KEAP1 inhibitors and uses thereof

Abstract

Compounds of formula (I) and their use in methods for activating Nrf2 by inhibiting KEAP1.

Description

VVID 754PCKEAP1 INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS[1] This application claims the benefit of U.S. provisional application serial no. 63 / 733,763 filed December 13, 2024, the contents of which are incorporated by reference herein in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING[2] The contents of the electronic sequence listing (18420000266.xml; Size: 1,767 bytes; and Date of Creation: December 5, 2025) is herein incorporated by reference in its entirety.FIELD OF THE DISCLOSURE[3] The disclosure relates to compounds and methods for modulating KEAP1, or modulating Nrf2 by mediating the inhibition of KEAP1.BACKGROUND OF THE DISCLOSURE[4] Immunological disorders, such as inflammatory bowel disease, Crohn’s disease, and ulcerative colitis, are widely abundant in the general population. Improved therapeutics are needed for treating these disorders.SUMMARY[5] Disclosed herein, in some aspects, are modulators of Kelch-like ECH-associated protein 1 (KEAP1). Some such aspects relate to a KEAP1 antagonist. The KEAP1 antagonist may include a compound described herein. The KEAP1 antagonist may be useful in a method described herein.[6] Disclosed herein, in some aspects, are compounds that activate nuclear factor erythroid-2 - related factor 2 (Nrf2). The activation of Nrf2 may be indirect. For example, some aspects relate to a KEAP1 antagonist that indirectly activates Nrf2. Some such aspects may include a Nrf2 activator. The Nrf2 activator may include a compound described herein. The Nrf2 activator may be useful in a method described herein. The activation ofNrf2 may include inhibition ofNrf2 degradation. For example, a Nrf2 activator may inhibit its degradation.[7] The present disclosure further provides for compounds having the general formula (I)1QB\184200.00266\99637562.4VVID 754PCwhereinX1is CH or N,X2is CH or N,X3is CH or N,X4is N or C-R4withR4is -H, -CN, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2, -F, or -Cl,X5 is N or C-R5withR5is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -O-CH3, -O-CH2-CH3, O-CH(CH3)2, -S-CH3, -N(CH3)2, -F or -Cl,X6is N or C-R6withR6is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2, -F, or -Cl,X7is C-R7or N-R7andR7ais H or -Ci.4alkyl,R76is -Ci.4alkyl, or -C3-4cycloalkyl, orR6and R7together form **-CH2-N(Ci.4alkyl)-C(O)-, **-CH2-CH2-N(Ci.4alkyl)-C(O)-, **=N-N(Ci.4alkyl)-C(O)-, **-CH=CH-N(Ci.4alkyl)-C(O)-, **-N=CH-N(Ci.4alkyl)-C(O)-, **-CH=N-N(Ci.4alkyl)-C(O)-, and in which * * marks the bond towards X6,X8is N or CH, with the proviso, that only 0, 1, 2 or 3 of X4, X5, X6or X8can be simultaneously N,X9is a direct single bond or CR9R9a, andR9is -H, -F, -Cl, or -Ci.4alkyl, andR9ais -H, -F, -Cl, -OH, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2,R10is -H, -F, -Cl, -CH3, -CH2-COOH, -O-CH3, or -CH2-O-CH3, -CH2-C(O)-NR10bR10c,R10ais -H, -F, or -OH,2QB\184200.00266\99637562.4VVID 754PCR10band R10cindependently of each other are -H or -CH3,R11is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -CH2-CN, -CH2-OH, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2O-CH(CH3)2,R12is -H, -C1.4 alkyl, -CH2-OH, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-O-CH(CH3)2, -CH2-CN, -CFH2, -CF2H, -CF3, orR10and R12together form -CH2-CH2- substituted with 0-4 F, or -CH2-O-CH2- substituted with 0-4 F, orR11and R12together form -CH2-CH2- substituted with 0-4 F, or -CH2-O-CH2- substituted with 0-4 F,R13is -H, -F, -OH, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2,R14is -F, -Cl, -CH3or -CN, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof with the proviso that said compound is not[8] The present disclosure further provides methods for the use of compounds of formula (I (II), or (III) in the treatment of various medical disorders, including immunological disorders.[9] The present disclosure further provides the compounds of formula (I), (II), or (III) to be formulated into medicaments for treatment of various medical disorders, including immunological disorders.INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the text of the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION

[0011] Nuclear factor erythroid-2 -related factor 2 (Nrf2) is a transcription factor that may play a central role in cyto-protection against electrophilic and oxidative stress. Nrf2 may up-regulate expression of a range of cytoprotective enzymes with antioxidant response elements in their promoter regions and thus can protect cells against oxidative damage or affect oxidative cell signaling.

[0012] In some cases, Nrf2 is constantly synthesized under normal conditions, but is degraded due to interaction with Kelch-like ECH-associated protein 1 (KEAP1). KEAP1 may be included as a substrate adapter protein in an E3 ubiquitin ligase complex with RBX1 and Cul3. In some cases, the E3 ubiquitin3QB\184200.00266\99637562.4VVID 754PC ligase continuously degrades Nrf2. KEAP1 behaves as a fast-acting thiol sensor to electrophiles and oxidants.

[0013] In some conditions such as oxidative stress or oxidative signaling, cysteine 151 of KEAP1 (and possibly other KEAP 1 cysteines) may be oxidized, and the E3 ubiquitin ligase complex may be destabilized. Nrf2 may accumulate and translocate to the nucleus, bind to an ARE element, and initiate transcription of genes that respond to the oxidative stress. Some compounds that bind cysteine 151 may be useful for modulating this pathway.

[0014] The transcription factor nuclear factor erythroid-2 -related factor 2 (Nrf2) up-regulates the expression of a range of cytoprotective enzymes with antioxidant response elements in their promoter regions and thus can protect cells against oxidative damage. Increasing Nrf2 activity may be useful as a therapeutic intervention in a range of chronic immunological disorders such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, lupus (including systemic lupus erythematous, cutaneous lupus, lupus nephritis), rheumatoid arthritis juvenile idiopathic arthritis, Still’s disease, spondyloarthritis, and scleroderma, and acute cytokine release syndrome. One mechanism by which Nrf2 is negatively regulated involves an interaction with the ubiquitination facilitator protein, KEAP1 that facilitates degradation of Nrf2. Inhibition of this process underlies the mode of action of a broad group of compounds that increase Nrf2 activity. Several natural products, including the isothiocyanate sulforaphane, up-regulate Nrf2 by interacting with KEAP1 in a covalent manner to stall its activity. Agents which increase levels or activity of Nrf2 in a cell may make the cell less susceptible to oxidative stress.

[0015] Disclosed herein are compounds and methods for activating Nrf2 by mediating the inhibition of KEAP 1. Some embodiments relate to a compound or method of activating Nrf2. The Nrf2 activation may be in vitro or in vivo. The Nrf2 activation may include contacting a KEAP1 protein with a compound disclosed herein. The Nrf2 activation may increase an antioxidant or improve an antioxidant capacity in a subject or cell. The compound for activating Nrf2 may be formulated for administration to a subject. The Nrf2 activation may be performed in a subject, where the subject may be a human or nonhuman animal.

[0016] Details and examples of some Nrf2 proteins may be found at www.uniprot.org under accession number QI 6236 (as of the priority date of this application). An Nrf2 protein may include a peptide of about 705 amino acids long, or that includes a mass of about 68 kD.

[0017] Some embodiments relate to a compound or method of inhibiting KEAP 1. The KEAP 1 inhibition may be in vitro or in vivo. The KEAP1 inhibition may include contacting the KEAP1 with a compound disclosed herein. The KEAP1 inhibition may increase an antioxidant or improve an antioxidant capacity in a subject or cell. The compound for inhibiting KEAP1 may be formulated for administration to a subject. The KEAP1 activation may be performed in a subject, where the subject is a human or non-human animal.4QB\184200.00266\99637562.4VVID 754PC

[0018] Details and examples of some KEAP1 proteins may be found at www.uniprot.org under accession number Q 14145 (as of the priority date of this application). A KEAP1 may include a peptide of about 624 amino acids long, or that includes a mass of about 70 kD.

[0019] The compounds disclosed herein may be useful for treatment of immunological disorders where Nrf2 activity may be a concern, such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, Lupus (including Systemic Lupus Erythematous, cutaneous lupus, lupus nephritis), rheumatoid arthritis juvenile idiopathic arthritis, Still’s disease, spondyloarthritis, and scleroderma, and acute cytokine release syndrome. (See Geertsema, Sem et al. Trends in Molecular Medicine, Volume 29, Issue 10, 830 - 842 (2023) (KEAP1 inhibition linked to medical indications via Nrf2 activation); Cuadrado, A., Rojo, A. I., Wells, G. et al. Nat Rev Drug Discov 18, 295-317 (2019) (A functional Nrf2 / KEAP1 axis is essential for protection against a plethora of diseases having oxidative stress and inflammation as underlying pathological features; experimental evidence for disease effect discussed)). In some cases, the compounds are useful in diseases where reductive stress is present, or when oxidative signaling is up-regulated. The compounds may be useful for treating a disorder associated with oxidative stress, or for reducing oxidative stress or damage.Compounds of the disclosure

[0020] The present disclosure provides compounds of formula (I)whereinX1is CH or N,X2is CH or N,X3is CH or N,X4is N or C-R4withR4is -H, -CN, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2, -F, or -Cl,X5 is N or C-R5withR5is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -O-CH3, -O-CH2-CH3, O-CH(CH3)2, -S-CH3, -N(CH3)2, -F or -Cl,X6is N or C-R6withR6is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2, -F, or -Cl,5QB\184200.00266\99637562.4VVID 754PCX7is C-R7or N-R7and, s^cycloalkyl, orR6and R7together form **-CH2-N(Ci.4alkyl)-C(O)-, **-CH2-CH2-N(Ci.4alkyl)-C(O)-, **=N-N(Ci. 4alkyl)-C(O)-, **-CH=CH-N(Ci.4alkyl)-C(O)-, **-N=CH-N(Ci.4alkyl)-C(O)-, **-CH=N-N(Ci. 4alkyl)-C(O)-, and in which * * marks the bond towards X6,X8is N or CH, with the proviso, that only 0, 1, 2 or 3 of X4, X5, X6or X8can be simultaneously N,X9is a direct single bond or CR9R9a, andR9is -H, -F, -Cl, or -Ci-4alkyl, andR9ais -H, -F, -Cl, -OH, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2,R10is -H, -F, -Cl, -CH3, -CH2-COOH, -O-CH3, or -CH2-O-CH3, -CH2-C(O)-NR10bR10c,R10ais -H, -F, or -OH,R10band R10cindependently of each other are -H or -CH3,R11is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -CH2-CN, -CH2-OH, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2O-CH(CH3)2,R12is -H, -C1.4 alkyl, -CH2-OH, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-O-CH(CH3)2, -CH2-CN, -CFH2, -CF2H, -CF3, orR10and R12together form -CH2-CH2- substituted with 0-4 F, or -CH2-O-CH2- substituted with 0-4 F, orR11and R12together form -CH2-CH2- substituted with 0-4 F, or -CH2-O-CH2- substituted with 0-4 F,R13is -H, -F, -OH, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2,R14-F, -Cl, -CH3or -CN, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof with the proviso that said compound is not

[0021] In some embodiments of formula (I), not all R9, R9a, R10, R10a, R11, R12and R13are simultaneously -H.

[0022] In some embodiments of formula (I), X9is not CH2.

[0023] In some embodiments of formula (I),X1is CH or N,6QB\184200.00266\99637562.4VVID 754PCX2is CH or N,X3is CH or N, wherein one and only one of X1, X2and X3is N,X4is N or C-R4withR4is -H, -CN, -O-CH3, or -F,X5is N or C-R5withR5is -H, -CH3, -CF3 or -O-CH3,X6is N or C-R6withR6is -H, -F, -CH3, or -O-CH3,X7is C-R7andR7is -CN, -C(O)-NH2, -C(O)-NH-CH3, or -C(O)-N(CH3)2, orR6and R7together form **-CH2-N(CH3)-C(O)-, **-CH2-CH2-N(CH3)-C(O)-, **-CH=CH- N(CH3)-C(O)-, **=N-N(CH3)-C(O)-, **-N=CH-N(CH3)-C(O)-, **-CH=N-N(CH3)- C(O)-, with ** indicating the bond towards X6,X8is N or CH, with the proviso, that only 0, 1, 2 or 3 of X4, X5, X6or X8can be simultaneously N,X9is a direct single bond or CR9R9a, withR9is -H, -F, -CH3, andR9ais -H, -F, -OH, -O-CH3,R10is -H, -F, -CH3, -CH2-COOH, -O-CH3, -CH2-O-CH3,R10ais -H, -F, or -OH,R11is -H, -CH3, -CH2-F, -CH2-OH, -CH2-O-CH3, orR12is -H, -CH3, -CH2-OH, -CH2-O-CH3, -CH2-CN, -CH2F,R10and R12or R11and R12form -CH2-CH2-, or -CH2-O-CH2-,R13is -H, -OH, -O-CH3R14is -F, -Cl, -CH3or -CN, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0024] The present disclosure also provides compounds of formula (II)QB\184200.00266\99637562.4VVID 754PC whereinX1is CH or N,X2is CH or N,X3is CH or N, wherein one and only one of X1, X2and X3is N,X4is N or C-R4withR4is -H, -CN, -O-CH3, or -F,X5is N or C-R5withR5is -H, -CH3, -CF3 or -O-CH3,X6is N or C-R6withR6is -H, -F, or -O-CH3,X7is C-R7withR7is -C(O)-NH-CH3, or -CN,R6and R7together form **-CH2-N(CH3)-C(O)-, **-CH2-CH2-N(CH3)-C(O)-, **-CH=CH-N(CH3)- C(O)-, **=N-N(CH3)-C(O)-, **-N=CH-N(CH3)-C(O)-, **-CH=N-N(CH3)-C(O)-, with ** indicating the bond towards X6,X8is N or CH with the proviso, that only 0, 1, or 2 of all X4, X5, X6, or X8can simultaneously be N,R9is -H, -F, or -CH3,R9ais -H, -F, -OH, -O-CH3,R10is -H, -F, -CH3, -CH2-COOH, -O-CH3, -CH2-O-CH3,R10ais -H, -F, or -OH,R11is -H, -CH3, -CH2-F, -CH2-OH, or -CH2-O-CH3,R12is -H, -CH3, -CH2-OH, -CH2-O-CH3, -CH2-CN, CH2F,R10and R12or R11and R12form -CH2-CH2- or -CH2-O-CH2-,R13is -H, -OH, or -OCH3,R14is -F, -Cl, -CH3or -CN, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0025] In some embodiments of formula (II), X1is CH.

[0026] In some embodiments of formula (II), X2is N.

[0027] In some embodiments of formula (II), X3is N.

[0028] In some embodiments of formula (II), X3is CH.

[0029] In some embodiments of formula (II), X4is N.

[0030] In some embodiments of formula (II), X5is CH.

[0031] In some embodiments of formula (II), X6is N.

[0032] In some embodiments of formula (II), X7is C-C(O)-NH-CH3.

[0033] In some embodiments of formula (II), X8is CH.

[0034] In some embodiments of formula (II), R6and R7together form **-CH2-N(CH3)-C(O)-.8QB\184200.00266\99637562.4VVID 754PC

[0035] In some embodiments of formula (II), R6and R7together form **-CH2-CH2-N(CH3)-C(O)-.

[0036] In some embodiments of formula (II), R9is H.

[0037] In some embodiments of formula (II), R9ais H.

[0038] In some embodiments of formula (II), R10is H.

[0039] In some embodiments of formula (II), R11is H.

[0040] In some embodiments of formula (II), R12is -CH3.

[0041] In some embodiments of formula (II), R12is -CH2-OH.

[0042] In some embodiments of formula (II), R12is -CH2-O-CH3.

[0043] In some embodiments of formula (II), R13is H.

[0044] In some embodiments of formula (II), R13is OH.

[0045] In some embodiments of formula (II), R14is Cl.

[0046] The present disclosure also provides compounds of formula (III)whereinX1is N or CH,X2is N or CH,X3is N or CH, with the proviso that only one of X1, X2or X3is N,X4is N or C-R4with,R4is -H, -O-CH3, or -F,X5is N or C-R5withR5is -H, -CH3, -CF3or -O-CH3,X6is N or C-R6withR6is -H,X7is C-R7withR7is -C(O)-NH-CH3, or -CN,R6and R7together form **-CH2-N(CH3)-C(O)-, **-CH2-CH2-N(CH3)-C(O)-, with ** indicating the bond towards X6,X8is CH or N9QB\184200.00266\99637562.4VVID 754PC with the proviso, that only 0, 1, or 2 of all X4, X5, X6, or X8can simultaneously be N,R10is H, -CH3,R11is H, -CH3, -CH2-OH, -CH2-CN, -CH2-O-CH3,R12is H, CH3, -CH2-OH, -CH2-O-CH3, -CH2-CN, CH2F, orR12and R11together form -CH2-O-CH2-,R13is H, OH, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0047] In some embodiments of formula (III), X1is CH.

[0048] In some embodiments of formula (III), X2is N.

[0049] In some embodiments of formula (III), X2is CH

[0050] In some embodiments of formula (III), X3is N.

[0051] In some embodiments of formula (III), X3is CH.

[0052] In some embodiments of formula (III), X4and X6are both simultaneously N.

[0053] In some embodiments of formula (III), X5is CH.

[0054] In some embodiments of formula (III), X7is C-C(O)-NH-CH3.

[0055] In some embodiments of formula (III), X8is CH.

[0056] In some embodiments of formula (III), R6and R7together form **-CH2-N(CH3)-C(O)-.

[0057] In some embodiments of formula (III), R6and R7together form **-CH2-CH2-N(CH3)-C(O)-.

[0058] In some embodiments of formula (III), R10is H.

[0059] In some embodiments of formula (III), R11is H.

[0060] In some embodiments of formula (III), R12is -CH3.

[0061] In some embodiments of formula (III), R12is -CH2-OH.

[0062] In some embodiments of formula (III), R12is -CH2-O-CH3.

[0063] In some embodiments of formula (III), R13is H.

[0064] In some embodiments of formula (III), R13is OH.

[0065] The compounds of Formula (I), (II), or (III) can be present in chiral or achiral form. The form may either be racemic or R or S configuration.

[0066] Compounds of the disclosure include, but are not limited to:Table A.10QB\184200.00266\99637562.4VVID 754PC11QB\184200.00266\99637562.4VVID 754PC12QB\184200.00266\99637562.4VVID 754PC13QB\184200.00266\99637562.4VVID 754PC14QB\184200.00266\99637562.4VVID 754PC15QB\184200.00266\99637562.4VVID 754PC16QB\184200.00266\99637562.4VVID 754PC17QB\184200.00266\99637562.4VVID 754PC18QB\184200.00266\99637562.4VVID 754PC19QB\184200.00266\99637562.4VVID 754PC20QB\184200.00266\99637562.4VVID 754PC21QB\184200.00266\99637562.4VVID 754PC22QB\184200.00266\99637562.4VVID 754PC23QB\184200.00266\99637562.4VVID 754PC24QB\184200.00266\99637562.4VVID 754PC25QB\184200.00266\99637562.4VVID 754PC26QB\184200.00266\99637562.4VVID 754PC27QB\184200.00266\99637562.4VVID 754PC28QB\184200.00266\99637562.4VVID 754PC29QB\184200.00266\99637562.4VVID 754PC30QB\184200.00266\99637562.4VVID 754PC31QB\184200.00266\99637562.4VVID 754PC32QB\184200.00266\99637562.4VVID 754PC33QB\184200.00266\99637562.4VVID 754PC34QB\184200.00266\99637562.4VVID 754PC35QB\184200.00266\99637562.4VVID 754PC36QB\184200.00266\99637562.4VVID 754PC37QB\184200.00266\99637562.4VVID 754PC38QB\184200.00266\99637562.4VVID 754PC39QB\184200.00266\99637562.4VVID 754PC40QB\184200.00266\99637562.4VVID 754PC41QB\184200.00266\99637562.4VVID 754PC42QB\184200.00266\99637562.4VVID 754PC43QB\184200.00266\99637562.4VVID 754PC44QB\184200.00266\99637562.4VVID 754PC45QB\184200.00266\99637562.4VVID 754PC46QB\184200.00266\99637562.4VVID 754PC47QB\184200.00266\99637562.4VVID 754PC48QB\184200.00266\99637562.4VVID 754PC49QB\184200.00266\99637562.4VVID 754PC50QB\184200.00266\99637562.4VVID 754PC51QB\184200.00266\99637562.4VVID 754PC52QB\184200.00266\99637562.4VVID 754PC53QB\184200.00266\99637562.4VVID 754PC54QB\184200.00266\99637562.4VVID 754PC55QB\184200.00266\99637562.4VVID 754PC56QB\184200.00266\99637562.4VVID 754PC57QB\184200.00266\99637562.4VVID 754PC58QB\184200.00266\99637562.4VVID 754PC59QB\184200.00266\99637562.4VVID 754PC60QB\184200.00266\99637562.4VVID 754PC61QB\184200.00266\99637562.4VVID 754PC62QB\184200.00266\99637562.4VVID 754PC63QB\184200.00266\99637562.4VVID 754PC64QB\184200.00266\99637562.4VVID 754PC65QB\184200.00266\99637562.4VVID 754PC66QB\184200.00266\99637562.4VVID 754PC

[0067] Further Forms of Compounds

[0068] In some aspects, a compound disclosed herein possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0069] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where watersolubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or67QB\184200.00266\99637562.4VVID 754PC more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0070] In one aspect, prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacokinetic, pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is known, the design of prodrugs of the compound is possible, (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series).

[0071] In some embodiments, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0072] In some embodiments, sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.

[0073] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0074] Compounds described herein include isotopically labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine such as, for example,2H,3H,13C,14C,15N,180,170,35S,18F,36C1, and125I. In one aspect, isotopically labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0075] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0076] “Pharmaceutically acceptable” as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or68QB\184200.00266\99637562.4VVID 754PC interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0077] The disclosure relates to compounds that selectively inhibit KEAP1 and to uses thereof. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound disclosed herein with a base to form a salt.

[0078] The disclosure relates to compounds that selectively inhibit KEAP1 and to uses thereof.

[0079] Compounds described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1 -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0080] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are69QB\184200.00266\99637562.4VVID 754PC considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0081] Methods of Treatment

[0082] In another aspect, provided herein is a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, for use in a method of activating Nrf2 by mediating the inhibition of KEAP 1. In some embodiments, provided herein is a method of activating Nrf2 by mediating the inhibition of KEAP 1, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0083] In another aspect, provided herein is a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof or use in a method of treating a disease. In some embodiments, provided herein is a method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof. In some embodiments, the disease is mediated by the inhibition of KEAP 1 and the activation of Nrf2.

[0084] In another embodiment, provided herein is a method of treating a disease mediated by the inhibition of KEAP 1 and the activation of Nrf2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0085] In some embodiments, the disease is associated with oxidative stress. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (II), or (III), o or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof) decreases oxidative stress.

[0086] In some embodiments, the disease is inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, lupus (including systemic lupus erythematous, cutaneous lupus, lupus nephritis), rheumatoid arthritis juvenile idiopathic arthritis, Still’s disease, spondyloarthritis, and scleroderma, or acute cytokine release syndrome.

[0087] In further embodiments the disease or condition is: a respiratory and non-respiratory disorder, including (but not limited to): COPD, asthma, fibrosis, chronic asthma, acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis an autoimmune and inflammatory disease, including rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, lupus, inflammatory bowel diseases, celiac disease, psoriasis, dermatitis / topical effects of radiation, polymyositis, mixed connective tissue disease, autoimmune -interstitial lung disease (AI-ILD), dermatomyositis, immunosuppression due to radiation exposure, a kidney disease, including diabetic nephropathy, chronic kidney disease, acute kidney injury (AKI), sepsis-induced acute kidney injury, kidney disease or malfunction seen during kidney transplantation,70QB\184200.00266\99637562.4VVID 754PC a cardiovascular disease, including pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, a neurological disorder, including Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's ataxia (FA), amyotrophic lateral sclerosis (ALS), epilepsy, and multiple sclerosis (MS), cancer, an ocular disease, including, retinosa pigmentosa (RP), glaucoma, cataracts, neovascular (dry) AMO and neovascular (wet) AMO, eye injury, Fuchs endothelial comeal dystrophy (FECD), uveitis or other inflammatory eye conditions, a liver indication, including non-alcoholic steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, preeclampsia, sickle cell disease, thalassemia, or high altitude sickness.

[0088] In another aspect, provided herein is a method of maintaining the activity of Nrf2 in a cell or subject, comprising administering to the cell or subject an effective amount of a compound of any of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof. In some embodiments, the compound inhibits KEAP1, thereby resulting in Nrf2 activation.

[0089] Dosing and Treatment Regimens

[0090] In one aspect, the compounds disclosed herein are used in the preparation of medicaments for the treatment of diseases or conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said subject.

[0091] In certain embodiments, the compositions containing the compound disclosed herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

[0092] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0093] In certain embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).71QB\184200.00266\99637562.4VVID 754PC

[0094] Doses employed for adult human treatment are typically in the range of 0.0 lmg-5000 mg per day or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.

[0095] Pharmaceutical Compositions

[0096] In another aspect, provided herein is a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof for use in the manufacture of a medicament.

[0097] In one aspect, the compounds described herein (e.g., compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, or solvates thereof) are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0098] A pharmaceutical composition, as used herein, refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fdling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism.

[0099] Pharmaceutical formulations described herein are administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0100] In some embodiments, the compounds disclosed herein are administered orally.72QB\184200.00266\99637562.4VVID 754PC

[0101] In some embodiments, the compounds disclosed herein are administered topically. In such embodiments, the compound disclosed herein is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments. In one aspect, the compounds disclosed herein are administered topically to the skin.

[0102] In another aspect, the compounds disclosed herein are administered by inhalation.

[0103] In another aspect, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0104] In another aspect, the compounds disclosed herein are formulated as eye drops.

[0105] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound disclosed herein is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by inhalation to the mammal; and / or (e) administered by nasal administration to the mammal; or and / or (f) administered by injection to the mammal; and / or (g) administered topically to the mammal; and / or (h) administered by ophthalmic administration; and / or (i) administered rectally to the mammal; and / or (j ) administered non-systemically or locally to the mammal.

[0106] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) the compound is administered continually; or (iv) the compound is administered continuously.

[0107] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound disclosed herein is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0108] In certain embodiments, the compound disclosed herein is administered in a local rather than systemic manner.

[0109] In some embodiments, the compound disclosed herein is administered topically. In some embodiments, the compound disclosed herein is administered systemically.

[0110] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations of the compounds disclosed herein are in the form of a capsule.73QB\184200.00266\99637562.4VVID 754PC

[0111] In one aspect, liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0112] For administration by inhalation, a compound disclosed herein is formulated for use as an aerosol, a mist, or a powder.

[0113] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[0114] In some embodiments, compounds disclosed herein are prepared as transdermal dosage forms.

[0115] In one aspect, a compound disclosed herein is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.

[0116] In some embodiments, the compound disclosed herein is be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.

[0117] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0118] Combination Treatments

[0119] In certain instances, it is appropriate to administer at least one compound disclosed herein in combination with another therapeutic agent.

[0120] In one specific embodiment, a compound disclosed herein is co-administered with a second therapeutic agent, wherein the compound disclosed herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0121] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[0122] If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms.

[0123] Definitions

[0124] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0125] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0126] “Oxo” refers to the =0 substituent.74QB\184200.00266\99637562.4VVID 754PC

[0127] “Alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, Ci-Cw alkyl, C1-C9 alkyl, Ci-C8alkyl, C1-C7 alkyl, Ci-C6alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8alkyl, Cs-Cs alkyl and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, w-propyl, 1-methylethyl (z-propyl), w-butyl, z-butyl, s-butyl. w-pentyl, 1,1 dimethylethyl ( / -butyl). 3- methylhexyl, 2-methylhexyl, 1 -ethyl -propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below.

[0128] “Alkylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0129] “Alkoxy” refers to a radical of the formula OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.

[0130] “Alkylamino” refers to a radical of the formula -NHR or -NRR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0131] The term “aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0132] “Aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.

[0133] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example,75QB\184200.00266\99637562.4VVID 754PC in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to:an e e.

[0134] “Cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. In some embodiments, a cycloalkyl is a C3-C, cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic or polycyclic. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, bicyclo [1.1. l]pentyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, bicyclo [2. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo [2.2.2] octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbomyl, decalinyl and adamantyl. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cyclcoalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the cycloalkyl is bicyclic. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups. In some embodiments, cycloalkyl groups are selected from among spiro[2.2]pentyl, bicyclo [1.1.1] pentyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, bicyclo [2. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo [2.2.2] octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbomyl, 3,4-dihydronaphthalen-l(2H)-one and decalinyl. In some embodiments, the cycloalkyl is polycyclic. Polycyclic radicals include, for example, adamantyl, and. In some embodiments, the polycyclic cycloalkyl is adamantyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

[0135] “Fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

[0136] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.76QB\184200.00266\99637562.4VVID 754PC

[0137] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2trifluoroethyl, l,2difluoroethyl, 3bromo2fluoropropyl, l,2dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0138] “Haloalkoxy” refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2trifluoroethoxy, l,2difluoroethoxy, 3bromo2fluoropropoxy, l,2dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0139] “Heterocycloalkyl” refers to a stable 3 to 14 membered nonaromatic ring radical comprising 2 to 10 carbon atoms and from one to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic ring (which may include a fused bicyclic heterocycloalkyl (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), bridged heterocycloalkyl or spiro heterocycloalkyl), or polycyclic. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic. In some embodiments, the heterocycloalkyl is bicyclic. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, loxothiomorpholinyl, l,ldioxothiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0140] “Heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,77QB\184200.00266\99637562.4VVID 754PC tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C-C hctcroaryl. In some embodiments, monocyclic heteroaryl is a Ci- C hctcroaryl. In some embodiments, monocyclic heteroaryl is a 5 -membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C, -C hctcroaiy l.

[0141] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-Cealkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO2alkyl, nitro, and amino, including mono and disubstituted amino groups (e.g., - NH2, -NHR, -NR2), and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NH(CHs), - N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0142] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:78QB\184200.00266\99637562.4VVID 754PC

[0143] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0144] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see,79QB\184200.00266\99637562.4VVID 754PC e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0145] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0146] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0147] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.EXAMPLES

[0148] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0149] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0150] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions,80QB\184200.00266\99637562.4VVID 754PCVolumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized.

[0151] AbbreviationsDCM: DichloromethaneDIEA: DiisopropylethylamineDMAP 4-(Dimethylamino)pyridineDMF: Dimethyl formamideDMSO: Dimethyl sulfoxideEA or EtOAc: Ethyl acetateESI: Electrospray ionizationHPLC: High performance liquid chromatographyHRMS: High resolution mass spectrometry h or hr(s): Hour(s)MeOH: MethanolMs: Mesyl, or methanesulfonyl min(s): Minutes m / z: Mass-to-charge ratio'H NMR: Proton nuclear magnetic resonance13C NMR: Carbon nuclear magnetic resonancePE: Petroleum ether rt: Room temperatureTLC: Thin layer chromatographyTFA: Trifluoroacetic acidGeneral Procedure 1

[0152] Synthesis of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l-carboxylate81QB\184200.00266\99637562.4VVID 754PCmixture of trans- and c / s-racemate

[0153] Step 1. 2-bromo-4-chloro-6-iodopyridine

[0154] To a solution of 2-bromo-4-chloropyridine (10.0 g, 52.0 mmol) in THF (100 mL) was added TMP MgCl LiCl (62.0 mL, 62.4 mmol) dropwise at 0 °C under N2. The reaction mixture was stirred for1 hour at 20 °C. Then, L (15.8 g, 62.4 mmol) was added at 0 °C and the reaction mixture was stirred for 2 hours at 0 °C. The mixture was quenched with saturated aqueous NH4CI (500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with Na2SOs (200 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-5% EtOAc / petroleum ether) and preparative HPLC (Welch Xtimate Cl 8, 250 x 70 mm, 10 pm; 38-84% ACN / H2O (10 mM NELHCOs)) to give 2-bromo-4-chloro-6-iodopyridine (6.50 g, 20.4 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.74 (d, J= 1.6 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H).

[0155] Step 2. tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpyrrolidine-l- carboxylate

[0156] To a solution of 2-bromo-4-chloro-6-iodopyridine (5.00 g, 15.7 mmol) in iPr2O (50 mL) was added iPrMgCl LiCl (15.0 mL, 20.4 mmol) dropwise at -20 °C. The reaction mixture was stirred at -20 °C for 1 hour. Then, a solution of tert-butyl 2-methyl-3-oxopyrrolidine-l-carboxylate (3.00 g, 15.7 mmol) in iPr2O (10 mL) was added dropwise at -20 °C and stirred at 25 °C for 2 hours. The mixture was poured into the saturated aqueous NH4CI (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 20-30% EtOAc / petroleum ether) to give tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpyrrolidine-l -carboxylate (2.10 g, 5.36 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.47 (d, J= 1.2 Hz, 1H), 7.39 (d, J = 1.2 Hz, 1H), 4.05 - 3.81 (m, 2H), 3.75 - 3.66 (m, 1H), 3.64 - 3.55 (m, 1H), 2.35 - 2.23 (m, 1H), 2.17 - 2.06 (m, 1H), 1.50 - 1.47 (m, 9H), 1.23 (d, J= 6.4 Hz, 3H).

[0157] Step 3. tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methyl-3-(((methylthio)carbono- thioyl)oxy)pyrrolidine-l-carboxylate82QB\184200.00266\99637562.4VVID 754PC

[0158] To a solution of tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpyrrolidine-l- carboxylate (2.10 g, 5.36 mmol) in THF (25 mb) was added CS2 (1.72 g, 43.0 mmol) dropwise at 0 °C and stirred at 25 °C for 30 minutes. Then, NaH (4.09 g, 53.8 mmol) was added at 25 °C and stirred at 25 °C for 50 minutes. CH3I (9.15 g, 64.5 mmol) was added to the reaction mixture and stirred at 25 °C for 2 hours under N2. The mixture was poured into the saturated aqueous NH4CI (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-10% Ethyl acetate / petroleum ether) to give tert-butyl 3-(6-bromo-4- chloropyridin-2-yl)-2-methyl-3-(((methylthio)carbono-thioyl)oxy)pyrrolidine-l-carboxylate (2.30 g, 4.78 mmol) as yellow solid. 'H NMR (400 MHz, CDCk) 5 ppm 7.39 (d, J= 1.6 Hz, 1H), 7.20 (d, J= 1.6 Hz, 1H), 4.67 - 4.55 (m, 1H), 3.49 - 3.33 (m, 2H), 2.79 (br d, J= 8.0 Hz, 2H), 2.53 (s, 3H), 1.49 (s, 9H), 1.34 (br d, J = 6.4 Hz, 3H).

[0159] Step 4. cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l-carboxylate

[0160] To a solution of tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methyl-3- (((methylthio)carbono-thioyl)oxy)pyrrolidine-l -carboxylate (2.20 g, 4.56 mmol) in toluene (25 mL) was added (n-Bu)3SnH (1.44 g, 4.94 mmol) and AIBN (1.12 g, 6.84 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 2 hours under N2. The mixture was diluted with water (25 mL) and extracted with EtOAc (35 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) and preparative HPLC (Agela DuraShell Cl 8, 250 x 70 mm, 10 pm; 55-90% ACN / H2O (10 mM NH4HCO3)) to give cis tert-butyl 3-(6-bromo-4- chloropyridin-2-yl)-2-methylpyrrolidine-l -carboxylate (830 mg, 2.21 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.41 (s, 1H), 7.14 (s, 1H), 4.31 (br d, J= 5.2 Hz, 1H), 3.64 - 3.34 (m, 3H), 2.59 - 2.34 (m, 1H), 2.19 - 2.09 (m, 1H), 1.48 (s, 9H), 0.80 (br s, 3H).

[0161] Step 5. Mixture of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine- 1-carboxylate and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate

[0162] To a solution of cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate (830 mg, 2.21 mmol) in MeCN (10 mL) was added DBU (336 mg, 2.20 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 12 hours under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to give a mixture of trans tert-butyl 3- (6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l-carboxylate and cis tert-butyl 3-(6-bromo-4- chloropyridin-2-yl)-2-methylpyrrolidine-l -carboxylate (750 mg, 2.00 mmol) as white solid.83QB\184200.00266\99637562.4VVID 754PCGeneral Procedure 2

[0163] Synthesis of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l-carboxylate

[0164] Step 1. ethyl (E)-3-(6-bromo-4-chloropyridin-2-yl)acrylate

[0165] To a solution of 2,6-dibromo-4-chloropyridine (5.00 g, 18.4 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (4.99 g, 22.1 mmol), K2CO3 (6.36 g, 46.1 mmol) and Pd(dppf)C12 (1.33 g, 1.84 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 4 hours under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to give ethyl (E)-3-(6-bromo-4-chloropyridin-2- yl)acrylate (3.10 g, 10.7 mmol) as white solid. 'H NMR (400 MHz, CDCI3) 5 ppm 7.57 - 7.45 (m, 2H), 7.35 (d, J= 1.6 Hz, 1H), 6.98 (d, J= 15.6 Hz, 1H), 4.35 - 4.21 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H).

