophenyl)methoxy] pyridin-2-yl}-1-methylpyrrole-3-carboxylate (235 mg, 0.45 mmol, 1 equiv) in HC1 in 1,4-dioxane (4 mL, 4 M) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. This resulted in methyl 5-[5-(azetidin-3-yl)-3-[(3,5-difluorophenyl)methoxy] pyridin-2-yl]-1-methylpyrrole- 3-carboxylate (185 mg, 97.7% yield) as a white solid.

[0682] LCMS (ESI) [M+H]+: 414.00.

[0683] Step 5: A solution of methyl 5-[5-(azetidin-3-yl)-3-[(3,5-difluorophenyl)methoxy]pyridin-2- yl]-1-methylpyrrole-3-carboxylate (185 mg, 0.44 mmol, 1 equiv) and acetyl chloride (42 mg, 0.53 mmol, 1.2 equiv) in DCM (2 mL) and pyridine (0.4 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-[5-(l-acetylazetidin-3-yl)-3-[(3,5-difluorophenyl)methoxy]pyridin-2- yl]-1-methylpyrrole-3-carboxylate (105 mg, 51.5% yield) as a white solid.

[0684] LCMS (ESI) [M+H]+: 456.00.

[0685] Step 6: A solution of methyl 5-[5-(l-acetylazetidin-3-yl)-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl]-1-methylpyrrole-3-carboxylate (105 mg, 0.23 mmol, 1 equiv), N-(3-amino-5-chlorophenyl)methanesulfona mide (61 mg, 0.27 mmol, 1.2 equiv) in PhMe (2 mL) was stirred for 10 min at 0 °C under nitrogen atmosphere. To the above mixture was added Al Me ? (0.6 mL, 430 pmol) in portions over 1 minute at 0 °C. The resulting mixture was stirred for additional 1 hour at 80 °C. The reaction was quenched with water at 0 °C. The aqueous layer was extracted with EtOAc (3x20 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5- [5-(l-acetylazetidin-3-yl)-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl]-A -(3-chloro-5- methanesulfo namidophenyl)-1-methylpyrrole-3-carboxamide (101.2 mg, 68.1% yield) as a white solid.

[0686] LCMS (ESI) [M+H]+: 644.15.

[0687] 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.25 (d, J = 1.8 Hz, 1H), 7.67 (dt, J = 11.1, 1.9 Hz, 2H), 7.66 (dt, J= 11.1, 1.9 Hz, 1H),7.6O (t, J= 1.9 Hz, 1H), 7.24 - 7.14 (m, 4H), 6.88 (t, J= 2.0 Hz, 1H), 5.34 (s, 2H), 4.52 (t, J = 8.2 Hz, 1H), 4.31 - 4.18 (m, 2H), 4.00 - 3.89 (m, 2H), 3.79 (s, 3H), 3.03 (s, 3H), 1.82 (s, 3H).

[0688] Example 93: N-( 3-chloro-5-methanesulfonami dophenyl)-5-(5-fhioro-3-{[3-fhioro-5-(2- hydroxypropan-2-yl)phenyl]methoxy}pyridin-2-yl)-1-methylpyrrole-3-carboxamide

[0689] Step 1: A solution of (3-bromo-5-fluorophenyl)methanol (500 mg, 2.43 mmol, 1 equiv) in THF (10 mL) was treated with n-BuLi (2.93 mL, 7.31 mmol, 3 equiv) for 40 min at -78 °C under nitrogen atmosphere followed by the addition of acetone (283.28 mg, 4.878 mmol, 2 equiv) dropwise at -78 °C. The resulting mixture was stirred for 30 minutes at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The aqueous layer was extracted with EtOAc (3x40 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2- [3-fluoro-5-(hydroxymethyl)phenyl]propan-2-ol (213 mg, 47.4% yield) as a colorless oil. LCMS (ESI) [M+H]+: 185.00.

[0690] Step 2: A solution of 2-[3-fluoro-5-(hydroxymethyl)phenyl]propan-2-ol (213 mg, 1.15 mmol, 1 equiv), methyl 5-(5-fluoro-3-3hydroxypyridin-2-2yl)-1-methyl-1H-pyrrole-3-carboxylate (345 mg, 1.38 mmol, 1.2 equiv) in THF (3 mL) was treated with PPh3(606 mg, 2.31 mmol, 2 equiv) for 3 minutes at room temperature under nitrogen atmosphere followed by the addition of DIAD (467 mg, 2.31 mmol, 2 equiv) dropwise at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-(5-fluoro-3-{[3-fluoro-5-(2- hydroxypropan- 2-yl)phenyl]methoxy}pyridin-2-yl)-1-methylpyrrole-3-carboxylate (180 mg, 37.3% yield) as a white solid.

[0691] LCMS (ESI) [M+H]+: 417.00.

[0692] Step 3: A solution of methyl 5-(5-fluoro-3-{[3-fluoro-5-(2-hydroxypropan-2- yl)phenyl]methoxy}pyridin-2-yl)- l-methylpyrrole-3-carboxylate (180 mg, 0.43 mmol, 1 equiv) and LiOH (145 mg, 3.45 mmol, 8 equiv) in EtOH (2 mL) and H2O (0.4 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5- (5-fluoro-3 - { [3-fluoro-5- (2-hydroxypropan-2-yl)phenyl] methoxy }pyridin-2-yl)- 1 - methylpyrrole-3-carboxylic acid (150 mg, 86.2% yield) as a white solid.

[0693] LCMS (ESI) [M+H]+: 403.00.

[0694] Step 4: A solution of 5-(5-fluoro-3-{[3-fluoro-5-(2-hydroxypropan-2- yl)phenyl]methoxy}pyridin-2-yl)-1- methylpyrrole-3-carboxylic acid (150 mg, 0.37 mmol, 1 equiv), N-( 3-amino-5-chlorophcnyl)mcthancsull'onamidc (98 mg, 0.44 mmol, 1.2 equiv), TCFH (156 mg, 0.55 mmol, 1.5 equiv) and NMI (91 mg, 1.11 mmol, 3 equiv) in ACN (2 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-( 3-chloro-5-mcthancsullbnami dophenyl)-5-(5- fluoro-3-{[3-fluoro-5-(2-hydroxypropan-2-yl)phenyl]methoxy}pyridin-2-yl)-1- methylpyrrole-3-carboxamide (130 mg, 57.6% yield) as a white solid.

[0695] LCMS (ESI) [M+H]+: 605.25.1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.81 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.71 (ddd, J= 17.1, 11.0, 2.2 Hz, 3H), 7.64 - 7.58 (m, 1H), 7.36 (s, 1H), 7.22 (d, J= 10.8 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.11 - 7.03 (m, 1H), 6.88 (t, J = 1.8 Hz, 1H), 5.28 (s, 2H), 5.13 (s, 1H), 3.75 (s, 3H), 3.05 (s, 3H), 1.36 (s, 6H).

[0696] Example 10

[0697] The compounds listed in the following table were prepared using a procedure similar to that described for example 93:

[0698] Examples 97 and 98: R and S \-(3-chloro-5-methanesull'onamidophenyl)-4-{5-fluoro-3- [1-(3-fluoro-5-methanesulfonylphenyl)ethoxy]pyridin-2-yl}-5-methylthiophene-2- carboxamide

[0699]

[0700] Step 1: To a stirred solution of 1-(3-bromo-5-fluorophenyl)ethan-1-one (2 g, 9.21 mmol), sodium methane sulfinate (1.21 g, 11.9 mmol) and Cui (700 mg, 3.68 mmol), K2CO3(3.80 g, 27.6 mmol), (L)-Proline (158 mg, 1.38 mmol) in DMSO (8 mL). Then the mixture was stirred for 3 hours at 100 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (55%) to afford 1-(3-fluoro-5- methanesulfonylphenyl)ethan-1-one (1.30 g, 6.01 mmol) as a yellow solid.

[0701] LCMS (ESI) [M + H]+: 217

[0702] Step 2: A solution of 1-(3-fluoro-5-methanesulfonylphenyl)ethan-1-one (1.25 g, 5.78 mmol), was stirred in dry THF (10 mL) at 0 °C under a nitrogen atmosphere. To this mixture was added LiAlH4(1.09 g, 28.9 mmol) over a period of 5 minutes. Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by flash chromatography eluted with PE / EA (70%) to afford1-(3-fluoro-5- methanesulfonylphenyl)ethan-1-ol (1 g, 4.58 mmol) as a white liquid.

[0703] LCMS (ESI) [M + H]+: 219

[0704] Step 3: To a stirred solution of 1-(3-fluoro-5-methanesulfonylphenyl)ethan-1-ol (950 mg, 4.35 mmol) and DMF (0.5 mL) in DCM (6 mL) was slowly added SOCl2(1.54 g, 13.0 mmol) at 0 °C. Then the mixture was stirred for 1 hour at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (63%) to afford1-(l-chloroethyl)-3-fluoro-5-methanesulfonylbenzene (980 mg, 4.14 mmol) as a white solid.

[0705] LCMS (ESI) [M + H]+: 237

[0706] Step 4: To a stirred solution of 1-(l-chloroethyl)-3-fluoro-5-methanesulfonylbenzene (980 mg, 4.14 mmol), K2CO3(1.71 g, 12.4 mmol) and methyl 4-(5-fluoro-3-hydroxypyridin-2-yl)- 5-methylthiophene-2-carboxylate (1.32 g, 4.96 mmol) in DMSO (8 mL). Then the mixture was stirred for 2 hours at 80 °C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN / H2O (55%, acidic system) to afford methyl 4- { 5- fluoro-3-[1-(3-fluoro-5-methanesulfonylphenyl) ethoxy]pyridin-2-yl}-5-methylthiophene-2- carboxylate (1 g, 2.13 mmol) as a white solid.

[0707] LCMS (ESI) [M + H]+: 468

[0708] Step 5: To a solution of methyl 4-{5-fluoro-3-[ 1-(3-fluoro-5- methanesulfonylphenyl)ethoxy]pyridin-2-yl}-5-methylthiophene-2-carboxylate (500 mg, 1.06 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (280 mg, 1.27 mmol) in PhMe (5 mL) was slowly added AlMe3(229 mg, 3.18 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at 80 °C. The residue was purified by silica gel column chromatography, eluted with PE / EA (40%) to afford N-(3-chloro-5-methane sulfonamidophenyl)-4-{5-fluoro-3-[1-(3-fluoro-5-methanesulfonylphenyl)ethoxy]pyridin-2- yl}-5-methyl thiophene-2-carboxamide (260 mg, 0.396 mmol) as a white solid.

[0709] LCMS (ESI) [M + H]+: 656

[0710] Step 6: Racemic N-(3-chloro-5-methane sulfonamidophenyl)-4-{5-fluoro-3-[1-(3-fluoro-5- methanesulfonylphenyl)ethoxy]pyridin-2-yl}-5-methyl thiophene-2-carboxamide was purified by Prep-SFC with the following conditions : Column Name : Cellulose SZ, Column Size : 0.46*5cm,3um; Mobile phase: Hex(0.1%DEA):ETOH=70:30, Flow rate: 1.67ml / min; Wave Length: 254 nm. Absolute stereochemistry was not determined.

[0711] First eluting peak (Example 97): RT 2.282 min; 54.4 mg as a white solid

[0712] LCMS (ESI) [M + H]+:656.05

[0713] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.04 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.74 - 7.60 (m, 5H), 7.45 (d, J = 9.4 Hz, 1H), 6.95 (t, J = 2.0 Hz, 1H), 5.82 (d, J = 6.4 Hz, 1H), 3.22 (s, 3H), 3.06 (s, 3H), 2.41 (s, 3H), 1.58 (d, J = 6.3 Hz, 3H).

[0714] Second eluting peak (Example 98): RT 2.956 min; 77.2 mg as a white solid LCMS (ESI) [M + H]+:656.05 ^NMR (400 MHz, DMSO-d6) 5 10.36 (s, 1H), 10.06 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 7.75 - 7.60 (m, 5H), 7.46 (d, J = 9.2 Hz, 1H), 6.94 (t, J = 1.9 Hz, 1H), 5.82 (d, J = 6.4 Hz, 1H), 3.23 (s, 3H), 3.06 (s, 3H), 2.41 (s, 3H), 1.58 (d, J = 6.3 Hz, 3H). Examples 99-112

[0715] The compounds listed in the following table were prepared using a procedure similar to that described for examples 97 and 98:

[0716] Ill

[0717] Examples 113 and 114: R and S 3-[1-[(2-{5-[(3-chloro-5-methanesulfonamidophenyl) carbamoyl]-2-methylthiophen-3-yl}-5-fluoropyridin-3-yl)oxy]ethyl]-5-fluoropyridin-1- ium-1-olate

[0718] Step 1: To a solution of methyl 4-bromo-5-methylthiophene-2-carboxylate (2 g, 8.50 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (2.06 g, 9.35 mmol) in PhMe (10 mL) was slowly added Al Me ? (2.44 g, 34.0 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at 80 °C. The mixture was quenched with MeOH. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford 4-bromo-N-(3- chloro-5-methanesulfonami dophenyl)-5-methylthiophene-2-carboxamide (2.10 g, 4.95 mmol) as a white solid.

[0719] LCMS [M+H]+: 423

[0720] Step 2: A solution of 4-bromo-N-(3-chloro-5-methanesulfonamidophenyl)-5- methylthiophene-2-carboxa mide (2.1 g, 4.95 mmol), B2pin2(2.51 g, 9.90 mmol), Pd(dppf)Cl2(352 mg, 0.495 mmol) and AcOK (1.45 g, 14.8 mmol) in dioxane (20 mL) was stirred for 5 hours at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-30%) to afford N-(3-chloro-5- methanesulfonamidophenyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)thiophene-2-carboxamide (1.80 g, 3.82 mmol) as a white solid.

[0721] LCMS [M+H]+: 644

[0722] Step 3: To a solution of 5-fluoropyridine-3-carbaldehyde (1 g, 7.99 mmol) and Et2O (30 mL) at room temperature. To the above mixture was added bromo(methyl)magnesium (20 mL, 15.9 mmol) in portions over 5 minutes at 0 °C. The resulting mixture was stirred for additional 2 hours at 0 °C. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (72%) to afford 1-(5-fluoropyridin-3- yl)ethan-1-ol (650 mg, 4.60 mmol) as a white solid.

[0723] LCMS (ESI) [M + H]+: 142

[0724] Step 4: To a stirred solution of 1-(5-fluoropyridin-3-yl)ethan-1-ol (650 mg, 4.60 mmol) in DMF (0.1 mL) and DCM (10 mL) at room temperature. To the above mixture was added SOCl2(5 mL, 13.7 mmol) in portions over 3 minutes at 0 °C. The resulting mixture was stirred for additional 2 hours at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (20%) to afford 3-(l-chloroethyl)- 5-fluoropyridine (500 mg, 3.13 mmol) as a white liquid.

[0725] LCMS (ESI) [M + H]+: 160

[0726] Step 5: To a stirred solution of 3-(l-chloroethyl)-5-fluoropyridine (500 mg, 3.13 mmol), mCPBA (1.61 g, 9.38 mmol) in DCM (10 mL).Then the mixture was stirred for 2 hours at 40 °C under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (35%) to afford 3-(l-chloroethyl)-5- fluoropyridin-1-ium-1-olate (180 mg, 1.02 mmol) as a yellow solid.

[0727] LCMS (ESI) [M + H]+: 176

[0728] Step 6: To a stirred solution of 3-(l-chloroethyl)-5-fluoropyridin- 1-ium- 1-olate (180 mg, 1.02 mmol), K2CO3(422 mg, 3.06 mmol) and 2-chloro-5-fluoropyridin-3-ol (179 mg, 1.22 mmol) in DMF (6 mL). Then the mixture was stirred for 3 hours at 25 °C. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / H2O (5-95%, acidic system) to afford 3-{ 1-[(2-chloro-5-fluoropyridin-3-yl)oxy]ethyl}-5-fluoropyridin-1- ium-1-olate (130 mg, 0.453 mmol) as a white solid.

[0729] LCMS (ESI) [M + H]+: 287

[0730] Step 7: Stirred a mixture of 3-{ 1-[(2-chloro-5-fluoropyridin-3-yl)oxy]ethyl}-5-fluoropyridin- 1-ium- 1-olate (420 mg, 1.46 mmol), N-(3-chloro-5-methanesulfonamidophenyl)-5-methyl-4- (4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2-yl)thiophene-2-carboxamide (823 mg, 1.75 mmol), K3PO4(929 mg, 4.38 mmol) and Pd(dppf)Cl2(119 mg, 0.146 mmol) in water (3 mL) and 1,4-dixoxane (10 mL). Then the mixture was stirred for 16 hours at 80 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (35%) to afford 3-{ 1-[(2-{5-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-2- methylthiophen-3-yl}-5-fluoropyridin-3-yl)oxy]ethyl}-5-fluoropyridin-1-ium-1-olate (234 mg,0. 393 mmol) as a yellow solid.

[0731] LCMS (ESI) [M + H]+: 595

[0732] Step 8: Racemic 3-{ 1-[(2-{5-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-2- methylthiophen-3-yl}-5-fluoropyridin-3-yl)oxy]ethyl}-5-fluoropyridin-1-ium-1-olate (234 mg) was purified by Prep-SFC with the following conditions: Column Name :Cellulose SB, Column Size : 0.46*5cm,3um; Mobile phase: Hex(0.1%DEA):EtOH=70:30,Fiow rate:1.67ml / min; Wave Length: 254 nm

[0733] First eluting peak: 74.2 mg, 0.124 mmol as a white solid

[0734] RT: 1.567 min

[0735] LCMS (ESI) [M + H]+:595.05

[0736] 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 10.06 (s, 1H), 8.42 (dt, J= 4.8, 1.9 Hz, 1H), 8.33 (d, J= 2.3 Hz, 1H), 8.13 - 8.03 (m, 2H), 7.69 (dd, J= 10.8, 2.4 Hz, 1H), 7.66 (t, J= 1.8 Hz, 1H), 7.62 (t, J= 1.9 Hz, 1H), 7.18 (dt, J= 8.1, 1.7 Hz, 1H), 6.95 (t, J= 1.9 Hz, 1H), 5.64 (d, J= 6.4 Hz, 1H), 3.07 (s, 3H), 2.42 (s, 3H), 1.57 (d, J= 6.4 Hz, 3H).

