Novel compounds and their uses

Abstract

The present invention relates to a compound represented by general formula (I) [Formula 1] TIFF2023507400000083.tif57170 (wherein LHS is LHSa and LHSb [Case 2] TIFF2023507400000084.tif47170, where an asterisk ( * ) indicates the point of attachment) or pharmaceutically acceptable prodrugs, salts, and / or solvates thereof. These compounds exhibit antibacterial activity against Gram-negative and Gram-positive bacteria, particularly Staphylococcus aureus, Escherichia coli, K. pneumoniae, and A. baumannii. Pharmaceutical compositions containing these compounds, their therapeutic uses, and methods for their preparation are also provided.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to antibiotic compounds, pharmaceutical compositions containing same and the use of these compounds and compositions for the treatment of bacterial infections. The present invention further relates to methods of making said compounds of the invention. [Background technology]

[0002] Background of the Invention Antibiotic resistance is rising to dangerously high levels in all regions of the world, threatening people's ability to effectively treat and prevent an ever-increasing variety of infectious diseases. Thus, there is a need for the development of new antibiotic compounds that can be active where existing antibiotics fail.

[0003] Although all types of bacteria (both Gram-negative and Gram-positive) are believed to develop some degree of antibiotic resistance, certain bacterial species, such as Staphylococcus aureus (S. aureus), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Escherichia coli (E. coli), are more associated with antibiotic resistance than others. Thus, there may be a particular need for novel antibiotic compounds active against one or more of these bacterial species.

[0004] A recently developed new class of antibiotic compounds are FabI inhibitors. These compounds inhibit NADH-dependent enoyl reductase (FabI) ​​from the type II bacterial fatty acid biosynthetic pathway (FAS-II), thereby providing an alternative approach for treating bacterial infections when existing antibiotics fail. Advantageously, this FabI mechanism of action is not expected to exhibit cross-resistance to existing antibiotics. However, while known FabI inhibitor compounds can be highly effective against some bacterial species, they may be inactive or have poor activity against other species, such as Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), A. baumannii (A. baumannii), and Klebsiella pneumoniae (K. pneumoniae), particularly the Gram-negative species E. coli, A. baumannii, and K. pneumoniae. This may be due to difficulties penetrating both the outer and inner membranes of these Gram-negative bacteria, a problem that may be further exacerbated by efflux. Thus, there remains a need for compounds and pharmaceutical compositions containing same that can exhibit antibacterial activity against one or more of Gram-positive and / or Gram-negative bacteria, particularly S. aureus, E. coli, K. pneumoniae, and A. baumannii, most particularly E. coli, K. pneumoniae, and A. baumannii (particularly when existing antibiotics fail). Furthermore, such compounds preferably do not result in cross-resistance to existing antibiotics, and it is desirable that such compounds result in a low / acceptable incidence of side effects. Summary of the Invention [Problem to be solved by the invention]

[0005] It is an object of the present invention to address one or more of these above-mentioned needs. Further objects and objectives underlying the present invention will become apparent from the following description of the invention. [Means for solving the problem]

[0006] Summary of the Invention The inventors have surprisingly found that the objects of the present invention can be achieved by the compounds, pharmaceutical compositions, therapeutic uses thereof and methods of synthesis of the present invention. The present invention includes, inter alia, the following items (representing various aspects and embodiments):

