KEAP1 inhibitors and uses thereof

Abstract

Compounds and methods for activating Nrf2 by inhibiting KEAP1.

Description

[0001] VVID 755PC KEAP1 INHIBITORS AND USES THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] [1] This application claims the benefit of U. S. provisional application serial no. 63 / 733,875 filed December 13, 2024, the contents of which are incorporated by reference herein in their entirety.

[0004] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0005] [2] The contents of the electronic sequence listing (18420000265. xml; Size: 1,767 bytes; and Date of Creation: December 10, 2025) are herein incorporated by reference in their entirety.

[0006] FIELD OF THE DISCLOSURE

[0007] [3] The disclosure relates to compounds and methods for modulating KEAP 1. or modulating Nrf2 by mediating the inhibition of KE API.

[0008] BACKGROUND OF THE DISCLOSURE

[0009] [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.

[0010] SUMMARY

[0011] [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.

[0012] [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.

[0013] [7] The present disclosure further provides for compounds having the general formula (I)

[0014]

[0015] wherein

[0016] 1

[0017] QBM84200.00265'99930245.1 VVID 755PC X1is N-C(O)-Ci.?alkyl, N-C(O)-Ci3haloalkyl, N-S(O)2-Ci-3alkyL N-S(O)2-Ci.3haloalkyl, N-R’, or 0,

[0018] XAis C-HorN,

[0019] Xflis C-H. C-F orN.

[0020] Xcis C-H or N,

[0021]

[0022] X3is C-R3or N and -R3is -H, -F, -Cl or -Br, -CN or -O-CII3,

[0023] X4is C-R4or N and -R4is -H, -F, -CI or -Br, -Chalky!, -CJialoalkyl, -O-CH3, -O-CHF2, or -O- CF3,

[0024] X5is C-R5or N and -R’’ is -H, -F, -Cl or -Br, -Cualkyl, -Ci.3haloalk l, -O-CH3. -O-CHF2, or -O- CF3.

[0025] X is N or CH,

[0026] X8is N or C-R8and -Rsis -H, -F, -Cl. -Chalky!, -O-CH3, -O-CHF2, or -O-CF3.

[0027] X9is N or C-R12and -R is -H or -Ci-3alkyl,

[0028] X10is N or C-R14and -R14is -H or -Ci-3alkyl,

[0029] n is 1 or 2,

[0030] R6is -CN, or -C(O)-NH-Ci.3 alkyl.

[0031] R9is -H, -Ci.3alkyl. -Ci. Jialoalkyl. -Cj.3hydroxy alkyl, or -Ci-3alkylene-O-Ci.3alkyl.

[0032] R10is -H, -Ci3alky 1. -Ci Jraloalkyl. or -Ci3alkylene-O-Ci.3alkyl. or

[0033] R10and R’ together form **-CH2-CH2-O-CH2- with ** indicating the bond towards X1,

[0034] R1' is -H, -CH2F, -CHF2. -Ci-3alkyl, -Cucyanoalkyl, -Ci-3alkylene-O-Ci-3alkyl,

[0035] R13is -Cwialkyl.

[0036] with a first proviso, that if XAis N, XBis CH, Xcis CH and R6is -C(O)-NH-Ci-3alkyl, R3must be -CN, and with a second proviso, that if XAis CH, XBis C-F, and X® is CH, R° cannot be -C(O)-NH-Ci3alkyl, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof

[0037] [8] Hie present disclosure further provides methods for the use of compounds of formula (I). (II), (III), or (IV) in the treatment of various medical disorders, including immunological disorders.

[0038] [9] The present disclosure further provides the compounds of formula (I), (II), (III), or (IV) to be formulated into medicaments for treatment of various medical disorders, including immunological disorders.

[0039] INCORPORATION BY REFERENCE

[0040] 2

[0041] QB\184200.00265\99930245.1 VVID 755PC

[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.

[0042] DETAILED DESCRIPTION

[0043]

[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.

[0044]

[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). KEAPI may be included as a substrate adapter protein in an E3 ubiquitin ligase complex with RBX1 and Cul3. In some cases, the E3 ubiquitin ligase continuously degrades Nr£2. KF. AP1 behaves as a fast-acting thiol sensor to electrophiles and oxidants.

[0045]

[0013] In some conditions such as oxidative stress or oxidative signaling, cysteine 151 of KEAPI (and possibly other KEAP1 cysteines) may be oxidized, and the E3 ubiquitin ligase complex may be destabilized. Nrf2 may accumulate and translocate to Ute 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.

[0046]

[0014] The transcription factor nuclear factor ervthroid-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 idiopatliic 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 KEAPI 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.

[0047]

[0015] Disclosed herein are compounds and methods for activating Nrf2 by mediating the inhibition of KEAPi. Some embodiments relate to a compound or method of activating Nrf2. The Nrf2 activation may be in vitro or in vivo. Tire Nrf2 activation may include contacting a KEAPI protein with a

[0048] 3

[0049] QBM84200.00265'99930245.1 VVID 755PC 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

[0050]

[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.

[0051]

[0017] Some embodiments relate to a compound or method of inhibiting KEAP1. The KEAP1 inhibition may7be in vitro or in vivo. The KEAP1 inhibition may include contacting the KEAP1 with a compound disclosed herein. The KE API inhibition may increase an antioxidant or improve an antioxidant capacity in a subject or cell. The compound for inhibiting KEA. P1 may be formulated for administration to a subject. The KE API activation may be performed in a subject, where the subject is a human or non-human animal.

[0052]

[0018] Details and examples of some KEAP1 proteins may be found at www.uniprot.org under accession number Q14145 (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,

[0053]

[0019] Tire compounds disclosed herein may be useful for treatment of immunological disorders where Nrf2 activity7may be a concern, such as inflammatory7bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, Lupus (including S stemic 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) (KE API inhibition linked to medical indications via Nrf2 activation): Cuadrado, A.. Rojo, A. I., Wells, G. et al. Nat Rev Drug Disc ov 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.

[0054] Compounds of the disclosure

[0055]

[0020] The present disclosure provides compounds of formula (1):

[0056] R9O

[0057]

[0058] cr A xAA R22

[0059] 4

[0060] QBM84200.00265'99930245.1 VVID 755PC wherein

[0061] X1is N-C(0)-Ci-sa1kyL N-C^-Ci-shaloalkyl. N-S(O)2-C1.3aikyl, N-S(O)2-Ci.3haioalkyl. N-R’, or O,

[0062] XAis C-H or N.

[0063] XBis C-H. C-F or N.

[0064] Xcis C-H or N,

[0065] O

[0066]

[0067] X3is C-R3or N and -R3is -H, -F, -Cl or -Br, -CN or -O-CIL,

[0068] X3is C-R3or N and -R1is -H, -F, -Cl or -Br, -Ci-ialkyl, -Crshaloalkyl, -O-CH3. -O-CHF?, or -O- CF3,

[0069] X5is C-R5or N and -R5is -H, -F, -Cl or -Br, -Ci.3alkyl. -Ci.3haloalkyi, -O-CH3. -O-CHF2. or -O- CF3.

[0070] X7is N or CH,

[0071] X8is N or C-R8and -Rsis -H, -F, -Cl. -Ci-salkyl, -O-CH3. -O-CHF?, or -O-CF?,.

[0072] X9is N or C-R13and -R is -H or -Ci-3alkyl,

[0073] X10is N or C-R1 1and -R13is -H or -Ci-3alkyl.

[0074] n is 1 or 2,

[0075] R6is -CN. or -C(0)-NH-Ci 3 alkyl,

[0076] R9is -H, -Ci.jalkyl, -Ci-shaloalkyl. -Ci.ahydroxyalkyl, or -Ci.3alkylene-O-C1-3alkyl,

[0077] R10is -H, -Ci.salkyl, -Cuhaloalkyl, or -Ci.salkylene-O-Ci.jalkyl, or

[0078] R10and R’ together form **-CH;:-CH:;-0-CH2- with ** indicating the bond towards X1,

[0079] R11is -H, -CH2F. -CHF?, -Ci-salkyl, -Cucyanoaikyl, -Ci3alkylene-O-C1-3alkyl,

[0080] R13is -C;.4alkyl.

[0081] with a first proviso, that if XAis N, XBis CH, X® is CH and R6is -C(O)-NH-C1-3alkyl, R3must be -CN, and with a second proviso, that if XAis CH, XBis C-F, and X° is CH, R6cannot be -C(O)-NH-Ci3alkyl, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0082]

[0021] Tire present disclosure also provides compounds of formula (I), wherein

[0083] X1is N-C(O)-CH3, N-S(O)2-CH3, N-R' or O,

[0084] XAis C-H or N,

[0085] XBis C-H, C-F or N,

[0086] Xcis C-H,

[0087] 5

[0088] QBM84200.00265'99930245.1 VVID 755PC

[0089]

[0090] X3is C-R3or N and R3is H, F. CN or -O-CH3,

[0091] X4is C-R4or N and R4is H. F, -CH3or -O-CH3.

[0092] X5is C-R5or N and R5is H, F, -CH3or -O-CH3.

[0093] X7is N or CH,

[0094] n is 1 or 2.

[0095] R6is -CN, or -C(O)-NH-CH3,

[0096] R9is H or -CH2-OH,

[0097] R10is H, or

[0098] Rluand R’ together form **-CH2-CH::-O-CH3- with ** indicating the bond towards X1,

[0099] R" is H or -CH3,

[0100] with a first proviso, that if XAis N, X3is CH, Xcis CH and R6is -C(O)-NH-CH3, R3must be -CN, and with a second proviso, that if XAis CH, X3is C-F, and X° is CH, R6cannot be -C(O)-NH-CH3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0101]

[0022] The present disclosure also provides compounds of formula (1) wherein

[0102]

[0103] 6

[0104] QB\l 84200.00265X99930245.1 VVID 755PC

[0105]

[0106] with a first proviso, that if XAis N, XBis CH. Xcis CH and R6is -C(O)-NH-CH3, R3must be -CN, and with a second proviso, that if XAis CH, XBis C-F. and X° is CH, Rscannot be -C(O)-NH-CH3.

[0107] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0108]

[0023] Tire present disclosure also provides compounds of formula (II)

[0109]

[0110] wherein

[0111] X1is N-C(O)-CH3, N-S(O)2-CH3or O,

[0112] O

[0113]

[0114] X4is CH or N,

[0115] X5is CH. N, or C-OCI-H,

[0116] X7is CH or N,

[0117] n is 1 or 2,

[0118] R3is -H or -CN,

[0119] R6is -CN or -C(O)-NH-CH3,

[0120] R11is H or -CH3,

[0121] 7

[0122] QBM84200.00265'99930245.1 VVID 755PC or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0123]

[0024] The present disclosure also provides compounds of formula (II), wherein

[0124]

[0125] stereoisomer, or tautomer thereof.

[0126]

[0025] The present disclosure also provides compounds of formula (II), wherein

[0127] X' is N-C(O)-CH3and N-S(O)z-CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0128]

[0026] Tire present disclosure also provides compounds of formula (II), wherein

[0129]

[0130] pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0131]

[0027] Tire present disclosure also provides compounds of formula (II), wherein

[0132] R3is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0133]

[0028] The present disclosure also provides compounds of formula (III):

[0134]

[0135] wherein

[0136] X1is N-C(O)-CH?„ X-SiO) -CH;. N-R' or O,

[0137] 8

[0138] QB\184200.00265\99930245.1 WID 755PC

[0139]

[0140] X3is C-R3or N and R3is H. F, CN or -O-CH3,

[0141] X4is C-R4or N and R4is H, F. -CH3or -O-CH,,

[0142] X5is C-R5or N and R5is H. F. -CH3 or -O-CH3,

[0143] X8is CH, C-CHs. or N,

[0144] X9is CH, C-CH3. or N,

[0145] R6is -CN or -C(O)-NH-CH3,

[0146] R9is H or -CH2-OH.

[0147] R1CIis H. or

[0148] R10and R’ together form ^-CHz-CHz-O-CIIz- with ** indicating the bond towards X1,

[0149] R11is H or -CH3,

[0150] with the proviso, that if R6is -C(O)-NH-CH3, R3is -CN,

[0151] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0152]

[0029] Tire present disclosure also provides compounds of formula (III), wherein

[0153] O

[0154]

[0155] 9

[0156] QB\l 84200.00265X99930245.1 VVID 755PC

[0157]

[0158] tautomer thereof.

[0159]

[0030] 'The present disclosure also provides compounds of formula (Il l), wherein

[0160] O °

[0161] T "C H

[0162] H i N-CH

[0163] N3T H V' N 3

[0164] .JN / A, >

[0165]

[0166] R- is or, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0167]

[0031] The present disclosure also provides compounds of formula (III), wherein X1N-C(O)-CH3or N-S(O)?-CH3, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0168]

[0032] Hie present disclosure also provides compounds of fonnula (III), wherein R9is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0169]

[0033] The present disclosure also provides compounds of formula (III), wherein R10is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0170]

[0034] The present disclosure also provides compounds of formula (III), wherein R11is -CH3 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0171]

[0035] The present disclosure also provides compounds of formula (IV),

[0172] wherein

[0173]

[0174] 10

[0175] QB\184200.00265\99930245.1 VVID 755PC X4is N or CH,

[0176] X' is N or CH,

[0177] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0178]

[0036] The present disclosure also provides compounds of formula (IV), wherein

[0179]

[0180] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0181]

[0037] In certain embodiments, X1in formula (I) is N-C(O)-CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof

[0182]

[0038] hr certain embodiments, X!in formula (I) is N-S(O)2-CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0183]

[0039] hi certain embodiments, X!in formula (I) is N-R’ or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0184]

[0040] In certain embodiments, X' in formula (I) is O or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0185]

[0041] In certain embodiments. XAin formula (I) is C-H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0186]

[0042] In certain embodiments, XAin formula (I) is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0187] [431 hi certain embodiments. XBm formula (I) is C-H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0188]

[0044] In certain embodiments, XBin formula (I) is C-F or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof

[0189]

[0045] hi certain embodiments. XBin formula (I) is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0190]

[0046] In certain embodiments, Xcin formula (I) is C-H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0191]

[0192]

[0047] In certain embodiments, R2in formula (1) is CN or a pharmaceutically acceptable salt. solvate, stereoisomer or tautomer thereof.

[0193] O

[0194]

[0048] In certain embodiments, R2in formula (I) is with a first proviso, that XA, X

[0195]

[0196] Band Xcare not simultaneously C-H (XA). C-F (XB), and C-H (Xc), and with a second proviso, that XA, Xb, X° arc not simultaneously N (XA), CH (XB), and CH (X°) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0197] 11

[0198] QBM84200.00265'99930245.1 VVID 755PC O

[0199]

[0049] In certain embodiments, R2in formula (I) is with a first proviso, that XA, XBand Xcare not simultaneously C-H (XA). C-F (X3), and C-H (Xc), and with a second proviso, that XA, X

[0200]

[0201] B, X° arc not simultaneously N (XA), CH (X3), and CH (Xc).

[0202] 0

[0203] „

[0204] NrCH3

[0205] H

[0206]

[0050] In certain embodiments, R2in formula (I

[0207]

[0208] ) is NC with the proviso, that XA, XBand Xcare not simultaneously C-H (XA). C-F (X3), and C-H (Xc) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof

[0209] O

[0210]

[0051] In certain embodiments. R2in formula (

[0211]

[0212] I) is ^4 -3, with the proviso, that XA, X3and Xcare not simultaneously C-H (XA). C-F (X3). and C-H (Xc) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0213] 0

[0214]

[0052] In certain embodiments. R2in formula (I

[0215]

[0216] ) is X3and Xcare not simultaneously C-H (XA). C-F (X3). and C-H (Xc) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0217]

[0053] In certain embodiments, R2in formula (I) is

[0218]

[0219] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0220] O

[0221] * / /

[0222]

[0054] In certain embodiments, R‘ in formula (I) is

[0223]

[0224] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0225]

[0055] In certain embodiments, R2in formula (1) is

[0226]

[0227] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0228] 12

[0229] QB\184200.00265\99930245.1 VVID 755PC O

[0230]

[0056] In certain embodiments, R2in formula (I) is

[0231]

[0232] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0233] O

[0234]

[0057] In certain embodiments, R2in formula (I) is

[0235]

[0236] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0237] O

[0238] hr certain embodiments, R2in formula (I

[0239]

[0240] ) is or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0241]

[0059]

[0242]

[0243] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0244]

[0060] In certain embodiments, R2in formula (I) is

[0245]

[0246] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0247]

[0061] In certain embodiments, R2in formula (I) is

[0248]

[0249] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0250] In certain embodiments, R2in formula (1) is

[0251]

[0252] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof

[0253]

[0063] In certain embodiments, R2in formula (I) is

[0254]

[0255] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0256]

[0064] In certain embodiments, R2in formula (I) is

[0257]

[0258] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0259] In certain embodiments, R2in formula (I) is

[0260]

[0261] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0262] 13

[0263] QBM84200.00265'99930245.1 VVID 755PC

[0264]

[0066] In certain embodiments, R2in formula (I

[0265]

[0266] ) is or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0267]

[0067] In certain embodiments, R2in formula (I

[0268]

[0269] ) is or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0270]

[0068] hr certain embodiments, R2in formula (I) is

[0271]

[0272] acceptable salt, solvate, stereoisomer or tautomer thereof.

[0273] H3C

[0069] In certain embodiments, R2in formula (I

[0274]

[0275] ) is acceptable salt, solvate, stereoisomer or tautomer thereof.

[0276]

[0070] In certain embodiments, R2in formula (I) is

[0277]

[0278] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0279]

[0071] In certain embodiments, R2in formula (I

[0280]

[0281] ) is or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof

[0282]

[0072] Jn certain embodiments, R2in formula (I) is

[0283]

[0284] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0285]

[0073] In certain embodiments, R2in formula (I

[0286]

[0287] ) is or a pharmaceutically acceptable salt, solvate. stereoisomer or tautomer thereof.

[0288]

[0074] In certain embodiments, R2in formula (I) is

[0289]

[0290] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0291] 14

[0292] QBM84200.00265'99930245.1 VVID 755PC

[0293] F y

[0294]

[0075] In certain embodiments. R -^> in formula (

[0295]

[0296] I) is PoHri3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof

[0297]

[0076] In certain embodiments, X3in formula (I) is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0298]

[0077] In certain embodiments, X3in formula (I) is C-R3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0299]

[0078] In certain embodiments, R3in formula (I) is CN or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0300]

[0079] In certain embodiments, R3in formula (I) is H, with the proviso, that XA, XB, Xc, and R6are not simultaneously N (XA), CH (XB), CH (Xc), and -C(O)-NH-CH3(R6) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0301]

[0080] In certain embodiments, R3in formula (I) is F, with the proviso, that XA, X'3, Xc. and R arc not simultaneously N (XA), CH (XB), CH (Xc), and -C(O)-NH-CH3 (R3) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0302]

[0081] In certain embodiments, R3in fonnula (I) is -O-CH3, with the proviso, that XA, XB, Xc. and R6are not simultaneously N (XA), CH (XB). CH (Xc). and -C(O)-NH-CH3(R6) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0303]

[0082] In certain embodiments, X4in fonnula (I) is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0304]

[0083] hr certain embodiments, X4in formula (I) is C-R4or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0305]

[0084] In certain embodiments, R4in formula (I) is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0306]

[0085] In certain embodiments, R4in formula (1) is F or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0307]

[0086] In certain embodiments, R4in formula (I) is -CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0308]

[0087] In certain embodiments, R4in formula (I) is-O-CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0309]

[0088] In certain embodiments, X5in formula (I) is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0310]

[0089] In certain embodiments, X5in formula (I) is C-R4or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0311]

[0090] In certain embodiments, R3in formula (I) is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0312] 15

[0313] QBM84200.00265'99930245.1 VVID 755PC

[0091] In certain embodiments. R9in formula (I) is F or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0314]

[0092] In certain embodiments, R5in formula (I) is -CH? or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0315]

[0093] In certain embodiments. R7in formula (I) is-O-CH3or a pharmaceutically acceptable salt, sol vate, stereoisomer or tautomer thereof.

[0316]

[0094] In certain embodiments, X7in formula (1) is N or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0317]

[0095] In certain embodiments, X' in formula (I) is C-H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0318]

[0096] In certain embodiments, n in R2in formula (I) is 1 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0319]

[0097] In certain embodiments, n in R2in formula (I) is 2 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0320]

[0098] hr certain embodiments, R6in formula (I) is -CN or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0321]

[0099] hi certain embodiments, R6in formula (I) is -C(0)-NH-CH3, with the proviso, that XA, XBand Xcare not simultaneously C-H (XA), C-F (XB), and C-H (Xc) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0322]

[0100] In certain embodiments, R9in formula (I) is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0323]

[0101] hr certain embodiments, R9in formula (I) is -CH2-OH or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0324]

[0102] In certain embodiments, R10in formula (I) is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0325]

[0103] In certain embodiments, R10together with R’ in formula (I) form **-CH2-CH2-O-CH2- with ** indicating the bond towards X1or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0326]

[0104] hr certain embodiments. R11in formula (I) is H or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0327]

[0105] In certain embodiments, R11in formula (I) is -CH3or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[0328]

[0106] The compounds of Formula (I), (II). (Ill), or (IV) can be present in chiral or achiral form. The form may either be racemic or R or S configuration.

[0329]

[0107] Compounds of the disclosure include, but are not limited to:

[0330] Table A.

[0331] 16

[0332] QB\184200.00265\99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0333] 0

[0334] .. J....

[0335] A J I I (S)-6-(l-acetyl-4-acryloylpiperazin-2-yl)-4-chloro- Compound 1 " N t?

[0336] CK ' •< V N-methyl-[2,4'-bipyridine] -2'-carboxamide

[0337] Ci

[0338] ..-AV

[0339] .. A

[0340] t f (R)-6-(l-acetyl-4-acryloylpiperazin-2-yl)-4-cliloro- Compound 2GJ =■ '' -:?-i 0

[0341] :A X A

[0342] ... N-metbyi-[2,4'-bipyridine]-2'-carboxamide

[0343] 0

[0344] (R)-6-(4-(4-acryloyl- 1 -(methylsulfonyl)piperazin-2- Compound 3. I,

[0345] C Al yl)-6-chloropyridin-2-yl)pyrimidine-4-carbonitTile

[0346] G

[0347] ... X..;.

[0348] r w •-■■- %. M.. J

[0349] ! X

[0350] (R)-2-(4-(l-acety1-4-acndoylpiperazin-2-y!)-6- Compound 4

[0351] chloropyridin-2-yl)thiazole-4-carbonitrile N --#

[0352] X

[0353]

[0354] 17

[0355] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0356] Q

[0357] r^-wA^

[0358] (S)-2-(4-(l-acetyl-4-acryloylpiperazin-2-yl)-6- Compound 5

[0359] C chloropyridin-2-yl)thiazole-4-carbonitrile

[0360] V s.»

[0361] N

[0362] M' ■'■-■>•

[0363] 4-((2R,3R)-l-acetyl-4-acnloyl-3-methylpiperazin- Compound 6

[0364] 2-yl)-6-cbloro-[2,3'-b!pyrid!ne]-5'-carbonitrile

[0365] q

[0366] k

[0367] 4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2- Compound 7

[0368] yl)-6-chIoro-[2,3'-bipyridineJ-5'-carbon!trile ' d-i;"

[0369] o

[0370] 1

[0371] 4'-((2R,3R)-l-acetyl-4-acryloyl-3-methy]piperazin- Compound 8

[0372] 1. 2-yl)-6'-chloro-[2,2'-bipyridine]-4-carbonitTile c? '¥'V

[0373] Y ' JI. ■■’<■■■■

[0374] X^4* JKVv- - 4'-((2S,3S)-l-acetyl-4-acryrloyl-3-methylpiperazin-2- Compound 9 6,SC yl)-6'-chloro-[2,2'-bipyridine]-4-carbonitri1e 1...¥

[0375] ¥ '¥

[0376]

[0377] 18

[0378] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0379] ■0

[0380] -x A J

[0381] 3-(4-((2R,3R)-l-acetyl-4-acrjloyl-3- 1 1 ■

[0382] Compound 10 mediylpiperazin-2-yi)-6-chloropyridin-2-yl)-4- metboxybenzonitrile

[0383] .. X ';

[0384] 0

[0385] •.. Ax

[0386] 3 -( 4-((2 S,3 S)- 1 -acetyI-4-acryioyI-3- Compound 11 r 0 methylpiperazin-2-yI)-6-chloropyridin-2-yl)-4- QK ’AC ' Ay”"

[0387] methoxy benzonitrile

[0388] A "

[0389] !

[0390] zJ.

[0391] 3 -(4-((2R,3R)- 1 -acetyl-4-acryloyl-3- Compound 12 r o..?<■ methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4- fluorobenzonitrik

[0392] > '■-C"

[0393] 9

[0394] -,. A 3-(4-((2S,3S)-l-acetyl-4-acryloyi-3- » X

[0395] Compound 13 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4- k 1

[0396] Cl fluorobenzonitrile

[0397] -C"'

[0398] 6-(4-((2R.3R)-4-acryIoyl-3-methylmorpholin-2-yl)- Compound 14

[0399] 6-chloropyridin-2-yl)pyrimidine-4-carbonitrile

[0400]

[0401] 19

[0402] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0403] ...... A.. - o....... A.

[0404] 6-(4-((2S.3S)-4-acnloyi-3-methylmorpholin-2-yl)- Com pound 15 r £ 6 -chlo ropy r idin -2 -y l)pyrim i din e -4 -c arbo nitril e N.... N

[0405] ■0

[0406] 3 '-((2R.3 R) - 1 -acety 1-4-acry loy 1-3 -me thy Ipiperazin- 0 -L., F

[0407] Compound 16 2-y l)-5 '-chloro-2'-fluoro-[ 1, 1 '-biphenyl] -3- r (..x

[0408] carbonitrile

[0409] A,

[0410] p

[0411] ’■YA?A

[0412] 3,-((2S,3S)-l-acetyl-4-aciyloyl-3-methylpiperazin-2- Compound 17 6 X, F

[0413] T ( yl)-5'-chloro-2'-fluoro-[l,r-biphenyl]-3-carbooitrile “'"'O'"

[0414] 0

[0415] X'? X X

[0416] ...... X., J...

[0417] 5-(3-((2R,3R)-l-acetyl-4-aciyloyl-3- 6.1 F

[0418] Compound 18 methylpiperazin-2-yl)-5-chloro-2- £ I

[0419] a.. fluoropbenyl)nicotinonitrile

[0420] N:

[0421] 0

[0422] •vx.. A 5-(3-((2S,3S)-l-acetyl-4-acryloyl-3- b.c

[0423] Compound 19 mcthy Ipipcrazin -2-y 1) - 5 -chloro -2 - L I

[0424] cY-w Y'X'"'"' fluoropbenyl)nicotinonitrile

[0425] '■'fX

[0426]

[0427] 20

[0428] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0429] o

[0430] J.. J 6-(3-((2RJR)-l-acetyl-4-acryloyl-3- Compound 20 I, I..i methylpiperazin-2-yl)-5-chloro-2- f ( „

[0431] y v" fluoropheny l)p icol inonitri le

[0432] .. il....

[0433] 6”(3-((2S,3S)-l-acetyl-4-acryloyI"3- 0 A -F

[0434] Compound 21 y o".;, N methylpiperazin-2-yl)-.5-chloro-2- fiuorophenyl)picoiinonitrile

[0435] ©

[0436] X, J.

[0437] 6'-((2S,3R)-l-acetyl-4-acryloyl-3-methylpiperazin- Compound 22 V /

[0438] i AN

[0439] J

[0440] .. ■•■.. A 2-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile u

[0441] 0

[0442] / '''" A*"'

[0443] X.- A xA

[0444] 6’-((2R,3S)-l-acetyl-4-aci'yloyl-3-niethylp!perazm- Compound 23

[0445] 2-yl)-4'-chioro-[2.2'-bipyricbne]-6-carbonitriie A y /

[0446] ... I.. O

[0447] r ■»■

[0448] r* J

[0449] 7 6-((2S.3R)-4-acryloyl-3-methylmorpholin-2-yl)-4- Compound 24 A 0

[0450] f is ■!

[0451] x- chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide

[0452]

[0453] 21

[0454] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0455] 0 Y x,

[0456] 6-((2R.3S)-4-acryloyl-3-methylmorpholin-2-yl)-4- Compound 25 < '"?■! 0

[0457] chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide

[0458] 0

[0459] p' ■<,-

[0460] ° iJ6'-((2S.3R)-4-acryloyl-3-methylmorpholin-2-yl)-4'- Compound 26

[0461] lx chloro-[2,2'-bipyridine]-6-carbonitrile cr -■ Y y

[0462] N '

[0463] 6'-((2R,3S)-4-ady'loyl-3-mcthy1morpholin-2-yl)-4'- Compound 27

[0464] A.44 chloro-[2,2'-bipyridine]-6-carbonitTile

[0465] Q

[0466] 4.<■

[0467] 4 '"£''

[0468] J. J 6'-((2S,3R)-4-acryloyI-3-methyl-l- 0% 1

[0469] Compound 28 (methylsulfonyl)piperazin-2-yl)-4'-chloro-[2,2'- £ Y

[0470] bipyridine]-6-carbonitrile

[0471] " IJ

[0472] :G

[0473] ii

[0474] f' 'N'

[0475] 6'-((2R,3 S)-4-acryloy 1-3-methyl- 1 - o b x

[0476] Compound 29 (methylsuIfonyl)piperazin-2-yl)-4'-chloro-[2,2'- rRY

[0477] bipyridine]-6-carbonitrile

[0478] '-xY'

[0479]

[0480] 22

[0481] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0482] 0

[0483] ....<

[0484] f' >1'

[0485] J. 6-((2S,3R)-4-aciy loy 1-3 -methyl- 1 - A l

[0486] Compound 30 " N 0 (methylsulfonyl)piperazin-2-yl)-4-chloro-N-methyl- k 1.-s U,

[0487] " ■'iz‘ " V [2.4'-bipyridine]-2'-carboxamide

[0488] 6-((2R,3 S) -4-acry loy 1-3 -methy 1 - 1 - 6 b i

[0489] Compound 31 ■ " 'N 0

[0490] 1!<:i (methylsulfonyl)piperazin-2-yl)-4-chloro-N-methyl- [2,4'-bipyridine]-2’-carboxamide

[0491] 3

[0492] C' - •x, K. J

[0493] 1 T ' 6-((2S3R)-l-acetyl-4-acryloyl-3-inethylpiperazin-2- Compound 320X * yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'- carboxamide

[0494] 0

[0495] .x 1...

[0496] ''N

[0497] 6-((2R,3S)-l-acetyl-4-aciyloyl-3-methylpiperazin-2- 6

[0498] Compound 33 yl)-4-chloro-N -methy l-[2,4'-bipy ridine]-2'- carboxamide

[0499] o

[0500] r r

[0501] V.,|sj.

[0502] 5-(4-((2R3R)-l-acetyl-4-acryloyl-3- I X

[0503] Compound 34 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-cr'^T< fluoro-2-methoxybenzonitrile

[0504] F-" 'o

[0505]

[0506] QB\l 84200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0507] 9

[0508] 5-(4-((2S,3S)-l-acetyl-4-acryloyl-3- Compound 35 r?t methyIpiperazin-2-yl)-6-chloropyridin-2-yl)-4- fluoro-2 -inethoxy benzonitrile

[0509] F X-..- -0

[0510] r

[0511] Q

[0512] ■ A:.

[0513] 6 X 3-(4-((2R,3R)-l-acetyl-4-aciyloyl-3- Compound 36 C I. metliy lpiperazin-2-y 1) -6-chloropy ridin-2-y 1) -4- cr ' tr yr

[0514] F fluoro-5-inethoxybenzonitrile

[0515] •g

[0516] C' F'

[0517] 3-(4-((2S,3S)-l-acetyl-4-aciyloyl-3- Compound 37 r methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4- fluoro-5 -methoxy benzonitril e

[0518] F

[0519] g

[0520] 3-(4-((2R,3R)-l-acetj’l-4-ac!yloyl-3- | I

[0521] Compound 38 r methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4- ci methoxy - 5 -m e thy Ibenzon itril e

[0522] a"

[0523] ! j

[0524]

[0525] 24

[0526] QB\l 84200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0527] 3-(4-((2S,3S)-l-acetyl-4-acryloyl-3- Compound 39 1 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4- methoxy -5 -methy Ibenzonitrile

[0528] A 'C ’

[0529] i 1

[0530] ■o

[0531] 1

[0532] A,

[0533] 3-(4-((2R,3R)-l-acetyl-4-aciyloyl-3- o

[0534] Compound 40 nicthylpipcrazin-2-yl)-6-chloropyridin-2-yl)-5- a- ■■'”'■>4'- fluoro-4-methoxybenzonitrile

[0535] ■a

[0536] v-V-- 3-(4-((2S,3S)-l-acetyi-4-actyioyI-3- Compound 41 1 A* methylpiperazin-2-yI)-6-chloropyridin-2-yl)-5- □■■■? C

[0537] iluoro-4-methoxybenzonitriie

[0538] i

[0539] •'< jK ■

[0540] 5-(4-((2R,3R)-l-acetYi-4-acryloyl-3- 1 J

[0541] Compound 42 1 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4- methoxy -2-methy Ibenzonitrile

[0542]

[0543] 25

[0544] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0545] 9

[0546] 5-(4-((2S,3S)-l-acetyl-4-acryloyl-3- Compound 43 mci.hylpipc razin-2-y I) -6-chloropy ridi n-2-y 1) -4- ci^ ^ssr’' '

[0547] methoxy -2-methy Ibenzonitrile tX""'

[0548] i

[0549] Q

[0550] 6-(4-((6R,9aS)-8-acryloyloctahydropyrazino[2,l- Compound 44 c][l,4]oxazm-6-yl)-6-chloropyridin-2- 1 1

[0551] yl)pyrimidinc-4-carbonitrilc

[0552] it

[0553] S / MN

[0554] it 4-((2S,3S)-l-acetyl-4-acrydoy!-3-methylpiperazin-2- Compound 45 r;} _ yl)-6-chloro-5'-methoxy-[2.4'-bipyridine]-2'- carbonitriie

[0555] ■cr

[0556] Q

[0557] .. 0...

[0558] r ' " x "

[0559] ■x. X. J.

[0560] x> J " 2-(4-((2R,3R)"4-acryloyl-3-methyl-l- Compound 46 JL (methylsulfonyl)piperazin-2-yl)-6-chloropyridin-2- ec w ' v x yl)thiazole-4-carboniirile

[0561] h.

[0562] H

[0563]

[0564] 26

[0565] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0566] G

[0567] ,. A - r" W

[0568] , S, Ax.

[0569] a o 2-(4-((2S,3S)-4-acryloyl-3-methyl-l- Compound 47 (methylsulfonyl)piperazin-2-yl)-6-chloropyridin-2- y l)thiazole -4-carbonitrile

[0570] A J„

[0571] I X ■ 6-(4-((2R,3R)-l-acetyl-4-aciy4oyl-3- Compound 48 1 1.... me thy lpiperazin-2 -y 1) -6-chloropy ridin-2-y 1) -2- cr" "w YC

[0572] 'V methoxypyrimidine-4-carbonitrile z &

[0573] ;■

[0574] vkA

[0575] AY 6-(4-((2S.3S)-l-acetyl-4-acryloyl-3- Compound 49 methvIpiperaziii-2-yl)-6-chloropyridin-2-yl)-2- N. 'v A' methoxypyrimidiiie-4-carbonitrile

[0576] A

[0577] g

[0578] .-A A (R)-6-(4-(l-acetyl-4-acryloylpiperazin-2-yl)-6- Compound 501j A„ t.? o chloropyridin-2-yl)-2-methyl-2,3-dihydro-lH- cr 'f> ' Y" '-'rC, py trol o [3,4-c] py ri din - 1 -one

[0579] Ax-Lr.

[0580]

[0581] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0582] 0

[0583] •s,. Z’ (S)-6-(4-(l-acetyl-4-acnloylpiperazin-2-yl)-6- Compound 51 ciiloropyridin-2-yl)-2-inethyl-2,3-dihydro-lH- "fl... |

[0584] py rrolo[3,4-c]pyridin-l -one

[0585] o

[0586] -v J.

[0587] 3 -(4-((2R,3R)-l -acetYi-4-acry loy 1-3 - O '

[0588] Compound 52 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4- fluoro-5-methylbenzonitrile

[0589] 0 3-(4-((2S,3S)-l-acetyl-4-acryloyi-3- s

[0590] Com pound 53 L methyIpiperazin-2-yl)-6-chloropyridm-2-yl)-4- cr" 'Nr y " V

[0591] fluoro-5 -methylbenzonitrile

[0592] p--

[0593] . J.

[0594] 4-((2R.3R)-l-acetyl-4-aciyioyl-3-methylpiperazin- i l '

[0595] Compound 54 2-yl)-6-chloro-5'-methoxy-6'-niethyl-[2.4'- " C: ":'

[0596] 0- AvbipyridineJ-2'-carbonitrile

[0597] - A

[0598] i;

[0599] ; - " '"'x;?

[0600] ' i?V4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2- 6, A

[0601] Compound 55 L I... A* yl)-6-chloro-5'-methoxy-6'-methyl-[2,4'-bipyridine]- Gl" -C V A' 2'-carbonitrilc

[0602] a Jl A -A

[0603] i 5

[0604]

[0605] 28

[0606] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0607] 'N

[0608] •. A J 4'-((2S.5S)-l-acetyl-4-acndoyl-5- Compound 56 (hydroxymethyl)piperaziii-2-yl)-6'-chloro-[2,2'- t 1 A

[0609] ci bipyridinc] -4-c arbonitrilc

[0610] .. A

[0611] c

[0612] .. J

[0613] f< -:"

[0614] 6....

[0615] 5-(4-((2R,3R)-4-acndoyi-3-methylmorpholin-2-y1)- X ' Q

[0616] Compound 57 J!,. J..... U, 6-chloropyridin-2-yl)-4-cyano-2-methoxy-N- CC? C V’ ' H

[0617] 8 S H methylbenzamide

[0618] c

[0619] A -A

[0620] 5-(4-((2S.3S)-4-acryloyl-3-methylmorpholin-2-yl)- 0

[0621] Compound 58 JI. A A... 6-chloropyridin-2-yl)-4-cyano-2-methoxy-N- s-- >r '?<r

[0622] J w mcihylbcnz amide

[0623] A ' y

[0624] Q

[0625] . A

[0626] J. 4-(6-((2S,3R)- 1 -acetyl-4-acryloyl-3- Compound 59 '■■N 0 me thj' lpiperazin-2-y l)-4-chloropyridin-2-y 1) -N - C' ’'4<r ' ' metbylpyrimidine-2-carboxarmde

[0627] . H

[0628] 0

[0629] f y J. - •. A A 4-(6-((2R,3 S)- 1 -acety 1-4-acry loy 1-3- I

[0630] Compound 60 melhylpiperazin-2-yl)-4-chloropyridin-2-yl)-N- ’ H "

[0631] •- Y T methylpyrimidiiie-2 -carboxamide

[0632]

[0633] 29

[0634] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0635] 0

[0636] r r•• ••

[0637] d 0 5-(4-((2R.3R)-4-acryloyI-3-methyl-I- Compound 61 1 1.. s. (methylsulfonyl)piperazin-2-yl)-6-chloropyridin-2-0. yl)-4-cyano-2-fluoro-N -methylbenzamide

[0638] j-- -gy- i vz.-..

[0639] L-> ' 5-(4-((2S,3S)-4-aciyloyl-3-methyl-l- 6

[0640] Compound 62 (methylsuifonyl)piperazin-2-yl)-6-chloropyridin-2- <4"' '?<’ ■'fj"" yl)-4-cyano-2-fluoro-N -methylbenzamide

[0641] f y Ji ■..