[0737] Second eluting peak: 88.6 mg, 0.148 mmol as a white solid

[0738] RT: 1.939 min

[0739] LCMS (ESI) [M + H]+:595.05

[0740] ’H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 10.06 (s, 1H), 8.42 (dt, J = 4.8, 1.9 Hz, 1H), 8.33 (d, 7= 2.3 Hz, 1H), 8.13 - 8.03 (m, 2H), 7.69 (dd, 7= 10.8, 2.4 Hz, 1H), 7.66 (t, 7= 1.8 Hz, 1H), 7.62 (t, 7= 1.9 Hz, 1H), 7.18 (dt, 7= 8.1, 1.7 Hz, 1H), 6.95 (t, 7= 1.9 Hz, 1H), 5.64 (d, 7= 6.4 Hz, 1H), 3.07 (s, 3H), 2.42 (s, 3H), 1.57 (d, 7= 6.4 Hz, 3H). Example 115

[0741] The compounds listed in the following table were prepared using a procedure similar to that described for examples 113 and 114, but no chiral separation is needed:

[0742] Example 116: N-(3-chloro-5-ethanesulfonamidophenyl)-1-[5-(3,3-difluoroazetidin-1-yl)-3-

[0743] [(5-fluoropyridin-3-yl)methoxy]-2-yl]-5-methylpyrrole-3-carboxamide

[0744] Step 1: A solution of 5-bromo-2-fhioropyridin-3-ol (1 g, 5.209 mmol, 1 equiv), 3- (chloromethyl)-5-fluoropyridine (0.91 g, 6.251 mmol, 1.2 equiv) and K2CO3(2.16 g, 15.627 mmol, 3 equiv) in DMSO (10 mL) was stirred for 1 hour at 80 °C. The reaction was allowed to cool down to room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-bromo-2-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridine (850 mg, 54.20% yield) as a white solid.

[0745] LCMS (ESI) [M+H]+: 300.97.

[0746] Step 2: A solution of 5-bromo-2-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridine (840 mg, 2.790 mmol, 1 equiv), methyl 5-methyl-l / / -pyrrole-3-carboxylate (582 mg, 4.185 mmol, 1.5 equiv) and K2CO3(1.16 g, 8.370 mmol, 3 equiv) in DMSO (10 mL) was stirred for 1 hour at 80 °C. The reaction was allowed to cool down to room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 1-{5-bromo-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl}-5-methylpyrrole-3-carboxylate (560 mg, 47.77% yield) as a white solid.

[0747] LCMS (ESI) [M+H]+: 420.03.

[0748] Step 3: A solution of methyl 1-{5-bromo-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}-5- methylpyrrole-3-carboxylate (540 mg, 1.285 mmol, 1 equiv), 3,3-difluoroazetidine hydrochloride (179 mg, 1.927 mmol, 1.5 equiv), Pd2(dba)3(235 mg, 0.257 mmol, 0.2 equiv), XantPhos (297 mg, 0.514 mmol, 0.4 equiv) and Cs2CO3(1.26 g, 3.855 mmol, 3 equiv) in toluene (10 mL) was stirred for 2 hours at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 1-[5-(3,3-difluoroazetidin-1-yl)-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl]-5-methylpyrrole-3-carboxylate (265 mg, 47.69% yield) as a white solid.

[0749] LCMS (ESI) [M + H]+: 433.14.

[0750] Step 4: To a stirred solution of methyl 1-[5-(3,3-difluoroazetidin-1-yl)-3-[(5-fluoropyridin-3- yl) methoxy] pyridin-2-yl]-5-methylpyrrole-3-carboxylate (115 mg, 0.266 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl) ethanesulfonamide (81 mg, 0.346 mmol, 1.3 equiv) in toluene (5 mL) was added Al(Me)3(0.2 mL, 0.4 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 1.5 hours at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 40 mL / min; Gradient: 52% B to 70% B in 7 min, 70% B; Wave Length: 254 / 220 nm; This resulted in N-(3-chloro-5-ethanesulfonamidophenyl)-1-[5- (3,3-difluoroazetidin-1-yl)-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl]-5-methylpyrrole- 3-carboxamide (119.2 mg, 69.83% yield) as a white solid.

[0751] LCMS (ESI) [M + H]+: 635.00.

[0752] 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.73 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.40 (s, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.64 - 7.52 (m, 4H), 7.06 (d, J = 2.4 Hz, 1H), 6.88 (t, J = 2.0 Hz, 1H), 6.52 - 6.47 (m, 1H), 5.29 (s, 2H), 4.47 (t, J = 12.3 Hz, 4H), 3.21 - 3.08 (m, 2H), 2.04 - 1.99 (m, 3H), 1.21 (t, 7= 7.3 Hz, 3H).

[0753] Example 117

[0754] The compounds listed in the following table were prepared using a procedure similar to that described for example 116:

[0755] Example 118: N-(3-chloro-5-methanesulfonamidophenyl)-4-[5-(3,3-difhioroazetidin-1- yl)-3-[(3,5-difluoro phenyl)methoxy]pyridin-2-yl]-5-methylthiophene-2-carboxamide

[0756]

[0757] Step 1: A solution of 5-bromo-2-iodopyridin-3-ol (500 mg, 1.667 mmol, 1 equiv), 1- (chloromethyl)-3,5-difluorobenzene (542.1 mg, 3.334 mmol, 2 equiv) and Cs2CO3(1.62 g, 5.001 mmol, 3 equiv) in DMSO (20 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The combined organic layers were washed with water (3 xlOO mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-bromo-3-[(3,5-difluorophenyl)methoxy]-2-iodopyridine (800 mg, 84.48%) LCMS (ESI) [M + H]+: 426 Step 2: A solution of 5-bromo-3-[(3,5-difluorophenyl)methoxy]-2-iodopyridine (580 mg, 1.362 mmol, 1 equiv), methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)thiophene-2-carboxylate (499.1 mg, 1.771 mmol, 1.3 equiv), Pd(dppf)Cl2(99.6 mg, 0.136 mmol, 0.1 equiv) and K3PO4(867 mg, 4.086 mmol, 3 equiv) and dioxane (20 mL) and H2O (3 mL) in was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (1 x 100 mL), dried over anhydrous Na2SO4.The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-{5-bromo-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl}thiophene-2-carboxylate (420 mg, 70.07%) as a white solid.

[0758] LCMS (ESI) [M + H]+: 440

[0759] Step 3: A solution of methyl 4-{5-bromo-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl}-5- methylthiophene-2-carboxylate (380 mg, 0.836 mmol, 1 equiv) and 3,3-difluoroazetidine (155.7 mg, 1.672 mmol, 2 equiv) and Pd2(dba)3(76.6 mg, 0.084 mmol, 0.1 equiv) and Xantphos (96.8 mg, 0.167 mmol, 0.2 equiv) and Cs2CO3(817.6 mg, 2.508 mmol, 3 equiv) in toluene (20 ml) was stirred for 3 hours at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (l x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-[5-(3,3-difluoroazetidin-1-yl)- 3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl]-5-methylthiophene-2-carboxylate (260 mg, 66.64%) as a white solid.

[0760] LCMS (ESI) [M + H]+: 467

[0761] Step 4: A solution of methyl 4-[5-(3,3-difluoroazetidin-1-yl)-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl]-5-methylthiophene-2-carboxylate (260 mg, 0.557 mmol, 1 equiv) and LiOH (40.1 mg, 1.671 mmol, 3 equiv) and EtOH (10 mL) and H2O (2 mL) in was stirred for 1 hour at 60 °C under air atmosphere. The mixture was acidified to pH 5 with HC1 (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-[5-(3,3-difluoroazetidin- l-yl)-3-[(3,5-difluorophenyl) methoxy]pyridin-2-yl]-5-methylthiophene-2-carboxylic acid (140 mg, 55.52%). as a white solid.

[0762] LCMS (ESI) [M + H]+:453

[0763] Step 5: A solution of 4-[5-(3,3-difluoroazetidin-1-yl)-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl]-5-methyl thiophene-2-carboxylic acid (120 mg, 0.265 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl)methane sulfonamide (70.2 mg, 0.318 mmol, 1.2 equiv) and TCFH (148.8 mg, 0.530 mmol, 2 equiv) and NMI (65.3 mg, 0.795 mmol, 3 equiv) and ACN (10 mL) was stirred for 1 hour at room temperature under air atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-( 3-chloro-5- methanesulfonamidophenyl)-4-[5-(3,3-difluoroazetidin-1-yl)-3-[(3,5-difluoro phenyl)methoxy]pyridin-2-yl]-5-methylthiophene-2-carboxamide (88.1 mg, 50.70%) as a white solid.

[0764] LCMS (ESI) [M + H]+: 654.80

[0765] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.06 (s, 1H), 8.15 (s, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.16 (t, J = 9.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 2H), 6.96 - 6.86 (m, 2H), 5.22 (s, 2H), 4.43 (t, J= 12.2 Hz, 4H), 3.05 (d, J= 1.0 Hz, 3H), 2.38 (s, 3H).

[0766] Examples 119-126

[0767] The compounds listed in the following table were prepared using a procedure similar to that described for example 118:

[0768] Example 127: N-( 3-chloro-5-methanesulfonamidophenyl)-1-[5-(3, 3-difluoroazetidin-1- yl)-3-{[3-fluoro-5-(trifluoromethyl)phenyl]methoxy}pyridin-2-yl]-5-methylpyrrole-3- carboxamide

[0769] Step 1: Under nitrogen, a solution of 5-bromo-2-fluoropyridin-3-ol (200 mg, 1.04 mmol, 1 equiv), bromo(methoxy)methane (260 mg, 2.08 mmol, 2 equiv) in DMF (2 mL) was added K2CO3(431 mg, 3.12 mmol, 3 equiv) at room temperature. The resulting solution was stirred for two hours at 40 °C. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EA / PE (52%) to afford 5- bromo-2-fluoro-3-(methoxymethoxy)pyridine (230 mg, 93.62%) as a white solid.

[0770] LCMS (ESI) [M+H]+: 236

[0771] Step 2: Under nitrogen, a solution of 5-bromo-2-fluoro-3-(methoxymethoxy)pyridine (230 mg, 0.97 mmol, 1 equiv), methyl 5-methyl-1H-pyrrole-3-carboxylate (136 mg, 0.97 mmol, 1 equiv) in DMSO (2 mL) was added Cs2CO3(953 mg, 2.92 mmol, 3 equiv) at RT. The resulting solution was stirred for two hours at 80 °C under N2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EA / PE (42%) to afford methyl 1-[5-bromo-3- (methoxymethoxy)pyridin-2-yl]-5-methylpyrrole-3-carboxylate (300 mg, 86.62%) as a white solid.

[0772] LCMS (ESI) [M+H]+: 355

[0773] Step 3: Under nitrogen, a solution of methyl 1-[5-bromo-3-(methoxymethoxy)pyridin-2-yl]- 5-methylpyrrole-3-carboxylate (300 mg, 0.85 mmol, 1 equiv), 3, 3 -difluoro azetidine (80 mg, 0.85 mmol, 1 equiv) and Pd2(dba)3(155 mg, 0.17 mmol, 0.2 equiv), Xantphous (49 mg, 84.5μmol, 0.1 equiv) in PhMe (3 mL) was added Cs2CO3(550 mg, 1.48 mmol, 3 equiv) at room temperature. The resulting solution was stirred for two hours at 100 °C under N2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EA / PE (52%) to afford methyl 1-[5-(3, 3- difluoroazetidin-1-yl)-3-(methoxymethoxy)pyridin-2-yl]-5-methylpyrrole-3-carboxylate (200 mg, 64.62%) as a white solid.

[0774] LCMS (ESI) [M+H]+: 368

[0775] Step 4: A solution of methyl 1-[5-(3, 3-difluoroazetidin-1-yl)-3-(methoxymethoxy)pyridin-2- yl]-5-methylpyrrole-3-carboxylate (200 mg, 0.54 mmol, 1 equiv) in HCl / dioxane (5 mL) was stirred for 2 hours at 30 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 1-[5-(3, 3-difluoroazetidin-1-yl)-3-hydroxypyridin-2-yl]-5-methylpyrrole-3-carboxylate (120 mg, 68.44%) as a white solid.

[0776] LCMS (ESI) [M + H]+: 324

[0777] Step 5: Under nitrogen, a solution of methyl 1-[5-(3, 3-difluoroazetidin-1-yl)-3- hydroxypyridin-2-yl]-5-methylpyrrole-3-carboxylate (120 mg, 0.37 mmol, 1 equiv), 1- (bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (95 mg, 0.37 mmol, 1 equiv) in DMSO (2 mL) was added Cs2CO3(363 mg, 1.12 mmol, 3 equiv) at room temperature. The resulting solution was stirred for two hours at 80 °C. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EA / PE (42%) to afford methyl 1-[5-(3, 3-difluoroazetidin-1-yl)-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl]-5-methylpyrrole-3-carboxylate (150 mg, 80.62%) as a white solid. LCMS (ESI) [M + H]+: 500

[0778] Step 6: A solution of methyl 1-[5-(3, 3-difluoroazetidin-1-yl)-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl]-5-methylpyrrole-3-carboxylate (150 mg, 0.3 mmol, 1 equiv), N-(3-amino-5-chlorophenyl)methanesulfonamide (66.7 mg, 0.3 mmol, 1 equiv) and Al(Me)3(0.5 mL) in Toluene (10 mL) was stirred for 1 hour at 80 °C under nitrogen atmosphere. The reaction mixture was concentrated under vacuum. The crude product (170 mg) was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triart C18 ExRS, 30*150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 70% B in 7 min; Wave Length: 254 / 220 nm; RTl(min): 7.77) to afford N-(3-chloro-5-methanesulfonamidophenyl)-1-[5-(3, 3- difluoroazetidin-1-yl)-3-{[3-fluoro-5-(trifluoromethyl)phenyl]methoxy}pyridin-2-yl]-5- methylpyrrole-3-carboxamide (52.5 mg, 25.44%) as a white solid.

[0779] LCMS (ESI) [M + H]+: 688

[0780] 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.73 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.67 - 7.58 (m, 3H), 7.55 (d, J = 2.3 Hz, 1H), 7.49 (s, 1H), 7.42 (dd, J = 9.3, 2.2 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.87 (t, J = 1.9 Hz, 1H), 6.51 (dd, 7= 2.0, 1.1 Hz, 1H), 5.32 (s, 2H), 4.51 (s, 1H), 4.44 (d, J = 12.3 Hz, 3H), 3.05 (s, 3H), 2.03 (d, 7= 0.9 Hz, 3H).

[0781] Example 128: N-( 3-chloro-5-methanesulfonamidophenyl)-5-{2,4-difhioro-6-[(5- fluoropyridin-3-yl )methoxy ]phenyl}- 1 -methyl- 1H-pyrrole-3-carboxamide Step 1: A solution of 2-bromo-3,5-difluorophenol (800 mg, 3.82 mmol), 3-(chloromethyl)-5- fluoropyridine (666 mg, 4.58 mmol) and K2CO3(400 mg, 2.89 mmol) in DMF (5 mL) was stirred for 1 hour at 80 °C. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, FA in H2O, 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in 3-[(2-bromo-3,5- difluorophenoxy)methyl]-5-fluoropyridine (400 mg, 69.3%) as a yellow solid.

[0782] LCMS (ESI) [M + H]+:318

[0783] Step 2: To a solution of 3-[(2-bromo-3,5-difluorophenoxy)methyl]-5-fluoropyridine (400 mg, 1.25 mmol) and methyl l-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrole-3-carboxylate (400 mg, 1.50 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)Cl2(102 mg, 125 pmol) and K3PO4(505 mg, 2.50 mmol). After stirring for 2 hours at 90 °C under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 3) to afford methyl methyl 5-{2,4-difluoro-6-[(5-fluoropyridin-3- yl)methoxy]phenyl}-1-methyl-1H-pyrrole-3-carboxylate (220 mg, 46.2%) as a yellow solid. LCMS (ESI) [M + H]+:377

[0784] Step 3: To a stirred solution of methyl 5-{2,4-difluoro-6-[(5-fluoropyridin-3- yl)methoxy]phenyl}-1-methyl-1H-pyrrole-3-carboxylate (220 mg, 584 pmol) and N-(3- amino-5-chlorophenyl)methanesulfonamide (128 mg, 584 pmol) in toluene (3mL) was added Al(Me)3(1 mL) at room temperature. The resulting mixture was stirred for 1 hour at 80 °C under nitrogen atmosphere. The reaction mixture was quenched by water. The residue was purified by reverse phase flash chromatography with the following conditions: Column: YMC-Actus Triart C18, 30*150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 52% B to 70% B in 7 min, 70% B; Wave Length: 254 / 220 nm; RTl(min): 5.08. This resulted in N-(3-chloro-5-methanesulfonamidophenyl)-5- {2,4-difluoro-6-[(5-fluoropyridin-3-yl)methoxy]phenyl}-1-methyl-1H-pyrrole-3- carboxamide (59.9 mg, 18.0%) as a white solid.

[0785] LCMS (ESI) [M + H]+:565.08

[0786] 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.75 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.40 (t, J= 1.8 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.64 - 7.57 (m, 2H), 7.13 (d, J = 11.0 Hz, 1H), 7.10 - 7.01 (m, 1H), 6.88 (t, J = 2.0 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 5.27 (s, 2H), 3.42 (s, 3H), 3.05 (s, 3H). Examples 129-130

[0787] The compounds listed in the following table were prepared using a procedure similar to that described for example 128: Example 131: N-(3-chloro-5-methanesulfonamidophenyl)-4-(5-fluoro-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-5-(hydroxymethyl)thiophene-2- carboxamide

[0788] Step 1: A solution of methyl 4-bromothiophene-2-carboxylate (9.5 g, 42.9 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (10.8 g, 42.9 mmol), Pd(dppf)Cl2(3.50 g, 4.29 mmol) and KOAc (12.5 g, 128 mmol) in 1,4-dioxane (100 mL) was stirred for 12 hours at 80 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:3) to afford methyl 4-(4, 4,5, 5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)thiophene-2-carboxylate (6.65 g, 24.8 mmol, 57.8% yield) as a white solid. LCMS (ESI) [M + H]+: 269.1

[0789] Step 2: A solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2- carboxylate (8.5 g, 31.7 mmol), 2-bromo-5-fluoropyridin-3-ol (6.68 g, 34.8 mmol), Pd(dppf)Cl2(2.58 g, 3.17 mmol) and K3PO4(20.1 g, 95.1 mmol) in 1,4-dioxane (85 mL) and

[0790] H2O (15 mL) was stirred for 12 hours at 80 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:3) to afford methyl 4-(5-fluoro-3-hydroxypyridin-2- yl)thiophene-2-carboxylate (3.51 g, 13.8 mmol, 43.7% yield) as a white solid.