[0007] 1. A compound represented by formula (I) or a pharmaceutically acceptable prodrug, salt and / or solvate thereof. [ka] (In the formula, LHS is LHSa and LHSb [ka] wherein the asterisk ( * ) indicates the point of attachment; Y is CH2, NH and NR d selected from the group consisting of: Q1 is O, S, NH and NC 1~4 selected from the group consisting of alkyl; R0 is selected from the group consisting of CH3 and Cl, or alternatively, R0 is R 14 Together with R 14 is attached to form a heterocycle having 5 to 8 ring members, preferably the only heteroatom in the ring is R 14 is the N to be bonded; R1 is H, F, Cl, Br, I, C 1~4 Alkyl, OR, CN, NR, CO-NR, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, NH-CO-C 1~4 Alkylene-R5, NH-CO-NR5R6, NH-COOR5, NHSO2-C 1~4 Alkylene-R5, C 3~6cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R2 is H, F, Cl, Br, I, C 1~4 Alkyl, OR5, C 1~4 Alkylene-OR5, CN, NR5R6, CO-NR5R6, C 1~4 Alkylene-NR5R6, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R3 is H, F, Cl, Br, I, CN, C 1~4 Alkyl, OC 1~4 Alkyl, OH, NH2, NHC 1~4 Alkyl and SC 1~4 selected from the group consisting of alkyl; R 3a , R 3b and R 3c are H, F, Cl, Br, I, CN, and C 1~4 Alkyl, OC 1~4 Alkyl, OH, NH2, NHC 1~4 Alkyl and SC 1~4 independently selected from the group consisting of alkyl; R4 is H, F, Cl, Br, I, C 1~4 Alkyl, OR5, CN, COR 10 , Phenyl, OH, NH2, SC 1~4 selected from the group consisting of alkyl, NR5R6, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S; R5 and R6 are H, COR 10 , C 1~4 Alkyl, C 3~6independently selected from the group consisting of cycloalkyl, SO2R7, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said cycloalkyl, phenyl, or heterocyclic groups can be optionally substituted with 1 to 3 R7 groups; R7 is H, F, I, Br, Cl, O, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, CONH2, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 Alkylene-NH2, NO2, CN, C 2~4 Alkynylene-OH, C 2~4 Alkynylene-NH2, SO2CH3 and OC 1~4 alkylene-OH; R8 and R9 are H, C 1~4 Alkyl, C 1~4 Alkyl-F, CN, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 independently selected from the group consisting of alkylene-NH; R 10 is H, C 1~4 Alkyl, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4 alkylene-NH2; R 11 and R 12 H, R d , C 1~4 Alkyl, CO-C 1~4 Alkyl, SO2(C 1~4 Alkyl)1, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4alkylene-NH, or alternatively, R 11 and R 12 together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said heterocyclic or heterocyclic spiro group can be substituted with 1 to 3 R groups; R 13 is H or R d selected from the group consisting of: R 14 is CH3 or alternatively, R 14 LHS a or LHS b Together with R0, R 14 is attached to form a heterocycle having 5 to 8 ring members, preferably the only heteroatom in the ring is R 14 is N to which is attached; and R d -PO3R e2 , -CH2-OPO3R e2 and R e is selected from the group consisting of H and cations suitable for forming pharmaceutically acceptable salts

[0008] 2. The compound according to item 1, wherein LHS is LHSa.

[0009] 3. The compound according to item 1, wherein LHS is LHSb.

[0010] 4. The compound according to any one of items 1 to 3, wherein Q1 is selected from the group consisting of O or S.

[0011] 5. R0 is CH3, and R 14 5. The compound according to any one of items 1 to 4, wherein is CH3.

[0012] 6.R0 is R14 Together with R 14 is attached to an N, and forms a heterocycle having 5 to 8, preferably 7, ring members, and preferably the only heteroatom in the ring is R 14 is N to which is attached.

[0013] 7.R1 is H, F, Cl, Br, C 1~4 Alkyl, OR5, CN, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, NH-CO-C 1~4 Alkylene-R5, NH-CO-NR5R6, NH-COOR5, NHSO2-C 1~4 Alkylene-R5, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl or heterocyclic group may be optionally substituted with 1 to 3 R groups, preferably R is H, F, Cl, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The compound according to any one of items 1 to 6, wherein the alkyl, cycloalkyl, phenyl or heterocyclic group may be optionally substituted with 1 to 3 R groups, and R, R and R are as described in item 1.