[0166] Step 2. ethyl 3-(6-bromo-4-chloropyridin-2-yl)-4-nitropentanoate

[0167] To a solution of nitroethane (3.55 g, 47.3 mmol) in THF (50 mL) was added CS2CO3 (1.40 g, 4.30 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under N2. The, (E)-3-(6- bromo-4-chloropyridin-2-yl)acrylate (2.50 g, 8.60 mmol) dissolved in THF (25 mL) was added at 0 °C. The mixture reaction was stirred at 25 °C for 12 hours under N2. The mixture was diluted with water (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to give ethyl 3-(6-bromo-4-84QB\184200.00266\99637562.4VVID 754PC chloropyridin-2-yl)-4-nitropentanoate (2.20 g, 6.02 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.51 - 7.34 (m, 1H), 7.25 - 7.09 (m, 1H), 5.09 - 4.83 (m, 1H), 4.14 - 4.02 (m, 2H), 3.89 - 3.57 (m, 1H), 3.32 - 3.00 (m, 1H), 2.97 - 2.55 (m, 1H), 1.74 - 1.62 (m, 2H), 1.38 (d, J= 6.4 Hz, 1H), 1.31 - 1.21 (m, 3H).

[0168] Step 3. ethyl 3-(6-bromo-4-chloropyridin-2-yl)-4-nitropentanoate

[0169] To a solution of ethyl 3-(6-bromo-4-chloropyridin-2-yl)-4-nitropentanoate (1.70 g, 4.64 mmol) in EtOH (30 mL) and water (7.5 mL) was added NH4CI (2.48 g, 46.49 mmol) and iron powder (1.29 g, 23.24 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was filtered, diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude ethyl 4-amino-3- (6-bromo-4-chloropyridin-2-yl)pentanoate (1.25 g, 3.72 mmol) as yellow oil.

[0170] Step 4. Mixture of trans 4-(6-bromo-4-chloropyridin-2-yl)-5-methylpyrrolidin-2-one and cis 4-(6-bromo-4-chloropyridin-2-yl)-5-methylpyrrolidin-2-one

[0171] To a solution of ethyl 4-amino-3-(6-bromo-4-chloropyridin-2-yl)pentanoate (1.70 g, 5.06 mmol) in MeOH (10 mL) was added TEA (769 mg, 7.59 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 36 hours. The mixture was concentrated under reduced pressure, diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 50-100% EtOAc / petroleum ether) to give a mixture of trans 4-(6-bromo-4-chloropyridin-2-yl)-5-methylpyrrolidin-2-one and cis 4-(6-bromo-4-chloropyridin-2-yl)-5- methylpyrrolidin-2-one (640 mg, 2.21 mmol) as brown oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.37 (t, J = 1.6 Hz, 2H), 7.13 - 7.03 (m, 2H), 5.96 (br d, J= 15.6 Hz, 2H), 4.12 - 4.04 (m, 2H), 3.96 - 3.89 (m, 1H), 3.82 (d, J= 8.0 Hz, 1H), 3.20 - 3.08 (m, 1H), 2.89 - 2.81 (m, 1H), 2.80 - 2.72 (m, 1H), 2.68 - 2.61 (m, 1H), 2.60 - 2.50 (m, 1H), 1.23 (d, J= 6.4 Hz, 3H), 0.80 (d, J= 6.4 Hz, 2H).

[0172] Step 5. Mixture of trans 2-bromo-4-chloro-6-(2-methylpyrrolidin-3-yl)pyridine and cis 2- bromo-4-chloro-6-(2-methylpyrrolidin-3-yl)pyridine

[0173] To a mixture of trans 4-(6-bromo-4-chloropyridin-2-yl)-5-methylpyrrolidin-2-one and cis 4-(6- bromo-4-chloropyridin-2-yl)-5-methylpyrrolidin-2-one (400 mg, 1.38 mmol) in THE (8 mL) was added BH3 THF (8471 mg, 9.66 mmol) at 0 °C. The mixture was stirred at 25 °C for 30 minutes and at 70 °C for 6 hours. The reaction mixture was quenched by MeOH (10 mL) and HCl / MeOH (4 M, 2 mL) at 0 °C. The mixture was stirred at 25 °C for 30 minutes and at 70 °C for 10 hours. The mixture was concentrated under reduced pressure to give a mixture of trans 2-bromo-4-chloro-6-(2-methylpyrrolidin-3-yl)pyridine and cis 2-bromo-4-chloro-6-(2-methylpyrrolidin-3-yl)pyridine (380 mg, 1.38 mmol) as yellow oil.85QB\184200.00266\99637562.4VVID 754PC

[0174] Step 6. Mixture of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine- 1-carboxylate and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate

[0175] To a mixture of trans 2-bromo-4-chloro-6-(2-methylpyrrolidin-3-yl)pyridine and cis 2-bromo- 4-chloro-6-(2-methylpyrrolidin-3-yl)pyridine in MeOH (3 mL) was added TEA (279 mg, 2.75 mmol) and BOC2O (451 mg, 2.06 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-20% EtOAc / petroleum ether) to give a mixture of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 3 -(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l -carboxylate (260 mg, 0.69 mmol) as yellow oil.

[0176] Step 7. trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate

[0177] To a mixture of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 3 -(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l -carboxylate (260 mg, 0.69 mmol) in MeCN (10 mL) was added DBU (105 mg, 0.690 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 24 hours under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to give trans tert-butyl 3-(6-bromo-4- chloropyridin-2-yl)-2-methylpyrrolidine-l -carboxylate (200 mg, 0.53 mmol) (ratio trans: cis = 5: 1) as yellow oil. 'H NMR (400 MHz, CD3OD) 5 ppm 7.57 (d, J= 1.6 Hz, 1H), 7.38 (d, J= 1.6 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.71 - 3.60 (m, 1H), 3.46 - 3.35 (m, 1H), 3.17 (br d, J= 3.6 Hz, 1H), 2.35 - 2.23 (m, 1H), 2.13 - 2.04 (m, 1H), 1.48 (s, 9H), 1.30 (d, J = 6.4 Hz, 3H).General Procedure 3

[0178] Synthesis of tert-butyl (2R,3R)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2- methylpyrrolidine-l-carboxylate and tert-butyl (2S,3S)-3-(6-bromo-4-chloropyridin-2-yl)-3- hydroxy-2-methylpyrrolidine-l-carboxylate

[0179] 2-bromo-4-chloro-6-iodopyridine was obtained as described in General Procedure 1, step 1.86QB\184200.00266\99637562.4VVID 754PC

[0180] Step 1. trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpyrrolidine- 1-carboxylate

[0181] To a solution of 2-bromo-4-chloro-6-iodopyridine (5.00 g, 15.7 mmol) in IPE (50 mL) was added iPrMgCl LiCl (15.7 mL, 20.4 mmol, 1.3 M in THF) dropwise at -20 °C. The reaction mixture was stirred at -20 °C for 1 hour. Then, a solution of tert-butyl 2-methyl-3-oxopyrrolidine-l -carboxylate (3.13 g, 15.7 mmol) in IPE (10 mL) was added dropwise at -20 °C and stirred at 25 °C for 2 hours. The mixture was poured into saturated aqueous NH4CI (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give crude trans tert-butyl 3 -(6-bromo-4-chloropyridin-2-yl)-3 -hydroxy-2 - methylpyrrolidine- 1 -carboxylate .

[0182] Step 2. Separation of tert-butyl (2R,3R)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2- methylpyrrolidine-l-carboxylate and tert-butyl (2S,3S)-3-(6-bromo-4-chloropyridin-2-yl)-3- hydroxy-2-methylpyrrolidine-l-carboxylate

[0183] The crude racemic trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2- methylpyrrolidine-1 -carboxylate was separated by SFC (DAICEL CHIRALCEL OJ, 250 x 50 mm, 10 pm; 15% EtOH / CCL). The first eluting isomer was randomly assigned as tert-butyl (2R,3R)-3-(6-bromo- 4-chloropyridin-2-yl)-3-hydroxy-2-methylpyrrolidine-l-carboxylate (830 mg, 2.12 mmol) and was obtained as yellow solid: 'H NMR (400 MHz, CDCh) 57.46 (d, J= 1.5 Hz, 1H), 7.38 (d, J= 1.5 Hz, 1H), 3.98 - 3.85 (m, 2H), 3.75 - 3.64 (m, 1H), 3.64 - 3.52 (m, 1H), 2.35 - 2.22 (m, 1H), 2.18 - 2.04 (m, 1H), 1.48 (s, 9H), 1.23 (d, J= 6.4 Hz, 3H). The second eluting isomer was randomly assigned as tertbutyl (2S,3S)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpyrrolidine-l-carboxylate (880 mg, 2.25 mmol) and was obtained as yellow solid: 'H NMR (400 MHz, CDCh) 57.46 (d, J= 1.5 Hz, 1H), 7.38 (d, J= 1.5 Hz, 1H), 3.97 - 3.81 (m, 2H), 3.75 - 3.64 (m, 1H), 3.64 - 3.54 (m, 1H), 2.33 - 2.23 (m, 1H), 2.15 - 2.05 (m, 1H), 1.48 (s, 9H), 1.23 (d, J= 6.4 Hz, 3H).General Procedure 4

[0184] Synthesis of tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)pyrrolidine-l-carboxylate

[0185] Step 1. 2-bromo-6-chloro-4-iodopyridine

[0186] To a solution of 2-bromo-6-chloropyridine (100 g, 520 mmol) in THF (1000 mL) was addedTMPMgCl LiCl (572 mL, 572 mmol) dropwise at 0 °C under N2. The mixture was stirred for 1 hour at 2087QB\184200.00266\99637562.4VVID 754PC°C. The mixture was cooled to 0 °C and I2 (145 g, 572 mmol) was added. The reaction mixture was stirred for 2 hours at 0 °C. This reaction was repeated two other times, beginning with 30g of 2-bromo-6- chloropyridine. All these reaction mixtures were combined by pouring into aqueous NH4CI (1000 mL). The resulting mixture was extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (1000 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was triturated with MTBE (300 mL) at 25 °C for 2 hours and filtered. The filter cake was washed with 100 mL MTBE and then dried under reduced pressure to give 2-bromo-6-chloro-4- iodopyridine (98 g, 308 mmol) as white solid. 'H NMR (400MHz, CDCI3) 5 ppm 7.86 - 7.80 (m, 1H), 7.72 - 7.66 (m, 1H).

[0187] Step 2. tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate

[0188] To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH- pyrrole-1 -carboxylate (1.55 g, 5.25 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added 2-bromo- 6-chloro-4-iodopyridine (1.59 g, 5.00 mmol), K2CO3 (1.73 g, 12.5 mmol) and Pd(dppf)C12 (0.181 g, 0.250 mmol). The reaction mixture was stirred at 75 °C for 12 hours. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2,5- dihydro-lH-pyrrole-1 -carboxylate (1347 mg, 3.75 mmol) as white solid. LCMS [M+H]+: 359 / 361, Retention Time: 2.748 min (Method 2).

[0189] Step 3. tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)pyrrolidine-l-carboxylate

[0190] In an autoclave, a mixture of tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2,5-dihydro-lH- pyrrole-1 -carboxylate (690 mg, 1.92 mmol) and PtO2 (21.8 mg, 0.096 mmol) in MeOH (4 mL) was stirred under EE-atmosphere (40 psi) for 4 hours at room temperature. The reaction mixture was filtered over Celite and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) give tert-butyl 3-(2-bromo-6-chloropyridin-4- yl)pyrrolidine-l -carboxylate (88.5 mg, 0.245 mmol) as colorless oil. LCMS [M+H]+: 361 / 363, Retention Time: 2.743 min (Method 2).General Procedure 5

[0191] Synthesis of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l-carboxylate88QB\184200.00266\99637562.4VVID 754PC

[0192] Step 1. l-(2-bromo-6-chloropyridin-4-yl)propan-2-one

[0193] To a solution of 2-bromo-6-chloro-4-methylpyridine (30.0 g, 145 mmol) in THF (300 mL) was added LDA (145 mL, 291 mmol) slowly at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour under N2. N-methoxy-N-methylacetamide (36.0 g, 349 mmol) in THF (50 mL) was added at -78 °C. The reaction mixture was allowed to warm to 0 °C and stirred at 0 °C for 1 hour. The mixture was poured into saturated aqueous NH4CI (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-18% EtOAc / petroleum ether) to give l-(2-bromo-6-chloropyridin-4-yl)propan-2-one (28.4 g, 114 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 ppm 7.27 (s, 1H), 7.14 (s, 1H), 3.71 (s, 2H), 2.26 (s, 3H).

[0194] Step 2. tert-butyl (3-(2-bromo-6-chloropyridin-4-yl)-4-oxopentyl)carbamate

[0195] To a solution of l-(2-bromo-6-chloropyridin-4-yl)propan-2-one (14.0 g, 56.3 mmol) in DMF (140 mL) was added CS2CO3 (23.9 g, 73.2 mmol) at 0 °C and the mixture was stirred at 0 °C for 30 minutes. Then, tert-butyl (2-bromoethyl)carbamate (13.9 g, 62.0 mmol) and Nal (9.29 g, 62.0 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-30% EtOAc / petroleum ether) to give tert-butyl (3-(2-bromo-6-chloropyridin-4- yl)-4-oxopentyl)carbamate (14.6 g, 37.3 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.31 (d, J= 1.2 Hz, 1H), 7.18 (d, J= 1.2 Hz, 1H), 4.57 (br s, 1H), 3.75-3.71 (m, 1H), 3.16 - 3.01 (m, 2H), 2.35 - 2.27 (m, 1H), 2.16 (s, 3H), 1.79 - 1.70 (m, 1H), 1.44 (s, 9H).

[0196] Step 3. 2-bromo-6-chloro-4-(5-methyl-3,4-dihydro-2H-pyrrol-4-yl)pyridine

[0197] To a solution of tert-butyl (3-(2-bromo-6-chloropyridin-4-yl)-4-oxopentyl)carbamate (14.6 g,37.3 mmol) was added DCM (150 mL) and TFA (100 mL) at 25 °C. The reaction mixture was stirred at89QB\184200.00266\99637562.4VVID 754PC25 °C for 30 minutes under N2. The mixture was concentrated under reduced pressure to give 2-bromo-6- chloro-4-(5-methyl-3,4-dihydro-2H-pyrrol-4-yl)pyridine (10.1 g, 36.9 mmol) as yellow oil and used into the next step without further purification.

[0198] Step 4. trans 2-bromo-6-chloro-4-2-methylpyrrolidin-3-yl)pyridine and cis 2-bromo-6- chloro-4-2-methylpyrrolidin-3-yl)pyridine

[0199] To a solution of 2-bromo-6-chloro-4-(5-methyl-3,4-dihydro-2H-pyrrol-4-yl)pyridine (9.00 g, 32.9 mmol) in MeOH (100 mL) was added NaBEL (6.22 g, 164 mmol) at 0 °C in small portions under N2. The reaction mixture was stirred at 25 °C under N2 for 1 hour. The mixture was poured into 1 N HC1 (60 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a mixture of trans 2-bromo-6-chloro-4-2- methylpyrrolidin-3-yl)pyridine and cis 2-bromo-6-chloro-4-2-methylpyrrolidin-3-yl)pyridine (9.00 g, 32.7 mmol) as yellow oil and used into the next step without purification.

[0200] Step 5. trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l-carboxylate

[0201] To a mixture of trans 2-bromo-6-chloro-4-2-methylpyrrolidin-3-yl)pyridine and cis 2-bromo- 6-chloro-4-2-methylpyrrolidin-3-yl)pyridine (9.00 g, 32.7 mmol) in MeOH (100 mL) was added BOC2O (9.23 g, 42.3 mmol) and DIPEA (7.37 mL, 42.31 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 5 hours. The mixture was diluted water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-5% EtOAc / petroleum ether) to give trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l-carboxylate (2.60 g, 6.92 mmol) as yellow solid:XH NMR (400 MHz, CDCh) 5 ppm 7.25 (d, J= 1.2 Hz, 1H), 7.12 (d, J= 1.2 Hz, 1H), 3.84 (br s, 1H), 3.65 (br s, 1H), 3.47 - 3.38 (m, 1H), 2.98 -2.83 (m, 1H), 2.34 - 2.23 (m, 1H), 1.95 - 1.83 (m, 1H), 1.49 (s, 9H), 1.29 (d, J= 6.4 Hz, 3H), and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- methylpyrrolidine-1 -carboxylate (1.20 g, 3.19 mmol) as yellow oil: 'H NMR (400 MHz, CDCh) 5 ppm 7.27 - 7.25 (m, 1H), 7.16 - 7.11 (m, 1H), 4.41 - 4.09 (m, 1H), 3.61 (br s, 1H), 3.51 - 3.31 (m, 2H), 2.32 - 2.19 (m, 1H), 2.19 - 2.08 (m, 1H), 1.50 - 1.45 (m, 9H), 0.82 (br s, 3H).General Procedure 6

[0202] Synthesis of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylate90QB\184200.00266\99637562.4VVID 754PC

[0203] 6-chloro-N-methylpyrimidine-4-carboxamide was obtained as described in General Procedure28, step 2.

[0204] Step 1. l-(2-bromo-6-chloropyridin-4-yl)-3-methoxypropan-2-one

[0205] To a solution of 2-bromo-6-chloro-4-methylpyridine (50.0 g, 242 mmol) in THF (500 mL) was added LDA (191 g, 484 mmol) slowly at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour under N2. Then, N,2-dimethoxy-N-methylacetamide (77.3 g, 581 mmol) in THF (80 mL) was added at - 78 °C. The reaction mixture was allowed to warm to 0 °C and stirred at 0 °C for 1 hour under N2. The mixture was poured into saturated aqueous NH4CI (500 mL) and extracted with EtOAc (500mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-12% EtOAc / petroleum ether) to give l-(2-bromo-6-chloropyridin-4-yl)-3-methoxypropan-2-one (33.0 g, 118 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 ppm 7.34 - 7.29 (m, 1H), 7.20 - 7.16 (m, 1H), 4.12 - 4.01 (m, 2H), 3.88 - 3.79 (m, 2H), 3.50 - 3.43 (m, 3H).

[0206] Step 2. tert-butyl (3-(2-bromo-6-chloropyridin-4-yl)-5-methoxy-4-oxopentyl)carbamate

[0207] To a solution of l-(2-bromo-6-chloropyridin-4-yl)-3-methoxypropan-2-one (30.0 g, 108 mmol) in DMF (300 mL) was added CS2CO3 (45.6 g, 140 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes under N2. Then, tert-butyl (2-iodoethyl)carbamate (36.2 g, 162 mmol) and Nal (17.7 g, 118 mmol) at 0 °C. The reaction mixture was stirred at 40 °C for 12 hours under N2. The mixture was poured into saturated aqueous NaCl (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced91QB\184200.00266\99637562.4VVID 754PC pressure. The crude product was purified by column chromatography (SiC>2, 20-30% EtOAc / petroleum ether) to give tert-butyl (3-(2-bromo-6-chloropyridin-4-yl)-5-methoxy-4-oxopentyl)carbamate (33.00 g, 78.30 mmol) as yellow oil. 'H NMR (400 MHz, DMSO-d6) 5 ppm 7.59 - 7.55 (m, 1H), 7.48 - 7.45 (m, 1H), 6.83 - 6.76 (m, 1H), 4.20 - 4.16 (m, 2H), 3.30 - 3.28 (m, 1H), 3.24 - 3.22 (m, 3H), 2.92 - 2.69 (m, 2H), 2.14 - 2.01 (m, 1H), 1.85 - 1.72 (m, 1H), 1.37 - 1.35 (m, 9H).

[0208] Step 3. 2-bromo-6-chloro-4-(5-(methoxymethyl)-3,4-dihydro-2H-pyrrol-4-yl)pyridine

[0209] To a solution of tert-butyl (3-(2-bromo-6-chloropyridin-4-yl)-5-methoxy-4- oxopentyl)carbamate (33.0 g, 78.3 mmol) in DCM (200 mb) was added TFA (200 mb) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated under reduced pressure to give 2-bromo-6-chloro-4-(5-(methoxymethyl)-3,4-dihydro-2H-pyrrol-4-yl)pyridine (23.0 g, 75.6 mmol) as yellow solid.

[0210] Step 4. Mixture of trans 2-bromo-6-chloro-4-(2-(methoxymethyl)pyrrolidin-3-yl)pyridine and cis 2-bromo-6-chloro-4-(2-(methoxymethyl)pyrrolidin-3-yl)pyridine

[0211] To a solution of 2-bromo-6-chloro-4-(5-(methoxymethyl)-3,4-dihydro-2H-pyrrol-4-yl)pyridine (23.0 g, 75.8 mmol) in MeOH (250 mb) was added NaBFU (15.1 g, 379 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes under N2. The mixture was quenched with IN HCl / MeOH (until pH = 7), filtered and concentrated under reduced pressure to give a mixture of trans 2-bromo-6- chloro-4-(2-(methoxymethyl)pyrrolidin-3-yl)pyridine and cis 2-bromo-6-chloro-4-(2- (methoxymethyl)pyrrolidin-3-yl)pyridine (22.0 g, 72.0 mmol) as yellow oil.

[0212] Step 5. Mixture of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylate

[0213] To a mixture of trans 2-bromo-6-chloro-4-(2-(methoxymethyl)pyrrolidin-3-yl)pyridine and cis 2-bromo-6-chloro-4-(2-(methoxymethyl)pyrrolidin-3-yl)pyridine (22.0 g, 72.0 mmol) in MeOH (200 mb) was added BOC2O (31.4 g, 144 mmol) and TEA (25.0 mL, 144 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 12-15% EtOAc / petroleum ether) to give a mixture of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-(methoxymethyl)pyrrolidine-l- carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-(methoxymethyl)pyrrolidine-l- carboxylate (20.0 g, 49.2 mmol) as white solid: 'H NMR (400 MHz, DMSO-de) 5 ppm 7.69 - 7.65 (m, 1H), 7.59 - 7.56 (m, 1H), 7.55 - 7.51 (m, 1H), 7.48 - 7.41 (m, 1H), 4.19 - 4.06 (m, 1H), 3.93 - 3.80 (m, 1H), 3.62 - 3.44 (m, 4H), 3.32 - 3.29 (m, 3H), 3.28 - 3.20 (m, 5H), 3.01 - 2.85 (m, 4H), 2.44 - 2.34 (m, 1H), 2.31 - 2.14 (m, 1H), 2.O1 (br s, 1H), 1.96 - 1.83 (m, 1H), 1.42 (d, J = 3.2 Hz, 18H).92QB\184200.00266\99637562.4VVID 754PC

[0214] Step 6. Mixture of trans tert-butyl 3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-4-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate and cis tert-butyl 3-(2-chloro-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)-2-(methoxymethyl)pyrrolidine-l- carboxylate

[0215] To a solution of mixture of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l -carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l -carboxylate (3.00 g, 7.39 mmol) in 1,4-dioxane (40 mL) was added Pin2B2 (2.81 g, 11.0 mmol), KOAc (1.40 g, 14.8 mmol) and Pd(dppf)C12'DCM (603 mg, 0.73 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give mixture of trans tert-butyl 3-(2-chloro-6-(4, 4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-4-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate and cis tert-butyl 3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l -carboxylate (3.30 g, 7.29 mmol) as brown oil.

[0216] Step 7. trans tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylate and cis tert-butyl 3-(2-chloro-6-(6-(methyl- carbamoyl)pyrimidin-4-yl)pyridin-4-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate

[0217] To a mixture of trans tert-butyl 3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-4-yl)-2-(methoxymethyl)pyrrolidine-l-carboxylate and cis tert-butyl 3-(2-chloro-6-(4, 4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-4-yl)-2-(methoxymethyl)pyrrolidine- 1 -carboxylate (3.30 g, 7.29 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was added 6-chloro-N-methylpyrimidine-4- carboxamide (1.20 g, 7.28 mmol), K2CO3 (2.00 g, 14.5 mmol) and Pd(dppf)C12 (527 mg, 0.720 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 30-50% EtOAc / petroleum ether) and by SFC (DAICEL CHIRALCEL OX, 250 x 30 mm, 10 pm; 40% MeOH (0.1%NH3H2O) / CO2) to give racemic trans tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)-2- (methoxymethyl)pyrrolidine- 1 -carboxylate (2.00 g, 4.33 mmol) as yellow solid: 'H NMR (400 MHz, CDCh) 5 ppm 9.23 (d, J= 0.8 Hz, 1H), 9.16 - 9.02 (m, 1H), 8.36 - 8.28 (m, 1H), 8.02 - 7.91 (m, 1H), 7.32 - 7.28 (m, 1H), 4.20 - 4.01 (m, 1H), 3.78 - 3.54 (m, 4H), 3.50 - 3.42 (m, 1H), 3.40 - 3.35 (m, 3H), 3.13 - 3.04 (m, 3H), 2.49 - 2.32 (m, 1H), 1.98 (br d, J= 6.0 Hz, 1H), 1.52 (s, 9H), and racemic cis tert- butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)-2-(methoxymethyl)pyrrolidine-l- carboxylate (210 mg, 0.430 mmol) as yellow solid: 'H NMR (400 MHz, CDCh) 5 ppm 9.26 (s, 1H), 9.12 (s, 1H), 8.39 (s, 1H), 8.01 (br d, J= 4.4 Hz, 1H), 7.43 (s, 1H), 4.26 - 4.03 (m, 1H), 3.72 - 3.42 (m,93QB\184200.00266\99637562.4VVID 754PC4H), 3.10 (d, J= 52 Hz, 3H), 3.07 (s, 3H), 2.98 (br d, J= 10.0 Hz, 1H), 2.77 - 2.52 (m, 1H), 2.20 - 2.08 (m, 1H), 1.50 (s, 9H).General Procedure 7

[0218] Synthesis of tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxypyrrolidine-l- carboxylateBoc

[0219] 2-bromo-6-chloro-4-iodopyridine was obtained as described in General Procedure 4, step 1.

[0220] To a solution of 2-bromo-6-chloro-4-iodopyridine (5.00 g, 15.7 mmol) in toluene (50 mL) was added iPrMgCl LiCl (15.7 mL, 20.4 mmol) dropwise at -20 °C. The reaction mixture was stirred at -20 °C for 1 hour. Then, a solution of tert-butyl 3 -oxopyrrolidine- 1 -carboxylate (2.91 g, 15.7 mmol) in toluene (12 mL) was added dropwise at -20 °C and stirred at -20 °C for 1 hour. The mixture was poured into NH4CI (100 mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-100% EtOAc / petroleum ether) to give tertbutyl 3 -(2-bromo-6-chloropyridin-4-yl)-3 -hydroxypyrrolidine- 1 -carboxylate (3.40 g, 9.00 mmol) as yellow oil.XH NMR (400 MHz, CDCh) 5 ppm 7.57 (d, J= 1.2 Hz, 1H), 7.44 (d,J= 1.1 Hz, 1H), 3.79 - 3.45 (m, 4H), 2.81 - 2.49 (m, 1H), 2.35 - 2.11 (m, 2H), 1.54 - 1.39 (m, 9H).General Procedure 8

[0221] Synthesis of tert-butyl (2R,3S)-3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxy-2- methylpyrrolidine-l-carboxylate and tert-butyl (2S,3R)-3-(2-bromo-6-chloropyridin-4-yl)-3- hydroxy-2-methylpyrrolidine-l-carboxylatestep 1 step 2 trans-racemate absolute stereochemistry randomly assigned

[0222] 2-bromo-6-chloro-4-iodopyridine was obtained as described in General Procedure 4, step 1.

[0223] Step 1. trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxy-2-methylpyrrolidine- 1-carboxylate

[0224] To a solution of 2-bromo-6-chloro-4-iodopyridine (2.00 g, 6.28 mmol) in DCM (20 mL) was added iPrMgCl LiCl (6.28 mL, 8.16 mmol) dropwise at -20 °C. The reaction mixture was stirred at -2094QB\184200.00266\99637562.4VVID 754PC°C for 1 hour. Then, a solution of tert-butyl 2-methyl-3-oxopyrrolidine-l-carboxylate (1.50 g, 7.53 mmol) in DCM (10 mL) was added dropwise at -20 °C and stirred at -20 °C for 2 hours. The mixture was poured into saturated aqueous NH4CI (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over ISfeSCL, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Si O . 20-30% EtOAc / petroleum ether) to give trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxy-2-methylpyrrolidine-l- carboxylate (1.00 g, 2.55 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.53 (d, J = 1.2 Hz, 1H), 7.41 (d, J= 1.2 Hz, 1H), 3.89 (br d, J= 6.0 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.62 - 3.51 (m, 1H), 2.24 - 2.16 (m, 1H), 2.15 - 2.08 (m, 1H), 1.50 (s, 9H), 1.25 (d, J= 6.4 Hz, 3H).

[0225] Step 2. Separation of tert-butyl (2R,3S)-3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxy-2- methylpyrrolidine-l-carboxylate and tert-butyl (2S,3R)-3-(2-bromo-6-chloropyridin-4-yl)-3- hydroxy-2-methylpyrrolidine-l-carboxylate

[0226] The racemic trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxy-2- methylpyrrolidine-1 -carboxylate (1.00 g, 2.55 mmol) was separated by SFC (DAICEL CHIRALPAK IG, 250 x 30 mm, 10 pm; 30% MeOH / CCL). The first eluting isomer was randomly assigned as tert-butyl (2R,3S)-3-(2-bromo-6-chloropyridin-4-yl)-3 -hydroxy-2 -methylpyrrolidine-1 -carboxylate (470 mg, 1.20 mmol) and was obtained as white solid: 'H NMR (400 MHz, CDCh) 5 ppm 7.53 (d, J= 1.2 Hz, 1H), 7.41 (d, J= 1.2 Hz, 1H), 3.89 (br d, J= 6.0 Hz, 1H), 3.69 (br d, J= 2.8 Hz, 1H), 3.62 - 3.53 (m, 1H), 2.24 - 2.18 (m, 1H), 2.15 - 2.09 (m, 1H), 1.50 (s, 9H), 1.25 (d, J= 6.4 Hz, 3H). The second eluting isomer was randomly assigned as tert-butyl (2S,3R)-3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxy-2- methylpyrrolidine-1 -carboxylate (460 mg, 1.17 mmol) and was obtained as white solid: 'H NMR (400 MHz, CDCh) 5 ppm 7.53 (d, J= 1.2 Hz, 1H), 7.41 (d, J= 1.2 Hz, 1H), 3.89 (br d, J= 6.0 Hz, 1H), 3.71 - 3.65 (m, 1H), 3.62 - 3.52 (m, 1H), 2.18 (s, 1H), 2.16 - 2.09 (m, 1H), 1.50 (s, 9H), 1.25 (d, J= 6.4 Hz, 3H).General Procedure 9

[0227] Synthesis of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-4-methylpyrrolidine-l- carboxylatetrans-racemate95QB\184200.00266\99637562.4VVID 754PC

[0228] Step 1. methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate

[0229] To a solution of 2-bromo-6-chloro-4-methylpyridine (5.00 g, 24.2 mmol) in THF (60 mL) was added LDA (24.2 mL, 48.4 mmol) slowly at -75 °C. The reaction mixture was stirred at -75 °C for 1 hour under N2. Dimethyl carbonate (5.23 g, 58.1 mmol) in THF (10 mL) was added to the mixture at -75 °C. The solution was allowed to warm to 0 °C and stirred for 1 hour at 0 °C. The mixture was poured into NH4CI (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography ( Si O2. 0-7% EtOAc / petroleum ether) to give methyl 2- (2-bromo-6-chloropyridin-4-yl)acetate (4.10 g, 15.5 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 ppm 7.38 (s, 1H), 7.25 (s, 1H), 3.74 (s, 3H), 3.60 (s, 2H).

[0230] Step 2. methyl 2-(2-bromo-6-chloropyridin-4-yl)-4-((tert-butoxycarbonyl)amino)-3- methylbutanoate

[0231] To a solution of methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (3.30 g, 12.5 mmol) in DMF (30 mL) was added CS2CO3 (5.28 g, 16.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under N2. Then, tert-butyl N-(2-bromopropyl)carbamate (3.27 g, 13.7 mmol) and Nal (2.06 g, 13.7 mmol) were added at 0 °C. The mixture was stirred at 25 °C for 12 hours under N2. The mixture was poured into saturated aqueous NaCl (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to give methyl 2-(2-bromo-6-chloropyridin-4-yl)-4-((tert- butoxycarbonyl)amino)-3-methylbutanoate (1.40 g, 3.45 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 ppm 7.43 (d, J= 12.4 Hz, 1H) 7.30 (d, J= 13.6 Hz, 1H) 4.78 - 4.32 (m, 1H) 3.79 - 3.70 (m, 4H) 3.43 - 3.28 (m, 1H) 3.20 - 2.92 (m, 2H) 1.50 - 1.41 (m, 9H) 1.10 - 0.69 (m, 3H).

[0232] Step 3. methyl 4-amino-2-(2-bromo-6-chloropyridin-4-yl)-3-methylbutanoate

[0233] To a solution of 2-(2-bromo-6-chloropyridin-4-yl)-4-((tert-butoxycarbonyl)amino)-3- methylbutanoate (1.40 g, 3.59 mmol) in MeOH (10 mL) was added HCl / MeOH(4 M, 10 mL) at 0 °C. The mixture was stirred at 25 °C for 30 minutes under N2. The reaction mixture was concentrated under reduced pressure to give methyl 4-amino-2-(2-bromo-6-chloropyridin-4-yl)-3-methylbutanoate (1.10 g, 3.42 mmol) as yellow solid.

[0234] Step 4. trans 3-(2-bromo-6-chloropyridin-4-yl)-4-methylpyrrolidin-2-one and cis 3-(2- bromo-6-chloropyridin-4-yl)-4-methylpyrrolidin-2-one

[0235] To a solution of methyl 4-amino-2-(2-bromo-6-chloropyridin-4-yl)-3-methylbutanoate (1.10 g, 3.42 mmol) in MeOH (20 mL) was added TEA (0.41 g, 4.13 mmol) at 0 °C. The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure and the crude product was96QB\184200.00266\99637562.4VVID 754PC purified by column chromatography (SiC>2, 80 - 100% EtOAc / petroleum ether) to give trans 3-(2-bromo- 6-chloropyridin-4-yl)-4-methylpyrrolidin-2-one (700 mg, 2.42 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.33 (d, J= 0.8 Hz, 1H) 7.20 (d, J= 0.8 Hz, lH) 5.89 (br s, 1H) 3.72 - 3.49 (m, 1H) 3.20 - 2.99 (m, 2H) 2.66 - 2.48 (m, 1H) 1.21 (d, J= 6.4 Hz, 3H). (only trans product and no cis product)

[0236] Step 5. trans 2-bromo-6-chloro-4-(4-methylpyrrolidin-3-yl)pyridine

[0237] To a solution of trans 3-(2-bromo-6-chloropyridin-4-yl)-4-methylpyrrolidin-2-one (700 mg, 2.42 mmol) in THF (10 mL) was added BH3THF solution (12.1 mb, 12.08 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes and at 70 °C for 16 hours under N2. The mixture was quenched with HCl / MeOH (4 M, 20 mL) at 0 °C, stirred at 25 °C for 30 minutes and at 60 °C for 3 hours under N2. The mixture was filtered and concentrated under reduced pressure to give trans 2-bromo-6- chloro-4-(4-methylpyrrolidin-3-yl)pyridine (666 mg, 2.42 mmol) as yellow oil. 'H NMR (400 MHz, CD3OD) 5 ppm 7.63 (s, lH) 7.51 (s, 1H) 3.82 - 3.65 (m, 3H) 3.14 - 2.91 (m, 3H) 2.51 - 2.43 (m, 1H) 1.07 (d, J = 6.4 Hz, 3H).

[0238] Step 6. trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-4-methylpyrrolidine-l- carboxylate

[0239] To a solution of trans 2-bromo-6-chloro-4-(4-methylpyrrolidin-3-yl)pyridine (666 mg, 2.42 mmol) in DCM (10 mL) was added TEA (367 mg, 3.62 mmol) and BOC2O (633 mg, 2.90 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours under N2. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced. The crude product was purified by column chromatography (SiO3, 0-50% EtOAc / petroleum ether) to give trans tert-butyl 3-(2-bromo-6- chloropyridin-4-yl)-4-methylpyrrolidine-l -carboxylate (700 mg, 1.86 mmol) as yellow oil. 'H NMR (400 MHz, DMSO-d6) 5 ppm 7.72 (s, 1H) 7.62 (s, 1H) 3.75 - 3.56 (m, 2H) 3.28 (td, J= 10.4, 5.2 Hz, 1H) 3.03 - 2.81 (m, 2H) 2.46 - 2.34 (m, 1H) 1.40 (d, J= 7.6 Hz, 9H) 0.87 (br t, J= 5.6 Hz, 3H).General Procedure 10

[0240] Synthesis of trans tert-butyl 4-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 4-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l-carboxylate97QB\184200.00266\99637562.4VVID 754PCmixture of trans- and c / s-racemate

[0241] Methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate was obtained from General Procedure 9, step

[0242] Step 1. methyl 2-(2-bromo-6-chloropyridin-4-yl)-4-((tert- butoxycarbonyl)amino)pentanoate

[0243] To a solution of methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (0.37 g, 1.40 mmol) in DMF (10 mL) was added CS2CO3 (0.59 g, 1.83 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under N2. Then, tert-butyl (l-bromopropan-2-yl)carbamate (0.50 g, 2.11 mmol) and Nal (0.23 g, 1.54 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was poured into saturated aqueous NaCl (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0-30% EtOAc / petroleum ether) to give methyl 2-(2-bromo-6-chloropyridin-4-yl)-4-((tert- butoxycarbonyl)amino)pentanoate (0.72 g, 1.71 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.41 - 7.34 (m, 1H), 7.27 - 7.23 (m, 1H), 4.31 - 4.19 (m, 1H), 3.79 - 3.72 (m, 1H), 3.71 (d, J= 4.8 Hz, 3H), 3.70 - 3.62 (m, 1H), 2.34 - 2.12 (m, 1H), 1.91 - 1.65 (m, 1H), 1.47 - 1.43 (m, 9H), 1.19 - 1.11 (m, 3H).