[0791] LCMS (ESI) [M + H]+: 254.2

[0792] Step 3: A solution of methyl 4-(5-fluoro-3-hydroxypyridin-2-yl)thiophene-2-carboxylate (1.2 g, 4.73 mmol), 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1.33 g, 5.20 mmol) and K2CO3(1.94 g, 14.1 mmol) in DMF (15 mL) was stirred for 12 hours at 80 °C. The mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 65% gradient in 20 min; detector, UV 254 nm to afford methyl 4-(5-fluoro-3-{[3-fluoro-5-(trifluoromethyl)phenyl] methoxy}pyridin-2- yl)thiophene-2-carboxylate (1.12 g, 2.61 mmol, 55.1% yield) as an off-white solid.

[0793] LCMS (ESI) [M + H]+: 430.3

[0794] Step 4: A solution of methyl 4-(5-fluoro-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)thiophene-2-carboxylate (1.02 g, 2.37 mmol) and NBS (2.10 g, 11.8 mmol) in DMF (10 mL) was stirred for 12 hours at 80 °C. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 65% gradient in 20 min; detector, UV 254 nm to afford methyl 5-bromo-4-(5-fluoro-3- { [3-fluoro-5-(trifluoromethyl)phenyl]methoxy }pyridin-2- yl)thiophene-2-carboxylate (900 mg, 1.77 mmol, 75% yield) as a yellow solid.

[0795] LCMS (ESI) [M + H]+: 509.2

[0796] Step 5: To a stirred solution of methyl 5-bromo-4-(5-fluoro-3-{[3-fluoro-5- (trifluoromethyl)phenyl] methoxy} pyridin-2-yl)thiophene-2-carboxylate (750 mg, 1.47 mmol) in THF (10 mL) was added chloro(propan-2-yl) magnesium (2.1 mL, 2.1 mmol) dropwise at -60 °C under nitrogen atmosphere. Then the mixture was stirred for 3 hours at - 60 °C under nitrogen atmosphere. To the above mixture was added V,V-di methylfornamide (160 mg, 2.20 mmol) dropwise at -60 °C under nitrogen atmosphere. Then the mixture was stirred for 8 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :3 ) to afford methyl 4-(5-fluoro-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-5-formylthiophene-2-car boxylate (330 mg, 0.721 mmol, 49.1% yield) as a yellow solid.

[0797] LCMS (ESI) [M + H]+: 458.3

[0798] Step 6: To a stirred solution of methyl 4-(5-fluoro-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-5-formylthiophene-2-carboxylate (330 mg, 0.721 mmol) in MeOH (5 mL) was added NaBtk (75 mg, 2.16 mmol) at 0 °C. Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 65% gradient in 20 min; detector, UV 254 nm to afford methyl 4-(5-fluoro-3- {[3-fluoro-5-(trifluoromethyl)phenyl] methoxy }pyridin-2-yl)-5-(hydroxymethyl)thiophene-2- carboxylate (230 mg, 0.500 mmol, 69.4% yield) as a yellow solid.

[0799] LCMS (ESI) [M + H]+: 460.3

[0800] Step 7: To a stirred mixture of methyl 4-(5-fluoro-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-5-(hydroxymethyl)thiophene-2-carboxylate (210 mg, 0.457 mmol) and N-(3-amino-5-chlorophenyl) methanesulfonamide (100 mg, 0.457 mmol) in toluene (3 ml) was added trimethylaluminium (99 mg, 1.3 mmol, 3 equiv) dropwise at 80 °C under nitrogen atmosphere. Then the mixture was stirred for 4 hours at 80 °C. The mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 60% gradient in 20 min; detector, UV 254 nm to afford N-(3-chloro-5-methanesulfonamidophenyl)-4-(5-fluoro-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-5-(hydroxymethyl)thiophene-2-carboxamide (125.9 mg, 0.193 pmol, 42.2% yield) as a white solid.

[0801] LCMS (ESI) [M - H]’: 646.1

[0802] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.05 (s, 1H), 8.59 - 8.05 (m, 2H), 7.77 (dd, J= 10.7, 2.4 Hz, 1H), 7.68 - 7.55 (m, 5H), 6.94 (t, J = 1.9 Hz, 1H), 5.78 (t, 7 = 5.7 Hz, 1H), 5.38 (s, 2H), 4.69 (d, J = 5.6 Hz, 2H), 3.05 (s, 3H). Examples 132-133

[0803] The compounds listed in the following table were prepared using a procedure similar to that described for example 131, with chiral separation of the final product (CHIRALPAK IH-3 column, 3.0*100 mm, 3 um; Flow rate: 2 mL / min; Wave Length: 220 nm): Example 134: N-( 3-chloro-5-methanesulfonamidophenyl)-1-{5-fhioro-3-[(3- fluoro-5- methanesulfonylphenyl) methoxy] pyridin-2-yl}-5-methyl-1H-pyrrole-3-carboxamide

[0804] Step 1: A solution of 2-bromo-5-fluoropyridin-3-ol (1 g, 5.20 mmol), 1-(chloromethyl)-3- fluoro-5-methane sulfonylbenzene (1.15 g, 5.20 mmol) and K2CO3(2.15 g, 15.6 mmol) in DMSO (10 mL) was stirred for 1 hour at 60 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 0% to 60% gradient in 20 min; detector, UV 254 nm to afford 2- bromo-5-fluoro-3-[(3-fluoro-5-methanesulfonylphenyl)methoxy]pyridine (800 mg, 2.11 mmol) as a white oil.

[0805] LCMS (ESI) [M+H]+: 377.95.

[0806] Step 2: A solution of 2-bromo-5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridine (200 mg, 528 pmol), methyl 5 -methyl-1H-pyrrole- 3-carboxylate (88 mg, 633 pmol), Pd2(dba)3(96 mg, 105 pmol), Cs2CO3(515 mg, 1.58 mmol) and Xantphos (122 mg, 211 pmol) in PhMe (3 mL) was stirred for 1 hour at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 1-{5-fluoro-3-[(3-fluoro-5-methanesulfonylphenyl)methoxy]pyridin-2-yl}-5- methyl-1H-pyrrole-3-carboxylate (200 mg, 458 pmol) as a white solid.

[0807] LCMS (ESI) [M+H]+: 437.00.

[0808] Step 3: A solution of methyl 1-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-5- methylpyrrole-3-carboxylate (180 mg, 0.41 mmol, 1 equiv) and LiOH-H2O (190 mg, 4.53 mmol, 11 equiv) in EtOH (2 mL) and

[0809] H2O (0.5 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The mixture was acidified to pH 7 with 1 M HC1 (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1- { 5- fluoro-3-[(3-fluoro-5-methanesulfonylphenyl)methoxy]pyridin-2-yl}-5-methyl-1H- pyrrole- 3-carboxylic acid (100 mg, 236 pmol) as a white solid.

[0810] LCMS (ESI) [M+H]+: 423.00.

[0811] Step 4: A solution of 1-{5-fluoro-3-[(3-fluoro-5-methanesulfonylphenyl)methoxy]pyridin-2- yl]-5-methyl-1H- pyrrole-3-carboxylic acid (100 mg, 236 pmol), N-(3-amino-5- chlorophenyl)methanesulfonamide (62 mg, 283 pmol), TCFH (99 mg, 354 pmol) and NMI (58 mg, 708 pmol) in ACN (2 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-(3-chloro-5-methanesulfonamidophenyl)-1-{5- fluoro-3-[(3- fluoro-5-methanesulfonylphenyl) methoxy] pyridin-2-yl }-5-methyl-1H-pyrrole- 3-carboxamide (104.3 mg, 166 pmol) as a light yellow solid.

[0812] LCMS (ESI) [M-H]-: 623.00.

[0813] 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.76 (s, 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.98 (dd, J = 10.0, 2.5 Hz, 1H), 7.77 - 7.67 (m, 4H), 7.60 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 6.87 (t, J = 2.0 Hz, 1H), 6.56 (s, 1H), 5.40 (s, 2H), 3.24 (s, 3H), 3.04 (s, 3H), 2.08 (s, 3H).

[0814] Examples 135-136

[0815] The compounds listed in the following table were prepared using a procedure similar to that described for example 134:

[0816] Example 137:

[0817] Step 1: A solution of l-bromo-3-(bromomethyl)-5-fluorobenzene (300 mg, 1.11 mmol), methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (277 mg, 1.11 mmol) and K2CO3(459 mg, 3.33 mmol) in DMSO (6 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was diluted with water. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:3) to afford methyl 5- { 3- [(3-bromo-5-fluorophenyl)methoxy] -5-fluoropyridin-2-yl } - 1 -methyl- 1 H- pyrrole-3-carboxylate (208 mg, 475 pmol) as a white oil.

[0818] LCMS (ESI) [M + H]+: 436.02.

[0819] Step 2: A solution of methyl 5-{3-[(3-bromo-5-fluorophenyl)methoxy]-5-fluoropyridin-2- yl}-1-methyl-1H-pyrrole-3-carboxylate (188 mg, 429 pmol), 3,3-difluoroazetidine (60 mg, 643 pmol), Pd(OAc)2(10 mg, 42.9 pmol), BINAP (53 mg, 85.8 pmol) and Cs2CO3(417 mg, 1.28 mmol) in toluene (4 mL) was stirred for 2 hours at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 5-(3-{[3-(3,3- difluoroazetidin- 1 -yl)-5-fluorophenyl]methoxy } -5 -fluoropyridin-2-yl)- 1 -methyl-1H-pyrrole- 3-carboxylate (113 mg, 58.8% yield) as a yellow solid.

[0820] LCMS (ESI) [M + H]+: 449.14

[0821] Step 3: A solution of methyl 5-(3-{[3-(3,3-difluoroazetidin-1-yl)-5-fluorophenyl]methoxy}- 5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (93 mg, 206 pmol) and N-(3- amino-5-chlorophenyl)methanesulfonamide (55 mg, 247 pmol) in toluene (2.5 mL) was stirred for 10 min at 0 °C under nitrogen atmosphere. To the above mixture was added AlMe3(0.3 mL, 618 pmol) dropwise over 1 minute at 0 °C. The resulting mixture was stirred for additional 1 hour at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 38% B to 70% B in 8 min, 70% B; Wave Length: 220 nm; RTl(min): 8.24) to afford N-(3-chloro-5-methanesulfonamidophenyl)-5-(3-{[3-(3,3-difluoroazetidin-1-yl)-5- fluorophenyl]methoxy}-5-fluoropyridin-2-yl)- 1-methyl-1H-pyrrole-3-carboxamide (94.7 mg, 71.7% yield) as a white solid.

[0822] LCMS (ESI) [M + H]+: 638.101H NMR (400 MHz, DMSO-d6) δ 9.92 (d, J = 62.0 Hz, 2H), 8.29 (d, J = 2.4 Hz, 1H), 7.81 - 7.65 (m, 3H), 7.58 (dd, 7 = 2.7, 1.5 Hz, 1H), 7.16 (dt, J= 2.0, 1.2 Hz, 1H), 6.89 (td, 7 = 2.0, 0.9 Hz, 1H), 6.62 (dt, 7= 9.6, 1.7 Hz, 1H), 6.49 (t, 7 = 1.6 Hz, 1H), 6.37 (dt, 7 = 10.9, 2.3 Hz, 1H), 5.21 (s, 2H), 4.26 (t, 7 = 12.2 Hz, 4H), 3.76 (s, 3H), 3.05 (s, 3H).

[0823] Example 138

[0824] The compounds listed in the following table were prepared using a procedure similar to that described for example 137: Example 139: N-(3-chloro-5-methanesulfonamidophenyl)-5-(5-fluoro-3-{[3-fluoro-5-

[0825] (methylsulfanyl)phenyl]methoxy}pyridin-2-yl)-1-methylpyrrole-3-carboxamide Step 1: A solution of l-bromo-3-(bromomethyl)-5-fluorobenzene (500 mg, 1.866 mmol, 1 equiv), methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)-1-methylpyrrole-3-carboxylate (467 mg, 1.866 mmol, 1 equiv) and K2CO3(774 mg, 5.598 mmol, 3 equiv) in DMSO (10 mL) was stirred for 1 hour at 80 °C. The reaction was allowed to cool down to room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na SCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 5- { 3-[(3- bromo-5-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}-1-methylpyrrole-3-carboxylate (560 mg, 68.63% yield) as a white solid.

[0826] LCMS (ESI) [M+H]+: 437.02

[0827] Step 2: A solution of methyl 5-{3-[(3-bromo-5-fluorophenyl)methoxy]-5-fluoropyridin-2- yl}-1-methylpyrrole-3 -carboxylate (540 mg, 1.235 mmol, 1 equiv), (methyl sulfanyl) sodium (260 mg, 3.705 mmol, 3 equiv), Pd2(dba)3(226 mg, 0.247 mmol, 0.2 equiv), XantPhos (286 mg, 0.494 mmol, 0.4 equiv) and K2CO3(512 mg, 3.705 mmol, 3 equiv) in toluene (10 mL) was stirred for 2 hour at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-(5-fluoro-3-{[3-fluoro-5-(methylsulfanyl) phenyl]methoxy}pyridin-2-yl)-1- methylpyrrole-3-carboxylate (326 mg, 65.27% yield) as a white solid.

[0828] LCMS (ESI) [M+H]+: 405.10

[0829] Step 3: To a stirred solution of methyl 5-(5-fluoro-3-{[3-fluoro-5- (methylsulfanyl)phenyl] methoxy }pyridin-2-yl)- 1 -methylpyrrole-3-carboxylate (306 mg, 0.757 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl) methane sulfonamide (217 mg, 0.984 mmol, 1.3 equiv) in toluene (5 mL) was added Al(Me)3(0.57 mL, 1.14 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for an additional 1.5 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5pm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 65% B in 7 min, 65% B; Wave Length: 254 / 220 nm; RTl(min): 6.07) to afford N-(3-chloro-5-methanesulfonamidophenyl)-5-(5-fluoro-3-{ [3-fluoro-5- (methylsulfanyl)phenyl]methoxy}pyridin-2-yl)-1-methylpyrrole-3-carboxamide (17.7 mg, 3.94% yield) as a white solid.

[0830] LCMS (ESI) [M + H]+: 592.95

[0831] 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.81 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.76 - 7.64 (m, 3H), 7.62 (s, 1H), 7.18 - 6.96 (m, 4H), 6.88 (t, J= 2.0 Hz, 1H), 5.27 (s, 2H), 3.75 (s, 3H), 3.05 (s, 3H), 2.44 (s, 3H).

[0832] Example 140:

[0833] A solution of N-(3-chloro-5-methanesulfonamidophenyl)-5-(5-fluoro-3-{[3-fluoro-5- (methylsulfanyl) phenyl] methoxy }pyridin-2-yl)- 1 -methylpyrrole-3-carboxamide (150 mg, 0.253 mmol, 1 equiv) and mCPBA (66 mg, 0.380 mmol, 1.5 equiv) in CH2C12 (2 ml) was stirred for 1 hour at 0 °C. The mixture was quenched with Na2S2O3(aq) and NaHCO3(aq). The resulting mixture was extracted with CH2Cl2(3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart Cl 8, 30*150 mm, 5pm; Mobile Phase A: water(0.1 % formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 53% B to 70% B in 7 min, 70% B; Wave Length: 254 / 220 nm; RTl(min): 6.07) to afford N-(3-chloro- 5-methanesulfonamidophenyl)-5-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl } - 1 -methylpyrrole-3-carboxamide (28.4 mg, 17.74% yield) as a white solid.

[0834] LCMS (ESI) [M + H]+: 625.00.

[0835] 1H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.80 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 7.82 - 7.60 (m, 6H), 7.15 (d, J = 2.0 Hz, 1H), 6.89 (t, J = 1.9 Hz, 1H), 5.42 (s, 2H), 3.77 (s, 3H), 3.26 (s, 3H), 3.06 (s, 3H).

[0836] Example 141

[0837] The compounds listed in the following table were prepared using a procedure similar to that described for example 140:

[0838] Example 142: N- (3-chloro-5-methanesuIfonamidophenyl)-5-{3-[(3-cyano-5- fluorophenyl)methoxy]-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl}-1-methyI-1H-pyrrole- 3-carboxamide

[0839] Step 1: A solution of 3-(chloromethyl)-5-fluorobenzonitrile (500 mg, 2.94 mmol), 5-bromo- 2-iodopyridin-3-ol (881 mg, 2.94 mmol) and K2CO3(1.21 g, 8.82 mmol) in DMSO (5 mL) was stirred for 1.5 hours at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was diluted with water. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-{[(5-bromo-2-iodopyridin-3-yl)oxy]methyl}-5-fluorobenzonitrile (460 mg, 36.2% yield) as a light yellow solid.

[0840] LCMS (ESI) [M + H]+: 431.88.

[0841] Step 2: A solution of 3-{[(5-bromo-2-iodopyridin-3-yl)oxy]methyl}-5- fluorobenzonitrile (440 mg, 1.01 mmol), methyl l-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (267 mg, 1.01 mmol), Pd(dppf)Cl2(82 mg, 101 pmol) and K3PO4(642 mg, 3.03 mmol) in 1 ,4-dioxane (9 mL) and H2O (3 mL) was stirred for 1.5 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford methyl 5-{5-bromo-3-[(3-cyano-5-fluorophenyl) methoxy]pyridin-2-yl} 4 -methyl-1H- pyrrole-3-carboxylate (225 mg, 50.2% yield) as a yellow solid.

[0842] LCMS (ESI) [M + H]+: 443.03

[0843] Step 3: A solution of methyl 5-{5-bromo-3-[(3-cyano-5-fhiorophenyl)methoxy]pyridin-2-yl}-

[0844] 1-methyl-1H-pyrrole-3-carboxylate (235 mg, 528 pmol), 3,3-difluoroazetidine (74 mg, 792 pmol), Palladium^ 1,3-bis [2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-l ,3-dihydro-2H- imidazol-2-ylidene]dichloro(3-chloropyridi ne-KN)-, (SP-4-1)- (26 mg, 26.4 pmol) and Cs2CO3(515 mg, 1.58 mmol) in 1,4-dioxane (5 mL) was stirred for 1.5 hours at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford methyl 5-{3-[(3-cyano-5-fhiorophenyl) methoxy]-5-(3,3-difluoroazetidin-1-yl)pyridin-

[0845] 2-yl]-1-methyl-1H-pyrrole-3-carboxylate (120 mg, 262 pmol) as a yellow oil.

[0846] LCMS (ESI) [M + H]+: 456.14

[0847] Step 4: A solution of methyl 5-{3-[(3-cyano-5-fluorophenyl)methoxy]-5-(3,3- difluoroazetidin-1-yl)pyridin-2-yl}-1-methyl-1H-pyrrole-3-carboxylate (100 mg, 219 pmol) and N-(3-amino-5-chlorophenyl)methane sulfonamide (58 mg, 262 pmol) in toluene (3 mL) was stirred for 10 minutes at 0 °C under nitrogen atmosphere. To the above mixture was added AlMe3 (0.33 mL, 219 pmol) dropwise over 5 min at 0 °C. The resulting mixture was stirred for additional 1 hour at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product (90 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; Mobile Phase A: Water(0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / rnin; Gradient: 45% B to 65% B in 7 min, 65% B; Wave Length: 254 / 220 nm; RTl(min): 5.88) to afford N-(3-chloro-5-methanesulfonamidophenyl)-5-{3-[(3-cyano-5-fluorophenyl)methoxy]- 5-(3,3-difluoroazetidin- 1 -yl)pyridin-2-yl } - 1 -methyl-1H-pyrrole-3-carboxamide (47.7 mg, 32.4% yield) as a white solid.