[0642] 5-(4-((2R.3R)-4-acryloyl-3-methylmorpbolin-2-yl)- Compound 63 6-chloropyridin-2-yl)-4-cyano-2-Iluoro-N- l't'zm ethy Ibenzami de

[0643] .. 1 zZ

[0644] r y

[0645] 5-(4-((2S,3S)-4-acryloyl-3-methylmorpholin-2-yl)- Compound 64 jC 6 6-chioropyridm-2-yl)-4-cyano-2-fluoro-N- methylbenz amide

[0646] fcr z-".-'- 1 "'•Z'z J' '"-KH

[0647] r9

[0648] -y^

[0649] 5-(4-((2R,3R)-l-acetyl-4-acryloyl-3- $.'-L,r.

[0650] Compound 65 methyIpiperazin-2-yl)-6-chloropyridin-2-yl)-4- cy ano-2-fluoro-N -me thy Ibenzamide

[0651]

[0652] 30

[0653] QB\184200.00265X99930245.1 WED 755PC Compound ID Structure Chemical Name

[0654] 0

[0655] f.. I •• ••

[0656] S A 5-(4-((2S,3S)-l-acetyl-4-acryloyI-3- Compound 66 meth

[0657] cr' n u

[0658] •i J > H1. ylpiperazin-2-yl)-6-chioropyridin-2-yl)-4- cyano-2-fluoro-N-methylbenzamide

[0659] ¥ ' ■

[0660] 0

[0661] ¥¥C':

[0662] 4-(6-((2S,3R)-4-aciyloyl-3-methyl“l- Compound 67 ¥■¥?? (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2-cr¥ 'T fl y 1 ) -N-me thy Ipy rimidine -2-c arboxamide

[0663] 0

[0664] X 1

[0665] 4-(6-((2R,3S)-4-aciy’loyl-3-methyl-l- Compound 68 £i i

[0666] f T >, 8. (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- <^VYY yl)-N-methylpyrimidme-2 -carboxamide

[0667] p

[0668] 6-((2S,3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2- Compound 69 « Q yl)-4-chloro-5'-cyano-N-mcthyl-[2,4'-bipyridinc]-2'- ij 1 carboxamide

[0669] a

[0670] rJi ^.-..

[0671] o J.. C 6-((2R,3S)-l-acetyl-4-acryloyl-3-methylpiperaziii-2- Compound 70 ” ‘81 yl)-4-cbloro-5'-cyano-N-methyl-[2,4'-bipyridine]-2'-, ¥x C H carboxamide

[0672]

[0673] 31

[0674] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0675] p

[0676] 6. J 4-(6-((2S.3R)-4-acn4ojd-3-metliylmorpholio-2-yl)- I "

[0677] Compound 71 c A C 4-chloropyridin-2-yl)-N-methyIpyriroidine-2- J Y X J- cr -TY >c"

[0678] H carboxamide

[0679] Y

[0680] P

[0681] 'A'""'

[0682] .• A 4-(6-((2R,3S)-4-aciy4oyl-3-methylmorpholin-2-yl)- Compo und 72 d'A; o 4-chloropyridin-2-yl)-N-metliylpyrimidine-2-Ci, Ji -iTY -y A

[0683] carboxamide

[0684] YA

[0685] 0

[0686] A *

[0687] 6-((2S,3R)-4-acryloy 1-3-methyl- 1 - < T$ I

[0688] Compound 73 if Y f (methylsulfonyl)piperaz.in-2-yl)-4-cbloro-5'-cyano- cr-'K^^Y'AfkVN''"

[0689] H N-mcthyl-[2,4'-bipy ridinc]-2'-carboxamidc A

[0690] 0

[0691] a

[0692] f -«■zi

[0693] •xA--x 6-((2R,3S)-4-acryloyl-3-methyl-l- Compound 74 * ¥4. f (mediylsulfonyl)piperazin-2-yl)-4-chloro-5'-cyano- C:- •••• Y-V 'M

[0694] H N-metbyl-[2,4'-bipyridine]-2'-carboxamide

[0695] 9

[0696] v., A J 6-(6-((2S,3R)-4-aciy’loyl-3-methyl-l- Compound 75 (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- yl)pyrazine-2-carbonitnle

[0697]

[0698] 32

[0699] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0700] 0

[0701] / 'A'

[0702] . A v.z. A % 6-(6-((2R,3S)-4-actyloyi-3-metliyl-l- Compound 76 o o 1. (m ethy i sulfony l)pipera zin-2 -y 1) -4-cb loropy ridin-2- AMA y i)py razine -2 -carbonitrile

[0703] FC'

[0704] g

[0705] 6-(4-((2R.3R)-4-aciyloyl-3-methyl-l- s Y " (methylsulfonyI)piperazin-2-yl)-6-chloropyridin-2- Compound 77 o - i

[0706] Fl. f yl)-2-methyl-2,3-dihydro-lH-pyrroio[3,4-c]pyridin-trvtX> 1-one

[0707] a

[0708] rAA^ 6-(4-((2S.3S)-4-acrykoyl-3-methyl-l- (methylsulfonyl)pipera zin-2 -y l)-6-chloropyridin-2- Compound 78 d"b

[0709] Cr 1 R1.. J • yl)-2-metiiyl-2,3-dihydro-]H-pyrrolo[3.4-c]pyridin- H....; S:~... Z 1-one

[0710] o1<s2-(6-((2S,3R)-4-acryloyl-3-melliylmorpliolin-2-yl)- Compound 79 4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H- O z r AS *

[0711] " 0 JI I^’”” pyrrolo[3,4-b]pyridin-7-one

[0712] 0

[0713] f- A, - AA 2-(6-((2R.3S)-4-acryloy!-3-methylmorpholin-2-yl)- Compound 80 (A p 4-chloropyridin-2-y 1) -6 -methy 1-5,6-dihydro-7H-,z:Is. T / '•••• py rrol o [3, 4 -b] py rid in - 7-one

[0714]

[0715] 33

[0716] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0717] 6-(6-((2S,3R)-l-acetyl-4-actyloyl-3- Compound 81 methylpiperazin-2-yl)-4-chloropyridin-2-, i

[0718] er - * y yl)pyrazine -2 -carbonitrile

[0719] 6-(6-((2R,3 S)- 1 -aceiyl-4-acry loy 1-3- Compound 82 methylpiperazin-2-yr)-4-chloropyridin-2- ci "■ Y5Y yl)pyrazine-2-carbonitrile

[0720] 0

[0721] y "-C

[0722] 6. J

[0723] 3-(6-((2S3R)-4-acryloyl-3-methylmorpholin-2-yl)- I ■

[0724] Compound 83 4-chloropyridin-2-yl)-6-methyl-6,7-dihydro-5H- pyrrolo [3,4-b]py razin-5 -one

[0725] 0

[0726] 3-(6-((2R.3 S)-4-acry loy l-3-methylmorpholin-2-yl)- Compound 84 tf 0 4-chloropyridin-2-yl)-6-methyl-6,7-dihydro-5H-,, X. Si.

[0727] !yirij ’T }J. pyrrolo [3,4-b]py razin-5 -one

[0728] a

[0729] 7-(4-((2R,3R)-4-acryloyl-3-methyl-l- o' b A (methylsulfonyl)piperazin-2-yl)-6-cbloropyridin-2- Compound 85

[0730] yl)-2-methyl-3,4-dihydro-2,6-naphthyridin-l(2H)- c ' ’ ’ N ' ' v K"

[0731] Ns A-A one

[0732]

[0733] 34

[0734] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0735] 0

[0736] .....

[0737] 7-(4-((2S,3S)-4-acrjdoyl-3-inetbyl-l- d... (methylsulfonyl)piperazin-2-yl)-6-chloropyridin-2- Compound 86

[0738] c * _yl)-2-methyl-3,4-dihydro-2,6-naphthyridin-l(2H)- C: " V 'V'5¥" ’V'

[0739] one

[0740] ...., 1...

[0741] ■o V *C

[0742] k X J 6-(4-((6S,9aR)-8-acryloyloctahv dropyrazino[2, 1 - Compound 87 c][l,4Joxazjn-6-yI)-6-chloiopyi!din-2-yl)-2-metbyl- X- X J

[0743] cr2,3 -dihy dro-1 H-pyrrolo [3,4-c]pyridin- 1 -one lx >

[0744] e

[0745] 0--- ■...■•••■■>.) •■•■•. _,-:- CXX 4!-((6S,9aR)-8-acryloyloctahydropyrazino[2, 1 - Compound 88 c][l,4]oxazm-6-yl)-6'-chloro-[2,2'-bipyridine]-4- 1X -; N

[0746] carbonitrile

[0747] *......c

[0748] rV

[0749] 6-((2S,3R)-4-aciyloyl-3-methyl-l- XV

[0750] Compound 89 X. Y... k, (niethylsulfonyl)piperazin-2-yl)-4-cbloro-6'- or ■■•-■" Y' ”'V N"

[0751] :! J H methoxy-N -m ethyl- [2,3 '-bipyridine | -5 '-carboxamide

[0752] r r

[0753] d“b 1 6-((2R,3S)-4-aciyloyl-3-methyl-l- 'N 0

[0754] Compound 90 J, k K z (methylsulfonyl)piperazin-2-yl)-4-chloro-6'- or Y' -'Y' Y

[0755] r i methoxy -N -methyl- [2,3 '-bipyridine] -5 '-carboxamide ""'Nk'sq

[0756]

[0757] 35

[0758] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0759] p

[0760] ,.... K 2-(6-((2S,3R)-4-acryloyl-3-methyl-l- A l ” (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- Compound 91 fl O

[0761] C, A. Y-V%...4 yl)-6-inethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-: N""

[0762] 7-one

[0763] 9

[0764] 2-(6-((2R,3S)-4-acryloyl-3-methyl-l- tf b A (methylsulfonyl)piperazin-2-yl)-4-chloropyridm-2- Compound 92 r i p yl)-6-inethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin- l 4.N"" 7-one

[0765] 0

[0766] Y Y^'

[0767] hi; 3 -(6-((2S.3 R) -4-aciy loy 1-3 -m ethy 1 - 1 - o X o Y 1 ' (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- Compound 93 YY p

[0768] yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3.4-b]pyrazin-;:'z'' fxY' Y-...

[0769] ■■ Y''z5 -one

[0770] £

[0771] s 3 -(6-((2R,3 S) -4-jicry loy 1-3 -me thy 1-1- O O / . (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- Compound 94 r 4 9

[0772] A A- a yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3.4-b|pyrazin- '' ljE> 5 -one

[0773] r¥Y. A

[0774] 3-(6-((2S,3R)-l-acetyl-4-acryloyl-3- Compound 95 n o methylpiperazin-2-yl)-4-chloropyridin-2-yl)-6- A.yA * - A

[0775] ( I >- methyl-6,7-dihydro-5H-pyrroIo[3,4-b]pyrazin-5-one '"'A

[0776]

[0777] 36

[0778] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0779] 0

[0780] 3-(6-((2R,3S)-l-acetyl-4-acryloyl-3- Compound 960n methylpiperazin-2-yl)-4-chloropyridin-2-yl)-6- As A. Ji. #

[0781] methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-onevI T >.

[0782] $

[0783] ..,?< >..

[0784] I X " 6-(4-((2R,3R)- 1 -acetyl-4-aciyloyl-3- Compound 97 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2- A-AYA-%... methyl-2,3 -diliy dro- 1 H-pyrrolo [3,4-c ]py ridin- 1 -one

[0785] 6-( 4-((2 S,3 S)- 1 -acetyl-4-acryioyl-3- £ 7

[0786] c As methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2- Compound 98

[0787] M s?

[0788] ci-" 'Y. methyl-2,3 -diliy dro- 1 H-pyrrolo [3,4-c jpy ridin- 1 -one A A - /

[0789] <1

[0790] .. A. - 2-(6-((2S,3R)-l-acetyl-4-acryloyl-3- 1 XX methylpiperazin~2-yl)-4-chloropyridin-2-yl)-6- Compound 99 p

[0791] metliyl-5,6-diliydro-7H-pyrrolo[3,4-b]pyridin-7-one.

[0792] ■Q

[0793] „X

[0794] r ¥x;- 2-(6-((2R,3S)-l-aceiyl-4-acryloyl-3- y

[0795] methylpiperaz!n-2-yl)-4-chloropyridin-2-yl)-6- Compound 1000A

[0796] methyI-5,6-diliydro-7H-pyrrolo[3,4-b]pyridin-7-one -WX6.

[0797]

[0798] 37

[0799] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0800] 0

[0801] A, A 7-(4-((2S,3S)-l-acetyl-4-actyloyl-3- I 0f A r

[0802] Compo methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2-und 101 r n H

[0803] C: " 'V'* V 'V' methy 1 -3, 4 -dihy dro -2, 6 -n aph thy ri din - 1 (2H) -one?1.,1... Y

[0804] Q

[0805] 7-(4-((2R,3R)-l-acetyl-4-acryloyl-3- 1 1, Compound 102 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2- r | |. C ' ’X ’ " Y ' Y-X’ 'Y methyl-3,4-dihydro-2,6-naphthyridin-l(2H)-one i. Y- -A

[0806] rJ^ R A. 4-((2R,3R)-4-actyloyl -3-methyl- 1 - A T ’ 1 A O Compound 103 (methylsuIfonyl)piperazin-2-yl)-6-chloro-5'-cyano- J J... U or ><’ v’Y A i.. M N-methyI-[2,4'-bipyridine]-2'-carboxamide A:’

[0807] 0

[0808] . a,sy... Y

[0809] ' <?N' -s. 4-((2S,3S)-4-acryloyl-3-methyl-l- ■.;1 x

[0810] Compound 104 (mcthylsulfonyl)pipcrazin-2-yl)-6-chloro-5'-cyano- r 1. 8 cc'--r V5Y -N -'

[0811] N-metbyl-[2,4‘-bipyridine]-2'-carboxamide

[0812] .. A..<■■ f' 'N"

[0813] -- A

[0814] 4-((2R,3R)-l-acetyl-4-acryloyl-3-methylpiperazin- 2-yr)-6-chloro-5'-methoxy-[2,4'-bipyridine]-2'- Compound 105 L ■} Y

[0815] carbonitrile

[0816] i

[0817]

[0818] 38

[0819] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0820] 0

[0821] .....1.

[0822] ft f Y > 2-(6-((2S,3R)-4-acE3rlojrI-3-methylmorpholin-2-\d)- Compound 106 ff I ■:'<! ' ft 4-chloropyridin-2-yl)-7-methyl-6.7-dihydro-L7- er Ji. J M '1" jl N’ > naphthyridin-8(5H)-one

[0823] 0

[0824] r -'i'

[0825] 2-(6-((2R,3S)-4-acryloyl-3-mctliylinorpholin-2-yl)- Compound 107 4-chloropyridin-2-y l)-7-methyl-6,7-dihydro- 1,7- 0! Y "Znaphtliyridin-8(5H)-one

[0826] 0

[0827] ,,xa

[0828] r r

[0829] O-S 3-(6-((2S.3R)-4-acryioyl-3-methylmorpholin-2-yl)- Compound 108 'h 8 4-chloropyridin-2-yl)-6-methyl-7,8- O AV " I JV di hy dropyrido [3,4-b] py raz in-5 (6H)-one

[0830] f W •••

[0831] -••■••A 3-(6-((2R.3 S)-4-acry loy 1-3-methy lmorpholin-2-y 1)- Compound 109 4-chloropyridin-2-yl)-6-niethyl-7,8- or X, X V Y A M dihy dropyrido [3,4-b] py razin-5 (6H)-one

[0832] <3

[0833] , K J 2-(6-((2S,3R)-l-acetyl-4-acryloyl-3- v T

[0834] Compound 110

[0835] 6methylpiperazin-2-yl)-4-chloropyridin-2-yl)-7- r S

[0836] ft:' ' y methyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one

[0837] 9

[0838] 2-(6-((2R, 3 S)- 1 -acetyl-4-acry loy 1-3- Compound 111 6 A methy lpiperazin-2-yI)-4-chloropyridin-2-yl)-7- 1.

[0839] CC'’ " C. A'" A methyl -6, 7-diliydro-l,7-naphthyridin-8(5H)-one

[0840]

[0841] 39

[0842] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0843] 0

[0844] r

[0845] 3 -(6-( (2S,3 R)- 1 -acetyl-4-ac ryloy 1-3- Compound 112 o JL methylpiperazin-2-yl)-4-cliloropyridm-2-yl)-6- me thy 1-7,8 -dihy dropy rido [3,4 -b] py razin-5 (6H) -one

[0846] 9

[0847] A •-i'- ■■'X jf v > 3-(6-((2R,3S)-l-acetyl-4-acryloyl-3- Compound 113 methylpiperazin-2-yl)-4-chloropyridin-2-yl)-6-, AJL A A,x methy 1-7, 8-dthy dropy ri do [3,4-b] py razin-5 (6H) -on e

[0848] a

[0849] ... 1Zz.

[0850] f- 2-(6-((2S.3R)-4-acryloyl-3-methyl-l- (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- Compound 114 o h 1

[0851] yl)-7-methyl-6,7-dihydro-l,7-naphthyridin-8(5H)-w' OJ one

[0852] 0

[0853] ... 1...

[0854] 2-(6-((2R,3S)-4-acryloyl-3-methyl-l- VAA (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- Compound 115 tf 'b...

[0855] if " A 9

[0856] .4. -A. M jl. y l)-7-methyl-6.7-dihydro- 1.7-naphthyridin-8( 5H)- a ' '•< r >r

[0857] one

[0858] a

[0859] 3-(6-((2S,3R)-4-acryloyl-3-methyl-l- A.

[0860] (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- Compound 116 A I ’

[0861] yl)-6-methyl-7,8-dihydropyrido|3,4-b]pyrazin- iJ!"' A, A Y. N. '".. Y A

[0862] 5(6H)-one

[0863] a

[0864] 3-(6-((2R,3S)-4-acryloyl-3-methyl-l- (methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2- Compound 117 o 'b A

[0865] r;;Il l;1 yl)-6-methyl-7,8-dihydropyrido[3,4-b]pyraziii- 5(6H)-one

[0866] 'fibVx-"'

[0867]

[0868] 40

[0869] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0870] 1

[0871] G-tfZS^RJ-l-acetyl^-acrjloyl-S-methylpiperazin^- Compound 1180: fj yl)-4-chloro-6'-methox}'-N-metbyl-[2,3'-bipyridine]- IjL 1.

[0872] [i JH5 '-carboxamide

[0873] 0

[0874] 1....

[0875] X y -'

[0876] 6-((2R,3S)-l-acetyl-4-aciyloyl-3-inethylpiperazin-2- Compound 119 y 1) -4-chloro-6'-methoxy -N -me thy 1- [2,3 '-bipyridine] -c,.- X., J,...3 ■,..

[0877] :: $ H 5’-carboxamide

[0878] ’s

[0879] 1

[0880] 6-((2R,5R)-l-acetyl-4-aciyloyl-5-methylpiperazin- Compound 120 2-yl)-4-chloro-N -methy l-[2.4'-bipyridine] -2'-0X:''X s

[0881] carboxamide

[0882] ■-. A:-.., A J 6-((2S,5S)-l-acetyl-4-acryJoyl-5-niethylpiperazin-2- Compound 121 I 1

[0883] !*' 'N 0 yl)-4-chioro-N-methyl-[2,4'-bipyridme]-2'- s!i: S

[0884] carboxamide

[0885] r

[0886] : a

[0887] I

[0888] N. X J 6-((2S,5S)-4-acryloyl-5-methyl-l- Compound 122 G (methylsulfonyl)piperazin-2-yl)-4-chloro-N-metliyl- 1- 11,. 11. [2,4'-bipyridine]-2'-carboxamide

[0889] ¥ Q

[0890] Y^'X^'

[0891] xs.. A„J 6-((2R,5R)-4-acryloyl-5-methyl-l- Compound 123 o ’b A (methylsulfonyl)piperazin-2-yl)-4-cbioro-N-methyl-,k X- - [2,4'-bipyridine]-2'-carboxamide

[0892] °.. 1 «

[0893]

[0894] 41

[0895] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0896] 0

[0897] 0... J 6-(4-((2R.3R)-4-acryloyl-3-methylmorpholin-2-yl)- Compound 124 6-chloropyridin-2-yl)-2-methyl-2.3-dihydro-lH- o. 1 py rrol o [3,4-c] py ri din - 1 -one

[0898] 0

[0899] c.. -Jx 6-(4-((2S.3S)-4-acryloyl-3-mcthylmorpholin-2-yl)- Compound 125 6-chloropyridin-2-yl)-2-methyl-2.3-dihydro-lH- fl...!

[0900] X X X pyrrolo[3,4-c]py ridin- 1 -one

[0901] : Sr; A ft....,

[0902] 7-(4-((2R3R)-4-acryloyl-3-niethylmorpholin-2-yl)- Compound 126 6-chloropyridin-2-yl)-2-methyl-3,4-dihydro-2.6- er" A '.{r" Y, <y- i naphthyridin- 1 (2H)-one

[0903] f.. • ft I. -i-.:.

[0904] 7-(4-((2S,3S)-4-acryloyl-3-methylmorpholin-2-yl)- Compound 127 6-chloropyridin-2-yl)-2-methyl-3,4-dihydro-2,6- fl f

[0905] cr 'w Y x-"' naphthy ridin- 1 (2H)-one

[0906] 0

[0907] zx i

[0908] ■, X. >

[0909] (S)-2'-(l-acetyl-4-acry4oylpiperazin-2-yl)-6'-chloro- Compound 128 I I

[0910] N-methyl-[4,4'-bipyridine]-2-carboxamide

[0911] a

[0912] ., A - ■-.. A J

[0913] £■' (R)-2'-(l-acetyl-4-acryloylpiperazin-2-yl)-6'-chloro- Compound 129 sy -s Q

[0914] X u. 4 N-methyl-[4,4'-bipytidine]-2-carboxaniide

[0915] <:: x -w ft

[0916]

[0917] 42

[0918] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0919] . A 0 - A J (S)-2'-(4-aciyloyl-l-(methylsulfonyl)piperazin-2- Compound 130 A I yI)-6'-chloro-N-inethyl-[4.4'-bipyridine]-2- r 10carboxamide

[0920] Q

[0921] 1,<

[0922] A,..., F (R)-2'-(4-aciyloyl-l"(inethylsulfonyl)piperazin-2- Compound 131 iFfe i. yl)-6'-cbloro-N-inethyl-[4,4'-bipyridjne]-2- carboxamide

[0923] 0

[0924] ■,.4. 6-(4-((2R,3R)-l-acetyl-4-aciyloyl-3- Compound 132 ° A? methylpiperazin-2-yI)-6-chloropy ridin-2-yl)-3- me thy Ipy rido [3,4-d] py rimidin-4(3H) -one "-z‘?f

[0925] ■■•,, K 6-(4-((2S,3S)-l-acetyl-4-acryloyl-3- Compound 1330-' ■'Fomethylpiperazin-2-yl)-6-chloropyridin-2-yl)-3- GJ-'" "?r methy Ipyrido [3,4-d] pyrimidin-4(3H)-one

[0926] c?

[0927] •¥> L - A <, 7-(4-((2R,3R)-l-acetyl-4-acryloyl-3- Compound 134 o A me thy ipiperazin-2 -y 1) -6-chloropy ridin-2-y 1) -2- 4X^L methy 1-2,6-naphthyridin- 1 (2H)-one

[0928] iJ-J

[0929] 0

[0930] ■ s-'-X 7-(4-((2S,3S)-l-acetyl-4-acryloyl-3- Compound 135 d -A methyIpiperazin-2-yl)-6-chloropyridin-2-yl)-2- O

[0931] N. 1.

[0932] Y'Y ¥ methyl-2,6-naphthyndin-l(2H)-one

[0933]

[0934] 43

[0935] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0936] ft

[0937] j

[0938] T Y.. 7-(4-((2R,3R)-l-acetYl-4-acryloyl-3- Compound 136 0 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2- or"' methy Ipy rido[3.4-d]pyridazin- 1 (2H)-one

[0939] Y A

[0940] 9

[0941] -. A 7-(4-((2S,3S)-l-acetyl-4-aciyloyi-3- Y

[0942] Compound 137 0 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2-;'r niethylpyrido[3,4-d|pyridazin- 1 (2H)-one Y, Y

[0943] 0

[0944] -'A'''

[0945] K Y 4-((2R,3R)-l-acetyl-4-acndoyl-3-metby1piperazin- £

[0946] Compound 138 d 1 ■ 2-yl)-6-chloro-5'-cyano-N-methyl-[2.4'-bipyridinej-! 1 t,

[0947] Ci"'' 2'-carboxamide

[0948] * XI 'f

[0949] N: V

[0950] 0

[0951] ' A '-: Z

[0952] 4-((2S.3S)-l-aceEyl-4-acnrloyl-3-methylpiperazin-2- i:

[0953] Compound 139 0 <'Y o yl)-6-chloro-5'-cyano-N-metliyl-f2,4'-bipyridinej-2'-!. zl

[0954] o -T-Y.1

[0955] r Y.

[0956] carboxamide

[0957] . A--..

[0958] p

[0959] v. A A. 2k(2S,3R)-l-acety1-4-acryloyl-3-metby1piperazin- Compound 140 K I ' 2-y l)-6'-chloro-N-methyl-[4, 4' -bipyridine] -2- Y "p Q

[0960] carboxamide

[0961] 0

[0962] •, Y 2'-((2R,3S)-l-acetyl-4-aciyloyl-3-methylp!perazm- 1 ■

[0963] Compound 141 2-y l)-6'-chloro-N-meihyl-[4.4' -bipyridine] -2- k jl a. carboxamide

[0964]

[0965] 44

[0966] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0967] ......

[0968] J 2'-((2S,3R)-4-acryloyl-3-methyl-l- Compound 142 o'o I (methylsulfonyl)pjperazin-2-yI)-6'-chloro-N-methyl- r i ° [4, 4'-bipyridine]-2 -carboxamide

[0969] z0

[0970] .xil

[0971] 'Vs..jk. A. 2'-((2R,3 S )-4-acry loy 1-3 -me tliyl- 1 - Compound 143 (niethylsulfonyl)piperazin-2-yl)-6'-chloro-N-niethyl- [4, 4'-bipyndine]-2 -carboxamide

[0972] 0

[0973] r ¥.

[0974] 7-(4-((2R.3R)- 1 -acetyl-4-acryloyl-3- Compound 144 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2.4- « CT y y: y dimethy i -2, 6-naphthyridin- 1 (2 H) -one

[0975] ¥. ■. A

[0976] 0

[0977] y.. y- a,5

[0978] 7-(4-((2 S,3 S) - 1 -acety 1 -4-acry loy 1 -3 - Compound 145 metiiylpiperazin-2-yl)-6-chloropyridin-2-yl)-2,4- c °rn fs W... i y.. dimethyl-2, 6-naphthyridin- 1 (2H)-one

[0979] r..... y 1 - 6-(4-((2RJR)-l-acetyl4-acryloyl-3- Compound 146 6 JL meihylpiperazin-2-yl)-6-chloropyridin-2-yl)-2.3- ci- £ 'is jl. "fX"y X N'. dimethy Ipy rido [3.4 -d] py rim idin-4(3 H) -one

[0980] y y

[0981] -.. x.-L 6-(4-((2S,3S)-l-acetyl-4-acryloyl-3- n T

[0982] Compound 147 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2,3- £ °£,•■jQ -N-' y.y. -yy,-' I y-.. dimethy Ipy rido [3.4 -d] py rimidin-4(3 H) -one v,--

[0983]

[0984] 45

[0985] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[0986] 1

[0987] 7-(4-((2R,3R)-l-acetyl-4-acryloyl-3- Compound 148 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2.4- O 1.

[0988] dimethylpyrido[3,4-d]pyridazin-l(2H)-one

[0989] 0

[0990] ,, 1.

[0991] ••AY 7-(4-((2S,3S)-l-acetyl-4-acryloyl-3- 6 A

[0992] Compound 149 metliy lpiperazin-2-y I) -6-chloropy ridin-2-y l)-2,4- £ 1 I

[0993] C:'“VN v ’xy V dimethylpyrido[3,4-d]pyridazin-l(2H)-one

[0994] 0

[0995] AY’

[0996] AA. 7-(4-((2R,3R)- 1 -acetyl-4-acryloyl-3- Compound 150 o £ A i methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2.3- r ji ~

[0997] C:'"' ■" M”' '' Y dimethy 1 -2.6-naphthy ridin- 1 (2H) -one

[0998] A-SA A--.

[0999] a

[1000] .- ' YA<-. A A 7-(4-((2S,3S)-l-acetyl-4-acryloyl-3- 1?:

[1001] Compound 151 methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2,3- ’A _ 8,

[1002] cr V Y Y Y dimethyl-2,6-naphthyridin- 1 (2H)-one:’xA'.

[1003] - JI

[1004] o... -A 4-((2S,3S)-4-aciyloyl-3-methylmorpholm-2-yl)-6- Compound 152 chloro-5'-cyano-N-mcthyl-[2,4'-bipyridinc]-2'- Ct' A N A' V' Y' A?4' - carboxamide

[1005] .•-'" A-., ''v'! <■

[1006] A

[1007] >a

[1008] . Il,.f

[1009] r' Y

[1010] 6,. -..v4-( (2R,3R)-4-acry loy l-3-methylmorpholin-2-y l)-6- Compound 153 chloro-5 Yy ano-N -methyl-[2,4'-bipyridine] -2'- Ci

[1011] A J,.-...1., carboxamide cr K v' ■ Y V

[1012] li J- H

[1013]

[1014] 46

[1015] QB\184200.00265X99930245.1 VVID 755PC Compound ID Structure Chemical Name

[1016]

[1017]

[0108] Further Forms of Compounds

[1018]

[0109] 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.

[1019]

[0110] hr some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent ding in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than tire parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have impro ved 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 (poly aminoacid) 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 or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[1020]

[0111] 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 47

[1021] QB\184200.00265\99930245.1 VVID 755PC of prodrags 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 Prodrag 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).

[1022]

[0112] In some embodiments, some of the herein-described compounds may be a prodrag for another derivative or active compound

[1023]

[0113] 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, by7way of example only, a halogen, or an alkyl group,

[1024]

[0114] 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.

[1025]

[0115] Compounds described herein include isotopically labeled compounds, wliich 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 iu nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxy gen. sulfur, fluorine, chlorine, and iodine such as. for example,2H.3H,13C.14C.i5N,!8O,!70,35S,18F,36C1, and125L In one aspect, isotopically labeled compounds described herein, for example those into which radioactive isotopes such as3H andi4C 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 stability7, such as, for example, increased in vivo half-life or reduced dosage requirements.

[1026]

[0116] 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.

[1027]

[0117] “Pharmaceutically acceptable” as used herein, refers 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 or interacting in a deleterious manner with any7of the components of the composition in which it is contained.

[1028]

[0118] Tire 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 48

[1029] QB\184200.00265\99930245.1 VVID 755PC 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.

[1030]

[0119] The disclosure relates to compounds that selectively inhibit KEAP1 and to uses thereof.

[1031]

[0120] 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, methane sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid. 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluene sulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3 -phenylpropionic acid, trimcthy lace tic acid, tertiary butylacctic 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 uot limited to. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-niefhylglucamine. dicyclohexy famine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysme, 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.

[1032]

[0121] 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 cry stallization 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 are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[1033]

[0122] Methods of T reatment

[1034]

[0123] hr another aspect, provided herein is a compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, for use in a method of activating Nrf2 by mediating the inhibition of KEAP1. In some embodiments, provided herein is a 49

[1035] QB\l84200.00265\99930245.1 VVID 755PC method of activating Nrf2 by mediating the inhibition of KEAP1. the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (1). (11). (Ill) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[1036]

[0124] In another aspect, provided herein is a compound of Formula (I), (II), (III) or (TV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, for 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), (III) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof. In some embodiments, the disease is mediated by the inhibition of KE API and the activation of Nrf2.

[1037]

[0125] In another embodiment, provided herein is a method of treating a disease mediated by the inhibition of KEAP1 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), (III) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

[1038]

[0126] 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), (III) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof) decreases oxidative stress.

[1039]

[0127] Tire disclosure relates to compounds that selectively inhibit KEAP1 and to uses thereof. In some embodiments, the disease is inflammatory bowel disease, microscopic colitis, diverticulitis, celiac disease, Crolm’s disease and ulcerative colitis (with or without fistulae), mucositis, psoriasis, psoriatic arthritis, lupus (including systemic lupus erythematous, cutaneous lupus, lupus nephritis), rheumatoid arthritisjuvenile idiopathic arthritis, Still’s disease, spondyloarthritis. and scleroderma, or acute cytokine release syndrome, acne, eczema

[1040]

[0128] In further embodiments the disease or condition is:

[1041] 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, lung dysfunction post injury such as skin bum.

[1042] an autoimmune and inflammatory disease, including rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, lupus (cutaneous and systemic), inflammatory bowel diseases, celiac disease, psoriasis, dermatitis / topical effects of radiation, polymyositis, mixed connective tissue disease, autoimmune-interstitial lung disease (Al-ILD). dermatomyositis, immunosuppression due to radiation exposure, vasculitis (various types)

[1043] a kidney disease, including diabetic nephropathy and 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 (AKI), sepsis-induced acute kidney injury', kidney disease or malfunction seen during kidney transplantation, Focal

[1044] 50

[1045] QB\184200.00265\99930245.1 VVID 755PC segmental glomerulosclerosis, hemolytic uremic syndrome, interstitial nephritis, lupus nephritis.primary hyperoxaluria

[1046] a cardiovascular disease, including pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure,

[1047] 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),

[1048] cancer,

[1049] an ocular disease, including, retinosa pigmentosa (RP), glaucoma, cataracts, neovascular (dry) AMO and neovascular (wet) AMO, eye injury', Fuchs endothelial corneal dystrophy (FECD), uveitis or other inflammatory eye conditions,

[1050] a liver indication, including non-alcoholic steatohepatitis (NASH), toxin-induced liver disease (e.g,, acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis,

[1051] preeclampsia, sickle cell disease, thalassemia, or high altitude sickness.

[1052]

[0129] In another aspect, provided herein is a method of maintaining the activity of. Nrfl in a cell or subject, comprising administering to the cell or subject an effective amount of a compound of any' of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof. In some embodiments, the compound inhibits KEAP1, thereby resulting in Nrf2 activation.

[1053]

[0130] Dosing and Treatment Regimens

[1054]

[0131] hi one aspect, the compounds disclosed herein are used in lire 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.

[1055]

[0132] 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.

[1056]

[0133] 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.

[1057]

[0134] In certain embodiments, the dose of ding being administered may be temporarily' reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).

[1058] 51

[1059] QB\184200.00265\99930245.1 VVID 755PC

[0135] Doses employed for adult human treatment are typically in the range of 0.01mg-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.

[1060]

[0136] Pharmaceutical Compositions

[1061]

[0137] In another aspect, provided herein is a compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof for use in the manufacture of a medicament.

[1062]

[0138] In one aspect, the compounds described herein (e.g., compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof) are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inacti ve 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 Deliver}' Systems, Seventh Ed, (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[1063]

[0139] 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, filling 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.

[1064]

[0140] 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.

[1065]

[0141] In some embodiments, the compounds disclosed herein are administered orally.

[1066] 52

[1067] QB\184200.00265\99930245.1 VVID 755PC

[0142] 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.

[1068]

[0143] In another aspect, the compounds disclosed herein are administered by inhalation

[1069]

[0144] In another aspect, the compounds disclosed herein are formulated for intranasal administration Such formulations include nasal sprays, nasal mists, and the like

[1070]

[0145] In another aspect, the compounds disclosed herein are formulated as eye drops.

[1071]

[0146] 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 rcctally to the mammal; and / or (j) administered non-systemically or locally to the mammal.

[1072]

[0147] hr 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.

[1073]

[0148] 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 evety 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.

[1074]

[0149] In certain embodiments, the compound disclosed herein is administered in a local rather than systemic manner.

[1075]

[0150] In some embodiments, the compound disclosed herein is administered topically. In some embodiments, the compound disclosed herein is administered systemically.

[1076]

[0151] hr some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodim ents, pharmaceutical formulations of the compounds disclosed herein are in the form of a capsule.

[1077] 53

[1078] QB\t84200.00265'99930245.1 VVID 755PC

[0152] 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.

[1079]

[0153] For administration by inhalation, a compound disclosed herein is formulated for use as an aerosol, a mist, or a powder.

[1080]

[0154] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[1081]

[0155] In some embodiments, compounds disclosed herein are prepared as transdermal dosage forms.

[1082]

[0156] In one aspect, a compound disclosed herein is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.

[1083]

[0157] 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.

[1084]

[0158] 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.

[1085]

[0159] Combination Treatments

[1086]

[0160] In certain instances, it is appropriate to administer at least one compound disclosed herein in combination with another therapeutic agent.

[1087]

[0161] 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.

[1088]

[0162] 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.

[1089]

[0163] If administration is simultaneous, die multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms

[1090]

[0164] Definitions

[1091]

[0165] 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.

[1092]

[0166] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[1093]

[0167] “Oxo” refers to the

[1094]

[1095] substituent.

[1096] 54

[1097] QB\184200.00265\99930245.1 VVID 755PC

[0168] “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-Cio alkyl. C1-C9 alkyl, Ci-C8alkyl, Ci-Ch alkyl. C,-C6alkyl, C1-C5 alkyl, C;-C,. alkyl, C1-C3 alkyl, Ci-C2alkyl, C2-C8alkyl, C2,-Cs alkyl and Ci-C8alkyl. Representative alky I groups include, but are not limited to, methyl, ethyl, H-propyl, 1-methylethyl (i-propyl), n-butyl, / -butyl,.s-butyl, w-pentyl, l,ldimethylethyl ( / -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-.

[1098]

[0169] “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 alky lene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[1099]

[0170] “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.

[1100]

[0171] “Alkylamino” refers to a radical of the formula -NHR or -NRR where each R is, independently, an alk l radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[1101]

[0172] Hie term “aromatic” refers to a planar ring having a delocalized p-electron s stem containing 4n+2 p electrons, where n is an integer. Aromatics can be optionally’ substituted. The term "aromatic” includes both ary l groups (e.g.. phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[1102]

[0173] " 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 ary l 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.

[1103]

[0174] “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 'ith a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxy lic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example,

[1104] 55

[1105] QB\184200.00265\99930245.1 VVID 755PC in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxy lie acid group Examples of bioisosteres of a carboxylic acid include, but are not limited to:

[1106]

[1107]

[0175] “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 Cs-Cecycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic or polycyclic. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cy clohexy 1. cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl. bicyclo[ 1.1.1 {pentyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, bicyclo[2.1. Ijhexane, 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 cyclcoalkvl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyd, cyclohexyl, cyclohepty l, 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, hr some embodiments, cycloalkyl groups are selected from among spiro[2.2]pentyl. bicyclofl.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 cycloalkyd group may be optionally substituted.

[1108]

[0176] “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 beteroaryl 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.

[1109]

[0177] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

[1110] 56

[1111] QB\l 84200.00265X99930245.1 VVID 755PC

[0178] " 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, 3bromo2fliioropropyl. l,2dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[1112]

[0179] “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.

[1113]

[0180] “Heterocycloalky 1” refers to a stable 3 to 14membered 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, die heterocycloalkyl radical may be a monocyclic, bicyclic ring (which may’ include a fused bicyclic heterocycloalkyl (when fused with an ary l or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), bridged hctcrocycloalkyl or spiro hctcrocycloalkyl), 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 quaternized. The heterocy cloalk l radical is partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, dec airy droisoquinol l, imidazoliny 1, inridazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl. octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl. 4piperidonyl, pyrrolidinyl, pyrazolidinyl. quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, tliiamorpholinyl, loxothiomorpholinyl, Lldioxothiomorpholinyl. 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, heterocycloalky Is 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, heterocycloalky' Is 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 heterocy cloaikyl ring). Unless stated otherwise specifically in the specification, a heterocycloalky l group may be optionally substituted.

[1114]

[0181] “Heteroaryl” refers to an ary l group that includes one or more ring heteroatoms selected from nitrogen, oxy’ en and sulfur. The heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl.