[0244] Step 2. methyl 4-amino-2-(2-bromo-6-chloropyridin-4-yl)pentanoate

[0245] To a solution of methyl 2-(2-bromo-6-chloropyridin-4-yl)-4-((tert-butoxycarbonyl)amino)- pentanoate (940 mg, 2.20 mmol) in MeOH (3 mL) was added HCl / MeOH (4 M, 10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2 and concentrated under reduced pressure to give crude methyl 4-amino-2-(2-bromo-6-chloropyridin-4-yl)pentanoate (716 mg, 2.23 mmol) as yellow oil. 'H NMR (400 MHz, CD3OD) 5 ppm 7.60 (s, 1H) 7.47 (s, 1H) 3.98 - 3.90 (m, 1H) 3.73 (d, J= 4.0 Hz, 3H) 3.37 - 3.33 (m, 1H) 2.54 - 2.27 (m, 1H) 2.18 - 1.83 (m, 1H) 1.32 (d, J= 6.4 Hz, 3H).98QB\184200.00266\99637562.4VVID 754PC

[0246] Step 3. Mixture of trans 3-(2-bromo-6-chloropyridin-4-yl)-5-methylpyrrolidin-2-one and cis 3-(2-bromo-6-chloropyridin-4-yl)-5-methylpyrrolidin-2-one

[0247] To a solution of methyl 4-amino-2-(2-bromo-6-chloropyridin-4-yl)pentanoate (716 mg, 2.23 mmol) in MeOH (10 mL) was added TEA (270 mg, 2.67 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 12 hours and concentrated under reduced pressure. The crude product was purified by column chromatography (80-100% EtOAc / petroleum ether) to give a mixture of trans 3-(2-bromo-6- chloropyridin-4-yl)-5-methylpyrrolidin-2-one and cis 3-(2-bromo-6-chloropyridin-4-yl)-5- methylpyrrolidin-2-one (470 mg, 1.62 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 ppm 7.44 - 7.39 (m, 1H) 7.30 (s, 1H) 6.14 - 5.96 (m, 1H) 3.98 - 3.81 (m, 1H) 3.77 - 3.62 (m, 1H) 2.78 - 2.37 (m, 1H) 2.30 - 1.72 (m, 1H) 1.38 - 1.30 (m, 3H).

[0248] Step 4. Mixture of trans 2-bromo-6-chloro-4-(5-methylpyrrolidin-3-yl)pyridine and cis 2- bromo-6-chloro-4-(5-methylpyrrolidin-3-yl)pyridine

[0249] To a solution of trans 3-(2-bromo-6-chloropyridin-4-yl)-5-methylpyrrolidin-2-one and cis 3-(2- bromo-6-chloropyridin-4-yl)-5-methylpyrrolidin-2-one (470 mg, 1.62 mmol) in THF (6 mL) was added BH3 THF (7.10 g, 8.11 mmol) at 0 °C. The mixture was stirred at 25 °C for 30 minutes and then at 70 °C for 16 hours under N2. The mixture was quenched with MeOH (30 mL) at 0 °C, stirred at 25 °C for 0.5 hour and then at 70 °C for 4 hours under N2. The mixture was filtered and concentrated under reduced pressure to give a mixture of trans 2-bromo-6-chloro-4-(5-methylpyrrolidin-3-yl)pyridine and cis 2- bromo-6-chloro-4-(5-methylpyrrolidin-3-yl)pyridine (447 mg, 1.62 mmol) as yellow oil which was used in the next step without further purification.

[0250] Step 5. Mixture of trans tert-butyl 4-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine- 1-carboxylate and cis tert-butyl 4-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l- carboxylate

[0251] To a solution of trans 2-bromo-6-chloro-4-(5-methylpyrrolidin-3-yl)pyridine and cis 2-bromo- 6-chloro-4-(5-methylpyrrolidin-3-yl)pyridine (447 mg, 1.62 mmol) in THF (9 mL) and water (6 mL) was added K2CO3 (336 mg, 2.43 mmol) and BOC2O (424 mg, 1.94 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0-20% EtOAc / petroleum ether) to give mixture of trans tert-butyl 4-(2-bromo-6- chloropyridin-4-yl)-2-methylpyrrolidine-l -carboxylate and cis tert-butyl 4-(2-bromo-6-chloropyridin-4- yl)-2-methylpyrrolidine-l -carboxylate (520 mg, 1.38 mmol) (ratio trans: cis = 1: 1) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.29 (s, 2H) 7.16 (s, 2H) 4.18 - 3.72 (m, 4H) 3.42 (br d, J= 6.0 Hz, 1H) 3.23 - 3.13 (m, 2H) 2.54 (dt, J= 12.8, 6.8 Hz, 1H) 2.20 - 2.07 (m, 1H) 2.04 - 1.91 (m, 1H) 1.65 (m, 2H) 1.49 (s, 18H) 1.35 (br d, J= 5.2 Hz, 3H) 1.26 (s, 3H).General Procedure 1199QB\184200.00266\99637562.4VVID 754PC

[0252] Synthesis of 2-bromo-6-chloro-4-((3S,5S)-5-(methoxymethyl)pyrrolidin-3-yl)pyridine

[0253] Methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate was obtained from General Procedure 9, step

[0254] Step 1. tert-butyl (R)-(l-iodo-3-methoxypropan-2-yl)carbamate

[0255] To a solution of tert-butyl (S)-(l -hydroxy-3 -methoxypropan-2-yl)carbamate (12.0 g, 58.5 mmol) in THF (120 mL) was added imidazole (11.9 g, 175 mmol) and PPhs (23.0 g, 87.7 mmol) at 25 °C under N2. Then, a solution of iodine (22.3 g, 87.7 mmol) in THF (20 mL) was added dropwise at 0 °C under N2. The reaction mixture was stirred at 25 °C under N2 for 3 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-50% EtOAc / petroleum ether) to give tert-butyl (R)-(l- iodo-3-methoxypropan-2-yl)carbamate (16.0 g, 50.8 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 4.92 (br s, 1H), 3.72 (br s, 1H), 3.66 - 3.59 (m, 1H), 3.38 (s, 6H), 1.46 (s, 9H).

[0256] Step 2. methyl (4S)-2-(2-bromo-6-chloropyridin-4-yl)-4-((tert-butoxycarbonyl)amino)-5- methoxypentanoate

[0257] To a solution of methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (10.7 g, 40.5 mmol) in DMF (120 mL) was added K2CO3 (7.26 g, 52.6 mmol) and tert-butyl (R)-(l-iodo-3-methoxypropan-2- yl)carbamate (12.7 g, 40.5 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 4 hours under N2. The mixture was diluted with saturated aqueous NaCl (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 20-40% EtOAc / petroleum ether) to give methyl (4S)-2-(2-bromo-6-chloropyridin-4-yl)-4-((tert- butoxycarbonyl)amino)-5-methoxypentanoate (9.40 g, 20.8 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.41 - 7.35 (m, 1H), 7.24 (s, 1H), 4.80 - 4.66 (m, 1H), 3.89 - 3.73 (m, 1H), 3.72 (d, J= 5.6 Hz, 3H), 3.69 - 3.63 (m, 1H), 3.42 - 3.38 (m, 1H), 3.33 (d, J= 8.4 Hz, 4H), 2.42 - 2.24 (m, 1H), 2.00 - 1.81 (m, 1H), 1.46 (d, J = 2.4 Hz, 9H).100QB\184200.00266\99637562.4VVID 754PC

[0258] Step 3. methyl (4S)-4-amino-2-(2-bromo-6-chloropyridin-4-yl)-5-methoxypentanoate

[0259] To a solution of methyl (4S)-2-(2-bromo-6-chloropyridin-4-yl)-4-((tert- butoxycarbonyl)amino)-5-methoxypentanoate (9.40 g, 20.8 mmol) in MeOH (100 mL) was added HCl / MeOH (4 M, 60 mL) at 25 °C. The reaction mixture was stirred at 30 °C for 1 hour. The mixture was concentrated under reduced pressure to give methyl (4S)-4-amino-2-(2-bromo-6-chloropyridin-4-yl)- 5-methoxypentanoate (7.30 g, 20.8 mmol) as yellow oil. 'H NMR (400 MHz, CD3OD) 5 ppm 7.61 - 7.57 (m, 1H), 7.48 - 7.45 (m, 1H), 3.95 (t, J= 7.6 Hz, 1H), 3.73 (d, J= 2.4 Hz, 3H), 3.62 - 3.53 (m, 1H), 3.52- 3.44 (m, 1H), 3.36 (d, J= 9.6 Hz, 4H), 3.27 - 3.14 (m, 1H), 2.55 - 2.37 (m, 1H), 2.06 (br d, J= 8.0 Hz, 1H).

[0260] Step 4. (3S,5S)-3-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)pyrrolidin-2-one

[0261] To a solution of methyl (4S)-4-amino-2-(2-bromo-6-chloropyridin-4-yl)-5-methoxypentanoate (7.30 g, 20.8 mmol) in MeOH (3 mL) was added TEA (2.52 g, 24.9 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 8 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 44-80% EtOAc / petroleum ether) to get (3S,5S)-3-(2-bromo-6-chloropyridin-4- yl)-5-(methoxymethyl)pyrrolidin-2-one (2.85 g, 8.92 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.40 (s, 1H), 7.28 (s, 1H), 6.12 (br s, 1H), 3.98 - 3.84 (m, 1H), 3.73 (t, J= 9.2 Hz, 1H), 3.50 - 3.45 (m, 1H), 3.41 (s, 3H), 3.39 - 3.34 (m, 1H), 2.45 - 2.23 (m, 2H).

[0262] Step 5. 2-bromo-6-chloro-4-((3S,5S)-5-(methoxymethyl)pyrrolidin-3-yl)pyridine

[0263] To a solution of (3S,5S)-3-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)pyrrolidin-2-one (2.85 g, 8.92 mmol) in THF (30 mL) was added BH3 THF (44.6 mL, 44.6 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes and then at 70 °C for 8 hours under N2. The mixture was quenched with MeOH (100 mL) at 0 °C, stirred 25 °C for 30 minutes, and then at 70 °C for 12 hours under N2. The mixture was filtered and concentrated under reduced pressure to give 2-bromo-6-chloro-4- ((3S,5S)-5-(methoxymethyl)pyrrolidin-3-yl)pyridine (2.72 g, 8.90 mmol) as yellow oil. 'H NMR (400 MHz, CD3OD) 5 ppm 7.63 (s, 1H), 7.51 (s, 1H), 4.16 - 4.06 (m, 1H), 4.00 - 3.85 (m, 1H), 3.80 - 3.72 (m, 2H), 3.71 - 3.66 (m, 2H), 3.45 (s, 3H), 2.35 - 2.31 (m, 1H), 2.30 - 2.24 (m, 1H).General Procedure 12

[0264] Synthesis of trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate101QB\184200.00266\99637562.4VVID 754PCstep 5

[0265] 4-bromo-2-chloro-6-iodopyridine was obtained as described in General Procedure 27, step 1.

[0266] Step 1. ethyl (E)-3-(4-bromo-6-chloropyridin-2-yl)acrylate

[0267] To a solution of 4-bromo-2-chloro-6-iodopyridine (10.0 g, 31.4 mmol) in 1,4-dioxane (150 mL) and water (20 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (8.52 g, 37.7 mmol), K2CO3 (10.9 g, 78.5 mmol) and Pd(dppf)C12 (2.27 g, 3.14 mmol at 25 °C. The reaction mixture was stirred at 80 °C for 4 hours under N2. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-3% EtOAc / petroleum ether) to give ethyl (E)-3-(4-bromo-6- chloropyridin-2-yl)acrylate (7.10 g, 24.4 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 7.73 - 7.33 (m, 3H), 6.97 (d, J= 15.5 Hz, 1H), 4.27 (q, J= 7.1 Hz, 2H), 1.33 (t, J= 6.9 Hz, 3H).

[0268] Step 2. ethyl 3-(4-bromo-6-chloropyridin-2-yl)-4-nitropentanoate

[0269] To a solution of nitroethane (4.87 g, 64.9 mmol) in THE (50 mL) was added CS2CO3 (2.07 g, 6.37 mmol) at 0 °C and stirred at 0 °C for 30 minutes under N2. Ethyl (E)-3-(4-bromo-6-chloropyridin-2- yl)acrylate (3.70 g, 12.7 mmol) was added to the reaction mixture at 0 °C and stirred at 25 °C for 12 hours under N2. The mixture was diluted with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-15% EtOAc / petroleum ether) to give ethyl 3-(4-bromo-6-chloropyridin-2-yl)-4-nitropentanoate (4.20 g, 11.5 mmol) as white solid. 'H NMR (400 MHz, CDCI3) 5 7.46 - 7.27 (m, 2H), 5.06 - 4.83 (m, 1H), 4.18 - 3.98 (m, 2H), 3.88 - 3.54 (m, 1H), 3.24 - 2.55 (m, 2H), 1.70 - 1.61 (m, 2H), 1.37 (d, J = 6.7 Hz, 1H), 1.22 - 1.12 (m, 3H).102QB\184200.00266\99637562.4VVID 754PC

[0270] Step 3. ethyl 4-amino-3-(4-bromo-6-chloropyridin-2-yl)pentanoate hydrochloride

[0271] Solution 1: ethyl 3-(4-bromo-6-chloropyridin-2-yl)-4-nitropentanoate (4.20 g, 11.5 mmol) and 4,4'-bipyridine (359 mg, 2.30 mmol) in DMF (42 mL). Solution 2: B2(OH)4(4.12 g, 46.0 mmol) in DMF (42 mL). The solution 1 and solution 2 were pumped to flow reactor at 25 °C for 10 minutes. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Phenomenex luna C18, 250 x 70 mm, 15 pm; 10-50% ACN / H2O (0.04% HC1)) to give ethyl 4-amino-3-(4-bromo-6-chloropyridin-2- yl)pentanoate (2.56 g, 6.88 mmol) as yellow solid.

[0272] Step 4. Mixture of trans 4-(4-bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one and cis 4-(4-bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one

[0273] To a solution of ethyl 4-amino-3-(4-bromo-6-chloropyridin-2-yl)pentanoate hydrochloride (2.56 g, 6.88 mmol) in MeOH (40 mL) was added TEA (0.962 mL, 696 mg, 6.88 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 12 hours. The mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 50-100% EtOAc / petroleum ether) to give a mixture of mixture of trans 4-(4-bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one and cis 4-(4- bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one (1.35 g, 4.66 mmol) as brown solid.

[0274] Step 4. trans 4-(4-bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one

[0275] To a mixture of trans 4-(4-bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one and cis 4-(4- bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one (1.75 g, 6.04 mmol) in MeCN (20 mL) was added DBU (0.452 mL, 460 mg, 3.02 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 12 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 60-80% EtOAc / petroleum ether) to give trans 4-(4-bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one (1.30 g, 4.49 mmol) as white solid. 'H NMR (400 MHz, CDC13) 5 7.43 (d, J= 1.4 Hz, 1H), 7.29 (s, 1H), 6.24 (s, 1H), 4.03 - 3.90 (m, 1H), 3.29 - 3.14 (m, 1H), 2.82 (dd, J= 16.8, 9.7 Hz, 1H), 2.68 (dd, J= 16.8, 9.0 Hz, 1H), 1.29 (d, J= 6.2 Hz, 3H).

[0276] Step 5. trans 4-bromo-2-chloro-6-(2-methylpyrrolidin-3-yl)pyridine

[0277] To a solution of trans 4-(4-bromo-6-chloropyridin-2-yl)-5-methylpyrrolidin-2-one (940 mg, 3.25 mmol) in THF (15 mL) was added BH3THF (9.74 mL, 9.74 mmol, 1 M in THF) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes and at 70 °C for 4 hours. The mixture was quenched with MeOH (30 mL) and HC1 (5 mL, 4 N in MeOH) at 0 °C. The mixture was stirred at 25 °C for 30 minutes and at 50 °C for 4 hours. The mixture was concentrated under reduced pressure to give crude103QB\184200.00266\99637562.4VVID 754PC trans 4-bromo-2-chloro-6-(2-methylpyrrolidin-3-yl)pyridine (1.33 g) as yellow oil which was used in the next step without further purification.

[0278] Step 6. trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate

[0279] To a solution of crude trans 4-bromo-2-chloro-6-(2-methylpyrrolidin-3-yl)pyridine (1.33 g) in MeOH (20 mL) was added TEA (1.35 m , 977 mg, 9.65 mmol) and di-tert-butyl decarbonate (1.58 g, 7.24 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-20% EtOAc / petroleum ether) to give trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2- methylpyrrolidine- 1 -carboxylate (970 mg, 2.58 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 7.39 (d, J = 1.5 Hz, 1H), 7.24 (d, J= 1.5 Hz, 1H), 4.06 - 3.91 (m, 1H), 3.73 - 3.64 (m, 1H), 3.44 - 3.34 (m, 1H), 3.06 (q, J= 6.8 Hz, 1H), 2.27 - 2.15 (m, 1H), 2.15 - 2.02 (m, 1H), 1.48 (s, 9H), 1.31 (d, J = 62 Hz, 3H).General Procedure 13

[0280] Synthesis of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperidine-l- carboxylate and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperidine-l-carboxylate(trans / cis = 2 / 3)

[0281] Step 1. 2-bromo-4-chloro-6-iodopyridine

[0282] To a solution of 2-bromo-4-chloropyridine (50.0 g, 260 mmol) in THE (250 mL) was added TMPMgCl LiCl (311 mL, 312 mmol) dropwise at 0 °C under N2. The reaction mixture was stirred for 1 hour at 20 °C. Then, I2 (69.2 g, 273 mmol) was added at 0 °C and the reaction mixture was stirred for 2 hours at 0 °C. The mixture was quenched with saturated NH4CI (500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with Na2SOs (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography104QB\184200.00266)99637562.4VVID 754PC(SiC>2, 0-10% EtOAc / petroleum ether) to give 2-bromo-4-chloro-6-iodopyridine (15.00 g, 47.1 mmol) as yellow solid.XH NMR (400 MHz, CDC13) 5 ppm 7.74 (d, J= 1.6 Hz, 1H), 7.51 (d, J= 1.6 Hz, 1H).

[0283] Step 2. tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpiperidine-l- carboxylate

[0284] To a solution of 2-bromo-4-chloro-6-iodopyridine (13.0 g, 40.8 mmol) in toluene (100 mb) was added iPrMgCl LiCl (40.8 mL, 53.1 mmol) dropwise at -20 °C and stirred at -20 °C for 1 hour. A solution of tert-butyl 2-methyl-3-oxopiperidine-l-carboxylate (9.58 g, 44.9 mmol) in toluene (50 mL) was added dropwise at -20 °C and the reaction mixture was stirred at -20 °C for 1 hour under N2. The mixture was poured into the saturated NH4CI (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4 filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2- methylpiperi dine- 1 -carboxylate (8.60 g, 21.20 mmol) as yellow oil. 'H NMR (400 MHz, CDCI3) 5 ppm 7.56 (d, J= 1.6 Hz, 1H), 7.43 (d, J= 1.6 Hz, 1H), 4.66 - 4.57 (m, 1H), 3.98 - 3.90 (m, 1H), 3.05 - 2.95 (m, 1H), 2.13 - 2.07 (m, 1H), 2.04 - 1.91 (m, 1H), 1.67 - 1.60 (m, 2H), 1.50 - 1.47 (m, 9H), 1.30 (d, J= 6.8 Hz, 3H).

[0285] Step 3. tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methyl-3-(((methylthio)carbono- thioyl)oxy)piperidine-l-carboxylate

[0286] To a solution of tert-butyl 3-(6-bromo-4-chloropyridin-2 -yl) -3 -hydroxy-2 -methylpiperidine- 1- carboxylate (2.10 g, 5.17 mmol) in THE (30 mL) was added NaH (1.60 g, 40.00 mmol, 60%) at 0 °C and the mixture was stirred at 25 °C for 30 minutes. Then, CS2 (3.90 g, 51.2 mmol) was added at 25 °C and the reaction mixture was stirred at 25 °C for another 50 minutes. Then, Mel (8.80 g, 62.0 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 hours under N2. The mixture was poured into saturated NH4CI (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to give tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methyl-3-(((methylthio)carbono-thioyl)oxy)piperidine-l- carboxylate (2.50 g, 5.04 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.65 (br s, 1H), 7.37 (s, 1H), 6.10 - 5.79 (m, 1H), 4.05 - 3.89 (m, 1H), 3.01 - 2.86 (m, 1H), 2.81 - 2.72 (m, 1H), 2.46 (s, 3H), 2.28 - 2.15 (m, 1H), 1.67 - 1.57 (m, 1H), 1.49 (s, 10H), 1.33 (d, J= 6.8 Hz, 3H).

[0287] Step 4. cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperidine-l-carboxylate

[0288] To a solution of tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methyl-3- (((methylthio)carbono-thioyl)oxy)piperidine-l -carboxylate (2.20 g, 4.43 mmol) in toluene (25 mL) was added (n-Bu)3SnH (1.82 g, 6.25 mmol) and AIBN (1.10 g, 6.64 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 2 hours under N2. The mixture was quenched with water (50 mL) and extracted105QB\184200.00266\99637562.4VVID 754PC with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCh, 0-5% EtOAc / petroleum ether) to give cis tert-butyl 3-(6-bromo-4-chloropyridin-2 -yl)-2 -methylpiperidine- 1- carboxylate (1.49 g, 3.82 mmol) as white solid. 'H NMR (400 MHz, CDCE) 8 ppm 7.37 (s, 1H), 7.15 (br s, 1H), 4.84 - 4.57 (m, 1H), 4.12 - 3.89 (m, 1H), 3.12 - 3.01 (m, 1H), 2.95 - 2.79 (m, 1H), 2.11 - 1.94 (m, 1H), 1.89 - 1.75 (m, 2H), 1.53 - 1.42 (m, 10H), 0.84 (d, J= 7.2 Hz, 3H).

[0289] Step 5. Mixture of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperidine-l- carboxylate and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperidine-l-carboxylate

[0290] To a solution of cis tert-butyl 3 -(6-bromo-4-chloropyridin-2 -yl)-2-m ethylpiperidine- 1- carboxylate (1.33 g, 3.41 mmol) in MeCN (15 mL) was added DBU (1.60 g, 10.2 mmol) at 25 °C under N2. The reaction mixture was warmed to 90 °C and stirred for 16 hours. The mixture was concentrated and the crude product was purified by preparative TLC (SiCE, petroleum ether: EtOAc =10: 1) to give a mixture of trans tert-butyl 3 -(6-bromo-4-chloropyridin-2-yl)-2 -methylpiperidine- 1 -carboxylate and cis tert-butyl 3 -(6-bromo-4-chloropyridin-2-yl)-2-methylpiperidine-l -carboxylate (910 mg, 2.34 mmol) as white solid (trans Ids = 2 / 3).General Procedure 14

[0291] Synthesis of tert-butyl (2R,3R)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2- methylpiperidine-l-carboxylate and tert-butyl (2S,3S)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpiperidine-l-carboxylateabsolute stereochemistry randomly assigned

[0292] 2-bromo-4-chloro-6-iodopyridine was obtained as described in General Procedure 13, step 1.

[0293] Step 1. trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpiperidine-l- carboxylate

[0294] To a solution of 2-bromo-4-chloro-6-iodopyridine (7.00 g, 22.0 mmol) in toluene (100 mL) was added iPrMgCl-LiCI (22.0 mL, 28.6 mmol, 1.3 M in THF) dropwise at -20 °C. The reaction mixture was stirred at -20 °C for 1 hour. Then, a solution of tert-butyl 2-methyl-3-oxopiperidine-l-carboxylate (5.16 g, 24.2 mmol) in toluene (50 mL) was added dropwise at -20 °C and stirred at -20 °C for 1 hour under N2. The mixture was poured into saturated aqueous NH4CI (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4,106QB\184200.00266\99637562.4VVID 754PC filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give trans tert-butyl 3-(6-bromo-4- chloropyridin-2-yl)-3 -hydroxy-2 -methylpiperidine- 1 -carboxylate (4.50 g, 11.1 mmol) as yellow oil. 'H NMR (400 MHz, DMSO-d6) 5 = 7.85 - 7.78 (m, 1H), 7.72 - 7.66 (m, 1H), 5.63 - 5.53 (m, 1H), 4.80 - 4.65 (m, 1H), 3.77 - 3.61 (m, 1H), 2.90 - 2.79 (m, 1H), 2.31 - 2.20 (m, 1H), 1.84 - 1.71 (m, 1H), 1.61 - 1.48 (m, 1H), 1.40 (s, 2H), 1.35 - 1.30 (m, 9H), 1.22 - 1.17 (m, 3H).

[0295] Step 2. Separation of tert-butyl (2R,3R)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2- methylpiperidine-l-carboxylate and tert-butyl (2S,3S)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy- 2-methylpiperidine-l-carboxylate

[0296] The racemic trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpiperidine- 1-carboxylate (4.50 g, 11.1 mmol) was separated by SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm; 22% iPrOH / CO?). The first eluting isomer was randomly assigned as tert-butyl (2R,3R)-3-(6-bromo- 4-chloropyridin-2-yl)-3-hydroxy-2-methylpiperidine-l-carboxylate (1.90 g, 4.68 mmol) and was obtained as yellow solid: 'H NMR (400 MHz, DMSO-d6 ) 5 = 7.81 (d, J= 1.5 Hz, 1H), 7.73 - 7.64 (m, 1H), 5.65 - 5.47 (m, 1H), 4.77 - 4.63 (m, 1H), 3.73 - 3.63 (m, 1H), 2.93 - 2.78 (m, 1H), 2.30 - 2.18 (m, 1H), 1.83 - 1.69 (m, 1H), 1.58 - 1.46 (m, 1H), 1.44 - 1.37 (m, 1H), 1.37 - 1.29 (m, 9H), 1.23 - 1.16 (m, 3H). The second eluting isomer was randomly assigned as tert-butyl (2S,3S)-3-(6-bromo-4-chloropyridin-2-yl)-3- hydroxy-2-methylpiperidine-l -carboxylate (1.80 g, 4.44 mmol) and was obtained as yellow solid. 'H NMR (400 MHz, DMSO-d6 ) 5 = 7.95 - 7.77 (m, 1H), 7.72 - 7.53 (m, 1H), 5.65 - 5.51 (m, 1H), 4.79 - 4.59 (m, 1H), 3.78 - 3.64 (m, 1H), 2.90 - 2.74 (m, 1H), 2.32 - 2.15 (m, 1H), 1.84 - 1.72 (m, 1H), 1.58 - 1.47 (m, 1H), 1.40 - 1.37 (m, 1H), 1.36 - 1.30 (m, 9H), 1.23 - 1.15 (m, 3H).General Procedure 15

[0297] Synthesis of tert-butyl (2S, 3S)-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l- carboxylate and tert-butyl (2R, 3R)-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l- carboxylate

[0298] Step 1. l-(2-bromo-6-chloropyridin-4-yl)propan-2-one

[0299] To a solution of 2-bromo-6-chloro-4-methylpyridine (10.0 g, 48.4 mmol) in THF (90 mb) was added LDA (48.43 mb, 96.87 mmol) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for107QB\184200.00266\99637562.4VVID 754PC1 hour under N2. N-methoxy-N-methylacetamide (12.0 g, 116 mmol) in THF (10 mL) was added dropwise at -78 °C. The reaction mixture was allowed to warm to 0 °C, stirred for 1 hour below 0 °C and then at 20 °C for 12 hours under N2. The mixture was poured into saturated NH4CI (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL. 0-7% EtOAc / petroleum ether) to give l-(2-bromo-6-chloropyridin-4- yl)propan-2-one (14.1 g, 45.5 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.28 (s, 1H), 7.15 (s, 1H), 3.71 (s, 2H), 2.27 (s, 3H).

[0300] Step 2. tert-butyl (4-(2-bromo-6-chloropyridin-4-yl)-5-oxohexyl)carbamate

[0301] To a solution of l-(2-bromo-6-chloropyridin-4-yl)propan-2-one (7.40 g, 29.8 mmol) in DMF (70 mL) was added CS2CO3 (12.6 g, 38.7 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour under N2. tert-butyl (3-bromopropyl)carbamate (7.80 g, 32.76 mmol) and Nal (4.91 g, 32.8 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was poured into saturated aqueous NaCl (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to give tert-butyl (4-(2-bromo-6-chloropyridin-4-yl)-5-oxohexyl)carbamate (13.0 g, 25.6 mmol, 80% purity) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.32 (s, 1H), 7.19 (d, J= 0.8 Hz, 1H), 4.55 (br s, 1H), 3.78 - 3.71 (m, 1H), 3.18 - 3.07 (m, 2H), 2.16 (s, 3H), 2.11 - 1.99 (m, 1H), 1.71 - 1.58 (m, 1H), 1.44 (s, 9H), 1.41 - 1.33 (m, 2H).

[0302] Step 3. 2'-bromo-6'-chloro-2-methyl-3,4,5,6-tetrahydro-3,4'-bipyridine

[0303] To a solution of tert-butyl (4-(2-bromo-6-chloropyridin-4-yl)-5-oxohexyl)carbamate (6.17 g, 15.2 mmol) in DCM (30 m) was added TFA (30 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 hour under N2. The mixture was concentrated to give crude 2'-bromo-6'-chloro-2 -methyl -3, 4,5,6- tetrahydro-3,4'-bipyridine (4.37 g, 15.2 mmol) as yellow solid. The crude product was used into the next step without further purification.

[0304] Step 4. 2-bromo-6-chloro-4-(2-methylpiperidin-3-yl)pyridine

[0305] To a solution of 2'-bromo-6'-chloro-2-methyl-3,4,5,6-tetrahydro-3,4'-bipyridine (4.37 g, 15.2 mmol) in MeOH (40 mL) was added NaBFL (1.73 g, 45.6 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 0.5 hour under N2. The mixture was quenched by 1 N HC1 (30 mL), diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 2- bromo-6-chloro-4-(2-methylpiperidin-3-yl)pyridine (4.40 g, 15.2 mmol) as yellow oil.108QB\184200.00266\99637562.4VVID 754PC

[0306] Step 5. trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l- carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l-carboxylate

[0307] To a solution of 2-bromo-6-chloro-4-(2-methylpiperidin-3-yl)pyridine (4.40 g, 15.2 mmol) in MeOH (40 mL) was added BOC2O (6.64 g, 30.4 mmol) and DIPEA (3.93 g, 30.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-5% EtOAc / petroleum ether) and preparative HPLC (Cl 8 SiC>2, 10 pm, 100 x 30 mm, 0-15% EtOH / heptane) to give trans tert- butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l-carboxylate (2.40 g, 6.16 mmol) as yellow solid: 'H NMR (400 MHz, CDC13) 5 ppm 7.38 (s, 1H), 7.25 (s, 1H), 4.63 (q, J= 6.4 Hz, 1H), 4.01 (dd, J = 4.0, 13.6 Hz, 1H), 2.93 (td, J= 3.6, 13.2 Hz, 1H), 2.76 (s, 1H), 2.19 - 2.08 (m, 1H), 1.83 - 1.75 (m, 1H), 1.53 (s, 9H), 1.50 - 1.45 (m, 1H), 1.43 - 1.32 (m, 1H), 1.30 (d, J= 7.2 Hz, 3H), and cis tert-butyl 3- (2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l-carboxylate (1.50 g, 3.85 mmol) as white solid: 'H NMR (400 MHz, CDCh) 5 ppm 7.30 (s, 1H), 7.16 (s, 1H), 4.73 - 4.31 (m, 1H), 4.16 - 3.89 (m, 1H), 2.99 - 2.77 (m, 2H), 1.98 - 1.76 (m, 3H), 1.50 (s, 9H), 1.35 - 1.29 (m, 1H), 0.86 (d, J= 7.2 Hz, 3H).

[0308] Step 6. Chiral separation of tert-butyl (2S, 3S)-3-(2-bromo-6-chloropyridin-4-yl)-2- methylpiperidine-l-carboxylate and tert-butyl (2R, 3R)-3-(2-bromo-6-chloropyridin-4-yl)-2- methylpiperidine-l-carboxylate

[0309] trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l-carboxylate was separated by preparative SLC (DAICEL CHIRALPAK AD, 250mm x 50mm, 10pm; 12.5% EtOH / CCL) to give as the first eluting enantiomer, tert-butyl (2S,3S)-3-(2-bromo-6-chloro-4-pyridyl)-2 -methylpiperidine- 1 -carboxylate as a pale yellow solid: 'H NMR (400 MHz, CDCI3) 5 ppm 7.39 (s, 1H), 7.27 - 7.26 (m, 1H), 4.75 - 4.59 (m, 1H), 4.19 - 3.94 (m, 1H), 3.00 - 2.83 (m, 1H), 2.78 - 2.70 (m, 1H), 2.20 - 2.03 (m, 1H), 1.90 - 1.73 (m, 1H), 1.50 (br s, 9H), 1.48 - 1.31 (m, 2H), 1.31 - 1.27 (m, 3H); and as the second eluting enantiomer, tert-butyl (2R,RS)-3-(2-bromo-6-chloro-4-pyridyl)-2-methyl-piperidine-l- carboxylate: 'H NMR (400 MHz, CDCh) 5 ppm 7.39 (s, 1H), 7.27 - 7.25 (m, 1H), 4.71 - 4.57 (m, 1H), 4.09 - 3.93 (m, 1H), 2.94 - 2.84 (m, 1H), 2.77 - 2.61 (m, 1H), 2.23 - 2.03 (m, 1H), 1.83 - 1.73 (m, 1H), 1.52 (s, 9H), 1.49 - 1.32 (m, 2H), 1.29 (d, J= 6.9 Hz, 3H).

[0310] Colorless needle-shaped single crystals of tert-butyl (2R,3R)-3-(2-bromo-6-chloropyridin-4- yl)-2 -methylpiperidine- 1 -carboxylate (first eluting isomer) were obtained from methanol-water (4: 1). The absolute stereochemistry was then determined and assigned by X-ray crystallography to be 2R, R.General Procedure 16

[0311] Synthesis of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-(methoxymethyl)piperidine-l-carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- methylpiperidine-l-carboxylate109QB\184200.00266\99637562.4VVID 754PC

[0312] Step 1. l-(2-bromo-6-chloropyridin-4-yl)-3-methoxypropan-2-one

[0313] To a solution of 2-bromo-6-chloro-4-methylpyridine (10.0 g, 48.4 mmol) in THF (100 mL) was added LDA (48.4 mL, 96.9 mmol, 2 M in w-heptane-THF) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 1 hour under N2. N,2-dimethoxy-N-methylacetamide (15.5 g, 116 mmol) in THF (30 mL) was dropwise added into the mixture at -78 °C under N2. The solution was allowed to warm to0 °C and stirred for 1 hour under 0 °C. The reaction mixture was poured into saturated NH4CI (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC 0-12% EtOAc / petroleum ether) to give l-(2-bromo-6-chloropyridin-4- yl)-3-methoxypropan-2-one (7.00 g, 25.1 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.30 (s, 1H), 7.17 (s, 1H), 4.05 (s, 2H), 3.81 (s, 2H), 3.45 (s, 3H).

[0314] Step 2. tert-butyl (4-(2-bromo-6-chloropyridin-4-yl)-6-methoxy-5-oxohexyl)carbamate

[0315] To a solution of l-(2-bromo-6-chloropyridin-4-yl)-3-methoxypropan-2-one (7.00 g, 25.1 mmol) in DMF (80 mL) was added CS2CO3 (10.65 g, 32.67 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour under N2. tert-butyl (3-bromopropyl)carbamate (6.58 g, 27.7 mmol) and Nal (4. 14 g, 27.7 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-25% EtOAc / petroleum ether) to give tert-butyl (4-(2-bromo-6-chloropyridin-4-yl)-6-methoxy-5-oxohexyl)carbamate (10.4 g, 23.9 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.34 (d, J= 0.8 Hz, 1H), 7.22 (d, J= 0.8 Hz, 1H), 4.56 (br s, 1H), 4.06 - 4.00 (m, 1H), 3.99 (s, 2H), 3.36 (s, 3H), 3.18 - 3.05 (m, 2H), 2.09 - 1.97 (m, 1H), 1.74 - 1.61 (m, 1H), 1.44 (s, 9H), 1.41 - 1.33 (m, 2H).

[0316] Step 3. 2'-bromo-6'-chloro-2-(methoxymethyl)-3,4,5,6-tetrahydro-3,4'-bipyridine\

[0317] To a solution of tert-butyl (4-(2-bromo-6-chloropyridin-4-yl)-6-methoxy-5- oxohexyl)carbamate (10.4 g, 23.9 mmol) in DCM (100 mL) was added TFA (100 mL) at 25 °C. The110QB\184200.00266\99637562.4VVID 754PC mixture was stirred at 25 °C for 0.5 hour under N2. The reaction mixture was concentrated under reduced pressure to give crude 2'-bromo-6'-chloro-2-(methoxymethyl)-3,4,5,6-tetrahydro-3,4'-bipyridine (7.58 g, 23.9 mmol) as yellow solid. The crude product was used into the next step without further purification.

[0318] Step 4. 2-bromo-6-chloro-4-(2-(methoxymethyl)piperidin-3-yl)pyridine

[0319] To a solution of 2'-bromo-6'-chloro-2-(methoxymethyl)-3,4,5,6-tetrahydro-3,4'-bipyridine (7.58 g, 23.87 mmol) in methanol (100 mL) was added Sodium borohydride (4.51 g, 119.33 mmol) at0 °C under N2. The reaction mixture was stirred at 25 °C for 0.5 hour under N2. The reaction mixture was quenched by 1 N HC1 (30 mL). Then, the mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give crude 2-bromo-6-chloro-4-(2- (methoxymethyl)piperidin-3-yl)pyridine (11.40 g, 23.18 mmol, 65% purity) as yellow oil. The crude product was used into the next step without further purification.