[0848] LCMS (ESI) [M + H]+: 645.20

[0849] 1H NMR (400 MHz, DMS0-d6) δ 9.99 (s, 1H), 9.75 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.75 - 7.65 (m, 3H), 7.63 (d, J = 8.2 Hz, 3H), 6.99 (d, J = 1.8 Hz, 1H), 6.87 (dd, J = 3.8, 2.0 Hz, 2H), 5.29 (s, 2H), 4.42 (t, J = 12.2 Hz, 4H), 3.69 (d, J = 1.5 Hz, 3H), 3.05 (d, J = 1.4 Hz, 3H).

[0850] Example 143: N-(3-chloro-5-methanesulfonamidophenyl)-4-[5-(3,3- difluoroazetidin-1- yl)-3-{[3-fluoro-5-(trifluoromethyl)phenyl]methoxy}pyridin-2-yl]-5-

[0851] (hydroxymethyl)thiophene-2-carboxamide

[0852] Step 1: To a stirred solution of methyl 4,5-dibromothiophene-2-carboxylate (10 g, 34.08 mmoL) in THF (120 mL) was added iPrMgCl (40.9 mL, 40.9 mmol) dropwise at -60 °C under nitrogen atmosphere. The reaction was stirred for 30 minutes at -60 °C. To the above mixture was added DMF (4.98 g, 68.2 mmol) dropwise at - 60 °C under nitrogen atmosphere. The mixture was stirred for another 3 hours at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with PE / EA (1:1) to afford methyl 4-bromo-5 -formylthiophene-2- carboxylate (2.60 g, 10.4 mmol) as a white solid. LCMS (ESI) [M + H]+: 250

[0853] Step 2: To a stirred solution of methyl 4-bromo-5-formylthiophene-2-carboxylate (2.6 g, 10.4 mmol) in CH3OH (15 mL) was added NaBH4(2.36 g, 62.4 mmol) at 0 °C. Then the mixture was stirred for 2 hours at 0 °C. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (1:2) to afford methyl 4-bromo-5- (hydroxymethyl) thiophene-2-carboxylate (1.20 g, 4.77 mmol) as a white solid.

[0854] LCMS (ESI) [M + H]+: 251

[0855] Step 3: A solution of methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate (1.2 g, 4.77 mmol), B2(pin)2(2.42 g, 9.54 mmol), Pd(dppf)Cl2(583 mg, 0.715 mmol) and AcOK (1.40 g, 14.3 mmol) in dioxane (15 mL) was stirred for 2 hours at 90 °C under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (1:1) to afford methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) thiophene-2-carboxylate (910 mg, 3.05 mmol) as a white solid.

[0856] LCMS (ESI) [M + H]+: 299

[0857] Step 4: A solution of methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) thiophene-2-carboxylate (910 mg, 3.05 mmol), 5-bromo-3-{[3-fluoro-5- (trifluoromethyl)phenyl] methoxy }-2-iodopyridine (1.59 g, 3.35 mmol), Pd(dppf)Cl2(373 mg, 457 pmol) and K3PO4(647 mg, 3.05 mmol) in dioxane (15 mL) and H2O (3 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (1:1) to afford methyl 4- (5-bromo-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-5- (hydroxymethyl)thiophene-2-carboxylate (700 mg, 1.34 mmol) as a yellow solid.

[0858] LCMS (ESI) [M + H]+: 520

[0859] Step 5: A solution of methyl 4-(5-bromo-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-5- (hydroxymethyl)thiophene-2- carboxylate (700 mg, 1.34 mmol), Pd2(dba)3(184 mg, 0.201 mmol), Xantphos (232 mg, 0.402 mmol), Cs2CO3(1.74 g, 5.36 mmol) and 3,3-difluoroazetidine (249 mg, 2.68 mmol) in PhMe (20 mL ) was stirred for 2 hours at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford methyl 4-[5-(3,3- difluoroazetidin-1-yl)-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy}pyridin-2-yl]-5- (hydroxymethyl)thiophene-2-carboxylate (400 mg, 0.751 mmol))as a yellow solid.

[0860] LCMS (ESI) [M + H]+: 532 Step 6: To a stirred solution of methyl 4-[5-(3,3-difluoroazetidin-1-yl)-3-{[3-fluoro-5- (trifluoromethyl) phenyl] methoxy }pyridin-2-yl]-5-(hydroxymethyl)thiophene-2- carboxylate (400 mg, 0.751 mmol) and N- (3-amino-5- chlorophenyl)methanesulfonamide (198 mg, 0.901 mmol) in PhMe (10 mL) was added Al(Me)3(162 mg, 2.25 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 3 hours at 80 °C. The mixture was concentrated and purified by flash chromatography eluted with PE / EA (1:2) to afford N-(3-chloro-5- methanesulfonamidophenyl)-4-[5-(3,3- difluoroazetidin-1-yl)-3-{[3-fluoro-5- (trifluoromethyl)phenyl]methoxy]pyridin-2-yl]-5-(hydroxymethyl)thiophene-2-carboxamide (100.9 mg, 0.135 mmol) as a white solid.

[0861] LCMS (ESI) [M + H]+: 720.85

[0862] 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 10.05 (s, 1H), 8.27 (s, 1H), 7.75 - 7.45 (m, 6H), 6.92 (d, J = 9.7 Hz, 2H), 5.75 (t, J = 5.7 Hz, 1H), 5.33 (s, 2H), 4.66 (d, J= 5.7 Hz, 2H), 4.44 (t, J= 12.2 Hz, 4H), 3.04 (s, 3H).

[0863] Example 144: N-( 3-chloro-5-methanesulfonamidophenyl)-3-{5-fhioro-3-[(3-fhioro-5- methanesulfonyl phenyl)methoxy]pyridin-2-yl}-1,2-thiazole-5-carboxamide

[0864] Step 1: To a stirred solution of 3-bromo-5-fluoropyridine-2-carbonitrile (10 g, 49.7 mmol) was added sulfuric acid (48.7 g, 497 mmol). Then the mixture was stirred for 2 hour at 60 °C. The mixture was acidified to pH 5 with citric acid. The resulting mixture was extracted with EA (200 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0-30%) to afford 3-bromo-5-fluoropyridine-2-carboxamide (7.60 g, 34.7 mmol) as white solid.

[0865] LCMS (ESI) [M + H]+: 219

[0866] Step 2: 3-bromo-5-fluoropyridine-2-carboxamide (7.6 g, 34.7 mmol) in dioxane (60 mL), chloro(chlorosulfanyl) methanone (9.08 g, 69.4 mmol) was added, and the mixture heated at reflux for 15 h. Upon cooling, all solvent was removed under reduced pressure and the resulting solid purified by flash column chromatography on silica gel, eluted with PE / EA (0- 60%) to afford 5-(3-bromo-5-fluoropyridin-2-yl)-2H-1,3,4-oxathiazol-2-one (6.00 g, 21.6 mmol) as a white solid.

[0867] LCMS (ESI) [M + H]+: 277

[0868] Step 3: A solution of 5-(3-bromo-5-fluoropyridin-2-yl)-2H-l,3,4-oxathiazol-2-one (6 g, 21.6 mmol) and ethyl prop-2-ynoate (8.47 g, 86.4 mmol) in 1,2-Dichlorobenzene (60 mL) was heated at 150 °C for 3 h. The mixture was concentrated under reduced pressure and the resulting mixture of two isomers (6.8 g, 97% total yield) partially separated by flash column chromatography on silica gel EA / PE (0-10%) to afford the desired isomer ethyl 3-(3-bromo- 5-fluoropyridin-2-yl)-1,2-thiazole-5-carboxylate (5.80 g, 17.5 mmol) as a yellow solid.

[0869] LCMS (ESI) [M + H]+: 331

[0870] Step 4: A solution of ethyl 3-(3-bromo-5-fluoropyridin-2-yl)-1,2-thiazole-5-carboxylate (2.2 g, 6.64 mmol), B2pin2(10.1 g, 39.8 mmol), Pd(dppf)Cl2(473 mg, 664 pmol) and KOAc (1.95 g, 19.9 mmol) in dioxane (22 mL) was stirred for overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-40%) to afford ethyl 3- [5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-1,2-thiazole-5- carboxylate (1.30 g, 3.43 mmol) as a white solid.

[0871] LCMS (ESI) [M + H]+: 379

[0872] Step 5: To a stirred solution of ethyl 3-[5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl]-1,2-thiazole-5-carboxylate (1.3 g, 3.43 mmol) in ACN (10 mL), H2O2 (1.16 g, 34.3 mmol) was added. Then the mixture was stirred for 5 hour at room temperature. The mixture was quenched with MnCE. The residue was purified by silica gel column chromatography, eluted with PE / EA (30-80%) to afford ethyl 3-(5-fluoro-3-hydroxypyridin- 2-yl)-1,2-thiazole-5-carboxylate (400 mg, 1.49 mmol) as a white solid.

[0873] LCMS (ESI) [M + H]+: 269

[0874] Step 6: To a solution of ethyl 3-(5-fluoro-3-hydroxypyridin-2-yl)-1,2-thiazole-5- carboxylate (400 mg, 1.49 mmol), K2CO3(616 mg, 4.47 mmol) and 1-(chloromethyl)-3- fluoro-5-methanesulfonylbenzene (362 mg, 1.63 mmol) in DMF (4 mL) was stirred for 2 hour at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30-60%) to afford ethyl 3-{5-fluoro-3-[(3-fluoro-5-methanesulfonyl phenyl)methoxy]pyridin-2-yl}-1,2- thiazole-5-carboxylate (300 mg, 0.660 mmol) as a white solid.

[0875] LCMS (ESI) [M + H]+: 455

[0876] Step 7: To a stirred solution of ethyl 3-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-1,2-thiazole-5-carboxylate (300 mg, 0.660 mmol) in EtOH (3 mL) and H2O (1 mL) was added LiOH (158 mg, 6.60 mmol).Then the mixture was stirred for 2h at room temperature. The mixture was acidified to pH 5 with citric acid. The precipitated solids were collected by filtration and washed with water .The resulting solid was dried under vacuum to afford 3-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-1,2-thiazole-5-carboxylic acid (180 mg, 0.422 mmol) as a yellow solid.

[0877] LCMS (ESI) [M + H]+: 427

[0878] Step 8: To a stirred solution of 3-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-1,2-thiazole-5-carboxylic acid (180 mg, 0.422 mmol), TCFH (470 mg, 1.68 mmol) and NMI (207 mg, 2.53 mmol) in ACN (2 mL) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (102 mg, 0.464 mmol). Then the mixture was stirred for Ih at room temperature. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / H2O (5-95%, acidic system) to afford N-(3-chloro-5-methanesulfonamidophenyl)-3-{5-fluoro-3-[(3-fluoro-5- methanesulfonyl phenyl)methoxy]pyridin-2-yl}-1,2-thiazole-5-carboxamide (95.0 mg, 0.151 mmol) as a white solid.

[0879] LCMS (ESI) [M + H]+: 6301H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.15 (s, 1H), 8.76 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 7.91 - 7.82 (m, 1H), 7.78 (d, J= 8.8 Hz, 2H), 7.73 - 7.64 (m, 2H), 7.00 (d, J= 2.1 Hz, 1H), 5.50 (s, 2H), 3.32 (s, 3H), 3.08 (s, 3H).

[0880] Example 145: \ -(3-chloro-5- methanesulfonamidophenyl)-5-{5-fluoro-3-[(6-fluoro-2- methyl-l,3-benzoxazol-4-yl)methoxy ]pyridin-2-yl}- 1 -methyl-1H-pyrrole-3-carboxamide

[0881]

[0882] Step 1: A solution of methyl 2-amino-3-bromo-5-fluorobenzoic acid (1 g, 4.27 mmol), Cu(acac)2(222 mg, 854 pmol) and BHMPO (557 mg, 1.70 mmol) in DMSO (30 mL) and H2O (10 mL) was treated with LiOH (537 mg, 12.8 mmol) under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 110 °C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with H2O (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (45%) to afford methyl 2-amino-5-fluoro-3-hydroxybenzoic acid (380 mg, 2.22 mmol) as a yellow solid.

[0883] LCMS (ESI) [M + H]+: 172

[0884] Step 2: A solution of methyl 2-amino-5-fluoro-3-hydroxybenzoic acid (380 mg, 2.22 mmol) in MeCN (10 mL) and MeOH (3 mL) was treated with TMSCHN2 (1.5 mL, IM) for 5min at 0 °C. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was extracted with EA (3x10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (33%) to afford methyl methyl 2-amino-5-fluoro-3-hydroxybenzoate (303 mg, 1.63 mmol) as a yellow solid.

[0885] LCMS (ESI) [M + H]+: 186 Step 3: To a stirred solution of methyl 2-amino-5-fluoro-3-hydroxybenzoate (303 mg, 1.63 mmol) in dioxane (10 mL) was treated with acetyl chloride (191 mg, 2.44 mmol) at RT. Then the mixture was stirred for 2 hours at 150 °C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN / H2O (45%, acidic system) to afford methyl 6-fluoro-2-methyl- l,3-benzoxazole-4-carboxylate (81.0 mg, 387 pmol) as an off yellow solid.

[0886] LCMS (ESI) [M + H]+: 210

[0887] Step 4: To a stirred solution of methyl 6-fluoro-2-methyl-l,3-benzoxazole-4-carboxylate (81 mg, 387 pmol) in THF (5 mL) was treated with DIBAL-H (0.85 mL, 2 M in THF) at 0 °C. Then the mixture was stirred for 1 hour at RT. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN / H2O (51%, acidic system) to afford (6-fluoro-2-methyl- 1,3-benzoxazol -4-yl)methanol (33.0 mg, 182 pmol) as an off white solid.

[0888] LCMS (ESI) [M + H]+: 182

[0889] Step 5: To a stirred solution of (6-fluoro-2-methyl-l,3-benzoxazol-4-yl)methanol (33 mg, 182 pmol) in DCM (3 ml) was treated with SOCl2(64.9 mg, 546 pmol) and DMF (5 mg, 18.2 pmol) at 0 °C. Then the mixture was stirred for 1 hour at RT. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / H2O (68%, acidic system) to afford 4-(chloromethyl)-6-fluoro-2- methyl- 1,3-benzoxazole (28.0 mg, 140 pmol) as an off white solid.

[0890] LCMS (ESI) [M + H]+: 200

[0891] Step 6: To a stirred solution of methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)- 1 -methyl- 1 / 7- pyrrole-3- carboxylate (85 mg, 339 pmol) and K2CO3(139 mg, 1.01 mmol) in DMF (5 mL) was treated with 4-(chloromethyl)-6-fluoro-2-methyl- 1,3-benzoxazole (67.6 mg, 339 pmol) at RT. Then the mixture was stirred for 1 hour at RT. The resulting mixture was extracted with EA (3 x50 mL). The combined organic layers were washed with H2O (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:3) to afford methyl 5-{5-fluoro-3-[(6-fluoro-2-methyl-l,3-benzoxazol-4-yl)methoxy]pyridin-2-yl}- l-methyl-1H-pyrrole-3-carboxylate (72.0 mg, 174 pmol) as an off white solid.

[0892] LCMS (ESI) [M + H]+: 414

[0893] Step 7: A solution of methyl methyl 5-{5-fluoro-3-[(6-fluoro-2-methyl-l,3-benzoxazol-4- yl)methoxy] pyridin-2-yl}-1-methyl-1H-pyrrole-3-carboxylate (72 mg, 174 pmol) and N-(3- amino-5-chlorophenyl) methanesulfonamide (38.3 mg, 174 pmol) in PhMe (3 mL) was stirred for 10 minutes at 0 °C under nitrogen atmosphere. To the above mixture was added Al Me ? (0.1 mL, 2 mol / L, 3 equiv) dropwise over 3 minutes at 0 °C. The resulting mixture was stirred for 1 hour at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (2 mL) at 0 °C. The crude product (89 mg) was purified by Prep-HPLC with the following conditions (Column:

[0894] CHIRALPAKIC3(3.0*50mm, 3.0um); Mobile Phase B: MeOH: ACN=1: l(0.1%DEA); Flow rate: 1.2 mL / min; Gradient: isocratic 25%B): 7.20; Number of Runs: 10 to afford N-(3-chloro- 5- methanesulfonamidophenyl)-5-{5-fluoro-3-[(6-fluoro-2-methyl-1,3-benzoxazol-4- yl)methoxy]pyridin-2-yl}-1-methyl-1H-pyrrole-3-carboxamide (49.5 mg, 81.7 pmol) as a white solid.

[0895] LCMS (ESI) [M + H]+: 602.05

[0896] 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.77 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.85 (dd, J= 10.9, 2.4 Hz, 1H), 7.70 - 7.63 (m, 3H), 7.61 (t, J = 1.9 Hz, 1H), 7.32 (dd, J = 10.5, 2.4 Hz, 1H), 7.13 (d, J= 1.9 Hz, 1H), 6.88 (t, J= 1.9 Hz, 1H), 5.53 (s, 2H), 3.73 (s, 3H), 3.05 (s, 3H), 2.63 (s, 3H).

[0897] Example 146: \-(3-chloro-5-methanesulfonamidophenyl)-4-{5-fluoro-3-|(6-fluoro-3,3- dimethyl- 1 -oxo-2, 3-dihydro-1H-isoindol-4-yl)methoxy]pyridin-2-yl}-5-methylthiophene- Step 1: A mixture of methyl 3-bromo-5-fluoro-2-methylbenzoate (3.5 g, 14.1 mmol), AIBN (115 mg, 0.705 mmol) and NBS (3.25 g, 18.3 mmol) in DCE (30 mL). Then the mixture was stirred for 1 hour at 85 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30%) to afford methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (3.00 g, 9.20 mmol) as a light yellow oil.

[0898] LCMS (ESI) [M + H]+: 325

[0899] Step 2: To a stirred solution of methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (3 g, 9.20 mmol) in THF (30 mL) was added 1-(4-methoxyphenyl)methanamine (2.52 g, 18.4 mmol) dropwise at 0 °C. Then the mixture was stirred for 12 hour at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (30%) to afford 4-bromo-6-fluoro-2-|(4-mcthoxyphcnyl)mcthyl ]-2,3-dihydro-1H-isoindol- 1 - one (2.50 g, 7.13 mmol) as a yellow solid.