[1115] 57

[1116] QB\184200.00265\99930245.1 VVID 755PC 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, beteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or fury l. 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 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1 -4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-Csheteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-C heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroary l. In some embodiments, a bicyclic heteroaryl is a CA-Cdieteroaryl.

[1117]

[0182] Tire 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, ary 1th io. alk lsulfoxide, arylsulfoxide, alkylsulfone. arylsulfone, -CN. alkyne, Ci-C ealkylalkyne, halogen, acyl, acyloxy, -CO2H. -CChalkyl, nitro, and amino, including mono and disubstituted amino groups (e.g., -NHz, -NHR. -NR2), and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NHtCHs), - NfCHs), -OH, -CO2H. and -COcalkyl. 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 (=O).

[1118]

[0183] 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:

[1119] 58

[1120] QBX184200.00265'99930245.1 VVID 755PC

[1121]

[1122]

[0184] Hie 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.

[1123]

[0185] 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 w ill 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 activity7, 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 severity7or frequency of the symptom(s), or elimination of the symptom(s). A “prophy lac tically 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 injury7, 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 “activity7decreasing 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.

[1124] 59

[1125] QB\l 84200.00265X99930245.1 VVID 755PC 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., Lippincot, Williams & Wilkins).

[1126]

[0186] 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.

[1127]

[0187] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but arc not limited to, humans. In one embodiment, the mammal is a human.

[1128]

[0188] Tire 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 prophy lac tically and / or therapeutically.

[1129] EXAMPLES

[1130]

[0189] 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.

[1131]

[0190] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein, h 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.

[1132]

[0191] 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 Sy nthesis. 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,

[1133] 60

[1134] QB\184200.00265\99930245.1 VVID 755PC Volumes 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 Writs.

[1135] 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.

[1136]

[0192] Abbreviations

[1137] DCM: Dichloromethane

[1138] DIE: Di isopropylethyl amine

[1139] DMAP 4-(Dimethylamino)pyridine

[1140] DMF: Dimethyl formamide

[1141] DMSO: Dimethyl sulfoxide

[1142] EAor EtOAc: Ethyl acetate

[1143] ESI: Electrospray ionization

[1144] HPLC: High performance liquid chromatography

[1145] HRMS: High resolution mass spectrometry

[1146] hor hr(s): Hour(s)

[1147] MeOH: Methanol

[1148] Ms: Mesyl, or methanesulfonyl

[1149] min(s): Minutes

[1150] m / z: Mass-to-charge ratio

[1151] !H NMR: Proton nuclear magnetic resonance

[1152] 13C NMR: Carbon nuclear magnetic resonance

[1153] PE: Petroleum ether

[1154] rt: Room temperature

[1155] TLC: Thin layer chromatography

[1156] TFA: Trifluoroacetic acid

[1157] General Procedure 1

[1158]

[0193] Synthesis of tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)piperazine-l-carboxylate Sn^CH^j HBpin Pci(PPh3)4Pt^H, B(CeF5)s toicene, 10'J‘C tcluene, 110JO

[1159]

[1160] step 1 step 2 step 3 step 4

[1161] 61

[1162] QB\184200.00265\99930245.1 VVID 755PC

[0194] Step 1 2-(trimethylstannyl)pyrazine

[1163]

[0195] To a solution of 2-iodopyrazine (11 2 g. 54.4 mmol) in toluene (120 ml) was added Sn2(CH3)6(35.6 g, 109 mmol) and Pd(PPh₃)₄ (6.28 g. 5.44 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 12 hours under N2. The mixture was poured into aq. KF (80 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 w'as purified by column chromatography (Al2O3, 0-3% EtOAc / petroleum ether) to give 2-(trimethylstannyl)-pyrazine (8.79 g, 36.2 mmol) as yellow oil. NMR (400 MHz, CDCk) 5 ppm 8.68 - 8.82 (m, 1 H) 8.60 (d. J-1.63 Hz, 1 H) 8.34 - 8.44 (m, 1 H) 0.33 - 0.50 (m, 9 H).

[1164]

[0196] Step 2 2-(6-bromo-4-chloropyridin-2-y!)pyrazine

[1165]

[0197] To a solution of 2,6-dibromo-4-chloropyridine (7.00 g, 25.80 mmol) in toluene (70 mL) was added 2-(trimethylstannyl)pyrazine (7.83 g, 25.80 mmol. 80% purity) and Pd(PPh3)4(1.49 g, 1.29 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 hours under N2. The reaction mixture was poured into water (200 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, 5-15% EtOAc / petroleum ether). 2-(6-bromo-4- chloropyridin-2-yl)pyrazine (2.11 g, 7.80 mmol) w as obtained as white solid. ‘H NMR (400 MHz, CDCI3) 6 ppm 9.62 (s, 1H), 8.69 - 8.61 (m, 2H), 8.38 (s, 1H), 7.59 (s, 1H).

[1166]

[0198] Step 3. 2-(6-bromo-4-chloropyridin-2-yI)piperazine

[1167]

[0199] To a solution of 2-(6-bromo-4-chloropyridin-2-yl)pyrazine (2.11 g, 7.80 mmol), N- phenylaniline (2,64 g, 15,60 mmol) and pinacolborane (4,99 g„ 39.00 mmol) in toluene (22 mL) w as added tris(2,3,4,5,6-pentafluorophenyl)borane (399 mg, 0.78 mmol) at 25 °C under N2. The mixture was stirred at 110 °C for 16 hours. The cooled reaction mixture w'as concentrated, diluted with water (30 mL) and extracted with MTBE (10 mL x 3). The aqueous phase was used into the next step without further purification.

[1168]

[0200] Step 4. tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate

[1169]

[0201] To a solution of 2-(6-bromo-4-chloropyridin-2-yl)piperazine (2.15 g, 7.77 mmol) in water (30 mL) w'as added NaHCOs (0.98 g, 11.66 mmol) at 0 °C Di-tert-butyl dicarbonate (1.70 g. 7.77 mmol) in MTBE (1 mL) was added dropwise to the mixture at 0 °C. The mixture w as stirred at 25 °C for 4 hours. The reaction mixture was 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 w'as purified by column chromatography (SiO2, 30-60% EtOAc / petroleum ether), tert-butyl 3-(6- bromo-4-chloropyridin-2-yl)piperazine-l-carboxylate (1.20 g, 3.19 mmol) was obtained as white solid.

[1170] General Procedure 2

[1171] 62

[1172] QB\184200.00265\99930245.1 VVID 755PC

[0202] Synthesis of trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-l-carboxylate

[1173] step 1 step 2 step 3

[1174] Boc₂O, Na₂CO₃ THF / H2O step 4 step 7

[1175] step S

[1176]

[1177] absolute stereochemistry randomly assigned

[1178]

[0203] Step I. l-(6-bromo-4-chloropyridin-2-yl)-2-chloropropan-l-one

[1179]

[0204] To a solution of 2,6-dibromo-4-chloropyridine (49.0 g, 181 mmol) in THF (500 mL) was added iPrMgCl·LiCl (167 mL, 217 mmol, 1.3 M in THF) at 0 °C under N2. After stirring for 30 minutes, 2-chloro-N-methoxy-N-methylpropanamide (32.9 g, 217 mmol) in THF (250 mL) was added at 0 °C under N2. The reaction mixture was stirred at 20 °C for 2 hours The mixture was quenched with saturated aqueous NH4C1 solution (400 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. This reaction procedure was repeated with 2,6-dibromo-4-chloropyridine (1 00 g, 3.69 mmol), iPrMgCLLiCl (1.3 M in THF) (3.40 mL, 4.42 mmol) and 2-chloro-N-methoxy-N-methylpropanamide (3.33 g, 4.22 mmol). The combined crude products were purified by column chromatography (SiO2, EtOAc / petroleum ether) to give 1-(6-bromo-4-chloropyridin-2-yl)-2-chloropropan-1-one (35.0 g, 124 mmol) as a yellow oil. ‘H1H NMR (400 MHz, CDCl3) 5 ppm 8.06 - 7.99 (m, IH), 7.76 - 7.68 (m. 1H), 5.87 - 5.76 (m, IH), 1.74 (d, J = 6.8 Hz, 3H).

[1180]

[0205] Step 2. 5-(6-bromo-4-chloropyridin-2-yi)-6-methyl-l,2,3,6-tetrahydropyrazine

[1181]

[0206] To a solution of 1-(6-bromo-4-chloropyridin-2-yl)-2-chloropropan-1-one (42.0 g, 148 mmol) in MeOH (400 mL) was added 4 A molecular sieves (11 g) and ethane- 1,2-diamine (32.5 g, 541 mmol) at 0 °C. The reaction mixture was stirred at 65 °C for 1 hour under N2and filtered. The filtrate containing 5- 63

[1182] QBM84200.00265'99930245.1 VVID 755PC (6-bromo-4-chloropyridin-2-yl)-6-methyl-l,2.3.6-tetrahydropyrazine was used in the next step without further purification.

[1183]

[0207] Step 3 Mixture of trans 2-(6-bromo-4-ch!oropyridin-2-yl)-3-methylpipeiazine and cis 2-(6- bromo-4-chloropyridin-2-yl)-3-methylpiperazine

[1184]

[0208] To a solution of 5-(6-bromo-4-chloropyridin-2-yl)-6-methyl- 1,2,3, 6-tetrahydropyrazine (42.0 g, 146 mmol) in MeOH (400 mL) was added NaBH4(28.1 g, 741 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was quenched by the addition of HC1 (1 M in MeOH) to adjust the pH to ~4. The mixture was filtered and concentrated under reduced pressure to afford a mixture of trans 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine and cis 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine (42.0 g) as a pale yellow solid, subsequently used without further purification.

[1185]

[0209] Step 4 trans di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-l,4-dicarboxylatc and cis di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate

[1186]

[0210] To a solution of 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine (42.0 g, 145 mmol) in THF (300 mL) and water (300 mL) was added di-tert-butyl dicarbonate (63.1 g, 289 mmol) and Na2CO3(30.6 g, 289 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. This reaction procedure was repeated with 11.0 g (37.9 mmol) 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine.

[1187] 16.5 g (75.7 mmol) di-tert-butyl decarbonate and 8.02 g (75.7 mmol) Na2CO3 in THF (30 mL) and water (30 mL). The reaction mixtures were combined, diluted with water (800 mL) and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product w as purified by column chromatography (SiO2, 0-7% EtOAc / petroleum ether). The first eluting isomer, cis di-tert-butyl 2-(6- bromo-4-chloropyridin-2-yl)-3-methylpiperazine-l,4-dicarboxylate (28.0 g. 57.0 mmol), was obtained as colorless oil.1H NMR (400 MHz, CDCl3) 5 ppm 7.40 (d, J = 1.6Hz, 1H), 7.18 (d, J = 1.5 Hz. 1H). 5.06 (d, J = 6.3 Hz. 1H). 4.63 (br t, J = 6.8 Hz, 1H), 4.28 - 4.20 (m. 1H). 3.65 - 3.54 (m, 3H), 1.48 (s, 9H). 1.26 (s, 9H). 1.01 (d, J= 7.1 Hz, 3H). The second eluting isomer, trans di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-1.4-dicarboxylate (14.0 g. 28.5 mmol), was obtained as colorless oil.1H NMR (400 MHz, CDCl3) 8 ppm 7.43 - 7.39 (m. 1H), 7.11 (br d, J = 16.9 Hz. 1H). 5.14 (s. 1H), 4.99 (s, 1H). 4.12 - 3.90 (m, 1H), 3.84 - 3.71 (m. 1H), 3.22 - 3.08 (m. 1H). 3.05 - 2.90 (m, 1H), 1.47 - 1.41 (m, 18H), 1.36 - 1.34 (m, 3H).

[1188]

[0211] Step 5 Epimerization of cis di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-l,4-dicarboxylate to trans di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate

[1189] 64

[1190] QB\184200.00265\99930245.1 VVID 755PC

[0212] To a solution of cis di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate (43.0 g, 87.6 mmol) in MeCN (200 mL) was added DBU (1.31 mL, 1.33 g, 8.76 mmol) at 25 °C under N2. The reaction mixture was stirred at 90 °C for 16 hours. The cooled mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-7% EtOAc / petroleum ether) to give trans di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate (39.0 g, 79.5 mmol) as yellow solid.1H NMR (400 MHz. CDCh) 5 ppm 7.46 - 7.33 (m, 1H). 7.17 - 7.04 (m, 1H), 5.34 (br d, J = 7.4 Hz, 1H). 5.15 - 4.97 (m, 1H), 4.10 - 3.86 (m. 1H), 3.83 - 3.53 (m, 1H), 3.24 - 3.08 (m, 1H), 3.07 - 2.82 (m, 1H). 1.55 - 1.37 (m, 18H), 1.37 - 1.32 (m, 3H).

[1191]

[0213] Step 6. trans 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine

[1192]

[0214] To a solution of trans di-tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate (3.20 g, 6.52 mmol) in MeOH (10 mL) was added HCl (20 mL, 4 M in MeOH). The reaction mixture was stirred at 30 °C for 1 hour. The mixture was filtered and concentrated to give trans 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine (1.89 g, 6.50 mmol) as white solid.

[1193]

[1194] NMR (400 MHz, CD3OD) 5 ppm 7.97 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 1.3 Hz, 1H), 4.78 (d, J = 10.8 Hz, 1H), 3.89 - 3.78 (m, 2H), 3.76 - 3.70 (m, 2H), 3.60 - 3.49 (m, 1H), 1.30 (d,.7= 6.6 Hz, 3H).

[1195]

[0215] Step 7. trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-l-carboxylate

[1196]

[0216] To a solution of trans 2-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine (1.89 g, 6.50 mmol) in DCM (20 mL) was added TEA (3.17 mL, 2.30 g. 22.8 mmol). The mixture was cooled to 0 °C and di-tert-butyl dicarbonate (1.63 g, 7.48 mmol) in DCM (10 mL) was added dropwise. The reaction mixture was slowly wanned to 25 °C and stirred for 12 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with brine (100 mL). 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 trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-1-carboxylate (1.00 g, 2.56 mmol) as white solid,!H NMR (400 MHz, CDCl3) 5 ppm 7.52 (d, J= 1.1 Hz, 1H), 7.40 (d, J = 1.1 Hz, 1H). 4.92 - 4.84 (m. 1H), 3.82 - 3.72 (m, 2H), 3.21 -3.07 (m, 1H). 2.73 - 2.64 (m, IH). 2.58 - 2.48 (m. 1H). 1.50 (s, 9H), 1.45 (d, J = 6.8 Hz, 3H).

[1197]

[0217] Step 8. Chiral separation of tert-butyl (2R,3S)-3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-1-carboxylate and tert-butyl (2S,3R)-3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-1-carboxylate

[1198]

[0218] Racemic trans tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperaz.ine- 1-carboxylate (13.0 g, 33.3 mmol) was separated by SFC (DAICEL CHIRALPAK IG (250 x 50 mm, 10 μm, 30% iPrOH / CO₂). The first eluting isomer was randomly designated as tert-butyl (2R,3S)-3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-l-carboxylate (5.80 g, 14.8 mmol) and was obtained as pale 65

[1199] QB\184200.00265\99930245.1 VVID 755PC yellow solid.1H NMR (400 MHz, CDCl3) 5 ppm 7.54 - 7.49 (m, 1H), 7.44 - 7.38 (m, 1H). 4.98 - 4.81 (m„ 1H), 3.83 - 3.71 (m. 2H). 3.20 - 3.08 (m, 1H). 2.80 - 2.66 (m. 1H), 2.62 - 2.45 (m. 1H), 1.51 - 1.48 (m, 9H), 1.47 - 1.45 (m. 3H). The second eluting isomer was randomly designated as tert-butyl (2S,3R)-3-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-1-carboxylate (5.60 g, 14.3 mmol) and was obtained as pale yellow solid.1H NMR (400 MHz, CDCl3) 5 ppm 7.51 (d, J = 1.1 Hz, 1H). 7.44 - 7.38 (m, 1H), 4.92 - 4.82 (m, 1H), 3.83 - 3.69 (m. 2H), 3.20 - 3.04 (m, 1H), 2.75 - 2.65 (m, 1H). 2.59 - 2.48 (m, 1H). 1.50 (s, 9H), 1.45 (d. J = 6.9 Hz, 3H)

[1200] General Procedure 3

[1201]

[0219] Synthesis of tert-butyl (2R,5R)-5-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-l-carboxylate

[1202] Br «^BF3K P<i(dppf)C;2, Na^COj acetone / H-0 Eton. 80 “V dioxane / HjO, 70 °C step 1 step 2 step 3 step 4

[1203] HCt'MeOH BOC2O. TEA

[1204] step 9 step 11

[1205]

[1206] DBU, MsCIM. SC °C step 10

[1207]

[0220] Step 1. 2-bromo-4-chIoro-6-vinylpyridine

[1208]

[0221] To a solution of 2,6-dibromo-4-chloropyridine (40.0 g, 147 mmol) in 1,4-dioxane (400 mL) and water (100 ml..) was added potassium vinyltrifluoroborate (5.92 g, 44.2 mmol), Na₂CO₃ (31.2 g, 295 mmol) and Pd(dppf)Cl2(10.7 g, 14.7 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for 12 hours under N2. The mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product as purified by column chromatography (S1O2, 0-5% EtOAc / petroleum ether) to give 2-bromo-4-chloro-6-vinylpyridine (8.00 g, 36.6 mmol) as white solid.1H NMR (400 MHz, CDCl3) 6 = 7.39 (d, J = 1.5 Hz, 1H), 7.27 - 7.25 (m, 1 H), 6.76 - 6.64 (m, 1H), 6.29 (d. J = 17.4 Hz, 1H). 5.60 (d, J = 10.8 Hz, 1H).

[1209] 66

[1210] QB\184200.00265\99930245.1 VVID 755PC

[0222] Step 2. l-(6-bromo-4-chloropyridin-2-yl)ethane-1 -diol

[1211]

[0223] To a solution of NMO (6.43 g, 54.9 mmol) in water (30 mL) was added K2OsO4·2H2O (241 mg. 0.732 mmol) and then 2-bromo-4-chloro-6-vinylpyridine (8.00 g, 36.6 mmol) in acetone (30 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours under N2. The mixture was quenched with saturated aqueous Na2SOs solution (80 mL) and extracted with EtOAc (80 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, 0-100% EtOAc / petroleum ether) to give l-(6-bromo-4-chloropyridin-2-yl)ethane-l,2-diol (5.80 g, 23.0 mmol) as white solid.1H NMR (400 MHz, CDCl3) 8 = 7.50 - 7.42 (m, 2H), 4.81 (t, J = 4.6 Hz. 1H), 4.03 - 3.92 (m, 1H), 3.87 - 3.77 (m, 1H).

[1212]

[0224] Step 3. 2-bromo-4-chloro-6-(oxiran-2-yl)pyridine

[1213]

[0225] To a solution of l-(6-bromo-4-chloropyridin-2-yl)ethane-1.2-diol (5.80 g, 23.0 mmol) in MeCN (50 mL) was added TEA (11.2 mL, 8.14 g, 80.4 mmol) and perfluorobutanesulfonyl fluoride (17.3 g, 57.4 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was quenched with saturated aqueous Na₂S₂O₃ solution (100 mL), stirred at 25 °C for 30 minutes and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 2-bromo-4-chloro-6-(oxiran-2-yl)pyridine (4.80 g, 20.5 mmol) as white solid.1H NMR (400 MHz, CDCl3) 8 = 7.46 (d. J= 1.5 Hz, 1H), 7.21 (d. J= 1.5 Hz, 1H).

[1214] 4.04 - 3.97 (m, 1H), 3.22 - 3.16 (m, 1H), 2.89 - 2.83 (m, 1H).

[1215]

[0226] Step 4. tert-butyl ((2R)-2-((2-(6-bromo-4-chloropyridm-2-yl)-2-hydroxyethyl)amino)propyl)-carbamate

[1216]

[0227] To a solution of 2-bromo-4-chloro-6-(oxiran-2-yl)pyridine (2.40 g, 10.2 mmol) in EtOH (30 mL) was added tert-butyl (R)-(2-aminopropyl)carbamate (2.14 g, 12.3 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 12 hours. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to give tert-butyl ((2R)-2-((2-(6-bromo-4-chIoropyridin-2-yl)-2-hydroxyethyr)amino)-propyl)-carbamate (3.10 g.

[1217] 7.58 mmol) as yellow oil. ’H NMR (400 MHz. CDCL) 8 - 7.58 - 7.49 (m. 1H), 7.41 (s, 1H). 4.88 - 4.76 (m, 1H). 4.74 - 4.65 (m. 1H). 3.25 - 2.68 (m, 6H), 1.45 (d, J = 4.1 Hz. 9H), 1.09 - 1.05 (m. 3H).

[1218]

[0228] Step 5. tert-butyl (2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxyethyl)((R)-l-((tert-butoxy-carbonyl)amino)propan-2-yl)carbamate

[1219]

[0229] To a solution of tert-butyl ((2R)-2-((2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxyethyl)amino)-propyl)carbamate (3.10 g, 7.58 mmol) in THF (30 mL) and water (20 mL) was added di-tert-butyl dicarbonate (1.99 g, 9.10 mmol) and K2CO3(1.36 g. 9.86 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 18 hours under N2The mixture was diluted with water (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (120 mL), dried over Na2SO4,

[1220] 67

[1221] QB\184200.00265\99930245.1 VVID 755PC filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography ( SiO 2, 0-60% EtOAc / petroleum ether) to give tert-butyl (2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxyethyl)((R)-1-((tert-butoxycarbonyl)amino)propan-2-yl)carbamate (3.40 g, 6.68 mmol) as white oil. NMR (400 MHz, CDCl3) 5 = 7.62 (br s, 1H), 7.41 (s, 1H). 5.53 - 5.46 (m. 1H), 5.46 - 5.34 (m, 1H). 5.12 - 4.83 (m, 2H), 4.12 - 3.99 (m, 1H), 3.63 - 3.05 (m, 5H). 1.51 - 1.40 (m. 18H). 1.18 - 1.04 (m, 3H).

[1222]

[0230] Step 6. tert-butyl (R)-(2-(6-bromo-4-chloropyridin-2-yl)-2-oxoethyl)(l-((tert-butoxy- carbonyl)amino)propan-2-yl)carbamate

[1223]

[0231] To a solution of tert-butyl (2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxyethyl)((R)-1-((tert-butoxycarbonyl)amino)propan-2-yl)carbamate in DCM (40 mL) was added PCC (2.16 g, 100 mmol) and Celatom (500 mg) at 0 °C. The reaction mixture was stirred at 30 °C for 16 hours under N2. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-50% EtOAc / petroleum ether) to give tert-butyl (R)-(2-(6-bromo-4-chloropyridin-2-yl)-2-oxoethyl)(1-((tert-butoxy-carbonyl)amino)propan-2-yl)carbamate (2.65 g, 5.23 mmol) as white oil. ‘H NMR (400 MHz, CDCI3) 8 = 8.05 - 7.98 (m, 1H), 7.78 - 7.68 (m. 1H), 5.83 - 5.35 (m, 1H), 5.12 - 4.81 (m, 1H), 4.53 - 4.28 (m, 2H), 3.52 - 3.24 (m, 1H), 3.00 - 2.53 (m, 1H), 1.50 - 1.39 (m, 18H), 1.17 - 1.11 (m, 3H).

[1224]

[0232] Step 7. (R)-5-(6-bromo-4-chloropyridin-2-yl)-2-methyl-l,2,3,6-teti abydropyrazine

[0233] To a solution of tert-butyl (R)-(2-(6-bromo-4-chloropyridin-2-yl)-2-oxoethyl)(1-((tert-butoxy-carbonyl)amino)propan-2-yl)carbamate (2.90 g, 5.72 mmol) in DCM (30 mL) was added TFA(15 mL) at 20 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated to give crude (R)-5-(6-bromo-4-chloropyridin-2-yl)-2-methyl-1,2,3,6-tetrahydro-pyrazine (1.60 g, 5.54 mmol) as yellow oil.

[1225]

[1226] NMR (400 MHz, CD3OD) 5 - 7.55 (d, J = 1.3 Hz, 1H), 7.30 (d, J = 1.3 Hz, 1H), 4.91 (br s. 2H), 3.74 - 3.65 (m, 1H), 3.57 - 3.51 (m, 1H), 3.08 - 3.01 (m, 1H), 1.33 (d, J = 6.6 Hz, 3H). The crude product was used in the next step without further purification.

[1227]

[0234] Step 8. (5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine

[1228]

[0235] To a solution of (R)-5-(6-bromo-4-chloropyridin-2-yl)-2-methyl-1,2,3,6-tetrahydropyrazine (1.60 g, 5.54 mmol) in AcOH (20 mL) was added Zn (2.28 g. 6.29 mmol, granular) at 10 °C The reaction mixture was stirred at 10 °C for 1 hour under

[1229]

[1230] The mixture was filtered and concentrated under reduced pressure to give crude (5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine (1.60 g, 5.51 mmol) as ellow solid. Hl NMR (400 MHz, CD3OD) 5 - 7.81 - 7.70 (m, 2H). 4.27 (t, J = 4.9 Hz, 1H), 3.79 - 3.72 (m. 1H), 3.48 -3.37 (m, 2H), 3.17 - 3.09 (m, 1H), 2.90 - 2.81 (m, 1H), 1.33 (d, J= 6.7Hz, 3H). The crude product was used in the next step without further purification.

[1231] 68

[1232] QBM84200.00265'99930245.1 VVID 755PC

[0236] Step 9. Mixture of di-tert-butyl (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-1,4-dicarboxylate and di-tert-butyl (2S,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-1,4-dicarboxylate

[1233]

[0237] To the solution of (5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine (1.60 g, 5.51 mmol) in DCM (20 mL) was added triethylamine (1.67 g, 2.30 mL, 16.5 mmol) and di-tert-butyl dicarbonate (3.61 g, 16.5 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 DCM (30 mL x 3). The combined organic layers were washed with brine (100 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 a mixture of trans di-fert-butyl (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarboxylate and cis di-t<?rt-butyl 2S,5R)-2-(6-bromo-4-chloropyridin-2-yl)- 5-methylpiperazine-l,4-dicarboxylate (1.10 g, 2.24 mmol, trans:cis -1:10) as white solid.

[1234]

[1235] 1H NMR (400 MHz, CDCl3) 5 = 7.45 - 7.38 (m, 1H). 7.19 (br s, 1H), 5.02 - 4.81 (m, 1H), 4.35 - 4.21 (m, 1H), 4.12 - 4.02 (m. 1H), 3.70 - 3.38 (m, 1H), 3.36 - 3.00 (m, 2H), 1.54 - 1.46 (m, 9H), 1.34 (br s, 9H), 1.23 - 1.13 (m, 3H).

[1236]

[0238] Step 10. di-tert-butyl (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4- dicarboxylate and di-tert-butyl (2S,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarboxylate

[1237]

[0239] To a mixture of trans di-ft’rt-butyl (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-1,4-dicarboxylate and cis di-tert-butyl (2S.5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarboxylate (1.34 g. 2.73 mmol) in MeCN (15 mL) was added DBLT (623 mg, 4.10 mmol) at 0 °C. The reaction mixture was stirred at 90 °C for 12 hours under N2. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (100 mL). dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-40% EtOAc / petroleum ether) to give di-tert-butyl (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-1,4-dicarboxylate (790 mg, 1.61 mmol) as white solid.1H NMR (400 MHz, CDCl3) 8 = 7.41 (br d. J= 5.5 Hz, lH), 7.21 - 7.11 (m, 1H). 5.29 - 4.92 (m, 1H), 4.81 - 4.38 (m. 1H), 4.34 - 4.20 (m. 1H). 3.73 - 3.60 (m, 1H). 3.56 - 3.36 (m, 2H). 1.46 - 1.25 (m, 18H), 1.22 (brd. J= 5.9 Hz. 3H). And di-tert-butyl (2S.5R)-2-(6-bromo-4- chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarboxylate (520 mg. 1.06 mmol) as white solid.1H NMR (400 MHz, CDCl3) 5 - 7.46 - 7.36 (m. 1H), 7.22 - 7.13 (m. 1H). 5.05 - 4.78 (m, 1H). 4.39 - 3.97 (m, 3H), 3.67 - 3.02 (m. 2H), 1.52 - 1.31 (m, 18H), 1.15 (d, J = 6.0 Hz, 3H)

[1238]

[0240] Step 11. (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine

[1239]

[0241] To a solution of di-tert-butyl (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-1,4-dicarboxylate (500 mg. 1.02 mmol) in MeOH (1 mL) was added HC1 (5 mL, 4N in MeOH). The reaction mixture was stirred at 30 °C for 30 minutes. The mixture was concentrated under reduced 69

[1240] QB\184200.00265\99930245.1 VVID 755PC pressure to give (2R.5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine (290 mg, 0.998 mmol) as white solid.1H NMR (400 MHz, D2O) 5 = 7.77 (br d, J = 5.3 Hz, 1 H), 7.61 (s. 1H). 4.82 (br s. 1H), 3.91 - 3.83 (m. 1H), 3.77 - 3.61 (m. 2H), 3.51 - 3.38 (m, 1H), 3.34 - 3.22 (m. 1H), 1.42 (br d, J - 6.0 Hz. 3H).

[1241]

[0242] Step 12. tert-butyl (2R,5R)-5-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-1-carboxylate

[1242]

[0243] To the solution of (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine (290 mg, 0.998 mmol) in DCM (10 mL) was added triethylamine (303 mg, 0.416 mL. 2.99 mmol) and di-tert-butyl dicarbonate (240 mg. 1.10 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was 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 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 (2R,5R)-5-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-1 -carboxylate (120 mg, 0.307 mmol) as yellow oil.1H NMR (400 MHz, CDCb) 5 = 7.55 (s, 1H), 7.42 (d, J - 1.1 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.21 - 4.13 (m. 1H), 4.11 - 4.06 (m, 1H), 3.60 - 3.51(m, 1H), 2.85 - 2.79 (m, 1H), 2.63 - 2.54 (m. 1H). 1.46 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H). And di- tert-butyl (2R,5R)-2-(6-bromo-4-chloropyridin-2-yl)-5-methy lpiperazine-1,4-dicarboxylate (220 mg, 0.448 mmol) as ellow oil.XH NMR (400 MHz, CDCl3) 5 = 7.49 - 7.34 (m. 1H), 7.14 (br s, 1H), 5.28 -4.94 (m, 1H), 4.77 - 4.46 (m, 1H), 4.33 - 4.17 (m, 1H). 3.75 - 3.20 (m, 3H), 1.54 - 1.40 (m, 9H), 1.39 -1.26 (m, 9H), 1.22 (br d, J - 6.0 Hz, 3H).

[1243] General Procedure 4

[1244]

[0244] Synthesis of tert-butyl (2S,5S)-5-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-1-carboxylate

[1245] 70

[1246] QB\184200.00265\99930245.1 VVID 755PC

[1247] NaOH MeOH, 20 " C step 1 step 2 step 3

[1248] BocjC, KzCOa TFA / DCM Zn / AcOH THF,'H2O st step 8 step 5 step 6 ep 7

[1249] BOC2O,! EA TEA

[1250] step 9

[1251]

[1252] step 10

[1253]

[0245] Step 1 1-(6-bromo-4-chloropyridin-2-yl)-2-chIoroethan-l-one

[1254]

[0246] To a solution of 2,6-dibromo-4-chloropyridme (20.0 g, 73.7 mmol) in THF (200 mL) was added iPrMgC LiCl (560 L, 72.8 mmol, 1.3 M in THF) at 0CC under N?. After stirring for 30 minutes at 0 °C, 2-chloro-N-methoxy-N-methylacetamide (11.2 g, 81.1 mmol) in THF (50 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 2 hours. The mixture was quenched with saturate aqueous NH4C1 (200 mL) and extracted with EtOAc (200 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 (SiOz, 5% F.tOAc / petroleum ether) to give 1- (6-bromo-4-chloropyridin-2-yl)-2-chloroethan-l-one (6.00 g. 22.3 mmol) as yellow solid. ‘H NMR (400 MHz, CDCl3) 8 ~ 8.04 (d, J - 1.6 Hz, 1H), 7.75 id.. / 1.8 Hz, 1H). 5.04 (s. 2H).

[1255]

[0247] Step 2. l-(6-bromo-4-chloropyridin-2-yl)-2-chloroethan-l-ol

[1256]

[0248] To a solution of l-(6-bromo-4-chloropyridin-2-yl)-2-chloroethan-l-one (6.00 g, 22,3 mmol) in MeOH (40 mL) was added NaBH4(710 mg, 18.8 mmol) at -40 °C. The reaction mixture was stirred at - 40 °C for 1 hour under ]SL. The mixture was quenched by the addition of HC1 ( 15 mL, 1 M in MeOH) to adjust the pH to ~6 and concentrated to give l-(6-bromo-4-chloropyridin-2-yl)-2-chloroelhan-l-ol (6.00 g. 22.1 mmol) as white solid.

[1257]

[1258] NMR(400 MHz, CDCh) 8 = 7.53 - 7.45 (m, 2H), 4.98 - 4.90 (m, 1H), 3.99 - 392 (m, 1H), 3.87 - 3.79 (m, 1H), 3.29 (br d, J= 5.4 Hz. 1H).

[1259]

[0249] Step 3. 2-bromo-4-ch]oro-6-(oxiran-2-yl)pyridine

[1260]

[0250] To a solution l-(6-bromo-4-chloropyridin-2-yl)-2-chloroethan-l-ol (6.00 g, 22.1 mmol) in MeOH (8 L) was added NaOH (974 mg, 24.4 mmol) in water (8 mL) at 0 °C. The reaction mixture was 71

[1261] QBM84200.00265'99930245.1 VVID 755PC stirred at 25CC for 12 hours under N2. The mixture was quenched with IN HC1 (2 mL) and extracted with DCM (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 (Sit) 0-40% EtOAc / petroleum ether) to give 2-bromo-4-chloro-6-(oxiran-2-yl)pyridine (4.50 g, 19.2 mmol) as white solid.

[1262]

[1263] NMR (400 MHz, CDCl3) 5 - 7.46 (d, J - 1.6 Hz, IH). 7.20 (d. J - 1.6 Hz, IH), 4.03 - 3.97 (m. 1H), 3.22 - 3 16 (m. 1 H), 2.88 - 2.83 (tn, IH).

[1264]

[0251] Step 4. tert-butyl ((2S)-2-((2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxyethyl)amino)propyl)-carbamate

[1265]

[0252] To a solution of 2-bromo-4-chloro-6-(oxiran-2-yl)pyridine (10.5 g, 44.8 mmol) in EtOH (110 L) was added tert-butyl (S)-(2-aminopropyl)carbamate (9.36 g, 53.7 mmol) at 20 °C The reaction mixture was stirred at 80 °C for 30 hours. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to give tert-butyl ((2S)-2-((2-(6-broino-4-clrioropyridin-2-yl)-2-hydroxyethyl)amino)-propyl)-carbamate (13.8 g, 33.8 mmol) as yellow oil. *H NMR (400 MHz, CDC'h) 8 - 7.44 (d., / - 2.9 Hz, IH), 7.32 (d, J - 2.6 Hz, IH), 4.97 - 4.78 (m, IH), 4.61 (td, J= 3.1, 8.3 Hz, IH), 3.23 - 3.10 (ro, IH). 3.07 - 2.94 (m, 2H), 2.87 - 2.57 (m, 2H), 1.44 (d, J- 4.2 Hz. 9H), 1.06 (dd, J-3.5, 6.5 Hz, 3H).

[1266]

[0253] Step 5. tert-butyl (2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxyethyl)((S)-l-((tert-butoxy-carbonyl)ammo)propan-2-yl)carbamate

[1267]

[0254] To a solution of tert-butyl ((2S)-2-((2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxvethyl)-amino)propvl)-carbamate (3.10 g, 7.58 mmol) in THF (30 L) and water (20 mL) was added di-tert-butyl decarbonate (2.15 g, 9.86 mmol) and K.. CO; (1.36 g, 9.86 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 18 hours under N2. The mixture rvas diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (220 mL), 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 tert-butyl (2-(6-bromo-4-chloropyridin-2-yl)-2 -hydroxy ethyl)((S)-l-((tert-butoxy-carbonyl)amino)propan-2-yl)carbamate (3,60 g, 7.07 mmol) as yellow oil. 11 NMR (400 MHz, CDCl3) 5 - 7.62 (br s. IH), 7.42 (s. IH), 5.59 - 5.33 (m. IH), 5.12 - 4.79 (m, 2H), 4.11 - 4,00 (m, IH), 3.68 - 3.00 (tn. 5H), 1.52 - 1 42 (m, 18H), 1.20 - 1.03 (m, 3H).

[1268]

[0255] Step 6. tert-butyl (S)-(2-(6-bromo-4-chloropyridin-2-yl)-2-oxoethyl)(l-((tert-butoxy-carbonyl)amino)propan-2-yl)carbamate

[1269]

[0256] To a solution of tert-butyl (2-(6-bromo-4-chloropyridin-2-yl)-2-hydroxyethyl)((S)-l-((tert-butoxy -carhouy l)amino)propan-2-yl)carbaniate (360 g, 7.07 mmol) in DCM (40 mL) w-as added PCC (2.29 g, 10.6 mmol) and Celatom (500 mg) at 0 °C. The reaction mixture was stirred at 30 °C for 16 hours under N2. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-50% EtOAc / petroleum ether) to give tert-butyl (S)-(2- 72

[1270] QBM84200.00265199930245.1 VVID 755PC (6-bromo-4-chloropyndin-2-yl)-2-oxoethyl)(l-((tert-butoxy-carbonyl)-amino)propan-2-yl)carbamate (2.75 g. 5.43 mmol) as white oil.lH NMR (400 MHz. CDCh) 8 = 8.04 - 7.95 (m. 1H), 7.78 - 7.68 (m, 1H). 5.83 - 5.33 (m, 1H), 5.09 - 4.80 (m. 1H). 4.70 - 4.28 (m, 2H). 3.51 - 3.25 (m, 1H). 2.94 - 2.55 (m.

[1271] 1H). 1.52 - 1.31 (HI. 18H), 1.18 - 1.09 (m. 3H).

[1272]

[0257] Step 7. (S)-5-(6-bromo-4-chloropyridin-2-yl)-2-methyl-l,2,3,6-tetrahydropyrazine

[0258] To a solution of / ert-butyl (S)-(2-(6-bromo-4-chloropyridin-2-yl)-2-oxoethyl)(l -((tert-butoxy-carbonyI)amino)propan-2-yl)carbamate (2.10 g, 4.14 mmol) in DCM (20 mL) was added TFA ( 10 mL) at 20 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was concentrated to give crude (S)-5-(6-bromo-4-chloropyridin-2-yl)-2-methyl-l,2,3,6-tetrahydro-pyrazine (1.10 g. 3.81 mmol) as yellow solid.

[1273]

[1274] NMR (400 MHz. CD3OD) 8 = 7.55 (d, J = 1.0 Hz, 1H), 7.30 (d. J = 1.0 Hz, 1H), 4.93 - 4.86 (m, 2H), 3.77 - 3.64 (m, 1H), 3.61 - 3.50 (m. 1H), 3.10 - 2.98 (m, 1H), 1.33 (d, J = 6.6 Hz, 3H).

[1275]

[0259] Step 8. (5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine

[1276]

[0260] To a solution of (S)-5-(6-bromo-4-chloropyridin-2-yl)-2-tnethyl-l,2,3,6-tetrabydropyrazine (1.10 g, 3.81 mmol) in AcOH (3 mL) was added Zn (1.34 g, 20.5 mmol, granular) at 10 °C. The reaction mixture was stirred at 10 °C for 1 hour under No. The mixture was filtered and concentrated under reduced pressure to give crude (5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine (1.10 g, 3.79 mmol) as yellow solid. The crude product was used in the next step without further purification.