[0320] Step 5. trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-(methoxymethyl)piperidine-l- carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l-carboxylate

[0321] To a solution of 2-bromo-6-chloro-4-(2-(methoxymethyl)piperidin-3-yl)pyridine (11.4 g, 23.2 mmol, 65% purity) in MeOH (150 mL) was added DIPEA (5.99 g, 46.36 mmol) and BOC2O (10.1 g, 46.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-15% EtOAc / petroleum ether) to give trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2- (methoxymethyl)piperidine-l -carboxylate (4.50 g, 10.7 mmol) as yellow solid: 'H NMR (400 MHz, CDCh) 5 ppm 7.40 (s, 1H), 7.27 (s, 1H), 4.61 (t, J= 6.8 Hz, 1H), 4.08 (d, J= 11.2 Hz, 1H), 3.61 (t, J = 9.2 Hz, 1H), 3.46 (dd, J= 6.0, 10.0 Hz, 1H), 3.37 (s, 3H), 3.14 - 3.09 (m, 1H), 2.85 (td, J= 3.2, 13.2 Hz, 1H), 2.13 - 2.03 (m, 1H), 1.79 (dd, J= 2.8, 14.0 Hz, 1H), 1.53 (s, 9H), 1.49 - 1.33 (m, 2H), and cis tert- butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-(methoxymethyl)piperidine-l-carboxylate (2.40 g, 5.72 mmol) as yellow oil: 'H NMR (400 MHz, CDCh) 5 ppm 7.35 (s, 1H), 7.22 (s, 1H), 4.70 - 4.30 (m, 1H), 4.22 - 3.96 (m, 1H), 3.36 (dd, J= 6.8, 10.4 Hz, 1H), 3.19 - 3.13 (m, 4H), 3.09 - 2.93 (m, 2H), 2.17 - 2.01 (m, 1H), 1.89 - 1.77 (m, 2H), 1.61 - 1.52 (m, 1H), 1.49 (s, 9H).General Procedure 17

[0322] Synthesis of tert-butyl 6-(2-bromo-6-chloropyridin-4-yl)-2-azabicyclo[2.2.2]octane-2- carboxylate111QB\184200.00266\99637562.4VVID 754PC

[0323] 2-bromo-6-chloro-4-iodopyridine was obtained as described in General Procedure 4, step 1.

[0324] Step 1. tert-butyl (lS,4R)-6-(((trifluoromethyl)sulfonyl)oxy)-2-azabicyclo[2.2.2]oct-5-ene- 2-carboxylate

[0325] To a solution of tert-butyl (lS,4R)-6-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (2.50 g, 11.1 mmol) in THF (100 mL) was added LiHMDS (1.0 M in THF, 16.6 mL, 16.6 mmol) dropwise at -78 °C. The reaction mixture was stirred for 2 hours and PhNTf2 (4.76 g, 13.3 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 1 hour. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / heptane) to give tert-butyl (lS,4R)-6- (((trifluoromethyl)sulfonyl)oxy)-2-azabicyclo[2.2.2]oct-5-ene-2 -carboxylate (5.41 g, 6.06 mmol, 40% purity) as slightly yellow oil. LCMS [M-C^s+H] : 302 Retention Time: 2.865 min (Method 2).

[0326] Step 2. tert-butyl (lS,4R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- azabicyclo [2.2.2] oct-5-ene-2-carboxylate

[0327] To a solution of tert-butyl (lS,4R)-6-(((trifhroromethyl)sulfonyl)oxy)-2-azabicyclo[2.2.2]oct- 5 -ene-2 -carboxylate (5.00 g, 5.59 mmol) in toluene (42 mL) was added Pin2B2 (1.85 g, 7.27 mmol), KOAc (1.54 g, 15.7 mmol) and Pd(dppf)C12 (202 mg, 0.280 mmol). The reaction mixture was stirred at 75 °C for 14 hours. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude tert-butyl (lS,4R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-azabicyclo[2.2.2] oct-5-ene-2- carboxylate. The crude product was used in the next step without further purification. LCMS [M- C4HS+H]+: 280 Retention Time: 1.624 min (Method 2).

[0328] Step 3. tert-butyl (lS,4R)-6-(2-bromo-6-chloropyridin-4-yl)-2-azabicyclo [2.2.2] oct- 5-ene-2- carboxylate

[0329] To a solution of tert-butyl (lS,4R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- azabicyclo[2.2.2]oct-5-ene-2-carboxylate (1.88 g, 5.59 mmol) and 2-bromo-6-chloro-4-iodo-pyridine (1.87 g, 5.87 mmol) in toluene (38 mL) and water (10 mL) was added Pd(dppf)C12 (202 mg, 0.280 mmol) and K2CO3 (1.93 g, 14.0 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The mixture was quenched by saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure. The crude product was112QB\184200.00266\99637562.4VVID 754PC purified by column chromatography (SiC>2, 0-100% EtOAc / heptane) to give tert-butyl (lS,4R)-6-(2- bromo-6-chloropyridin-4-yl)-2-azabicyclo [2.2.2]oct-5-ene-2-carboxylate (1.24 g, 3.09 mmol) as yellow oil. LCMS [M+H]+: 399 / 401 Retention Time: 2.861 min (Method 2).

[0330] Step 4. tert-butyl (lS,4R)-6-(2-bromo-6-chloropyridin-4-yl)-2- azabicyclo [2.2.2] octane-2- carboxylate

[0331] To a solution of tert-butyl (lS,4R)-6-(2-bromo-6-chloropyridin-4-yl)-2-azabicyclo[2.2.2]oct-5- ene-2 -carboxylate (1.24 g, 3.09 mmol) in MeOH (51 mb) was added PtO2 (35.1 mg, 0.155 mmol). The reaction mixture was stirred under H2-atmosphere (40 psi) for 4 hours at room temperature. The mixture was filtered over Celite and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl (lS,4R)-6-(2-bromo-6- chloropyridin-4-yl)-2-azabicyclo[2.2.2]octane-2 -carboxylate (73.4 mg, 0.183 mmol) as colorless oil. LCMS [M+H]+: 401 / 403 Retention Time: 2.794 min (Method 2).General Procedure 18

[0332] Synthesis of exo tert-butyl 2-(2-bromo-6-chloropyridin-4-yl)-8- azabicyclo [3.2.1] octane-8- carboxylate

[0333] 2-bromo-6-chloro-4-iodopyridine was obtained as described in General Procedure 4, step 1.

[0334] Step 1. tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate

[0335] To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2. l]octane-8-carboxylate (7.50 g, 33.29 mmol) in methanol (80 mb) was added NaBEL (1.51 g, 39.94 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was acidified with IN HC1 to pH = 7, poured into water (70 mb) and extracted with EtOAc (70 mb x 3). The combined organic layers were washed with brine (70 mb x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give tert-butyl 3- hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (7.56 g, 33.3 mmol) as white solid. 'H NMR (400 MHz, CD3OD) 5 ppm 4.22 - 4.12 (m, 2H), 4.07 - 4.01 (m, 1H), 2.25 - 2.16 (m, 1H), 2.09 - 2.02 (m, 1H), 1.90 (br d, J = 5.2 Hz, 3H), 1.80 - 1.65 (m, 2H), 1.57 - 1.49 (m, 1H), 1.47 (d, J= 6.8 Hz, 9H).

[0336] Step 2. tert-butyl 8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

[0337] To a solution of tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (3.20 g, 14.1 mmol) in toluene (35 m ) was added Burgess reagent (6.70 g, 28.2 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 2 hours under N2. The mixture was diluted with water (25 m ) and extracted113QB\184200.00266\99637562.4VVID 754PC with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-10% EtOAc / petroleum ether) to give tert-butyl 8-azabicyclo[3.2.1]oct-2-ene-8- carboxylate (1.30 g, 6.21 mmol) as colorless oil. 'H NMR (400 MHz, CDCL) 5 ppm 6.05 - 5.92 (m, 1H), 5.58 - 5.46 (m, 1H), 4.29 (br d, J= 4.8 Hz, 2H), 2.76 (br d, J= 16.8 Hz, 1H), 2.23 - 2.11 (m, 1H), 2.01 - 1.85 (m, 2H), 1.83 - 1.75 (m, 1H), 1.72 - 1.60 (m, 1H), 1.46 (s, 9H).

[0338] Step 3. exo tert-butyl 2-(2-bromo-6-chloropyridin-4-yl)-8-azabicyclo [3.2.1] octane-8- carboxylate

[0339] To a solution of tert-butyl 8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2.15 g, 10.3 mmol) in DMF (20 mL) was added 2-bromo-6-chloro-4-iodopyridine (8.18 g, 25.7 mmol), piperidine (3.06 g, 36.0 mmol), Pd(OAc)2(PPh3)2 (616 mg, 0.820 mmol) and HCOOH (1.23 g, 26.7 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for 14 hours under N2. The mixture was diluted with water (45 mL) and extracted with EtOAc (45 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 SiO2 (250 x 70; 10 pm) 55-85% ACN / H2O (10 mM NH4HCO3)) to give exo tert- butyl 2-(2-bromo-6-chloropyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.620 mmol) as yellow solid. 'H NMR (400 MHz, CDCI3) 5 ppm 7.42 (s, 1H) 7.30 (s, 1H) 4.57 - 4.26 (m, 2H) 2.80 (br d, J= 6.8 Hz, 1H) 2.23 - 2.10 (m, 2H) 2.04 - 1.92 (m, 2H) 1.89 - 1.80 (m, 2H) 1.77 - 1.68 (m, 1H) 1.66 - 1.57 (m, 1H) 1.39 - 1.21 (m, 9H).General Procedure 19

[0340] Synthesis of exo tert-butyl 6-(2-bromo-6-chloropyridin-4-yl)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate

[0341] 2-bromo-6-chloro-4-iodopyridine was obtained as described in General Procedure 4, step 1.

[0342] Step 1. tert-butyl 7-hydroxy-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate

[0343] To a solution of tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3. l]nonane-9-carboxylate (5.00 g, 20.7 mmol) in MeOH (50 mL) was added NaBEL (941 mg, 24.9 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was acidified with IN HC1 to pH = 7, poured into water (70 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (70 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (5.04 g, 20.7 mmol) as white114QB\184200.00266\99637562.4VVID 754PC solid. 'H NMR (400 MHz, CD30D) 5 ppm 4.03 (br d, J= 4.0 Hz, 2H) 3.91 - 3.79 (m, 3H) 3.68 (br d, J= 11.2 Hz, 2H) 2.18 - 2.06 (m, 2H) 1.76 (br d, J= 14.8 Hz, 2H) 1.43 (d, J= 0.8 Hz, 9H).

[0344] Step 2. tert-butyl 3-oxa-9-azabicyclo [3.3.1] non-6-ene-9-carboxylate

[0345] To a solution of tert-butyl 7-hydroxy-3-oxa-9-azabicyclo[3.3. l]nonane-9-carboxylate (5.00 g, 18.5 mmol) in pyridine (50 mb) was added SOCI2 (2.64 g, 22.2 mmol) at -40 °C. The reaction mixture was stirred at 25 °C for 2 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (75 mL) and extracted with DCM (75 mb x 3). The combined organic layers were concentrated under reduced pressure and the crude product was purified by column chromatography (SiC>2, 0-10 % EtOAc / petroleum ether) to give tert-butyl 3-oxa-9-azabicyclo[3.3.1]non-6-ene-9- carboxylate (1.70 g, 7.55 mmol) as white solid. 'H NMR (400 MHz, CDCI3) 5 ppm 6.03 (br s, 1H) 5.91 - 5.71 (m, 1H) 4.52 - 4.31 (m, 1H) 4.24 - 3.96 (m, 2H) 3.88 - 3.70 (m, 3H) 3.67 - 3.52 (m, 2H) 1.47 (s, 9H).

[0346] Step 3. exo tert-butyl 6-(2-bromo-6-chloropyridin-4-yl)-3-oxa-9-azabicyclo[3.3.1]nonane- 9-carboxylate

[0347] To a solution of tert-butyl 3-oxa-9-azabicyclo[3.3. l]non-6-ene-9-carboxylate ( 1.00 g, 4.43 mmol) in DMF (10 mL) was added 2-bromo-6-chloro-4-iodopyridine (3.53 g, 11.1 mmol), piperidine (1.32 g, 15.5 mmol), Pd(OAc)2(PPh3)2 (266 mg, 0.350 mmol) and HCOOH (531 mg, 11.5 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for 7 hours under N2. The mixture was diluted with water (35 mL) and extracted with EtOAc (35 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified twice by preparative HPLC (C18 SiC>2, 1stcolumn (250 x 100 mm; 10 pm); 2ndcolumn (150 x 40 mm; 10 pm) 40-75% ACN / H2O (10 mM NH4HCO3)) to give exo tert-butyl 6-(2-bromo-6-chloropyridin- 4-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (188 mg, 0.450 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.41 (s, 1H) 7.29 (s, 1H) 4.34 - 4.16 (m, 1H) 4.15 - 4.01 (m, 1H) 3.96 - 3.71 (m, 4H) 3.08 (br d, J= 3.2 Hz, 1H) 2.78 - 2.64 (m, 1H) 2.19 - 1.97 (m, 1H) 1.89 - 1.66 (m, 2H) 1.51 - 1.35 (m, 9H).General Procedure 20

[0348] Synthesis of tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-methoxypiperidine-l- carboxylate115QB\184200.00266\99637562.4VVID 754PC

[0349] 2-bromo-6-chloro-4-iodopyridine was obtained as described in General Procedure 4, step 1.

[0350] Step 1. tert-butyl 2'-bromo-6'-chloro-5,6-dihydro-[3,4'-bipyridine]-l(2H)-carboxylate

[0351] To a solution of 2-bromo-6-chloro-4-iodo-pyridine (955 mg, 3.00 mmol) and l-Boc-5,6- dihydro-2H-pyridine-3-boronic acid pinacol ester (974 mg, 3.15 mmol) in 1,4-dioxane (8 mb) and water (2 mb) was added Pd(dppf)C12 (109 mg, 0.15 mmol) and K2CO3 (1037 g, 7.5 mmol). The reaction mixture at 75 °C for 12 hours under N2. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / heptane) to give tert-butyl 2'-bromo-6'-chloro-5,6-dihydro-[3,4'-bipyridine]-l(2H)-carboxylate (869 mg, 2.33 mmol) as white solid. LCMS [M+H]+: 373 / 375 Retention Time: 1.662 min (Method 6).

[0352] Step 2. tert-butyl l-(2-bromo-6-chloropyridin-4-yl)-7-oxa-3-azabicyclo[4.1.0]heptane-3- carboxylate

[0353] To a solution of tert-butyl 2'-bromo-6'-chloro-5,6-dihydro-[3,4'-bipyridine]-l(2H)-carboxylate (1.87 g, 5.00 mmol) in DCM (8 mb) was added 3 -chloroperbenzoic acid (4.48 g, 20.0 mmol). The reaction mixture was stirred at room temperature for 48 hours. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with IN NaOH solution, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl l-(2-bromo-6-chloropyridin-4- yl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (876 mg, 2.25 mmol) as white solid. LCMS [M+H]+: 389 / 391 Retention Time: 2.885 min (Method 4).

[0354] Step 3. tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxypiperidine-l-carboxylate

[0355] To a solution of tert-butyl l-(2-bromo-6-chloropyridin-4-yl)-7-oxa-3-azabicyclo[4.1.0]heptane- 3-carboxylate (585 mg, 1.50 mmol) in THF (2 mb) was added LiAlEL (1.0 M in THF, 3.0 mb, 3.0 mmol) dropwise at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C. The mixture was quenched with saturated aqueous potassium sodium tartrate solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxypiperidine-l-carboxylate (236 mg, 0.600 mmol) as white solid. LCMS [M+H]+: 391 / 393 Retention Time: 2.621 min (Method 2).

[0356] Step 4. tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-methoxypiperidine-l-carboxylate

[0357] To a solution of tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-3-hydroxypiperidine-l- carboxylate in THF (5 mL) was added NaH (60% in mineral oil, 70.0 mg, 1.95 mmol) at 0 °C. After stirring for 10 minutes, Mel (65.3 pL, 149 mg, 1.05 mmol) was added at 0 °C. The reaction mixture was116QB\184200.00266\99637562.4VVID 754PC slowly warmed to room temperature and stirred for 5 hours. The mixture was quenched with saturated aqueous NH C I -solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over ISfeSCE, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / heptane) to give tert-butyl 3-(2-bromo-6- chloropyridin-4-yl)-3 -methoxypiperidine- 1 -carboxylate (103 mg, 0.255 mmol) as colorless oil. LCMS [M+H]+: 405 / 407 Retention Time: 2.765 min (Method 2).General Procedure 21

[0358] Synthesis of tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-methoxy-4-methylpiperidine-l- carboxylate

[0359] Step 1. tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-oxopiperidine-l-carboxylate

[0360] To a solution of 4-bromo-2,6-dichloropyridine (4.54 g, 20.0 mmol) and tert-butyl 4- oxopiperidine- 1 -carboxylate (4.38 g, 22.0 mmol) in THF (250 mb) was added Xantphos Pd G3 (0.948 g, 1.00 mmol and KOPh (5.29 g, 40.0 mmol). The reaction mixture was stirred at 60 °C for 72 hours. The mixture was quenched with saturated aqueous NH4CI solution and was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-oxopiperidine-l -carboxylate (3.43 g, 9.93 mmol) as white solid. LCMS [M+H]+: 345 Retention Time: 2.610 min (Method 2).

[0361] Step 2. tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-hydroxy-4-methylpiperidine-l- carboxylate

[0362] To a solution of tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-oxopiperidine-l-carboxylate (1.46 g, 4.22 mmol) in THF (17 mb) was added MeMgBr (3.0 M in diethyl ether, 7.03 mb, 21.1 mmol) dropwise at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl 3- (2,6-dichloropyridin-4-yl)-4-hydroxy-4-methylpiperidine-l-carboxylate (939 mg, 2.60 mmol) as white foam. LCMS [M+H]+: 361 Retention Time: 2.631 min (Method 2).117QB\184200.00266\99637562.4VVID 754PC

[0363] Step 3. tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-methoxy-4-methylpiperidine-l- carboxylate

[0364] To a solution of tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-hydroxy-4-methylpiperidine-l- carboxylate (537 mg, 1.49 mmol) in THF (15 mL) was added NaH (60% in mineral oil, 594 mg, 14.9 mmol) at 0 °C. After stirring for 10 minutes, Mel (1265 mg, 0.555 mL, 8.91 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 5 hours. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl 3 -(2,6-dichloropyridin-4-yl)-4-methoxy-4-methylpiperidine-l -carboxylate (428 mg, 1.14 mmol) as a colorless oil and as a mixture of diastereomers. LCMS [M+H]+: 375 Retention Time: 2.774 min & 2.864 min (Method 2).General Procedure 22

[0365] Synthesis of tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-methoxypiperidine-l-carboxylate

[0366] tert-butyl 3 -(2,6-dichloropyridin-4-yl)-4-oxopiperidine-l -carboxylate was obtained from General Procedure 21, step 1.

[0367] Step 1. tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-hydroxypiperidine-l-carboxylate

[0368] To a solution of tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-oxopiperidine-l-carboxylate (518 mg, 1.50 mmol) in MeOH (12 mL) was added NaBH4(170 mg, 4.50 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl 3-(2,6- dichloropyridin-4-yl)-4-hydroxypiperidine-l -carboxylate (508 mg, 1.46 mmol) as white solid and as a mixture of diastereomers. LCMS [M+H]+: 347 Retention Time: 2.508 min & 2.553 min (Method 2).

[0369] Step 2. tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-methoxypiperidine-l-carboxylate

[0370] To a solution of tert-butyl 3-(2,6-dichloropyridin-4-yl)-4-hydroxypiperidine-l-carboxylate (263 mg, 0.757 mmol) in THF (8 mL) was added NaH (60% in mineral oil, 151 mg, 3.78 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes and Mel (0.141 mL, 322 mg, 2.27 mmol) was added at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 5 hours. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined118QB\184200.00266\99637562.4VVID 754PC organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / heptane) to give tert-butyl 3 -(2,6-dichloropyridin-4-yl)-4-methoxypiperidine-l -carboxylate (145 mg, 0.402 mmol) as colorless oil and as a mixture of diastereomers. LCMS [M+H]+: 361 Retention Time: 2.697 min & 2.777 min (Method 2).General Procedure 23

[0371] Synthesis of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-hydroxypiperidine-l- carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-hydroxypiperidine-l-carboxylate

[0372] Step 1. tert-butyl 3-oxo-3,6-dihydropyridine-l(2H)-carboxylate

[0373] To a solution of tert-butyl 3-hydroxy-3,6-dihydropyridine-l(2H)-carboxylate (20.0 g, 100 mmol) in DCM (800 m ) was added Dess-Martin periodinane (85.1 g, 201 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was poured into saturated NaHCOs (800 mb) and extracted with DCM (500 mb x 3). The combined organic layers were washed with brine (300 mb x 2), dried over ISfeSCh, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCh, 0-30% EtOAc / petroleum) to give tert-butyl 3-oxo-3,6-dihydropyridine- 1(2H) -carboxylate (12.0 g, 60.8 mmol) as brown oil.1H NMR (400 MHz, CDCh) 5 ppm 7.11 - 6.95 (m, 1H) 6.19 (dt, J= 10.4, 2.4 Hz, 1H) 4.24 (br s, 2H) 4.14 - 4.10 (m, 2H) 1.49 (s, 9H).

[0374] Step 2. tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-oxopiperidine-l-carboxylate

[0375] To a solution of 2-bromo-6-chloropyridine (35.1 g, 183 mmol) in THF (400 m ) was added TMPEi MgCl EiCl (219 mb, 219 mmol) dropwise at 0 °C under N2. The reaction mixture was stirred at 20 °C for 1 hour. Then, Cui (17.4 g, 91.3 mmol) was added at 0 °C under N2. The mixture was stirred for 20 °C for 1 hour. Then, a mixture of tert-butyl 3-oxo-3,6-dihydropyridine-l(2H)-carboxylate (12.0 g, 60.8 mmol) and TMSC1 (13.2 g, 122 mmol) in THF (400 mb) at 0 °C under N2. The reaction mixture was stirred at 20 °C for 2 hours. The mixture was poured into saturated NH4CI (500 mb) and MeOH (60 mb) and extracted with EtOAc (200 mb x 3). The combined organic layers were washed with brine (150 mb x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 10-50% EtOAc / petroleum ether) to give compound tert-butyl 3-(2- bromo-6-chloropyridin-4-yl)-5-oxopiperidine-l-carboxylate (10.5 g, 26.9 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.31 (s, 1H) 7.17 (s, 1H) 4.31 - 3.97 (m, 3H) 3.70 - 3.37 (m, 1H) 3.30 (tt, J= 9.2, 4.8 Hz, 1H) 2.88 - 2.74 (m, 1H) 2.71 - 2.56 (m, 1H) 1.45 (s, 9H).119QB\184200.00266\99637562.4VVID 754PC

[0376] Step 3. trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-hydroxypiperidine-l- carboxylate and cis tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-hydroxypiperidine-l-carboxylate

[0377] To a solution of tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-oxopiperidine-l-carboxylate (4.00 g, 10.3 mmol) in THF (40 mL) was added L-selectride (20.5 mL, 20.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. The mixture was quenched with aqueous IN HC1 (50 mL) at 0 °C and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 10-50% EtOAc / petroleum ether) to give tertbutyl 3-(2-bromo-6-chloropyridin-4-yl)-5-hydroxypiperidine-l-carboxylate (1.40 g, 3.57 mmol) as yellow oil. tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-hydroxypiperidine-l-carboxylate (1.30 g, 3.31 mmol) was separated by preparative HPLC (Agela DuraShell NH2150 mm x 30 mm, 5 pm; 5-45% 4: 1 IPA:ACN / heptane) to give trans tert-butyl 3 -(2-bromo-6-chloropyridin-4-yl)-5 -hydroxypiperidine- 1- carboxylate (420 mg, 1.07 mmol) as yellow oil: 'H NMR (400 MHz, CDCk) 5 ppm 7.31 (s, 1H) 7.17 (s, lH) 4.10 (br s, 3H) 3.27 - 3.15 (m, 1H) 3.12 - 2.74 (m, 2H) 2.11 (br d, J= 13.6 Hz, 1H) 1.83 - 1.73 (m, 2H) 1.49 (s, 9H); and cis tert-butyl 3 -(2-bromo-6-chloropyridin-4-yl)-5 -hydroxypiperidine- 1 -carboxylate (560 mg, 1.43 mmol) as white solid: 'H NMR (400 MHz, CDCh) 5 ppm 7.32 (s, 1H) 7.18 (s, 1H) 4.44 - 4.01 (m, 2H) 3.86 - 3.69 (m, 1H) 2.83 - 2.44 (m, 3H) 2.29 (br d, J= 13.2 Hz, 1H) 1.56 (br s, 2H) 1.48 (s, 9H).General Procedure 24

[0378] Synthesis of tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)piperidine-l- carboxylate

[0379] 2-bromo-6-chloro-4-iodopyridine was obtained as described in General Procedure 1, step 1.

[0380] Step 1. tert-butyl 5-bromo-3-(hydroxymethyl)-3,4-dihydropyridine-l(2H)-carboxylate

[0381] To a solution of 5-bromo-l-(tert-butoxycarbonyl)-l,2,3,4-tetrahydropyridine-3-carboxylic acid (2.38 g, 7.77 mmol) in THF (80 mL) was added BH3 SMe2(1.18 g, 1.47 mL, 15.5 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 14 hours. The mixture was quenched by the dropwise addition of MeOH (40 mL) at 0 °C and concentrated under reduced pressure.120QB\184200.00266\99637562.4VVID 754PCThe residue was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried over ISfeSCE, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCh, 0-100% EtOAc / heptane) to give tert-butyl 5-bromo-3-(hydroxymethyl)- 3,4-dihydropyridine-l(2H)-carboxylate (1200 mg, 4.11 mmol) as colorless oil. 'H NMR (400 MHz, DMSO) 5 7.00 (d, J= 24.5 Hz, 1H), 3.55 (t, J= 6.8 Hz, 1H), 3.43 - 3.37 (m, 1H), 3.29 (dd, J= 10.7, 7.2 Hz, 1H), 2.37 (ddt, J= 17.3, 5.7, 1.4 Hz, 1H), 2.19 (ddd, J= 17.2, 8.8, 2.1 Hz, 1H), 1.88 - 1.81 (m, 1H), 1.58 - 1.49 (m, 1H), 1.44 (s, 9H).

[0382] Step 2. tert-butyl 5-bromo-3-(methoxymethyl)-3,4-dihydropyridine-l(2H)-carboxylate

[0383] To a solution of tert-butyl 5-bromo-3-(hydroxymethyl)-3,4-dihydropyridine-l(2H)-carboxylate (1112 mg, 3.81 mmol) in THF (15 mL) was added NaH (228 mg, 5.71 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred for 15 minutes and Mel (810 mg, 0.355 mL, 5.71 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 14 hours. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give tert-butyl 5-bromo-3-(methoxymethyl)-3,4-dihydropyridine-l(2H)-carboxylate (396 mg, 1.29 mmol) as yellowish oil. LCMS [M+Na]+: 328 / 330 Retention Time: 1.633 min (Method 6).

[0384] Step 3. tert-butyl 3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydropyridine-l(2H)-carboxylate

[0385] To a solution of tert-butyl 5-bromo-3-(methoxymethyl)-3,4-dihydro-2H-pyridine-l-carboxylate (392 mg, 1.28 mmol) in toluene (5 mL) was added Ph EE (423 mg, 1.66 mmol), Pd(dppf)C12 (46.3 mg, 0.064 mmol) and KOAc (352 mg, 3.58 mmol). The reaction mixture was stirred at 80 °C for 14 hours. The cooled reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tertbutyl 3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-l(2H)- carboxylate. The crude product was used in the next step without further purification. LCMS [M- C5HSO2+H]+: 254 Retention Time: 2.847 min (Method 2).

[0386] Step 4. tert-butyl 2'-bromo-6'-chloro-5-(methoxymethyl)-5,6-dihydro-[3,4'-bipyridine]- l(4H)-carboxylate

[0387] To a solution of crude tert-butyl 3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-3,4-dihydro-2H-pyridine-l -carboxylate (452 mg, 1.28 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was added 2-bromo-6-chloro-4-iodo-pyridine (427 mg, 1.34 mmol), K2CO3 (442 mg, 3.20 mmol) and Pd(dppf)C12 (46.3 mg, 0.064 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The121QB\184200.00266\99637562.4VVID 754PC combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / heptane) to give tert-butyl 2'-bromo-6'-chloro-5-(methoxymethyl)-5,6-dihydro-[3,4'-bipyridine]-l(4H)-carboxylate (176 mg, 0.422 mmol) as yellow oil. LCMS [ M-C Hs+HI : 361 / 363. Retention Time: 2.933 min (Method 2)

[0388] Step 5. 2-bromo-6-chloro-4-(5-(methoxymethyl)piperidin-3-yl)pyridine

[0389] To a solution of tert-butyl 5-(2-bromo-6-chloro-4-pyridyl)-3-(methoxymethyl)-3,4-dihydro- 2H-pyridine-l -carboxylate (176 mg, 0.421 mmol) in DCM (1.5 m ) and TFA (1.5 m ) was added Et.SiH (490 mg, 0.673 mb, 4.21 mmol) at 0 °C. The reaction mixture was stirred for 12 hours at 60 °C. The mixture was concentrated under reduced pressure to give crude 2-bromo-6-chloro-4-(5- (methoxymethyl)piperidin-3-yl)pyridine which was used in the next step without further purification.

[0390] Step 6. tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)piperidine-l- carboxylate

[0391] To a solution of crude 2-bromo-6-chloro-4-[5-(methoxymethyl)-3-piperidyl]pyridine (135 mg, 0.421 mmol) in DCM ( 4 mb) was added TEA (213 mg, 0.294 mb, 2.11 mmol) and BOC2O (184 mg, 0.843 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature, diluted with water and extracted with DCM (3x). The combined organic layers were dried over ISfeSCh, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / heptane) to give tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-5- (methoxymethyl)piperidine-l -carboxylate (47.2 mg, 0.113 mmol) as colorless oil. LCMS [M+H]+:419 / 421 Retention Time: 2.811 min (Method 2).General Procedure 25

[0392] Synthesis of tert-butyl (2R,5R)-5-(2-bromo-6-chloropyridin-4-yl)-2-(hydroxymethyl)piperidine-l-carboxylate and tert-butyl (2R,5S)-5-(2-bromo-6-chloropyridin-4-yl)-2-(hydroxymethyl)piperidine-l-carboxylate122QB\184200.00266\99637562.4VVID 754PC

[0393] Step 1. methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate

[0394] To a solution of 2-bromo-6-chloro-4-methylpyridine (25.0 g, 121 mmol) in THF (300 mL) was added LDA (121 mL, 242 mmol, 2 M in w-heptane / THF) dropwise at -78 °C under N2. The reaction mixture was stirred at -78 °C for 1 hour. Then, dimethyl carbonate (26.2 g, 291 mmol) in THF (50 mL) was added dropwise at -78 °C under N2. The mixture was warmed to 0 °C and stirred for 1 hour. Then, the mixture was warmed to 20 °C and stirred for another 2 hours. The mixture was poured into saturated aqueous NH4CI (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-5% EtOAc / petroleum ether) to give methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (29.0 g, 110 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 ppm 7.38 (s, 1H), 7.25 (s, 1H), 3.74 (s, 3H), 3.60 (s, 2H).

[0395] Step 2. dimethyl (5R)-2-(2-bromo-6-chloropyridin-4-yl)-5-((ter / -butoxycarbonyl)amino)- hexanedioate

[0396] To a solution of methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (11.5 g, 43.5 mmol) in DMF (110 mL) was added CS2CO3 (18.4 g, 56.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour under N2. Then, methyl (R)-2-((tert-butoxycarbonyl)amino)-4-iodobutanoate (13.4 g, 39.1 mmol) was added at 0 °C and the reaction mixture was stirred at 25 °C for 2 hours. The mixture was poured into brine (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 20-50% EtOAc / petroleum ether) to give dimethyl (5R)-2-(2-bromo-6-chloropyridin-4-yl)-5-((tert-butoxycarbonyl)amino)hexanedioate (16.4 g, 34.1 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 ppm 7.38 (d, J= 10.8 Hz, 1H), 7.27 - 7.23 (m, 1H), 5.13 - 5.04 (m, 1H), 4.42 - 4.29 (m, 1H), 3.76 (d, J= 7.6 Hz, 3H), 3.72 (d, J= 6.0 Hz, 3H), 3.69 - 3.50 (m, 1H), 2.20 - 2.06 (m, 1H), 1.87 - 1.72 (m, 2H), 1.67 - 1.51 (m, 1H), 1.45 (s, 9H).

[0397] Step 3. dimethyl (2R)-2-amino-5-(2-bromo-6-chloropyridin-4-yl)hexanedioate

[0398] To a solution of dimethyl (5R)-2-(2-bromo-6-chloropyridin-4-yl)-5-((tert- butoxycarbonyl)amino)hexanedioate (16.0 g, 33.4 mmol) in MeOH (100 mL) was added HCl / methanol (4 M, 30 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated under reduced pressure to give dimethyl (2R)-2-amino-5-(2-bromo-6-chloropyridin-4- yl)hexanedioate (13.77 g, crude) as HC1 salt as yellow solid. The crude product was used in the next step without further purification. 'H NMR (400 MHz, MeOD-< ) 5 ppm 7.57 (t, J= 1.2 Hz, 1H), 7.45 (t, J = 1.2 Hz, lH), 4.10 (t, J= 6.0 Hz, 1H), 3.85 (d, J= 4.4 Hz, 3H), 3.83 - 3.78 (m, 1H), 3.72 (s, 3H), 2.31 - 2.10 (m, 1H), 2.00 - 1.68 (m, 3H).

[0399] Step 4. methyl (2R)-5-(2-bromo-6-chloropyridin-4-yl)-6-oxopiperidine-2-carboxylate123QB\184200.00266\99637562.4VVID 754PC

[0400] To a solution of dimethyl (2R)-2-amino-5-(2-bromo-6-chloropyridin-4-yl)hexanedioate (13.77 g, 36.27 mmol) in MeOH (100 mL) was added TEA (4.40 g, 43.5 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 80-100% EtOAc / petroleum ether) to give methyl (2R)-5-(2-bromo-6- chloropyridin-4-yl)-6-oxopiperidine-2 -carboxylate (11.00 g, 31.65 mmol) as yellow oil. 'H NMR (400 MHz, CDC13) 5 ppm 7.33 (d, J= 8.4 Hz, 1H), 7.21 (d, J= 8.8 Hz, 1H), 6.63 (br s, 1H), 4.28 - 4.20 (m, 1H), 3.87 - 3.81 (m, 3H), 3.62 - 3.50 (m, 1H), 2.44 - 2.25 (m, 1H), 2.23 - 2.11 (m, 2H), 1.99 - 1.85 (m, 1H).

[0401] Step 5. (2R)-5-(2-bromo-6-chloropyridin-4-yl)-6-oxopiperidine-2-carboxylic acid

[0402] To a solution of methyl (2R)-5-(2-bromo-6-chloropyridin-4-yl)-6-oxopiperidine-2 -carboxylate (11.0 g, 31.7 mmol) in THE (100 mL) and water (20 mL) was added LiOHH2O (1.46 g, 34.8 mmol) at0 °C. The reaction mixture was stirred at 25 °C for 1.5 hour under N2. The mixture was adjusted to pH = 2 with HC1 (3 M, 15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude (2R)-5-(2-bromo-6-chloropyridin-4-yl)-6-oxopiperidine-2 -carboxylic acid (10.1 g, 30.4 mmol) as yellow oil. The crude product was used in the next step without further purification. 'H NMR (400 MHz, McOD-^) 5 ppm 7.52 (s, 1H), 7.40 - 7.39 (m, 1H), 4.31 - 4.20 (m, 1H), 3.78 - 3.69 (m, 1H), 2.38 - 2.11 (m, 2H), 2.06 - 1.79 (m, 2H).

[0403] Step 6. ((2R)-5-(2-bromo-6-chloropyridin-4-yl)piperidin-2-yl)methanol

[0404] To a solution of (2R)-5-(2-bromo-6-chloropyridin-4-yl)-6-oxopiperidine-2 -carboxylic acid (10.0 g, 30.0 mmol) in THF (50 mL) was added BH3 THF (150 mL, 150 mmol, 1 M in THF) dropwise at 0 °C under N2. The reaction mixture was stirred at 25 °C for 30 minutes and at 70 °C for 2 hours under N2. The mixture was quenched with MeOH (30 mL) at 0 °C, stirred at 25 °C for 0.5 hour and then at70 °C for 4 hours under N2. The mixture was filtered and concentrated under reduced pressure to give crude ((2R)-5-(2-bromo-6-chloropyridin-4-yl)piperidin-2-yl)methanol (9.16 g, 30.0 mmol) as yellow oil. The crude product was used into the next step without further purification.