[0900] LCMS (ESI) [M + H]+: 350

[0901] Step 3: To a solution of 4-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H- isoindol-1-one (2.5 g, 7.13 mmol) in THF (25 mL) was added NaH (280 mg, 11.7 mmol) at 0 °C. The resulting mixture was stirred under nitrogen for 30 minutes. To the reaction mixture was added CH3I (10.1 g, 71.3 mmol) at 0 °C, then this was heated at 70 °C overnight, allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (25%) to afford 4-bromo-6-fluoro-2-[(4- methoxyphenyl) methyl]-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (810 mg, 2.14 mmol) as a white solid.

[0902] LCMS (ESI) [M + H]+: 378

[0903] Step 4: A mixture of 4-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-2,3- dihydro-1H-isoindol-1-one (1 g, 2.64 mmol), SEM-BF3K (943 mg, 3.96 mmol), Pd(OAc)2(88 mg, 0.528 mmol), RuPhos (489 mg, 1.05 mmol) and Cs2CO3(2.58 g, 7.92 mmol) in dioxane (20 mL) and H2O (2 mL) was stirred for 16 hour at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30%) to afford 6-fluoro- 2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-4-({[2-(trimethylsilyl) ethoxy]methoxy}methyl)- 2,3-dihydro-1H-isoindol-1-one (320 mg, 0.696 mmol) as a white solid.

[0904] LCMS (ESI) [M + H]+: 430 Step 5: To a stirred solution of 6-fluoro-2-[(4-mcthoxyphcnyl)mcthyl ]-3,3-dimcthyl-4-{ [2- (trimethylsilyl) ethoxy] methyl} -2,3 -dihydro-1H-isoindol- 1 -one (1 g, 2.32 mmol) in DCM (20 mL) was added BF3-Et2O (3.29 g, 23.2 mmol) dropwise at 0 °C for 2 h. The resulting mixture was concentrated under vacuum. The mixture was purified by flash chromatography on silica gel eluting with EA / PE (0-90%) to afford 6-fluoro-4-(hydroxymethyl)-2-[(4- methoxyphenyl)methyl]-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (320 mg, 0.97 15 mmol) as a yellow solid.

[0905] LCMS (ESI) [M + H]+: 330

[0906] Step 6: To a stirred solution of 6-fluoro-4-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]-

[0907] 3.3-dimethyl-2,3-dihydro-1H-isoindol-1-one (320 mg, 0.9715 mmol), 2-chloro-5- fluoropyridin-3-ol (156 mg, 1.06 mmol) and PPh3(508 mg, 1.94 mmol) in THF (10 mL) was added DEAD (252 mg, 1.45 mmol). Then the mixture was stirred for 2 hour at room temperature. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / H2O (5-95%, acidic system) to afford 4-{[(2-chloro-5-fluoropyridin-3- yl)oxy]methyl}-6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-2,3-dihydro-1H- isoindol-1-one (290 mg, 0.6319 mmol) as a yellow solid.

[0908] LCMS (ESI) [M + H]+: 459

[0909] Step 7: To a stirred solution of 4-{[(2-chloro-5-fluoropyridin-3-yl)oxy]methyl}-6-fluoro-2- [(4-methoxyphenyl) methyl]-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (290 mg, 0.6319 mmol) in ACN (10 mL) and H2O (10 mL) was added CAN (668 mg, 1.26 mmol). Then the mixture was stirred for 5 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford 4-{[(2-chloro-5-fluoropyridin-3-yl)oxy]methyl}-6- fluoro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (110 mg, 0.3247 mmol) as a yellow solid.

[0910] LCMS (ESI) [M + H]+: 339

[0911] Step 8: A mixture of 4-{[(2-chloro-5-fluoropyridin-3-yl)oxy]methyl}-6-fluoro-3,3-dimethyl-

[0912] 2.3-dihydro-1H-isoindol-1-one (110 mg, 0.3247 mmol), Pd(dppf)Cl2(23.7 mg, 0.03247 mmol), K3PO4(206 mg, 0.9740 mmol) and N-(3-chloro-5-methanesulfonamidophenyl)-5- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiophene-2-carboxamide (168 mg, 0.3571 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred for 2 hour at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford N-(3-chloro-5-methanesulfonamidophenyl)-4-{5-fluoro-3-[(6-fluoro-3,3-dimethyl-1- oxo-2,3-dihydro-1H-isoindol-4-yl)methoxy]pyridin-2-yl}-5-methylthiophene-2-carboxamide (66.7 mg, 0.1030 mmol) as a white solid.

[0913] LCMS (ESI) [M + H]+: 647.15

[0914] 1H NMR (300 MHz, Methanol-d4) δ 8.27 (d, J = 2.3 Hz, 1H), 7.94 (s, 1H), 7.80 (dd, J = 10.2, 2.4 Hz, 1H), 7.62 (t, J= 1.9 Hz, 1H), 7.50 (t, J= 1.9 Hz, 1H), 7.41 (s, 1H), 7.38 (q, J= 2.6 Hz, 1H), 7.04 (t, J= 1.9 Hz, 1H), 5.40 (s, 2H), 3.04 (s, 3H), 2.42 (s, 3H), 1.55 (s, 6H).

[0915] Example 147: 5-chloro-N-(3-chloro-5-methanesulfonamidophenyl)-1-{5-fhioro-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

[0916] Step 1: A stirred solution of 2-bromo-5-fluoropyridin-3-amine (2 .05g, 10.4 mmol) in H2SO4 (8.4 mL) and H2O (30 mL) was stirred for 3 minutes at 0 °C. To the reaction mixture was added NaNO2(1.43 g, 20.8 mmol) in H2O (11.4 mL) at 0 °C. The resulting mixture was stirred for overnight. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 18% of ethyl acetate in petroleum ether to afford 2- bromo-5-fluoropyridin-3-ol (1.40 g, 7.29 mmol, 70.3%) as a white solid.

[0917] LCMS [M+H]+: 192

[0918] Step 2: To a mixture of 2-bromo-5-fluoropyridin-3-ol (800 mg, 4.16 mmol), 3- (chloromethyl)-5-fluoropyridi ne (726 mg, 4.99 mmol), K2CO3(1.71 g, 12.4 mmol) was added DME (8 mL). The resulting mixture was stirred for 2 hours at 60 °C. The reaction mixture was extracted with ethyl acetate. The organic was washed with water three times. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% of ethyl acetate in petroleum ether to afford 2-bromo-5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridine (700 mg, 56.0%) as a white solid. LCMS [M+H]+: 301

[0919] Step 3: To a mixture of 2-bromo-5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridine (700 mg, 2.32 mmol), methyl 1H-pyrrole-3-carboxylate (347 mg, 2.78 mmol), (1R,2S)-N1,N2- dimethylcyclohexane-1,2-diamine (132 mg, 928 pmol), Cui (88.3 mg, 464 pmol) and K2CO3(960 mg, 6.96 mmol) was added ACN (5 mL). The resulting mixture was stirred for 2 hours at 90 °C under N2 atmosphere. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% of ethyl acetate in petroleum ether to afford methyl 4-( 1H- pyrazol- l -yl)thiophcnc-2-carboxylatc (230 mg, 24.1%) as a yellow solid.

[0920] LCMS [M+H]+: 356

[0921] Step 4: To a mixture of methyl 1-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}-1H- pyrrole-3-carboxylate (400 mg, 1.15 mmol) and NCS (168 mg, 1.26 mmol) in AcOH (0.8 mL) and DMF (4 mL) at 80 °C for two hours. Then it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 65% of acetonitrile in water (0.1%NH4HCO3) to afford methyl 5-chloro-1-{5-fluoro-3-[(5-fluoropyridin-3- yl)methoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate (150 mg, 34.4%) as a white solid.

[0922] LCMS [M+H]+: 441

[0923] Step 5: To a stirred solution of methyl 5-chloro-1-{5-fluoro-3-[(5-fluoropyridin-3- yl)methoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate (150 mg, 394 pmol) in 1 mL of EtOH and 1 mL of water was added LiOH (82.7 mg, 1.97 mmol). The resulting mixture was stirred over night at 40 °C. Then it was concentrated, and the PH value of the residue solution was adjusted to 3 with 1 M of HC1 (aq). The product was precipitated from the solution. The mixture was filtered and the filter cake was washed with water (2 mL) to afford 5-chloro-1- {5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (80.0 mg, 55.5%) as a white solid.

[0924] LCMS [M+H]+: 366

[0925] Step 6: To a mixture of 5-chloro-1-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (80 mg, 218 pmol) and N-(3-amino-5- chlorophenyl)methanesulfonamide (57.5 mg, 261 pmol) in ACN (1 mL) was added TCFH (91.5 mg, 327 pmol) and NMI (53.6 mg, 654 pmol) at room temperature for two hours. Then it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 60% of acetonitrile in water (0.1 %FA) to afford 5-chloro-N-(3- chloro-5-methanesulfonamidophenyl)-1-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxamide (54.4 mg, 44.2%) as a white solid.

[0926] LCMS [M+H]+: 567.85

[0927] 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.92 (s, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.45 (d, J= 1.8 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 9.9, 2.5 Hz, 1H), 7.80 (d, 7 = 2.1 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.58 (d, J = 1.9 Hz, 1H), 6.93 - 6.85 (m, 2H), 5.37 (s, 2H), 3.05 (s, 3H).

[0928] Example 148: N-( 3-chloro-5-methanesulfonamidophenyl)-1-{4-fluoro-2-[(3-fluoro-5- methanesulfonylphenyl)methoxy ]-6-methylphenyl}-1H-pyrazole-4-carboxamide

[0929] Step 1: A solution of 2-bromo-4-fluoro-6-methylaniline (1 g, 4.90 mmol, 1 equiv) in 20% HCI (7 mL) was added dropwise a solution of NaNO2(0.37 g, 5.39 mmol, 1.1 equiv) in H2O (8 mL) at -5 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 hour at - 5 °C under nitrogen atmosphere. To the above mixture was dropwise into stannous chloride (2.32 g, 12.105 mmol, 2.47 equiv) in HCI (40 mL) at -15 °C. The resulting mixture was stirred for additional 12 hour at 35 °C. The mixture was allowed to cool down to 0 °C. The mixture was adjusted to pH 9 with saturated NH4CI (aq.). The aqueous layer was extracted with EtOAc (3x40 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (2-bromo-4-fluoro-6-methylphenyl) hydrazine (426 mg, 39.6% yield) as a white solid. LCMS (ESI) [M+H]+: 219.00

[0930] Step 2: A solution of (2-bromo-4-fluoro-6-methylphenyl)hydrazine (426 mg, 1.94 mmol, 1 equiv) and ethyl 2-formyl-3-oxopropanoate (420 mg, 2.92 mmol, 1.5 equiv) in EtOH (5 mL) was stirred for 1 hour at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford ethyl 1-(2-bromo-4-fluoro-6- methylphenyl)pyrazole-4-carboxylate (310 mg, 48.7% yield) as a white solid.

[0931] LCMS (ESI) [M+H]+: 327.00

[0932] Step 3: A solution of ethyl 1-(2-bromo-4-fluoro-6-methylphenyl)pyrazole-4-carboxylate (310 mg, 0.94 mmol, 1 equiv), bis(pinacolato)diboron (360 mg, 1.42 mmol, 1.5 equiv), Pd(dppf)Cl2(138 mg, 0.19 mmol, 0.2 equiv) and KO Ac (278 mg, 2.84 mmol, 3 equiv) in dioxane (4 mL) was stirred for 1 hour at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford ethyl 1-[4-fluoro-2-methyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carboxylate (220 mg, 62.0% yield) as a white solid.

[0933] LCMS (ESI) [M+H]+: 375.00

[0934] Step 4: A solution of ethyl 1-[4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl] pyrazole-4-carboxylate (220 mg, 0.58 mmol, 1 equiv) and H2O2 (59 mg, 1.76 mmol, 3 equiv) in THF (3 mL) was stirred for 2 hour at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (15 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3*30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 1-(4-fluoro-2-hydroxy-6-methylphenyl) pyrazole-4- carboxylate (130 mg, 83.6% yield) as a white solid.

[0935] LCMS (ESI) [M+H]+: 453.05

[0936] Step 5: A solution of ethyl 1-(4-fluoro-2-hydroxy-6-methylphenyl)pyrazole-4-carboxylate (130 mg, 0.49 mmol, 1 equiv), 1-(chloromethyl)-3-fluoro-5-methanesulfonylbenzene (131 mg, 0.59 mmol, 1.2 equiv) and K2CO3(203 mg, 1.47 mmol, 3 equiv) in DMF (2 mL) was stirred for 1 hour at 60 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 1-{4-fluoro-2-[(3-fluoro-5-methanesulfonyl phenyl) methoxy] -6-methylphenyl}pyrazole-4-carboxylate (109 mg, 49.1% yield) as a white solid. LCMS (ESI) [M+H]+: 451.00

[0937] Step 6: A solution of ethyl 1-{4-fluoro-2-[(3-fluoro-5-methanesulfonylphenyl)methoxy]-6- methylphenyl}-1H- pyrazole-4-carboxylate (89 mg, 197 pmol), N-(3-amino-5- chlorophenyl)methanesulfonamide (52.0 mg, 236 pmol) and AIMc? (43 mg, 0.59 mmol, 3 equiv) in PI1CH3(2 mL) was stirred for 1 hour at 80 °C under nitrogen atmosphere. The reaction was quenched with water at 0 °C. The aqueous layer was extracted with EtOAc (3*20 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-(3-chloro-5-methanesulfonamidophenyl)-1-{4-fluoro-2-[(3- fl uoro-5-mcthancsullbnyIphenyl) methoxyl -6- methyl phenyl }-1H-pyrazolc-4-carboxam ide (62.7 mg, 50.8% yield) as a white solid.

[0938] LCMS (ESI) [M+H]+: 625.05

[0939] 1H NMR (300 MHz, DMSO-d6) δ 10.07 (d, J = 16.9 Hz, 2H), 8.55 (s, 1H), 8.31 (s, 1H), 7.74 - 7.63 (m, 3H), 7.58 (t, J = 1.8 Hz, 1H), 7.38 (d, J = 9.3 Hz, 1H), 7.18 - 7.09 (m, 1H), 7.00 - 6.89 (m, 2H), 5.30 (s, 2H), 3.21 (s, 3H), 3.06 (s, 3H), 2.07 (d, J = 4.1 Hz, 3H).

[0940] Example 149: N-( 3-chloro-5-methanesulfonamidophenyl)-5-cyano-4-{5-fluoro-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl}thiophene -2-carboxamide

[0941] Step 1: A solution of methyl 4-(5-fluoro-3-hydroxypyridin-2-yl)thiophene-2-carboxylate (510 mg, 2.014 mmol, 1 equiv), 3-(chloromethyl)-5-fluoropyridine (352 mg, 2.417 mmol, 1.2 equiv) and K2CO3(835 mg, 6.042 mmol, 3 equiv) in DMF(10 mL) was stirred for 4 hours at 80 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 60% gradient in 20 min; detector, UV 254 nm to afford methyl 4-{5-fluoro-3-[(5-fluoropyridin-3- yl)methoxy]pyridin-2-yl}thiophene-2-carboxylate (600 mg, 78.11% yield) as a yellow solid. LCMS (ESI) [M + H]+: 363.3

[0942] Step 2: To a stirred mixture of methyl 4-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin- 2-yl}thiophene-2-carboxylate (600 mg, 1.65 mmol) in DMF(10 ml) was added NBS (1.46 g, 8.25 mmol) at 80 °C under nitrogen atmosphere. Then the mixture was stirred for 4 hours at 80 °C. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 60% gradient in 20 min; detector, UV 254 nm to afford methyl 5-bromo-4-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin- 2-yl} thiophene-2-carboxylate (600 mg, 1.35 mmol, 82.4% yield) as a yellow solid.

[0943] LCMS (ESI) [M + H]+: 442.2

[0944] Step 3: A solution of methyl 5-bromo-4-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin- 2-yl} thiophene-2-carboxylate (320 mg, 0.725 mmol) and LiOH (10 mg, 2.5 mmol) in THF (10 mL) was added H2O (2 mL) was stirred for 2 hours at 60 °C. The mixture was acidified to pH 5 with citric acid. The precipitated solids were collected by filtration and washed with water. The resulting solid was dried under vacuum to afford 5-bromo-4-{5-fluoro-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl}thiophene-2-carboxylic acid (210 mg, 0.491 mmol, 67.9 yield) as a yellow solid.

[0945] LCMS (ESI) [M + H]+: 428.2

[0946] Step 4: To a stirred solution of 5-bromo-4-{5-fluoro-3-[(5-fluoropyridin-3- yl)methoxy]pyridin-2-yl}thiophene-2-carboxylic acid (210 mg, 0.491 mmol), TCFH (207 mg, 0.7365 mmol) and NMI (121 mg, 1.473 mmol) in ACN (5.00 mL) was added N-(3- amino-5-chlorophenyl)methanesulfonamide (108 mg, 0.491 mmol) at room temperature. Then the mixture was stirred for 4 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 50% gradient in 20 min; detector, UV 254 nm to afford 5-bromo-N-( 3- chloro-5-methanesulfonamidophenyl)-4-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin- 2-yl}thiophene-2-carboxamide (142 mg, 0.226 mmol, 45.9% yield) as a white solid.

[0947] LCMS (ESI) [M + H]+: 630.9

[0948] Step 5: A solution of 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)-4-{5-fluoro-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl}thiophene-2-carboxamide (150 mg, 0.238 mmol) and CuCN (213 mg, 2.38 mmol) in DMF (2 mL) was stirred for 4 hours at 120 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: Column: Gemini-NX C18 AXAI Packed, 21.2* 150mm 5pm; Mobile Phase A: Water (0.05% TFA ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 35% B to 65% B in 8 min; Wave Length: 254 nm; RTl(min): 9.33) to afford N-( 3-chloro-5-mcthancsull'onamidophcnyl)-5- cyano-4-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}thiophene -2-carboxamide (12.7 mg, 0.0217 mmol, 9.12 % yield) as a yellow solid.

[0949] LCMS (ESI) [M + H]+: 576.05

[0950] 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.14 (s, 1H), 8.56 (dd, J = 7.0, 2.3 Hz, 2H), 8.52 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 10.7, 2.3 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.62 (dt, J= 7.0, 1.9 Hz, 2H), 7.00 (t, J = 1.9 Hz, 1H), 5.44 (s, 2H), 3.07 (s, 3H).