[1277]

[0261] Step 9. Mixture of di-tert-buty! (2S,5S)-2-(6-bromo-4-chIoropyridin-2-yI)-5- methylpiperazine-1,4-dicarboxylate and di-tert- butyl (2R,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine- 1,4-dicar boxylate

[1278]

[0262] To the solution of (5S)-2-(6-bromo-4-chloropyridin-2-yI)-5-methyIpiperazine (1.10 g, 3.79 mmol) in DCM (20 mL) was added triethylamine (1.15 g, 11.4 mmol) and di-terLbutyl dicarbonate (2.48 g, 11.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under Nz. The mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers ere washed with brine (100 mL), dried over NazSO-i, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOz. 0-100% EtOAc / petroleum ether) to give a mixture of trans di-terZ-butyl (2S,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarboxylate and cis di-tert-butyl (2R,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-1,4-dicarboxylate (1.50 g, 3.06 mmol) as yellow' solid. Hl NMR (400 MHz, CDCl3) 8 - 7.42 (d, J=== 1.0 Hz, 1H). 7.24 - 7.12 (m, 1H), 5.06 - 4.77 (m, 1H), 4.58 - 3.84 (m, 3H), 3.78 - 3.02 (m, 2H), 1.56 - 1.24 (m. 17H), 1.24 - 1.13 (m. 3H).

[1279] 73

[1280] QBM84200.00265'99930245.1 VVID 755PC

[0263] Step 10. di-tert-butyl (2S,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarboxylate and di-tert-butyl (2R,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpipcrazine-l,4-dicarboxylate

[1281]

[0264] To a mixture of trans di-tert-butyl (2S.5S)-2-(6-bromo-4-chloropyridin-2-y1)-5-methylpiperazine-l,4-dicarboxylate and cis di-tert-butyl (2R,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarbox late (1.50 g, 3.06 mmol) in MeCN (15 mL) was added DBU (465 mg, 3.06 mmol) at 0 °C. The reaction mixture was stirred at 90 °C for 12 hours under N2. The mixture was 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 Na2SO.i, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-40% EtOAc / petroleum ether) to give di¬ tert-butyl (2S,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-l,4-dicarboxylate (470 mg, 0.958 mmol) as yellow oil. *H NMR (400 MHz, CDCl3) 3 = 7.46 - 7.35 (m, IH), 7.23 - 7.10 (m, IH), 5.28 - 4.92 (m, IH), 4.81 - 4.47 (m, IH), 4.33 - 4.05 (m, 1H). 3.73 - 3.22 (m, 3H), 1.56 - 1 27 (m. 18H), 1.22 (br s, 3H). And di-tert-butyl (2R,5S)-2-(6-bromo-4-chloropyridm-2-yl)-5-methylpiperazine-l,4-dicarboxylate (890 mg, 1.81 mmol) as yellow solid.JH NMR (400 MHz, CDCl3) 6 = 7.45 - 7.37 (m, IH), 7.24 - 7.11 (m, IH), 5.28 - 4.82 (m, IH), 4.80 - 4.00 (m, 3H). 3.74 - 3.38 (tn, 1H), 3.32 - 3.03 (m, IH), 1.60 - 1.26 (m, 18H), 1.25 - 1.12 (m, 3H).

[1282]

[0265] Step 11. (2S,5S)-2-(6-bronw-4-chloropyridin-2-yl)-5-niethylpiperazine

[1283]

[0266] To a solution of di-tert-butyl (2S,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine-1.4-dicarboxylate (940 mg. 1.92 mmol) in MeOH (2 mL) was added HO (10 mL, 4N in MeOH) 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 (2S.5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine (556 mg, 1.91 mmol) as yellow solid. Ti NMR (400 MHz, CD3OD) 5 = 7.94 (s, IH), 7.88 - 7.82 (m, IH), 5.07 - 4.99 (m. IH), 4.12 - 4.02 (m, IH). 3.83 - 3.69 (m. 2H), 3.56 - 3.43 (m.2H), 1.51 (d, J - 6.4 Hz, 3H).

[1284]

[0267] Step 12. tert-butyl (2S,5S)-5-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-l-carboxylate

[1285]

[0268] To a solution of (2S,5S)-2-(6-bromo-4-chloropyridin-2-yl)-5-methylpiperazine (329 mg, 1.13 mmol) in DCM (10 mL) was added triethylamine (344 mg, 3.40 mmol) and di-tert-butyl dicarbonate (272 mg, 1.25 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed w4th 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 tert-butyl (2S,5S)-5-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine-l-carboxylate (180 mg, 0.461 mmol) as white solid.XII NMR (400 MHz, CDCl3) 5 - 7.55 (s, IH), 7.40 (d, J - 1.4 Hz, IH), 4.43 - 4.34 (m, IH), 4.19 - 4.10 (m, IH), 4.02 (br d. 2.1 Hz, IH). 3.57 - 3.47 (m, IH), 2.80 - 2.72 (m. IH), 2.60 - 2.50 (m. 2H), 1.46 (s, 9H), 1.30 (d, J = 6.8 Hz, 3H).

[1286] 74

[1287] QBM84200.00265'99930245.1 VVID 755PC

[1288] Genera! Procedure 5

[1289]

[0269] Synthesis of trans tert-butyl 2-(6-bromo-4-chloropyridin-2-yl)-3-methylmorpholine-4- carboxylate

[1290] DIPEA DTBAD, PPh-s MeOH 25 -C C step 4 step 5

[1291]

[1292] trans-racemate

[0270] l-(6-bromo-4-chloropyridin-2-yl)-2-chloropropan- 1-one was obtained from General Procedure 2. step 1.

[1293]

[0271] Step 1. l-(6-bromo-4-chloropyridin-2-yl)-2-chloropropan-l-ol

[1294]

[0272] To a solution of l-(6-bromo-4-chloropyridin-2-yl)-2-chloropropan-l-one (33.0 g. 117 mmol) in MeOH (330 mL) was added NaBH.i (7.10 g. 188 mmol) at -40 °C. The mixture was stirred at -40 °C for 1 hour under N2. This reaction procedure was repeated with 2.00 g (7.07 mmol) l-(6-bromo-4- chloropyridin-2-yl)-2-chloropropan-l-one and 0.430 g (11.4 mmol) NaBIL. The combined reaction mixtures were quenched by the addition of aqueous NH^Cl solution (600 mL) at 0 °C, diluted with water (300 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (600 mL), dried over Na:: SOi, filtered and concentrated under reduced pressure to give crude l-(6- bromo-4-chloropyridin-2-yl)-2-chloropropan-l-ol (32.8 g) which was used in the next step without further purification.XH NMR (400 MHz, CDCl3) 5 ppm 7.52 - 742 (m. 2H). 4.78 (s, 1H), 4.67 - 4.49 (m, 1H), 3.32 (s. 1H), 1.61 (brd, J = 6.8 Hz, 3H).

[1295]

[0273] Step 2. cis 2-bromo-4-chloro-6-(3-methyloxiran-2-yl)pyridine

[1296]

[0274] To a solution of l-(6-bromo-4-chloropyridin-2-yl)-2-chloropropan-l-ol (32.8 g, 115 mmol) in MeOH (328 mL) was added NaOH (5.06 g, 127 mmol) in water (328 mL) at 0 °C. The reaction mixture was stirred for 16 hours at 25 °C under N The mixture was poured into aqueous HC1 (150 mL, 1 N) and extracted with EtOAc (350 mL x 3). The combined organic layers were washed with brine (250 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford cis 2-bromo-4-chloro-6-(3- methyloxiran-2-yl)pyridine (28.3 g. 114 mmol) as yellow oil. ’H NMR (400 MHz, CDCl3) 5 ppm 7.46 ( d. 1.6 Hz. 1H), 7.27 (s, 1H), 4.12 (d, J = 4.3 Hz. 1H), 3.51 - 3.36 (m, 1H), 1.15 (d, J- 5.5 Hz, 3H).

[1297] 75

[1298] QBM84200.00265'99930245.1 VVID 755PC

[0275] Step 3. l-(6-bromo-4-chloropyridin-2-yl)-2-((2-hydroxyethyl)amino)propan-l-oI

[0276] To a solution of cis 2-bromo-4-chloro-6-(3-methyloxiran-2-yl)pyridine (28.3 g, 114 mmol) in n-BuOH (283 mL) was added 2-aminoethan-l-ol (12.4 mL, 12.5 g. 205 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 12 hours under N2. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL. EtOAc) to give l-(6-bromo- 4-chloropyridin-2-yl)-2-((2-bydroxyethyl)amino)-propan-l-ol (16.5 g. 533 mmol) as yellow oil.

[1299]

[1300] NMR (400 MHz, CDCl3) 8 ppm 7.49 - 7.45 (m, 1H), 7.43 - 7.39 (m, 1H), 4.40 (d, J = 6.4 Hz, 1 H), 3.66 -3.59 (m. 2H), 3.27 (br s, 3H), 3.02 - 2.94 (m, 1H), 2.83 - 2.75 (m. 1H), 2.58 - 2.50 (m, 1H), 1.11 - 1.04 (m, 3H).

[1301]

[0277] Step 4 tert-butyl (l-(6-bromo-4-chloropyridin-2-yl)-1 -hydroxypropan-2-yl)(2-hydroxy-ethyl)carbamate

[1302]

[0278] To a solution of l-(6-broino-4-chloropyridin-2-yl)-2-((2-hydroxyethyl)amino)-propan-l-o1 (16.5 g, 53.3 mmol) in MeOH (165 mL) was added DIPEA (4.64 mL, 3.44 g, 26.6 mmol) and di-tert-butyl dicarbonatc (23.3 g, 107 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by column chromato raphy (SiO-. 25-50% EtOAc / petroleum ether) to give tert-butyl (l-(6-bromo-4-chloropyridin-2-yl)-l-hydroxypropaii-2-yl)(2-hydroxy-ethyl)carbamate (17.4 g, 42.5 mmol) as light yellow oil.!H NMR (400 MHz, CDCl3) (5 ppm 7.54 (br s, 1H). 7.41 (br s, 1H), 6.08 (s, 1H), 4.70 (s, 1H). 4.25 - 4.15 (m, 1H), 3.83 - 3.51 (m, 2H), 3.50 - 2.94 (m, 3H), 1.46 - 1.38 (m.3H). 1.36 (s, 9H).

[1303]

[0279] Step 5. trans tert-butyl 2-(6-bromo-4-chloropyridm-2-yl)-3-methylmorpholine-4- carboxylate

[1304]

[0280] To a solution of tert-butyl (l-(6-bromo-4-chloropyridin-2-yl)-l-hydroxypropan-2-yl)(2-hydroxy -ethylcarbamate (17.4 g. 42.5 mmol) in toluene (175 mL) was added PPh3(16.7 g. 63.7 mmol) and di-tert-butyl azodicarboxylate (14.7 g, 63.7 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was diluted wdth water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed wdth brine (200 ml., x 2). dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product 'as purified by column chromatography (SiO₂,

[1305] 20-30% EtOAc / petroleum ether) to afford trans tert-butyl 2-(6-bromo-4-cbloropyridin-2-yl)-3- methylmorpholine-4-carboxylate (12.6 g, 32.2 mmol) as a white solid. ^-I NMR (400 MHz, CDCl3) 8 ppm 7.52 - 7.49 (m, 1H), 7.44 - 7.40 (m. 1H), 5.18 - 5.08 (m, 1H), 4.59 - 4.50 (m. 1H). 3.75 - 3.66 (m, 2H). 3.64 - 3.54 (m, 1H), 3 28 - 3.17 (m, 1H), 1.48 (s, 9H), 1.42 (d..7= 6.8 Hz, 3H).

[1306] General Procedure 6

[1307]

[0281] Synthesis of trans tert-butyl 3-(3-bromo-5-chloro-2-fluorophenyl)-2-methylpiperazine-l-carboxylate

[1308] 76

[1309] QB\184200.00265\99930245.1 VVID 755PC

[1310] 3FC separation

[1311] step 8

[1312]

[1313] absolute stereochemistry randomly assigned

[1314]

[0282] Step 1. l-(3-bromo-5-chloro-2-fluorophenyl)-2-chloropropan-l-one

[1315]

[0283] To a solution of 2-bromo-4-chloro-l -fluorobenzene (8.50 g, 40.6 mmol) in THF (80 mL) was added LDA (24.4 mL, 48.7 mmol, 2 M) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 1 hour under N2. Then, a solution of 2-chloro-N-methoxy-N-methylpropanamide (8.00 g. 52.8 mmol) in THF (80 mL) was added dropwise to the mixture at -78 °C. The mixture was stirred at -78 °C for 1 hour under N2The reaction mixture was poured into saturated NHJCI (50 ml..) at 0 °C, diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL). dried over NazSO i. filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO-. 0-10% EtOAc / petroleum ether) to give l-(3-bromo-5-chloro-2-fluorophenyl)-2-chloropropan-l-one (6.00 g, 20.0 mmol) as colorless oil.1H NMR (400 MHz. CDCI3) 8 ppm 7.80 - 7.72 (m. 2H), 5.13 (q, J = 6.8 Hz. I H), 1.74 (dd. J = 08. 6.8 Hz. 3H).

[1316]

[0284] Step 2 5-(3-bromo-5-chloro-2-fluorophenyl)-6-methyl-l,2,3,6-tetrahydropyrazine

[0285] To a mixture of l-(3-bromo-5-chloro-2-fluorophenyl)-2-chloropropan-l-one (6.00 g, 20.0 mmol) and 4A molecular sieves (6.00 g) in MeOH (90 mL) was added ethane- 1.2-diamine (3.61 g, 60.0 mmol) at 0 °C. The mixture was stirred at 65 °C for 1 hour. The reaction mixture was filtered and washed with MeOH (10 mL). The filtrate was used into the next step without further workup.

[1317]

[0286] Step 3. trans 2-(3-bromo-5-chloro-2-fliiorophenyl)-3-methylpiperazme and cis 2-(3-bromo- 5-chloro-2-fluorophenyl)-3-methylpiperazine

[1318]

[0287] To a solution of 5-(3-bromo-5-chloro-2-fluorophenyl)-6-methyl-l,2,3,6-tetrahydropyrazine (5.50 g, 18.0 mmol) in MeOH (100 mL) was added NaBH.i (3.40 g. 90.0 mmol) in portions at 0 °C under N2. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with HCl / MeOH (1

[1319] 77

[1320] QB\184200.00265\99930245.1 VVID 755PC N. 5 nil), filtered, and washed with MeOH (5 mL x 3). The filler cake was collected to give the crude mixture of trans 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine and cis 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine (12.0 g) as HC1 sail as white solid. The crude product was used into the next step without further purification,

[1321]

[0288] Step 4. trans di-tert-butyl 2-(3-bromo-5-chloro-2-fluoropbenyl)-3-methylpiperazine-l,4-dicarboxylate and cis di-tert-buty! 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine-l,4-dicarboxylate

[1322]

[0289] To a mixture of trans 2-(3-bromo-5-chloro-2-fluoropbenyl)-3-metbylpiperazine and cis 2-(3- bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine (12.0 g) as HC1 salt in THF (18 mL) and water (90 mL) was added di-terf-butyl dicarbonate (17.0 g, 78.0 mmol) and NaHCOj (6.56 g, 78.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted w ith water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NazSO i. filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCL, 0-10% EtOAc / petroleum ether) to give trans di-tert-butyl 2-(3-bromo-5-chloro-2-fhiorophenyl)-3-mcthylpiperazine-1,4-dicarboxylate (2.75 g, 5.42 mmol) as colorless oil. ’H NMR (400 MHz, CDCl3) 8 ppm 7.49 (s, 1H), 7.39 - 7.28 (in, 1H), 5.47 - 5.13 (m, 1H), 4.82 - 4.59 (m, 1H), 4.09 - 3.68 (m, 2H). 3.24 - 2.72 (m, 2H), 1.56 - 1.29 (m, 21H); and cis di-tert-butyl 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine-l,4-dicarboxylate (0.320 g, 0.630 mmol) as yellow' oil.SH NMR (400 MHz, CDCl3) 6 ppm 7.47 (dd. J - 2.4, 5.6 Hz, 1H), 7.14 (dd, J- 2.4. 5.6 Hz. 1H), 5.32 (d. J = 6.4 Hz, 1H). 4.64 - 4.55 (m, 1H), 4.39 - 4.32 (tn. 1H), 3.64 - 3.57 (m, 1H), 3.55 - 3.46 (m, 2H). 1.49 (s, 9H), 1.26 (s, 9H), 1.05 (d, J- 7.2 Hz. 3H).

[1323]

[0290] Step 5. trans 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine

[1324]

[0291] A mixture of trans di-tert-butyl 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine-l,4-dicarboxylate (2.75 g, 5.42 mmol) in HCl / MeOH (2 M, 30 mL) was stirred at 25 °C for 1 hour under N2. The reaction mixture was concentrated to give crude trans 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine (1.66 g. 5.40 mmol) as HCJ salt as yellow solid. The crude product w'as used into the next step without further purification. Hl NMR (400 MHz. D-O) 8 ppm 7.88 (dd. J = 2.8, 6.0 Hz, 1H), 758 (dd, J= 2.4. 5.2 Hz. 1H), 4.08 - 3.98 (m. 1H). 3.86 - 3.76 (m, 2H), 3.65 - 3.53 (m. 2H), 3.37 - 330 (m, HI). 1.21 (d. J- 6.4 Hz, 3H).

[1325]

[0292] Step 6. trans tert-butyl 3-(3-bromo-5-chloro-2-fluorophenyl)-2-methylpiperazine-l-carboxylate

[1326]

[0293] To a solution of crude trans 2-(3-bromo-5-chloro-2-fluorophenyl)-3-methylpiperazine as HCl salt (1.66 g, 5.40 mmol) in DCM (30 mL) was added TEA (1.64 g, 16.2 mmol) and di-tert-butyl dicarbonate (1.30 g, 5.94 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted w’ith water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic 78

[1327] QB\184200.00265\99930245.1 VVID 755PC layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-50% EtOAc / petroleum ether) to give trans Zerf -butyl 3-(3-bromo-5-chloro-2-fluorophenyl)-2-methylpiperazine-l-carboxylate (458 mg, 1,12 mmol) as colorless oil.

[1328]

[1329] NMR (400 MHz. CDCh) 5 ppm 7.47 (dd. J= 2.8, 5,6 Hz, 1H). 742 (dd, J- 2.8, 6.0 Hz. 1 H), 4.53 (q, J- 6.8 Hz. 1H), 4.09 (s, 1H), 3.89 - 3.82 (m. 1H), 3.14 (td, -4.4, 12.8 Hz. 1 H). 2.74 - 2.60 (tn, 2H), 1 52 (s, 9H), 1.42 (d, J = 6.8 Hz, 3H).

[1330]

[0294] Step 7. trans tert-buty! 4-acetyl-3-(3-bromo-5-chloro-2-fluorophenyI)-2-methylpiperazine-1 -carboxylate

[1331]

[0295] To a solution of trans / ert-butyl 3-(3-bromo-5-chloro-2-fluorophenvl)-2-methylpiperazine-l-carboxylate (458 mg, 1.12 mmol) in DCM (5 mL) was added TEA (0.470 mL, 341 mg, 3.37 mmol) and acetyl chloride (0.104 mL, 115 mg, 1.46 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes. The mixture was diluted with water (10 ml.,) and extracted with EtOAc (10 mL x 3). The combined organic layers were crashed with brine (10 mL), dried over NazSO^ filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOz, 0-50% EtOAc / petroleum ether) to give trans tert-butyl 4-acetyl-3-(3-bromo-5-chloro-2-fluorophenyl)-2- methylpiperazme-1 -carboxylate (430 mg, 0.956 mmol) as colorless oil. 'H NMR (400 MHz, CDCl3) 5 ppm 7.59 - 7.46 (m, 1H), 7.44 - 7.28 (m, 1H), 5.93 - 4.84 (m. 1H), 4.83 - 4.69 (m. 1H). 4.55 - 4.38 (m, 1H), 3.87 - 3.53 (m, 1H). 3.30 - 2.61 (m, 2H), 2.30 - 2.18 (m. 3H), 1.51 - 1.43 (m, 9H), 1.40 - 1.29 (m, 3H).

[1332]

[0296] Step 8. Chiral separation of tert-butyl (2R,3R)-4-acetyl-3-(3-bromo-5-chloro-2- fluorophenyl)-2-methylp!perazine-l-earboxylate and tert-butyl (2S,3S)-4-acetyI-3-(3-bromo-5- chloro-2-fluorophenyl)-2-methylpiperazine-l -carboxylate

[1333]

[0297] Racemic trans tert-butyl 4-acetyl-3-(3-bromo-5-chloro-2-fluorophenyI)-2-methyIpiperazine-l- carboxylate (1.60 g, 3.56 mmol) was separated by SEC (Chiralpak IG-3, 50 x 4.6mm, 3 pm; mobile phase: A: CO;: B: ElOH + MeCN (0.05% DEA)). Tire first eluting isomer was randomly designated as tert-butyl (2R.3R)-4-acetyl-3-(3-broino-5-chloro-2-fluorophenyl)-2-inethyl-piperazine-l-carboxylate (0.800 g. 1.78 mmol) and was obtained as yellow oil. ’H NMR (400 MHz, CDCl3) 5 ppm 7.59 - 7.46 (m, 1H). 7.44 - 7.28 (tn, 1H), 5.93 - 4.84 (m, 1H). 4.83 - 4.69 (m. 1H), 4.55 - 4.38 (m, 1H). 3 87 - 3.53 (m, 1H). 3.30 - 2.61 (m, 2H), 230 - 2.18 (m, 3H), 1.51 - 1.43 (m, 9H), 1.40 - 1.29 (m, 3H). The second eluting isomer was randomly designated as tert-butyl (2S,3S)-4-acetyl-3-(3-bromo-5-chloro-2-fluorophenyl)-2-methylpiperazine-l -carboxydate (0.790 g, 1.76 mmol) and ’as obtained as yellow oil.1H NMR (400 MHz, CDCl3) 3 ppm 7.59 - 7.46 (m, 1H), 7.44 - 7.28 (in, 1H), 5.93 - 4.84 (m, 1H), 4.83 - 4.69 (m, 1H). 4.55 - 4.38 (tn, 1H), 3.87 - 3.53 (nt, 1H), 3.30 - 2.61 (m, 2H), 2.30 - 2.18 (tn. 3H), 1.51 - 1.43 (m. 9H), 1.40 - 1.29 (m, 3H).

[1334] Genera! Procedure 7

[1335] 79

[1336] QB\184200.00265\99930245.1 VVID 755PC

[1337]

[0298] Synthesis of tert-butyl (S)-3-(2-bromo-6-chloropy ridin-4-yl)piperazine-l -carboxylate and tert-butyl (R)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l-carboxylate

[1338]

[1339]

[0299] Step 1. 2-(2-bromo-6-chloropyridin-4-yl) pyrazine

[1340]

[0300] lb a solution of 2-bromo-6-chloropyridine (90.0 g, 468 mmol) in THF (900 mL) was added dropwise TMPMgClLiCl (170 g. 702 mmol) at 0 °C under N2. The mixture was stirred for 1 hour at 20 °C, cooled to 0 °C and then ZnCh (95.60 g, 701.52 mmol) was added to the mixture The mixture was allow cd to warm to 20 °C and was then stirred for 1 hour. Next, 2-iodopyrazine (96.3 g, 468 mmol) and Pd(PPh;)4 (13.5 g, 11.7 mmol) were successively added. The mixture was stirred for 12 hours at 25 °C, diluted with water (800111L) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (500 mL). dried over NacSOzi, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOj. 30-50% EtOAc / petroleum ether) to give 2-(2-bromo-6-chloropyridin-4-yl)pyrazine (148 g. 547 mmol) as yellow solid.1II NMR (400MHz, CDCL) 8 ppm 9.11 - 903 (m. 1 H). 8.74 - 8.65 (tn, 2H), 8.11 - 8.02 (m, 1H), 7.99 - 7.88 (m. 1H).

[1341]

[0301] Step 2 2-(2-bromo-6-chloropyridin-4-yl)piperazine

[1342]

[0302] To a solution of 2-(2-bromo-6-chloropyridin-4-yl)pyrazine (50.0 g, 185 mmol), PhzNH (62.6 g, 370 mmol) and HBPin (118 g, 924 mmol) in toluene (500 mL) was added FhC.-Tzy (946 g, 18.5 mmol) under bL at 25 °C. The reaction mixture was stirred at 110 °C for 1 hours. The mixture was concentrated under reduced pressure, diluted with water (1000 mL) and extracted with MTBE (500 mL). The organic layer was extracted with water (250 mL x 3), and the aqueous phases were used in the next step without purification.

[1343]

[0303] Step 3. tert-butyl 3-(2-bromo-6-chloropyridin-4-y!)piperazine-l-carboxylate

[1344]

[0304] The crude solution of 2-(2-bromo-6-chloropyridin-4-yl)piperazme (51.0 g, 184 mmol) and NaHCOj (30.98 g, 368.82 mmol) in water (1000 mL) was treated with BOC2O (20.1 g, 92.2 mmol) in THF (100 mL) under N2 at 20CC and stirred at 20 °C for 12 hours. The mixture was extrac ted with EtOAc (500 mLx 3). The combined organic layers were washed with brine (500 mL), dried over

[1345] 80

[1346] QB\184200.00265\99930245.1 VVID 755PC Na2SCk filtered, concentrated under reduced pressure. The crude product was triturated with hexane (800 ml.,) at 20 °C for 12 hours and filtered. The filter cake was washed with 100 mb hexane and dried under reduced pressure to give tert-butyl 3-(2-bromo-6-chloropyridin-4-yT)piperazine-l-carbox late (83.0 g, 203 mmol) as white solid.

[1347]

[1348] NMR (400MHz. CDCh) 5 ppm 7.52 - 7.50 (m, 1H). 7.40 - 7.36 (m. 1 H).

[1349] 4.05 - 3.81 (m. 2H), 3.76 - 3.67 (m, HI). 3.12 - 2.90 (m, 2H). 2.88 - 2.57 (m. 2H), 1.47 (s, 9H).

[1350]

[0305] Step 4. Separation of tert-butyl (S)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l-carboxylate and tert-butyl (R)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l-carboxylate

[0306] Racemic tert-butyl 3-(2-bromo-6-chloropyridin-4-yl)piperazine-l -carboxylate (95 g, 252.20 mmol) was separated by SFC (Daicel Chiralpak AD column (250 mm x 30 mm x 10 pm), 25% MeOH / COz isocratic elution, with 200g / min flow rate; column temperate of 40 °C; system back pressure of 100 bar), tert-buty l (S)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l -carboxylate (45.0 g, 119 mmol) was obtained as the first eluting isomer and as a yellow solid: ’H NMR (400 MHz, CDCfi) 5 ppm 7.56 -7.46 (m, 1H), 7.42 - 7.32 (m, 1H), 4.10 - 3.91 (m, 2H), 3.78 - 3.64 (m, 1H), 3.10 - 3.00 (m. 1H), 2.99 -2.89 (m, 1H), 2.87 - 2.58 (m, 2H), 1.52 - 1.46 (m, 9H).

[1351]

[0307] =-14.5° (c = 1.074, CH3C ). tert-butyl (R)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-1 -carboxylate (41 g, 118.85 mmol) was obtained as the second eluting isomer and as yellow solid. 'H NMR (400 MHz, CDCl3) 5 ppm 7.56 - 7.50 (m, 1H), 7.42 - 7.35 (m, HI). 4.16 - 3.92 (m, 2H), 3.78 - 3.67 (m, 1H), 3.10 - 3.02 (m. 1H). 3.02 - 2.91 (m, 1H). 2.90 - 2.54 (m, 2H), 1.50 - 1.48 (m. 9H). [a]g° = +13.9° (c - 1.017, CHsCN).

[1352]

[0308] The absolute stereochemistry’ of tert-buty I (S)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l-carbox late and tert-buty 1 (R)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l-carboxylate was determined by conversion of tert-butyl (S)-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l -carboxylate into (S)-4-(l-acetyl-4-acryloylpiperazin-2-yd)-6-chloro-6'-fluoro-N-methyl-[2,4'-bipyridme]-2'-carboxamide. The absolute configuration of (S)-4-(l-acetyl-4-acryloylpiperazin-2-y1)-6-cbloro-6'-fluoro- N-methyl-[2,4'-bipyridine]-2'-carboxamide was determined using X-ray cry stallography of obtained cr stals.

[1353] 81

[1354] QB\184200.00265\99930245.1 VVID 755PC

[1355]

[1356]

[0309] Step 1. tert-butyl (S)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yI)piperazine-l-carboxylate

[0310] To a solution of tert-butyl (S)-3-(2-bromo-6-chloropyridin-4-yl)piperazuie-l -carboxylate (5.00 g. 13.3 mmol) in DCM (50 mL) was added DIPEA (4.62 mL, 3.43 g, 26.5 mmol) and acetyl chloride (1.25 g. 15.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was quenched with water (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers ere washed with brine (50 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The crude product was triturated with MTBE (15 mL) at 15 °C for 16 hours. The mixture was filtered and the filter cake was dried under reduced pressure to afford tert-but l (S)-4-acet l-3-(2-bromo-6-ch1oropyridin-4-y1)piperazine-l-carboxylate (3.80 g. 9.08 mmol) as white solid.

[1357]

[1358] NMR (400 MHz. DMSO-ds) 5 ppm 7.56 (s, 1H), 7.43 (s, HI), 5.57 - 5.13 (m, 1H), 4.50 - 4.09 (m. 1H), 3.90 - 3.56 (m, 2H), 3.50 - 3.33 (m, 1H), 3.30 - 3.10 (m, 1H), 3.08 - 2.70 (m. 1H), 2.23 - 1.95 (m, 3H). 1.32 (s. 9H).

[1359]

[0311] Step 2. tert-butyl (S)-4-acetyl-3-(6-chloro-2'-fluoro-6'-(methylcarbamoyl)-[2,4'-bipyridin]-4-yl)piperazine-l-carboxylate

[1360]

[0312] To a solution of tert-but l (S)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)piperazine-l-carboxylate (3.80 g, 9.08 mmol) in 1.4-dioxane (32 mL) and water (8 mL) was added 6-fluoro-N-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide (2.54 g, 9.08 mmol), Pd(dppf)C12 (0.0657 g, 0.0908 mmol) and K2CO3 (2.51 g, 18.2 mmol). The reaction mixture was stirred at 80 °C for 16 hours under N?. The mixture was quenched with water (48 mL) and filtered. The filter cake was dried under reduced pressure to give tert-butyl (S)-4-acetyl-3-(6-chloro-2'-fluoro-6'-(metliylcarbamoyl)-[2,4'-bipyridin]-4-yl)piperazine-l -carboxy’ late (4.90 g) as pale yellow solid which was used in the next step without further purification.1H NMR (400 MHz, DMSO-rfg ) 5 ppm 8.79 (br d, J = 4.50 Hz. HI), 8.57 (s, 1H), 8.23 - 7.90 (m, 2H). 7.52 (br s. 1H), 5.64 - 5.17 (m, 1H), 4.60 - 4.14 (m, 1H). 3.98 - 3.62 (m, 2H), 3.51 - 3.35 (m, 2H), 3.27 - 2.97 (m. HI), 2.83 (br d. 4.50 Hz, 3H), 2.28 - 1.94 (m, 3H). 1.46 - 1.10 (m, 9H).

[1361] 82

[1362] QB\184200.00265\99930245.1 VVID 755PC

[0313] Step 3. (S)-4-(l-acetylpiperazin-2-yl)-6-chloro-6'-fluoro-N-methyl-[2,4'-bipyridine]-2'-carboxamide

[1363]

[0314] A solution of tert-butyl (S)-4-acetyl-3-(6-chloro-2'-fluoro-6'-(methylcarbamoyl)-[2.4'-bipyridin]-4-yl)piperazine-l-carboxylate (430 g. 8,74 mmol) in HCl / dioxane (43 ml) was stirred at 20 °C. The mixture was filtered and the filter cake was dried under reduced pressure to afford (S)-4-(l-acetylpiperazin-2-yl)-6-chloro-6,-fluoro-N-methyl-[2,4'-bipyridine]-2'-carboxaniide (3.80 g, 887 mmol) as white solid

[1364]

[1365] NMR (400 MHz. DMSO-ds) 8 ppm 9.87 - 10.26 (m, 1 H). 9.00 - 8.75 (m, 2H), 8.65 (s, 1H), 8.33 - 8.06 (m, 2H), 7.51 (s, 1H). 5.99 - 5.51 (m, 1H).4.34 - 3.90 un. 2H), 3.50 - 3.28 (m, 2H), 3.12 (br s, 2H), 284 (d,.7= 4.75 Hz, 3H), 2.34 - 2.01 (ra, 3H).

[1366]

[0315] Step 4. (S)-4-(l-acetyl-4-acryloylpiperazin-2-yl)-6-chloro-6’-fluoro-N-methyI-[2,4’-bipyridine]-2'-carboxamide

[1367]

[0316] To a solution of (S)-4-(l-acetylpiperazin-2-yl)-6-chloro-6'-fluoro-]SI-metbyl-[2,4'-bipyridine]-2 '-carboxamide (1.00 g, 2.55 mmol) in THF (10 mL) and water (10 mL) was added NaHCOs (0.750 g, 8.93 mmol). A solution of acryloyl chloride (0.228 mL, 0.254 g, 2.81 mmol) in THF (3 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 10 °C for 30 minutes. 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), dried over NasSCL, filtered and concentrated under reduced pressure to give (S)-4-(l-acetyl-4-acryloylpiperazin-2-yl)-6-chloro-6,-fluoro-N-inethyl-[2,4'-bipyridine]-2'-carboxamide (1.00 g, 2.24 mmol) as a white solid.1H NMR (400 MHz, DMSO de ) 5 ppm 8.79 (br d, J 4.63 Hz. 1H), 8.58 (br s, 1H). 8.31 - 7.94 (m, 2H), 7.62 - 7.38 (m. 1H), 7.02 - 6.56 (m, 1H). 6.28 - 5.90 (m, 1H). 5.75 - 5.31 (m, 2H), 4.94 - 4.22 (m, 1H). 4.00 - 3.83 (m, 2H), 3.69 - 3.34 (m.3H), 2.84 (d, J - 4.88 Hz, 3H). 2,26 - 2.01 (tn, 3H).

[1368]

[0317] Crystalline solids of (S)-4-(l-acetyl-4-acryloylpiperazin-2-yl)-6-chloro-6'-fluoro-N-methyl-[2,4'-bipyridine]-2'-carboxamide were cultivated for absolute stereochemistry determination by X-ray crystal structure analysis: 12 mg of (S)-4-(l-acetyl-4-acryloylpiperazin-2-yl)-6-chloro-6'-fluoro-N-methyl-[2,4'-bipyridine]-2'-carboxamide was dissolved in 200 pL isopropanol and placed in a 4 ml, vial (no lid). The vial was placed into a 40 mL chamber vial containing 5 mL of cyclohexane. The outer chamber vial was sealed, and the solvents were allowed to exchange by diffusion. Crystals were observed on the second day and were isolated by filtration. These crystals were suitable for determination of the absolute stereochemistry by crystal x-ray diffraction, showing that the piperazine stercochemistrv is (S). This allows for absolute assignment of stereochemistry' of products from General Procedure 7, step 4.

[1369] General Procedure 8

[1370]

[0318] S nthesis of tert-butyl (2R,3R)-4-acetyl-3-(2-broino-6-chloropy ridin-4-yl)-2-methylpiperazine-1 -carboxylate and tert-butyl (2Sr3S)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l -carboxylate

[1371] 83

[1372] QBM84200.00265'99930245.1 VVID 755PC

[1373] BoojO, N&i

[1374]

[1375]

[0319] Step 1. l-(2-bromo-6-chloropyridin-4-yl)-2-chloropropan-l-one

[1376]

[0320] To the solution of 2-bromo-6-chloro-4-iodopyridine (1.00 kg. 3141 mmol) in toluene (10 L) was added i-PrMgCl LiCl (3.14 L, 4083.68 mmol, 1.3 M) dropwise at -10 °C under N2. The mixture was stirred at -10 °C for 1 hour. Then a solution of 2-chloro-N-methoxy-N-methvlpropanamide (619.05 g. 4083.68 mmol) in toluene (2 L) was dropwise added to the mixture at -10 °C under N2The resulting mixture was allowed to warm to 25 °C and stirred for 1 hour under N2. The reaction mixture was poured into IN HC1 (71.,). The organic phase was separated, then the aqueous layer was extracted with EtOAc (2 L x 2). The combined organic layers were washed with brine (3 L), dried over Xa. SX ).. filtered, and concentrated under reduced pressure below 45 °C The crude product was purified by column chro atography (0-10% EtOAc / petroleum ether) to give l-(2-bronio-6-chloropyridin-4-yl)-2- chloropropan-l-onc (520 g, 1837.78 mmol) as white solid.1H NMR (400 MHz, CDCl3): 8 ppm 7.89 (d, J= 0.8 Hz, 1H), 7.77 (d,. Z = 1.2 Hz, lH), 5.03 (q, J= 6.4 Hz, 1H), 1.75 (d,.7 = 6.4 Hz, 3H).

[1377]

[0321] Step 2. 5-(2-bromo-6-chloropyridin-4-yl)-6-methyl-l,2,3,6-tetraliydropyrazme

[1378]

[0322] To a mixture of l-(2-bromo-6-chloropyridin-4-yl)-2-chloropropan-l-one (515 g, 1820 mmol) and 4A molecular sieve (500 g) in MeOH (5000 mL) was added ethane- 1,2-diamine (328 g, 5460 mmol) dropwise at 0 °C under N2. The reaction mixture was stirred at 65 °C for I hour under N2. The reaction mixture was filtered over celite, and the filter cake was washed with MeOH (300 mL x 2). The filtrate was used into the next step without further work up.

[1379]

[0323] Step 3. 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine

[1380]

[0324] To a solution of 5-(2-bromo-6-chloropyridin-4-yl)-6-metliyl-l,2,3,6-tetrahydropyrazine (525 g.

[1381] 1820 mmol) in MeOH (5600 mL) was added NaBH.; (344 g, 9100 mmol) in portions at 10 °C under N2.

[1382] 84

[1383] QB\184200.00265\99930245.1 VVID 755PC The reaction mixture was stirred at 20 °C for 0.5 hour under N2. The reaction mixture was quenched by HCl / MeOH (4 M. 2500 ml.,) and filtered. The filter cake was washed with THF (300 ml, x 2), dried in vacuum below 45 °C to afford 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine (1.20 kg) as HC1 salt as light yellow solid. Tire crude product was used in the next step without further purification.

[1384]

[0325] Step 4. trans di-tef -butyl 2-(2-bromo-6-chloropyridin-4-yl)-3-niethylpiperazine-1,4- dicarboxylate and cis di- rt-butyl 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine-1,4-dicarboxylate

[1385]

[0326] To a solution of 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine (1.20 kg, 4130 mmol) in THF (3.6 L) and water (12 L) was added di-terr-butyl dicarbonate (1802 g, 82596 mmol) and sodium carbonate (963 g, 9085 mmol) at 20 °C The mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (1000 mL x 2). the filtrate was separated, the aqueous layer was extracted with EtOAc (500 ml, x 3). The combined organic layers were washed with brine (1000 mL), dried over NaAO;. filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) and the cis and trans isomers were separated: trans di-tert-butyl 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine-l,4-dicarboxylate (220 g) was obtained as white solid. *H NMR (400 MHz, CDCl3): 5 ppm 7.45 - 7.38 (m, 1H), 7.32 - 7.27 (m, 1H), 5.24 - 4.72 (111, 2H), 4.11 - 3.60 (m, 2H), 3.21 - 2.99 (m, 1H), 2.79 - 2.54 (m, 1H). 1.67 - 1.40 (m, 18H), 1.38 - 1.28 (m, 3H); and cis di- / er / -butyl 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine-l,4-dicarboxylate (58 g) was obtained as white solid. ‘H NMR (400 MHz, CDCl3): 6 ppm 7.29 (s, 1H). 7.16 (s, 1H), 4.95 (d, J = 6.0 Hz, 1H). 4.50 - 4.41 (m, 1H), 4.36 -4.23 (111, HI), 3.59 - 3.48 (m, 3H), 1.49 (s, 9H), 1.28 (s, 9H), 1.04 (d.. / :::7.2 Hz, 3H).