[0405] Step 7. tert-butyl (2R,5R)-5-(2-bromo-6-chloropyridin-4-yl)-2-(hydroxymethyl)piperidine- 1-carboxylate and tert-butyl (2R,5S)-5-(2-bromo-6-chloropyridin-4-yl)-2- (hydroxymethyl)piperidine-l-carboxylate

[0406] To a solution of ((2R)-5-(2-bromo-6-chloropyridin-4-yl)piperidin-2-yl)methanol (9.16 g, 30.0 mmol) in THF (90 mL) and water (60 mL) was added K2CC>3 (6.21 g, 44.96 mmol) and Boc2O (7.85 g, 35.97 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were124QB\184200.00266\99637562.4VVID 754PC washed with brine (50 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 20-50% EtOAc / petroleum ether) and the diastereomers were separated by SFC (DAICEL CHIRALPAK IC, 250 x 50 mm, 10 pm; 35% isopropylalcohol / CO?) to give as the first eluting isomer, tert-butyl (2R,5S)-5-(2-bromo-6-chloropyridin- 4-yl)-2-(hydroxymethyl)piperidine-l -carboxylate (3.90 g, 9.61 mmol) as yellow oil: 'H NMR (400 MHz, CDC13) 5 ppm 7.29 (s, lH), 7.16 (s, 1H), 4.54 - 4.34 (m, 1H), 4.15 - 3.99 (m, 1H), 3.86 (dd, J= 8.8, 10.8 Hz, 1H), 3.70 (dd, J = 6.4, 11.2 Hz, 1H), 3.01 - 2.73 (m, 1H), 2.71 - 2.60 (m, 1H), 1.95 - 1.77 (m, 3H), 1.70 - 1.61 (m, 1H), 1.48 (s, 9H); and as the second eluting isomer, tert-butyl (2R,5R)-5-(2-bromo-6- chloropyridin-4-yl)-2-(hydroxymethyl)piperidine-l -carboxylate (7.30 g, 17.99 mmol) as yellow oil: 'H NMR (400 MHz, CDCh) 5 ppm 7.40 (s, 1H), 7.27 (s, 1H), 4.14 - 4.02 (m, 2H), 3.87 - 3.81 (m, 1H), 3.73 (dd, J = 52, 11.2 Hz, 1H), 3.46 (dd, J= 4.4, 14.4 Hz, 1H), 2.94 - 2.87 (m, 1H), 2.14 - 2.05 (m, 1H), 1.84 - 1.74 (m, 1H), 1.69 - 1.54 (m, 2H), 1.51 (s, 9H).General Procedure 26

[0407] Synthesis of trans tert-butyl 5-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l- carboxylate

[0408] Methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate was obtained as described in GeneralProcedure 25, Step 1.

[0409] Step 1. methyl 2-(2-bromo-6-chloropyridin-4-yl)-5-((tert- butoxycarbonyl)amino)hexanoate

[0410] To a solution of methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (4.60 g, 17.39 mmol) in DMF (50 mL) was added CS2CO3 (7.37 g, 22.6 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour under N2. tert-butyl (4-bromobutan-2-yl)carbamate (4.39 g, 17.4 mmol) and Nal (2.61 g, 17.4 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was poured into brine (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2. 20-50% EtOAc / petroleum ether) to125QB\184200.00266\99637562.4VVID 754PC give methyl 2-(2-bromo-6-chloropyridin-4-yl)-5-((tert-butoxycarbonyl)amino)hexanoate (4.60 g, 10.6 mmol) as yellow oil. 'H NMR (400 MHz, CDC13) 5 ppm 7.42 - 7.36 (m, 1H), 7.29 - 7.23 (m, 1H), 4.34 - 4.23 (m, 1H), 3.79 - 3.49 (m, 5H), 2.16 - 2.05 (m, 1H), 1.84 - 1.67 (m, 1H), 1.44 (s, 9H), 1.42 - 1.32 (m, 2H), 1.12 (dd, J = 5.2, 6.4 Hz, 3H).

[0411] Step 2. methyl 5-amino-2-(2-bromo-6-chloropyridin-4-yl)hexanoate

[0412] A mixture of methyl 2-(2-bromo-6-chloropyridin-4-yl)-5-((tert- butoxycarbonyl)amino)hexanoate (3.80 g, 8.72 mmol) in HCl / methanol (4 M, 50 mb) was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give crude methyl 5-amino-2-(2- bromo-6-chloropyridin-4-yl)hexanoate (2.92 g, 8.70 mmol) as HC1 salt as yellow solid. The crude product was used in the next step without further purification. 'H NMR (400 MHz, MeOD-< ) 5 ppm 7.59 (s, 1H), 7.47 (s, 1H), 3.81 - 3.75 (m, 1H), 3.72 (s, 3H), 3.30 - 3.24 (m, 1H), 2.21 - 2.09 (m, 1H), 1.92 - 1.80 (m, 1H), 1.71 - 1.40 (m, 2H), 1.28 (dd, J= 5.2, 6.4 Hz, 3H).

[0413] Step 3. trans 3-(2-bromo-6-chloropyridin-4-yl)-6-methylpiperidin-2-one and cis 3-(2- bromo-6-chloropyridin-4-yl)-6-methylpiperidin-2-one

[0414] To a solution of methyl 5-amino-2-(2-bromo-6-chloropyridin-4-yl)hexanoate as HC1 salt (2.92 g, 8.70 mmol) in MeOH (50 mb) was added TEA (1.06 g, 10.4 mmol). The reaction mixture was stirred at 80 °C for 12 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (80 mb) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCE, 0-47% EtOAc / petroleum ether) to give trans 3-(2-bromo-6- chloropyridin-4-yl)-6-methylpiperidin-2-one (1.29 g, 4.25 mmol) as white solid: 'H NMR (400 MHz, CDCI3) 5 ppm 7.32 (s, lH), 7.19 (s, 1H), 6.16 (br s, 1H), 3.71 - 3.61 (m, 1H), 3.49 (dd, J= 6.0, 11.6 Hz, 1H), 2.23 - 2.15 (m, 1H), 2.09 - 2.01 (m, 1H), 1.93 - 1.81 (m, 1H), 1.58 - 1.45 (m, 1H), 1.25 (d, J= 6.0 Hz, 3H), and cis 3-(2-bromo-6-chloropyridin-4-yl)-6-methylpiperidin-2-one (560 mg, 1.84 mmol) as white solid: 'H NMR (400 MHz, CDCh) 5 ppm 7.33 (s, 1H), 7.21 (s, 1H), 6.44 (br s, 1H), 3.71 - 3.59 (m, 2H), 2.21 - 2.10 (m, 1H), 2.07 - 1.96 (m, 1H), 1.95 - 1.86 (m, 1H), 1.54 - 1.42 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H).

[0415] Step 4. trans 2-bromo-6-chloro-4-(6-methylpiperidin-3-yl)pyridine

[0416] To a solution of trans 3-(2-bromo-6-chloropyridin-4-yl)-6-methylpiperidin-2-one (1.20 g, 3.95 mmol) in THF (15 mL) was added BH3 THF (19.8 mL, 19.8 mmol, 1 M in THF) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 hour and then at 70 °C for 2 hours. The mixture was quenched with MeOH (30 mL) at 0 °C, stirred for 0.5 hour at 25 °C and then at 70 °C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude trans 2- bromo-6-chloro-4-(6-methylpiperidin-3-yl)pyridine (1.14 g, 3.94 mmol) as yellow oil. The crude product was used into the next step without further purification.1H NMR (400 MHz, MeOD-< ) 5 ppm 7.48 (d, J126QB\184200.00266\99637562.4VVID 754PC= 1.2 Hz, 1H), 7.36 (d, J= 0.8 Hz, 1H), 3.10 - 3.04 (m, 1H), 2.74 - 2.63 (m, 3H), 2.00 - 1.92 (m, 1H), 1.86 - 1.78 (m, 1H), 1.74 - 1.54 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H).

[0417] Step 5. trans tert-butyl 5-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l- carboxylate

[0418] To a solution of trans 2-bromo-6-chloro-4-[rac-(3S,6R)-6-methyl-3-piperidyl]pyridine (1.14 g, 3.94 mmol) in THF (15 mL) and water (10 mL) was added K2CO3 (816 mg, 5.90 mmol) and BOC2O (1.03 g, 4.72 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-8% EtOAc / petroleum ether) to give trans tert-butyl 5-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperidine-l-carboxylate (1.19 g, 3.05 mmol) as colorless oil. 'H NMR (400 MHz, CDCh) 5 ppm 7.43 (s, 1H), 7.31 (s, 1H), 4.38 - 4.26 (m, 2H), 3.27 (dd, J= 4.0, 14.4 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.21 - 2.10 (m, 1H), 1.85 - 1.76 (m, 1H), 1.67 - 1.56 (m, 2H), 1.51 (s, 9H), 1.20 (d, J= 6.8 Hz, 3H).General Procedure 27

[0419] Synthesis of trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperidine-l- carboxylate and cis tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperidine-l-carboxylate(translcis = 2 / 3)

[0420] Step 1. 4-bromo-2-chloro-6-iodopyridine

[0421] To a solution of 4-bromo-2 -chloropyridine (20.0 g, 104 mmol) in THF (250 mL) was added TMPMgCl LiCl (125 mL, 125 mmol) dropwise at 0 °C under N2. The reaction mixture was stirred for 1 hour at 20 °C. Then, I2(27.7 g, 109 mmol) was added at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C. The mixture was quenched with saturated NH4CI (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with saturated Na2SO3 (200 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to give 4-bromo-2-chloro-6-iodopyridine (6.80 g,127QB\184200.00266)99637562.4VVID 754PC21.40 mmol) as yellow solid. 'H NMR (400 MHz, CDC13) 5 ppm 7.87 (d, J= 1.2 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H).

[0422] Step 2. tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-3-hydroxy-2-methylpiperidine-l- carboxylate

[0423] To a solution of 4-bromo-2-chloro-6-iodopyridine (2.00 g, 6.28 mmol) in toluene (20 mL) was added iPrMgCl LiCl (6.28 mL, 8.16 mmol) dropwise at -20 °C and stirred at -20 °C for 1 hour. Then, a solution of tert-butyl 2-methyl-3-oxopiperidine-l-carboxylate (1.34 g, 6.28 mmol) in toluene (5 mL) was added dropwise at -20 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was poured into saturated NH4CI (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL. 20-30% EtOAc / petroleum ether) to give tert-butyl 3 -(4-bromo-6-chloropyridin-2-yl)-3-hydroxy-2-methylpiperidine-l -carboxylate (900 mg, 2.22 mmol) as yellow oil. 'H NMR (400 MHz, CDC13) 5 ppm 7.69 (d, J= 1.2 Hz, 1H), 7.44 (d, J= 1.2 Hz, 1H), 4.77 - 4.52 (m, 1H), 4.05 - 3.82 (m, 1H), 3.60 (br s, 1H), 3.07 - 2.89 (m, 1H), 2.48 (t, J= 6.8 Hz, 1H), 2.15 - 1.74 (m, 3H), 1.51 - 1.47 (m, 9H), 1.30 (d, J= 6.8 Hz, 3H).

[0424] Step 3. tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methyl-3-(((methylthio)carbono- thioyl)oxy)piperidine-l-carboxylate

[0425] To a solution of tert-butyl 3-(4-bromo-6-chloropyridin-2 -yl) -3 -hydroxy-2 -methylpiperidine- 1- carboxylate (900 mg, 2.22 mmol) in THF (20 mL) was added NaH (686 mg, 17.1 mmol, 60%) at 0 °C and stirred at 25 °C for 0.5 hour. Then, CS2 (1.67 g, 22.0 mmol) was added at 25 °C and the mixture was stirred at 25 °C for 50 minutes. Then, Mel (3.77 g, 26.6 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 hours under N2. The mixture was poured into saturated NH4CI (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to give tert-butyl 3-(4- bromo-6-chloropyridin-2-yl)-2-methyl-3-(((methylthio)carbono-thioyl)oxy)piperidine-l-carboxylate (650 mg, 1.31 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.77 (br s, 1H), 7.38 (d, J= 1.2 Hz, 1H), 6.20 - 5.77 (m, 1H), 4.10 - 3.74 (m, 1H), 3.04 - 2.87 (m, 1H), 2.80 - 2.68 (m, 1H), 2.46 (s, 3H), 2.31 - 2.15 (m, 1H), 1.50 (s, 10H), 1.33 (d, J= 6.8 Hz, 4H).

[0426] Step 4. cis tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperidine-l-carboxylate

[0427] To a solution of tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methyl-3- (((methylthio)carbono-thioyl)oxy)piperidine-l -carboxylate (650 mg, 1.31 mmol) in toluene (10 mL) was added (n-Bu)3SnH (550 mg, 1.88 mmol) and AIBN (0.400 g, 1.96 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 2 hours under N2. The mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under128QB\184200.00266\99637562.4VVID 754PC reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-5% EtOAc / petroleum ether) to give cis tert-butyl 3-(4-bromo-6-chloropyridin-2 -yl)-2 -methylpiperidine- 1- carboxylate (540 mg, 1.25 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.53 - 7.27 (m, 2H), 4.91 - 4.56 (m, 1H), 4.31 - 3.87 (m, 1H), 3.21 - 2.97 (m, 1H), 2.94 - 2.61 (m, 1H), 2.50 - 2.37 (m, 1H), 2.12 - 1.91 (m, 1H), 1.90 - 1.81 (m, 1H), 1.51 - 1.45 (m, 10H), 0.99 - 0.79 (m, 3H).

[0428] Step 5. Mixture of trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperidine-l- carboxylate and cis tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperidine-l-carboxylate

[0429] To a solution of cis tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperidine-l- carboxylate (540 mg, 1.25 mmol) in MeCN (7 mb) was added DBU (500 mg, 3.75 mmol) at 25 °C under N2. The reaction mixture was warmed to 90 °C and stirred for 16 hours. The mixture was concentrated, and the crude product was purified by column chromatography (SiC>2, 0-10% EtOAc / petroleum ether) to give mixture of trans tert-butyl 3 -(4-bromo-6-chloropyridin-2-yl)-2-m ethylpiperidine- 1 -carboxylate and cis tert-butyl 3 -(4-bromo-6-chloropyridin-2-yl)-2-methylpiperidine-l -carboxylate (350 mg, 0.44 mmol) as white solid (trans / cis = 2 / 3).General Procedure 28

[0430] Synthesis of N-methyl-6-(trimethylstannyl)pyrimidine-4-carboxamide

[0431] Step 1. 6-chloropyrimidine-4-carbonyl chloride

[0432] To a solution of 6-hydroxypyrimidine-4-carboxylic acid (7.00 g, 50.0 mmol) in SOCI2 (70.3 mb, 969 mmol) was added DMF (0.292 g, 4.00 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 12 hours under N2. The mixture was concentrated under reduced pressure to give 6- chloropyrimidine-4-carbonyl chloride (8.50 g, 48.0 mmol) which was used in the next step without further purification. 'H NMR (400 MHz, CDCh) 5 ppm 9.25 (s, 1H), 8.02 (d, J= 0.9 Hz, 1H).

[0433] Step 2. 6-chloro-N-methylpyrimidine-4-carboxamide

[0434] To a solution of MeNH2HC1 (4.22 g, 64.4 mol) in DCM (40 mL) was added TEA (26.7 mb, 19.4 g, 192 mmol) at 0 °C under N2. Then, a solution of 6-chloropyrimidine-4-carbonyl chloride (8.50 g, 48.0 mmol) in DCM (80 mL) was added dropwise at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified with column chromatography (SiC>2, 0 - 30% EtOAc / petroleum ether) to give 6-chloro-N-methylpyrimidine-4-carboxamide (8.00 g,129QB\184200.00266\99637562.4VVID 754PC46.6 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.99 (s, 1H), 8.16 (d, J= 0.9 Hz, 1H), 8.03 - 7.76 (m, 1H), 3.07 (d, J= 5.1 Hz, 3H).

[0435] Step 3. N-methyl-6-(trimethylstannyl)pyrimidine-4-carboxamide

[0436] To a solution of 6-chloro-N-methylpyrimidine-4-carboxamide (20 g, 117 mmol) in toluene (200 mL) was added 1,1,1,2,2,2-hexamethyldistannane (57.30 g, 174.85 mmol) and Pd(PPh3)4(13.47 g, 11.66 mmol) at 25 °C. The mixture was stirred at 100 °C for 8 hours under N2. The mixture solution was poured into saturated aqueous KF (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4. filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 5% EtOAc / petroleum ether) to afford N-methyl-6-trimethylstannyl-pyrimidine-4-carboxamide (22.30 g, 74.3 mmol) as a white solid. 'H NMR (400 MHz, CDCh) 5 ppm 9.32 - 9.16 (m, 1H), 8.27 (d, J= 1.6 Hz, 1H), 8.01 (br s, 1H), 3.04 (d, J= 5.2 Hz, 3H), 0.48 - 0.33 (m, 9H).General Procedure 29

[0437] Synthesis of 6-chloro-N,2-dimethylpyrimidine-4-carboxamide

[0438] Step 1. 6-chloro-2-methylpyrimidine-4-carbonyl chloride

[0439] To a solution of 6-hydroxy-2-methylpyrimidine-4-carboxylic acid (7.94 g, 51.5 mmol) in SOCh (80 mL) was added DMF (0.397 mL, 0.377 g, 5.15 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 12 hours under N2. The mixture was concentrated under reduced pressure and crude 6-chloro-2-methylpyrimidine-4-carbonyl chloride (9.84 g, 51.5 mmol) was obtained as yellow solid. The crude product was used in the next step without further purification.

[0440] Step 2. 6-chloro-N,2-dimethylpyrimidine-4-carboxamide

[0441] To a solution of MeNH2HC1 (4.50 g, 66.7 mmol) and TEA (18.2 g, 180 mmol) in DCM (50 mL) was added 6-chloro-2-methylpyrimidine-4-carbonyl chloride (9.80 g, 51.3 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. The mixture was diluted with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to give 6-chloro-N,2- dimethylpyrimidine-4-carboxamide (5.67 g, 30.5 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.02 - 7.84 (m, 2H), 3.05 (d, J= 5.1 Hz, 3H), 2.75 (s, 3H).130QB\184200.00266\99637562.4VVID 754PCGeneral Procedure 30

[0442] Synthesis of 6-chloro-2-methoxy-N-methylpyrimidine-4-carboxamide

[0443] Step 1. 6-hydroxy-2-methoxypyrimidine-4-carboxylic acid

[0444] To a solution of NaOH (12.8 g, 319 mmol) in water (160 mL) was added methyl carbamimidate hydrochloride (11.7 g, 106 mmol) and diethyl 2-oxosuccinate (20.0 g, 106 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 4 hours. Then, HC1 (12 M) was added to adjust the pH to 1. The mixture was stirred for 10 minutes and filtered. The filter cake was dried under reduced pressure to give 6-hydroxy-2-methoxypyrimidine-4-carboxylic acid (12.0 g, 70.5 mmol) as white solid. 'H NMR (400 MHz, DMSO-d6) 5 ppm 13.82 - 12.13 (m, 2H), 6.51 (s, 1H), 3.92 (s, 3H).

[0445] Step 2. 6-chloro-2-methoxypyrimidine-4-carbonyl chloride

[0446] To a solution of 6-hydroxy-2-methoxypyrimidine-4-carboxylic acid (12.0 g, 70.5 mmol) in DCM (120 mL) was added SOCL (25.6 mL, 42.0 g, 353 mmol) and DMF (0258 g, 3.53 mmol) at 0 °C. The reaction mixture was stirred at 40 °C for 16 hours under N2. The mixture was concentrated under reduced pressure to give crude 6-chloro-2-methoxypyrimidine-4-carbonyl chloride (14.6 g, 70.5 mmol) was obtained as yellow solid which was used in the next step without further purification.

[0447] Step 3. 6-chloro-2-methoxy-N-methylpyrimidine-4-carboxamide

[0448] To a solution of MeNH2HC1 (7.14 g, 106 mmol) and TEA (14.3 g, 141 mmol) in DCM (50 mL) was added 6-chloro-2-methoxypyrimidine-4-carbonyl chloride (14.6 g, 70.5 mmol) in DCM (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-25% EtOAc / petroleum ether) to give 6-chloro-2- methoxy-N-methylpyrimidine-4-carboxamide (5.20 g, 25.8 mmol) as pale yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.78 (s, 2H), 4.09 (s, 3H), 3.03 (d, J= 5.1 Hz, 3H).General Procedure 31

[0449] Synthesis of 6-chloro-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide131QB\184200.00266\99637562.4VVID 754PC

[0450] Step 1. 4-chloro-6-methoxy-2-(trifluoromethyl)pyrimidine

[0451] To a solution of 4,6-dichloro-2-(trifhioromethyl)pyrimidine (25.0 g, 115 mmol) in MeOH (250 mL) was added NaOMe (21.8 g, 121 mmol, 30% purity) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 12 hours under N2. The mixture was concentrated, diluted with water (60 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-chloro-6-methoxy-2- (trifhioromethyl)pyrimidine (24.0 g, 113 mmol) as yellow green oil. 'H NMR (400 MHz, CDCh) 5 ppm 6.92 (s, 1H) 4.09 (s, 3H).

[0452] Step 2. methyl 6-methoxy-2-(trifluoromethyl)pyrimidine-4-carboxylate

[0453] To a solution of 4-chloro-6-methoxy-2-(trifluoromethyl)pyrimidine (30.0 g, 141 mmol) in MeOH (300 mL) was added Pd(dppf)C12 (10.2 g, 14.1 mmol) and TEA (59.2 mL, 42.8 g, 423 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 12 hours under CO (50 psi). The mixture was filtered, concentrated under reduced pressure, diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-20% EtOAc / petroleum ether) to give methyl 6-methoxy-2-(trifluoromethyl)pyrimidine-4- carboxylate (23.0 g, 97.4 mmol) as white solid. 'H NMR (400 MHz, CDCL) 5 ppm 7.58 (s, 1H) 4.14 (s, 3H) 4.04 (s, 3H).

[0454] Step 3. 6-methoxy-2-(trifluoromethyl)pyrimidine-4-carboxylic acid

[0455] To a solution of methyl 6-methoxy-2-(trifluoromethyl)pyrimidine-4-carboxylate (23.0 g, 97.4 mmol) in THE (230 mL) and water (23 mL) was added LiOH (11.7 g, 487 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. The pH was adjusted to pH 4-5 by aq. HC1 (I N) and the mixture was extracted with EtOAc (50 mL x 6). The combined organic layers were concentrated under reduced pressure to give 6-methoxy-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (19.0 g, 85.5 mmol) as white solid. The crude product was used in the next step without further purification.1H NMR (400 MHz, CD3OD) 5 ppm 7.60 (s, 1H) 4.12 (s, 3H).

[0456] Step 4. 6-methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide132QB\184200.00266)99637562.4VVID 754PC

[0457] To a solution of 6-methoxy-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (12.0 g, 54.0 mmol) in DCM (120 mL) was added MeNTfc HCl (5.55 g, 81.0 mmol), T4P (58.4 g, 81.0 mmol) and TEA (30.2 mL, 21.9 g, 216 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 5 hours under N2. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (S iO2. 0-30% EtOAc / petroleum ether) to give 6-methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide(11.6 g, 49.3 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.88 (br s, 1H) 7.66 (s, 1H) 4.11 (s, 3H) 3.06 (d, J=5. 13 Hz, 3H).

[0458] Step 5. 6-hydroxy-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide

[0459] A solution of 6-methoxy-N-methyl-2-(trifhioromethyl)pyrimidine-4-carboxamide (5.00 g, 21.3 mmol) in Hbr / AcOH (50 mL) was stirred at 60 °C for 12 hours under N2. The mixture was concentrated under reduced pressure. The crude product was triturated with petroleum ether to give 6-hydroxy-N- methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide (4.60 g, 20.8 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.82 (br s, 1H) 7.60 (s, 1H) 3.08 (d, J=5.13 Hz, 3H).

[0460] Step 6. 6-chloro-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide

[0461] A solution of 6-hydroxy-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide (4.60 g, 20.8 mmol) in POCh (40 mL) was stirred at 110 °C for 5 hours. The mixture was diluted with water (100 mL) at 30 - 40 °C, adjusted to pH 6-8 by aq. NaHCCh and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCh, 0-30% EtOAc / petroleum ether) to give 6-chloro-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide (4.30 g, 17.9 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.34 (s, 1H) 7.85 (br s, 1H) 3.10 (d, J = 5.13 Hz, 3H).General Procedure 32

[0462] Synthesis of 5-fluoro-N-methyl-4-(3,3,4,4-tetramethyl-113,2,5-bromadioxolan-l- yl)picolinamide

[0463] Step 1. 4-chloro-5-fluoro-N-methylpicolinamide

[0464] To a solution of 2-bromo-4-chloro-5 -fluoropyridine (10.0 g, 47.5 mmol) in m-xylene (100 mL) was added MeNH2HC1 (4.88 g, 71.3 mmol), K3PO4 (30.3 g, 143 mmol), Pd(OAc)2(1.07 g, 4.75 mmol)133QB\184200.00266\99637562.4VVID 754PC and Xantphos (2.75 g, 4.75 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 12 hours under CO (50 psi). The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 40-60% EtOAc / petroleum ether) to give 4-chloro-5-fhioro-N-methylpicolinamide (3.50 g, 18.6 mmol) as white solid.XH NMR (400 MHz, CDC13) 5 ppm 8.40 (s, 1H), 8.31 (d, J= 6.1 Hz, 1H), 7.80 (br s, 1H), 3.04 (d, J = 5.1 Hz, 3H).

[0465] Step 2. 5-fluoro-N-methyl-4-(3,3,4,4-tetramethyl-113,2,5-bromadioxolan-l-yl)picolinamide

[0466] To a solution of 4-chloro-5-fhioro-N-methylpicolinamide (110 mg, 0.583 mmol) in 1,4- dioxane (2 mL) was added Pin2B2 (193 mg, 0.758 mmol), KOAc (172 mg, 1.75 mmol) and XPhos-Pd G2 (45.9 mg, 0.0583 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 5-fhioro-N-methyl-4-(3,3,4,4-tetramethyl-113,2,5-bromadioxolan-l- yl)picolinamide (163 mg, 0.582 mmol). The crude product was used in the next step without further purification. 'H NMR (400 MHz, CDCh) 5 ppm 8.53 (d, J= 4.8 Hz, 1H), 8.35 (s, 1H), 7.97 - 7.77 (m, 1H), 3.04 (d, J = 5.0 Hz, 3H), 1.28 (s, 12H).General Procedure 33

[0467] Synthesis of 5-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)picolinamide

[0468] 4-chloro-5-fluoro-N-methylpicolinamide was obtained as described in General Procedure 32, step 1.

[0469] Step 1. 4-chloro-5-methoxy-N-methylpicolinamide

[0470] To a solution of 4-chloro-5-fluoro-N-methylpicolinamide in MeOH (15 mL) was added NaOMe (3.82 g, 21.2 mmol) at 25 °C under N2. The reaction mixture was stirred at 60 °C for 12 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to give 4-chloro-5-methoxy-N-methylpicolinamide (300 mg, 1.50 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 8.22 (s, 1H), 8.16 (s, 1H), 7.76 (s, 1H), 4.05 (s, 3H), 3.02 (d, J= 5.1 Hz, 3H).134QB\184200.00266\99637562.4VVID 754PC

[0471] Step 2. 5-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide

[0472] To a solution of 4-chloro-5-methoxy-N-methylpicolinamide (180 mg, 0.897 mmol) in 1,4- dioxane (5 mL) was added Pin2B2(296 mg, 1.17 mmol), KO Ac (264 mg, 2.69 mmol) and XPhos-Pd G2 (70.6 mg, 0.0897 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 5-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide (215 mg, 0.736 mmol) as yellow solid. The crude product was used in the next step without further purification. 'H NMR (400 MHz, CDCh) 5 8.39 (s, 1H), 8.15 (s, 1H), 7.85 - 7.74 (m, 1H), 3.97 (s, 3H), 3.01 (d, J = 5.1 Hz, 3H), 1.36 (s, 12H).General Procedure 34

[0473] Synthesis of 2-bromo-N,5-dimethylisonicotinamide

[0474] Step 1. 2-chloro-N,5-dimethylisonicotinamide

[0475] To a solution of 2-chloro-5-methylisonicotinic acid (1.80 g, 10.5 mmol) in DCM (20 mL) was added MeNH2HC1 (1.06 g, 15.7 mmol), T4P (15.1 g, 21.0 mmol) and DIPEA (5.48 mL, 4.07 g, 31.5 mmol). The reaction mixture stirred for 1 hour at 25 °C under N2and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-50% EtOAc / petroleum ether) to give 2-chloro-N,5-dimethylisonicotinamide (1.90 g, 10.3 mmol) as a yellow solid. 'H NMR (400 MHz, CDCh) 5 = 8.27 (s, 1H), 7.28 (s, 1H), 5.86 (br s, 1H), 3.02 (d, J= 4.9 Hz, 3H), 2.39 (s, 3H).

[0476] Step 2. 2-bromo-N,5-dimethylisonicotinamide

[0477] To a solution of 2-chloro-N, 5 -dimethylisonicotinamide (1.90 g, 10.3 mmol) in MeCN (20 mL) was added TMSBr (3.94 g, 25.7 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 12 hours under N2. The mixture was added TMSBr (3.94 g, 25.7 mmol) at 25 °C and again stirred at 80 °C. The mixture was added TMSBr (3.94 g, 25.7 mmol) at 25 °C and again stirred at 80 °C. The mixture was concentrated und reduced pressure, diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 20-60% EtOAc / petroleum ether) to give 2-bromo-N,5-dimethylisonicotinamide (1.50 g, 4.91 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 = 8.32 - 8.24 (m, 1H), 7.43 (s, 1H), 5.89 - 5.68 (m, 1H), 3.02 (d, J= 4.9 Hz, 3H), 2.41 - 2.36 (m, 3H).135QB\184200.00266\99637562.4VVID 754PCGeneral Procedure 35

[0478] Synthesis of 2-bromo-5-methoxy-N-methylisonicotinamidestep 1 step 2

[0479] Step 1. 2-bromo-5-fluoro-N-methylisonicotinamide

[0480] To a solution of MeNH2HC1 (3.59 g, 53.2 mmol) in DCM (90 mL) was added DIPEA (14.3 mL, 10.6 g, 81.8 mmol), 2-bromo-5 -fluoroisonicotinic acid (9.00 g, 40.9 mmol) and T4P (44.2 g, 61.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water (90 mL) and extracted with DCM (90 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 25-50% EtOAc / petroleum ether) to give 2-bromo-5-fluoro-N- methylisonicotinamide (8.70 g, 37.3 mmol) as white solid. 'H NMR (400 MHz, CDCL) 5 8.35 (d, J= 2.2 Hz, 1H), 8.10 (d, J= 5.5 Hz, 1H), 6.68 (s, 1H), 3.05 (dd, J= 4.9, 1.1 Hz, 3H).

[0481] Step 2. 2-bromo-5-methoxy-N-methylisonicotinamide

[0482] To a solution of 2-bromo-5-fluoro-N-methylisonicotinamide (4.20 g, 18.0 mmol) in MeOH (40 mL) was added NaOMe (1.17 g, 21.6 mmol) dropwise at 20 °C. The reaction mixture was stirred at 20 °C for 18 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was recrystallized from petroleum ether (100 mL) to give 2-bromo-5-methoxy-N- methylisonicotinamide (3.70 g, 15.1 mmol) as white solid. 'H NMR (400 MHz, CDCL) 5 8.17 (s, 1H), 8.16 (s, 1H), 7.63 (s, 1H), 4.06 (s, 3H), 3.01 (d, J= 4.9 Hz, 3H).General Procedure 36

[0483] Synthesis of 5-bromo-4-cyano-2-fluoro-N-methylbenzamide

[0484] Step 1. 4-amino-5-bromo-2-fluoro-N-methylbenzamide

[0485] To a solution of 4-amino-5-bromo-2-fluorobenzoic acid (3.90 g, 16.7 mmol) in DMF (40 mL) was added DIPEA (1.65 g, 50.0 mmol), MeNH2HC1 (1.35 g, 20.0 mmol) and HATU (9.50 g, 25.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (55 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (55 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified136QB\184200.00266\99637562.4VVID 754PC by column chromatography (SiC>2, 0-20% EtOAc / petroleum ether) to give 4-amino-5-bromo-2-fhioro-N- methylbenzamide (3.70 g, 15.0 mmol) as a colorless oil. 'H NMR (400 MHz, CDCh) 5 8.19 (d, J= 8.1 Hz, 1H), 6.56 (s, 1H), 6.43 (d, J= 13.5 Hz, 1H), 2.99 (dd, J= 4.8, 1.2 Hz, 3H).

[0486] Step 2. 5-bromo-2-fluoro-4-iodo-N-methylbenzamide

[0487] To a solution of Cui (1.25 g, 6.58 mmol) in MeCN (8 mL) was added tert-butyl nitrite (0.678 g, 6.58 mmol) at 20 °C and stirred at 65 °C for 15 min. Then, a solution of 4-amino-5-bromo-2-fluoro-N- methylbenzamide (0.650 g, 2.63 mmol) in MeCN (2 mL) was added at 65 °C and the reaction mixture was stirred at 65 °C for 2 hours under N2. The mixture was dilute with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified with column chromatography ( SiO2- 0-10% EtOAc / petroleum ether) to give 5-bromo-2-fluoro-4-iodo-N-methylbenzamide (0.70 g, 1.96 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.39 - 8.21 (m, 1H), 7.69 - 7.57 (m, 1H), 6.72 - 6.48 (m, 1H), 3.11 - 2.90 (m, 3H).

[0488] Step 3. 5-bromo-4-cyano-2-fluoro-N-methylbenzamide

[0489] To a solution of 5-bromo-2-fluoro-4-iodo-N-methylbenzamide (1.60 g, 4.47 mmol) in DML (20 mL) was added Zn(CN)2(0.577 g, 4.92 mmol), Pd(PPh3)4 (0.517 g, 0.447 mmol) and XPhos (0.213 g, 0.447 mmol). The reaction mixture was stirred at 80 °C for 6 hours. The mixture was diluted with water (150 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 1-9% EtOAc / petroleum ether) to afford 5-bromo-4- cyano-2-fluoro-N-methylbenzamide (1.00 g, 3.89 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.41 (d, J= 6.8 Hz, 1H), 7.52 - 7.29 (m, 1H), 6.87 - 6.51 (m, 1H), 3.09 - 3.03 (m, 3H).General Procedure 37

[0490] Synthesis of 4-cyano-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide

[0491] Step 1. Mixture of 5-bromo-4-cyano-2-methoxybenzoic acid and 3-bromo-4-cyano-2- methoxybenzoic acid137QB\184200.00266\99637562.4VVID 754PC

[0492] To a solution of 4-cyano-2-methoxybenzoic acid (10.0 g, 56.4 mmol) in TFA (150 mL) was added NBS (11.1 g, 62. 1 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 6 hours. The mixture was diluted with water (500 mL), stirred at 25 °C for 20 minutes and filtered. The filter cake was dried under reduced pressure to afford a mixture of 5-bromo-4-cyano-2-methoxybenzoic acid and 3- bromo-4-cyano-2-methoxybenzoic acid (14.0 g, 54.7 mmol).

[0493] Step 2. 5-bromo-4-cyano-2-methoxy-N-methylbenzamide

[0494] To a solution of 5 -bromo-4-cyano-2 -methoxybenzoic acid and 3-bromo-4-cyano-2- methoxybenzoic acid (14.0 g, 54.7 mmol) in DCM (150 mL) was added DIPEA (29.6 mL, 22.0 g, 170 mmol) and MeNEE HCl (5.74 g, 84.9 mmol). The mixture was stirred at 25 °C for 20 minutes. Then, T4P (61.2 g, 84.9 mmol) was added at 0 °C. The reaction mixture stirred for 1 hour at 25 °C. The mixture was diluted with water (200 mL) and extracted with DCM (400 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was stirred with MeCN (50 mL) for 30 minutes and filtered. The filter cake was dried under reduced pressure and recrystallized from MeOH (30 mL) to afford 5-bromo-4-cyano-2-methoxy-N- methylbenzamide (2.00 g, 7.43 mmol) as white solid. 'H NMR (400 MHz, DMSO-de) 5 ppm 8.33 (br d, J= 4.4 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 3.90 (s, 3H), 2.77 (d, J= 4.8 Hz, 3H).

[0495] Step 3. 4-cyano-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- benzamide

[0496] To a solution of 5-bromo-4-cyano-2-methoxy-N-methylbenzamide (270 mg, 1.00 mmol) in 1,4 dioxane (3 mL) was added KO Ac (197 mg, 2.00 mmol), PimEL (382 mg, 1.50 mmol) and Pd(dppf)C12'DCM (81.9 mg, 0.100 mmol) at 25 °C under N2. The reaction mixture was stirred at 90 °C for 2 hours. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to give crude 4-cyano-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (317 mg) as brown solid, which was used without further purification.General Procedure 38

[0497] Synthesis of 4-chloro-5-cyano-N-methylpicolinamidestep 1 step 2

[0498] Step 1. 5-bromo-4-chloro-N-methylpicolinamide

[0499] To a solution of 5-bromo-4-chloropicolinic acid (5.00 g, 21.1 mmol) in DCM (50 mL) was added TEA (5.35 g, 52.9 mmol), HATU (9.65 g, 25.4 mmol) and MeNH2HC1 (2.14 g, 31.7 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried138QB\184200.00266\99637562.4VVID 754PC over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-30% EtOAc / petroleum ether) to give 5-bromo-4-chloro-N- methylpicolinamide (5.00 g, 20.0 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.66 (s, 1H), 8.28 (s, 1H), 7.86 (br s, 1H), 3.04 (d, J= 5.1 Hz, 3H).

[0500] Step 2. 4-chloro-5-cyano-N-methylpicolinamide

[0501] A mixture of 5-bromo-4-chloro-N-methylpicolinamide (4.50 g, 18.0 mmol), Zn(CN)2 (4.27 g, 36.4 mmol) and Pd(PPh3)4(2.08 g, 1.80 mmol) in NMP (50 mL) was stirred at 130 °C for 16 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to give 4-chloro-5-cyano-N-methylpicolinamide (300 mg, 1.53 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.78 (br s, 1H), 8.38 (br s, 1H), 7.90 (br s, 1H), 3.07 (br d, J= 4.2 Hz, 3H).General Procedure 39

[0502] Synthesis of 6-methyl-2-(trimethylstannyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0503] Step 1. methyl 3-(bromomethyl)-6-chloropicolinate

[0504] To a solution of methyl 6-chloro-3-methylpicolinate (9.50 g, 51.2 mmol) in DCE (100 mL) was added AIBN (420 mg, 2.55 mmol) and NBS (10.9 g, 61.4 mmol) at 20 °C. The mixture was stirred at 85 °C for 0.5 hour under N2. The reaction mixture was diluted with water (120 mL) and extracted with DCM (90 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCE, 0-12% EtOAc / petroleum ether) to give methyl 3-(bromomethyl)-6-chloropicolinate (9.00 g, 31.60 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.86 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.0 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H).