[0951] Example 150: N-( 3-chloro-5-methanesulfonamido phenyl)-5-{5-fhioro-3-[(3-fhioro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-2H-pyrazole-3-carboxamide

[0952] Step 1: To a solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (200 mg, 0.98 mmol, 1 equiv), SEM-C1 (488 mg, 2.93 mmol, 3 equiv) in DCM (5 mL) was added DIEA (252 mg, 1.95 mmol, 2 equiv) at room temperature. The reaction mixture was stirred for 2 hours. The reaction was quenched with water (10 mL). then the mixture was extracted with EtOAc (3*15 mL). Dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EA / PE (22%) to afford methyl 5- bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (250 mg, 76.43% yield) as a yellow solid.

[0953] LCMS (ESI) [M + H]+: 335

[0954] Step 2: Under nitrogen, a solution of methyl 5-bromo-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (250 mg, 0.746 mmol, 1 equiv), bis(pinacolato)diboron (151 mg, 0.597 mmol, 0.8 equiv) and Pd(dppf)Cl2(109 mg, 0.149 mmol, 0.2 equiv) in DMSO (7 mL) was added KO Ac (220 mg, 2.238 mmol, 3 equiv) at room temperature. The resulting solution was stirred for two hours at 100 °C. The reaction was quenched with water (5 mL) and then the mixture was extracted with EtOAc (3*100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography elute with EA / PE (33%) to afford methyl 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-{ [2-(trimethylsilyl)ethoxy]methyl} pyrazole-3-carboxylate (200 mg, 70.15% yield) as a yellow solid.

[0955] LCMS (ESI) [M + H]+: 383

[0956] Step 3: Under nitrogen, a solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2- {[2- (trimethyl silyl)ethoxy]methyl}pyrazole-3-carboxylate (200 mg, 0.523 mmol, 1 equiv), 2-chloro-5-fluoro-3-[(3-fluoro-5-methanesulfonylphenyl)methoxy]pyridine (175 mg, 0.523 mmol, 1 equiv) and Pd(dppf)Cl2(77 mg, 0.105 mmol, 0.2 equiv) in dioxane (5 mL) and H2O (2 mL) was added K3PO4(386 mg, 1.821 mmol, 3 equiv) at room temperature. The resulting solution was stirred for two hours at 80 °C. The reaction was quenched with water (5 mL) and then the mixture was extracted with ether / EtOAc (3*100 mL). dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography elute with EA / PE (34%) to afford methyl 5-{5-fluoro-3-[(3-fluoro- 5-methanesulfonyl phenyl)methoxy]pyridin-2-yl}-2-{ [2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (180 mg, 62.1 5% yield) as a yellow solid.

[0957] LCMS (ESI) [M + H]+: 554

[0958] Step 4: A solution of methyl 5-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (150 mg, 0.271 mmol, 1 equiv) , 1 equiv), N-(3-amino-5-chlorophenyl)methanesulfonamide (60 mg, 0.271 mmol, 1 equiv) and trimethylaluminium (39 mg, 0.542 mmol, 2 equiv) in methylbenzene (5 mL) was stirred for 1 hour at 80 °C under nitrogen atmosphere. The reaction mixture was concentrated under vacuum. The crude product (180 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 47% B in 8 min, 47% B; Wave Length: 220 nm; RTl(min): 8.08 to afford N-(3-chloro- 5-methanesulfonamidophenyl)-5-{5-fluoro-3-[(3-fluoro-5- methanesulfonylphenyl)methoxy]pyridin-2-yl}-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxamide (170 mg, 84.53% yield) as a white solid.

[0959] LCMS (ESI) [M + H]+: 742 Step 5: A solution of N-(3-chloro-5-methanesulfonamidophenyl)-5-{5-fluoro-3-[(3-fluoro-5- methanesulfonyl phenyl)methoxy]pyridin-2-yl}-2-{ [2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxamide (170 mg, 0.229 mmol, 1 equiv) and TFA (104 mg, 0.916 mmol, 4 equiv) in DCM (7 mL) was stirred for 1 hour at RT. The reaction mixture was concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 60% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.82 to afford N-(3-chloro-5-methanesulfonamido phenyl)-5-{5-fluoro-3-[(3- fluoro-5-methanesulfonylphenyl)methoxy]pyridin-2-yl}-2H-pyrazole-3-carboxamide (59 mg, 42.09% yield) as a white solid.

[0960] LCMS (ESI) [M - H]’: 610.00

[0961] 1H NMR (400 MHz, DMSO-d6) δ 14.06 (s, 1H), 10.39 (s, 1H), 10.02 (s, 1H), 8.36 (d, J= 2.3 Hz, 1H), 7.98 (s, 1H), 7.88 - 7.77 (m, 4H), 7.67 (t, 7= 1.9 Hz, 1H), 7.24 (s, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.52 (s, 2H), 3.33 (s, 3H), 3.08 (s, 3H).

[0962] Example 151: 4-{5-cyano-3-[(3,5-difhiorophenyl)methoxy]pyridin-2-yl}-N-( 3- methanesulfonamidophenyl)-5-methylthiophene-2-carboxamide

[0963] Step 1: A solution of methyl 4-(5-bromo-3-hydroxypyridin-2-yl)-5-methylthiophene-2- carboxylate (300 mg, 0.914 mmol), Cs2CO3(893 mg, 2.74 mmol) and 1-(bromomethyl)-3,5- difluorobenzene (225 mg, 1.09 mmol) in DMSO (3 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford methyl 4-{5-bromo-3-[(3,5-difluorophenyl) methoxy]pyridin-2-yl}-5- methylthiophene-2-carboxylate (240 mg, 0.528 mmol) as a white solid.

[0964] LCMS (ESI) [M + H]+: 453

[0965] Step 2: To a stirred solution of methyl 4-{5-bromo-3-[(3,5-difluorophenyl)methoxy]pyridin- 2-yl}-5-methylthiophene-2-carboxylate (240 mg, 0.528 mmol) in EtOH (3 mL) and H2O (0.5 mL) was added LiOH (126 mg, 5.27 mmol). Then the mixture was stirred for 2 hours at room temperature. The mixture was acidified to pH 5 with citric acid. The precipitated solids were collected by filtration and washed with water. The resulting solid was dried under vacuum to afford 4- { 5 -bromo-3 - [(3 ,5-difluorophenyl)methoxy]pyridin-2-yl } -5-methylthiophene-2- carboxylic acid (180 mg, 0.408 mmol) as a yellow solid.

[0966] LCMS (ESI) [M + H]+: 440

[0967] Step 3: To a stirred solution of 4-{5-bromo-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl}-5- methylthiophene-2-carboxylic acid (180 mg, 0.408 mmol), TCFH (456 mg, 1.63 mmol) and NMI (200 mg, 2.44 mmol) in ACN (2 mL) was added N-(3-aminophenyl) methanesulfonamide (83.4 mg, 0.448 mmol). Then the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / H2O (5-95%, acidic system) to afford 4-{5-bromo-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl}-N-(3-methanesulfonamidophenyl)-5-methylthiophene- 2-carboxamide (140 mg, 0.230 mmol) as a white solid.

[0968] LCMS (ESI) [M + H]+: 608

[0969] Step 4: A solution of 4-{5-bromo-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl}-N-(3- methanesulfona midoph enyl)-5-methylthiophene-2-carboxamide (140 mg, 0.230 mmol), Zn(CN)2(21.6 mg, 0.184 mmol), Pd(PPh3)4 (26.5 mg, 0.0230 mmol) in NMP (3 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford 4-{5-cyano-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl}-N-(3-methanesulfonamidophenyl)-5-methylthiophene- 2-carboxamide (70.5 mg, 0.127 mmol) as a white solid.

[0970] LCMS (ESI) [M + H]+: 555.10

[0971] ’ H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.78 (s, 1H), 8.76 (d, J = 1.6 Hz, 1H), 8.30 - 8.21 (m, 2H), 7.67 (t, 7 = 2.1 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.22 - 7.07 (m, 3H), 6.93 (dd, J = 8.1, 2.1 Hz, 1H), 5.32 (s, 2H), 3.00 (s, 3H), 2.45 (s, 3H). Example 152: N-( 3-chloro-5-methanesulfo namidophenyl)-5-{3-[(3,5-dimethyl-1,2- oxazol-4-yl)methoxy]-5-fhioropyridin-2-yl}-1-methylpyrrole-3-carboxamide

[0972] Step 1: A solution of (5-bromopyridin-3-yl)methanol (1 g, 5.31 mmol) in DMF (15 mL) was treated with Imidazole (361 mg, 5.31 mmol) for 10 minutes at 0 °C under nitrogen atmosphere followed by the addition of TBSCI (2.39 g, 15.9 mmol) dropwise at 0 °C. The final reaction mixture was irradiated with microwave radiation for 1.5 hour at room temperature. The resulting mixture was diluted with H2O (15 mL). The resulting mixture was extracted with EA (3 * 10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:3) to afford 3-bromo-5-{[(tert- butyldi methyl si I yl)oxy| methyl (pyridine (833 mg, 52% yield) as a white solid.

[0973] LCMS (ESI) [M + H]+: 302

[0974] Step 2: A solution of 3-bromo-5-{ |(tert-butyldimcthylsilyl)oxy| methyl (pyridine (783 mg, 2.59 mmol) in THF (15 mL) was stirred for 10 minutes at -

[0975] 78 °C under nitrogen atmosphere. To the above mixture was added n-BuLi (331 mg, 5.18 mmol) dropwise over 30min at -78 °C. The resulting mixture was stirred for additional Ih at - 78 °C. To the above mixture was added propan-2-one (225 mg, 3.88 mmol) dropwise over 5 minutes at -78 °C. The resulting mixture was stirred for additional 1 hour at room temperature. The reaction was quenched by the addition of water (10 mL) at 0 °C. The resulting mixture was diluted with H2O (15 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:5) to afford 2-(5-{ [(tert-butyldimethylsilyl)oxy]methyl}pyridin-3-yl)propan-2-ol (510 mg, 69.9% yield) as an off-white solid.

[0976] LCMS (ESI) [M + H]+: 282

[0977] Step 3: A solution of 2-(5-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-3-yl)propan-2- ol (510 mg, 1.81 mmol) and TBAF (707 mg, 2.71 mmol) in THF (5 mL) was stirred for 4 hour at 35 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (15 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with H2O (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford 2-[5-(hydroxymethyl)pyridin-3- yl]propan-2-ol (230 mg, 76.1% yield) as a white solid.

[0978] LCMS (ESI) [M + H]+: 168

[0979] Step 4: A solution of 2-[5-(hydroxymethyl)pyridin-3-yl]propan-2-ol (230 mg, 1.37 mmol), methyl 5-(5-fluoro-3-hydroxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (342 mg, 1.37 mmol) and PPh3(429 mg, 1.64 mmol) in THF (4 mL) was stirred for 15 minutes at 0 °C under nitrogen atmosphere. To the above mixture was added DIAD (331 mg, 1.64 mmol) dropwise over 3 minutes at 0 °C. The resulting mixture was stirred for additional 1.5 hour at room temperature. The resulting mixture was diluted with H2O (15 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:5) to afford methyl 5-(5-fluoro-3-{[5-(2- hydroxypropan-2-yl)pyridin-3-yl]methoxy}pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (130 mg, 23.7% yield) as a yellow oil.

[0980] LCMS (ESI) [M + H]+: 400

[0981] Step 5: A solution of methyl 5-(5-fluoro-3-{[5-(2-hydroxypropan-2-yl)pyridin-3- yl]methoxy}pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (220 mg, 550 pmol) and N-(3- amino-5-chlorophenyl)methanesulfona mide (145 mg, 659 pmol) in toluene (4 mL) was stirred for 10 minutes at 0 °C under nitrogen atmosphere. To the above mixture was added AlMe3 (0.82 mL, 1.64 mmol) dropwise over 1 minute at 0 °C. The resulting mixture was stirred for additional 1.5 hour at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (0.4 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 70% B in 7 min, 70% B; Wave Length: 254 / 220 nm; RTl(min): 5.38 to afford N-(3-chloro-5-methanesulfo namidophenyl)-5-{3-[(3,5-dimethyl-1,2-oxazol-4- yl)methoxy]-5-fluoropyridin-2-yl}-1-methylpyrrole-3-carboxamide (96.1 mg, 48.4% yield) as a white solid.

[0982] LCMS (ESI) [M + H]+: 588.15

[0983] 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.79 (s, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.89 (t, J = 2.2 Hz, 1H), 7.79 (dd, J = 11.0, 2.4 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.60 (t, J = 1.9 Hz, 1H), 7.11 (d, 7 = 2.0 Hz, 1H), 6.88 (t, J = 2.0 Hz, 1H), 5.32 (s, 2H), 5.19 (s, 1H), 3.74 (s, 3H), 3.05 (s, 3H), 1.40 (s, 6H).

[0984] Example 153: N-( 3-chloro-5-methanesuIfonamidophenyl)-5-(5-fIuoro-3-{[(5- fluoropyridin-3-yl)oxy]methyl}pyridin-2-yl)-1-methyIpyrroIe-3-carboxamide

[0985] Step 1: A solution of 2-bromo-5-fluoro-3-methylpyridine (500 mg, 2.631 mmol, 1 equiv), NBS (468 mg, 2.631 mmol, 1 equiv) and BPO (67 mg, 0.263 mmol, 0.1 equiv) in CCI4 (10 mL) was stirred for 2 hours at 85 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-bromo-3-(bromomethyl)-5-fluoropyridine (230 mg, 32.50% yield) as a white solid.

[0986] LCMS (ESI) [M+H]+: 267.87. Step 2: A solution of 2-bromo-3-(bromomethyl)-5-fluoropyridine (210 mg, 0.781 mmol, 1 equiv), 5-fluoropyridin-3-ol (106 mg, 0.937 mmol, 1.2 equiv) and K2CO3(324 mg, 2.343 mmol, 3 equiv) in DMSO (5 mL) was stirred for 1 hour at 80 °C. The reaction was allowed to cool down to room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford 2-bromo-5-fluoro-3-{[(5-fluoropyridin-3-yl)oxy]methyl}pyridine (185 mg, 78.68% yield) as a white solid.

[0987] LCMS (ESI) [M+H]+: 300.97.

[0988] Step 3: A solution of 2-bromo-5-fluoro-3-{[(5-fluoropyridin-3-yl)oxy]methyl}pyridine (185 mg, 0.614 mmol, 1 equiv), methyl l-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrrole-3-carboxylate (163 mg, 0.614 mmol, 1 equiv), Pd(dppf)Cl2(45 mg, 0.061 mmol, 0.1 equiv) and K2CO3(255 mg, 1.842 mmol, 3 equiv) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 1 hour at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-(5-fluoro-3-{ [(5-fluoropyridin-3-yl)oxy | methyl }pyridin-2-yl)- 1 - methylpyrrole-3-carboxylate (150 mg, 67.94% yield) as a white solid.

[0989] LCMS (ESI) [M + H]+: 360.11

[0990] Step 4: To a stirred solution of methyl 5-(5-fluoro-3-{[(5-fluoropyridin-3- yl)oxy]methyl}pyridin-2-yl)-1-methylpyrrole-3-carboxylate (130 mg, 0.362 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl)methane sulfonamide (104 mg, 0.471 mmol, 1.3 equiv) in toluene (2 mL) was added Al(Me)3(0.27 mL, 0.54 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 1.5 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 60% B in 8 min, 60% B; Wave Length: 254 / 220 nm; RTl(min): 7.22) to afford N-(3-chloro- 5-methanesulfonamidophenyl)-5-(5-fluoro-3-{[(5-fluoropyridin-3-yl)oxy|methyl}pyridin-2- yl)-1-methylpyrrole-3-carboxamide (133.3 mg, 67.03% yield) as a white solid.

[0991] LCMS (ESI) [M + H]+: 547.90!H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.80 (s, 1H), 8.72 (d, J = 2.9 Hz, 1H), 8.32 - 8.19 (m, 2H), 8.07 (dd, J = 9.4, 2.9 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.65 (t, J = 1.9 Hz, 1H), 7.60 (t, J = 1.9 Hz, 1H), 7.53 (dt, J = 11.0, 2.4 Hz, 1H), 6.94 - 6.85 (m, 2H), 5.27 (s, 2H),3.68 (s, 3H), 3.05 (s, 3H).

[0992] Example 154: N-( 3-chloro-5-methanesulfonamidophenyl)-5-{5-fhioro-3-[(5- fluoropyridin-3-yl )methoxy ]pyridin-2-yl}- 1 -methyl-1H-pyrrole-3-carboxamide

[0993] Step 1: A solution of 2-bromo-5-fluoropyridin-3-ol (520 mg, 2.70 mmol), 3-(chloromethyl)- 5-fluoropyridine (314 mg, 2.16 mmol) and K2CO3(1.11 g, 8.10 mmol) in DMF (5.00 mL) was stirred for 2 hours at 80 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (3:2) to afford 2-bromo-5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridine (430 mg, 1.42 mmol) as a yellow solid.

[0994] LCMS (ESI) [M + H]+: 301

[0995] Step 2: A solution of 2-bromo-5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridine (430 mg, 1.42 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3- carboxylate (356 mg, 1.42 mmol), Pd(dppf)Cl2(115 mg, 142 pmol) and K3PO4(903 mg, 4.26 mmol) in 1,4-dioxane (20.00 mL) was stirred for 12 hours at 80 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 0% to 50% gradient in 20 min; detector, UV 254 nm to afford methyl 5-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate (260 mg, 752 pmol) as an off-white solid.

[0996] LCMS (ESI) [M + H]+: 346

[0997] Step 3: To a solution of methyl 5-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}- 1H- pyrrole-3-carboxylate (260 mg, 752 pmol) in THF (5 mL) was added NaH (90 mg, 3.76 mmol) at 0 °C. Then the mixture was stirred for 20 minutes at 0 °C under nitrogen atmosphere. To the above mixture was added CH3I (319 mg, 2.25 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 hours at 0 °C under nitrogen atmosphere. The reaction was quenched with NH4Cl(aq) at 0 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:2) to afford methyl 5-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}-1- methyl-1H-pyrrole-3-carboxylate (110 mg, 306 pmol) as a yellow solid.

[0998] LCMS (ESI) [M + H]+: 360

[0999] Step 4: A solution of methyl 5-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}-1- methyl-1H-pyrrole-3-carboxylate (110 mg, 306 pmol) and LiOH (35 mg, 1.53 mmol) in EtOH (10.00 mL) and H2O (10.00 mL) was stirred for 2 hours at room temperature. The mixture was acidified to pH 5 with citric acid. The precipitated solids were collected by filtration and washed with water. The resulting solid was dried under vacuum to afford 5- { 5- fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (60.0 mg, 173 pmol) as a yellow solid.