[1386]

[0327] Step 5. trans 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine bishydrochloride 1328] To a solution of trans di-fert-butyl 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine-l,4-dicarboxylate (220 g, 448.23 mmol) in MeOH (440 mL) was added HCl / MeOH(4 M, 2200 mL) at 20CC. The mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated in vacuum to give crude trans 2-(2-bronio-6-chloropyridin-4-yl)-3-methylpiperazine (162 g, 446 mmol) as HCI salt as white solid. The crude product was used for the next step without further purification.

[1387]

[0329] Step 6. trans tert-butyl 3-(2-bromo-6-chIoropyridin-4-yl)-2-methylpiperazine-l-carboxylate

[1388]

[0330] To the solution of trans 2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazine as HCI salt (162 g, 446 mmol) in DCM (1600 mL) was added triethylamine (135 g, 1337 mmol) and di-tert-butyl dicarbonate (117 g, 535 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into H2O (2000 mL) and extracted with DCM (500 mL x 3). The combmed organic layers were washed with brine (1000 mL), dried over Na-,: SOi, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum 85

[1389] QB\184200.00265\99930245.1 VVID 755PC ether) to give trans tert-bulyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate (145 g. 371 mmol) as off-white solid. ’H NMR (400 MHz, CDCl3): 8 ppm 7.58 (s. 1H), 7.46 (s, 1H), 4.68 (q, 6.8 Hz, 1H), 3.75 (dd. J = 2.8, 13.6 Hz, 1H), 3.69 (s, 1H), 3.03 (td. J= 3.6, 12.8 Hz, 1H), 2.70 (dd, J = 2.4, 13.6 Hz. 1H). 2.53 (td,.7 = 4.0. 12.8 Hz, 1H), 1.51 (s, 9H), 1.39 (d, J= 6.8 Hz, 3H).

[1390]

[0331] Step 7. trans tert-butyl 4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate

[1391]

[0332] To a solution of trans tert-bulyl 3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate (75.33 g. 192.80 mmol) in DCM (750 mL) was added triethylamine (39.02 g, 385.61 mmol) at 0 °C. Then a solution of acetyl chloride (22.70 g, 289.20 mmol) in DCM (80 mL) was dropwise added to the mixture at 0 °C under N3. The reaction mixture was stirred at 0 °C for 1 hour under N2. The reaction mixture was poured into water (400 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over NazSO.,. filtered, and concentrated under reduced pressure to give a crude product. The crude product was triturated with M'T'BE (100 mL) and filtered. The filter cake was collected to give trans tert-butyl 4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)- 2-methylpiperazine-l -carboxylate (73 g, 169 mmol) as white solid, ’H NMR (400 MHz, DMSO-<4): 3 ppm 7.57 - 7.44 (m, 1H), 7.42 - 7.32 (m, 1H), 5.56 - 5.43 (m. 1 II ), 4.81 (q, J = 6.8 Hz, 1H), 3.80 - 3.49 (m, 2H), 3.26 - 2.88 (m, 2H), 2.27 - 2.04 (m. 3H), 1.45 - 1.32 (m. 9H), 1.30 - 1.10 (m, 3H).

[1392]

[0333] Step 8. Chiral separation of tert-butyl (2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate and tert-butyl (2S,3S)-4-acetyi-3-(2-bronw-6-ch!oropyridin-4-yl)-2-methylpiperazine-l-carboxylate

[1393]

[0334] Racemic trans tert-butyl 4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate (4.13 g, 9.55 mmol) was separated with SI C (DAI CEL CHIRALPAK IC, 250 x 50 mm, 10 pm; mobile phase: A: CO2: B: 1PA(O.1% NH3H2O); B%: 35-35%. 6.00mm). tert-butyl (2R,3R)-4-acetyl- 3 -(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazme-l -carboxylate (2.00 g, 4.62 mmol) was obtained as the first eluting isomer and as yellow solid.rH NMR (400 MHz. CDCh) 8 ppm 7.43 - 7.35 (m, 1H), 7.26 (br s, 1H). 5.79 - 5.57 (m, 1H), 5.15 - 471 (m, 1H), 4.64 (s. 1H). 3.97 - 3.49 (m, 2H), 3.27 - 2.80 (m. 2H), 2.35 - 2.16 (m, 3H), 1.61 - 1.43 (in, 9H), 1.31 - 1.20 (m. 3H). tert-butyl (2S,3S)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l-carboxylate (2.10 g. 4.85 mmol) was obtained as the second eluting isomer and as yellow solid.lH NMR (400 MHz, CDCl3) 3 ppm 743 - 7.35 (m, 1H), 7.26 (br s. 1H). 5.79 - 5.57 (m. 1H), 5 15 - 4.71 (m, 1H), 4.64 (s. 1H), 3.97 - 3.49 (m, 2H), 3.27 - 280 (m. 2H). 2.35 - 2.16 (m, 3H), 1 61 - 1.43 (m, 9H), 1.31 - 1.20 (m, 3H).

[1394]

[0335] The absolute stereochemistry7of tert-butyl (2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridm-4-yl)- 2 -methylpiperazine-1 -carboxylate and tert-butyl (2S,3S)-4-acetyl-3-(2-bromo-6-chloropyridm-4-yl)-2- meth lpiperazine- 1 -carboxylate was determined by conversion of tert-butyl (2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l -carboxylate into 6-(4-((2R,3R)-l-acetyl-4-acryloyl-3- 86

[1395] QBM84200.00265'99930245.1 VVID 755PC methylpiperazin-2-yl)-6-chloropyridiii-2-vl)-N-methylpyrimidine-4-carboxamide. The absolute configuration of 6-(4-((2R.3R)-l-acetyL4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-N-methy lpyrimidine-4-carboxamide was determined using X-ray crystallography of obtained crystals.

[1396] SrC separator HCI / MeOH TEA. DCM step 8 step 9 step 19 trans-racemate Peak! Peak 2 tR. RJ-ensntiomer (S, S) -enantiomer

[1397]

[1398] absolute stereochemistry

[1399] rJetermined by X-ray

[1400]

[0336] Step 9. 1 -((2R R)-2-(2-bromo-6-chk)ropyridin-4-yl)-3-methylpiperazin-l-yl)ethan-1-one

[0337] To a solution of tert-butyl (2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-rnethylpiperazine-l-carboxylate (500 mg. 1.16 mmol) in MeOH (3 mL) was added HC1 (10 mL, 2 N in MeOH) at 20 °C. The reaction mixture was stirred at 30 °C for 2 hours. The mixture was concentrated under reduced pressure to give crude l-((2R,3R)-2-(2-bromo-6-chIoropyridin-4-yl)-3- ethylpiperazin-l-yl)ethan-l-one (360 mg. 1.08 mmol) as white solid. The crude product was used in the next step without further purification.

[1401]

[0338] Step 10. l-((2R R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazin-l-yl)prop-2-en-l-one

[1402]

[0339] To a solution of l-((2R.3R)-2-(2-bromo-6-cliloropyridin-4-yl)-3-methylpiperazin-l-yl)ethan-l- one (350 mg, 1.05 mmol) in DCM (10 L) was added TEA (0574 L, 426 mg. 4.21 mmol) and acryloyl chloride (0.103 mL, 114 mg, 1.26 mmol) at °C. The reaction mixture was stirred at 25 °C for 30 minutes under N2. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL x 2). 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 (SiOz, 45-65% EtOAc / petroleum ether) to give l-((2R,3R)-4-acetyl-3-(2-bromo-6-cliloropyridin-4-yl)-2-mcthylpipcrazin-l-yl)prop-2-cn-l-onc (360 mg, 0.931 mmol) as white solid. *H NMR (400 MHz, CDClz) S = 7.42 - 7.28 (in, 1H), 7.25 (s. 1H). 6.72 - 6.25 (m, 2H), 5.94 - 5.70 (m, 2H), 5.57 - 5.41 tin. 1H), 4.71 - 4.31 (m, 1H), 3.83 - 3.39 (m, 2H), 3.22 - 3.02 (m. 1H), 2.37 - 2.15 (m, 3H), 1.47 - 1.30 (m, 3H).

[1403] 87

[1404] QB\184200.00265\99930245.1 VVID 755PC

[1405]

[0340] Step 11. 6-(4-((2R R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide

[1406]

[0341] To a solution of 1 -((2R.3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-y])-2-metliy]piperazin-l-yl)prop-2-en-l-one (45.0 mg, 0.116 mmol) in toluene (2 mL) was added N-methyl-6-(trimethylstannyl)pyrimidine-4-carboxamide (33 2 mg. 0.111 m ol), Pd(PPh2). (134 mg, 0.0116 mmol) and LiCl (0.5 mg, 0.0116 mmol). The reaction mixture was stirred at 120 °C for 12 hours. 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 Na2S04, filtered and concentrated under reduced pressure. The crude product was purified with preparative TLC (SiO2. EtOAc) to give 6-(4-((2R,3R)-l-acetyl-4-acndoyl’3-inethylpiperazin-2-yl)-6-cbloropyridin-2-yl)-N-methylpyrimidine-4-carboxamide (17.0 mg, 0.0384 mmol). ’H NMR (400 MHz, CDCl3) 3 = 9.29 - 9.19 (m, i ll). 9.07 (d, J = 10.1 Hz, 1H), 8.43 - 8.33 (m, 1H), 7.99 (br d.. / 4.6 Hz, 1H), 7.45 - 7.29 (m, 1H). 6.79 - 6.19 (m, 2H), 5.90 - 5.82 (m, 1H), 5.78 - 5.54 (m, 1H), 4.93 - 4.79 (m, 1H), 4.61 - 4.34 (m, 1H), 3.81 - 3.65 (m, 1H), 3.58 - 3.43 (m, 1H), 3.30 - 3.16 (m, HI), 3.09 (br d, J- 5.0 Hz, 3H), 2.36 - 2.26 (m, 3H), 1.51 - 1.35 (m, 3H).

[1407]

[0342] Crystalline solids of 6-(4-((2R,3R)-l-acetyl-4-acryloyl-3-metliylpiperazm-2-yl)-6-chloropyridiii-2-yl)-N-methy lpyrimidine-4-carboxamide were cultivated for absolute stereochemistry determination by X-ray crystal structure analysis: 1 mg of 6-(4-((2R,3R)-l-acetyl-4-acryloyl-3- methy lpiperazin-2- l)-6-chloropyridin-2-yl)-N-methylpyriinidiiie-4-carboxamide was dissolved in 20011L MeOH and kept in a 1 mL vial. The solution evaporated slow' ly at room temperature. Crystals were observed on the second day and were isolated by filtration. These cry stals 'ere suitable for determination of the absolute stereochemistry by crystal x-ray diffraction, showing that the stereochemistry is 2R, 3R. This allows for absolute assignment of stereochemistry of products from General Procedure 8, step 8.

[1408] General Procedure 9

[1409]

[0343] Synthesis of l-((2R,3R)-4-acetyl-3-(2-chIoro-6-(4,4?5,5-tetramethyl-l,3,2-dioxaboroIaii-2-yl)pyridin-4-yl)-2-methylpiperazin-l -yl)prop-2-en- 1 -one

[1410]

[1411]

[0344] tert-butyl (2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazine-l- carboxylate was obtained as described in General Procedure 8, step 8

[1412]

[0345] Step 1. l-((2R,3R)-2-(2-bromo-6-chloropyridm-4-yl)-3-methylpiperazin-l-yl)etlian-l-one

[1413] 88

[1414] QB\184200.00265\99930245.1 VVID 755PC

[0346] To a solution of tert-butyl (2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methyl-piperazine-1 -carboxylate (2.00 g. 4.62 mmol) in MeOH (5 mL) was added HCl / MeOH (15 mL). The reaction mixture was stirred at 30 °C for 2 hours. The mixture was concentrated under reduced pressure to give l-((2R.3R)-2-(2-bromo-6-chloropyridin-4-yl)-3-methy1piperazin-l-yl)ethan-l-one (1.53 g, 4.60 mmol) as yellow solid. Hl NMR (400 MHz. CD3OD) 5 ppm 7.61 (s, 1H). 7.49 (s, 1H). 5.63 - 5.47 (m, 1 H). 4.46 - 4.34 (m, 1H), 431 - 4.08 (m. 1H).3.60 - 3.42 (m. 2H), 3.24 - 3.12 (m, 1 H). 2.29 (br s. 3H), 1.49 (brd.,7= 5.9 Hz, 3H).

[1415] [ 347 j Step 2. l-((2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperttzin-l -yl)prop-2-en-l-one

[1416]

[0348] To a solution of 1 -((2R,3R)-2-(2-bromo-6-chloropyridin-4-yl)-3-methylpiperazin-l -yl)ethan-l - one (1.54 g, 4.63 mmol) in DCM (15 mL) was added TEA (0.937 g, 9.26 mmol) and acryloyl chloride (0.451 mL, 0.503 g, 5,56 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 10 minutes under N2. The mixture was diluted with water (20 L) and extracted with DCM (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 a crude product. The crude product was purified by column chromatography (SiO2. 45-60% EtOAc / petroleum ether) to afford l-((2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)- 2-methylpiperazin-l-yl)prop-2-en-l-one (1.60 g, 4.14 mmol) as pale yellow solid. ’H NMR (400 MHz, CDCl3) 8 ppm 7.46 - 7.28 (m, 1H), 7.26 - 7.10 (m, 1H), 6.68 - 6.25 (m, 2H), 5.95 - 5.76 (m, 1H), 5.73 -5.39 (m, 1H), 4.80 - 4.31 (m, 1H). 3.80 - 3.31 (m, 2H). 3.20 - 2.60 (m, 1H), 2.35 - 2.22 (m. 3H), 1.35 - 1.34 (m, 1H), 1.47 - 1.18 (m, 3H).

[1417]

[0349] Step 3. l-((2R13R)-4-acetyl-3-(2-chIoro-6-(4,4,5,5-tetraHiethyJ-l,3,2-dioxaboroJan-2- yl)pyridin-4-yl)-2-methylpiperazin-l-yI)prop-2-en-l-one

[1418]

[0350] To a solution of l-((2R,3R)-4-acetyl-3-(2-bromo-6-chloropyridin-4-yl)-2-methylpiperazin-l-yl)prop-2-en-l-one (300 mg. 0.776 mmol) m 1,4-dioxane (5 mL) was added Ptn2B2(197 mg, 0.776 mmol), KOAc (152 mg, 1.55 mmol) and Pd(dppf)Cl2DCM (63.4 mg, 0.0776 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours under bi2. The mixture was diluted with water (20 L) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure to give crude l-((2R,3R)-4-acetyl- 3-(2-chloro-6-(4.4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)-2-methylpiperazin-l-yl)prop-2- en-l-one (300 mg) as brown oil which was used in the next step without further purification.

[1419] General Procedure 10

[1420]

[0351] Synthesis of tert-butyl (6R,9aR)-6-(2-bromo-6-chloropyridin-4-yl)hexahydropyrazino[2,l- c][l,4]-oxazine-8(lH)-carboxylate and tert-butyl (6S,9aR)-6-(2-bromo-6-chloropyridin-4-yl)hexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate

[1421] 89

[1422] QB\184200.00265\99930245.1 VVID 755PC

[1423]

[1424]

[0352] Step 1 2-bromo-6-chloro-4-iodopyridine

[1425]

[0353] To a solution of 2-bromo-6-chloropyridine (100 g, 519.64 mmol) in THF (1000 mL, 0.51 M) was added TMPMgCl LiCl (571.61 mL, 571.61 mmol) dropwise at 0 °C under N2. The mixture was stirred for 1 hour at 20 °C, and then cooled to 0 °C, and I2(145.08 g, 571.61 mmol) was added to the mixture. The 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 layer was washed with brine (1000111L) and dried over Na2SO4, filtered, and concentrated under reduced pressure to give the erode product. The erode product was triturated with MTBE (300 mL) at 25 °C for 2 hours, then the suspension was 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.

[1426]

[1427] NMR (400MHz. CDCL,) 5 ppm 7.86 - 7.80 (m, 1H), 7.72 - 7.66 (m, 1H).

[1428]

[0354] Step 2. 2-bromo-6-chIoro-4-vinylpyridine

[1429]

[0355] To a solution of 2-bromo-6-chloro-4-iodopyridine (50.0 g, 157 mmol) in 1,4-dioxane (500 mL) and water (80 mL) was added potassium vinyltrifluoroborate (21 0 g. 157 mmol), K2CO3 (43.4 g. 314 mmol) and Pd(dppf)CL (11.4 g, 15.7 mmol) at 25 °C under N2. Then the mixture was warmed to and stirred at 60 °C for 2 hours. This reaction was repeated on two other times, beginning with 40g of 2- bromo-6-chloro-4-iodopyridine. All these reaction mixtures were combined by pouring into water (1000 mL). The resulting mixture was then extracted with EtOAc (500 mL x 2). The combined organic layer was washed with brine (500 mL) and dried over Na2SO, filtered, and then concentrated under reduced pressure. The erode product w as purified by column chromatography (SiO2. 0-5% EtOAc / petroleum ether) to give 2-bromo-6-chloro-4-\ inylpyridine (62 g, 284 mmol) as white solid. ‘H NMR (400 MHz,

[1430] 90

[1431] QBM84200.00265'99930245.1 VVID 755PC CDCL) 5 ppm 7.44 - 7.37 (m. IH), 7.27 (s, 1H). 6.63 - 6.52 (m, IH), 6.04 - 5.95 (m. 1H), 5.64 - 5.58 (m. IH).

[1432]

[0356] Step 3 2-bromo-6-chloro-4-(oxiran-2-yl)pyridine

[1433]

[0357] m-CPBA (37.17 g, 183.08 mmol) was added to a solution of 2-bromo-6-chloro-4-vin Ipyridine (16 g. 73.23 mmol) in DCM (480 mL. 0.15 M) at 0 °C. The mixture was then warmed to and stirred at 50 °C for 48 hours. The mixture was quenched by addition of aqueous NaiSOs (200 mL) and the mixture was stirred at 25 °C for 30 min. extracted by DCM (150 mL x 2), dried over NazSO and filtered. The filtrate rvas concentrated under reduced pressure The crude product was purified by column chromatography (SiO2, 0-20% EiOAc / pctroieum ether) to get 2-bromo-6-chloro-4-(oxiran-2-yl)pyridine (9 g, 38.38 mmol) as a yellow solid.

[1434]

[1435] 1H NMR (400 MHz, CDCl3) 8 ppm 7.35 (d, J = 0.88 Hz, IH) 7.22 (d,. Z = 0.88 Hz, 1H) 3.82 (dd,. Z= 4.06, 2.44 Hz, 1H) 3.21 (dd, J = 5.50. 4.13 Hz, IH) 2.75 (dd, J = 5.63, 2.38 Hz, IH).

[1436]

[0358] Step 4. tert-butyl (3R)-3-(((2-(2-bromo-6-chloropyridin-4-yl)-2-hydroxyethyl)amino)-methyl)morpholine-4-carboxylate

[1437]

[0359] To a solution of 2-bromo-6-chloro-4-(oxiran-2-yl)pyridine (11.3 g, 48 mmol) in EtOH (90 L) was added tert-butyl (R)-3-(aminomethyl)morpholine-4-carbox lale (13.0 g, 48 mmol, 80% purity). The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture w as concentrated to give tert butyl 3-(((2-(2-bromo-6-chloropyridin-4-yl)-2-hydrox ethyI)amino)-methyl)morpholiiie-4-carboxylate (crude) which was used in the next step without further purification. LCMS [M-CJHL+Hf =394 / 396 Retention Time: 1.241 min (Method 2).

[1438]

[0360] Step 5. tert-butyl (3R)-3-(((2-(2-bromo-6-chloropyridin-4-yl)-2-hydroxyethyl)(tert-butoxy-carbonyl)amino)methyl)morpholine-4-carboxyIate

[1439]

[0361] To a solution of tert-butyl (3R)-3-(((2-(2-bromo-6-chloropyridin-4-yl)-2-hydroxyethyl)amino)-meth l)morpholine-4-carbox late (23.1 g, 51.2 mmol) in THF (200 mL) and H2O (130 mL) was added di-tert butyl dicarbonate (11.2 g. 51.2 mmol) and K2CO3 (106 g, 76,4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over NaeSOzi, filtered and concentrated. The crude product was purified by column chromatography (SiCL, 0-100% EtOAc, ''heptane) to afford tert-butyl (3R)-3-(((2-(2-bromo-6-chloropyridin-4-yl)-2-hydroxyethyl)(tert-butoxy-carbonyl)amino)methyl)morpholine-4-carboxylate (30.5 g, 55.4 mmol) as white solid. LCMS [M+Najd: 572 / 574, Retention Time: 2.525 min (Method 4).

[1440]

[0362] Step 6. tert-butyl (R)-3-(((2-(2-broino-6-chloropyridin-4-yl)-2-oxoethyl)(tert-butoxy-carbonyl)amino)methyl)morpholine-4-carboxylate

[1441] 91

[1442] QB\184200.00265\99930245.1 VVID 755PC

[0363] To a solution of tert-butyl (3R)-3-(((2-(2-bromo-6-chloropyrid -4-yl)-2-hydroxyethyl)(terf-butoxy-carbonyl)amino)methyl)morphoiine-4-carboxylate (28.2 g, 51.2 mmol) in DCM (200 mL) was added Celite (30 g) and pyridinium chlorocliromate (22.1 g, 102 mmol). The reaction mixture was stirred at 40 °C for 16 hours. The mixture was concentrated and purified by column chromatography (SiO2. 0-100% EtOAc / heptane) to give rert butyl 3-(((2-(2-bromo-6-chloropyridin-4-yl)-2-oxoethyl)(tert- butoxycarbonyl)amino)methyl)morpholine-4-carboxylate (20.8 g. 37.9 mmol) as yellow oil. LCMS [M+Naf: 570 / 572. Retention Time: 1.378 min (Method 6).

[1443]

[0364] Step 7. (R)-l -(2-bromo-6-cbloropyridin-4-yl)-2-((morpholin-3-ylmethyI)amino)ethan-l -one

[1444]

[0365] To a solution of tert-butyl (R)-3-(((2-(2-bromo-6-chloropyridin-4-y1)-2-oxoethyl)(tert-butoxy-carbonyl)amino)methyl)morpholine-4-carboxylate (20.8 g, 37.9 mmol) in DCM (100 mL) was added TFA (100 ml.,) at 0 °C. The mixture was stirred at room temperature for 1 hour and then concentrated to give l-(2-bromo-6-chloropyridin-4-yl)-2-((inorpholin-3-ylmethyl)amino)ethan-l-one (crude) which was used in the next step immediately. LCMS [M-H2O+H]+: 330 / 332, Retention Time: 2.135 min (Method 4).

[1445]

[0366] Step 8. (9aR)-6-(2-bromo-6-chloropyridin-4-yl)octahydropyrazino[2,l-c][l,4]oxazine

[0367] To a solution of (R)-l-(2-bromo-6-chloropyridin-4-yl)-2-((morpholin-3-ylmethyl)amino)ethan-1-one (12.6 g, 37.9 mmol) inAcOH (250 mL) was added zinc (6.19 g, 94.7 mmol) at 0°C. The mixture was allowed to warm to room temperature and stirred overnight. I'he mixture was filtered over Celite and concentrated to afford (9aR)-6-(2-bromo-6-chloropyridin-4-yl)octahydropyrazino[2.1-c][1.4]oxazine (12.6 g) which was used in the next step without further purification.

[1446]

[0368] Step 9. terCbutyl (6R^9aR)-6-(2-bromo-6-ehloropyridin-4-yl)hexahydropyrazino[2,l-c] [1,4]-oxazine-8(l H)-carboxylate

[1447]

[0369] To a solution of (9aR)-6-(2-bromo-6-chloropyridin-4-yl)octahy dropyrazino[2, 1-c] [1.4]oxazine (12.6 g. 37.9 mmol) in THF (200 mL) and water (80 mL) was added di-fert buty l dicarbonate (12.4 g, 56.8 mmol) and K2CO3 (15.7 g. 114 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over KfrSO i. filtered and concentrated. The crude product was purified by¬ column chromatography (SiO2, 0-100% EtOAc / heptane). The first eluting isomer is terr-butyl (6S,9aR)-6-(2-bromo-6-chloropyridin-4-yl)hexahydropyrazino[2,l -c] [ l,4]oxazine-8(lH)-carboxylate (8.23 g, 19.0 mmol). The second eluting isomer is te / 7-butyl (6R,9aR)-6-(2-bromo-6-chloropyridin-4-yl)hexahydropyrazino[2,l-c][l,4]-oxazine-8(lH)-carboxylate (7.39 g. 17.1 mmol) LCMS [M+H]4: 432 / 434 Retention Time: 2.127 min (Method 2).

[1448] General Procedure 11

[1449] 92

[1450] QB\184200.00265\99930245.1 VVID 755PC

[0370] Synthesis of l-((2S,5S)-4-acetyI-5-(2-bromo-6-chIoropyridin-4-yl)-2-(hydroxymethyl)-piperazin-l-yl)prop-2-en-l-one

[1451] DBU, MeCN. 90 ’C step 7

[1452]

[1453]

[0371] 2-bromo-6-chloro-4-(oxiran-2-yl)pyridine was obtained as described in General Procedure 10, step 3.

[1454]

[0372] Step 1. tert-butyl ((2S)-2-((2-(2-bromo-6-chloropyridin-4-yl)-2-hydroxyethyl)amino)-3-methoxypropyl)carbamate

[1455]

[0373] To a solution of 2-bromo-6-chloro-4-(oxiran-2-yl)pyridine (13.5 g, 57.6 mmol) in EtOH (150 ml.,) was added tert-butyl (S)-(2-amino-3-methoxyrpropyl)carbamate (14.1 g, 69.1 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 16 hours under N,. The mixture w as concentrated under reduced pressure and the crude product was purified by column chromatography t Si()-. 0-55% EtOAc / petroleum ether) to give tert-butyl ((2S)-2-((2-(2-bromo-6-chloropyridin-4-yl)-2-hydroxyethyl)amino)-3-methoxypropyl)carbamate (23.4 g, 53.3 mmol) as yellow oil.1H NMR(400 MHz, CDCls) 67.44 (d, J = 3.1 Hz. 1H).7.31 (d. J= 2.8 Hz, 1H). 4.93 - 4.76 (m, 1H). 465 - 4.52 (m, 1H), 3.44 - 3.39 (m. 1H), 3.38 - 3.34 (m. 3H), 3.33 - 3.24 (m, 1H), 3.18 - 3.00 (m. 2H), 2.96 - 2.79 (m. 2H), 2.70 - 2.61 (m, 1H), 1.83 - 1.53 (m. 2H). 1.50 - 1.38 (m.9H).

[1456]

[0374] Step 2. tert-butyl (2-(2-broino-6-chloropyridin-4-yl)-2-hydroxyethyl)((S)-l-((tert-butoxycarbonyl)amino)-3-methoxypropan-2-yl)carbamate

[1457] 93

[1458] QBM84200.00265'99930245.1 VVID 755PC

[0375] To a solution of tert-butyl ((2S)-2-((2-(2-bromo-6-chloropyridiii-4-yl)-2-hydroxyethyl)amino)-3-methoxypropyl)carbamate (23.4 g, 53.3 mmol) in THF (240 mb) and water (160 mL) was added K2CO3 (11.1 g. 80 mmol) and BOC2O (15.1 g, 69.3 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 20 hours. The mixture was diluted with water (300 mL) and extracted with EtOAc (300 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 (SiCL, 0-28% EtOAc / petroleum ether) to give tert-butyl (2-(2-bronio-6-chloropyridin-4-y1)-2-hydroxyethyl)((S)-l-(( / ert-butoxycarbonyl)amino)-3-methoxypropan-2-yl)carbamate (24.3 g, 45.1 mmol) as a yellow oil. ’H NMR (400 MHz, CDCL,) 87.62 - 7.46 (m, 1H). 7.46 - 7.31 (m, 1H), 5.77 - 4.65 (m, 3H), 4.44 - 4.04 (m, HI), 4.01 - 3.48 (m, 4H). 3.52 - 3.40 (m, 3H). 3.38 - 3.06 (m, 2H), 1.66 - 1.42 (m, 18H).

[1459]

[0376] Step 3. tert-butyl (S)-(2-(2-bromo-6-chloropyridin-4-yl)-2-oxoethyl)(l-((tert-butoxycarbonyl)amino)-3-methoxypropan-2-yl)carbamate

[1460]

[0377] To a solution of tert-butyl (2-(2-bromo-6-chloropyridin-4-yl)-2-hydroxyethyI)((S)-l-((tert- butoxycarbonyl)aroino)-3-methoxypropan-2-yl)carbamate (19.5 g, 36.2 mmol) in DCM (250 ml.) was added PCC (19.5 g, 90.5 mmol) and eelatom (19.5 g) at 0 °C. The reaction mixture was stirred at 35 °C for 12 hours under hL. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO?, 0-18% EtOAc / petroleum ether) to afford lerl-butyl (S)-(2-(2-bromo-6-chloropyridiii-4-yl)-2-oxoethyl)(l-((tert-butoxycarbonyl)amino)-3- methoxypropan-2-yl)carbamate (9.60 g. 17.9 mmol) as yellow oil. 11 NMR (400 MHz, CDCl3) 8 7.89 - 7.79 (111, HI), 7.77 - 7.65 (m, HI), 5.40 - 4.93 (m. 1H), 4.73 - 4.59 (m. 1H), 4.57 - 4.46 (m, HI), 4.46 - 4.23 (tn, 1H), 3.57-3.34 (m, 4H), 3.22 -3.09 (m. 3H). 1.57- 1.37 (m. 18H).

[1461]

[0378] Step 4. (S)-5-(2-bromo-6-chIoropyridin-4-yl)-2-(methoxymethyl)-l,3,6-tetrahydropyrazine

[1462]

[0379] To a solution of tert-butyl (S)-(2-(2-bronio-6-chloropyridin-4-yl)-2-oxoethyl)(l-((tert-butoxycarbonyl)amino)-3-methoxypropan-2-yl)carbamate (12.0 g, 22.4 mmol) in DCM (120 mL) was added TFA (60 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N?. The mixture was concentrated under reduced pressure to give crude (S)-5-(2-bromo-6-chloropyridm-4-yl)-2- (methoxymethyl)-l,2,3,6-tetrahydropyrazine (7.12 g, 22.3 mmol) as yellow solid which was used in the next step without further purification

[1463]

[0380] Step 5. (5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxyinethyl)piperazme

[1464]

[0381] To a solution of (S)-5-(2-bronio-6-chloropyridin-4-yl)-2-(methoxyinethyl)-l, 2,3.6-tetrahydropyrazine (7.12 g, 22.3 mmol) in AcOH (70 mL) was added zinc (7.11 g, 109 mmol) at 10 °C. The reaction mixture was stirred at 20 °C for 1 hour under N?. The mixture was filtered and concentrated

[1465] 94

[1466] QBM84200.00265'99930245.1 VVID 755PC under reduced pressure to give crude (5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)piperazine (7.16 g. 22.3 mmol) as yellow oil.

[1467]

[0382] Step 6 i-tert-butyl (2S^S)-2-(2-bromo-6-chloropyridin-4-yl)-5- (methoxymethyl)piperazine-l,4-dicarboxylate and di- rt-butyl (2R,5S)-2-(2-bromo-6- chloropyridin-4-yl)-5-(methoxymethyl)piperazine-l,4-dicarboxylate

[1468]

[0383] To a solution of (5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)piperazine (7.16 g, 22.3 mmol) in DCM (100 mL) was added TEA (15.5 mL, 11 3 g. 112 mmol) and BocjO (14.6 g, 67.0 mmol) at 0CC. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2). dried over NaeSCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to give di-tert- butyl (2S,5S)-2-(2-bromo-6-chloropyridiii-4-yl)-5-(methoxymethyl)piperazine-l,4-dicarboxylate (2.20 g, 4.22 mmol) as yellow oil. ’H NMR (400 MHz, CDCl3) 37.42 - 7.32 (m, 1H). 7.25 - 7.18 (m, 1H), 5.29 - 4.86 (m, HI), 4.44 - 3.90 (m, 3H), 3.60 - 3.39 (m, 3H), 3.36 (d, J - 7.5 Hz, 3H), 3.30 - 2.83 (m, 1H), 1.53 - 1.45 (m, 18H); and di-tert-butyl (2R,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5- (methoxymethyl)piperazine-l,4-dicarboxylate (5.40 g, 10.4 mmol) as yellow oil.1H NMR (400 MHz, CDCI3) 3 ppm 7.25 (s, 1H), 7.12 (s, 1H), 4.93 - 4.71 (m, 1H), 4.42 - 4.20 (m, 2H), 4.14 - 4.00 (m, 1H), 3.54 (s, 1H), 3.44 - 3.36 (m, 1H). 3.33 (s, 3H), 3.32 - 3.25 (m, 1H), 3.07 - 2.92 (m, 1H), 1.50 (s, 18H).

[1469]

[0384] Step 7. di-terf-butyl (2S^S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)piperazine-l,4-dicarboxylate

[1470]

[0385] To a solution of di-tert-butyl (2R,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxyinethyJ)-piperazme-l,4-dicarboxylate (5.40 g, 10.4 mmol) 111 MeCN (40 mL) was added DBU (1.55 mL, 1.58 g, 10.4 mmol) at 25 °C. The reaction mixture was stirred at 90 °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 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 (SiCL. 0-10% EtOAc / petroleum ether) to give di-tert-butyl (2S,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)piperazine-l,4-dicarboxylate (3.30 g. 6.34 mmol) as yellow oil.

[1471]

[0386] Step 8. (2S,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(niethoxymethyl)piperazine

[0387] To a solution of di-ferLbutyl (2S,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)-piperazine-l,4-dicarboxylate (6.0 g. 11.5 mmol) in MeOH (10 mL) was added HCl / MeOH (80 mL, 4 N) at 25 °C The reaction mixture was stirred at 25CC for 1 hour under N2. The mixture was concentrated mid reduced pressure to give crude (2S,5S)-2-(2-bromo-6-chloropyridin-4-yi)-5-(methoxymethyl)piperazine (3.60 g, 11.2 mmol).

[1472] 95

[1473] QB\184200.00265\99930245.1 VVID 755PC

[0388] Siep 9. tert-butyl (2S^S)-5-(2-bromo-6-chIoropyridin-4-yl)-2-(methoxymethyl)piperazine-1 -carboxylate

[1474]

[0389] To a solution of (2S,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(methoxymethyl)piperazine (1.52 g, 4.74 mmol) in DCM (50 mL) was added TEA (1.98 mb, 1.44 g, 142 mmol) and Boc2O (1.24 g. 5.69 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with w'ater (20 mL) and extracted with DCM (2.0 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 as purified by column chromatography (SiO-. 0-25% EtOAc / petroleum ether) to give tert-butyl (2S.5S)-5-(2-bromo-6-chloropyridin-4-yl)-2-(methoxymethyl)piperazme-l-carboxylate (1.50 g, 3.57 mmol) as yellow solid.

[1475]

[0390] Step 10. tert-butyl (2S, 5S)-4- acetyl- 5-(2-bromo-6-chloropyridm-4-yl)-2-(methoxymethyl)-piperazine-1 -carboxylate

[1476]

[0391] To a solution of tert-butyl (2S,5S)-5-(2-bromo-6-chloropyridin-4-yl)-2-(methoxymethyl)-pipcrazinc-1 -carboxylate (1.50 g, 3.57 mmol) in DCM (20 mL) was added TEA (0.991 mL, 0.722 g, 7.13 mmol) and acetyl chloride (0.420 g, 5.35 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under N2. The mixture w as diluted with water (20 L) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried overNazSCU filtered and concentrated wider reduced pressure. The crude product was purified by column chromatography (SiO,-.

[1477] 0-25% EtOAc / petroleum ether) to give tert-butyl (2S,5S)-4-acetyl-5-(2-broino-6-chloropyridin-4-yl)-2-(methoxymethyl)-piperazine-l -carboxylate (1.45 g, 3.13 mmol) as yellow solid. TI NMR(400 MHz, CDCI3) 8 ppm 7.40 - 7.34 (m, 1H), 7.25 - 7.21 (m, HI), 5.86 - 5.69 (m, 1H), 4.42 (dd.. / :::47.3, 14.6 Hz, 1H). 4.30 - 4.06 (m, 1H), 3.86 (dd. J = 25.1, 14.2 Hz. 1H). 3.54 - 3.42 (m, 1H). 339 (s, 3H), 3.36 - 3.14 (m. 2H), 3.12 - 2.98 (111, 1H), 2.22 (d,.7= 5.1 Hz, 3H). 1.58 - 1.50 (m, 9H).

[1478]

[0392] Step 11. l-((2S,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(hydroxymethyl)piperazin-l-yl)ethan-l-one

[1479]

[0393] To a solution of tert-butyl (2S,5S)-4-acetyl-5-(2-bromo-6-ch1oropyridin-4-yl)-2-(metboxy- methyl)piperazine-l -carboxy late (1.15 g, 2.49 mmol) in DCM (20 mL) ' s added BBr3(3.11 g, 12.4 mmol) at 0CC. The reaction mixture was stirred at 30 °C for 1 hour under N2. The mixture wus diluted with MeOH (30 mL) and NallCOs (1 g). The resulting mixture was filtered and the filter cakes w as washed with EtOAc (50 mL x 3). The combined filtrates w ere concentrated under reduced pressure, diluted with v. atcr (30 mL) and extracted with EtOAc (50 mL x 5). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 1 -((2S,5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(hydroxymethyl)piperazin-l-yl)ethan-l-one (1 09 g, 2.35 mmol) as yellow solid. ’H NMR (400 MHz, MeOD) 8 ppm 7.52 (s, 1H). 7.41 (s, 1H), 5.32 (s, 1H), 4.59 (s, 1H), 3.90-3.78 (m, 1H), 3.70-3.42 (m. 4H), 3.28 -3.19 (m, 1H), 3.15 (dd. J = 13.4, 4.9 Hz, 1H), 3.07 - 3.00 (m, 1H), 2.27 - 2.14 (m, 3H).

[1480] 96

[1481] QBM84200.00265'99930245.1 VVID 755PC

[1482]

[0394] Step 12. l-((2S^S)-4-acetyl-5-(2-bromo-6-chloropyridin-4-yl)-2-(hydroxymethyl)piperazm-l-yl)prop-2-en-l-one

[1483]

[0395] To a solution of l-((2S..5S)-2-(2-bromo-6-chloropyridin-4-yl)-5-(hydroxymethyl)piperazm-l- l)ethan-l-one (1.00 g, 2.87 mmoi) in THF (15 mL) and water (1.5 m ) was added MgO (1.73 g. 43.0 mmol) and acryloyl chloride (0.233 mL. 0.260 g. 2.87 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes The mixture was diluted with water (10 mL) and extracted with EtOAc (1 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried overNacSO-i, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-55% EtOAc / petroleum ether) to give l-((2S.5S)-4-acetyl-5-(2-bromo-6-chloropyridin-4-yl)-2- (hydroxymethyl)piperazin-l-yl)prop-2-en-l-one (900 mg, 2.24 mmol) as colorless oil.1H NMR (400 MHz, CDCl3) 3 ppm 7.45 - 7.33 (m, 1H), 7.31 - 7.08 (m, 1H), 6.61 - 6.28 (m, 2H), 5.96 - 5.60 (m, 2H), 5.05 - 4.56 (m, 1H), 4.08 - 3.90 (m, 2H), 3.85 - 3 59 (m, 3H). 3.46 - 3.05 (m, 2H), 2.35 - 2.20 (m. 3H).

[1484] General Procedure 12

[1485]

[0396] Synthesis of trans tert- butyl 2-(2-bromo-6-chloropyridin-4-yl)-3-methylmorpholine-4-carboxylate

[1486] NaBFg MeOH, -40 °c n-BuOH. 120 " C

[1487] step 1 step 3

[1488] Bo&jO DTBAD. PPh3MeOH, 25 °C toluene 25 °C step 4 steps

[1489]

[1490]

[0397] l-(2-bromo-6-chloropyridin-4-yl)-2-chloropropan-l -one was obtained as described in General Procedure 8, step 1.