[0505] Step 2. 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0506] To a solution of methyl 3-(bromomethyl)-6-chloropicolinate (1.00 g, 3.78 mmol) in MeOH (10 mL) was added TEA (765 mg, 7.56 mmol), and MeNH2 (30% in MeOH) (1.57 g, 15.1 mmol) at 25 °C. Then the reaction mixture was stirred at 70 °C for 12 hours. The mixture was poured into water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 70-100% EtOAc / petroleum ether) to give 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-139QB\184200.00266)99637562.4VVID 754PC b]pyridin-7-one (550.0 mg, 3.01 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.78 (d, J = 8.4 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 4.40 (s, 2H), 3.27 (s, 3H).

[0507] Step 3. 6-methyl-2-(trimethylstannyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0508] To a solution of 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (300 mg, 1.64 mmol) in toluene (5 mb) was added Sn2(CH2)6 (1010 mg, 3.08 mmol) and Pd(dtbpf)C12 (106 mg, 0.164 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 12 hours under N2. The mixture was poured into aqueous KF (30 mb) and extracted with EtOAc (30 mb x 2). The combined organic layers were washed with brine (50 mb x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to afford 6-methyl-2-(trimethylstannyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (200 mg, 0.322 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.66 - 7.62 (m, 1H), 7.59 - 7.54 (m, 1H), 4.35 (s, 2H), 3.27 (s, 3H), 0.48 - 0.28 (m, 9H).General Procedure 40

[0509] Synthesis of 2-methyl-6-(trimethylstannyl)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-onestep 1 step 2 step 3

[0510] Step 1. methyl 5-(bromomethyl)-2-chloroisonicotinate

[0511] To a solution of methyl 2-chloro-5-methylisonicotinate (4.00 g, 21.5 mmol) in DCE (60 mL) was added AIBN (0.14 g, 0.86 mmol) and NBS (4.98 g, 28.0 mmol) at 25 °C. The reaction mixture was stirred at 85 °C for 30 minutes under N2. The mixture was diluted with water (80 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-20% EtOAc / petroleum ether) to give methyl 5-(bromomethyl)-2-chloroisonicotinate (5.20 g, 19.7 mmol) as yellow oil. 'H NMR (400 MHz, CDC13) 5 ppm 8.52 (s, 1H), 7.81 (s, 1H), 4.86 (s, 2H), 4.00 (s, 3H).

[0512] Step 2. 6-chloro-2-methyl-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-one

[0513] To a solution of methyl 5-(bromomethyl)-2-chloroisonicotinate (5.16 g, 19.5 mmol) in MeOH (80 mL) was added TEA (3.94 g, 39.0 mmol), and MeNH2(30% in MeOH) (8.09 g, 78.0 mmol) at 25 °C. Then, the reaction mixture was stirred at 70 °C for 12 hours. The mixture was poured into water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 50-70% EtOAc / petroleum ether) to give 6-chloro-2-methyl-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin- 1-one (3.00 g, 16.4 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.56 (s, 1H), 7.73 (s, 1H), 4.47 (s, 2H), 3.22 (s, 3H).140QB\184200.00266(99637562.4VVID 754PC

[0514] Step 3. 2-methyl-6-(trimethylstannyl)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-one

[0515] To a solution of 6-chloro-2-methyl-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin- 1-one (800 mg, 4.38 mmol) in toluene (5 mL) was added Sm ClDe (2153 mg, 6.57 mmol) and Pd(dtbpf)C12 (282 mg, 0.438 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 12 hours under N2. The mixture was poured into aqueous KF (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 20-30% EtOAc / petroleum ether) to afford 2-methyl-6-(trimethylstannyl)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-one (1000 mg, 3.22 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 9.02 - 8.88 (m, 1H), 7.98 - 7.85 (m, 1H), 4.49 - 4.37 (m, 2H), 3.23 (s, 3H), 0.59 - 0.36 (m, 9H).General Procedure 41

[0516] Synthesis of 6-methyl-3-(trimethylstannyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

[0517] Step 1. methyl 3-(bromomethyl)-6-chloropyrazine-2-carboxylate

[0518] Solution 1: methyl 6-chloro-3-methylpyrazine-2-carboxylate (3.50 g, 18.75 mmol) and DBBMH (10.72 g, 37.51 mmol) and TFA (2.13 g, 18.75 mmol) in MeCN (90 mL). Solution 2: diethyl phosphite (6.98 g, 37.51 mmol) and DIEA (9.69 g, 75.03 mmol) in MeCN (15 mL). The solution 1 was pumped by Pump 1 to flow reactor 1 under 455 nm,400 W light at 40 °C. The solution 2 was pumped by Pump 1 to flow reactor 1 at 30 °C. The residence time of flow reactor 1 was 20 min. The residence time of flow reactor 2 was 2 mins. The mixture was poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-20% EtOAc / petroleum ether) to afford methyl 3-(bromomethyl)-6-chloropyrazine-2-carboxylate (3.40 g, 12.80 mmol) as white solid. 'H NMR (400 MHz, CDC13) 5 ppm 8.74 - 8.69 (m, 1H), 5.02 - 4.94 (m, 2H), 4.05 (s, 3H).

[0519] Step 2. 3-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

[0520] To a solution of methyl 3-(bromomethyl)-6-chloropyrazine-2 -carboxylate (3.00 g, 11.30 mmol) in Methanol (20 mL) was added TEA (2.28 g, 22.60 mmol), and MeNH2 (30% in MeOH) (3.97 g, 38.34 mmol) at 25 °C. Then, the reaction mixture was stirred at 25 °C for 8 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-60% EtOAc / petroleum ether) to afford 3-chloro-6-methyl-6,7-dihydro-5H-141QB\184200.00266(99637562.4VVID 754PC pyrrolo[3,4-b]pyrazin-5-one (3.30 g, 8.99 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.68 (s, 1H), 4.51 (s, 2H), 3.32 (s, 3H).

[0521] Step 3. 6-methyl-3-(trimethylstannyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

[0522] To a solution of 3-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (300 mg, 1.63 mmol) in toluene (5 mb) was added Sn2(CH2)6 (803 mg, 2.45 mmol) and Pd(dtbpf)2 (73.6 mg, 0.114 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 4 hours under N2. The mixture was poured into aqueous KF (10 mb) and extracted with EtOAc (10 mb x 2). The combined organic layers were washed with brine (10 mb x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (A12O2, 1-9% EtOAc / petroleum ether) to afford 6-methyl-3-(trimethylstannyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (260 mg, 0.833 mmol) as yellow solid. 'H NMR (400 MHz, CDCI3) 5 ppm 8.65 (s, 1H), 4.44 (s, 2H), 3.31 (s, 3H), 0.55 - 0.33 (m, 9H).General Procedure 42

[0523] Synthesis of 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-onestep 1 step 2 step 3

[0524] Step 1. methyl 2-chloro-5-methylpyrimidine-4-carboxylate

[0525] To a solution of 2-chloro-5-methylpyrimidine-4-carboxylic acid (4.50 g, 26. 1 mmol) in DCM (50 mb) was added DMF (57.2 mg, 0.780 mmol), (COC1)2(4.96 g, 39.1 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours under N2. The mixture was quenched with MeOH (10 mb), stirred for 10 minutes, diluted with water (50 mb) extracted with DCM (50 mb x 3). The combined organic layers were washed with brine (30 mb x 2), dried over Na2SO4, filtered and concentrated under reduced. The crude product was purified by column chromatography (SiO2, 0-20% EtOAc / petroleum ether) to give methyl 2-chloro-5-methylpyrimidine-4-carboxylate (5.00 g, 24.1 mmol) as white solid. 'H NMR (400 MHz, DMSO-d6) 5 ppm 8.89 (s, 1H), 3.91 (s, 3H), 2.42 (s, 3H).

[0526] Step 2. methyl 5-(bromomethyl)-2-chloropyrimidine-4-carboxylate

[0527] To a solution of methyl 2-chloro-5-methylpyrimidine-4-carboxylate (4.50 g, 24.1 mmol) in CHCI3 (50 mb) was added AIBN (158 mg, 0.96 mmol) and then NBS (5.58 g, 31.35 mmol) after 3 minutes at 20 °C. The reaction mixture was stirred at 85 °C for 30 minutes under N2. The mixture was diluted with water (30 mb) and extracted with DCM (30 mb x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Agela DuraShell C18, 250 x 70 mm, 10 pm; 20-55% ACN / H2O (10 mM NH4HCO3)) to give methyl 5-(bromomethyl)-2-chloropyrimidine-4-carboxylate (2.00 g, 7.53 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.85 (s, 1H), 4.81 (s, 2H), 4.06 (s, 3H).142QB\184200.00266\99637562.4VVID 754PC

[0528] Step 3. 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0529] To a solution of methyl 5-(bromomethyl)-2-chloropyrimidine-4-carboxylate (1.10 g, 4. 14 mmol) in MeCN (10 mL) was added MeNIT (40% in H2O) (0.96 g, 12.4 mmol) at 25 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give 2-chloro-6-methyl-5,6-dihydro-7H- pyrrolo[3,4-d]pyrimidin-7-one (380 mg, 2.06 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.99 (s, 1H), 4.62 (s, 2H), 3.26 (s, 3H).General Procedure 43

[0530] Synthesis of 6-bromo-5-fluoro-2-methylisoindolin-l-onestep 1 step 2

[0531] Step 1. methyl 5-bromo-2-(bromomethyl)-4-fluorobenzoate

[0532] To a solution of methyl 5-bromo-4-fluoro-2 -methylbenzoate (700 mg, 2.83 mmol) in CHCI3 (10 mL) was added AIBN (18.0 mg, 0.110 mmol) and NBS (504 mg, 2.83 mmol) at 20 °C. The reaction mixture was stirred at 85 °C for 0.5 hour under N2. The mixture was diluted with water (25 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-6% EtOAc / petroleum ether) to give methyl 5-bromo-2-(bromomethyl)- 4-fluorobenzoate (550 mg, 1.68 mmol) as colorless oil. 'H NMR (400 MHz, CDCI3) 5 ppm 8.24 (d, J = 7.2 Hz, 1H), 7.28 - 7.25 (m, 1H), 4.90 (s, 2H), 3.95 (s, 3H).

[0533] Step 2. 6-bromo-5-fluoro-2-methylisoindolin-l-one

[0534] To a solution of methyl 5-bromo-2-(bromomethyl)-4-fluorobenzoate (550 mg, 1.68 mmol) in DMF (5 mL) was added MelSTL HCl (170 mg, 2.53 mmol) and K2CO3 (699 mg, 5.06 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was poured into saturated aqueous NaCl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-50% EtOAc / petroleum ether) to give 6-bromo-5-fluoro-2-methylisoindolin-l- one (160 mg, 0.650 mmol) as white solid. 'H NMR (400 MHz, CDCI3) 5 ppm 8.04 (d, J= 6.4 Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 4.34 (s, 2H), 3.20 (s, 3H).143QB\184200.00266\99637562.4VVID 754PCGeneral Procedure 44

[0535] Synthesis of 6-bromo-5-methoxy-2-methylisoindolin-l-onestep 1 step 2

[0536] Step 1. methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate

[0537] To a solution of methyl 5-bromo-4-methoxy-2-methylbenzoate (7.50 g, 28.9 mmol) in CHCI3 (100 mL) was added AIBN (190 mg, 1.15 mmol) and NBS (6.69 g, 37.6 mmol) at 20 °C. The reaction mixture was stirred at 85 °C for 0.5 hour under N2. The mixture was diluted with water (150 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate (7.28 g, 21.5 mmol) as white solid. 'H NMR (400 MHz, CDCI3) 5 ppm 8.23 (s, 1H), 6.96 (s, 1H), 4.97 (s, 2H), 3.99 (s, 3H), 3.93 (s, 3H).

[0538] Step 2. 6-bromo-5-methoxy-2-methylisoindolin-l-one

[0539] To a solution of methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate (2.50 g, 7.39 mmol) in DMF (60 mL) was added MeNFF HCl (0.540 g, 8.13 mmol) and K2CO3 (1.53 g, 11.1 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give 6-bromo-5-methoxy-2- methylisoindolin-l-one (570 mg, 2.23 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.01 (s, 1H), 6.94 (s, 1H), 4.31 (s, 2H), 3.97 (s, 3H), 3.18 (s, 3H).General Procedure 45

[0540] Synthesis of 6-bromo-2-methyl-l-oxoisoindoline-5-carbonitrilestep 1 step 2

[0541] Step 1. 6-bromo-5-iodo-2-methylisoindolin-l-one

[0542] To a solution of Cui (395 mg, 2.07 mmol) in MeCN (8 mL) was added t-BuONO (213 mg, 2.07 mmol) at 20 °C. The reaction mixture was stirred at 65 °C for 15 min. 5-amino-6-bromo-2- methylisoindolin-l-one (200 mg, 0.820 mmol) was added at 65 °C. The reaction mixture was stirred at 65 °C for 2 hours under N2. The mixture was diluted with H2O (20 mL) and extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and144QB\184200.00266\99637562.4VVID 754PC concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc) to give 6-bromo-5-iodo-2-methylisoindolin-l-one (140 mg, 0.390 mmol) as white solid. 'H NMR (400 MHz, CDC13) 5 ppm 8.08 (s, 1H), 7.99 (s, 1H), 4.29 (s, 2H), 3.19 (s, 3H).

[0543] Step 2. 6-bromo-2-methyl-l-oxoisoindoline-5-carbonitrile

[0544] A mixture of 6-bromo-5-iodo-2-methylisoindolin-l-one (140 mg, 0.390 mmol), Zn(CN)2 (100 mg, 0.850 mmol) and Pd(PPh3)4(45.0 mg, 0.030 mmol) and XPhos (18.0 mg, 0.030 mmol) in DMF (3 mb) was stirred at 80 °C for 6 hours under N2. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to give 6-bromo-2 -methyl- 1 -oxoisoindoline-5 - carbonitrile (90.0 mg, 0.350 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.18 - 8.13 (m, 1H), 7.77 (s, 1H), 4.41 (s, 2H), 3.24 (s, 3H).General Procedure 46

[0545] Synthesis of 6-bromo-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3(2H)-onestep 1 step 2

[0546] Step 1. 6-bromo-[l,2,4]triazolo[4,3-a]pyrazin-3(2H)-one

[0547] To a solution of 2-bromo-5-hydrazineylpyrazine (900 mg, 4.76 mmol) in THF 15 mL) was added triphosgene (1.55 g, 5.24 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-bromo-[l,2,4]triazolo[4,3- a]pyrazin-3(2H)-one (987 mg, 4.59 mmol) as yellow solid. 'H NMR (400 MHz, DMSO) 5 13.15 (s, 1H), 8.79 (d, J= 1.6 Hz, 1H), 8.19 (d, J= 1.6 Hz, 1H).

[0548] Step 2. 6-bromo-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3(2H)-one

[0549] To a solution of 6-bromo-[l,2,4]triazolo[4,3-a]pyrazin-3(2H)-one (987 mg, 4.59 mmol) in DMF (15 mL) was added K2CO3 (1.27 g, 9.18 mmol) and Mel (1.30 g, 9.18 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-bromo-2-methyl- [l,2,4]triazolo[4,3-a]pyrazin-3(2H)-one (740 mg, 3.23 mmol) as black solid. 'H NMR (400 MHz, DMSO) 5 8.81 (d, J= 1.6 Hz, 1H), 8.26 (d, J= 1.6 Hz, 1H), 3.61 (s, 3H).145QB\184200.00266\99637562.4VVID 754PCGeneral Procedure 47

[0550] Synthesis of 7-methyl-2-(trimethylstannyl)-6,7-dihydro-l,7-naphthyridin-8(5H)-onestep 4 step 5

[0551] Step 1. methyl 3-(2-(( / er / -butoxycarbonyl)amino)ethyl)-6-chloropicolinate

[0552] To a solution of methyl 3-bromo-6-chloropicolinate (6.00 g, 24.0 mmol) in toluene (80 mL) and water (20 mL) was added potassium 2-(boc-aminoethyl)trifhioroborate (7.22 g, 28.7 mmol), CS2CO3 (15.6 g, 47.9 mmol) and Pd(dtbpf)C12 (1.54 g, 2.40 mmol) at 25 °C under N2. The system was degassed and charged with N2 (3x). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to afford methyl 3-(2-((tert- butoxycarbonyl)amino)ethyl)-6-chloropicolinate (4.00 g, 12.7 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 7.65 (br d, J= 8.1 Hz, 1H), 7.43 (d, J= 8.2 Hz, 1H), 4.85 (br s, 1H), 3.98 (s, 3H), 3.46 - 3.37 (m, 2H), 3.10 (brt, J= 6.8 Hz, 2H), 1.40 (s, 9H).

[0553] Step 2. methyl 3-(2-aminoethyl)-6-chloropicolinate

[0554] To a solution of methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloropicolinate (4.00 g, 12.7 mmol) in DCM (50 mL) was added TFA (20 mL) as 20 °C. The reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure to give methyl 3-(2-aminoethyl)-6- chloropicolinate (2.72 g, 12.7 mmol) as yellow oil. 'H NMR (400 MHz, CD3OD) 5 ppm 7.88 (d, J= 8.3 Hz, 1H), 7.64 (d, J= 8.3 Hz, 1H), 3.98 (s, 3H), 3.25 (s, 4H).

[0555] Step 3. 2-chloro-6,7-dihydro-l,7-naphthyridin-8(5H)-one

[0556] To a solution of methyl 3-(2-aminoethyl)-6-chloropicolinate (2.72 g, 12.7 mmol) in MeOH (30 mL) was added TEA (5.30 mL, 3.85 g, 38.0 mmol) at 20 °C. The reaction mixture was stirred at 60 °C for 12 hours under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to afford 2-chloro-6,7-dihydro-l,7-naphthyridin-8(5H)-one (1.18 g, 6.46146QB\184200.00266\99637562.4VVID 754PC mmol) as yellow solid. 'H NMR (400 MHz, CDC13) 5 ppm 7.59 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 7.31 (br s, 1H), 3.66 - 3.60 (m, 2H), 3.05 (t, J= 6.6 Hz, 2H).

[0557] Step 4. 2-chloro-7-methyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one

[0558] To a solution of 2-chloro-6,7-dihydro-l,7-naphthyridin-8(5H)-one (140 mg, 0.767 mmol) in DMF (3 mL) was added NaH (60% in mineral oil) (61.3 mg, 1.53 mmol). The mixture was stirred at 0 °C for 30 min, and then Mel (131 mg, 0.920 mmol) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 hour under N2. The reaction mixture was quenched with a saturated aqueous NH4CI solution (15 mL) and extracted with DCM / iPrOH (6: 1 v / v) (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-100% EtOAc / petroleum ether) to give 2-chloro-7-methyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one (110 mg, 0.559 mmol) as white solid.'H NMR (400 MHz, CDCk) 5 ppm 7.53 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 3.62 (t, J= 6.7 Hz, 2H), 3.21 (s, 3H), 3.05 (t, J= 6.7 Hz, 2H).

[0559] Step 5. 7-methyl-2-(trimethylstannyl)-6,7-dihydro-l,7-naphthyridin-8(5H)-one

[0560] To a solution of 2-chloro-7-methyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one (80.0 mg, 0.332 mmol) in 1,4-dioxane (3 mL) was added Sn2(CH3)e (160 mg, 0.366 mmol) and Pd(dtbpf)C12 (21.4 mg, 0.0332 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 4 hours under N2. The mixture was quenched with saturated aqueous KF (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified with column chromatography (AI2O3, 0 - 100% EtOAc / petroleum ether) to afford 7- methyl-2-(trimethylstannyl)-6,7-dihydro-l,7-naphthyridin-8(5H)-one (60.0 mg, 0.185 mmol) as a yellow solid. 'H NMR (400 MHz, CDCI3) 5 ppm 7.48 (d, J= 7.4 Hz, 1H), 7.40 - 7.36 (m, 1H), 3.58 (t, J= 6.7 Hz, 2H), 3.20 (s, 3H), 3.01 (t, J = 6.7 Hz, 2H), 0.48 - 0.24 (m, 9H).General Procedure 48

[0561] Synthesis of 2-methyl-7-(trimethylstannyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-onestep 4 step 5

[0562] Step 1. methyl 5-(2-((ter / -butoxycarbonyl)amino)ethyl)-2-chloroisonicotinate147QB\184200.00266\99637562.4VVID 754PC

[0563] To a solution of methyl 5-bromo-2-chloroisonicotinate (19.0 g, 75.8 mmol) in toluene (200 mL) and water (50 mL) were added potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (22.8 g, 91.0 mmol), CS2CO3 (49.4 g, 152 mmol) and Pd(dtbpf)C12 (4.80 g, 7.58 mmol) at 25 °C under N2. The system was degassed and then charged with nitrogen (3x). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was poured into ice-water (100 mL), stirred for 5 min and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-50% EtOAc / petroleum ether) to give methyl 5-(2-((tert- butoxycarbonyl)amino)ethyl)-2-chloroisonicotinate (18.0 g, 57.2 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.39 - 8.27 (m, 1H), 7.83 - 7.69 (m, 1H), 4.85 - 4.60 (m, 1H), 4.01 - 3.87 (m, 3H), 3.46 - 3.31 (m, 2H), 3.22 - 3.01 (m, 2H), 1.42 - 1.39 (m, 9H).

[0564] Step 2. methyl 5-(2-aminoethyl)-2-chloroisonicotinate

[0565] To a solution of methyl 5-(2-((tert-butoxycarbonyl)amino)ethyl)-2-chloroisonicotinate (18.0 g, 57.2 mmol) in DCM (200 mL) was added TFA (20 mL) dropwise at 20 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give methyl 5-(2- aminoethyl)-2-chloroisonicotinate (13.0 g, 57.50 mmol) as yellow oil. 'H NMR (400 MHz, CD3OD) 5 ppm 8.52 - 8.40 (m, 1H), 7.95 - 7.84 (m, 1H), 4.95 - 4.91 (m, 2H), 3.99 - 3.94 (m, 2H), 3.29 - 3.20 (m, 3H).

[0566] Step 3. 7-chloro-3,4-dihydro-2,6-naphthyridin-l(2H)-one

[0567] To a solution of methyl 5-(2-aminoethyl)-2-chloroisonicotinate (13.0 g, 57.5 mmol) in MeOH (200 mL) was added TEA (16.1 g, 160 mmol) at 20 °C. Then the reaction mixture was stirred at 60 °C for 12 hours under N2. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 30-80% EtOAc / petroleum ether) to give 7-chloro-3,4-dihydro-2,6-naphthyridin-l(2H)-one (9.50 g, 52.0 mmol) as pale yellow solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.42 - 8.28 (m, 1H), 7.97 - 7.85 (m, 1H), 6.40 - 6.11 (m, 1H), 3.74 - 3.58 (m, 2H), 3.11 - 2.93 (m, 2H).

[0568] Step 4. 7-chloro-2-methyl-3,4-dihydro-2,6-naphthyridin-l(2H)-one

[0569] To a solution of 7-chloro-3,4-dihydro-2,6-naphthyridin-l(2H)-one (9.50 g, 52.0 mmol) in DMF (100 mL) was added NaH (4.30 g, 110 mmol). The mixture was stirred at 0 °C for 30 min, and then Mel (9.30 g, 65.7 mmol) in DMF (5 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour under N2. The reaction mixture was quenched with saturated NH4CI (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 30-80% EtOAc / petroleum ether) to give 7-chloro-2-methyl-3,4-dihydro-148QB\184200.00266\99637562.4VVID 754PC2,6-naphthyridin-l(2H)-one (7.80 g, 39.7 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 ppm 8.39 - 8.26 (m, 1H), 7.99 - 7.89 (m, 1H), 3.66 - 3.60 (m, 2H), 3.20 - 3.15 (m, 3H), 3.06 - 2.99 (m, 2H).

[0570] Step 5. 2-methyl-7-(trimethylstannyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-one

[0571] To a solution of 7-chloro-2-methyl-3,4-dihydro-2,6-naphthyridin-l(2H)-one (2.00 g, 10.2 mmol) in toluene (20 mL) was added Sn2(CH3)e (5.00 g, 15.3 mmol) and Pd(PPh3)4 (73.6 mg, 0.114 mmol) at 25 °C. The mixture was stirred at 120 °C for 4 hours under N2. The mixture was poured into aqueous KF (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to afford 2- methyl-7-(trimethylstannyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-one (1.80 g, 5.54 mmol) as colorless oil. 'H NMR (400 MHz, CDCh) 5 ppm 8.69 (s, 1H), 8.04 - 8.01 (m, 1H), 3.64 - 3.56 (m, 2H), 3.19 - 3.15 (m, 3H), 3.03 - 2.91 (m, 2H), 0.45 - 0.35 (m, 9H).General Procedure 49

[0572] Synthesis of 6-methyl-3-(trimethylstannyl)-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-onestep 4 step 5

[0573] Step 1. methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloropyrazine-2-carboxylate

[0574] To a solution of methyl 3-bromo-6-chloropyrazine-2 -carboxylate (2.00 g, 7.95 mmol) in toluene (40 mL) and was (10 mL) was added potassium 2-(boc-aminoethyl)trifluoroborate (2.40 g, 9.54 mmol), Pd(dtbpf)C12 (0.512 g, 0.795 mmol) and CS2CO3 (5.18 g, 15.9 mmol) at 25 °C under N2. The system was degassed and then charged with nitrogen (3x). The reaction mixture was stirred at 85 °C for 16 hours. The mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-25% EtOAc / petroleum ether) to afford methyl 3-(2-((tert- butoxycarbonyl)amino)ethyl)-6-chloropyrazine-2 -carboxylate (530 mg, 1.68 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 ppm 8.68 (s, 1H), 5.05 - 4.89 (m, 1H), 4.01 (s, 3H), 3.65 - 3.56 (m, 2H), 3.35 (t, J= 6.4Hz, 2H), 1.40 (s, 9H).149QB\184200.00266\99637562.4VVID 754PC

[0575] Step 2. methyl 3-(2-aminoethyl)-6-chloropyrazine-2-carboxylate

[0576] To a solution of methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloropyrazine-2- carboxylate (520 mg, 1.65 mmol) in DCM (8 mL) was added TFA (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give methyl 3- (2-aminoethyl)-6-chloropyrazine-2-carboxylate (340 mg, 1.58 mmol) as yellow solid.

[0577] Step 3. 3-chloro-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one

[0578] To a solution of methyl 3-(2-aminoethyl)-6-chloropyrazine-2-carboxylate (160 mg, 0.742 mmol) in MeOH (5 mL) was added TEA (0.310 mL, 225 mg, 2.23 mmol) at 20 °C. The reaction mixture was stirred at 60 °C for 12 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give 3-chloro-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one (135 mg, 0.735 mmol) as yellow solid. 'H NMR (400 MHz, CDC13) 5 ppm 7.59 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 7.31 (br s, 1H), 3.66 - 3.60 (m, 2H), 3.05 (t, J= 6.6 Hz, 2H).

[0579] Step 4. 3-chloro-6-methyl-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one

[0580] To a solution of 3-chloro-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one (1.34 g, 7.30 mmol) in DMF (15 mL) was added NaH (60%, 584 mg, 14.6 mmol). The mixture was stirred at 0 °C for 30 minutes and then Mel (1.24 g, 8.76 mmol) in DMF (3 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under N2. The mixture was poured into aq. NH4CI (20 mL) and extracted with DCM (20 mL x 5). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified with column chromatography (SiO3. 0 - 100% acetate / petroleum ether) to afford 3-chloro-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one (490 mg, 2.48 mmol) as yellow solid. ’H NMR (400 MHz, CDCL) 5 ppm 8.59 (s, 1H), 3.72 (t, J= 6.8 Hz, 2H), 3.29 (t, J= 6.8 Hz, 2H), 3.23 (s, 3H).

[0581] Step 5. 6-methyl-3-(trimethylstannyl)-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one

[0582] To a solution of 3-chloro-6-methyl-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one (490 mg, 2.48 mmol) in toluene (5 mL) was added Sn2(CH3)e (1.22 g, 3.72 mmol) and Pd(dtbpf)C12 (160 mg, 0.248 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 4 hours under N2. The mixture was poured into aq. KF (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na3SO4. filtered and concentrated under reduced pressure. The crude product was purified with column chromatography (SiO3, 0 - 100% EtOAc / petroleum ether) to give 6-methyl-3-(trimethylstannyl)-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one (630 mg, 1.93 mmol) as yellow solid. 'H NMR (400 MHz, CDC13) 5 ppm 8.55 (s, 1H), 3.67 (t, J= 6.7 Hz, 2H), 3.28 - 3.21 (m, 5H), 0.52 - 0.34 (m, 9H).150QB\184200.00266\99637562.4VVID 754PCGeneral Procedure 50

[0583] Synthesis of 2-methyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-onestep 4

[0584] Step 1. 5-bromo-2-chloro-N-methylisonicotinamide

[0585] To a solution of 5-bromo-2-chloroisonicotinic acid (5.00 g, 21.1 mmol) in DCM (50 mL) was added MeNH2HC1 (2.14 g, 31.7 mmol), T4P (22.9 g, 31.7 mmol) and DIPEA (7.37 mL, 5.47 g, 42.3 mmol) at 0 °C. The reaction mixture stirred at 25 °C for 30 minutes. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 50-100% EtOAc / petroleum ether) to give5-bromo-2-chloro- N-methylisonicotinamide (4.50 g, 18.0 mmol) as yellow oil. 'H NMR (400 MHz, CDCL) 5 = 8.53 (s, 1H), 7.53 - 7.37 (m, 1H), 6.52 - 6.21 (m, 1H), 3.09 - 2.91 (m, 3H).

[0586] Step 2. (E)-2-chloro-5-(2-ethoxyvinyl)-N-methylisonicotinamide

[0587] To a solution of 5-bromo-2-chloro-N-methylisonicotinamide (2.50 g, 10.0 mmol) in 1,4- dioxane (20 mL) and water (5 mL) was added / ram-2-cthoxyvmylboronic acid pinacol ester (1.98 g, 10.0 mmol), K2CO2(2.08 g, 15.0 mmol) and Pd(PPh3)4 (1.10 g, 0.952 mmol) at 25 °C under N2. The reaction mixture stirred at 110 °C for 2 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 1-9% EtOAc / petroleum ether) to give a 1: 1 mixture of (E)-2-chloro-5-(2- ethoxyvinyl)-N-methylisonicotinamide (1.50 g, 6.23 mmol) and (E)-5-bromo-2-(2-ethoxyvinyl)-N- methylisonicotinamide (1.78 g, 6.23 mmol) as white oil. The mixture was used in the next step without further separation.

[0588] Step 3. 7-chloro-2-methyl-2,6-naphthyridin-l(2H)-one

[0589] To a mixture of (E)-2-chloro-5-(2-ethoxyvinyl)-N-methylisonicotinamide (1.50 g, 6.23 mmol) and (E)-5-bromo-2-(2-ethoxyvinyl)-N-methylisonicotinamide (1.78 g, 6.23 mmol) in toluene (30 mL) was added TsOH (537 mg, 3.12 mmol) at 25 °C. The reaction mixture was stirred at 85 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined151QB\184200.00266\99637562.4VVID 754PC organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (WePure Biotech XP tC18, 250 x 70 mm, 10 pm, 10-55% ACN / H2O (lOmM NH4HCO3)) to give 7-chloro-2 -methyl -2, 6-naphthyridin-l(2H)- one (800 mg, 4. 11 mmol) as yellow solid.1H NMR (400 MHz, CDCh) 5 = 8.76 (s, 1H), 8.23 (s, 1H), 7.18 (d, J = 7.4 Hz, 1H), 6.56 (d, J= 7.4 Hz, 1H), 3.63 (s, 3H).

[0590] Step 4. 2-methyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-one

[0591] To a solution of 7-chloro-2-methyl-2,6-naphthyridin-l(2H)-one (400 mg, 2.06 mmol) in toluene (5 mL) was added Sn2(CH3)e (1.68 g, 2.49 mmol) and Pd(dtbpf)C12 (132 mg, 0.206 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 3 hours under N2. The mixture was poured into aq. KF (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 1-9% EtOAc / petroleum ether) to give 2-methyl-7- (trimethylstannyl)-2,6-naphthyridin-l(2H)-one (530 mg, 1.64 mmol) as white oil. 'H NMR (400 MHz, CDC13) 5 = 9.O9 (d, J= 0.7 Hz, 1H), 8.34 (s, 1H), 7.18 (d, J= 7.3 Hz, 1H), 6.53 (d, J= 7.3 Hz, 1H), 3.63 (s, 3H), 0.49 - 0.30 (m, 9H).General Procedure 51

[0592] Synthesis of 2,3-dimethyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-oneStep 4

[0593] Step 1. (E)-2-chloro-5-(2-nitroprop-l-en-l-yl)isonicotinic acid

[0594] To a mixture of 1-nitroethane (5.11 g, 4.87 mL, 68.1 mmol) in THF (30 mL) was added CS2CO3 (2.18 g, 6.69 mmol) at 0 °C and stirred at 0 °C for 30 minutes under N2. A solution of methyl 2- chloro-5-formyl-pyridine-4-carboxylate (2.67 g, 13.4 mmol) in THF (10 mL) was added to the reaction mixture at 0 °C and stirred at 30 °C for 12 hours under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The aqueous layer adjusted to pH ~ 2 by 3 N HC1 and filtered. The filter cake was dried under reduced pressure to give (E)-2-chloro-5 -(2 -nitroprop- 1-en-l- yl)isonicotinic acid (2.00 g, 8.24 mmol) as yellow solid. 'H NMR (400 MHz, CD3OD) 5 = 8.48 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 2.26 (s, 3H).

[0595] Step 2. 7-chloro-3-methyl-2,6-naphthyridin-l(2H)-one

[0596] To a mixture of (E)-2-chloro-5-(2-nitroprop-l-en-l-yl)isonicotinic acid (2.20 g, 9.07 mmol) inAcOH (20 mL) was added Fe (3.55 g, 63.5 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for152QB\184200.00266\99637562.4VVID 754PC12 hours under N2. The mixture was concentrated under reduced pressure. The residue was diluted with aq. NaHC03 (150 mL) and filtered. The obtained solid material was stirred in MeOH (150 mL) for 1 hour at 25 °C, filtered and concentrated under reduced pressure to give 7-chloro-3-methyl-2,6- naphthyridin-l(2H)-one (1.32) as yellow solid. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was triturated with hexane / DCM (20 mL, 1: 1 v / v) for 1 hour at 25 °C for 1 hour. The suspension was filtered, and the filter cake was dried under reduced pressure to give 7-chloro-3- methyl-2,6-naphthyridin-l(2H)-one (0.38 g) as yellow solid. Both batches were combined to obtain 7- chloro-3-methyl-2,6-naphthyridin-l(2H)-one (1.70 g, 8.74 mmol) as yellow solid. 'H NMR (400 MHz, CD3OD) 5 = 8.76 (S, 1H), 8.05 (s, 1H), 6.53 (s, 1H), 2.34 (d, J = 0.9 Hz, 3H).

[0597] Step 3. 7-chloro-2,3-dimethyl-2,6-naphthyridin-l(2H)-one

[0598] To a solution of 7-chloro-3-methyl-2,6-naphthyridin-l(2H)-one (1.60 g, 8.22 mmol) in DML (20 mL) was added CS2CO3 (5.36 g, 16.4 mmol) and Mel (1.75 g, 12.3 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was quenched with water (70 mL) at 0 °C and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (70 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 7-chloro-2,3-dimethyl- 2,6-naphthyridin-l(2H)-one (1.00 g, 4.79 mmol) as yellow solid. The crude product was used in the next step without further purification. 'H NMR (400 MHz, CDCh) 5 = 8.67 (s, 1H), 8.17 (s, 1H), 6.43 (s, 1H), 3.62 (s, 3H), 2.46 (s, 3H).

[0599] Step 4. 2,3-dimethyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-one

[0600] To a solution of 7-chloro-2,3-dimethyl-2,6-naphthyridin-l(2H)-one (400 mg, 1.92 mmol) in toluene (8 mL) was added Sn2(CH3)e (1.19 g, 3.63 mmol) and Pd(dtbpf)C12 (123 mg, 0.192 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 8 hours under N2. The mixture was poured into aqueous KE (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 20% EtOAc / petroleum ether) to afford 2,3- dimethyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-one (500 mg, 1.48 mmol) as brown solid. 'H NMR (400 MHz, CDCh) 5 = 9.01 (s, 1H), 8.31 - 8.23 (m, 1H), 6.41 (s, 1H), 3.63 (s, 3H), 2.46 (s, 3H), 0.49 - 0.29 (m, 9H).General Procedure 52

[0601] Synthesis of 2,4-dimethyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-one153QB\184200.00266\99637562.4VVID 754PC

[0602] Step 1. N-allyl-5-bromo-2-chloro-N-methylisonicotinamide

[0603] To a solution of 5-bromo-2-chloro-pyridine-4-carboxylic acid (2.00 g, 8.46 mmol) in DCM (15 mL) was added A-Mcthylallylaminc (722 mg, 10.2 mmol), DIPEA (2.19 g, 2.95 mL, 16.9 mmol) and T4P (9.14 g, 12.7 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-35% EtOAc / petroleum ether) to give N- allyl-5-bromo-2-chloro-N-methylisonicotinamide (2.40 g, 8.29 mmol) as yellow solid. 'H NMR (400 MHz, CDCL) 5 8.58 (d, J= 2.5 Hz, 1H), 7.30 (s, 1H), 5.99 - 5.67 (m, 1H), 5.45 - 5.14 (m, 2H), 4.22 (d, J= 71.0 Hz, 1H), 3.83 - 3.66 (m, 1H), 3.18 - 2.82 (m, 3H).