[1000] LCMS (ESI) [M + H]+: 346

[1001] Step 5: To a stirred solution of 5-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}- l-methyl-1H-pyrrole-3-carboxylic acid (60 mg, 173 pmol), TCFH (73 mg, 259 pmol) and NMI (43 mg, 519 pmol) in ACN (5.00 mL) was added N-(3-amino-5- chlorophenyl)methanesulfonamide (38 mg, 173 pmol) at room temperature. Then the mixture was stirred for 4 hours at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5pm; Mobile Phase A: Water (0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 19% B to 45% B in 7 min, 45% B; Wave Length: 220 nm; RTl(min): 6.72 to afford W(3-chloro-5- methanesulfonamidophenyl)-5-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2-yl}-1- methyl-1H-pyrrole-3-carboxamide (6.4 mg, 98.396% purity) as a white solid.

[1002] LCMS (ESI) [M + H]+: 548.201H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.81 (s, 1H), 8.60 - 8.52 (m, 2H), 8.31 (d, J = 2.3 Hz, 1H), 7.80 (ddd, J = 13.3, 10.3, 2.3 Hz, 2H), 7.68 (t, J= 1.6 Hz, 2H), 7.62 (t, J= 1.9 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.89 (t, J= 1.9 Hz, 1H), 5.37 (s, 2H), 3.74 (s, 3H), 3.06 (s, 3H).

[1003] Example 155: N-( 3-chloro-5-methanesulfonamidophenyl)-5-[5-(3,3-difluoroazetidin-1- yl )-3-{ [ (5-fluoropyridin-3-yl)oxy]methyl}pyridin-2-yl]-1-methyl-1H-pyrrole-3- carboxamide

[1004] Step 1: To a stirred solution of 2-bromo-5-chloro-3-methylpyridine(2 g, 9.68 mmol) and BPO (234 mg, 968 pmol) in CCl4(50 mL) was added NBS (1.72 g, 9.68 mmol) at room temperature. Then the mixture was stirred for 12 hours at 85 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford 2-bromo-3-(bromomethyl)-5- chloropyridine (2.00 g, 7.00 mmol)) as an off yellow solid.

[1005] LCMS (ESI) [M + H]+: 283.5

[1006] Step 2: To a stirred solution of 2-bromo-3-(bromomethyl)-5-chloropyridine (1.9 g, 6.65 mmol) and 5- fluoropyridin-3-ol (752 mg, 6.65 mmol) in DMSO (16 mL) was added K2CO3(2.74 g, 19.9 mmol) at room temperature. Then the mixture was stirred for 1 hour at room temperature. The reaction was diluted with water. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 55% gradient in 20 min; detector, UV 254 nm to afford 2-bromo-5-chloro-3-{[(5-fluoropyridin-3- yl)oxy]methyl}pyridine (930 mg, 2.92 mmol) as a yellow solid.

[1007] LCMS (ESI) [M + H]+: 316.9

[1008] Step 3: To a stirred solution of 2-bromo-5-chloro-3-{[(5-fluoropyridin-3- yl)oxy]methyl}pyridine (520 mg, 1.63 mmol), methyl l-methyl-5-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (432 mg, 1.63 mmol) and Pd(dppf)Cl2(178 mg, 0.244 mmol) in dioxane (12 mL) and H2O (4 mL) was added K2CO3(674 mg, 4.89 mmol) at room temperature. Then the mixture was stirred for 1 hour at 90 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:4) to afford methyl 5- (5-chloro-3-{[(5-fluoropyridin-3-yl)oxy]methyl}pyridin-2-yl)-1-methyl-1H-pyrrole-3- carboxylate (330 mg, 878 pmol) as an off yellow solid.

[1009] LCMS (ESI) [M + H]+: 376.08

[1010] Step 4: To a stirred solution of methyl 5-(5-chloro-3-{[(5-fluoropyridin-3- yl)oxy]methyl}pyridin-2-yl)-1- methyl-1H-pyrrole-3-carboxylate (330 mg, 0.878 mmol), 3,3- difluoroazetidine (82 mg, 0.878 mmol) and CAS: 1814936-54-3 (43 mg, 0.044 mmol) in dioxane (10 mL) was added Cs2CO3(854 mg, 2.63 mmol) at room temperature. Then the mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:4) to afford methyl 5-[5-(3,3-difluoroazetidin-1-yl)- 3-{[(5-fluoropyridin-3-yl)oxy]methyl} pyridin-2-yl]- 1-methyl-1H-pyrrole-3-carboxylate (191mg, 441pmol) as an off yellow solid.

[1011] LCMS (ESI) [M + H]+: 433.14

[1012] Step 5: To a stirred solution of methyl 5-[5-(3,3-difluoroazetidin-1-yl)-3-{[(5-fluoropyridin- 3-yl)oxy]methyl} pyridin-2-yl]-1-methyl-1H-pyrrole-3-carboxylate (191 mg, 441 pmol) in EtOH (6 mL) and H2O (2 mL) was added LiOH (32 mg, 1.32 mmol) at room temperature. Then the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 30% gradient in 15 min; detector, UV 254 nm to afford 5-[5-(3,3- dilluoroazctidin- l-yl)-3-{ |(5-fluoropyridin-3-yl) oxy|mcthyl }pyridin-2-yl|- l-mcthyl- l / ¥- pyrrole-3-carboxylic acid (150 mg, 358 pmol) as an off white solid.

[1013] LCMS (ESI) [M + H]+: 419.13

[1014] Step 6: To a stirred solution of 5-[5-(3,3-difluoroazetidin-1-yl)-3-{[(5-fluoropyridin-3- yl)oxy]methyl}pyridin-2-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (150 mg, 358 pmol), N- (3-amino-5-chlorophenyl)methane sulfonamide (79 mg, 358 pmol) and TCFH (150 mg, 537pmol) in ACN (6 mL) was added NMI (145 mg, 1.78 mmol) at room temperature. Then the mixture was stirred for 1 hour at room tmeperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 5% to 25% gradient in 20 min; detector, UV 254 nm to afford N-(3-chloro-5- methanesulfonamidophenyl)-5-[5-(3,3-difluoroazetidin-1-yl)-3-{[(5-fluoropyridin-3- yl)oxy]methyl}pyridin-2-yl]-1-methyl-1H-pyrrole-3-carboxamide (103.2 mg, 163 pmol) as a white solid.

[1015] LCMS (ESI) [M + H]+: 621.10

[1016] 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.73 (s, 1H), 8.26 - 8.17 (m, 2H), 8.08 (d, J = 2.8 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.46 (dt, J= 11.0, 2.4 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 6.88 (t, J= 1.9 Hz, 1H), 6.74 (d, J= 1.9 Hz, 1H), 5.15 (s, 2H), 4.44 (t, J= 12.2 Hz, 4H), 3.62 (s, 3H), 3.05 (s, 3H).

[1017] Example 156: N-(3-chloro-5-methanesulfonamidophenyI)-5-[5-(3,3-difluoroazetidin-1- yl)-3-[(3-fluoro-5-methanesulfonylphenyl)methoxy]pyridin-2-yl]-1-methylpyrrole-3- carboxamide

[1018]

[1019] Step 1: A solution of 5-bromo-2-iodopyridin-3-ol (2 g, 6.669 mmol, 1 equiv), bromo(methoxy)methane (1.25 g, 10.003 mmol, 1.5 equiv) and K2CO3(2.77 g, 20.007 mmol, 3 equiv) in DMSO (30 mL) was stirred for 1 hour at room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-bromo-2-iodo-3- (methoxymethoxy) pyridine (1.8 g, 78.47% yield) as a white solid.

[1020] LCMS (ESI) [M + H]+: 343.87

[1021] Step 2: A solution of 5-bromo-2-iodo-3-(methoxymethoxy)pyridine (1.8 g, 5.233 mmol, 1 equiv), methyll-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate (1.39 g, 5.233 mmol, 1 equiv), Pd(dppf)Cl2(0.38 g, 0.523 mmol, 0.1 equiv) and K2CO3(2.17 g, 15.699 mmol, 3 equiv) in 1,4-dioxane (30 mL) and H2O (6 mL) was stirred for 1 hour at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-[5-bromo-3-(methoxymethoxy)pyridin-2-yl]-1-methylpyrrole-3-carboxylate (1.2 g, 64.56% yield) as a white solid.

[1022] LCMS (ESI) [M + H]+: 355.02

[1023] Step 3: A solution of methyl 5-[5-bromo-3-(methoxymethoxy)pyridin-2-yl]-1-methylpyrrole- 3-carboxylate (1.2 g, 3.378 mmol, 1 equiv), 3,3-difluoroazetidine (0.47 g, 5.067 mmol, 1.5 equiv), Pd(0Ac)2(80 mg, 0.338 mmol, 0.1 equiv), BINAP (420 mg, 0.676 mmol, 0.2 equiv) and Cs2CO3(3.30 g, 10.134 mmol, 3 equiv) in toluene (30 mL) was stirred for 2 hours at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-[5-(3,3-difluoroazetidin-1-yl)-3-(methoxymethoxy)pyridin-2-yl]-1-methylpyrrole-3- carboxylate (850 mg, 68.49% yield) as a white solid.

[1024] LCMS (ESI) [M + H]+: 368.13

[1025] Step 4: A solution of methyl 5-[5-(3,3-difluoroazetidin-1-yl)-3-(methoxymethoxy)pyridin-2- yl]-1-methyl pyrrole-3-carboxylate (850 mg, 2.314 mmol, 1 equiv) in HCl / l,4-dioxane (10 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5:1) to afford methyl 5-[5-(3,3-difluoroazetidin-1-yl)-3- hydroxypyridin-2-yl]-1-methylpyrrole-3-carboxylate (700 mg, 93.57% yield) as a white solid.

[1026] LCMS (ESI) [M + H]+: 324.11

[1027] Step 5: A solution of methyl 5-[5-(3,3-difhioroazetidin-1-yl)-3-hydroxypyridin-2-yl]-1- methylpyrrole-3-carboxylate (450 mg, 1.392 mmol, 1 equiv), 1-(chloromethyl)-3-fluoro-5- (methylsulfanyl)benzene (265 mg, 1.392 mmol, 1 equiv) and K2CO3(577 mg, 4.176 mmol, 3 equiv) in DMSO (10 mL) was stirred for 1 hour at 80 °C. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-[5-(3,3-difluoroazetidin-1-yl)- 3-{[3-fluoro-5-(methylsulfanyl)phenyl]methoxy}pyridin-2-yl]-1-methylpyrrole-3- carboxylate (380 mg, 57.17% yield) as a white solid.

[1028] LCMS (ESI) |M + H]+: 478.13

[1029] Step 6: To a stirred solution of methyl 5-[5-(3,3-difluoroazetidin-1-yl)-3-{[3-fluoro-5- (methylsulfanyl) phenyl] methoxy }pyridin-2-yl]- l-methylpyrrole-3-carboxylate (360 mg, 0.754 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl)methanesulfonamide (250 mg, 1.131 mmol, 1.5 equiv) in toluene (5 mL) was added Al(Me)3(1 mL) dropwise at 0 °C. The resulting mixture was stirred for additional 1.5 hours at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-(3-chloro-5- methanesulfonamidophenyl)-5-[5-(3,3-difluoroazetidin-1-yl)-3-{[3-fluoro-5-(methylsulfanyl) phenyl]methoxy}pyridin-2-yl]-1-methylpyrrole-3-carboxamide (280 mg, 55.75% yield) as a white solid.

[1030] LCMS (ESI) [M + H]+: 666.11

[1031] Step 7: A solution of N-( 3-chloro-5-methanesulfonamidophenyl)-5-[5-(3,3-difluoroazetidin- l-yl)-3-{[3-fluoro-5-(methylsulfanyl)phenyl]methoxy}pyridin-2-yl]-1-methylpyrrole-3- carboxamide (260 mg, 0.390 mmol, 1 equiv) in H2O2(5 mL) was stirred for 1 day at room temperature. The reaction was quenched with Na2S2O3(aq) and diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B in 8 min, 55% B; Wave Length: 220 nm; RTl(min): 7.52) to afford N-(3-chloro-5-methanesulfonamidophenyl)-5-[5-(3,3-difluoroazetidin-1-yl)-3- [(3-fluoro-5-methanesulfonylphenyl)methoxy]pyridin-2-yl]-1-methylpyrrole-3-carboxamide (14.2 mg, 5.07% yield) as a white solid.

[1032] LCMS (ESI) [M + H]+: 698.35

[1033] 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.75 (s, 1H), 7.84 (t, J = 1.5 Hz, 1H), 7.74 (dt, 7 = 7.8, 2.2 Hz, 1H), 7.68 (d, J = 2.1 Hz, 2H), 7.63 (dq, J = 4.4, 2.0 Hz, 3H), 6.98 (d, J = 2.0 Hz, 1H), 6.88 (q, 7= 2.0 Hz, 2H), 5.36 (s, 2H), 4.42 (t, 7= 12.3 Hz, 4H), 3.71 (s, 3H), 3.25 (s, 3H), 3.05 (s, 3H).

[1034] Example 157: N-( 3-chloro-5-methanesulfonamidophenyl)-5-{3-[(3,5- difluorophenyl)methoxy]-5-[(l-methylazetidin-3-yl)oxy]pyridin-2-yl}-1-methylpyrrole- 3-carboxamide

[1035]

[1036] Step 1: A solution of 2-bromo-5-chloropyridin-3-ol (1 g, 4.798 mmol, 1 equiv), MOMBr (0.72 g, 5.758 mmol, 1.2 equiv) and K2CO3(1.99 g, 14.394 mmol, 3 equiv) in DMF (10 mL) was stirred for 2 hours at RT. The resulting mixture was extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with water (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-bromo-5-chloro-3-(methoxymethoxy)pyridine (1.02 g, 84.2% yield) as a yellow solid.

[1037] LCMS [M+H]+: 252 Step 2: To a stirred solution of 2-bromo-5-chloro-3-(methoxymethoxy)pyridine (1.02 g, 4.040 mmol, 1 equiv), methyl l-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrrole-3-carboxylate (1.61 g, 6.060 mmol, 1.5 equiv), Pd(dppf)Cl2(0.30 g, 0.404 mmol, 0.1 equiv), K2CO3(1.67 g, 12.120 mmol, 3 equiv) in l,4-dioxane( 10.00 mL)and H2O (3 mL). Then the mixture was stirred for 2 hours at 80 °C under N2. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x30 mL). The combined organic layers were washed with water (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-[5-chloro-3- (methoxymethoxy)pyridin-2-yl]-1-methylpyrrole-3-carboxylate (833 mg, 66.3% yield) as a white solid.

[1038] LCMS [M+H]+: 311

[1039] Step 3: A mixture of methyl 5-[5-chloro-3-(methoxymethoxy)pyridin-2-yl]-1-methylpyrrole- 3-carboxylate (833 mg, 2.681 mmol, 1 equiv) in HC1 (gas) in 1,4-dioxane (8 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 5-(5-chloro-3- hydroxypyridin-2-yl)-1-methylpyrrole-3-carboxylate (750 mg, 104.9% yield) as a white solid.

[1040] LCMS [M+H]+: 267

[1041] Step 4: A solution of methyl 5-(5-chloro-3-hydroxypyridin-2-yl)-1-methylpyrrole-3- carboxylate (750 mg, 2.812 mmol, 1 equiv), 1-(bromomethyl)-3,5-difluorobenzene (698 mg, 3.374 mmol, 1.2 equiv) and K2CO3(1166 mg, 8.436 mmol, 3 equiv) in DMSO (8 mL) was stirred for 2 hours at room temperature. The resulting mixture was extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with water (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 5-{5-chloro-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl}-1-methylpyrrole-3- carboxylate (630 mg, 57.0% yield) as a yellow solid.

[1042] LCMS [M+H]+: 393

[1043] Step 5: A solution of methyl 5-{5-chloro-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl}-1- methylpyrrole-3-carboxylate (630 mg, 1.604 mmol, 1 equiv), Pd(OAc)2(36 mg, 0.160 mmol, 0.1 equiv), boric acid (149 mg, 2.406 mmol, 1.5 equiv), t-BuBrettPhos (155 mg, 0.321 mmol, 0.2 equiv) and Cs2CO3(1045 mg, 3.208 mmol, 2 equiv) in NMP (7 mL). Then the mixture was stirred for 2 hours at 80 °C under N2. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x20 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford methyl 5-{3-[(3,5- difluorophenyl)methoxy]-5-hydroxypyridin-2-yl}-1-methylpyrrole-3-carboxylate (298 mg, 49.6% yield) as a yellow oil liquid.

[1044] LCMS [M+H]+: 375

[1045] Step 6: A solution of methyl 5-{3-[(3,5-difluorophenyl)methoxy]-5-hydroxypyridin-2-yl]-1- methylpyrrole-3-carboxylate (298 mg, 0.796 mmol, 1 equiv) and tert-butyl 3-iodoazetidine-1- carboxylate (270 mg, 0.955 mmol, 1.2 equiv) and K2CO3(330 mg, 2.388 mmol, 3 equiv) in DMSO (3 mL) was stirred for 2 hours at 60 °C. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl 5-(5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl)-1-methylpyrrole-3-carboxylate (235 mg, 55.7% yield) as a white solid.

[1046] LCMS [M+H]+: 530

[1047] Step 7: A solution of methyl 5-(5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}-3-[(3,5- difluorophenyl) methoxy] pyridin-2-yl)-1-methylpyrrole-3-carboxylate (235 mg, 0.444 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl) methanesulfonamide (117 mg, 0.533 mmol, 1.2 equiv) in Toluene (3 mL) and under the protection of nitrogen, AlMe3 (0.14 mL, 1.332 mmol, 3 equiv) was add at 0 °C, then reacted at 80 °C for two hours. The reaction was quenched with water at 0 °C. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-[(6-{4-[(3-chloro-5-methanesul fonamidophenyl)carbamoyl]-1-methylpyrrol-2-yl]-5-[(3,5-difluorophenyl)methoxy]pyridin- 3-yl)oxy] azetidine- 1 -carboxylate (190 mg, 59.6% yield) as a yellow solid.

[1048] LCMS [M+H]+: 718

[1049] Step 8: A solution of tert-butyl 3-[(6-{4-[(3-chloro-5-methanesul fonamidophenyl)carbamoyl]-1-methylpyrrol-2-yl]-5-[(3,5-difluorophenyl)methoxy]pyridin- 3-yl)oxy] azetidine- 1 -carboxylate (190 mg, 0.265 mmol, 1 equiv) in DCM (1 mL), then added TFA (2 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 1% to 80% gradient in 25 min; detector, UV 254 nm. This resulted in 5- [5-(azetidin-3-yloxy)-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl]-N-(3-chloro-5- methanesulfonamidophenyl)-1-methyl-1H-pyrrole-3-carboxamide (150 mg, 78.95% yield) as a white solid.