[1491]

[0398] Step 1. l-(2-bromo-6-chloropyridin-4-yl)-2-chloropropan-l-ol

[1492]

[0399] To a solution of l-(2-bromo-6-chloropyridin-4-yl)-2-chloropropan-l-one (10.0 g, 35.3 mmol) in MeOH (100 mL) was added NaBH4 (2.09 g, 55.2 mmol) at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour under N2to give a solution of l-(2-bromo-6-chloropyridin-4-yl)-2-chloropropan-l-ol (10.0 g) in MeOH which was used in the next step without further purification.

[1493]

[0400] Step 2. cis 2-bromo-6-chloro-4-(3-methyloxiran-2-yl)pyridine

[1494] 97

[1495] QB\l84200.00265\99930245.1 VVID 755PC

[0401] To a solution of l-(2-bromo-6-chloropyridin-4-yl)-2-chloropropan-l-ol (10.0 g)) in MeOH (100 mL) was added NaOH (1.54 g, 38.6 mmol) in water (100 mL) at -10 °C. The reaction mixture was stirred at 25 ° for 16 hours under N2. The mixture was poured into aqueous HC1 (1 N, 100 mL) and extracted with EtOAc (100 ml. x 3) The combined organic layers were washed with brine (100 L x 2), dried oi er o.a SO.. filtered and concentrated under reduced pressure to give cis 2-bromo-6-chloro-4-(3-methyloxiran-2-yl)py ridine (9.00 g) as yellow oil which was used in the next step without further purification. '!H NMR (400 MHz. CDCi3) 8 ppm 7.38 (s. 1H), 7.25 (s. IH), 3.97 (d, J = 4.3 Hz. IH), 3.48 - 3.34 (m, IH), 1.12 (d, J- 5.4 Hz, 3H).

[1496]

[0402] Step 3. trans l-(2-bromo-6-chloropyridin-4-yl)-2-((2-hydroxyethyl)amino)propan-l-ol

[0403] To a solution of cis 2-bromo-6-chloro-4-(3-methyloxiran-2-yl)pyridine (900 g) in n-BuOH (90 mL) was added 2-aniinoethan-l-ol (3.32 g, 54.3 mmol) at 25 °C. The reaction mixture was stirred at 130 °C for 18 hours under N2. The mixture was concentrated under reduced pressure and purified by column chromatography (Si().. EtOAc) to afford trans l-(2-bromo-6-chloropyridin-4-yl)-2-((2-hydroxyethy l)amino)propan-l-ol (6.80 g, 22.0 mmol) as yellow oil.1H NMR (400 MHz, CDCl o 3 ppm 7.39 (s, IH), 7.25 (s, IH), 5.23 (s, IH), 4.11 (d, J= 7.3 Hz, IH), 3.67 (t. J = 5.1 Hz, 2H), 2.94 - 2.76 (m, IH), 2.67 - 2.50 (m, 2H), 2.45 - 2.20 (m, 2H), 1.04 (d, J- 6.5 Hz, 3H).

[1497]

[0404] Step 4. trans tert-butyl (l-(2-bromo-6-chloropyridin-4-yi)-l-hydroxypropan-2-yl)(2-hydroxyethyl)carbamate

[1498]

[0405] lb a solution of trans I-(2-brorno-6-chioropyridin-4-yl)-2-((2-hydroxyethyi)amino)propan-l-ol (4.80 g, 15.5 mmol) in MeOH (50 mL) was added di-tert-butyl decarbonate (4.06 g, 18.6 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture was concentrated under reduced pressure and purified by column chromatography (S1O2, 25-30% EtOAc / petroleum ether) to afford trans tert-butyl (l-(2-bromo-6-chloropyridin-4-yl)-l-hydroxypropan-2-yl)(2-hydroxyethyl)carbamate (6.00 g, 14.6 mmol) as yellow oil.

[1499]

[1500] NMR (400 MHz, CDCis) 6 ppm 7.44 (s, IH). 7.31 (s, IH), 5.66 (br d. J - 2.6 Hz, IH). 4.74 (br s. IH), 3.98 - 3.69 (m. 2H), 3.67 - 3.48 (m, IH).

[1501] 3.38 - 2.90 (m. 2H), 2.22 - 1.98 (m. IH), 1.47 (s, 8H), 1.36 - 1.13 (m. 3H).

[1502]

[0406] Step 5. trans tert-butyl 2-(2-bromo-6-cbloropyridin-4-yl)-3-methylniorpholine-4-carboxylate

[1503]

[0407] To a solution of trans tert-butyl (l-(2-bromo-6-chloropyridin-4-yl)-l-hydroxypropan-2-yl)(2-hydroxyethyl)carbamate (6.00 g, 14.6 mmol) in toluene (60 mL) was added PPh-< (5.76 g, 22.0 mmol) and di-tert-butyl azodicarboxylate (5.06 g. 22.0 mmol) at 0 °C. The reaction mixture was stirred at 30 °C for 12 hours under H:. 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 overNazSO^. filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 20-30% EtOAc / petroleum ether) to afford trans tert-butyl 2-(2-bromo-6-chloropyridin-4-yl)-3- 98

[1504] QB\184200.00265\99930245.1 VVID 755PC methylmorpholine-4-carboxylate (2.40 g. 6.13 mmol) as white solid. ‘H NMR (400 MHz. CDCh) 5 ppm 7.55 (s. 1H), 7.43 (s. 1H). 4.73 - 4.63 (m. 1H). 4.51 (s. 1H), 3.76 - 3.52 (m. 2H). 3.41 - 3.15 (m, 2H). 1.52 (s. 9H), 1.45 (d, J - 6.8 Hz, 3H).

[1505] General Procedure 13

[1506]

[0408] Synthesis of te / -butyl 3-(4-bromo-6-chloropyri(lin-2-yI)piperazine-l -carboxylate

[1507]

[1508]

[0409] 4-bromo-2-chloro-6-iodopyridine was obtained as described in General Procedure 14, step 1.

[1509]

[0410] Step 1. l-(4-bromo-6-chloropyridin-2-yI)-2-ch]oroethan-l-one

[1510]

[0411] To a solution of 4-bromo-2-chloro-6-iodopyridine (8.50 g, 26.6 mmol) in toluene (100 mL) was added iPrMgCl LiCl (26.7 mL, 34.7 mmol, 1.3 M in THF) at -20 °C under Nj. After stirring for 1 hour at -20 °C, 2-chloro-N-methoxy-N-methylacetamide (4.77 g. 34.7 mmol) in toluene (15 mL) was added dropw ise at -20 °C under N2The reaction mixture was stirred at 25 °C for 2 hours. The mixture was quenched with IN HC1 (120 mL) and extracted w ith EtOAc (130 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na-SCL, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOc, 0-5% EtOAc / petroleum ether) and triturated with w-hexane (15 mL) to give l-(4-bromo-6-chloropyridin-2-yl)-2-chloroethan-l-one (1.60 g. 5.95 mmol) as white solid.lH NMR (400 MHz, CDCl3) 5 = 8.17 (d. J= 1.5 Hz. 1H). 7.77 (d.. / - 1.5 Hz, 1H). 5.03 (s, 2H).

[1511]

[0412] Step 2. 5-(4-bromo-6-chloropyridin-2-yl)-l,2,3,6-tetrahydropyrazine

[1512]

[0413] To a solution of l-(4-bromo-6-chloropyridin-2-yl)-2-chloroethan-l-one (466 mg, 1.73 mmol) in 1,4-dioxane (10 mL) was added 4 A molecular sieves (500 mg) and ethane- 1,2-diamine (360 mg, 5.99 mmol) at 0 °C. The reaction mixture!as stirred at 60 °C for 2 hours under N2. The mixture was filtered and concentrated under reduced pressure to give crude 5-(4-bromo-6-chloropyridin-2-yl)-l, 2,3.6-tetrahydropyrazine (465 mg, 1.73 mmol) which was used in the next step without further purification.

[1513]

[0414] Step 3. 2-(4-bromo-6-chloropyridin-2-yl)piperazine

[1514]

[0415] To a solution of 5-(4-bromo-6-chloropyridin-2-yl)-l,2,3,6-tctrahydropyrazinc (475 mg, 1.73 mmol) in MeOH (8 mL) was added NaBIfi (320 mg, 8.46 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes. The mixture was quenched by the addition of HC1 (10 mL, 4 N in MeOH) to give crude 2-(4-bromo-6-chloropyridin-2-yl)piperazine (475 mg, 1,72 mmol). The crude product in MeOH was used in the next step without further purification.

[1515] 99

[1516] QB\l84200.00265\99930245.1 VVID 755PC

[0416] Step 4. tert-butyl 3-(4-biomo-6-chloropyriditi-2-yl)piperaziiie-l-carboxylate

[1517]

[0417] To the solution of 2-(4-bromo-6-chloropyridin-2-yl)piperazine (475 mg, 1.72 mmol) in MeOH (5 mL) was added triethylamine (348 mg. 3.44 mmol) and di-tert-butyl dicarbonate (375 mg, 1.72 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes under N?. 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). dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOz, 40-50% EtOAc / petroleum ether) to give tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)piperazine-l-carboxylate (250 mg, 0.664 mmol) as yellow oil.1H NMR (400 MHz, CDCl3) S = 7.53 (br s, 1H), 7.44 (s, 1H), 432 - 4.14 (m, 1H), 3.94 (br d, J = 11.6 Hz, 1H). 3.88 - 3.78 (m. 1H), 3.09 - 2.79 (m, 4H), 2.19 - 2.07 (m, 1H), 1.48 (s, 9H).

[1518] General Procedure 14

[1519]

[0418] Synthesis of trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperazine-l-carboxylate

[1520] k I TMPMQCHJCI THF 0 - 20 '-C sstep 1

[1521] frans-racemate c / s- racemate

[1522] BocgO. NEtg □CM, 25 °C step 8

[1523]

[1524] trans<acemate

[1525]

[0419] Step 1. 4-bromo-2-chloro-6-iodopyridine

[1526]

[0420] To a solution of’4-bromo-2-chloropyridine (28.0 g, 146 mmol) in THF (200 mL) was added TMPMgCl LiCl (174 mL, 174 mmol, 1.0 M in THF) drop w. sc at 0 °C under Nz. The mixture was stirred for 1 hour at 0 °C and then iodine (38.8 g, 153 mmol) was added at 0 °C. The mixture was stirred for 2 hours at 20 °C. quenched with saturated aqueous NH4C1 solution (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with saturated aqueous NazSOj solution (200 mL), dried over NazSO^ filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOz, 0-2% EtOAc / petroleum ether) to give 4-bromo-2-chloro-6-

[1527] 100

[1528] QB\l84200.00265\99930245.1 VVID 755PC iodopyridine (24.0 g, 67.9 mmol) as yellow solid. ‘H NMR (400 MHz. CDCh) 8 = 7.87 (s, 1H), 7.50 (s, 1H).

[1529]

[0421] Step 2 1-(4-bromo-6-chloropyridin-2-yl)-2-chIoropropan- 1-one

[1530]

[0422] To a solution of l-(4-bromo-6-chloropyridin-2-yl)-2-chloropropan-l-one (17.4 g. 54.7 mmol) in toluene (170 ml) was added iPrMgCl LiCl (54.0 mL. 70.2 mmol, 1.3 M in THF) at -20 °C under N2. After stirring for 30 minutes at -20 °C, 2-chloro-N-methoxy-N-methylpropanamide (10.8 g, 71.1 mmol) in toluene (20 mL) was added dropwise at -20 °C under Nz. The reaction mixture was stirred at 25 °C for 2 hours The mixture was quenched with saturated aqueous NH4C1 solution (300 mL) and extracted with EtOAc (300 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 (SiO20-1% EtOAc / petroleum ether) to give l-(4-bromo-6-chloropyridin-2-yl)-2-chloropropan-l-one (9.40 g, 33.2 mmol) as colorless oil.1H NMR (400 MHz, CDCI3) 8 8.16 (d, J = 1.5 Hz, 1H), 7.75 (d,.7 = 1.6 Hz, 1H), 5.88 - 5.77 (m, 1H), 1.75 (d,.7= 6.9 Hz, 3H).

[1531]

[0423] Step 3. 5-(4-bromo-6-chloropyridin-2-yl)-6-methyl-l,2,3,6-tetrahydropyTazine

[1532]

[0424] To a solution of 1-(4-bromo-6-chloropyridin-2-yl)-2-chloropropan-1-one (9.40 g, 33.2 mmol) in MeOH (100 mL) was added 4 A molecular sieves (10 g) and ethane-i,2-dianiine (6.62 g, 110 mmol) at 0 °C. The reaction mixture was stirred at 65 °C for 1 hour under N2 and filtered. The filtrate containing 5-(4-bromo-6-chloropyridin-2-yl)-6-methyl-1,2,3,6-tetrahydropyrazine was used in the next step without further purification.

[1533]

[0425] Step 4. 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine

[1534]

[0426] To a solution of 5-(4-bromo-6-chloropyridin-2-yl)-6-methyl-l,2,3,6-tetrahydropyrazine (8.00 g. 27.7 mmol) in MeOH (70 mL) was added NaBH4 (5.85 g, 155 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under Nz. The mixture was quenched by the addition of HCl (40 mL, 4 N in MeOH) and concentrated under reduced pressure to afford 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine (7.00 g. 24.2 mmol) as yellow solid. The crude product was used in the next step w ithout further purification.

[1535]

[0427] Step 5. Mixture of trans di-tot-butyl 2-(4-bromo-6-chloropyridin-2-yI)-3-methylpiperazine-l,4-dicarboxylate and cis di-tert-butyl 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate

[1536]

[0428] To the solution of 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine (8.50 g. 21.8 mmol) in DCM (100 ml.,) was added triethylamine (6.60 g, 9.07 mL, 65.3 mmol) and di-tert-butyl dicarbonate (9.50 g, 43.5 mmol) at 0 °C. The reaction mixture slowly warmed to 25 °C and stirred for 12 hours under Nz. The mixture was diluted with water (150 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under 101

[1537] QBM84200.00265'99930245.1 VVID 755PC reduced pressure. The crude product was purified by column chromatography (SiO2, 0-5% EtOAc / petroleum ether) to give a mixture of trans di-tert-butyl 2-(4-bromo-6-chloropyridin-2-yI)-3-methylpiperazine-1,4-dicarboxylate and cis di-tert-butyl 2-(4-bromo-6-chloropyridin-2-yl)-3- methylpiperazine- 1,4-dicarboxylate (8.40 g, 13.7 mmol, trans:cis -1:2) as white solid.

[1538]

[1539] NMR (400 MHz, CDCl3) 8 - 7.41 (d., / - 1.3 Hz, 1H), 7.31 (d. J - 1.3 Hz, 1H). 5.04 (d. J - 6.3 Hz, 1H). 4.63 (br t. J = 6.8 Hz, 1H), 4.29 - 4.19 (m, 1H).3.97 - 3.74 (m, 1H), 3.19 - 2.98 (m, 1H). 1.47 - 1.40 (m, 9H), 1.38 - 1.33 (m. 2H), 1.26 (s. 9H), 1.01 (d, J= 7.1 Hz, 3H).

[1540]

[0429] Step 6. trans di-tert-butyl 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate

[1541]

[0430] To a mixture of trans di-tert-butyl 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine-1.4-dicarboxylate and cis di-tert-butyl 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine-l,4-dicarboxylate (6.40 g, 13.0 mmol) in MeCN (80 ml.,) was added DBU (2.93 mL, 2.98 g, 19.6 mmol) at 0 °C. The reaction mixture was stirred at 90 °C for 12 hours under N2. The cooled mixture was diluted with water (100 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0-5% EtOAc / petroleum ether) and prep-HPLC (Welch Xtimate C18, 250 x 100 mm, 10 μm, 55 - 90% ACN / H2O (10 mM NH4HCO3)) to give trans di-tert- butyl 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine-l,4-dicarboxylate (5.65 g. 11.5 mmol) as white solid. 'H NMR (400 MHz. CDCL) 5 - 7.41 (br d, J = 9.7 Hz, 1H), 7.22 (s. 1H), 5.38 - 5.26 (m, 1H), 5.18 - 4.89 (m, 1H). 4.14 - 3.86 (m, 1H), 3.84 - 3.64 (m, 1H), 3.24 - 2.89 (m, 2H), 1.56 - 1.38 (m, 18H). 1.35 (br d, J = 6.8 Hz, 3H).

[1542]

[0431] Step 7. trans 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine

[1543]

[0432] To a solution of trans di-tert-butyl 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine-1,4-dicarboxylate (5.65 g, 11.5 mmol) in MeOH (30 mL) was added HC1 (30 mL. 4 N in MeOH). The mixture was stirred at 30 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude trans 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine (3.30 g, 11.4 mmol) as HC1 salt as white solid. The crude product was used for the next step without further purification.1H NMR (400 MHz, CD3OD) 5 = 7.99 (s, 2H). 4.79 - 4.72 (m. 1H). 3.87 - 3.64 (m. 4H), 3.60 - 3.46 (m, 1H), 1.28 (d, J = 6.6 Hz, 3H).

[1544]

[0433] Step 8. trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yI)-2-methylpiperazine-l-carboxylate

[1545]

[0434] To the solution of trans 2-(4-bromo-6-chloropyridin-2-yl)-3-methylpiperazine as HCl salt (3.30 g, 11.4 mmol) in DCM (30 mL) was added trie thy lamine (4.02 g, 5.54 mL, 39.7 mmol). Di-tert-butyl dicarbonate (2.73 g, 12.5 mmol) in DCM (10 mL) was added dropw’ise at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2. The mixture w as concentrated wider reduced pressure, diluted 102

[1546] QBM84200.00265'99930245.1 VVID 755PC with water (100 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with brine (100 mL), 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 trans tert-butyl 3-(4-bromo-6-chloropyridin-2-yl)-2-methylpiperazine-1-carboxylate (1.61 g, 4.12 mmol) as white solid.

[1547]

[1548] NMR (400 MHz, CDCl3) 8 - 7.64 (s. 1H), 7.41 (d, J - 0.8 Hz, 1H), 4.88 (br d, J - 6.8 Hz. 1H). 3.82 - 3.75 (m, 2H), 3.20 - 3.08 (m. 1H), 2.67 (brd,.7 = 1.9 Hz. 1H). 2.57 - 2.47 (m, 1H), 1.51 (s. 9H), 1.45 (d, J= 6.9 Hz. 3H).

[1549] General Procedure 15

[1550]

[0435] Synthesis of 2-methyl-6-(trimethylstannyl)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-1-one, Sn2(CH3)6T| NBS AIBN II (30% in MeOH) / / Pd(dtbpf)Cl2W "o' - -blWv - -UYMN- -

[1551]

[1552] DCE, 80 °C iV A., Br TEA. MeOH, 70 °C toluene. 120 °C step 1 step 2 step 3

[1553]

[0436] Step 1. methyl 5-(bromomethyl)-2-chloroisonicotinate

[1554]

[0437] 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 mixture was stirred at 85 °C for 0.5 hour under N2. The reaction mixture was diluted with water (80 mL). The mixture was extracted with DCM (50 mL x 3). dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product w as 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. 'H1H NMR (400 MHz, CDCl3) 8 ppm 8.52 (s, 1H), 7.81 (s, 1H), 4.86 (s. 2H), 4.00 (s, 3H).

[1555]

[0438] Step 2. 6-chloro-2-methyl-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-one

[1556]

[0439] 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 phase was 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-1H-pyrrolo[3,4-c]pyridin-1-one (3.00 g, 16.4 mmol) as white solid. H NMR (400 MHz, CDCl3) 5 ppm 8.56 (s, 1H), 7.73 (s. 1H), 4.47 (s, 2H), 3.22 (s, 3H).

[1557]

[0440] Step 3. 2-methyl-6-(triniethylstannyl)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-one

[0441] To a solution of 6-chloro-2-methyl-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-one (800 mg. 4.38 mmol) in toluene (5 mL) was added Sn2(CH3)6(2153 mg, 6.57 mmol) and Pd(dtbpf)Cl2(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 103

[1558] QB\184200.00265\99930245.1 VVID 755PC 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 (Al2O3, 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.

[1559]

[1560] NMR (400 MHz, CDCl3) 8 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).

[1561] General Procedure 16

[1562]

[0442] Synthesis of 6-methyl-2-(trimethylstannyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one MeNH2Sn2(CH3)6NBS, AIBN (30% in MeOH) o CH N, JJ DCE, 85 °C toluene 120 °C

[1563]

[1564] step 1 step 2 step 3

[1565]

[0443] Step 1. methyl 3-(bromomethyl)-6-chloropicolinate

[1566]

[0444] To a solution of methyl 6-chIoro-3-methylpicolinate (9.50 g, 51.2 mmol) in DCE (100 mL) was added AIBN (420.00 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 Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 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, CDCl3) 8 ppm 7.86 (d, J- 8.0 Hz, 1H), 7.49 (d.. / - 8.0 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H).

[1567]

[0445] Step 2, 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin- 7-one

[1568]

[0446] To a solution of methyl 3-(bromomethyl)-6-chloropicolinate (1.00 g, 3.78 mmol) in MeOH (10 mL) was added TEA (765 nig, 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-b]pyridin-7-one (550.0 mg, 3.01 mmol) as white solid.1H NMR (400 MHz. CDCI3) 8 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).

[1569]

[0447] Step 3 6-methyl-2-(trimethylstannyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0448] 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 mL) was added Sn2(CH3)6(1010 mg, 3.08 mmol) and Pd(dtbpf)Cl2(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 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4. filtered and concentrated under reduced

[1570] 104

[1571] QBM84200.00265'99930245.1 VVID 755PC pressure. The crude product was purified by column chromatography (SiCL, 0-100% EtOAc / petroleum ether) to afford 6-metbyJ-2-(trimethylstannyl)-5.6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (200 mg. 0.322 mmol) as yellow solid.1H NMR (400 MHz, CDCl3) 5 ppm 7.66 - 7.62 (m, 1H), 7.59 - 7.54 (m, 1H), 4.35 (s. 2H), 3.27 (s, 3H), 048 - 028 (m, 9H).

[1572] General Procedure 17

[1573]

[0449] Synthesis of 6-methyi-3-(trimethylstannyl)-6,7-dihy(lro-5H-pyrrolo[3,4-b]pyrazin-5-one0O MeNHi Sn2(CH3)6NxXz1 DBDMH. TFAQ(30% in MeOH)C| N» Pd(dtbpf)Cl2J[ "" T^ X Cl - ► Y 'V' O - ► p i| \, _ _ < |T _ L Ji 2. (OEt)2P(O)H, DIEA TEA, 25 °C toluene, 120 °C

[1574]

[1575] step 1 step 2 step 3

[1576]

[0450] Step 1. methyl 3-(bromomethyl)-6-chloropyrazine-2-carboxylate

[1577]

[0451] Solution 1: methyl 6-chloro-3"methylpyrazine-2-carboxylate (3.50 g, 18.75 mmol) and DBDMH (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 w ater (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was dried with anhydrous Na2SO4filtered 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. ’ll NMR (400 MHz, CDCl3) 5 ppm 8.74 - 8.69 (m, 1H), 5.02 - 4.94 (m, 2H), 4.05 (s, 3H)

[1578]

[0452] Step 2. 3-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

[1579]

[0453] To a solution of methyl 3-(bromomethyl)-6-chloropyrazine-2-carboxylate (3.00 g, 11.30 mmol) in MeOH (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 phase was dried with anhydrous 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-pyrrolo[3,4-b]pyrazin-5-one (3.30 g, 8.99 mmol) as white solid. ‘H NMR (400 MHz, CDCl3) 6 ppm 8.68 (s, 1H), 4.51 (s. 2H), 3.32 (s, 3H).

[1580]

[0454] Step 3. 6-jnethyl-3-(trimethylstanny!)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

[0455] 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 mL) was added Sn2(CH3)6(803 mg, 2.45 mmol) and Pd(dtbpf)Cl2(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 105

[1581] QBM84200.00265'99930245.1 VVID 755PC 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 (Al2O3, 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.lH NMR (400 MHz, CDCl3) 5 ppm 8.65 (s. 1H). 4.44 (s, 2H), 3.31 (s, 3H). 0.55 - 0.33 (m, 9H).

[1582] General Procedure 18

[1583]

[0456] Synthesis of 2-methyl-7-(trimethylstannyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-one

[1584]

[1585]

[0457] Step 1 methyl 5-(2-((r<?rt-butoxycarbonyl)amino)ethyl)-2-chIoroisonicotinate

[1586]

[0458] 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)CL (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 Na2SO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 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, CDCl3) 3 ppm 8.39 - 8.27 (in, 1 H), 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).

[1587]

[0459] Step 2. methyl 5-(2-aminoethyl)-2-chloroisonicotinate

[1588]

[0460] To a solution of methyl 5-(2-(( / err-butoxycarbonyl)amino)ethyJ)-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.1H NMR (400 MHz, CD3OD) 6 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).

[1589] 106

[1590] QB\184200.00265\99930245.1 VVID 755PC

[0461] Step 3. 7-chloro-3,4-dihydro-2,6-naphthyridin-l(2H)-one

[1591]

[0462] 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 N2The 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.1H NMR (400 MHz, CDCl3) 3 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 (ra, 2H).

[1592]

[0463] Step 4 7-chloro-2-methyI-3,4-dihydro-2,6-naphthyridin-l(2H)-one

[1593]

[0464] 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 w as purified by column chromatography (SiO2, 30-80% EtOAc / petroleum ether) to give 7-chloro-2-methyl-3,4-dihydro-2,6-naphthyridin-1(2H)-one (7.80 g, 39.7 mmol) as yellow' oil.1H NMR (400 MHz, CDCl3) δ 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 (in. 2H).

[1594]

[0465] Step 5. 2-methyl-7-(trimethylstannyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-one

[1595]

[0466] 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)6(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 w'ith EtOAc (10 mL x 2). The combined organic layers were w'ashed 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-1(2H)-one (1.80 g, 5.54 mmol) as colorless oil.1H NMR (400 MHz, CDCl3) 8 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).

[1596] General Procedure 19

[1597]

[0467] Synthesis of 7-methyl-2-(trimethylstannyl)-6,7-dihydro-1,7-naphthyridin-8(5H)-one

[1598] 107

[1599] QB\184200.00265\99930245.1 VVID 755PC F

[1600] toluene, N2, 80 °C step 1 step 2 step 3

[1601]

[1602] toluene 110 °C step 4 step 5

[1603]

[0468] Step 1. methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloropicolinate

[1604]

[0469] 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)trifluoroborate (7.22 g, 28.7 mmol), CS2CO3 (15.6 g, 47.9 mmol) and Pd(dtbpf)Cl2(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 Na2SO4. filtered and concentrated under reduced pressure. The crude product was purified by column chromatography ( SiO20-100% EtOAc / petroleum ether) to afford methyl 3-(2-((tert- butoxycarbonyl)amino)ethyl)-6-chloropicolinate (4.00 g, 12.7 mmol) as white solid.1H NMR (400 MHz, CDCl3) δ 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).

[1605]

[0470] Step 2. methyl 3-(2-aminoethyI)-6-chloropicolinate

[1606]

[0471] To a solution of methyl 3-(2-((ferr-butoxycarbonyl)amino)ethyl)-6-chloropicolinate (4.00 g, 12.7 mmol) in DCM (50 mL) was added TFA (20 mL) at 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) 8 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).

[1607]

[0472] Step 3. 2-chloro-6,7-dihydro-l,7-naphthyridin-8(5H)-one

[1608]

[0473] 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,

[1609] 0-100% EtOAc / petroleum ether) to afford 2-chloro-6,7-dihydro-l,7-naphthyridin-8(5H)-one (1.18 g, 6.46 mmol) as yellow solid. Hl NMR (400 MHz, CDCI3) 8 ppm 7.59 (d, J - 8.0 Hz, 1 H ), 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).

[1610] 108

[1611] QB\184200.00265\99930245.1 VVID 755PC

[0474] Step 4. 2-chloro-7-methyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one

[1612]

[0475] To a solution of 2-chloro-6.7-dihydro-1.7-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 Na2SO4. filtered and concentrated under reduced pressure The crude product was purified by column chromatography (SiO2, 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.1H NMR (400 MHz, CDCl3) δ ppm 7.53 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 3.62 (t, J = 6.7 Hz,

[1613] 2H), 3.21 (s. 3H), 3.05 (t. J = 6.1 Hz, 2H)

[1614]

[0476] Step 5. 7-methyl-2-(trimethylstannyI)-6,7-dihydro-l,7-naphthyridin-8(5H)-one

[1615]

[0477] 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)6(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 sat. KF (20 mL) and extracted with EtOAc (25 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 (AI2O3. 0-100% EtOAc / petroleum ether) to afford 7-methyl-2-(trimethylstannyl)-6,7-dihydro-1,7-naphthyridin-8(5H)-one (60.0 mg, 0.185 mmol) as a yellow solid. 'H NMR (400 MHz, CDCl3) 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).

[1616] General Procedure 20

[1617]

[0478] Synthesis of 6-methyl-3-(trimethylstannyl)-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one

[1618] step 1 step 2 step 3

[1619] Sn2(CH3)6o - NaH, DMF, 0 - 25 " C J Pd(dtbpf)Cl2

[1620]

[1621] toluene, 120 °C step 4 step 5

[1622]

[0479] Step 1, methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloropyrazine-2-carboxylate

[0480] To a solution of methyl 3-bromo-6-chloropyrazine-2-carboxylate (2.00 g, 7.95 mmol) in toluene (40 mL) and water (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 109

[1623] QB\l84200.00265\99930245.1 VVID 755PC 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 ntL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (50 mL). brine (50 mL). dried over Na2SO4. filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 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. *14 NMR (400 MHz, CDCl3) 8 ppm 8.68 (s. IH), 5.05 - 4.89 (m, 1H), 4.01 (s. 3H), 3.65 - 3.56 (m. 2H), 3.35 (t, J = 6.4 Hz, 2H), 1.40 (s, 9H).

[1624]

[0481] Step 2. methyl 3-(2-aminoethyl)-6-chloropyrazine-2-carboxylate

[1625]

[0482] 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, Tire mixture was concentrated under reduced pressure to give methyl 3- (2-aminoethyl)-6-chloropyrazine-2-carboxylate (340 mg, 1.58 mmol) as yellow solid.

[1626]

[0483] Step 3. 3-chloro-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one

[1627]

[0484] 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 w ater (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 ( SiO 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.lH NMR (400 MHz, CDCl3) δ 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).

[1628]

[0485] Step 4. 3-chloro-6-methyl-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one

[1629]

[0486] 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 as poured into aq. NffL. Cl (20 mL) and extracted wdlh DCM (20 L x 5). 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 3-chloro-6-methyl-7,8-dihydropyrido[3.4-b]pyrazin-5(6H)-one (490 mg, 2.48 mmol) as yellow' solid.iH NMR (400 MHz, CDCl3) 8 ppm 859 (s. IH). 3.72 (t, J= 6.8 Hz. 2H), 3.29 (t, J = 6.8 Hz. 2H), 3.23 (s, 3H).

[1630]

[0487] Step 5. 6-methyl-3-(trimethylstannyI)-7,8- dihydropyrido [3,4-b] pyrazin-5(6H)-one

[1631] 110

[1632] QBM84200.00265'99930245.1 VVID 755PC

[0488] 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 Sm CHals (1.22 g. 3.72 mmol) and Pd(dtbpf)Ch (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 NaiSO:. filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOz, 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.1H NMR (400 MHz, CDCl3) 5 ppm 8.55 (s, 1H. 3.67 (t, J- 6.7 Hz, 2H, 3.28 - 3.21 (m. 511), 0.52 - 0.34 (m, 9H).

[1633] General Procedure 21

[1634]

[0489] Synthesis of 2-methyl-7-(trimethylstannyl)-2,6-naphthyridin-l (2H)-one

[1635] TsOH toluene, 35 °C step 1 step 2 step 3

[1636]

[1637] toluene, 120 X step 4

[1638]

[0490] Step 1. 5-bromo-2-chloro-N-methylisonicotmamide

[1639]

[0491] To a solution of 5-bromo-2-chloroisonicotinic acid (5.00 g, 21 1 mmol) in DCM (50 mL) was added MeNHz HCl (2.14 g. 31.7 mmol). T4P (22.9 g, 31.7 mmol) and DIPEA (7.37 mL, 547 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 layer was washed with brine (30 mL x 2), dried over Na SOi, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO. 50-100% EtOAc / petroleum ether) to give5-bromo-2-chloro- N-methylisomcotinamide (4.50 g, 18.0 mmol) as yellow oil. 'H NMR (400 MHz, CDCl3) 5 ~ 8.53 (s, 1H). 7.53 - 7.37 (m, lH), 6.52 - 6.21 (m, 1H), 3.09 - 2.91 (m, 3H).

[1640]

[0492] Step 2. (E)-2-chloro-5-(2-ethoxyvinyl)-N-methylisomcotmaniide

[1641]

[0493] To a solution of 5-bronio-2-chloro-N-methylisonicotinamide (2.50 g, 10,0 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added tran, s-2 -ethoxy vinylboronic acid pinacol ester (1.98 g, 10.0 mmol), K2CO3 (2,08 g, 15,0 mmol) and Pd / PPhyL. (1.10 g, 0.952 mmol) at 25 °C under Nz. 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 layer was washed with brine (30 mL), dried over NazSO / i, filtered, and concentrated under reduced pressure. The crude product was purified by column

[1642] 111

[1643] QB\184200.00265\99930245.1 VVID 755PC chromatography ( S1O2, 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-meth lisonicotinamide (1.78 g, 6.23 mmol) as white oil. The mixture was used in the next step without further separation.

[1644]

[0494] Step 3. 7-chloro-2-nietliyl-2,6-naplithyridiii-1 (2H)-one

[1645]

[0495] 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 combined organic layers were washed with brine (20 mL), dried over Na2SO4, 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 NH3HCO3)) to give 7-chloro-2-methyl-2,6-naphthyridin-l(2H)-one (800 mg, 4.11 mmol) as yellow solid.XH NMR (400 MHz, CDCb) 5 = 8.76 (s, 1H), 8.23 (s, 1 H), 7.18 (d, J- 7.4 Hz, 1H), 6.56 (d, J - 7.4 Hz, 1H), 3.63 (s, 3H).

[1646]

[0496] Step 4. 2-methyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-one

[1647]

[0497] To a solution of 7-chloro-2-niethyl-2,6-naphthyridin-l(2H)-one (400 mg, 2.06 mmol) in toluene (5 mL) was added SmtCHOe (1.68 g, 2.49 mmol) and Pd(dtbpl 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 w ith EtOAc (20 L x 3). The combined organic layers were washed with brine (20 mL), dried over NaeSCh, filtered and concentrated under reduced pressure. The crude product w as 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.lH NMR (400 MHz. CDCI3) 5 = 9.09 (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).

[1648] General Procedure 22

[1649]

[0498] Synthesis of 2 -dimethyI-7-(trimethylstannyl)-2,6-naphthyridin- 1 (2H)-one

[1650] Step "12Step 2 step 3 Sn2(CH;j6Pd(a(bpf)CI2

[1651]

[1652] toiuene, 120 'C Step 4

[1653]

[0499] Step 1. (E)-2-chloro-5-(2-nitroprop-l-en-l-yl)isonicotimc acid

[1654]

[0500] 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- 112

[1655] QBM84200.00265'99930245.1 VVID 755PC chloro-5-formyl-pyridine-4-carboxylate (2.67 g. 13.4 mmol) m 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-1-yl)isonicotinic acid (2.00 g. 8.24 mmol) as yellow' solid. ’ll NMR (400 MHz, CD3OD) 6 ~ 8.48 (s, 1H).

[1656] 8.36 (s, 1H), 800 (s, Iff).2.26 (s. 3H).

[1657]

[0501] Step 2. 7-chloro-3-methyl-2,6-naphthyridin-l(2H)-one

[1658]

[0502] To a mixture of (E)-2-chloro-5-(2 -nitroprop- 1 -en-l-yl)isonicotinic acid (2.20 g, 9.07 mmol) in AcOH (20 mL) was added Fe (3.55 g, 63.5 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 12 hours under N7„ The mixture was concentrated under reduced pressure. The residue was diluted with aq. NaHCO3 (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 Na2SO4, filtered and concentrated under reduced pressure. The residue as 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.1H NMR (400 MHz, CD3OD) 5 - 8.76 (s, Iff), 8.05 (s, 1H), 6.53 (s, 1H), 2.34 (d, J = 0.9 Hz, 3H).

[1659]

[0503] Step 3. 7-chloro-2 -dimethyl-2,6-naphthyridin-l(2II)-one

[1660]

[0504] To a solution of 7-chloro-3-methyl-2,6-naphthyridin-l(2H)-one ( 1.60 g. 8.22 mmol) in DMF (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 L x 2), dried over Na SCfi. 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.rH NMR (400 MHz, CDCl3) 5 8.67 (s. Iff), 8.17 (s. Ill), 6.43 (s, 1H).

[1661] 3.62 (s, 3H), 2.46 (s, 3H).

[1662]

[0505] Step 4 2 -dimethyl-7-(trimethylstannyl)-2,6-naphthyridin-l(2H)-one

[1663]

[0506] 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 Snz(CH3)6 (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 KF (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over NazSO.., filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3. 20% EtOAc / petroleum ether) to afford 2,3- 113

[1664] QBM84200.00265'99930245.1 VVID 755PC dimethyl-7-(trimethylstaimyl)-2,6-naphthyridin-l(2H)-one (500 mg. 1.48 mmol) as brown solid.1H NMR (400 MHz. CDCU) 5 = 9.01 (s. IH), 8.31 - 8.23 (nt, IH), 6.41 (s. IH). 3.63 (s, 3H), 2.46 (s, 3H), 0.49 - 0.29 (m, 9H).

[1665] General Procedure 23

[1666]

[0507] Synthesis of 2,4-diniethyl-7-(trimethylstannyl)-2,6-naphthyridin-l (2H)-one

[1667] O ■' O Pd(OAc)2O Sn2{CH3ls | O H Cl. M®NCy2. PCy3^ Cl>^ AN^ P< J{ctbpf)CI2. Lia LR DIPEA NL%.1DMA. 100 " C toluene, 120 °C DCM i I

[1668]

[1669] Step 1 Step 2 Step 3

[1670]

[0508] Step 1. N-allyl- bromo-2-chloro-N-methylisomcotinamide

[1671]

[0509] 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-Metliylallylamine (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 NazSO.s, filtered and concentrated under reduced pressure. The crude product w as purified by column chromatography (SiOz. 0-35% EtOAc / petroleum ether) to give N- allyl-5-bromo-2-chloro-N-metbylisonicotinarnide (2.40 g. 8.29 mmol) as yellow solid.1H NMR (400 MHz, CDCl3) 88.58 (d, J = 2.5 Hz, 1 H), 7.30 (s. IH), 5.99 - 5.67 (m. IH), 545 - 5.14 (m, 2H), 4.22 (d,. / == 71.0 Hz, IH), 383 - 3.66 (m, IH), 3.18 - 2.82 (m. 3H).

[1672]

[0010] Step 2. 7-chloro-2,4-dimethyl-2,6-naphthyridin-l(2H)-one

[1673]

[0511] To a solution of N-allyl-5-bromo-2-chloro-N-methylisomcotinamide (2.20 g, 7.60 mmol) in DMA (25 mL) was added Pd(OAc)? (85.3 mg, 0.380 mmol), A'. A'-Dicyclohexylmethylamine (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 Na^SO^, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOz, 0-70% EtOAc / petroleum ether) to give 7-chloro-2,4-dimcthyl-2,6-naphthyridin-l(2H)-onc (830 mg, 3.98 mmol) as yellow' solid.!H NMR (400 MHz, CDCl3) 5 - 8.82 (s, IH), 8.25 (s, IH), 6.94 (s, IH), 3.59 (s, 3H). 2.35 (s, 3H).