[0604] Step 2. 7-chloro-2,4-dimethyl-2,6-naphthyridin-l(2H)-one

[0605] To a solution of N-allyl-5-bromo-2-chloro-N-methylisonicotinamide (2.20 g, 7.60 mmol) in DMA (25 mL) was added Pd(OAc)2 (85.3 mg, 0.380 mmol), A.A-Dicyclohcxylmcthylaminc (5.94 g, 30.4 mmol) and Tricyclohexylphosphine (213 mg, 0.760 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-70% EtOAc / petroleum ether) to give 7-chloro-2,4-dimethyl-2,6-naphthyridin-l(2H)-one (830 mg, 3.98 mmol) as yellow solid. 'H NMR (400 MHz, CDCL) 5 = 8.82 (s, 1H), 8.25 (s, 1H), 6.94 (s, 1H), 3.59 (s, 3H), 2.35 (s, 3H).

[0606] Step 3. 2,4-dimethyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-one

[0607] To 7-chloro-2,4-dimethyl-2,6-naphthyridin-l(2H)-one (830 mg, 3.98 mmol) in toluene (15 mL) was added Sn2(CH3)e (2.13 g, 6.50 mmol) and Pd(dtbpf)C12 (256 mg, 0.398 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 10 hours under N2. The mixture was poured into aqueous KL (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 0-35% EtOAc / petroleum ether) to afford 2,4-dimethyl-7- (trimethylstannyl)-2,6-naphthyridin-l(2H)-one (870 mg, 2.58 mmol) as yellow solid. 'H NMR (400 MHz, CDCL) 5 = 9.21 (d, J= 0.8 Hz, 1H), 8.37 (d, J= 0.8 Hz, 1H), 6.94 (d, J= 1.0 Hz, 1H), 3.60 (s, 3H), 2.34 (d, J= 1.1 Hz, 3H), 0.51 - 0.27 (m, 9H).General Procedure 53

[0608] Synthesis of 2-methyl-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one154QB\184200.00266\99637562.4VVID 754PC

[0609] Step 1. methyl 2-chloro-5-vinylisonicotinate

[0610] To a solution of methyl 5-bromo-2-chloro-pyridine-4-carboxylate (9.50 g, 37.9 mmol) in 1,4- dioxane (100 mb) and water (20 mb) was added potassium vinyltrifluoroborate (5.59 g, 41.7 mmol), K2CO3 (10.5 g, 75.9 mmol) and Pd(dppf)C12 (2.74 g, 3.79 mmol) at 25 °C under N2. The reaction mixture stirred at 80 °C for 16 hours. The mixture was diluted with water (50 mb) and extracted with EtOAc (50 mb x 3). The combined organic layers were concentrated under reduced pressure and the crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give methyl 2-chloro- 5-vinylisonicotinate (5.90 g, 29.9 mmol) as yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 = 8.84 - 8.75 (m, 1H), 7.77 (s, 1H), 7.19 - 7.08 (m, 1H), 6.01 - 5.92 (m, 1H), 5.58 - 5.50 (m, 1H), 3.93 - 3.84 (m, 3H).

[0611] Step 2. methyl 2-chloro-5-formylisonicotinate

[0612] To a solution of methyl 2-chloro-5-vinylisonicotinate (5.93 g, 30.0 mmol) in MeCN (60 mL) and water (10 mL) was added NalCE (13.0 g, 60.0 mmol) and R11CI3 (311 mg, 1.50 mmol) at 25 °C under N2. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure and the crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to give methyl 2-chloro-5 -formylisonicotinate (3.40 g, 17.0 mmol) as yellow solid. 'H NMR (400 MHz, CDC13) 5 = 10.60 (s, 1H), 8.95 (s, 1H), 7.83 (s, 1H), 4.04 (s, 3H).

[0613] Step 3. 7-chloropyrido[3,4-d]pyridazin-l(2H)-one

[0614] To a solution of methyl 2-chloro-5-formylisonicotinate (3.40 g, 17.0 mmol) in EtOH (50 mL) was added hydrazine monohydrate (1.78 g, 35.6 mmol) at 25 °C under N2. The reaction mixture was stirred at 60 °C for 3 hours. The mixture was concentrated under reduced pressure to give crude 7- chloropyrido[3,4-d]pyridazin-l(2H)-one (3.10 g, 17.1 mmol) as yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 = 9.20 (s, 1H), 8.54 (s, 1H), 8.10 (s, 1H). The crude product was used in the next step without further purification.

[0615] Step 4. 7-chloro-2-methylpyrido[3,4-d]pyridazin-l(2H)-one155QB\184200.00266\99637562.4VVID 754PC

[0616] To a solution of 7-chloropyrido[3,4-d]pyridazin-l(2H)-one (3.10 g, 17.1 mmol) in DMF (35 mL) was added K2CO3 (7.08 g, 51.2 mmol) and Mel (7.27 g, 51.2 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were concentrated under reduced pressure and the crude product was purified by column chromatography (SiC>2, 0-100% EtOAc / petroleum ether) to give 7- chloro-2-methylpyrido[3,4-d]pyridazin-l(2H)-one (2.50 g, 12.8 mmol) as yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 = 9.21 (s, 1H), 8.59 (s, 1H), 8.13 (s, 1H), 3.74 (s, 3H).

[0617] Step 5. 2-methyl-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one

[0618] To a solution of 7-chloro-2-methylpyrido[3,4-d]pyridazin-l(2H)-one (500 mg, 2.56 mmol) in toluene (6 mL) was added Sn2(CH3)6 (1.34 g, 4.09 mmol) and Pd(dtbpf)C12 (165 mg, 0.256 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 4 hours under N2. The mixture was poured into aq. KF (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to give 2-methyl-7- (trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one (540 mg, 1.67 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 = 9.24 (s, 1H), 8.42 - 8.34 (m, 1H), 8.23 (s, 1H), 3.88 (s, 3H), 0.53 - 0.33 (m, 9H).General Procedure 54

[0619] Synthesis of 2,4-dimethyl-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one

[0620] Step 1. 7-chloro-4-methylpyrido[3,4-d]pyridazin-l(2H)-one

[0621] To a solution of methyl 5-acetyl-2-chloro-pyridine-4-carboxylate (2.00 g, 9.36 mmol) in EtOH (30 mL) was added hydrazine monohydrate (0.940 g, 18.8 mmol) at 25 °C under N2. The reaction mixture was stirred at 60 °C for 3 hours and concentrated under reduced pressure to give 7-chloro-4- methylpyrido[3,4-d]pyridazin-l(2H)-one (1.83 g, 9.36 mmol) as yellow solid. The crude product was used in the next step without further purification.1H NMR (400 MHz, DMSO) 5 9.22 - 9.11 (m, 1H), 8.07 (d, J= 0.8 Hz, 1H), 2.57 (s, 3H).

[0622] Step 2. 7-chloro-2,4-dimethylpyrido[3,4-d]pyridazin-l(2H)-one

[0623] To a solution of 7-chloro-4-methylpyrido[3,4-d]pyridazin-l(2H)-one (1.80 g, 9.20 mmol) in DMF (25 mL) was added K2CO3 (3.82 g, 27.6 mmol) and Mel (3.92 g, 27.6 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0 - 45% EtOAc / petroleum156QB\184200.00266\99637562.4VVID 754PC ether) to give 7-chloro-2,4-dimethylpyrido[3,4-d]pyridazin-l(2H)-one (1.80 g, 8.59 mmol) as yellow solid. 'H NMR (400 MHz, DMSO) 5 9.22 (d, J= 0.9 Hz, 1H), 8.11 (d, J = 0.9 Hz, 1H), 3.69 (s, 3H), 2.61 (s, 3H).

[0624] Step 3. 2,4-dimethyl-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one

[0625] To a solution of 7-chloro-2,4-dimethylpyrido[3,4-d]pyridazin-l(2H)-one (1.00 g, 4.77 mmol) in toluene (20 mL) was added Sn2(CH3)e (2.35 g, 7.17 mmol) and Pd(dtbpf)C12 (307 mg, 0.477 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 12 hours under N2. The mixture was poured into aqueous KF (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (A12O3, 0 - 35% EtOAc / petroleum ether) to afford 2,4- dimethyl-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one (1.30 g, 3.85 mmol) as yellow solid. 'H NMR (400 MHz, CDC13) 5 9.31 (d, J= 1.2 Hz, 1H), 8.38 (d, J= 1.2 Hz, 1H), 3.82 (d, J= 1.1 Hz, 3H), 2.63 (d, J= 1.1 Hz, 3H), 0.51 - 0.30 (m, 9H).General Procedure 55

[0626] Synthesis of 3-methyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0627] Step 1. 6-bromopyrido[3,4-d]pyrimidin-4(3H)-one

[0628] A solution of 5 -amino-2 -bromoisonicotinic acid (2.50 g, 11.5 mmol) in formamide (22.5 mL) was stirred at 135 °C for 16 hours and filtered. The filter cake was washed with water (10 mL x 2) and dried under reduced pressure to give crude 6-bromopyrido[3,4-d]pyrimidin-4(3H)-one (2.30 g, 10.2 mmol) as yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 = 12.76 (br s, 1H), 8.88 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H). The crude product was used in the next step without further purification.

[0629] Step 2. 6-bromo-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0630] To a solution of 6-bromopyrido[3,4-d]pyrimidin-4(3H)-one (4.00 g, 17.7 mmol) in DMF (50 mL) was added K2CO3(4.89 g, 35.4 mmol) and Mel (5.02 g, 35.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under N2. The mixture concentrated under reduced pressure, diluted with water (20 mL) and extracted with DCM (15 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was triturated with hexane:EtOAc (20: 1 v / v, 30 mL) to give 6-bromo-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (4.15 g, 17.3 mmol) as yellow solid. 'H NMR (400 MHz, CDC13) 5 = 8.92 (s, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 3.63 (s, 3H).157QB\184200.00266\99637562.4VVID 754PC

[0631] Step 3. 3-methyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0632] To a solution of 6-bromo-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (500 mg, 2.08 mmol) in toluene (10 mL) was added Sn2(CHs)6 (1.02 g, 3.12 mmol) and Pd(dtbpf)C12 (134 mg, 0.208 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 6 hours under N2. The mixture was poured into aqueous KF (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 50-100% EtOAc / petroleum ether) to afford 3- methyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one (630 mg, 1.95 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 = 9.30 (d, J= 0.6 Hz, 1H), 8.23 (d, J= 0.8 Hz, 1H), 8.11 (s, 1H), 3.63 (s, 3H), 0.51 - 0.30 (m, 9H).General Procedure 56

[0633] Synthesis of 2,3-dimethyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-oneStep 1 Step 2 Step 3

[0634] Step 1. 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0635] A solution of 5-amino-2-chloro-pyridine-4-carboxamide (3.00 g, 17.5 mmol) in triethyl orthoacetate (28.4 g, 32.1 mL, 175 mmol) was stirred at 110 °C for 12 hours under N2 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0 - 50% EtOAc / petroleum ether) to give 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1.30 g, 6.65 mmol) as yellow solid. 'H NMR (400 MHz, CD3OD) 5 8.76 (s, 1H), 8.01 (d, J= 0.6 Hz, 1H), 2.47 (s, 3H).

[0636] Step 2. 6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one

[0637] To a solution of 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1.30 g, 6.65 mmol) in DMF (15 mL) was added K2CO3 (1.84 g, 13.3 mmol) and Mel (2.00 g, 14.1 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 hours under N2. The mixture was diluted with water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0 - 50% EtOAc / petroleum ether) to give 6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (1.10 g, 5.25 mmol) as white solid. 'H NMR (400 MHz, CDCL) 5 8.86 (s, 1H), 8.06 (s, 1H), 3.65 (s, 3H), 2.66 (s, 3H).

[0638] Step 3. 2,3-dimethyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0639] To a solution of 6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (340 mg, 1.62 mmol) in toluene (5 mL) was added Sn2(CH3)e (800 mg, 2.44 mmol) and Pd(dtbpf)C12 (104 mg, 0. 162 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 8 hours under N2. The mixture was poured into158QB\184200.00266\99637562.4VVID 754PC aqueous KF (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over ISfeSCL, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 20% EtOAc / petroleum ether) to afford 2,3- dimethyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one (430 mg, 1.02 mmol) as yellow solid. ‘H NMR (400 MHz, CDCh) 5 = 9.21 (s, 1H), 8.16 (s, 1H), 3.66 (s, 3H), 2.67 (s, 3H), 0.52 - 0.29 (m, 9H).Example 1

[0640] Compound 163: 6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'- bipyridine]-2'-carboxamide, Compound 164: 6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4- chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, Compound 281: 6-((2S,3S)-l-acryloyl-2- methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, and Compound 281: 6- ((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamiderelative configuration determined with 2D NMR - absolute stereochemistry randomly assigned

[0641] The mixture of trans and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine- 1 -carboxylate was obtained as described in General Procedure 1, step 5.

[0642] Step 1. Mixture of trans tert-butyl 3-(4-chloro-2'-(methylcarbamoyl)-[2,4'-bipyridin]-6-yl)- 2-methylpyrrolidine-l-carboxylate and cis tert-butyl 3-(4-chloro-2'-(methylcarbamoyl)-[2,4'- bipyridin]-6-yl)-2-methylpyrrolidine-l-carboxylate

[0643] To a mixture of trans and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine- 1-carboxylate (250 mg, 0.665 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added N-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide (227 mg, 0.865 mmol), K2CO3 (184 mg, 1.33159QB\184200.00266\99637562.4VVID 754PC mmol) and Pd(dppf)C12 (48.2 mg, 0.0665 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 20-50% EtOAc / petroleum ether) to give a mixture of trans tert-butyl 3-(4-chloro-2'-(methylcarbamoyl)- [2,4'-bipyridin]-6-yl)-2-methylpyrrolidine-l-carboxylate and cis tert-butyl 3-(4-chloro-2'- (methylcarbamoyl)-[2,4'-bipyridin]-6-yl)-2-methylpyrrolidine-l-carboxylate (250 mg, 0.580 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 = 8.67 (s, 1H), 8.66 (d, J= 5.0 Hz, 1H), 8.22 - 8.17 (m, 1H), 8.10 (br d, J= 4.0 Hz, 1H), 7.83 (s, 1H), 7.24 (d, J= 0.9 Hz, 1H), 4.31 - 4.01 (m, 1H), 3.78 - 3.59 (m, 1H), 3.48 - 3.41 (m, 1H), 3.23 - 3.16 (m, 1H), 3.09 (d, J= 5.0 Hz, 3H), 2.37 - 2.26 (m, 1H), 2.23 - 2.12 (m, 1H), 1.37 (br d, J= 5.8 Hz, 3H), 1.25 (s, 9H).

[0644] Step 2. Mixture of trans 4-chloro-N-methyl-6-(2-methylpyrrolidin-3-yl)-[2,4'-bipyridine]- 2'-carboxamide and cis 4-chloro-N-methyl-6-(2-methylpyrrolidin-3-yl)-[2,4'-bipyridine]-2'- carboxamide

[0645] To a mixture of trans tert-butyl 3-(4-chloro-2'-(methylcarbamoyl)-[2,4'-bipyridin]-6-yl)-2- methylpyrrolidine-1 -carboxylate and cis tert-butyl 3-(4-chloro-2'-(methylcarbamoyl)-[2,4'-bipyridin]-6- yl)-2-methylpyrrolidine-l -carboxylate (230 mg, 0.534 mmol) in MeOH (3 mL) was added HC1 (2 mL, 4 N in MeOH) at 25 °C. The reaction mixture was stirred at 30 °C for 1 hour under N2. The mixture was concentrated under reduced pressure to give crude mixture of trans 4-chloro-N-methyl-6-(2- methylpyrrolidin-3-yl)-[2,4'-bipyridine]-2'-carboxamide and cis 4-chloro-N-methyl-6-(2- methylpyrrolidin-3-yl)-[2,4'-bipyridine]-2'-carboxamide (176 mg, 0.532 mmol) as yellow solid. 'H NMR (400 MHz, CD3OD) 5 = 9.02 (s, 1H), 8.85 (d, J= 5.5 Hz, 1H), 8.52 - 8.47 (m, 1H), 8.25 (d, J= 1.4 Hz, 1H), 7.67 (d, J= 1.4 Hz, 1H), 4.25 - 4.18 (m, 1H), 3.67 - 3.60 (m, 1H), 3.53 (s, 1H), 3.46 (d, J= 8.5 Hz, 1H), 3.05 (s, 3H), 2.62 - 2.55 (m, 1H), 2.50 - 2.40 (m, 1H), 1.47 (d, J= 6.6 Hz, 3H). The crude product was used in the next step without further purification.

[0646] Step 3. Mixture of trans 6-(l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'- bipyridine]-2'-carboxamide and cis 6-(l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'- bipyridine] -2'-carboxamide

[0647] To a mixture of trans 4-chloro-N-methyl-6-(2-methylpyrrolidin-3-yl)-[2,4'-bipyridine]-2'- carboxamide and cis 4-chloro-N-methyl-6-(2-methylpyrrolidin-3-yl)-[2,4'-bipyridine]-2'-carboxamide (176 mg, 0.532 mmol) in DCM (5 mL) was added TEA (162 mg, 1.60 mmol) and acryloyl chloride (51.9 pL, 57.8 mg, 0.638 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 30 minutes under N2. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO?. 80-100% EtOAc / petroleum ether) and preparative HPLC (Waters Xbridge BEH C18, 100 x 30 mm, 10160QB\184200.00266\99637562.4VVID 754PC pm; 30-60% ACN / H2O (10 mM NH4HCO3)) to give a mixture of trans 6-(l -acryloyl -2- methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide and cis 6-(l -acryloyl -2- methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide (110 mg, 0.286 mmol) as white solid. 'H NMR (400 MHz, CDCI3) 5 = 8.67 - 8.61 (m, 2H), 8.13 - 8.07 (m, 2H), 7.85 - 7.80 (m, 1H), 7.26 - 7.22 (m, 1H), 6.51 - 6.33 (m, 2H), 5.72 - 5.66 (m, 1H), 4.56 - 4.45 (m, 1H), 3.98 - 3.86 (m, 1H), 3.78 - 3.68 (m, 1H), 3.38 - 3.19 (m, 1H), 3.08 (d, J= 5.1 Hz, 3H), 2.50 - 2.42 (m, 1H), 2.41 - 2.30 (m, 1H), 1.44 (d, J= 6.3 Hz, 3H).

[0648] Step 4. Chiral separation of 6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N- methyl-[2,4'-bipyridine]-2'-carboxamide, 6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro- N-methyl-[2,4'-bipyridine]-2'-carboxamide, 6-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4- chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, and 6-((2R,3R)-l-acryloyl-2-methylpyrrolidin- 3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide

[0649] The racemic mixture of trans 6-(l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'- bipyridine]-2'-carboxamide and cis 6-(l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'- bipyridine]-2'-carboxamide (110 mg, 0.286 mmol) was separated by SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm; 35% MeOH (0.1% NH3H2O) / CO2) and a second SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm; 30% MeOH (0.1% NH3H2O) / CO2). The first eluting isomer, Compound 163, was randomly designated as 6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'- bipyridine] -2'-carboxamide (21.1 mg, 0.0547 mmol) and was obtained as yellow solid. 'H NMR (400 MHz, CDCh) 5 = 8.73 - 8.59 (m, 2H), 8.19 - 8.05 (m, 2H), 7.90 - 7.75 (m, 1H), 7.27 - 7.23 (m, 1H), 6.60 - 6.33 (m, 2H), 5.77 - 5.63 (m, 1H), 4.59 - 4.42 (m, 1H), 4.00 - 3.84 (m, 1H), 3.79 - 3.60 (m, 1H), 3.40 - 3.20 (m, 1H), 3.08 (d, J= 5.2 Hz, 3H), 2.50 - 2.18 (m, 2H), 1.45 (d, J= 6.4 Hz, 3H). LCMS [M+H]+: 385.3 Retention Time: 1.45 min (Method 1). The second eluting isomer, Compound 164, was randomly designated as 6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'- carboxamide (18.5 mg, 0.0480 mmol) and was obtained as yellow solid. 'H NMR (400 MHz, CDCI3) 5 = 8.72 - 8.57 (m, 2H), 8.18 - 8.05 (m, 2H), 7.91 - 7.74 (m, 1H), 7.25 (br s, 1H), 6.60 - 6.28 (m, 2H), 5.78 - 5.63 (m, 1H), 4.59 - 4.43 (m, 1H), 4.03 - 3.83 (m, 1H), 3.79 - 3.60 (m, 1H), 3.24 (br d, J= 4.8 Hz, 1H), 3.08 (d, J= 5.2 Hz, 3H), 2.50 - 2.18 (m, 2H), 1.45 (d, J= 6.4 Hz, 3H). LCMS [M+H]+: 385.3 Retention Time: 1.45 min (Method 1). The trans configuration of Compound 163 and Compound 164 was determined by 2D-NMR. The third eluting isomer, Compound 281, was randomly designated as 6- ((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide (7.1 mg, 0.0184 mmol) and was obtained as yellow solid. 'H NMR (400 MHz, CDCh) 5 = 8.81 - 8.61 (m, 2H), 8.22 - 8.01 (m, 2H), 7.85 (s, 1H), 7.28 (br s, 1H), 6.61 - 6.39 (m, 2H), 5.81 - 5.67 (m, 1H), 4.91 - 4.53 (m, 1H), 3.96 - 3.58 (m, 3H), 3.09 (d, J= 5.2 Hz, 3H), 2.94 - 2.54 (m, 1H), 2.40 - 2.25 (m, 1H), 0.93 (d, J= 6.4 Hz, 3H). LCMS [M+H]+: 385.3 Retention Time: 1.45 min (Method 1). The fourth eluting isomer, Compound 282, was randomly designated as 6-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4- chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide (6.9 mg, 0.0179 mmol) and was obtained as yellow161QB\184200.00266\99637562.4VVID 754PC solid. 'H NMR (400 MHz, CDC13) 5 = 8.80 - 8.62 (m, 2H), 8.20 - 8.00 (m, 2H), 7.84 (d, J= 1.2 Hz, 1H), 7.28 (br d, J= 0.8 Hz, 1H), 6.60 - 6.36 (m, 2H), 5.81 - 5.65 (m, 1H), 4.90 - 4.54 (m, 1H), 3.98 - 3.60 (m, 3H), 3.09 (d, J= 5.2 Hz, 3H), 2.93 - 2.54 (m, 1H), 2.41 - 2.27 (m, 1H), 0.93 (d, J= 6.4 Hz, 3H). LCMS [M+H]+: 385.3 Retention Time: 1.45 min (Method 1). The cis configuration of Compound 281 and Compound 282 was determined with 2D-NMR.Example 2

[0650] Compound 187: 2-(6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6- methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one and Compound 188: 2-(6-((2S,3R)-l-acryloyl-2- methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-oneabsolute stereochemistry randomly assigned

[0651] The mixture of trans and cis tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine- 1 -carboxylate was obtained as described in General Procedure 1, step 5. 6-methyl-2-(trimethylstannyl)- 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one was obtained from General Procedure 39, step 3.

[0652] Step 1. Mixture of trans tert-butyl 3-(4-chloro-6-(6-methyl-7-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)pyridin-2-yl)-2-methylpyrrolidine-l-carboxylate and cis tert-butyl 3-(4- chloro-6-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)pyridin-2-yl)-2- methylpyrrolidine-l-carboxylate

[0653] A mixture of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l- carboxylate and cis tert-butyl 3 -(6-bromo-4-chloropyridin-2-yl)-2-methylpyrrolidine-l -carboxylate (150 mg, 0.399 mmol) in toluene (3 m ) was added 6-methyl-2-(trimethylstannyl)-5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one (149 mg, 0.479 mmol), LiCl (1.69 mg, 0.0399 mmol) and Pd(PPh3)4(46.1162QB\184200.00266\99637562.4VVID 754PC mg, 0.0399 mmol) at 25 °C under N2. The reaction mixture was stirred at 120 °C for 12 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc) to give a mixture of trans tert-butyl 3-(4-chloro-6-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-2-yl)pyridin-2-yl)-2-methylpyrrolidine-l -carboxylate and cis tert-butyl 3-(4-chloro-6-(6- methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)pyridin-2-yl)-2-methylpyrrolidine-l- carboxylate (68 mg, 0.154 mmol) as yellow solid. 'H NMR (400 MHz,CDC13) 5 = 8.69 - 8.60 (m, 2H), 7.92 (d, J= 7.8 Hz, 1H), 7.21 (d, J= 1.5 Hz, 1H), 5.31 (s, 1H), 4.47 (s, 2H), 4.42 - 3.99 (m, 1H), 3.87 - 3.56 (m, 1H), 3.55 - 3.42 (m, 1H), 3.32 (s, 3H), 3.22 - 3.13 (m, 1H), 2.38 - 2.27 (m, 1H), 2.24 - 2.10 (m, 1H), 1.53 - 1.46 (m, 9H), 1.41 - 1.24 (m, 3H), 0.93 - 0.79 (m, 1H).

[0654] Step 2. Mixture of trans 2-(4-chloro-6-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-6-methyl-5,6- dihydro-7H-pyrrolo [3,4-b] pyridin-7-one and cis 2-(4-chloro-6-(2-methylpyrrolidin-3-yl)pyridin-2- yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0655] To a mixture of trans 2-(4-chloro-6-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-6-methyl-5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one and cis 2-(4-chloro-6-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-6- methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (116 mg, 0.262 mmol) in MeOH (2 mL) was added HC1 (5 mL, 4 N in MeOH) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was filtered and concentrated under reduced pressure to give a crude mixture of trans 2-(4- chloro-6-(2-methylpyrrolidin-3 -yl)pyridin-2-yl)-6-methyl-5 ,6-dihydro-7H-pyrrolo [3 ,4-b]pyridin-7 -one and cis 2-(4-chloro-6-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one (99.0 mg, 0.289 mmol) as yellow solid. The crude product was used in the next step without further purification.

[0656] Step 3. trans 2-(6-(l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one and cis 2-(6-(l-acryloyl-2-methylpyrrolidin-3-yl)-4- chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0657] To a mixture of trans 2-(4-chloro-6-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-6-methyl-5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one and cis 2-(4-chloro-6-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-6- methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (99.0 mg, 0.289 mmol) in DCM (5 mL) was added TEA (58.4 mg, 0.578 mmol) and acryloyl chloride (28.2 pL, 31.4 mg, 0.347 mmol) at 25 °C under N2. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over ISfeSCh, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give trans 2-(6-(l -acryloyl -2- methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-on (55.0 mg, 0.139 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 = 8.70 - 8.60 (m, 1H), 8.46 (s, 1H), 7.90163QB\184200.00266\99637562.4VVID 754PC(t, J= 7.6 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.59 - 6.36 (m, 2H), 5.76 - 5.65 (m, 1H), 4.68 - 4.47 (m, 1H), 4.46 (s, 2H), 4.07 - 3.81 (m, 1H), 3.77 - 3.63 (m, 1H), 3.36 - 3.14 (m, 4H), 2.50 - 2.37 (m, 1H), 2.34 - 2.16 (m, 1H), 1.49 - 1.40 (m, 3H). And cis 2-(6-(l -acryloyl -2 -methylpyrrolidin-3-yl)-4-chloropyridin-2- yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-on (12.0 mg, 0.030 mmol) as white solid. 'H NMR (400 MHz, CDCh) 5 = 8.69 - 8.62 (m, 2H), 7.98 - 7.93 (m, 1H), 7.26 - 7.21 (m, 1H), 6.60 - 6.39 (m, 2H), 5.76 - 5.69 (m, 1H), 4.92 - 4.53 (m, 1H), 4.48 (d, J = 2.9 Hz, 2H), 3.96 - 3.84 (m, 1H), 3.81 - 3.61 (m, 2H), 3.32 (s, 3H), 2.82 - 2.58 (m, 1H), 2.42 - 2.27 (m, 1H), 0.94 (d, J= 6.6 Hz, 3H).

[0658] Step 4. Chiral separation of 2-(6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4- chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one and 2-(6-((2S,3R)-l- acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one

[0659] The racemic trans 2-(6-(l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl- 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (50.0 mg, 0.126 mmol) was separated by SFC (DAICEL CHIRALPAK AD, 250 x 30 mm, 10 pm; 25-40% EtOH (0.1% NH3H2O) / CO2). The first eluting isomer, Compound 187, was randomly designated as 2-(6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4- chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (15.0 mg, 0.037 mmol) and was obtained as white solid: 'H NMR (400 MHz, CDCE) 5 ppm 8.66 - 8.60 (m, 1H), 8.58 - 8.47 (m, 1H), 7.89 (t, J= 8.0 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.58 - 6.49 (m, 1H), 6.47 - 6.38 (m, 1H), 5.73 - 5.65 (m, 1H), 4.69 - 4.46 (m, 1H), 4.45 (s, 2H), 4.06 - 3.80 (m, 1H), 3.78 - 3.64 (m, 1H), 3.34 - 3.16 (m, 4H), 2.50 - 2.39 (m, 1H), 2.33 - 2.17 (m, 1H), 1.49 - 1.40 (m, 3H); LCMS [M+H]+: 397.3 Retention Time: 1.38 min (Method 1). The second eluting isomer, Compound 188, was randomly designated as 2-(6- ((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one (16.0 mg, 0.040 mmol) and was obtained as white solid: 'H NMR (400 MHz, CDCls) 5 ppm 8.68 - 8.60 (m, 1H), 8.59 - 8.48 (m, 1H), 7.90 (t, J= 7.2 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.60 - 6.48 (m, 1H), 6.48 - 6.38 (m, 1H), 5.74 - 5.64 (m, 1H), 4.69 - 4.47 (m, 1H), 4.46 (s, 2H), 4.07 - 3.81 (m, 1H), 3.79 - 3.63 (m, 1H), 3.37 - 3.15 (m, 4H), 2.51 - 2.36 (m, 1H), 2.34 - 2.16 (m, 1H), 1.50 - 1.40 (m, 3H); LCMS [M+H]+: 397.3 Retention Time: 1.36 min (Method 1).Example 3

[0660] Compound 215: 3-(6-((2R,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-4- chloropyridin-2-yl)-6-methyl-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one164QB\184200.00266\99637562.4VVID 754PC

[0661] tert-butyl (2R,3R)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2-methylpyrrolidine-l- carboxylate was obtained as described in General Procedure 3, step 2. 6-methyl-3-(trimethylstannyl)-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one was obtained as described in General Procedure 49, step 5.

[0662] Step 1. tert-butyl (2R,3R)-3-(4-chloro-6-(6-methyl-5-oxo-5,6,7,8-tetrahydropyrido[3,4- b]pyrazin-3-yl)pyridin-2-yl)-3-hydroxy-2-methylpyrrolidine-l-carboxylate

[0663] To a solution of tert-butyl (2R,3R)-3-(6-bromo-4-chloropyridin-2-yl)-3-hydroxy-2- methylpyrrolidine-1 -carboxylate (150 mg, 0.383 mmol) in toluene (5 mb) was added 6-methyl-3- (trimethylstannyl)-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one (125 mg, 0.383 mmol), LiCl (1.62 mg, 0.0383 mmol) and Pd(PPh,)4 (44.3 mg, 0.0383 mmol) at 25 °C under N2. The reaction mixture was stirred at 120 °C for 12 hours under N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 45-75% EtOAc / petroleum ether) to give tert-butyl (2R,3R)-3-(4-chloro-6-(6-methyl-5-oxo-5, 6,7,8- tetrahydropyrido [3 ,4-b]pyrazin-3 -yl)pyridin-2-yl)-3 -hydroxy-2 -methylpyrrolidine- 1 -carboxylate (130 mg, 0.274 mmol) as yellow oil. 'H NMR (400 MHz, CDCh) 5 9.57 (s, 1H), 8.58 (d, J= 1.8 Hz, 1H), 7.49 (d, J= 1.8 Hz, 1H), 4.12 (q, J = 7.1 Hz, 1H), 4.06 - 3.93 (m, 1H), 3.79 - 3.72 (m, 3H), 3.65 (d, J= 7.1 Hz, 1H), 3.38 (t, J= 6.8 Hz, 2H), 3.27 (s, 3H), 2.39 - 2.27 (m, 1H), 2.23 - 2.13 (m, 1H), 1.50 (s, 9H), 1.31 - 1.20 (m, 3H).

[0664] Step 2. 3-(4-chloro-6-((2R,3R)-3-hydroxy-2-methylpyrrolidin-3-yl)pyridin-2-yl)-6-methyl- 7,8-dihydropyrido [3,4-b] pyrazin-5(6H)-one

[0665] To a solution of tert-butyl (2R,3R)-3-(4-chloro-6-(6-methyl-5-oxo-5, 6,7,8- tetrahydropyrido [3 ,4-b]pyrazin-3 -yl)pyridin-2-yl)-3 -hydroxy-2 -methylpyrrolidine- 1 -carboxylate (130 mg, 0.274 mmol) in DCM (3 mL) was added TFA (1 mL) at 25 °C under N2. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated under reduced pressure to give crude 3-(4-chloro-6-((2R,3R)-3-hydroxy-2-methylpyrrolidin-3-yl)pyridin-2-yl)-6-methyl-7,8-dihydro- pyrido[3,4-b]pyrazin-5(6H)-one (102 mg, 0.273 mmol) as brown oil. The crude product was used in the next step without further purification.

[0666] Step 3. 3-(6-((2R,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-4-chloropyridin-2- yl)-6-methyl-7,8-dihydropyrido [3,4-b] pyrazin-5(6H)-one

[0667] To a solution of 3-(4-chloro-6-((2R,3R)-3-hydroxy-2-methylpyrrolidin-3-yl)pyridin-2-yl)-6- methyl-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one (102 mg, 0.273 mmol) in DCM (5 mL) was added TEA (114 pL, 82.8 mg, 0.819 mmol) and acryloyl chloride (26.6 pL, 29.6 mg, 0.327 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 minutes under N2. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by preparative165QB\184200.00266\99637562.4VVID 754PCHPLC (WePure Biotech XP tC18, 150 x 30 mm, 7 pm; 10-40% ACN / H20 (10 mM NH4HCO3)) to give 3-(6-((2R,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one (43.7 mg, 0.101 mmol) as yellow solid. 'H NMR (400 MHz, CDCh) 5 = 9.63 - 9.45 (m, 1H), 8.58 (s, 1H), 7.60 - 7.36 (m, 1H), 6.61 - 6.33 (m, 2H), 5.74 (br d, J = 10.5 Hz, 1H), 4.68 - 4.15 (m, 2H), 4.03 - 3.81 (m, 2H), 3.81 - 3.71 (m, 2H), 3.39 (br t, J= 5.8 Hz, 2H), 3.28 (d, J= 1.5 Hz, 3H), 2.50 - 2.23 (m, 2H), 1.42 - 1.32 (m, 3H).

[0668] The following compounds were made by methods similar to those described in Example 1 to Example 3.Table 1.166QB\184200.00266\99637562.4VVID 754PC167QB\184200.00266\99637562.4VVID 754PC168QB\184200.00266\99637562.4VVID 754PC169QB\184200.00266\99637562.4VVID 754PC170QB\184200.00266\99637562.4VVID 754PC171QB\184200.00266\99637562.4VVID 754PCExample 4

[0669] Compound 51: 6-(4-(l-acryloylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine- 4-carboxamide172QB\184200 ,00266\99637562.4VVID 754PC

[0670] tert-butyl 3 -(2-bromo-6-chloropyridin-4-yl)pyrrolidine-l -carboxylate was obtained as described in General Procedure 4, step 3. 6-chloro-N-methylpyrimidine-4-carboxamide was obtained from General Procedure 28, step 2.

[0671] Step 1. tert-butyl 3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4- yl)pyrrolidine-l-carboxylate

[0672] To a solution of tert-butyl 3 -(2-bromo-6-chloropyridin-4-yl)pyrrolidine-l -carboxylate (88.0 mg, 0.243 mmol) in toluene (3 mL) was added Pin2B2 (92.7 mg, 0.365 mmol), KOAc (47.8 mg, 0.487 mmol) and Pd(dppf)C12 (4.4 mg, 0.006 mmol). The reaction mixture was stirred at 75 °C for 16 hours. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, fdtered and concentrated under reduced pressure to give tert-butyl3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)pyrrolidine-l-carboxylate (crude) which was used in the next step without further purification. LCMS | M-C.Hiu+H | : 327, Retention Time: 2.446 min (Method 2).

[0673] Step 2. tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4- yl)pyrrolidine-l-carboxylate

[0674] To a solution of tert-butyl 3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)pyrr°lidine-l -carboxylate (99.9 mg, 0.244 mmol) in toluene (1.2 mL) and water (0.12 mL) was added 6-chloro-N-methyl-pyrimidine-4-carboxamide (46.1 mg, 0.269 mmol), K2CO3 (67.5 mg, 0.489 mmol) and Pd(dppf)C12 (4.4 mg, 0.006 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was concentrated and purified by column chromatography (SiC 0-100% acetone / heptane) to give tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)pyrrolidine-l- carboxylate (58.7 mg, 0.141 mmol) as white solid. LCMS [M-CsHs+H] : 362, Retention time: 1.495 min (Method 6).

[0675] Step 3. 6-(6-chloro-4-(pyrrolidin-3-yl)pyridin-2-yl)-N-methylpyrimidine-4-carboxamide hydrochloride

[0676] A mixture of tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4- yl)pyrrolidine-l -carboxylate (58.0 mg, 0.139 mmol) in HCl / l,4-dioxane (4N, 2.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was suspended in DCM and concentrated again (3x) to afford 6-(6-chloro-4-(pyrrolidin-3-yl)pyridin-2-yl)-N-methylpyrimidine-4- carboxamide hydrochloride which was used in the next step without further purification. LCMS [M+H- HC1]+: 318, Retention time: 0.143 min (Method 3).