[1050] LCMS [M+H]+: 618

[1051] Step 9: A solution of 5-[5-(azetidin-3-yloxy)-3-[(3,5-difluorophenyl)methoxy]pyridin-2-yl]- N-( 3-chloro-5-mcthancsullbnamidophcnyl)- l -mcthylpyrrolc-3-carboxamidc (157 mg, 0.254 mmol, 1 equiv) in formalde hyde (1 mL) and CH3OH (1 mL) was stirred for overnight at room temperature, then add STAB (161 mg, 0.762 mmol, 3 equiv), was stirred for 20 minutes at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in N-( 3-chloro-5- methanesulfonamidophenyl)-5- { 3- [(3 ,5-difluorophenyl)methoxy] -5- [( 1 -methylazetidin-3- yl)oxy]pyridin-2-yl}-1-methylpyrrole-3-carboxamide (79.9 mg, 49.7% yield) as a light yellow solid.

[1052] LCMS [M+H]+: 632.10

[1053] 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.72 - 7.60 (m, 3H), 7.14 (ddt, J= 18.5, 13.8, 10.4 Hz, 5H), 6.89 (d, 7 = 2.2 Hz, 1H), 5.29 (s, 2H), 4.92 (p, J = 5.6 Hz, 1H), 3.74 (d, J= 12.7 Hz, 5H), 3.06 (s, 3H), 3.00 (dd, J= 8.0, 5.5 Hz, 2H), 2.30 (s, 3H).

[1054] Example 158: N-( 3-chloro-5-methanesulfonamidophenyl)-4-{3-[(3,5- difluorophenyl)methoxy]-5-[(l-methylazetidin-3-yl)oxy]pyridin-2-yl}-5- methylthiophene-2-carboxamide

[1055]

[1056] Step 1: A solution of 5-bromo-6-chloropyridin-3-ol (3 g, 14.393 mmol, 1 equiv) and tertbutyl 3-iodoazetidine-1-carboxylate (4.48 g, 15.832 mmol, 1.1 equiv) and Cs2CO3(7.03 g, 21.590 mmol, 1.5 equiv) in DMSO (30 mL) was stirred for 2 hours at 80 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl 3-[(5-bromo-6-chloropyridin-3-yl)oxy]azetidine-1-carboxylate (3.4 g, 64.96% yield) as a white solid.

[1057] LCMS (ESI) [M + H]+: 363

[1058] Step 2: A solution of tert-butyl 3-[(5-bromo-6-chloropyridin-3-yl)oxy]azetidine-1- carboxylate (3.4 g, 9.350 mmol, 1 equiv) and (3,5-difluorophenyl)methanol (1.48 g, 10.285 mmol, 1.1 equiv) and Cui (0.18 g, 0.935 mmol, 0.1 equiv) and Cs2CO3(4.57 g, 14.025 mmol, 1.5 equiv) and 1,10-phen (3.37 g, 18.700 mmol, 2 equiv) in toluene (15 mL) was stirred for 2 hours at 110 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-({6-chloro-5-[(3,5- difluorophenyl)methoxy]pyridin-3-yl}oxy) azetidine- 1 -carboxylate (1.6 g, 40.09% yield) as a brown solid.

[1059] LCMS (ESI) [M + H]+: 427 Step 3: A solution of tert-butyl 3-({6-chloro-5-[(3,5-difluorophenyl)methoxy]pyridin-3- yl}oxy)azetidine-1-carboxylate (590 mg, 1.382 mmol, 1 equiv) and methyl 5-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (468.0 mg, 1.658 mmol, 1.2 equiv) and Pd(dppf)Cl2(101.1 mg, 0.138 mmol, 0.1 equiv) and K3PO4(880.2 mg, 4.146 mmol, 3 equiv) in dioxane (6 mL) and H2O (2 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-({5-[(3,5-difluorophenyl)methoxy]-6-[5-(methoxycarbonyl)-2- methylthiophen-3-yl]pyridin-3-yl}oxy)azetidine-1-carboxylate (340 mg, 45.00% yield) as a brown solid.

[1060] LCMS (ESI) [M + H]+: 547

[1061] Step 4: A solution of tert-butyl 3-({5-[(3,5-difluorophenyl)methoxy]-6-[5- (methoxycarbonyl)-2-methylthiophen -3-yl]pyridin-3-yl}oxy)azetidine-1-carboxylate (340 mg, 0.622 mmol, 1 equiv) and TFA (2 mL, 26.926 mmol, 43.29 equiv) in DCM (5 mL) was stirred for 2 hours at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude resulting mixture was used in the next step directly without further purification. This resulted in methyl 4-[5-(azetidin-3-yloxy)-3-[(3,5- difluorophenyl) methoxy]pyridin-2-yl]-5-methylthiophene-2-carboxylate (600 mg, crude) as a yellow solid.

[1062] LCMS (ESI) [M + H]+: 447

[1063] Step 5: A solution of methyl 4-[5-(azetidin-3-yloxy)-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl]-5-methylthi ophene-2-carboxylate (600 mg, 1.344 mmol, 1 equiv) and STAB (569.6 mg, 2.688 mmol, 2 equiv) in formaldehyde (2 mL) was stirred for 3 hours at room temperature under air atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford methyl 4-{3-[(3,5- difluoro phenyl)methoxy]-5-[(l-methylazetidin-3-yl)oxy]pyridin-2-yl}-5-methylthiophene-2- carboxylate (230 mg, 37.17% yield) as a yellow solid.

[1064] LCMS (ESI) [M + H]+: 461

[1065] Step 6: A solution of methyl 4-{3-[(3,5-difluorophenyl)methoxy]-5-[(l-methylazetidin-3- yl)oxy]pyridin-2-yl}-5-methylthiophene-2-carboxylate (230 mg, 0.499 mmol, 1 equiv) and LiOH (59.8 mg, 2.495 mmol, 5 equiv) in EtOH (3 mL) and H2O (1 mL) was stirred for 2 hours at 60 °C under air atmosphere. The mixture was acidified to pH 6 with HC1 (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-{3-[(3,5-difluorophenyl)methoxy]-5-[(l- methylazetidin-3-yl)oxy] pyridin-2-yl}-5-methylthiophene-2-carboxylic acid (150 mg, 67.27% yield) as a white solid.

[1066] LCMS (ESI) [M + H]+: 447

[1067] Step 7: A solution of 4-{3-[(3,5-difluorophenyl)methoxy]-5-[(l-methylazetidin-3- yl)oxy]pyridin-2-yl}-5-methylthiophene-2-carboxylic acid (150 mg, 0.336 mmol, 1 equiv) and N-(3-amino-5-chlorophenyl)methane sulfonamide (89.0 mg, 0.403 mmol, 1.2 equiv) and TCFH (141.4 mg, 0.504 mmol, 1.5 equiv) and NMI (82.8 mg, 1.008 mmol, 3 equiv) in ACN (5 mL) was stirred for 2 hours at room temperature under air atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-( 3-chloro-5-mcthancsullbnamidophcnyl)-4-{3- [(3,5-difluorophenyl)methoxy] -5- [( 1 -methylazetidin-3-yl)oxy]pyridin-2-yl } -5- methylthiophene-2-carboxamide (119.1 mg, 54.61% yield) as a white solid.

[1068] LCMS (ESI) [M + H]+: 649.15

[1069] 1H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.50 (t, J= 1.9 Hz, 1H), 7.11 (d, J= 2.4 Hz, 1H), 7.02 (t, J= 2.0 Hz, 1H), 6.96 - 6.91 (m, 2H), 6.85 (dt, J = 9.2, 2.4 Hz, 1H), 5.21 (s, 2H), 4.97 (p, J = 5.3 Hz, 1H), 3.92 - 3.78 (m, 2H), 3.33 (d, J = 5.4 Hz, 2H), 3.02 (s, 3H), 2.43 (d, J = 11.4 Hz, 6H).

[1070] Example 159: 4-[5-(azetidin-3-yloxy)-3-[(3,5-difhiorophenyl)methoxy]pyridin-2-yl]-2V-

[1071] (3-chloro-5-metha nesulfonamidophenyl)-5-methylthiophene-2-carboxamide

[1072] Step 1: A solution of tert-butyl 3-({5-[(3,5-difluorophenyl)methoxy]-6-[5-

[1073] (methoxycarbonyl)-2-methylthio phen-3-yl]pyridin-3-yl}oxy)azetidine-1-carboxylate (340 mg, 0.622 mmol, 1 equiv) and LiOH (74.5 mg, 3.110 mmol, 5 equiv) in EtOH (3 ml) and H2O (1 mL) was stirred for 2 hours at 60 °C under air atmosphere. The mixture was acidified to pH 6 with HC1 (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-(5-{[1-(tert-butoxycarbonyl) azetidin-3-yl]oxy}-3-[(3,5- difluorophenyl)methoxy]pyridin-2-yl)-5-methylthiophene-2-carboxylic acid (260 mg, 78.49% yield) as a yellow solid.

[1074] LCMS (ESI) [M + H]+: 533

[1075] Step 2: A solution of 4-(5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}-3-[(3,5- difluorophenyl)methoxy]pyri din-2-yl)-5-methylthiophene-2-carboxylic acid (260 mg, 0.488 mmol, 1 equiv) and N-(3-amino-5-chloro phenyl)methanesulfonamide (129.3 mg, 0.586 mmol, 1.2 equiv) and TCFH (205.5 mg, 0.732 mmol, 1.5 equiv) and NMI (120.3 mg, 1.464 mmol, 3 equiv) in ACN (5 mL) was stirred for 2 hours at room temperature under air atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 3-[(6-{5-[(3- chloro-5-methanesulfonamidophenyl) carbamoyl]-2-methylthiophen-3-yl}-5-[(3,5- difluorophenyl)methoxy]pyridin-3-yl)oxy] azetidine- 1 -carboxy late (210 mg, 58.51% yield) as a yellow solid.

[1076] LCMS (ESI) [M + H]+: 735

[1077] Step 3: A solution of tert-butyl 3-[(6-{5-[(3-chloro-5- methanesulfonamidophenyl)carbamoyl]-2-methylthio phen-3-yl}-5-[(3,5- difluorophenyl)methoxy]pyridin-3-yl)oxy] azetidine- 1 -carboxylate (210 mg, 0.286 mmol, 1 equiv) and TFA (2 mL) in DCM (5 mL) was stirred for 2 hours at room temperature under air atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-[5-(azetidin-3-yloxy)-3-[(3,5-difhiorophenyl)methoxy]pyridin-2-yl]-N-(3- chloro-5-metha nesulfonamidophenyl)-5-methylthiophene-2-carboxamide (170.1 mg, 93.77% yield) as a yellow solid.

[1078] LCMS (ESI) [M + H]+: 635.15

[1079] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.63 (dq, J = 3.7, 1.9 Hz, 2H), 7.17 (ddd, J = 9.3, 6.9, 2.5 Hz, 2H), 7.08 (d, J = 7.3 Hz, 2H), 6.93 (t, J = 2.0 Hz, 1H), 5.26 (s, 2H), 5.18 (s, 1H), 4.37 (s, 1H), 3.97 (s, 1H), 3.86 (s, 1H), 3.66 (s, 2H), 3.05 (s, 3H), 2.40 (s, 3H).

[1080] Example 160: 5-chloro-N-( 3-chloro-5-methanesulfonamidophenyl)-4-{5-fhioro-3-[(5- fluoropyridin-3-yl)methoxy]pyridin-2-yl}thioph ene-2-carboxamide

[1081] Step 1: A mixture of methyl 4-{5-fluoro-3-[(5-fluoropyridin-3-yl)methoxy]pyridin-2- yl } thiophene-2- carboxylate (390 mg, 1.07 mmol), NCS (1.70 g, 12.8 mmol) in DMF (10 mL). Then the mixture was stirred for 1 hour at 60 °C. The mixture was concentrated and purified by flash chromatography eluting with EA / PE (45%) to afford methyl 5-chloro-4-{5- fluoro-3-[(5-fluoropyridin-3-yl)methoxy] pyridin-2-yl}thiophene-2-carboxylate (270 mg, 0.680 mmol) as a yellow solid.

[1082] LCMS (ESI) [M + H]+: 397

[1083] Step 2: To a stirred solution of methyl 5-chloro-4-{5-fluoro-3-[(5-fluoropyridin-3- yl)methoxy]pyridin-2-yl} thiophene-2-carboxylate (270 mg, 0.680 mmol) in EtOH (5 mL) and H2O (5 mL) was added LiOH (162 mg, 6.80 mmol). Then the mixture was stirred for 30 minutes at 60 °C. The mixture was acidified to pH 5 with HC1 (2 M). The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN / H2O (50%, acidic system) to afford 5-chloro-4-{5-fluoro-3-[(5-fluoropyridin-3- yl)methoxy]pyridin-2-yl}thiophene-2-carboxylic acid (90.0 mg, 0. 235 mm...

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein:J is N or CH;J1is N or CX1;X1and X2are each independently H, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, CN, or C(O)RX;Rxis H, -OH, -OC1-4alkyl, or C1-4alkyl,Z is N or CRZ;Rzis H, halo, cyano, C1-4alkyl, Cwhaloalkyl, OR3a, or C(O)NR3bR3c; one of T1and T2is O and the other is -CRT1RT2-;R71and R72are each independently H, D, halo, or C1-4alkyl;R1is C1-4alkyl or C3-6cycloalkyl; wherein the Cwalkyl or C3-6cycloalkyl are each optionally and independently substituted with 1 to 3 halo or OH;Ring A is 5 to 6-membered monocyclic heteroaryl;Ring B is phenyl, 6-membered monocyclic heteroaryl, 9-membered bicyclic heterocyclyl, or 9-membered bicyclic heteroaryl; m is 0 to 3; n is 1 to 3; each R2is independently selected from C1-4alkyl, C3-6cycloalkyl, halo, OR2a, cyano, -NR2bR2c, -SO2R2a, -C(O)R2d, and -C(O)NR2bR2c, wherein the Cwalkyl and C3-6cyclo alkyl are optionally substituted with 1 to 4 R2e;R2ais H, C1-4alkyl, C1-4haloalkyl or C1-4alkoxyC1-4alkyl;R2dis H, C1-4alkyl, C3-6cycloalkyl, OR2a, phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the Cwalkyl is optionally substituted with 1 to 3 halo;R2band R2care each independently selected from H, C1-4alkyl, C3-6cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R2band R2c, together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R2d; each R2eis independently selected from halo, cyano, NR2bR2c, OR2a, phenyl, and 4 to 6 membered monocyclic heterocyclyl;R3is halo, cyano, C1-4alkyl, Cwhaloalkyl, OR3a, - NR3bR3c, -C(O)R3a, - C(O)OR3a, C(O)NR3bR3c, C3-6cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C1-4alkyl, C3-6cycloalkyl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R5;R3ais H, C1-6alkyl, or 4 to 6-membered monocyclic heterocyclyl, wherein the C1-6alkyl is optionally substituted with one or more halo or -OH and the 4 to 6- membered monocyclic heterocyclyl is optionally substituted with one or more C1- 4alkyl;R3band R3care each independently selected from H, C1-4alkyl, and C1- 4haloalkyl, or R3band R3c, together with the atom to which they are attached form 4 to 6-membered monocyclic heterocyclyl optionally substituted with one or more substituents selected from halo, C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; each R4is independently selected from C1-4alkyl, Cwhaloalkyl, halo, OR4a, cyano, -NR4bR4c, -C(O)R4a, -C(O)OR4a, -C(O)NR4bR4c, -NR4bC(O)R4a- NR4bC(O)OR4a, -SR4a, -S(O)R4a, -NR4bSO2R4a, -SO2R4a, -S(O)(NR4b)R4a, - SO2NR4bR4c, or -P(O)R4bR4c; or 2 R4together with the atom to which they are attached, form oxo;R4ais H, C1-4alkyl, C1-4haloalkyl, or C3-6cycloalkyl;R4band R4care each independently selected from H, C1-4alkyl, C1-4haloalkyl, or C1-4alkoxy, or R4band R4c, together with the atom to which they are attached form 4 to 6-membered monocyclic heterocyclyl optionally substituted with one or more substituents selected from halo, C1-4alkyl, C1-4haloalkyl, and -OR4a;each R5is independently C1-4alkyl, C1-4haloalkyl, halo, OR5a, -C(O)R5a, or 4 to 6-membered monocyclic heterocyclyl, wherein the 4 to 6-membered monocyclic heterocyclyl is optionally substituted with one or more C1-4alkyl,R5ais H, C1-4alkyl, or C1-4haloalkyl; provided that: when ring B is phenyl:(i) n is 2 or 3; or(ii) at least one R4is -SO2R4aor -P(O)R4bR4c; andsalt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X2is H.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1is H or halo.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1is H, -F, or -Cl.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1is -Cl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein T1is O and T2is -CRT1RT2-.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein RT1is H and R72is H or -CH3.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Z is N.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein J is CH and J1is CX1.

10. The compound of any one of claim 1 to 9, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

11. The compound of claim 1, wherein the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof, wherein X1is H, halo, C1-4alkyl, C1- 4haloalkyl, Cwalkoxy, or CN, and R72is H or C1-4alkyl.

12. The compound of claim 1, wherein the compound is represented by Formula (III):or a pharmaceutically acceptable salt thereof, wherein:X1is H or halo;R1is C1-3alkyl;R2is C1-3alkyl or C1-3haloalkyl;R3is halo or C1-3haloalkyl;R4is halo, C1-3haloalkyl, -P(O)R4bR4c, or -SO2R4a;R4a, R4b, and R4care each C1-3alkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Q is N.

14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Q is CR4.

15. The compound of any one of claims 12 to 14, or a pharmaceutically acceptable salt thereof, wherein:X1is H or Cl;R1is CH3;R2is -CH3or -CH2CF3;R3is -F or -CF3;R4is -F, -CH3, -SO2CH3, or -P(O)(CH3)2.

16. The compound of claim 1, wherein the compound is represented by Formula (IVA) or(IVB):or a pharmaceutically acceptable salt thereof, wherein:X1is H or halo;Q is N or CR4;R1is C1-4alkyl;R2is C1-4alkyl optionally substituted with 1 or 2 R4e;R4eis OH;R3is halo; each R4is independently selected from halo, C1-3haloalkyl, cyano, - P(O)R4bR4c, -SO2R4a, or -S(O)(NR4b)R4a;R4aand R4care each C1-3alkyl;R4bis H or C1-3alkyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein Q is N.

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein Q is CR4.

19. The compound of any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof, wherein:X1is H or Cl;R1is CH3;R2is -CH3or -CH2OH;R3is -F;R4is -F, -CH3, -CN, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -SO2CH3, or - P(O)(CH3)2.

20. The compound of claim 1, wherein the compound is selected from Examples 1-189, or a pharmaceutically acceptable salt thereof.

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