[1674]

[0512] Step 3. 2,4-dimethyl-7-(triniethylstaniiyl)-2,6-naphthyridin-l(2H)-one

[1675]

[0513] To 7-chloro-2,4-dimethyl-2,6-naphthyridin-l(2H)-one (830 mg, 3.98 mmol) in toluene (15 mL) was added Sii2(CH3)6 (2.13 g, 6.50 mmol) and Pd(dtbpf)Cl2 (256 g, 0.398 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 10 hours under Nj. The mixture was poured into aqueous KF (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over NazSO-i, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ALOj, 0-35% EtOAc / petroleum ether) to afford 2,4-dimethy l-7- 114

[1676] QB\184200.00265\99930245.1 VVID 755PC (trimethylstannyl)-2.6-naphthyridin-l(2H)-one (870 mg. 2.58 mmol) as yellow solid.1H NMR (400 MHz. CDCh) 6 = 9.21 (d, J = 0.8 Hz. 1 H), 8.37 (d, J = 0.8 Hz. 1 H). 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).

[1677] General Procedure 24

[1678]

[0014] Synthesis of 2-methyl-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l (2H)-one

[1679] o o o II A Na: O4, RuCk NHnNH2H2O 9 - - - - V Y0- - - H Y ° - - -CIY'',Y%I NYABI. Pct(dppf)C,2, KJCO3N'A MBCN / HP. 25 °C EtOH. 60 °C dioxane / HjO, 80 C step 1 step 2;tep 3 Mel, KjCO, Sn2(CH3)6DMF. 25 °C Pd(ci'L'pf; Clj toluene 120 °C

[1680]

[1681] step 4 step 5

[1682]

[0515] Step 1. methyl 2-chloro-5-vinylisonicotmate

[1683]

[0516] To a solution of methyl 5-bromo-2-chloro-pyridine-4-carboxylate (9.50 g, 37.9 mmol) in 1.4- dioxanc (100 mL) and water (20 mL) was added potassium vinyltrifluoroboratc (5,59 g, 41.7 mmol), K2CO3 (10.5 g, 75.9 mmol) and Pd(dppf)Cl; (2.74 g. 3.79 mmol) at 25 °C under N?. The reaction mixture stirred at 80 °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 (SKA, 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) 3 = 8.84 - 8.75 (m, 1H), 7.77 (s. 1 H), 7.19 - 7.08 (m, 1H), 6.01 - 5.92 (m, 1H). 5.58 - 5.50 (m, HI), 3.93 - 3.84 (m. 3H).

[1684] 15171 Step 2. methyl 2-chloro-5-formylisomcotinate

[1685]

[0518] To a solution of methyl 2-chloro-5-vinylisonicotmate (5.93 g, 30.0 mmol) in MeCN (60 mL) and water (10 mL) was added NaIO4(13,0 g, 60.0 mmol) and RuCh ( 11 mg, 1.50 mmol) at 25 °C under Nz. 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 ( Sit). 0-100% EtOAc / petroleum ether) to give methyl 2-chloro-5-formylisonicotinate (3.40 g, 1.0 mmol) as yellow solid.

[1686]

[1687] NMR (400 MHz, CDC13) 8 = 10.60 (s. 1H), 8.95 (s, 1H), 7.83 (s, 1H), 4.04 (s, 3H)

[1688]

[0519] Step 3. 7-chloropyrsdo[3,4-d]pyridazin-l(2H)-one

[1689]

[0520] To a solution of methyl 2-chloro-5-formylisonicotinate (3.40 g, 17.0 mmol) in EtOH (50 L) was added hydrazine monohydrate (1.78 g, 35.6 mmol) at 25 °C under N;, The reaction mixture was stirred at 60 °C for 3 hours. The mixture was concentrated under reduced pressure to give crude 7- 115

[1690] QBM84200.00265'99930245.1 VVID 755PC chloropyrido[3,4-d]pyridazin-l(2H)-one (3.10 g. 17.1 mmol) as yellow solid.1H NMR (400 MHz. DMSO-d6) 5 = 9.20 (s, 1H), 8,54 (s, 1 H). 8.10 (s. 1H). The crude product was used in the next step without further purification.

[1691]

[0521] Step 4. 7-chloro-2-methylpyrido[3,4-d]pyridazin-l(2H)-one

[1692]

[0522] To a solution of 7-chIoropyrido[3.4-d]pyridazin-l(2H)-one (3.10 g, 17.1 mmol) in DMF (35 mL) was added K;CO3(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 w-ith 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 (SiOz, 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.

[1693]

[1694] NMR (400 MHz, DMSO-d6) 5 = 9.21 (s, 1H), 8.59 (s, 1H), 8.13 (s, 1H), 3.74 (s, 3H).

[1695]

[0523] Step 5. 2-methyl-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one

[1696]

[0524] To a solution of 7-chloro-2-methylpyrido[3,4-d]pyridazin-l(2H)-one (500 nig, 2.56 mmol) in toluene (6 mL) was added Sm CHab (1.34 g, 4.09 mmol) and Pd(dtbpf)Cb. (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 NaiSOi, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (S> O.. 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) 8 - 9.24 (s, 1H), 8.42 - 8.34 (m. HI), 8.23 (s, 1H), 3.88 (s, 3H). 0.53 - 0.33 (m, 9H).

[1697] General Procedure 25

[1698]

[0525] Synthesis of 2 -dimethyl-7-(trimethylstannyl)pyrido|3,4-d|pyridazin-l(2H)-one

[1699]

[1700]

[0526] Step 1. 7-chloro-4-methylpyrido[3,4-d]pyridazin-l(2H)-one

[1701]

[0527] 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. Hie crude product was used in the next step without further purification.1H NMR (400 MHz, DMSO) 89.22 - 9.11 (m, 1H), 8.07 (d, J= 0.8 Hz, 1H), 2.57 (s, 3H).

[1702]

[0528] Step 2. 7-chloro-2,4-dimethylpyrido[3,4-d]pyridazin-l(2H)-one

[1703] 116

[1704] QBM84200.00265'99930245.1 VVTD 755PC

[0529] 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 mJ., x 3). The combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography (SiCb. 0 -• 45% EtOAc / petroIeum ether) to give 7-chloro-2,4-dimethylpyrido[3,4-d]pyridazin-l(2H)-one ( 1.80 g. 8 59 mmol) as yellow solid. NMR (400 MHz. DMSO) 59.22 id. J = 0.9 Hz, 1H), 8.11 (d, J = 0.9 Hz. 1H), 3.69 (s, 3H). 2.61 (s, 3H).

[1705]

[0530] Step 3. 2,4-dimethyi-7-(trimethylstannyl)pyrido[3,4-d]pyridazin-l(2H)-one

[1706]

[0531] 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 SnztCHsje (2.35 g, 7.17 mmol) and PdfdtbpflCh (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 Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (AI2O3, 0 - 35% EtOAc / petroIeum ether) to afford 2,4- diinethyl-7-(trimethylstamryl)pyrido[3,4-d]pyridazin-l(2H)-one (1.30 g, 3.85 mmol) as yellow solid. ’H NMR (400 MHz, CDCl3) 59.31 (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).

[1707] General Procedure 26

[1708]

[0532] Synthesis of 3-methyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[1709] SnjfCHJg HjN^O Pd(dfepf)Cl2, MCI DMF Soluene, 120 °c

[1710]

[1711] Step 1 Step 2 Steps

[0533] Step 1. 6-bromopyrido[3,4-d]pyrimidin-4(3H)-one

[1712]

[0534] A solution of -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 wras 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, 102 mmol) as yellow solid1H NMR (400 MHz. DMSO-d6) 8 = 12.76 (br s, 1H), 8.88 (s, 1H), 8.26 (s. 1 H).

[1713] 8.10 (s, TH). The crude product was used in the next step without further purification.

[1714]

[0535] Step 2. 6-bromo-3-methy]pyrido[3,4-d]pyrimidin-4(3H)-one

[1715]

[0536] 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 K2CO (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 w ith DCM (15 mL x 3). The combined organic layers w ere dried over 117

[1716] QB\184200.00265\99930245.1 VVID 755PC Na2SCk filtered and concentrated under reduced pressure. The crude product was triturated with hexane: EtOAc (20:1 v / v. 30 mb) to give 6-bromo-3-metbylpyrido[3.4-d]pyrimidin-4(3H)-one (4 15 g, 17.3 mmol) as yellow solid, ’ll NMR (400 MHz. CDCb) 5 - 8.92 (s, 1H). 8.28 (s, 1H), 8.12 (s. 1H). 3.63 (s, 3H).

[1717]

[0537] Step 3. 3-methyl-6-(trimethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[1718]

[0538] 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(CII3)6 (1.02 g. 3.12 mmol) and Pd(dtbpf)C12 (134 mg, 0.208 mmol) at 25CC. The reaction mixture was stirred at 120 °C for 6 hours under FL. 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 Na2SO4, 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-(trimethylstamiyl)pyrido[3,4-d]pyrimidin-4(3H)-one (630 nig, 1.95 mmol) as yellow solid.1H NMR (400 MHz, CDCI3) 8 = 9.30 (d. J = 0.6 Hz, 1H), 8.23 (d, J = 0.8 Hz, 1 H), 8.11 (s, 1 H), 3.63 (s, 3 H), 0.51 - 0.30 (m, 911).

[1719] General Procedure 27

[1720]

[0539] Synthesis of 2 -dimethyl-6-(trimethyIstaniiyl)pyrido[3,4-d]pyrimidin-4(3H)-one O O O Sn2(CH-psc. X CHsC(OE%r, X Mel. KjCOs _ I, Pd(d»pOCi2. UCI toiuene, 12u °C

[1721]

[1722] Step 1 Step 2 Step 3

[1723]

[0540] Step 1. 6-chloro-2-methylpyrido[3,4-d]pyrimidm-4(3H)-one

[1724]

[0541] A solution of 5-amino-2-chloro-pyridine-4-carboxamide (300 g, 17,5 mmol) in triethyl orthoacetate (28.4 g, 32.1 mL, 175 mmol) was stirred at 110 °C for 12 hours under N2and 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.

[1725]

[1726] NMR (400 MHz, CD3OD) 88.76 (s, 1H). 8.01 (d. J - 0.6 Hz. 1H). 2.47 (s, 3H).

[1727]

[0542] Step 2. 6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one

[1728]

[0543] To a solution of 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1.30 g, 665 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 N?„ 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. Hl NMR (400 MHz, CDCI3) 38.86 (s, 1H). 8.06 (s, HI), 3.65 (s, 3H), 2.66 (s, 3H).

[1729] 118

[1730] QB\184200.00265\99930245.1 VVID 755PC

[1731]

[0544] Step 3. 2 -dimethyl-6-(triniethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[1732]

[0545] 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(CH:<)6 (800 mg. 2.44 mmol) and Pd(dtbpf)Cl2(104 mg. 0.162 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 8 hours under Ns. 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 NasSO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ALOs, 20% EtOAc / petroleum ether) to afford 2,3- dimethyl-6-(trirnethylstannyl)pyrido[3,4-d]pyrimidin-4(3H)-one (430 nig. 1.02 mmol) as yellow solid.5H NMR (400 MHz, CDCI3) 8 = 9.21 (s, 1H), 8.16 (s, 1H). 3.66 (s, 3H), 2.67 (s. 3H), 0.52 - 0.29 (m, 9H).

[1733] General Procedure 28

[1734]

[0546] Synthesis of methyl 4-(trimethylstannyl)pyrimid e-2-carboxyIate

[1735] Pd(PPh3) o4

[1736] Sn2(CH3)6-x J

[1737] Ck, N.. A _, N

[1738] r iiu■ r ii

[1739]

[1740] toluene, 100 °C T.

[1741]

[0547] To a solution of methyl 4-chloropyrimidine-2-carboxylate (1.00 g, 5.79 mmol) in toluene (10 mL) was added Sn2(CH3)6 (2.87 g, 8.76 mmol) and Pd / PPh,), (0.670 g, 0.579 mmol) at 25 °C. The reaction mixture w as stirred at 100 °C for 12 hours under N2. The mixture was diluted with w ater (20 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 meth l 4- (triniethylstannyl)pyriniidine-2-carboxylate (1,60 g, 5.32 mmol) as yellow oil.

[1742]

[1743] NMR (400 MHz, CDCl3) 6 ppm 8.67 (d, J - 4.6 Hz, 1H), 7.61 (d, J - 4.6 Hz, 1H), 4.05 (s, 3H), 0.75 - 0.48 (m, 9H), 0.43 (s, 9H).

[1744] General Procedure 29

[1745]

[0548] Synthesis of methyl 3-((5-cyano-2-(methylcarbamoyl)pyridm-4-yl)sulfonyl)propanoate MeNHj HCI HATU, DI PEA DCM. 25 °C

[1746]

[1747] step 1 step 2 step 3

[1748]

[0549] Step I. 5-bromo-4-chloro-N-methylpicolinamide

[1749]

[0550] 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 m ol) and MeNH2HCl (2.14 g, 31.7 mmol) The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (1 mL) and extracted with DCM (15 mL x 3) The combined organic layers were washed with brine (20 mL). dried over NtuSOi. filtered and concentrated under reduced pressure. The crude product was purified by¬ column chromatography (SiOi, 0-30% EtOAc / petroleum ether) to give 5-bromo-4-chloro-N- 119

[1750] QB\184200.00265\99930245.1 VVID 755PC methylpicolinamide (5.00 g, 20.0 mmol) as white solid.1H NMR (400 MHz, CDCl3) 5 ppm 8.66 (s, 1H), 8.28 (s, lH), 7.86 (br s, 1 H), 3.04 (d, J = 5.1 Hz. 3H).

[1751]

[0551] Step 2 4-chloro-5-cyano-N-methylpicolinamide

[1752]

[0552] Amixture of 5-bromo-4-chloro-N-methylpicolinamide (4.50 g, 18.0 mmol), Zn(CN)2 (4.27 g, 36.4 mmol) and Pd(PPhj)4 (2.08 g, 1.80 mmol) in NMP (50 ml) was stirred at 130 °C for 1 hours The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed ith brine (50 mL), dried over NaiSOt, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOz. 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, CDCls) 8 ppm 8.78 (br s, 1 H), 8.38 (br s. 1H), 7.90 (br s, 1H), 3.07 (br d. J = 42 Hz, 3H).

[1753]

[0553] Step 3. methyl 3-((5-cyano-2-(methyIcarbamoyl)pyridin-4-yi)siiIfonyl)propanoate

[0554] To a solution of 4-chloro-5-cyano-N-methylpicolinamide (260 mg, 1.33 mmol) in DMSO (5 mL) was added Cui (481 mg, 2.53 mmol) and sodium 3-methoxy-3-oxopropane-I-sulfonate (463 mg, 2.66 mmol) at 25 °C The reaction mixture was stirred at 110 °C for 1 hour under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL). The combined organic layers ere washed with brine (10 mL x 2). dried oxer Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiOc, 0-30% EtOAc / petroleum ether) to afford methyl 3-((5-cyano-2-(methylcarbamoyl)pyridin-4-yl)sulfonyl)propanoaie (220 mg, 0.707 mmol) as yellow solid. ’H NMR (400 MHz, CDCl3) 5 ppm 9.07 (s, 1H), 8.84 (s, 1H). 7.90 (br d, J = 2.4 Hz, 1H), 3.73 (t, J- 7.1 Hz, 2H), 3.65 (s, 3H), 3.11 (d, J- 5.2 Hz, 3H), 2.91 (t, - 7.2 Hz, 2H).

[1754] General Procedure 30

[1755]

[0555] Synthesis of 4-cyano-2-methoxy-N-methyI-5-(4,4,5,5-tetramethyl-l,3,2-dio aborolan-2-yl)benzamide

[1756] Pd<cppf> Cl2xJ P;n2B2, KOAc 1, jy dioxane SO ’C 1

[1757] NO 'O

[1758]

[1759] step 3 *

[0556] Step 1. Mixture of 5-bromo-4-cyano-2-methoxybenzoic acid and 3-bromo-4-cyano-2-methoxybenzoic acid

[1760]

[0557] 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 120

[1761] QBM84200.00265'99930245.1 VVID 755PC 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).

[1762]

[0558] Step 2. 5-bromo-4-cyano-2-methoxy-N-methylbenzamide

[1763]

[0559] To a solution of 5-bromo-4-cyano-2-methoxybenzoic acid and 3-bromo-4-cyano-2- methoxy benzoic acid (14.0 g, 547 mmol) in DCM (150 L) was added D1PEA (29.6 mL, 22.0 g, 170 mmol) and MeNH₂·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 L), dried over Na-SO.i, 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 recry stallized from MeOH (30 mL) to afford 5-bromo-4-cyano-2 -methoxy -N-methylbenzamide (2.00 g, 7.43 mmol) as white solid.rH NMR (400 MHz, DMSO-dg) 8 ppm 8.33 (br d,. / == 4.4 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 3.90 (s, 3H), 2.77 (d, J- 4.8 Hz, 3H).

[1764]

[0560] Step 3. 4-cyano-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzamide

[1765]

[0561] 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 KOAc (197 mg, 2.00 mmol), Pin₂B₂(382 mg, 1.50 mmol) and Pd(dppf)Cl2DCM (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 L) 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)benzarnide (317 mg) as brown solid, which was used without further purification.

[1766] General Procedure 31

[1767]

[0562] Synthesis of 5-bromo-4-cyano-2-fluoro-N-methylbenzamide

[1768]

[1769]

[0563] Step 1. 4-amino-5-bromo-2-fhioro-N-methylbenzamide

[1770]

[0564] 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), MeNHj-HCl (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 purified 121

[1771] QB\184200.00265\99930245.1 VVID 755PC by column chromatography (S1O2, 0-20% EtOAc / petroleum ether) to give 4-amino-5-bromo-2-fluoro-N-methylbenzamide (3.70 g, 15.0 mmol) as a colorless oil.]H NMR (400 MHz. CDCls) 8 ppm 8.19 (d. J = 8.1 Hz, 1H), 6.56 (s, 1H), 6.43 (d,. / == 13.5 Hz, 1H), 2.99 (dd. J- 4.8. 1.2 Hz. 3H).

[1772]

[0565] Step 2. 5-bromo-2-fluoro-4-iodo-N-methylbenzamide

[1773]

[0566] 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 diluted with water (15 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, 0-10% EtOAc / petroleum ether) to give 5-bromo-2-fluoro-4-iodo-N-methylbenzamide (0.70 g, 1.96 mmol) as yellow solid.SH NMR (400 MHz, CDCl3) 8 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).

[1774]

[0567] Step 3. 5-bromo-4-cyano-2-fluoro-N-methylbenzamide

[1775]

[0568] To a solution of 5-bromo-2-fluoro-4-iodo-N-methylbenzamide (1.60 g, 4.47 mmol) in DMF (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, CDCl3) 6 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).

[1776] General Procedure 32

[1777]

[0569] Synthesis of methyl 3-((6-cyanopyrazm-2-yl)sulfonyl)propanoate

[1778] Bt- N O \ ^s. •? / N

[1779] Cui, DMSO, 110 °C ° if#J

[1780]

[1781] N

[1782]

[0570] To a solution of 6-bromopyrazine-2-carbonitrile (760 mg, 4.13 mmol) in DMSO (10 mL) was added Cui (1495 mg, 7.85 mmol) and sodium 3-methoxy-3-oxo-propane-l-sulfinate (1079 mg. 6.20 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 2 hours under N2. The mixture 'as diluted with brine (30 L) 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 t SiO220-80% EtOAc / petroleum ether) to afford methyl 3-((6-cyanopyrazin-2-

[1783] 122

[1784] QBM84200.00265'99930245.1 VVID 755PC yl)sulfonyl)-propanoate (520 mg. 2.04 mmol) as yellow solid.

[1785]

[1786] NMR (400 MHz, CDCl3) 5 ppm 9.44 (s, 1H). 9.18 (s. 1H). 3.80 (t J= 7.1 Hz. 2H). 3.70 (s, 3H). 2.95 (t. J = 7.2 Hz. 2H).

[1787] General Procedure 33

[1788]

[0571] Synthesis of 4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[1789] O NH4HCO3O Pd(dppf)Cl2

[1790] TFAA, TEA Pin₂B₂, KOAc DCM, 0 °C dioxane, 90 °C

[1791]

[1792] step 1 step 2 step 3

[1793]

[0572] Step 1. 5-bromo-4-fluoro-2-methoxybenzamide

[1794]

[0573] To a solution of 5-bromo-4-fluoro-2-methoxybenzoic acid (3.90 g, 15.7 mmol) in THF (80 mL) was added pyridine (2.53 mL, 2.48 g. 31.3 mmol) and NH4HCO3 (2.48 g. 31.3 mmol) at 25 °C. Di-terr- butyl dicarbonate (7.20 mL. 6.84 g. 31.3 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. This reaction procedure was repeated with 1.00 g (4.02 mmol) 5-bromo-4-fhioro-2 -methoxy ben zoic acid. 0.650 L (0.635 g. 8.03 mmol) pyridine. 0.635 g (8.03 mmol) NH4HCO3 and 1.75 g (8.03 mmol) di-tert-butyl decarbonate. The combined mixtures were diluted with water (500 mL) and filtered. The filter cake was dried under reduced pressure to afford 5-bromo-4-fluoro-2-methoxybenzamide (3.20 g, 12.9 mmol) as white solid.lH NMR (400 MHz, DMSO-de) 8 ppm 7.99 (d. J = 1.1 Hz, 1H), 7.65 (d.. / == 11.0 Hz, 2H), 7.26 (d, J- 1.1 Hz, 1H), 3.90 (s. 3H).

[1795]

[0574] Step 2. 5-bromo-4-fluoro-2-methoxybenzonitrile

[1796]

[0575] To a solution of 5-bromo-4-fluoro-2-methoxybenzamide (2.70 g, 10.9 mmol) in DCM (40 mL) was added TEA (3.15 mL, 2.20 g, 21.8 mmol mmol) and TFAA (23.1 mL, 34.3 g, 163 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was concentrated, and the crude product was purified by column chromatography (SiO₂, 0-10% EtOAc / petroleum ether) to give 5-bromo-4- fluoro-2 -methoxy benzonitrile (1.12 g, 4.87 mmol) as white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 11.2 Hz, 1H), 3.93 (s, 3H).

[1797]

[0576] Step 3. 4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0577] Amixture of 5-bromo-4-fluoro-2-methoxybenzonitrile (0.800 g, 3.48 mmol), Pin₂B₂ (1.32 g, 5.22 mmol). Pd(dppf)C12 (1.42 g, 1.74 mmol) and KOAc (1.02 g. 10.4 mmol) in 1,4-dioxane was degassed and purged with N (3x), The reaction mixture was stirred at 90 °C for 4 hours under N2. The mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na₂SO₄ filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO₂, 0-7% EtOAc / petroleum ether) to afford 4-fluoro-2-methoxy- 123

[1798] QB\184200.00265\99930245.1 VVID 755PC 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.780 g, 2.81 mmol) as white solid.1H NMR (400 MHz. CDCl3) δ ppm 7.99 (d, J = 6.8 Hz, 1H), 6.65 (d, J = 10.8 Hz, 1H), 3.95 (s, 3H), 1.35 (s,

[1799] 12H).

[1800] General Procedure 34

[1801]

[0578] Synthesis of (5-cyano-2-fluoro-3-methoxyphenyl)boronic acid

[1802] Pin2B2

[1803] [Ir(OMe)(cod)]2

[1804] ligand A

[1805] m-xytene, 110 “C

[1806]

[1807]

[0579] To a solution of 4-fluoro-3-methoxybenzonitrile (2.00 g, 13.2 mmol) in m-xylene (20 mL) was added Pin₂B₂ (5.04 g. 19.8 mmol). [Ir(OMe)(cod)]2(2.63 mg, 0.397 mmol) and ligand A (296 mg. 0.794 mmol) at 25 °C Then the reaction was stirred at 110 °C for 12 hours under N 2. The reaction was diluted with water (40 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’ i SiO 15-20% EtOAc / petroleum ether) and prep-HPLC (CD05-Phenomenex luna C IS.

[1808] 150 x 40 mm, 10 pm, ACN / H2O -t- 0.1% HCOOH) to give (5-cyano-2-fluoro-3-methoxyphenyl)boronic acid (282 mg, 1.47 mmol) as white solid.rH NMR (400 MHz, DMSO-dg) 8 ppm 8.54 (br s, 2H), 7.73 - 7.65 (m. 1H), 7.57 - 7.44 (m, 1H), 3.88 (s, 3H).

[1809] General Procedure 35

[1810]

[0580] Synthesis of 4-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[1811] NH4HCO3 Pa(.:ls.pf)0i2(BocfeO, pyridine TFAA, TEA Pin2B2, KOAC THF, 0 " C dioxane. 80 ”C

[1812]

[1813] step 1 step 2 step 3

[1814]

[0581] Step 1 3-bromo-4-methoxy-5-methylbenzamide

[1815]

[0582] To a solution of 3-bromo-4-methoxy-5-methylbenzoic acid (1000 mg, 4.08 mmol) in THF (5 mL) was added pyridine (0.660 mL, 646 mg, 8.16 mmol) and NH4HCO3 (645 mg, 8.16 mmol) at 25 °C. Di-tert-butyl dicarbonate (1,87 mL, 1781 mg, 8 16 mmol) was added dropwise at 0 °C. The reaction 124

[1816] QB\184200.00265\99930245.1 VVID 755PC mixture was stirred at 25 °C for 1 hour, diluted with water (25 mL) and filtered. The filter cake was dried under reduced pressure to afford 3-bromo-4-methoxy-5-methylbenzamide (800 mg. 3.28 mmol) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.83 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 5.95 (d, J = 63.0 Hz, 2H), 3.84 (d, J = 1.0 Hz, 3H), 2.36 (s, 3H).

[1817]

[0583] Step 2. 3-bromo-4-methoxy-5-methylbenzonitrile

[1818]

[0584] To a solution of 3-bromo-4-methoxy-5-methylbenzamide (800 mg, 3.28 mmol) in DCM (15 mL) was added TEA (0.948 mL, 663 mg, 6.56 mmol) and TFAA (6.02 mL, 8.95 g. 42.6 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (10 mL x2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO21-5% EtOAc / petroleum ether) to give 3-bromo-4-methoxy-5-methylbenzonitrile (600 mg, 2.65 mmol) as white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.70 (d, J = 2.0 Hz, 1H), 7.49 - 7.37 (m, 1H), 3.86 (s, 3H), 2.44 - 2.30 (m, 3H).

[1819]

[0585] Step 3. 4-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0586] To a solution of 3-bromo-4-methoxy-5-methylbenzonitrile (550 mg, 2.43 mmol) in 1,4 dioxane (8 mL) was added KOAc (716 mg, 7.30 mmol), Pin₂B₂ (1236 mg, 4.87 mmol) and Pd(dppf)Cl2(352 mg, 0.49 mmol) at 25 °C under N?. The reaction mixture was stirred at 80 °C for 2 hours. 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), 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 4- methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)benzonitrile (500 mg. 1.46 mmol) as blue solid.SH NMR (400 MHz, CDCl3) 6 ppm 7.86 (d, J = 2.0 Hz. 1H). 7.53 (d, J = 1.6 Hz, 1H), 3.85 (s, 3H), 2.28 (s. 3H), 1.37 (s, 12H).

[1820] General Procedure 36

[1821]

[0587] Synthesis of 3-fluoro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[1822] Br CN t-BuONO, CuBr Pin₂B₂, KOAc DMF, 145 °C MeCN, 65 °C dioxane, 80 °C

[1823]

[1824] step 2 step 3

[1825]

[0588] Step 1 3-amino-5-fluoro-4-methoxybenzonitrile

[1826]

[0589] To a solution of 5-bromo-3-fluoro-2-methoxyaniline (3.50 g, 15 9 mmol) in DMF (40mL) was added CuCN (7.12 g. 79.5 mmol) at 20°C. The reaction mixture was stirred at 145°C for 12 hours under N2. The mixture was diluted with w;ater (40 mL) and extracted with EtOAc (30 mL x 3). The combined 125

[1827] QBM84200.00265'99930245.1 VVID 755PC organic layers were washed with brine (50 mL x 3), 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 3-amino-5-fluoro-4-methoxy benzonitrile (1.60 g, 9.63 mmol) as yellow solid, NMR (400 MHz. CDCh) 5 ppm 6.80 - 6.73 (m. 2H), 4.51 - 4.04 (m. 2H). 4.02 (d. J = 2.4 Hz, 3H).

[1828]

[0590] Step 2. 3-bromo-5-fluoro-4-methoxy benzonitrile

[1829]

[0591] To a solution of CuBr (1.30 g. 9.03 mmol) in MeCN (8 mL) was added tert-butyl nitrite (0.93 g, 9.03 mmol) at 20 °C and stirred at 65 °C for 1 min. 'Then, a solution of 3-amino-5-fluoro-4-methoxybenzonitrile (1.00 g, 6.02 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 diluted with water 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, 0-10% EtOAc / petroleum ether) to give 3-bromo-5-fluoro-4-methoxybenzonitrile (0.70 g, 3.04 mmol) as yellow solid. ‘H1H NMR (400 MHz, CDCl3) 5 ppm 7.66 (t, J = 1.6 Hz, 1H), 7.42 - 7.34 (m, 1H), 4.10 (d, J = 3.2 Hz. 3H).

[1830]

[0592] Step 3. 3-fluoro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0593] To a solution of 3-bromo-5-fluoro-4-methoxybenz.onitrile (600 mg, 2.61 mmol) in 1,4 dioxane (6 mL) was added KOAc (512 mg, 5.22 mmol), Pin₂B₂(994 mg, 3.91 mmol) and Pd(dppf)Cl2·DCM (213 mg. 0.261 mmol) at 20 °C under Nz. The reaction mixture was stirred at 80 °C for 2 hours. The mixture was diluted with water (10 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 w as purified by column chromatography (SiO₂, 0-20% EtOAc / petroleum ether) to afford 3-fluoro-4-methoxy-5-(4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)benzonitrile (400 mg. 0.866 mmol) as yellow solid.1H NMR (400 MHz. DMSO-d6) δ ppm 8.06 - 7.97 (m, 1H), 7.70 (s, 1H), 3.92 (d, J = 1.8 Hz, 3H), 1.31 (s,

[1831] 12H).

[1832] General Procedure 37

[1833]

[0594] Synthesis of 4-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzonitrile

[1834] 126

[1835] QB\184200.00265\99930245.1 VVID 755PC

[1836]

[1837]

[0595] Step 1. 5-bromo-4-niethoxy-2-niethylbenzoic acid

[1838]

[0596] To a solution of methyl 5-bromo-4-methoxy-2-methylbenzoate (5.00 g, 19.3 mmol) in THF (25 mL), water (25 mL) and MeOH (25 mL) was added LiOH H2O (4.86 g, 116 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The mixture was acidified with 1N HCl to pH = 2 and extracted with DCM (200 mL x 2), The combined organic layers were washed with brine (300 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 5-bromo-4-methoxy-2-methylbenzoic acid (4.20 g, 17.1 mmol) as a white solid.

[1839]

[1840] NMR (400 MHz, DMSO-de) δ ppm 13.47 - 11.55 (m, 1H), 7.99 (s, 1H), 7.01 (s, 1H), 3.89 (s, 3H), 2.52 (s, 3H).

[1841]

[0597] Step 2. 5-bromo-4-methoxy-2-methylbenzamide

[1842]

[0598] To a solution of 5-bromo-4-methoxy-2-methylbenzoic acid (4.20 g, 17.1 mmol) in THF (50 mL) was added pyridine (2.77 mL, 2.71 g, 34.3 mmol) and NH4HCO3 (2.71 g, 34.3 mmol) at 25 °C. Di-tert-butyl dicarbonate (7.87 mL, 7.48 g, 34.3 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours and filtered. The filter cake was washed w ith petroleum ether (50 mL) and dried under reduced pressure to afford 5-bromo-4-methoxy-2 -methylbenzamide (3.20 g, 13.1 mmol) as white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.69 (s, 1H), 6.75 (s, 1H), 5.67 (br d, J = 12.8 Hz, 2H), 3.93 (s, 3H), 2.51 (s, 3H).

[1843]

[0599] Step 3. 5-bromo-4-methoxy-2-methylbenzonitrile

[1844]

[0600] To a solution of 5-bromo-4-methoxy-2-methylbenzamide (3.20 g, 13.1 mmol) in DCM (70 mL) was added TEA (5.69 mL, 3.98 g, 39.3 mmol) and TFAA (22.2 mL, 33.0 g, 157 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture w as diluted w ith water (110 mL) and extracted with DCM (60 mL x 3). The combined organic layers wrere washed with water (200 mL), brine (200 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO₂, 0-8% EtOAc / petroleum ether) to give 5-bromo-4-methoxy-2-methylbenzonitrile (2.30 g, 10.2 mmol) as white solid,

[1845]

[1846] NMR (400 MHz, CDCl3) 5 ppm 7.74 (s, 1H), 6.79 (s. 1H), 3.95 (s, 3H), 2.52 (s, 3H).

[1847]

[0601] Step 4. 4-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzonitrile

[1848] 127

[1849] QB\184200.00265\99930245.1 VVID 755PC

[0602] To a solution of 5-bromo-4-methoxy-2-methylbenzonitrile (2.30 g, 10.2 mmol) in 1.4 dioxane (25 mL) was added KOAc (3.00 g, 30.5 mmol). Pin2B2(3.88 g. 15.3 mmol) and Pd(dppf)Cl2DCM (0.83 g. 1.02 mmol). The reaction mixture was stirred at 90 °C for 2 hours under N2. The mixture was diluted with water (80 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, 0-10% EtOAc / petroleum ether) to afford 4-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.70 g. 6.22 mmol) as a brown solid.!H NMR (400 MHz, CDCl3) 8 ppm 7.92 (s, 1H). 6.74 (s, 1H), 3.88 (s. 3H), 2.54 (s, 3H), 1.35 (s, 12H).

[1850] General Procedure 38

[1851]

[0603] Synthesis of 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile Pd(dppf)Cl2NH3·H2O Pin2B2, KOAc MeOH, 25 °C dioxane, 90 °C

[1852]

[1853] step 1 step 3

[1854]

[0604] Step 1. 4-bromo-5-methoxypicolinamide

[1855]

[0605] To a solution of methyl 4-bromo-5-methoxypicolinate (1.00 g, 4.06 mmol) in MeOH (5 mL) was added NH3H2O (2 mL). The reaction mixture was stirred at 60 °C for 2 hours and filtered. The filter cake was dried under reduced pressure to afford 4-bromo-5-methoxypicolinamide (0.79 g, 3.42 mmol) as white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 8.16 (s, 1H), 8.00 (br s, 1H), 7.62 (br s, 1H), 4.06 (s, 3H),

[1856]

[0606] Step 2. 4-bromo-5-methoxypicolinonitrile

[1857]

[0607] To a solution of 4-bromo-5-methoxypicolinamide (0.720 g, 3 12 mmol) in DCM (7 mL) was added TEA (0.869 mL, 0.631 g, 6.23 mmol) and TFAA (5.72 mL, 8.51 g, 40.5 mmol) dropwise at 0 °C. The reaction mixture was concentrated, 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 under reduced pressure. The crude product was triturated with EtOAc (1 mL) and filtered to give 4-bromo-5-methoxypicolinonitrile (0.50 g, 2.35 mmol) as white solid1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.43 (s, 1H), 4.08 (s, 3H).

[1858]

[0608] Step 3. 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile

[1859]

[0609] To a solution of 4-bromo-5-methoxypicolinonitrile (250 mg, 1.17 mmol) in 1,4 dioxane (3 mL) was added KOAc (346 mg, 3.52 mmol). Pin2B2(447 mg. 1.76 mmol) and Pd(dppf)Cl2DCM (95.8 mg, 0.12 mmol). The reaction mixture was stirred at 90 °C for 2 hours under N2. The mixture was concentrated under reduced pressure, diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and

[1860] 128

[1861] QB\184200.00265\99930245.1 VVID 755PC concentrated under reduced pressure to give crude 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (300 mg) as yellow solid that was used without further purification.

[1862] General Procedure 39

[1863]

[0610] S nthesis of 4-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileh;? N-|PYBrCuCN Pin2B2, t-BuONOFBsiOHU DM" DMF 140 " C r^''^ MeCN. 80 “C

[1864]

[1865] step 1step 2 step 3

[1866]

[0611] Step 1. 5-bromo-2-fluoro-3-methylaniline

[1867]

[0612] To a solution of 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (3.00 g. 12.8 mmol) in DMF (30 mL) was added B2(OH)4(4.60 g, 51.3 mmol) and 4,4'-bipyridine (200 mg. 1.28 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 minute. The mixture was diluted with water (40 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 5-bromo-2-fluoro-3-methylaniline (2.8 g, 13.7 mmol) as yellow solid. ’H NMR (400 MHz, CDCl3) 8 ppm 6.80 - 6.69 (m. 1H), 6.69 - 6.62 (m, 1H), 3.74 (s, 2H), 2.19 (s. 3H).

[1868]

[0613] Step 2. 3-amino-4-fluoro-5-methylbenzonitrile

[1869]

[0614] To a solution of 5-bromo-2-fluoro-3-methylaniline (820 mg, 4.02 mmol) in DMF (10 ml.) was added CuCN (1800 mg, 20.1 mmol) at 20 °C. The reaction mixture was stirred at 140 °C for 12 hours under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (20 mL x 3), 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 3-amino-4-fluoro-5-methyl-benzonitrile (280 mg, 1.86 mmol) as yellow solid. ‘H NMR (400 MHz, CDCl3) 6 ppm 6.95 - 6.80 (m, 2H), 3.80 (s, 2H), 2.26 (s, 3H).

[1870]

[0615] Step 3. 4-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0616] To a solution of 3-amino-4-fluoro-5-methylbenzonitrile (510 mg, 3.40 mmol) in MeCN (8 mL) was added Pin2B2(949 mg, 3.74 mmol) and t-BuONO (525 mg, 5.09 mmol) at 20 °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 dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2.

[1871] 0-10% EtOAc / petroleum ether) to afford 4-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (830 mg, 3.18 mmol) as yellow solid.

[1872]

[1873] NMR (400 MHz, CDCl3) 3 ppm 7.91 - 7.83 (m, 1H), 7.60 - 7.51 (m, 1H), 2.29 (d, J = 2.2 Hz, 3H), 1.36 (s, 12H).

[1874] General Procedure 40

[1875] 129

[1876] QB\184200.00265\99930245.1 VVID 755PC

[0617] Synthesis of 4-bromo-5-methoxy-6-methylpicolinonitrile

[1877] m-CPBA TMSCN, TEA

[1878]

[1879] 9 Y DCM, 25 ' C Y Yl° MeCN, 85 ”0 9 i

[1880] step 1step 2

[1881]

[0618] Step 1. 4-bromo-3-methoxy-2-methylpyridine-N-oxide

[1882]

[0619] lb a solution of 4-bromo-3-methoxy-2-methylpyridine (2.00 g, 9.90 mmol) in DCM (20 mL) was added m-CPBA (2.41 g. 11.9 mmol 85 % purity) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours under N2. The mixture was quenched with saturated aqueous Na2SO3solution (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO₂,

[1883] 60-80% EtOAc / petroleum ether) to afford 4-bromo-3-methoxy-2-methylpyridine-N-oxide (2.10 g, 9.63 mmol) as colorless oil.

[1884]

[1885] NMR (400 MHz, CDCl3) 8 ppm 7.99 (d. J - 7.0 Hz, 1H), 7.30 (d, J - 7.0 Hz, 1H). 3.86 (s, 3H), 2.53 (s, 3H).