[0677] Step 4. racemic 6-(4-(l-acryloylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine-4-carboxamide173QB\184200.00266\99637562.4VVID 754PC

[0678] To a solution of 6-(6-chloro-4-(pyrrolidin-3-yl)pyridin-2-yl)-N-methylpyrimidine-4- carboxamide hydrochloride (55.5 mg, 0.157 mmol) in DMF (1 mL) was added TEA (109 pL, 79.3 mg, 0.783 mmol) and acryloyl chloride (38.2 pL, 42.5 mg, 0.470 mmol) at 0 °C. The reaction mixture was stirred for 30 minutes, fdtered, and purified by preparative HPLC (C18 SiCE, 0-100% ACN / H2O (0.1% HCO2H)) to give Compound 51, racemic 6-(4-(l-acryloylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine-4-carboxamide (5.1 mg, 0.0136 mmol) as white solid. 'H NMR (400 MHz, CD3CN) 5 9.20 (t, J= 1.2 Hz, 1H), 8.73 (t, J= 1.5 Hz, 1H), 8.29 (d, J= 1.6 Hz, 1H), 8.08 (s, 1H), 7.44 (d, J= 1.5 Hz, 1H), 6.49 (ddd, J= 16.9, 10.3, 5.2 Hz, 1H), 6.14 (ddd, J= 16.8, 4.3, 2.3 Hz, 1H), 5.57 (ddd, J= 10.3, 7.1, 2.3 Hz, 1H), 4.04 - 3.89 (m, 1H), 3.76 - 3.63 (m, 1H), 3.61 - 3.34 (m, 3H), 2.88 (d, J= 5.0 Hz, 3H), 2.43 - 2.23 (m, 1H), 2.00 - 1.90 (m, 1H). LCMS [M+H]+: 372.3, Retention time: 1.31 min (Method 1). The following compound was synthesized as described in Example 1.Example 5

[0679] Compound 76: 6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine-4-carboxamide and Compound 77: 6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3- yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamideabsolute stereochemistry was randomly assigned

[0680] trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l-carboxylate as described in General Procedure 5, step 5. 6-chloro-N-methylpyrimidine-4-carboxamide was obtained from General Procedure 28, step 2.

[0681] Step 1. trans tert-butyl 3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 4-yl)-2-m ethylpy r r oli dine- 1 - carb oxylate

[0682] To a solution of trans tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpyrrolidine-l- carboxylate (400 mg, 1.06 mmol) in 1,4-dioxane (5 mL) was added Ph EE (406 mg, 1.59 mmol), KO Ac (209 mg, 2.12 mmol) and Pd(dppf)C12'DCM (86.9 mg, 0.100 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was concentrated under reduced pressure, diluted with water (10 mL) and174QB\184200.00266\99637562.4VVID 754PC extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give trans tert-butyl 3-(2-chloro- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)-2-methylpyrrolidine-l-carboxylate (450 mg, 1.06 mmol) as brown oil.

[0683] Step 2. trans tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)-2- methylpyrrolidine-l-carboxylate

[0684] To a solution of trans tert-butyl 3-(2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-4-yl)-2-methylpyrrolidine-l-carboxylate (450 mg, 1.06 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added 6-chloro-N-methylpyrimidine-4-carboxamide (183 mg, 1.06 mmol), K2CO3 (294 mg, 2.12 mmol) and Pd(dppf)C12 (77.0 mg, 0.100 mmol). The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 100-90% Ethyl acetate / MeOH) to give trans tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4- yl)pyridin-4-yl)-2-methylpyrrolidine-l-carboxylate (400 mg, 0.920 mmol) as colorless oil. 'H NMR (400 MHz, DMSO-d6) 5 ppm 9.41 (d, J= 1.2 Hz, 1H), 9.11 (br d, J= 4.4 Hz, 1H), 8.74 (d, J= 1.2 Hz, 1H), 8.35 (s, 1H), 7.70 (s, 1H), 3.91 - 3.78 (m, 1H), 3.61 - 3.46 (m, 1H), 3.30 - 3.16 (m, 1H), 2.87 (d, J= 4.8 Hz, 3H), 2.36 - 2.23 (m, 2H), 2.06 - 1.99 (m, 1H), 1.46 - 1.41 (m, 9H), 1.24 (br d, J= 6.0 Hz, 3H).

[0685] Step 3. trans 6-(6-chloro-4-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-N-methylpyrimidine-4- carboxamide

[0686] To a solution of trans tert-butyl 3-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4- yl)-2-methylpyrrolidine-l -carboxylate (400 mg, 0.920 mmol) in MeOH (4 mL) was added HCl / MeOH(4 M, 4 mL). The reaction mixture was stirred at 30 °C for 2 hours. The mixture was concentrated under reduced pressure to give trans 6-(6-chloro-4-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-N-methylpyrimidine- 4-carboxamide (300 mg, 0.900 mmol) as white solid.

[0687] Step 4. trans 6-(4-(l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine-4-carboxamide

[0688] To a solution of trans 6-(6-chloro-4-(2-methylpyrrolidin-3-yl)pyridin-2-yl)-N- methylpyrimidine-4-carboxamide (300 mg, 0.900 mmol) in DCM (3 mL) was added acryloyl chloride (107 mg, 1.17 mmol), TEA (183 mg, 1.80 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. The mixture was poured into water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 90-100% EtOAc / petroleum ether) to give trans 6-(4-( 1 -acryloyl -2 -methylpyrrolidin-3-yl)-6- chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide (160 mg, 0.410 mmol) as white solid. 'H NMR175QB\184200.00266\99637562.4VVID 754PC(400 MHz, CDCh) 5 ppm 9.24 (s, 1H), 9.11 (s, 1H), 8.40 - 8.23 (m, 1H), 8.01 (br d, J = 3.2 Hz, 1H), 7.35- 7.29 (m, 1H), 6.55 - 6.36 (m, 2H), 5.82 - 5.70 (m, 1H), 4.42 - 4.12 (m, 1H), 4.00 - 3.79 (m, 1H), 3.77 - 3.48 (m, 1H), 3.10 (d, J= 5.2 Hz, 3H), 2.56 - 2.35 (m, 1H), 2.21 - 2.02 (m, 1H), 1.76 - 1.57 (m, 1H), 1.43 (d, J= 6.4 Hz, 3H).

[0689] Step 5. Chiral separation of 6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6- chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide and 6-(4-((2S,3S)-l-acryloyl-2- methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide

[0690] The racemic trans 6-...

Claims

VVID 754PCCLAIMSWhat is claimed is:1) A compound having the structure of formula (I)whereinX1is CH or N,X2is CH or N,X3is CH or N,X4is N or C-R4withR4is -H, -CN, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2, -F, or -Cl,X5 is N or C-R5withR5is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -O-CH3, -O-CH2-CH3, O-CH(CH3)2, -S-CH3, -N(CH3)2, -F or -Cl,X6is N or C-R6withR6is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2, -F, or -Cl,X7is C-R7or N-R7andR7ais H or -Ci.4alkyl,R76is -Ci.4alkyl, or -C3-4cycloalkyl, orR6and R7together form **-CH2-N(Ci.4alkyl)-C(O)-, **-CH2-CH2-N(Ci.4alkyl)-C(O)-, **=N-N(Ci.4alkyl)-C(O)-, **-CH=CH-N(Ci.4alkyl)-C(O)-, **-N=CH-N(Ci.4alkyl)-C(O)-, **-CH=N-N(Ci.4alkyl)-C(O)-, and in which * * marks the bond towards X6,X8is N or CH, with the proviso, that only 0, 1, 2 or 3 of X4, X5, X6or X8can be simultaneously N,X9is a direct single bond or CR9R9a, andR9is -H, -F, -Cl, or -Ci.4alkyl, andR9ais -H, -F, -Cl, -OH, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2,414QB\184200.00266\99637562.4VVID 754PCR10is -H, -F, -Cl, -CH3, -CH2-COOH, -O-CH3, or -CH2-O-CH3, -CH2-C(O)-NR10bR10c,R10ais -H, -F, or -OH,R10band R10cindependently of each other are -H or -CH3,R11is -H, -Ci.4alkyl, -CFH2, -CF2H, -CF3, -CH2-CN, -CH2-OH, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2O-CH(CH3)2,R12is -H, -C1.4 alkyl, -CH2-OH, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-O-CH(CH3)2, -CH2-CN, -CFH2, -CF2H, -CF3, orR10and R12together form -CH2-CH2- substituted with 0-4 F, or -CH2-O-CH2- substituted with 0-4 F, orR11and R12together form -CH2-CH2- substituted with 0-4 F, or -CH2-O-CH2- substituted with 0-4 F,R13is -H, -F, -OH, -O-CH3, -O-CH2-CH3, -O-CH(CH3)2,R14is -F, -Cl, -CH3or -CN, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof with the proviso that said compound is not2) The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof with the proviso, that not all R9, R9a, R10, R10a, R11, R12and R13are simultaneously -H.3) The compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof wherein X9is not CH2.4) The compound of claim 1 or 2 whereinX1is CH or N,X2is CH or N,X3is CH or N, wherein one and only one of X1, X2and X3is N,X4is N or C-R4withR4is -H, -CN, -O-CH3, or -F,X5 is N or C-R5withR5is -H, -CH3, -CF3 or -O-CH3,X6is N or C-R6withR6is -H, -F, -CH3, or -O-CH3,X7is C-R7andR7is -CN, -C(O)-NH2, -C(O)-NH-CH3, or -C(O)-N(CH3)2, or415QB\184200.00266\99637562.4VVID 754PCR6and R7together form **-CH2-N(CH3)-C(O)-, **-CH2-CH2-N(CH3)-C(O)-, **-CH=CH- N(CH3)-C(O)-, **=N-N(CH3)-C(O)-, **-N=CH-N(CH3)-C(O)-, **-CH=N-N(CH3)- C(O)-, with ** indicating the bond towards X6,X8is N or CH, with the proviso, that only 0, 1, 2 or 3 of X4, X5, X6or X8can be simultaneously N,X9is a direct single bond or CR9R9a, withR9is -H, -F, -CH3, andR9ais -H, -F, -OH, -O-CH3,R10is -H, -F, -CH3, -CH2-COOH, -O-CH3, -CH2-O-CH3,R10ais -H, -F, or -OH,R11is -H, -CH3, -CH2-F, -CH2-OH, -CH2-O-CH3, orR12is -H, -CH3, -CH2-OH, -CH2-O-CH3, -CH2-CN, -CH2F,R10and R12or R11and R12form -CH2-CH2-, or -CH2-O-CH2-,R13is -H, -OH, -O-CH3R14is -F, -Cl, -CH3or -CN, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.5) The compound of claim 1 or 2 having the structure of formula (II)whereinX1is CH or N,X2is CH or N,X3is CH or N, wherein one and only one of X1, X2and X3is N,X4is N or C-R4withR4is -H, -CN, -O-CH3, or -F,X5is N or C-R5withR5is -H, -CH3, -CF3or -O-CH3,X6is N or C-R6withR6is -H, -F, or -O-CH3,416QB\184200.00266\99637562.4VVID 754PCX7is C-R7withR7is -C(O)-NH-CH3, or -CN,R6and R7together form **-CH2-N(CH3)-C(O)-, **-CH2-CH2-N(CH3)-C(O)-, **-CH=CH-N(CH3)- C(O)-, **=N-N(CH3)-C(O)-, **-N=CH-N(CH3)-C(O)-, **-CH=N-N(CH3)-C(O)-, with ** indicating the bond towards X6,X8is N or CH with the proviso, that only 0, 1, or 2 of all X4, X5, X6, or X8can simultaneously be N,R9is -H, -F, or -CH3,R9ais -H, -F, -OH, -O-CH3,R10is -H, -F, -CH3, -CH2-COOH, -O-CH3, -CH2-O-CH3,R10ais -H, -F, or -OH,R11is -H, -CH3, -CH2-F, -CH2-OH, or -CH2-O-CH3,R12is -H, -CH3, -CH2-OH, -CH2-O-CH3, -CH2-CN, CH2F,R10and R12or R11and R12form -CH2-CH2- or -CH2-O-CH2-,R13is -H, -OH, or -OCH3,R14is -F, -Cl, -CH3or -CN, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.6) The compound of claim 5 wherein X1is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.7) The compound of any one of claims 5-6 wherein X2is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.8) The compound of any one of claims 5-7wherein X3is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.9) The compound of any one of claims 5-7 wherein X3is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.10) The compound of any one of claims 5-9 wherein X4is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.11) The compound of any one of claims 5-10 wherein X5is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.12) The compound of any one of claims 5-11 wherein X6is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.13) The compound of any one of claims 5-12 wherein X7is C-C(O)-NH-CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.14) The compound of any one of claims 5-13 wherein X8is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.15) The compound of any one of claims 5-14 wherein R6and R7together form **-CH2-N(CH3)-C(O)- or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.417QB\184200.00266\99637562.4VVID 754PC16) The compound of any one of claims 5-14 wherein R6and R7together form **-CH2-CH2-N(CHs)- C(O)- or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.17) The compound of any one of claims 5-16 wherein R9is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.18) The compound of any one of claims 5-17 wherein R9ais H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.19) The compound of any one of claims 5-18 wherein R10is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.20) The compound of any one of claims 5-19 wherein R11is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.21) The compound of any one of claims 5-20 wherein R12is -CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.22) The compound of any one of claims 5-20 wherein R12is -CH2-OH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.23) The compound of any one of claims 5-20 wherein R12is -CH2-O-CH3 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.24) The compound of any one of claims 5-23 wherein R13is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.25) The compound of any one of claims 5-23 wherein R13is OH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.26) The compound of any one of claims 5-25 wherein R14is Cl or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.27) The compound of claim 1 having the structure of formula (III)whereinX1is N or CH,X2is N or CH,X3is N or CH, with the proviso that only one of X1, X2or X3is N,418QB\184200.00266\99637562.4VVID 754PCX4is N or C-R4withR4is -H, -O-CH3, or -F,X5 is N or C-R5withR5is -H, -CH3, -CF3 or -O-CH3,X6is N or C-R6withR6is -H,X7is C-R7withR7is -C(O)-NH-CH3, or -CN,R6and R7together form **-CH2-N(CH3)-C(O)-, **-CH2-CH2-N(CH3)-C(O)-, with ** indicating the bond towards X6,X8is CH or N with the proviso, that only 0, 1, or 2 of all X4, X5, X6, or X8can simultaneously be N,R10is H, -CH3,R11is H, -CH3, -CH2-OH, -CH2-CN, -CH2-O-CH3,R12is H, CH3, -CH2-OH, -CH2-O-CH3, -CH2-CN, CH2F, orR12and R11together form -CH2-O-CH2-,R13is H, OH, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.28) The compound of claim 27 wherein X1is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.29) The compound of any one of claims 27-28 wherein X2is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.30) The compound of any one of claims 27-28 wherein X2is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.31) The compound of any one of claims 27-30 wherein X3is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.32) The compound of any one of claims 27-30 wherein X3is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.33) The compound of any one of claims 27-32 wherein X4and X6are both simultaneously N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.34) The compound of any one of claims 27-33 wherein X5is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.35) The compound of any one of claims 27-34 wherein X7is C-C(O)-NH-CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.36) The compound of any one of claims 27-35 wherein X8is CH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.37) The compound of any one of claims 27-36 wherein R6and R7together form **-CH2-N(CH3)- C(O)- or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.419QB\184200.00266\99637562.4VVID 754PC38) The compound of any one of claims 27-36 wherein R6and R7together form **-CH2-CH2-N(CHs)- C(O)- or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.39) The compound of any one of claims 27-38 wherein R10is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.40) The compound of any one of claims 27-39 wherein R11is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.41) The compound of any one of claims 27-40 wherein R12is -CH, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.42) The compound of any one of claims 27-40 wherein R12is -CH2-OH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.43) The compound of any one of claims 27-40 wherein R12is -CH2-O-CH3 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.44) The compound of any one of claims 27-43 wherein R13is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.45) The compound of any one of claims 27-43 wherein R13is OH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.46) The compound of claim 1 wherein the compound is:6-(4-((3R,6S)-l-acryloyl-6-(hydroxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3S,6R)-l-acryloyl-6-(hydroxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,6R)-l-acryloyl-6-(hydroxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3S,6S)-l-acryloyl-6-(hydroxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,6S)-l-acryloyl-6-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,5R)-l-acryl,oyl-5-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5S)-l-acryloyl-5-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,6R)-l-acryloyl-6-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3S,6S)-l-acryloyl-6-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3S,5R)-l-acryloyl-5-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine- 4-carboxamide,420QB\184200.00266\99637562.4VVID 754PC6-(4-((3R,5R)-l-acryloyl-5-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3S,6R)-l-acryloyl-6-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,5R)-l-acryloyl-5-methoxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5S)-l-acryloyl-5-methoxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,6R)-l-acryloyl-6-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,6S)-l-acryloyl-6-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,6S)-l-acryloyl-6-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,6R)-l-acryloyl-6-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5S)-l-acryloyl-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5R)-l-acryloyl-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5S)-l-acryloyl-5-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5R)-l-acryloyl-5-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5R)-l-acryloyl-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5S)-l-acryloyl-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,(R)-6-(4-(l-acryloyl-5,5-difluoropiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,(S)-6-(4-(l-acryloyl-5,5-difluoropiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5S)-l-acryloyl-5-methoxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5R)-l-acryloyl-5-methoxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5R)-l-acryloyl-5-hydroxy-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,421QB\184200.00266\99637562.4VVID 754PC6-(4-((3S,5S)-l-acryloyl-5-hydroxy-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine- 4-carboxamide, 6-(4-((3R,6S)-l-acryloyl-6-(fluoromethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,6R)-l-acryloyl-6-(fluoromethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide, 6-(4-((3R,5S)-l-acryloyl-5-fluoropiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5R)-l-acryloyl-5-fluoropiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,2-((3S,5R)-l-acryloyl-5-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)piperidin-3- yl)acetic acid, 2-((3R,5S)-l-acryloyl-5-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)piperidin-3- yl)acetic acid,2-((3R,5R)-l-acryloyl-5-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)piperidin-3- yl)acetic acid,2-((3S,5S)-l-acryloyl-5-(2-chloro-6-(6-(methylcarbamoyl)pyrimidin-4-yl)pyridin-4-yl)piperidin-3- yl)acetic acid, 6-(4-((3R,5S)-l-acryloyl-5-hydroxy-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3S,5R)-l-acryloyl-5-hydroxy-5-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,5R)-l-acryloyl-5-fluoropiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5S)-l-acryloyl-5-fluoropiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,6R)-l-acryloyl-6-(fluoromethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide, 6-(4-((3S,6S)-l-acryloyl-6-(fluoromethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,(S)-6-(4-(l-acryloyl-3-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,(R)-6-(4-(l-acryloyl-3-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide, 6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,422QB\184200.00266\99637562.4VVID 754PC6-(4-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-(l-acryloylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-(l-acryloyl-3-methoxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide, 6-(4-(l-acryloyl-4,4-difluoropiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide, 6-(4-(l-acryloyl-4-fluoro-4-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-(l-acryloyl-4-hydroxy-4-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,4R)-l-acryloyl-3-hydroxy-4-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,6-(4-((3R,4S)-l-acryloyl-3-hydroxy-4-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,6-(4-((3R,4S)-l-acryloyl-4-methoxy-4-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,4R)-l-acryloyl-4-methoxy-4-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,4R)-l-acryloyl-4-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,4S)-l-acryloyl-4-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,4R)-l-acryloyl-4-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,4S)-l-acryloyl-4-hydroxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,4R)-l-acryloyl-4-methoxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,4S)-l-acryloyl-4-methoxypiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,4R)-l-acryloyl-4-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,4S)-l-acryloyl-4-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2S,3R)-l-acryloyl-2-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,423QB\184200.00266\99637562.4VVID 754PC6-(4-((2R,3S)-l-acryloyl-2-(methoxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,4S)-l-acryloyl-4-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,4R)-l-acryloyl-4-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5S)-l-acryloyl-5-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5R)-l-acryloyl-5-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5R)-l-acryloyl-5-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3S,5S)-l-acryloyl-5-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((lS,2R,5S)-8-acryloyl-8-azabicyclo[3.2.1]octan-2-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((lR,2S,5R)-8-acryloyl-8-azabicyclo[3.2.1]octan-2-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((lS,4R,6S)-2-acryloyl-2-azabicyclo[2.2.2]octan-6-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((lR,4S,6R)-2-acryloyl-2-azabicyclo[2.2.2]octan-6-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2S,3R)-l-acryloyl-2-(hydroxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2R,3S)-l-acryloyl-2-(hydroxymethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((lR,5S,6R)-9-acryloyl-3-oxa-9-azabicyclo[3.3.1]nonan-6-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,6-(4-((lS,5R,6S)-9-acryloyl-3-oxa-9-azabicyclo[3.3.1]nonan-6-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,424QB\184200.00266\99637562.4VVID 754PC4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloro-5'-fluoro-N-methyl-[2,4'-bipyridine]-2'- carboxamide,4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloro-5'-fluoro-N-methyl-[2,4'-bipyridine]-2'- carboxamide,4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloro-5'-methoxy-N-methyl-[2,4'-bipyridine]-2'- carboxamide,4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloro-5'-methoxy-N-methyl-[2,4'-bipyridine]-2'- carboxamide,6-(4-((2S,3R)-l-acryloyl-2-(methoxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2R,3S)-l-acryloyl-2-(methoxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N,2-dimethylpyrimidine-4- carboxamide,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N,2-dimethylpyrimidine-4- carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methoxy-N-methylpyrimidine-4-carboxamide,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methoxy-N-methylpyrimidine-4-carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide,6-(4-((2S,3R)-l-acryloyl-2-(hydroxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2R,3S)-l-acryloyl-2-(hydroxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N,2-dimethylpyrimidine-4- carboxamide,6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N,2-dimethylpyrimidine-4- carboxamide,4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloro-5'-fluoro-N-methyl-[2,4'-bipyridine]-2'- carboxamide,4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloro-5'-fluoro-N-methyl-[2,4'-bipyridine]-2'- carboxamide,6-(4-((lR,2R,5R)-8-acryloyl-8-azabicyclo[3.2.1]octan-2-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,425QB\184200.00266\99637562.4VVID 754PC6-(4-((lS,2S,5S)-8-acryloyl-8-azabicyclo[3.2.1]octan-2-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methoxy-N- methylpyrimidine -4-carboxamide ,6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methoxy-N- methylpyrimidine -4-carboxamide ,6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide,6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide,4'-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6'-chloro-5-fluoro-N-methyl-[2,2'-bipyridine]-4- carboxamide,4'-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6'-chloro-5-fluoro-N-methyl-[2,2'-bipyridine]-4- carboxamide,6-(4-((3R,5R)-l-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3S,5S)-l-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloro-5'-methoxy-N-methyl-[2,4'-bipyridine]-2'- carboxamide,4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloro-5'-methoxy-N-methyl-[2,4'-bipyridine]-2'- carboxamide,6-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((3R,5R)-l-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,4'-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6'-chloro-5-methoxy-N-methyl-[2,2'-bipyridine]-4- carboxamide,4'-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6'-chloro-5-methoxy-N-methyl-[2,2'-bipyridine]-4- carboxamide,6-(4-((3S,5S)-l-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide,6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carbonitrile,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)pyrimidine-4-carbonitrile,6-(4-((lR,5S,6R)-8-acryloyl-3-oxa-8-azabicyclo[3.2.1]octan-6-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,426QB\184200.00266\99637562.4VVID 754PC6-(4-((lR,5S,6R)-8-acryloyl-3-oxa-8-azabicyclo[3.2.1]octan-6-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,3-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)benzonitrile,4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloro-[2,3'-bipyridine]-5'-carbonitrile,4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloro-[2,3'-bipyridine]-5'-carbonitrile,6-(4-((3S,5S)-l-acryloyl-5-(cyanomethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3R)-l-acryloyl-2-(cyanomethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide, 6-(4-((2S,3S)-l-acryloyl-2-(cyanomethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3R)-l-acryloyl-2-(cyanomethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2S,3S)-l-acryloyl-2-(cyanomethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((3R,5R)-l-acryloyl-5-(cyanomethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2S,3R)-l-acryloyl-2-(fluoromethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3S)-l-acryloyl-2-(fluoromethyl)piperidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2S,3R)-l-acryloyl-2-(fluoromethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3S)-l-acryloyl-2-(fluoromethyl)pyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,5-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-4-cyano-2-fluoro-N- methylbenzamide,5-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-4-cyano-2-fluoro-N- methylbenzamide,5-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-4-cyano-2-methoxy-N- methylbenzamide,5-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-4-cyano-2-methoxy-N- methylbenzamide,6'-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile,6'-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile,4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloro-5'-cyano-N-methyl-[2,4'-bipyridine]-2'- carboxamide,427QB\184200.00266\99637562.4VVID 754PC4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloro-5'-cyano-N-methyl-[2,4'-bipyridine]-2'- carboxamide, 6-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, 6-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, 6-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, 6-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, 6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-methoxy-2-methylisoindolin- 1-one,6-(4-((2S,3 S)- 1 -acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-methoxy-2-methylisoindolin- 1 - one, 6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-fluoro-2-methylisoindolin-l- one,6-(4-((2S,3 S)- 1 -acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-fluoro-2-methylisoindolin- 1 - one,6-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,6-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,6'-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile,6'-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile, 6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,3-dihydro-lH- pyrrolo[3 ,4-c]pyridin- 1 -one,6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,3-dihydro-lH- pyrrolo[3 ,4-c]pyridin- 1 -one, 6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,7-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3,4-dihydro-2,6- naphthyridin- 1 (2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3,4-dihydro-2,6- naphthyridin- 1 (2H)-one,6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,3-dihydro-lH- pyrrolo [3 ,4-c]pyridin- 1 -one, 6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,3-dihydro-lH- pyrrolo [3 ,4-c]pyridin- 1 -one,6-(4-((2R, 3 S)-l-acryloyl-3 -hydroxy-2 -methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2 -methyl -2,3- dihydro- lH-pyrrolo[3,4-c]pyridin- 1 -one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,3- dihydro- lH-pyrrolo[3,4-c]pyridin- 1 -one,7-(4-((2R, 3 S)-l-acryloyl-3 -hydroxy-2 -methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3, 4- dihydro-2,6-naphthyridin- 1 (2H)-one,428QB\184200.00266\99637562.4VVID 754PC7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3,4- dihydro-2, 6-naphthyridin- 1 (2H)-one,6-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-l-oxoisoindoline-5- carbonitrile,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-l-oxoisoindoline-5- carbonitrile,6-(4-((2R,3S)-l-acryloyl-3 -hydroxy-2 -methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-fluoro-2- methylisoindolin- 1 -one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-fluoro-2- methylisoindolin- 1 -one,6-(4-((2R,3S)-l-acryloyl-3 -hydroxy-2 -methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-methoxy-2- methylisoindolin- 1 -one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-5-methoxy-2- methylisoindolin- 1 -one,7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3,4-dihydro-2,6- naphthyridin- 1 (2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3,4-dihydro-2,6- naphthyridin- 1 (2H) -one ,6-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-N- methylpyrimidine -4-carboxamide ,6-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,3- dihydro- lH-pyrrolo[3,4-c]pyridin- 1 -one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,3- dihydro- lH-pyrrolo[3,4-c]pyridin- 1 -one,3-(6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-6,7-dihydro-5H- pyrrolo [3 ,4-b]pyrazin-5 -one,3-(6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-6,7-dihydro-5H- pyrrolo [3 ,4-b]pyrazin-5 -one,2-(6-((2R, 3 S)-l -acryloyl -2 -methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-b]pyridin-7 -one,2-(6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-b]pyridin-7 -one,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-methylpyridin-2-yl)-N-methylpyrimidine-4- carboxamide,3 -(4-((2R, 3 S)-l-acryloyl-3 -hydroxy-2 -methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-fluoro-6-methyl- 6,7-dihydro-5H-pyrrolo [3 ,4-b]pyridin-5 -one,429QB\184200.00266\99637562.4VVID 754PC3-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-fluoro-6-methyl- 6,7-dihydro-5H-pyrrolo [3 ,4-b]pyridin-5 -one,6-(4-((2R,3R)- 1 -acryloyl -2-methylpiperidin-3 -yl)-6-chloropyridin-2-yl)-2-methyl-[ 1 ,2,4]triazolo [4,3 - a]pyrazin-3(2H)-one,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-[l,2,4]triazolo[4,3- a]pyrazin-3(2H)-one,(S)-6-(4-(l-acryloyl-3-hydroxypyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,(R)-6-(4-(l-acryloyl-3-hydroxypyrrolidin-3-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,3-(6-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-6,7-dihydro-5H- pyrrolo [3 ,4-b]pyrazin-5 -one,3-(6-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-6,7-dihydro-5H- pyrrolo [3 ,4-b]pyrazin-5 -one,2-(2-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-4-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-d]pyrimidin-7 -one,2-(2-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-4-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-d]pyrimidin-7 -one,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-cyanopyridin-2-yl)-N-methylpyrimidine-4- carboxamide2-(6-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-b]pyridin-7 -one,2-(6-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-b]pyridin-7 -one,6'-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile,3-(6-((2R,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one,3-(6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one,2-(6-((2R,3 S)- 1 -acryloyl -2 -methylpyrrolidin-3 -yl)-4-chloropyridin-2-yl)-7 -methyl-6,7-dihydro- 1,7- naphthyridin-8(5H)-one,2-(6-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-7-methyl-6,7-dihydro-l,7- naphthyridin-8(5H)-one,3-(6-((2R,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one,3-(6-((2S,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one,430QB\184200.00266\99637562.4VVID 754PC2-(6-((2R,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-7-methyl-6,7- dihydro- 1 ,7-naphthyridin-8(5H)-one, 2-(6-((2S,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-4-chloropyridin-2-yl)-7-methyl-6,7- dihydro- 1 ,7-naphthyridin-8(5H)-one,7-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3,4- dihydro-2, 6-naphthyridin- 1 (2H)-one,7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-3,4- dihydro-2, 6-naphthyridin- 1 (2H)-one, 7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-6-fluoro-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-6-fluoro-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-6-methoxy-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-6-methoxy-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,4'-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6'-chloro-N,5-dimethyl-[2,2'-bipyridine]-4-carboxamide, 4'-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6'-chloro-N,5-dimethyl-[2,2'-bipyridine]-4-carboxamide, 7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2, 6-naphthyridin- l(2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2, 6-naphthyridin- l(2H)-one,7-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,6- naphthyridin- 1 (2H)-one,7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,6- naphthyridin- 1 (2H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methylpyrido[3,4- d] pyridazin- 1 (2H)-one ,7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methylpyrido[3,4-d]pyridazin- l(2H)-one,7-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methylpyrido[3,4- d] pyridazin- 1 (2H) -one,7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2-methylpyrido[3,4- d] pyridazin- 1 (2H) -one,6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-3-methylpyrido[3,4- d]pyrimidin-4(3H)-one, 6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-3-methylpyrido[3,4- d]pyrimidin-4(3H)-one,431QB\184200.00266\99637562.4VVID 754PC6-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-3-methylpyrido[3,4- d]pyrimidin-4(3H)-one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-3-methylpyrido[3,4- d]pyrimidin-4(3H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3-dimethyl-2,6-naphthyridin- l(2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3-dimethyl-2,6-naphthyridin- l(2H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4-dimethyl-2,6-naphthyridin- l(2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4-dimethyl-2,6-naphthyridin- l(2H)-one,6-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3-dimethylpyrido[3,4- d]pyrimidin-4(3H)-one,6-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3-dimethylpyrido[3,4- d]pyrimidin-4(3H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4-dimethylpyrido[3,4- d] pyridazin- 1 (2H) -one ,7-(4-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4-dimethylpyrido[3,4- d] pyridazin- 1 (2H) -one,7-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4-dimethyl-2,6- naphthyridin- 1 (2H)-one,7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4-dimethyl-2,6- naphthyridin- 1 (2H)-one,6-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3- dimethylpyrido[3,4-d]pyrimidin-4(3H)-one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3- dimethylpyrido[3,4-d]pyrimidin-4(3H)-one,7-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4- dimethylpyrido [3 ,4-d] pyridazin- 1 (2H) -one,7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,4- dimethylpyrido [3 ,4-d] pyridazin- 1 (2H) -one,7-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3-dimethyl-2,6- naphthyridin- 1 (2H)-one,7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpyrrolidin-3-yl)-6-chloropyridin-2-yl)-2,3-dimethyl-2,6- naphthyridin- 1 (2H)-one,2-(2-((2R, 3 S)-l -acryloyl -2 -methylpyrrolidin-3-yl)-6-chloropyridin-4-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-d]pyrimidin-7 -one,432QB\184200.00266\99637562.4VVID 754PC2-(2-((2S,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-6-chloropyridin-4-yl)-6-methyl-5,6-dihydro-7H- pyrrolo [3 ,4-d]pyrimidin-7 -one,2-(6-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-7-methyl-6,7-dihydro-l,7- naphthyridin-8(5H)-one,2-(6-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-7-methyl-6,7-dihydro-l,7- naphthyridin-8(5H)-one,3-(6-((2R,3S)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8-dihydropyrido[3,4- b]pyrazin-5(6H)-one,3-(6-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8-dihydropyrido[3,4- b]pyrazin-5(6H)-one,2-(6-((2R,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-7-methyl-6,7- dihydro- 1 ,7-naphthyridin-8(5H)-one,2-(6-((2S,3S)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-7-methyl-6,7-dihydro- l,7-naphthyridin-8(5H)-one,3-(6-((2R,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one,3-(6-((2S,3S)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-4-chloropyridin-2-yl)-6-methyl-7,8- dihydropyrido[3,4-b]pyrazin-5(6H)-one,6-(4-((2R,3S)-l-acryloyl-3 -hydroxy-2 -methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-[ 1 ,2,4]triazolo [4,3 -a]pyrazin-3 (2H)-one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2 -methyl-[ 1 ,2,4]triazolo [4,3 -a]pyrazin-3 (2H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-6-methoxy-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-6-methoxy-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,6-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-fluoropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2S,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-fluoropyridin-2-yl)-N-methylpyrimidine-4- carboxamide,6-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-3-methylpyrido[3,4- d]pyrimidin-4(3H)-one,6-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-3-methylpyrido[3,4- d]pyrimidin-4(3H)-one,7-(4-((2R,3R)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-6-fluoro-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,7-(4-((2S,3S)-l-acryloyl-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-6-fluoro-2-methyl-3,4- dihydroisoquinolin- 1 (2H)-one,433QB\184200.00266\99637562.4VVID 754PC4'-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6'-chloro-N,5-dimethyl-[2,2'-bipyridine]-4- carboxamide, 4'-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6'-chloro-N,5-dimethyl-[2,2'-bipyridine]-4- carboxamide,7-(4-((2R, 3 S)-l-acryloyl-3 -hydroxy-2 -methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2 -methyl -2,6- naphthyridin- 1 (2H)-one, 7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methyl-2,6- naphthyridin- 1 (2H)-one, 7-(4-((2R,3S)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methylpyrido[3,4- d]pyridazin- 1 (2H)-one, 7-(4-((2S,3R)-l-acryloyl-3-hydroxy-2-methylpiperidin-3-yl)-6-chloropyridin-2-yl)-2-methylpyrido[3,4- d]pyridazin- 1 (2H)-one, 6-((2S,3S)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, or 6-((2R,3R)-l-acryloyl-2-methylpyrrolidin-3-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

47. A pharmaceutical formulation comprising a compound of any one of claims 1 to 46, and a pharmaceutically acceptable excipient or carrier.

48. A method of modulating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

49. The method according to claim 48, wherein the disease or condition is selected from microscopic colitis, diverticulitis, Crohn’s disease, ulcerative colitis with fistulae, ulcerative colitis without fistulae, mucositis, psoriatic arthritis, lupus, systemic lupus erythematous, lupus nephritis, rheumatoid arthritis, juvenile idiopathic arthritis, Still’s disease, spondyloarthritis, scleroderma, acute cytokine release syndrome, acne, eczema, respiratory disorders, non-respiratory disorders, COPD, asthma, fibrosis, chronic asthma, acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, lung dysfunction post injury such as skin bum, autoimmune diseases, inflammatory diseases, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, cutaneous lupus, systemic lupus, inflammatory bowel diseases, psoriasis, dermatitis, topical effects of radiation, polymyositis, mixed connective tissue disease, autoimmune-interstitial lung disease, dermatomyositis, immunosuppression due to radiation exposure, vasculitis, kidney disease, diabetic nephropathy, Ig- nephropathies, glomerular diseases, Fabray’s disease, renal diseases due to ANCA vasculitis / beta-thalassemia, complement mediated nephropathies, anticancer agent induced kidney damage, chronic kidney disease, acute kidney injury, sepsis-induced acute kidney injury, malfunction during kidney transplantation, focal segmental glomerulosclerosis, hemolytic uremic syndrome, interstitial nephritis, lupus nephritis, primary hyperoxaluria, cardiovascular diseases, pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, neurological disorders, Parkinson's disease, Alzheimer's disease, Friedreich's ataxia, amyotrophic lateral sclerosis, epilepsy,434QB\184200.00266\99637562.4VVID 754PC multiple sclerosis, cancer, ocular diseases, retinosa pigmentosa, glaucoma, cataracts, , neovascular (dry) AMO, neovascular (wet) AMO, eye injury, Fuchs endothelial corneal dystrophy, uveitis, inflammatory eye conditions, liver indications, non-alcoholic steatohepatitis, toxin-induced liver disease, acetaminophen-induced hepatic disease, viral hepatitis, cirrhosis, preeclampsia, sickle cell disease, thalassemia, or high altitude sickness.435QB\184200.00266\99637562.4

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