[0014] 8.R2 is H, F, Cl, Br, C 1~4 Alkyl, OR5, C 1~4 Alkylene - OR5, CN, NR5R6, C 1~4 Alkylene-NR5R6, C 3~6 cycloalkyl, wherein said C 1~4The alkyl and cycloalkyl may be optionally substituted with one to three R groups, preferably R is C 1~4 The compound according to any one of items 1 to 7, wherein R5, R6 and R7 are selected from the group consisting of alkyl, H, F, Cl, OR5 and NR5R6, and R5, R6 and R7 are as described in item 1.

[0015] 9. R3 is H, F, Cl, Br, OH, NH2 and NHC 1~4 The compound according to any one of items 1 to 8, wherein R3 is selected from the group consisting of H, F, Cl, OH and NH2.

[0016] 10.R 3a , R 3b and R 3c are H, F, Cl, Br, OH, NH2 and NHC 1~4 alkyl, preferably R 3a , R 3b and R 3c is independently selected from the group consisting of H, F, Cl, OH and NH2.

[0017] 11.R4 is H, F, Cl, Br, OR5, COR 10 , OH, NH2 and NR5R6, wherein R4 is preferably selected from the group consisting of H, F, Cl, OR5, OH, NH2 and NR5R6.

[0018] 12.R7 is H, F, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene-OH, C 1~4 Alkylene-NH2 and OC 1~4 Alkylene-OH, C 2~4 Alkynylene-OH and C 2~4alkynylene-NH2, preferably R7 is selected from the group consisting of H, F, C 1~4 Alkyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 The compound according to any one of items 1 to 11, selected from the group consisting of alkylene-NH2.

[0019] 13. R8 and R9 are H, C 1~4 Alkyl, C 1~4 Alkyl-F, OC 1~4 alkyl, and preferably R and R are independently selected from the group consisting of H and C 1~4 13. The compound according to any one of items 1 to 12, wherein the compound is independently selected from the group consisting of alkyl.

[0020] 14.R 10 is H, C 1~4 Alkyl, C 1~4 alkyl-F, preferably R 10 is H and C 1~4 14. The compound according to any one of items 1 to 13, wherein the compound is selected from the group consisting of alkyl.

[0021] 15.R 11 and R 12 H, R d , C 1~4 Alkyl, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4 alkylene-NH, or alternatively, R 11 and R 12together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclic group or heterocyclic spiro group can be substituted with 1 to 3 R groups, preferably R 11 and R 12 H, R d and C 1~4 alkyl, and R and R d The compound according to any one of items 1 to 14, wherein is as described in item 1.

[0022] 16.R1 is H, F, Cl, Br, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, NH-CO-C 1~4 Alkylene-R5, NH-CO-NR5R6, NH-COOR5, NHSO2-C 1~4 Alkylene-R5, C 3~6 cycloalkyl, wherein said C 1~4 The alkyl and cycloalkyl may be optionally substituted with 1 to 3 R7 groups; R2 is H, F, Cl, Br, C 1~4 Alkyl, OR5, C 1~4 Alkylene - OR5, CN, NR5R6, C 1~4 Alkylene-NR5R6, C 3~6 cycloalkyl, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R3 is H, F, Cl, Br, OH, NH2 and NHC 1~4 selected from the group consisting of alkyl; R 3a , R 3b and R 3c are H, F, Cl, Br, OH, NH2 and NHC 1~4independently selected from the group consisting of alkyl; R4 is H, F, Cl, Br, OR5, COR 10 , OH, NH2, and NR5R6; R7 is H, F, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 Alkylene-NH2, OC 1~4 Alkylene-OH, C 2~4 Alkynylene-OH and C 2~4 alkynylene-NH2; R8 and R9 are H, C 1~4 Alkyl, C 1~4 Alkyl-F and OC 1~4 independently selected from the group consisting of alkyl; R 10 is H, C 1~4 Alkyl and C 1~4 alkyl-F; and R 11 and R 12 H, R d , C 1~4 Alkyl, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4 alkylene-NH, or alternatively, R 11 and R 12 together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclic group or heterocyclic spiro group can be substituted with 1 to 3 R groups, and R, R, and R dThe compound according to any one of items 1 to 15, wherein is as described in item 1.