[1886]

[0620] Step 2. 4-bromo-5-methoxy-6-methylpicolinonitrile

[1887]

[0621] To a solution of 4-bromo-3-methoxy-2-methylpyridine-N-oxide (2.10 g. 9.63 mmol) in MeCN (20 mL) was added TEA (1.34 mL, 0.97 g, 9.63 mmol) and TMSCN (4.82 mL, 3.82 g. 38.5 mmol) The reaction mixture was stirred at 85 °C for 48 hours under N2. The mixture was diluted with saturated aqueous K2CO3 solution (60 mL) and extracted with DCM (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, 0-15% EtOAc / petroleum ether) to afford 4-bromo-5-methoxy-6-methylpicolinonitrile (0.75 g, 3.30 mmol) as white solid, ’H NMR (400 MHz, CDCI3) 6 ppm 7.75 (s, 1H), 3.91 (s, 3H), 2.59 (s, 3H).

[1888] General Procedure 41

[1889]

[0622] Synthesis of 2-(trimethylstannyl)isonicotinonitrile

[1890] Pd(PPh3)4

[1891] Sn2(CH3)6^Sn. ^CN

[1892]

[1893] NssY’ toluene, i 00 °C

[1894]

[0623] To a solution of 2-bromoisonicotinonitrile (500 mg, 2.73 mmol) in toluene (5 mL) was added Sn2(CH3)6(1342 mg, 4.10 mmol) and Pd(PPh3)4(316 mg, 0.273 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 12 hours under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL). 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 (Al2O3, 0-30% EtOAc / petroleum ether) to give 2-(trimethylstannyl)isonicotinonitrile (360 mg, 0.674 mmol) as yellow solid. NMR (400 MHz, CDCl3) 8 ppm 8.93 (d. J = 5,0 Hz, 1H), 7.66 (d, J = 0.6 Hz, 1H), 7.37 - 7.34 (m, 1H), 0.49 - 0.30 (m. 9H).

[1895] 130

[1896] QB\184200.00265\99930245.1 VVID 755PC

[1897] Example 1

[1898]

[0624] Compound 1: (S)-6-(l-acetyl-4-acryloylpiperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide and Compound 2: (R)-6-(1-ae.etyi-4-acryIoylp!perazin-2-yl)-4-chioro-N-methyl-[2,4'-bipyridine]-2'-carboxamide

[1899] Pd(cippf)CI2, KJCO3dioxane / l-I^O, 80CC step 4

[1900]

[1901] absolute stereochemistry randomly assigned

[1902]

[0625] tert-butyl 3-(6-bromo-4-chIoropyridin-2-yl)piperazine-l -carboxylate was obtained as described in General Procedure 1, step 4.

[1903]

[0626] Step 1. tert-butyl 4-acetyl-3-(6-bromo-4-chloropyridin-2-yl)piperazine-l-carboxylate

[0627] To a solution of tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)piperazine-l-carboxylate (1.00 g, 2.65 mmol) in DCM ( 10 mL) was added triethylamine (537 mg, 5.31 mmol). Then acetyl chloride (313 mg, 3.98 mmol) in DCM (1 mL) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at 20CC for 2 hours The reaction mixture was poured into 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 NajSCU filtered and concentrated under reduced pressure. The crude product was purified by column chromatography < Sit).. 50-70% EtOAc / petroleum ether). 7ert-butyl 4-acetyl-3-(6-bromo-4-chloropyridin-2-y 1) piperazine- 1 -carboxylate (364 mg, 0.87 mmol) was obtained as yellow solid. 'H NMR (400 MHz, CDCl3) 5 ppm 7.50 - 7.36 (m, 1H), 7.24 - 7.04 (m, 1H). 5.75 - 4.38 (m, 2H), 4.12 -3.81 (m, 1H), 3.78 - 3.66 (m. 1H), 3.60 - 3.19 (m, 2H). 3.05 - 2.86 (m, 1H). 2.32 - 2.10 (m, 3H), 1.42 (s, 9H).

[1904]

[0628] Step 2. l-(2-(6-bromo-4-chloropyridin-2-yl)piperazin-l-yl)ethan-l-one

[1905]

[0629] To a solution of tert-butyl 4-acetyl-3-(6-brorao-4-chloropyridin-2-yl)piperazine-l-carboxylate (360 mg, 0.86 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL) at 0 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give crude l-(2-(6-bromo-4-chloropyridin-2-yl)piperazin-l-yl)ethan-l-one (270 mg, 0.85 mmol) as TFA salt as yellow' oil. The crude product was used in the next step without further purification.

[1906] 131

[1907] QBM84200.00265'99930245.1 VVID 755PC

[1908]

[0630] Step 3. l-(4-acetyl-3-(6-bromo-4-chloropyridin-2-yl)piperazin-l-yl)prop-2-en-l -one

[0631] To a solution of l-(2-(6-bromo-4-chloropyridin-2-yl)piperazin-l-yl)ethan-l-one (270 mg, 0.85 mmol) as TFA salt in DCM (5 mL) was added triethylamine (172 mg. 1.69 mmol) and acryloyl chloride (115 mg, 1.27 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 1 hour. The reaction 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 NasSO:, filtered and concentrated under reduced pressure 'The crude product was purified by preparative TLC (SiO, EtOAc / MeOH = 5 / 1 v / v) to give l-(4-acetyl-3-(6-bromo-4-chloropyridin-2-y1)piperazin-l-yl)prop-2-en-l-one (230 mg. 062 mmol) as yellow solid,1H NMR (400 MHz, CDCl3) 8 ppm 7.49 - 7.37 (m, 1H), 7.14 - 6.96 (m, 1H), 6.96 - 6.72 (m, 1H), 6.27 (d, J = 16.0 Hz. 1H), 5.92 - 5.67 (m, 2H). 5.14 - 4.97 (tn, 1H), 468 - 4.47 (m, 1H), 3.80 (d, J= 13.6 Hz, 1H), 3.62 - 3.23 (m, 2H), 2.98 - 2.80 (m, 1H), 2.37 - 2.11 (m, 3H).

[1909]

[0632] Step 4. 6-(l-acetyl-4-acryloylpiperazin-2-yl)-4-chloro-N-methyl-[2«4'-bipyridine]-2'- carboxamide

[1910]

[0633] To a solution of l-(4-acetyl-3-(6-bromo-4-chloropyridin-2-yl)piperazin-l-yl)prop-2-en-l-one (200 mg, 0.54 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added N-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (141 mg, 0,54 mmol), potassium carbonate (148 mg, 1.07 mmol) and Pd(dppf)C12 (39 mg, 0.05 mmol) at 25 °C. The mixture was stirred at 80 °C for 7 hours under N2. The reaction mixture w as poured into water (15 mL) and extracted with EtOAc (1 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 preparative TLC (SiO?, EtOAc / MeOH = 5 / 1 v / v) to give 6-(l-acetyl-4-acryloylpiperazin-2-yl)-4-chloro-N-methyl-[2,4'- bipyridine]-2'-carboxamide (130 mg, 0.30 mmol) as green solid.

[1911]

[0634] Step 5. Chiral separation of (S)-6-(l-acetyl-4-a...

Claims

VVID 755PC CLAIMSWhat is claimed is:

1. A compound having the structure of formula (I)R9Owherein X1is N-C(O)-C1-3alkyl, N-C(O)-C1-3haloalkyl, N-S(O)2-C1-3alkyl, N-S(O)2-C1-3haloalkyl, N-R’, or O. XAis C-H or N, XBis C-H, C-F or N, Xcis C-H or N,X3is C-R3or N and -R3is -H, -F. -Cl or -Br, -CN or -O-CH3,X4is C-R4or N and -R4is -H, -F, -Cl or -Br, -C1-3alkyl, -C1-3haloalkyl, -O-CH3, -O-CHF2, or -O- CF3.X’ is C-R5or N and -R5is -H, -F, -Cl or -Br, -Ci-3alkyl, -C1-3haloalkyl, -O-CH3. -O-CHF2, or -O- CF3,X7is N or CH,X8is N or C-R8and -R8is -H, -F, -Cl, -C1-3alkyl, -O-CH3, -O-CHF2, or -O-CF3,X9is N or C-R12and -R12is -H or -C1-3alkyl,X10is N or C-R14and -R14is -H or -C1-3alkyl,11 is 1 or 2,R6is -CN, or -C(O)-NH-Ci-3alkyl,R9is -H, -C1-3alkyl, -C1-3haloalkyl, -C1-3hydroxyalkyl, or -C1-3alkylene-O-C1-3alkyl,R10is -H, -C1-3alkyl, -C1-3haloalkyl, or -C1-3alkylene-O-C1-3alkyl, orR10and R’ together form **-CH2-CH2-O-CH2- with ** indicating the bond towards X1,253QB\l84200.00265\99930245.1VVID 755PC R11is -H, -CH2F, -CHF2, -C1-3alkyl, -C1-3cyanoalkyl, -C1-3alkylene-O-C1-3alkyl.R13is -C1-3alkyl.with a first proviso, that if XAis N. XBis CH, Xcis CH and R6is -C(O)-NH-C1-3alkyl, R3must be -CN, and with a second proviso, that if XAis CH, XBis C-F, and X° is CH, R° cannot be -C(O)-NH-C1-3alkyl, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

2. The compound of claim 1 whereinX1is N-C(O)-CH3, N-S(O)2-CH3, N-R’ or O,XAis C-H or N,XBis C-H, C-F or N,Xcis C-H,*x. o * v7Y \N-Y I liX:t - X5x3 / R2is CN, X4or X4X3is C-R3or N and R3is H, F, CN or -O-CH3,X4is C-R4or N and R4is H, F, -CH3or -O-CH3,X’ is C-R5or N and R5is H, F, -CH3or -O-CH3,X ' is N or CH,n is 1 or 2R6is -CN, or -C(O)-NH-CH3,R9is H or -CH2-OH,R10is H, orRluand R’ together form **-CH2-CH2-O-CH2- with ** indicating the bond towards X1,R11is H or -CH3,with a first proviso, that if XAis N. XBis CH, Xcis CH and R6is -C(O)-NH-CH3, R3must be -CN. and with a second proviso, that if XAis CH. XBis C-F. and Xcis CH, R6cannot be -C(O)-NH-CH3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

3. The compound of claim 1 wherein254QB\184200.00265\99930245.1VVID 755PCwith a first proviso, that if XAis N, XBis CH, XCis CH and R6is -C(O)-NH-CH3, R3must be -CN, and with a second proviso, that if XAis CH, XBis C-F. and Xcis CH, R6cannot be -C(O)-NH-CH3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

4. The compound of claim 1 having the structure of formula (II)255QB\l 84200.00265X99930245.1VVID 755PC whereinX1is N-C(O)-CH3. N-S(O)2-CH3or O.0X4is CH or N,X5is CH, N, or C-OCH3,X7is CH or N,n is 1 or 2.R3is -H or -CN,R6is -CN or -C(O)-NH-CH3,R11is H or -CH3,or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

5. The compound of claim 4 whereinstereoisomer or tautomer thereof.

6. The compound of claim 4 wherein X1is N-C(O)-CH3and N-S(O)2-CH3or a pharmaceutically acceptable salt or solvate, stereoisomer or tautomer thereof.256QB\l 84200.00265X99930245.1VVID 755PC o o7. The compound of claim 4 wherein R2isI X / N“CH3, I N XyN-CH3O °TTYHS, or i NH3.or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

8. The compound of claim 4 wherein R3is H or a pharmaceutically acceptable salt, solvate.stereoisomer or tautomer thereof.

9. The compound of claim 1 having the structure of formula (III)whereinX1is N-C(O)-CH3, N-S(O)2-CH3, N-R’ or O,O / CH,XsX3is C-R3or N and R3is H, F, CN or -O-CH3,X4is C-R4or N and R is H. F. -CH3or -O-CH3,Xsis C-R5or N and R5is H, F, -CH3or -O-CH3,X8is CH, C-CH3, or N,X9is CH, C-CH3, or N,R6is -CN. or -C(O)-NH-CH3.R9is H or -CH2-OH,R10is H, orRluand R’ together form **-CH2-CH?.-O-CH2- with ** indicating the bond towards X1,257QB\l 84200.00265X99930245.1VVID 755PC R11is H or -CH3,with the proviso, that if R&is -C(O)-NH-CH?,. R ’ is -CN.or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

11. The compound of claim 9 wherein258QB\l 84200.00265X99930245.1VVID 755PC or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

12. The compound of claim 9 wherein X1is N-C(O)-CH3or N-S(O)2-CH3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

13. The compound of claim 9 wherein R9is H. or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

14. The compound of claim 9 wherein R10is H, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

15. The compound of claim 9 wherein R11is -CH3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

16. The compound of claim 1 having the structure of formula (IV)owhereinis N or CH,is N or CH,or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

17. The compound of claim 16 whereinor a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

18. The compound of claim 1, wherein the compound is:(S)-6-(l-acetyl-4-acry'loylpiperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide.259QB\184200.00265\99930245.1VVID 755PC (R)-6-(1-acetyl-4-acryloylpiperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, (R)-6-(4-(4-acryloyl-l-(methylsulfonvl)piperazin-2-yl)-6-ch1oropyridin-2-yl)pyriniidine-4-carbonitrile. (R)-2-(4-(l-acetyl-4-acrjloylpiperazin-2-yl)-6-chloropyridin-2-yl)thiazole-4-carbonitrile,(S)-2-(4-(1-acetyl-4-acryloylpiperazin-2-yl)-6-chloropyridin-2-yl)thiazole-4-carbonitrile,4-((2R,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloro-[2,3'-bipyridine]-5'-carbonitrile, 4-((2S,3S)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloro-[2,3'-bipyridine]-5'-carbonitrile,4'-((2R,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6'-chloro-[2,2'-bipyridine]-4-carbonitrile, 4'-((2S,3S)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6'-chloro-[2,2'-bipyridine]-4-carbonitrile, 3-(4-((2R,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-methoxybenzonitrile, 3-(4-((2S,3S)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-methoxybenzonitrile, 3-(4-((2R,3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-fluorobenzonitrile, 3-(4-((2S,3S)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-fluorobenzonitrile, 6-(4-((2R,3R)-4-acryloyl-3-methylmorpholin-2-yl)-6-cbloropyridin-2-yl)pyrimidme-4-carbomtrile. 6-(4-((2S,3S)-4-acryloyl-3-methylmorpholin-2-yl)-6-chloropyridin-2-yl)pyrimidine-4-carbonitrile, 3'-((2R,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-5'-chloro-2'-fluoro-[1,1'-biphenyl]-3-carbonitrile,3'-((2S,3S)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-5'-chloro-2'-fluoro-[1,1'-biphenyl]-3-carbonitrile, 5-(3-((2R,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-5-chloro-2-fluorophenyl)nicotinonitrile, 5-(3-((2S,3S)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-5-chloro-2-fluorophenyl)nicotinonitrile, 6-(3-((2R,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-5-chloro-2-fluorophenyl)picolinonitrile, 6-(3-((2S,3S)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-5-chloro-2-fluorophenyl)picolinonitrile, 6'-((2S,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile, 6’-((2R,3S)-l-acetyrl-4-acry'loyl-3-methylpiperazin-2-yl)-4'-chloro-[2.2'-bipyridine]-6-carbonitrile, 6-((2S,3R)-4-actyloyi-3-methylmorpholin-2-yl)-4-chIoro-N-methyl-[2,4’-bipyridine]-2'-carboxaniide, 6-((2R,3S)-4-acryloyl-3-methylmorpholin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide, 6'-((2S,3R)-4-acryloyl-3-methylmorpholin-2-yl)-4'-chloro-[2,2'-bipyridine|-6-carbonitrile.6'-((2R.3 S)-4-acryloyl-3-methyImorpholm-2-yl)-4'-chloro-[2.2' -bipyridine] -6-carbonitrile,6'-((2S,3R)-4-acryloyl-3-methyl-1-(methylsulfonyl)piperazin-2-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile,6-((2R,3S)-4-acryloyl-3-methyl-1-(methylsulfonyl)piperazin-2-yl)-4'-chloro-[2,2'-bipyridine]-6-carbonitrile,6-((2S,3R)-4-acryloyl-3-methyl-1-(methylsulfonyl)piperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,6-((2R,3S)-4-acryloyl-3-methyl-1-(methylsulfonyl)piperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,6-((2S,3R)-1-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,260QB\l84200.00265\99930245.1VVID 755PC 6-((2R,3 S)- 1 -acety 1-4-acryloy 1-3 -methy lpiperazin-2-y l)-4-chloro-N -methy l-[2,4'-bipy ridine] -2'-carboxamide,5-(4-((2R,3R)-l-acetyl-4-acryloyl-3-metiiylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-fluoro-2-methoxy ben zonitri le.5-(4-((2S,3S)-l-acetyl-4-acry4oyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-fluoro-2-methoxybenzonitrile.3-(4-((2R,3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-fluoro-5-methoxy benzonitrile.3-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yi)-6-chloropyridin-2-yl)-4-fluoro-5-metho xybenzonitrile,3-(4-((2R,3R)-l-acetyl-4-acryloyl-3-rnethylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-methoxy-5- methy 1 benzonitrile,3-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-metlioxy-5-methylbenzonitrile,3-(4-((2R,3R)-l -acety 1-4-acryloy l-3-rncthylpipcrazin-2-yl)-6-chloropyridin-2-yl)-5-fluoro-4- methoxy benzonitrile,3-(4-((2S,3S)-l-acetyl-4-acry4oyi-3-me11iylpiperazin-2-yl)-6-chloropyridin-2-yl)-5-fluoro-4-methoxybenzonitrile,5-(4-((2R,3R)-l -acety 1-4-acryloy l-3-niethylpiperazin-2-yl)-6-chloropyridiii-2-yl)-4-methoxy-2-methy Ibenzonitrile,5-(4-((2S,3S)-l-acetyl-4-acryloyI-3-methylpiperazin-2-yl)-6-chloropyridin-2-yi)-4-methoxy-2-methy Ibenzoni trile,6-(4-((6R.9aS)-8-acryloyloctahydropyrazino[2, 1 -cj [ 1,4]oxazin-6-y l)-6-chloropyridin-2-yl)pyrimidine-4-carbonitrile.4-((2S,3S)-l-acetyl-4-acryJoyl-3-metliylpiperazin-2-yi)-6-chloro-5'-methoxy-[2,4'-bipyridme]-2'- carbomtrile.2-(4-((2R3R)-4-acryloyl-3-methyl-l-(methylsulfon l)piperazin-2-yl)-6-chloropyridin-2-yl)thiazole-4-carbonitrile,2-(4-((2S,3S)-4-acryloyl-3-methy 1-1 -(methy lsulfonyl)piperazin-2-yl)-6-chloropyridin-2-yl)thiazole-4-carboni trile,6-(4-((2R,3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2-methoxypyrimidine- 4-carbonitrile,6-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2-methoxypyrimidine- 4-carbonitrile.(R)-6-(4-(l-acetyl-4-acryIoylpiperazin-2-yl)-6-chloropyridin-2-yl)-2-methyl-2,3-dihydro-lH-pyrrolo[3.4- c]pyridin-l-one,(S)-6-(4-(l-acetyl-4-acryloylpiperazin-2-yl)-6-chloropyridin-2-yl)-2-methyl-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-one,261QB\l84200.00265\99930245.1VVID 755PC 3-(4-((2R.3R)-l-acetyl-4-acryloyl-3-me(hylpiperazin-2-yl)-6-chloropyridm-2-yl)-4-fliioro-5-m ethy 1 benzonitrile,3-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazui-2-yl)-6-chloropyridm-2-yl)-4-fluoro-5-methy Ibe nzon itri le.4-((2R,3R)-l-acetyl-4-aciyloyl-3-methylpiperdzin-2-yl)-6-chloro-5'-methoxy-6'-methyl-[2.4'-bipyridine]- 2'-carbotiitrile.4-((2S,3S)-l-acetyl-4-acryloy1-3-methylpiperazin-2-yl)-6-chloro-5'-methoxy-6'-methyl-[2,4'-bipyridine]- 2'-carbonitrile,4^(2S,5S)-l-acetyl-4-acryloyl-5-(hydroxymethyl)piperazin-2-yl)-6'-chloro-[2,2'-bipyridine]-4-carbonitrile,5-(4-((2R,3R)-4-acryloyl-3-methylmorpholm-2-yl)-6-chloropyridin-2-yl)-4-cyano-2-methoxy-N- methylbenzamide,5-(4-((2S, 3 S)-4-acryloyl-3-methy Im orpholin-2-yl)-6-cbloropyridin-2-yl)-4-cyano-2 -methoxy -N- methy Ibenzam ide,4-(6-((2S,3R)-l-acctyl-4-acryloyl-3-mcthylpipcrazin-2-yl)-4-chloropyridin-2-yl)-N-mcthylpyrimidmc-2- carboxamide,4-(6-((2R,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-4-chloropyridin-2-yl)-N-methylpyrimidme-2- carboxamide,5-(4-((2R,3R)-4-acryloyl-3-meth l-l-(meth lsulfonyl)piperazin-2-yl)-6-chloropyridin-2-yl)-4-cyano-2-fluoro-N -methy Ibenzamide,5-(4-((2S,3S)-4-acryloyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-6-chloropyridm-2-yl)-4-cyano-2-fluoro -N -me thy Ibenzamide,5-(4-((2R.3R)-4-acryloyl-3- ethylmorpholin-2-yl)-6-chloropyridin-2-yl)-4-cyano-2-fluoro-N-meth Ibenzamide.5-(4-((2S.3 S)-4-acryloyl-3-methyhnorpholin-2-yl)-6-chloropyridm-2-yJ)-4-cyano-2 -fluoro-N- m ethy 1 benzamide,5-(4-((2R3R)-l-aceiyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-4-cyaiio-2-fk!oro-N-methy Ibenzam ide,5-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yI)-4-cyano-2-fliioro-N-m ethy Ibenzamide.4-(6-((2S,3R)-4-acryloyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2-yl)-N- methy lpyri idine-2-carboxa ide,4-(6-((2R,3S)-4-acryloyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2-yl)-N-methy lpyrimidine-2-carboxamide,6-((2S,3R)-l-acetyl-4-acryloyl-3-methylpiperazm-2-yl)-4-chloro-5'-cyano-N-methyl-[2,4'-bipyrid e]-2'- carboxamide,6-((2R,3S)-1 -acetyl-4-ac 4oyl-3-methylpiperazin-2-yl)-4-chloro-5'-cyano-N-methy1-[2,4'-bipyridine]-2'-carboxamide,262QB\l84200.00265\99930245.1VVID 755PC 4-(6-((2S.3R)-4-acryloyi-3-niethylmorpholin-2-yl)-4-chloropyridin-2-yl)-N-melhylpyrimidine-2-carboxamide,4-(6-((2R,3S)-4-acryloyl-3-methylmorphoIin-2-yl)-4-chloropyridin-2-yl)-N-methylpyrimidine-2-carboxamide,6-((2S.3R)-4-acryloyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloro-5'-cyano-N-methyl-[2,4'-bipyridine] -2'-carboxam ide,6-((2R,3S)-4-acryloyl-3-methyl-l -(methylsulfonyl )piperazin-2-yl)-4-ch1oro-5'-cyano-N-methyl-|2,4'-bipyridme]-2'-carboxamide,6-(6-((2S,3R)-4-acryloyl-3-methy l-l-(methylsulfonyl)pipera zin-2 -yl)-4-chloropyridin-2-yl)pyrazine-2-carbonitrile,6-(6-((2R,3S)-4-acryloyl-3-methy1-1 -(methylsulfonyl)piperazin-2-yl)-4-cbloropyridin-2-yl)pyrazine-2- carbonilrile,6-(4-((2R,3R)-4-acryloyl-3-methyl-l -(methylsulfonyl)piperazin-2-yl)-6-chloropyridin-2-yl)-2-methyl- 2,3 -dihydro- 1 H-pyrrolo [3,4-c jpyridin- 1 -one,6-(4-((2S,3S)-4-acryloyl-3-mcthyl-l-(mcthylsulfonyl)pipcraziii-2-yl)-6-chloropyridin-2-yl)-2-mctliyl- 2,3 -dihydro- 1 H-pyrrolo [3,4-c jpyridin- 1 -one,2-(6-((2S,3R)-4-acryloyl-3-methylmorpholin-2-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one,2-(6-((2R,3S)-4-acryloy l-3-methylmorpholin-2-y l)-4-chloropy ridin-2-y l)-6-melhy l-5,6-dihydro-7H- py irolo [3,4-b] py ridin-7-one,6-(6-((2S,3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-4-chloropyridin-2-yl)pyrazine-2-carbonitrile, 6-(6-((2R.3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-4-chloropyridin-2-yl)pyrazine-2-carbomtrile, 3-(6-((2S,3R)-4-acryloyl-3-methylmorphoIin-2-yl)-4-chloropyridin-2-yl)-6-methyl-6,7-dihydro-5H-py rrolo [3.4-b] p razin-5 -one,3-(6-((2R.3S)-4-acryloyl-3-methylmorpholin-2-yl)-4-cbloropyridin-2-yl)-6-methyl-6,7-dihydro-5H- py rrol o 13,4-b j py razin-5 -one.7-(4-((2R3R)-4-acryloyl-3-methyl-l-(methylstilfon i)piperazin-2-yl)-6-chloropyridin-2-yl)-2-melhyl- 3.4-dihy dro-2,6-naphthyridin- 1 (2H)-one,7-(4-((2S,3S)-4-aciyloyl-3-methyl-l-(methylsuIfonyl)piperazin-2-yl)-6-chloropyridin-2-yl)-2 -methyl- 3.4-dihydro-2,6-napbtbyridin-l(2H)-one,6-(4-((6S,9aR)-8-acryloyloctahydropyrazino[2,l-c][l,4]oxazin-6-yl)-6-chloropyridin-2-yl)-2-methyl-2,3- dihydro-1 H-pyrrolo[3,4-c]pyri din-1 -one,4'-((6S,9aR)-8-acryloyloctahydropyrazino[2,l-c|[l,4]oxaz -6-yl)-6'-chloro-[2,2'-bipyridine]-4-carbonitrile,6-((2S,3R)-4-aciyloyl-3-methyl-l -(methylsulfonyl)piperazin-2-yl)-4-chIoro-6' -methoxy -N-methyl-[2, 3'- bipyridine] -5'-carboxamide,6-((2R,3S)-4-aciy1oyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloro-6'-metboxy-N-methyl-[2,3'-bipyridine] -5'-carboxamide,263QB\l84200.00265\99930245.1VVID 755PC 2-(6-((2S.3R)-4-acryloyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2-yl)-6-methyl- 5.6-dihydro-7H-pyrroio|3.4-b]pyridin-7-one,2-(6-((2R,3S)-4-acryloyI-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2-yl)-6-metliyl- 5.6-dihydro-7H-pyrrolo[3.4-b]pyridin-7-one.3-(6-((2S,3R)-4-acrjloyi-3-methyl-i-(methylsulfonyl)piperazin-2-yl)-4-chloropyridin-2-yl)-6-methyl- 6.7 -d thy dro-5 H -pyrrolo [3,4-b] py raz n -5 -one,3-(6-((2R,3S)-4-acryloyl-3-methy1-l-(methy1suIfonyl)piperazin-2-yl)-4-chloropyridin-2-yl)-6-methyl- 6.7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one,3-(6-((2S,3R)-l-ace1y’l-4-acryloyl-3-methylpiperazin-2-yl)-4-chloropyridin-2-yl)-6-methyl-6.7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one,3-(6-((2R,3S)-l-acetyl-4-acryloyI-3-methylpiperazin-2-yl)-4-chloropyridin-2-yl)-6-tnethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazm-5-one,6-(4-((2R,3R)-l -acetyl-4-acryloyi-3-metby1piperazin-2-yl)-6-chloropyridin-2-yl)-2-methyl-2,3-dihydro- 1 H-pyrrolo [3, 4-c]pyri din- 1 -one,6-(4-((2S,3S)-l-acctyl-4-acryloyl-3-mcthylpipcrazin-2-yl)-6-cliloropyridin-2-yl)-2-mcthyl-2,3-dihydro- 1 H-pyrrolo [3,4-cjpyridin- 1 -one,2-(6-((2S,3R)-l-acelyl-4-acryloyl-3-mediylpiperazin-2-yl)-4-chloropyridin-2-yl)-6-methyl-5,6-dihydro- 7H-pyrrolo [3,4-b]py ridin -7-one,2-(6-((2R,3S)-l-acelyl-4-aciyloyl-3-niethylpiperazin-2-yl)-4-chloropyri din-2 -yl)-6-methy 1-5, 6-dihydro-7H-pyrrolo [3,4-b]py iidin-7-one,7-(4-((2S,3S)-l-acetyl-4-acryloyI-3-methylpiperazin-2-yl)-6-clrioropyridin-2-yl)-2-roethyl-3.4-dihydro- 2.6-naphthy ridin- 1 (2H)-one,7-(4-((2R.3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-cMoropyridin-2-yl)-2-methyl-3,4-dihydro- 2.6-naphthy ridin- 1 (2H)-one,4-((2R,3R)-4-acryloyl-3-methyl-l -(tnethyisulfonyi)piperazin-2-yi)-6-chloro-5'-cyano-N-inethyl-[2,4'-bipyndine] -2'-carboxamide,4-((2S,3S)-4-acryloyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-6-chloro-5'-cyano-N-methyl-[2.4'-bipyridine] -2'-carboxamide,4-((2R,3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloro-5'-methoxy-[2.4'-bipyridine]-2'-carbonitrile,2-(6-((2S,3R)-4-acryloyl-3-methylmorpholin-2-yl)-4-chloropyridin-2-yl)-7-methyl-6,7-dihydro-l,7-n aphtbyri din -8(5 H) -one,2-(6-((2R,3S)-4-acryloyI-3-methylmorpholin-2-yl)-4-chloropyridin-2-yl)-7-methyl-6,7-dihydro-l,7-naphthy ridin-8(5 H ) -one,3-(6-((2S,3R)-4-acryloyl-3-methylmorpbolin-2-yl)-4-chloropyridin-2-yl)-6-methyl-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one,3-(6-((2R,3S)-4-acryloyl-3-methylinorpholin-2-yl)-4-chloropyridin-2-yl)-6-methyl-7,8-dihydropyrido[3,4-b]pyrazin-5(6H)-one,264QB\l84200.00265\99930245.1VVID 755PC 2-(6-((2S.3R)-l -acetyl-4-acryloyl-3-methylpiperazin-2-yl )-4-chioropyridm-2-yl)-7-methyl-6,7-dihy dro- 1.7 -naphthy ridin -8(5H) -one,2-(6-((2R,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-4-chloropyridin-2-yl)-7-methyl-6,7-dihydro- 1.7-naphthyridin-8(5H)-one,3-(6-((2S,3R)-l-acetyl-4-acrydoyl-3-methylpiperazin-2-yl)-4-chloropyridin-2-yl)-6-methyl-7.8-dihydropyrido[3.4-b]pyrazin-5(6H)-one,3-(6-((2R,3S)-l-acetyl-4-acry1oyl-3-metbylpiperazin-2-yl)-4-chioropyridin-2-yl)-6-methyl-7.8- dihy dropy rido [3.4-b]py razin-5 (6H)-one.2-(6-((2S,3R)-4-acryioyI-3-methy l-l-(methylsulfonyl)pipera zin-2 -yl)-4-chloropyridin-2-yI)-7-methyl- 6.7-dihy dro- 1,7-naphthyridin-8(5H)-one,2-(6-((2R,3S)-4-acryloyl-3-methy1-1 -(methy1suIfonyl)piperazin-2-yl)-4-chloropyridin-2-yl)-7-methyl- 6.7-dihydro-l,7-naphtiiyridin-8(5H)-one,3-(6-((2S,3R)-4-acryloyl-3-methyl-l-(methylsulfotiyl)piperaziii-2-yl)-4-chloropyridin-2-yl)-6-metbyl- 7.8-dihydropyrido[3,4-b]pyraziri-5(6H)-orie,3-(6-((2R,3S)-4-acryloyI-3-nicthyl-l-(mclhylsiilfonyl)pipcrazm-2-yl)-4-chloropyridin-2- l)-6-mcthyl- 7.8-dihy dropy rido[3,4-b]pyrazin-5(6H)-one.6-((2S,3R)-l-acety'l-4-aciyloyl-3-methylpiperazin-2-yl)-4-chloro-6,-methoxy-N-methyl-[2,3'-bipyridme]- 5 '-carboxamide,6-((2R,3S)-l-acetyl-4-acryloyl-3-metliylpiperazin-2-yl)-4-chioro-6'-methoxy-N-meLliyl-[2,3,-bipyridiiie]- 5 -carboxamide.6-((2R,5R)-l-acetyl-4-acryloyl-5-methylpiperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2'-carboxamide,6-((2R,5R)-l-acetyl-4-acryloyl-5-methylpiperazin-2-yl)-4-chloro-N-niethyl-[2,4'-bipyridine]-2'-carboxamide,6-((2S,5S)-l-acetyl-4-acryJoyl-5-methyipiperazin-2-yl)-4-chloro-N-niethyl-[2.4'-bipyridme]-2'-carboxamide,6-((2S,5S)-l-acetyl-4-acryloyl-5-methylpiperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]-2‘-carboxamide,6-((2S.5S)-4-acryloyl-5-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloro-N-metiiyl-[2,4'-bipyridiiie]- 2-carboxamide.6-((2S,5S)-4-acryloyl-5-methyl-l-(methylsulfonyl)piperazin-2-yl)-4-chloro-N-methvl-[2.4'-bipyridine]- 2'-carboxamide,6-((2R,5R)-4-acryloyl-5-methyl-l-(methyIsulfonyl)piperazin-2-yl)-4-chloro-N-methy1-[2,4'-bipyridiiie]- 2-carboxamide,6-((2R,5R)-4-acty4oyl-5-metliyl-l-(methylsulfonyi)piperazin-2-yl)-4-chloro-N-methyl-[2,4'-bipyridine]- 2-carboxamide,6-(4-((2R,3R)-4-acry1oyl-3-methy1morpholin-2-yl)-6-cbloropyridin-2-yl)-2-methyl-2,3 -dihydro- 1H- pyrrolo[3,4-c]pyridin-l-one,265QB\l84200.00265\99930245.1VVID 755PC 6-(4-((2S.3S)-4-aciyloyl-3-methylmorpholm-2-yl)-6-chloropyridin-2-yl)-2-metliyl-2,3-dihydro-lH-pyrrolo[3,4-cjpyridin-l-one,7-(4-((2R,3R)-4-acryloyl-3-methylmorpholin-2-yl)-6-chloropyridin-2-yl)-2-meth l-3.4-dihydro-2.6-napbthyridin-1 (2H)-one,7-(4-((2S,3S)-4-aciyloyl-3-methylmorpholin-2-yl)-6-chloropyridin-2-yl)-2-methyl-3.4-dihydro-2.6-naphthy ridin- 1 (2H)-one,(S)-2'-(l-acetyl-4-acry4oylpiperazin-2-yl)-6'-chloro-N-methyl-[4,4'-bipyridme] -2 -carboxamide, (R)-2'-(l-acetyl-4-acryloylpiperazin-2-yl)-6'-chloro-N-methyl-[4,4'-bipyridine]-2-carboxamide.(S)-2'-(4-acryloyl-l-(methylsulfonyl)piperazin-2-yl)-6'-ch1oro-N-methyl-[4,4'-bipyridine]-2- carboxamide,(R)-2'-(4-acrydoyI-l-(methyIsulfonyl)piperazin-2-yI)-6'-chIoro-N-methyl-[4.4'-bipyridine]-2- carboxamide,6-(4-((2R,3R)-l -acetyl-4-acryloyi-3-metby1piperazin-2-yl)-6-chloropyridin-2-yl)-3-inethylpyrido[3,4- d]pyrimidin-4(3H)-one,6-(4-((2S,3S)4-acctyl-4-acryloyl-3-mcthylpipcrazin-2-yl)-6-cWoropyridin-2-yl)-3-mcthylpyrido[3,4-d]pyrim idin-4(3H)-onc,7-(4-( (2R,3R)- 1 -aceiyl-4-acryloyl-3-methylpiperazin-2-y l)-6-chloropyridin-2 -yl)-2-me thy 1-2,6- napbtby ri din - 1 (2H) -one,7-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2-methyl-2,6- naphthy ridin- 1 (2H)-one,7-(4-((2R_3R)-l-acetyl-4-acryloyl-3-niethylpiperazin-2-yl)-6-chloropyridin-2-y])-2-methylpyrido[3,4-d]py ridazin- 1 (2H)-one,7-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yI)-2-methyIpyrido[3,4-d]pyridazin- 1 (2H)-one,4-((2R,3R)-l-acetyl-4-acryloyl-3-inetliylpiperaztn-2-yl)-6-cbloro-5'-cyano-N-tnetbyi-[2.4'-bipyridine]-2'-carboxamide,4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloro-5'-cyano-N-methyl-[2,4'-bipyriduie]-2'-carboxamide,2'-((2S.3R)-l-acetyl-4-acryloyl-3-meihylpiperazin-2-yr)-6'-chloro-N-methyl-[4,4'-bipyridine]-2-carboxamide,2'-((2R,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6’-chloro-N-methyl-[4,4'-bipyridine]-2-carboxamide,2‘-((2S,3R)-4-acrydoyl-3-methyl- l-(methy lsulfonyl)piperazin-2-y l)-6'-chloro-N-methyl-[4,4'-bipyridine]- 2-carboxamide,2'-((2R,3S)-4-aciyTloyl-3-methyl-l-(methylsulfonyl)piperazin-2-yl)-6'-ch1oro-N-methyl-[4,4'-bipyridine]- 2-carboxamide,7-(4-((2R,3R)-l -acetyl -4-acryloy1-3-metby1 piperazin-2 -yl)-6-chloropyridin-2-yl)-2,4-dimethyl-2.6- naphthy ridin- 1 (2H) -one,266QB\l84200.00265\99930245.1VVID 755PC 7-(4-((2S.3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yI)-2,4-dimethyl-2.6-naphthy ridin- 1 (2 H) -one.6-(4-((2R,3R)-l-acetyl-4-acryloyl-3-methylpiperazin-2-y l)-6-chloropyridin-2-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one,6-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2,3-dimethylpyrido[3,4-d]pyrim idin-4(3H)-one,7-(4-((2R,3R)-l-acetyl-4-acryloyl-3-methylpiperazii'i-2-yl)-6-chloropyridin-2-yl)-2,4-dimethy Ipyrido [3,4-d]pyridazin- 1 (2H)-one,7-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2,4-dimethylpyrido[3,4-d]pyridazin-l(2H)-one.7-(4-((2R,3R)-l-acetyl-4-acryloyl-3-raethylpiperazin-2-yl)-6-chloropyridin-2-yl)-2,3-dimethyl-2,6- naphthy ridin- 1 (2H)-one,7-(4-((2S,3S)-l-acetyl-4-acryloyl-3-methylpiperazin-2-yl)-6-chloropyridin-2-yl)-2,3-dimethyl-2,6-naphthy ridin- 1 (2H)-one,4-((2S,3S)-4-acryloy l-3-mcthylmorpholin-2-y l)-6-cliloro-5'-cyano-N-mcthyl-[2,4'-bipyridinc]-2'- carboxamide, or4-((2R,3R)-4-acryloyl-3-meth lmorpholm-2-yl)-6-chloro-5,-cyano-N-methyl-[2,4'-bipyridine]-2'- carboxamide,or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

19. A pharmaceutical formulation comprising a compound of any one of claims 1-18, and a pharmaceutically acceptable excipient or carrier.

20. 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 1-18, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

21. The method according to claim 20, 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, s temic 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 bunt, autoimmune diseases, inflammatory diseases, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, cutaneous lupus, systemic lupus, inflammatory7bowel diseases, psoriasis, dermatitis, topical effects of radiation, polym ositis, mixed connective tissue disease, autoimmune-interstitial lung disease, dermatomyositis, immunosuppression due to radiation exposure, vasculitis, kidney disease.267QBM84200.00265'99930245.1VVID 755PC 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 injuty, 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, 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 sieatohepatitis, toxin-induced liver disease, acetaminophen-induced hepatic disease, viral hepatitis, cirrhosis, preeclampsia, sickle cell disease, thalassemia, or high altitude sickness.268QBM84200.00265'99930245.1

Images