[0023] 17.R1 is H, F, Cl, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R2 is H, F, Cl, OR5, C 1~4 selected from the group consisting of alkyl and NR5R6; R3 is selected from the group consisting of H, F, Cl, OH, and NH2; R 3a , R 3b and R 3c are independently selected from the group consisting of H, F, Cl, OH, and NH; R4 is selected from the group consisting of H, F, Cl, OR5, OH, NH2 and NR5R6; R7 is H, F, C 1~4 Alkyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 alkylene-NH2; R8 and R9 are H and C 1~4 independently selected from the group consisting of alkyl; R 10 is H and C 1~4 selected from the group consisting of alkyl; and R 11 and R 12 H, R d and C 1~417. The compound according to any one of items 1 to 16, wherein R5 and R6 are independently selected from the group consisting of alkyl, and R6 is as described in item 1.

[0024] 18. The compound according to any one of items 1 to 17, wherein Y is CH2.

[0025] 19. The compound according to any one of items 1 or 18, wherein Y is NH.

[0026] 20. LHS is LHSa; Y is CH; Q1 is O or S, most preferably O; R0 is CH3; R1 is H, F, Cl, Br, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, NH-CO-C 1~4 Alkylene-R5, NH-CO-NR5R6, NH-COOR5, NHSO2-C 1~4 Alkylene-R5, C 3~6 cycloalkyl, wherein said C 1~4 The alkyl and cycloalkyl may be optionally substituted with one to three R groups, where R is preferably H, F, Cl, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R2 is H, F, Cl, Br, C 1~4 Alkyl, OR5, C 1~4 Alkylene - OR5, CN, NR5R6, C 1~4 Alkylene-NR5R6, C 3~6cycloalkyl, wherein said C 1~4 The alkyl, cycloalkyl, phenyl or heterocyclic group may be optionally substituted with one to three R groups, and R is preferably H, F, Cl, OR, C 1~4 selected from the group consisting of alkyl and NR5R6; R3 is H, F, Cl, Br, OH, NH2 and NHC 1~4 alkyl, preferably selected from the group consisting of H, F, Cl, OH and NH; R4 is H, F, Cl, Br, OR5, COR 10 , OH, NH2 and NR5R6, preferably selected from the group consisting of H, F, Cl, OR5, OH, NH2 and NR5R6; R7 is H, F, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 Alkylene-NH2, OC 1~4 Alkylene-OH, C 2~4 Alkynylene-OH and C 2~4 Alkynylene-NH, preferably H, F, C 1~4 Alkyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 alkylene-NH2; R8 and R9 are H, C 1~4 Alkyl, C 1~4 Alkyl-F and OC 1~4 From the group consisting of alkyl, preferably H and C 1~4 independently selected from the group consisting of alkyl; R 10 is H, C 1~4 Alkyl and C 1~4From the group consisting of alkyl-F, preferably H and C 1~4 selected from the group consisting of alkyl; R 11 and R 12 H, R d , C 1~4 Alkyl, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4 alkylene-NH, or alternatively, R 11 and R 12 together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclic group or heterocyclic spiro group can be substituted with 1 to 3 R groups, preferably R 11 and R 12 H, R d and C 1~4 independently selected from the group consisting of alkyl; and R 14 is CH3, and R5, R6 and R d The compound according to item 1, wherein:

[0027] 21.LHS is LHSb; Y is CH; Q1 is O or S, most preferably O; R0 is CH3; R1 is H, F, Cl, Br, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, NH-CO-C 1~4 Alkylene-R5, NH-CO-NR5R6, NH-COOR5, NHSO2-C 1~4 Alkylene-R5, C 3~6 cycloalkyl, wherein said C 1~4The alkyl and cycloalkyl may be optionally substituted with one to three R groups, where R is preferably H, F, Cl, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R 3a , R 3b and R 3c are H, F, Cl, Br, OH, NH2 and NHC 1~4 independently selected from the group consisting of alkyl, preferably H, F, Cl, OH and NH; R7 is H, F, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 Alkylene-NH2, OC 1~4 Alkylene-OH, C 2~4 Alkynylene-OH and C 2~4 Alkynylene-NH, preferably H, F, C 1~4 Alkyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 alkylene-NH2; R8 and R9 are H, C 1~4 Alkyl, C 1~4 Alkyl-F and OC 1~4 From the group consisting of alkyl, preferably H and C 1~4independently selected from the group consisting of alkyl; R 10 is H, C 1~4 Alkyl and C 1~4 From the group consisting of alkyl-F, preferably H and C 1~4 selected from the group consisting of alkyl; R 11 and R 12 H, R d , C 1~4 Alkyl, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4 alkylene-NH, or alternatively, R 11 and R 12 together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclic group or heterocyclic spiro group can be substituted with 1 to 3 R groups, preferably R 11 and R 12 H, R d and C 1~4 independently selected from the group consisting of alkyl; and R 14 is CH3, and R5, R6 and R d The compound according to item 1, wherein:

[0028] 22. LHS is LHSa; Y is NH or NR d , preferably NH; Q1 is O or S, most preferably O; R0 is CH3; R1 is H, F, Cl, Br, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, NH-CO-C 1~4Alkylene-R5, NH-CO-NR5R6, NH-COOR5, NHSO2-C 1~4 Alkylene-R5, C 3~6 cycloalkyl, wherein said C 1~4 The alkyl and cycloalkyl may be optionally substituted with one to three R groups, where R is preferably H, F, Cl, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R2 is H, F, Cl, Br, C 1~4 Alkyl, OR5, C 1~4 Alkylene - OR5, CN, NR5R6, C 1~4 Alkylene-NR5R6, C 3~6 cycloalkyl, wherein said C 1~4 The alkyl, cycloalkyl, phenyl or heterocyclic group may be optionally substituted with one to three R groups, and R is preferably H, F, Cl, OR, C 1~4 selected from the group consisting of alkyl and NR5R6; R3 is H, F, Cl, Br, OH, NH2 and NHC 1~4 alkyl, preferably selected from the group consisting of H, F, Cl, OH and NH; R4 is H, F, Cl, Br, OR5, COR 10 , OH, NH2 and NR5R6, preferably selected from the group consisting of H, F, Cl, OR5, OH, NH2 and NR5R6; R7 is H, F, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 Alkylene-NH2, OC 1~4 Alkylene-OH, C 2~4 Alkynylene-OH and C 2~4 Alkynylene-NH, preferably H, F, C 1~4 Alkyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 alkylene-NH2; R8 and R9 are H, C 1~4 Alkyl, C 1~4 Alkyl-F and OC 1~4 From the group consisting of alkyl, preferably H and C 1~4 independently selected from the group consisting of alkyl; R 10 is H, C 1~4 Alkyl and C 1~4 From the group consisting of alkyl-F, preferably H and C 1~4 selected from the group consisting of alkyl; R 11 and R 12 H, R d , C 1~4 Alkyl, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4 alkylene-NH, or alternatively, R 11 and R 12 together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclic group or heterocyclic spiro group can be substituted with 1 to 3 R groups, preferably R 11 and R 12 H, Rd and C 1~4 independently selected from the group consisting of alkyl; and R 14 is CH3, and R5, R6 and R d The compound according to item 1, wherein:

[0029] 23.LHS is LHSb; Y is NH or NR d , preferably NH; Q1 is O or S, most preferably O; R0 is CH3; R1 is H, F, Cl, Br, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, NH-CO-C 1~4 Alkylene-R5, NH-CO-NR5R6, NH-COOR5, NHSO2-C 1~4 Alkylene-R5, C 3~6 cycloalkyl, wherein said C 1~4 The alkyl and cycloalkyl may be optionally substituted with one to three R groups, where R is preferably H, F, Cl, C 1~4 Alkyl, OR5, NR5R6, C 1~4 Alkylene-NR5R6, C 1~4 Alkylene-OR5, C 3~6 cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said C 1~4 The alkyl, cycloalkyl, phenyl, or heterocyclic group may be optionally substituted with 1 to 3 R7 groups; R2 is H, F, Cl, Br, C 1~4 Alkyl, OR5, C 1~4 Alkylene - OR5, CN, NR5R6, C 1~4 Alkylene-NR5R6, C 3~6 cycloalkyl, wherein said C 1~4The alkyl, cycloalkyl, phenyl or heterocyclic group may be optionally substituted with one to three R groups, and R is preferably H, F, Cl, OR, C 1~4 selected from the group consisting of alkyl and NR5R6; R3 is H, F, Cl, Br, OH, NH2 and NHC 1~4 alkyl, preferably selected from the group consisting of H, F, Cl, OH and NH; R4 is H, F, Cl, Br, OR5, COR 10 , OH, NH2 and NR5R6, preferably selected from the group consisting of H, F, Cl, OR5, OH, NH2 and NR5R6; R7 is H, F, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 Alkylene-NH2, OC 1~4 Alkylene-OH, C 2~4 Alkynylene-OH and C 2~4 Alkynylene-NH, preferably H, F, C 1~4 Alkyl, OH, NH2, OC 1~4 Alkyl, NH-C 1~4 Alkyl, N(C 1~4 Alkyl)2, C 1~4 Alkylene -OH and C 1~4 alkylene-NH2; R8 and R9 are H, C 1~4 Alkyl, C 1~4 Alkyl-F and OC 1~4 From the group consisting of alkyl, preferably H and C 1~4 independently selected from the group consisting of alkyl; R 10 is H, C 1~4 Alkyl and C 1~4 From the group consisting of alkyl-F, preferably H and C 1~4 selected from the group consisting of alkyl; R 11 and R 12 H, R d , C 1~4 Alkyl, C 1~4 Alkyl-F, C 1~4 Alkylene -OH and C 1~4 alkylene-NH, or alternatively, R 11 and R 12 together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclic group or heterocyclic spiro group can be substituted with 1 to 3 R groups, preferably R 11 and R 12 H, R d and C 1~4 independently selected from the group consisting of alkyl; and R 14 is CH3, and R5, R6 and R d The compound according to item 1, wherein:

[0030] 24. (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-N-methylacrylamide, (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-N-methylacrylamide (azepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-3-(3-acetamido-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)- 3-(4-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylamide, (E)-3-((R)-3-((2S,6R)-2,6-dimethylmorpholino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl) 2. The compound according to item 1, selected from the group consisting of (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-l)methyl)acrylamide and (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-l)methyl)acrylamide, and any pharmaceutically acceptable prodrug, salt and / or solvate of any of the above.

[0031] 25. (E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide 5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7- Amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzo[b]thiophen-2-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((4-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide, (E)-3-((S)-7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide -yl)-N-((4-(((1r,4r)-4-aminocyclohexyl)oxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide, (S,E)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methyl- 3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (E)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-6, 7,8,9-Tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (E)-3-(7-(1,1-dioxidethiomorpholino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-(4-(methylsulfonyl)piperazin-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (S,E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(2-oxa-6- Azaspiro[3.3]heptan-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, ((S,E)-3-(7-(3-hydroxyazetidin-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-N-((7-amino-2- (S,E)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methylacrylamide and (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide, as well as pharmaceutically acceptable prodrugs, salts, and / or solvates thereof.

[0032] 26. A pharmaceutical composition comprising a compound according to any one of the preceding items 1 to 25.

[0033] 27. A compound or composition according to any preceding item 1 to 26 for use in a method of treatment.

[0034] 28. The compound or composition for use according to item 27, wherein the method of treatment is a method of treating a bacterial infection.

[0035] 29. The compound or composition for use according to item 28, wherein the bacterial infection is associated with one or more bacteria selected from the group consisting of Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), K. pneumoniae and A. baumannii.

[0036] 30. The compound or composition for use according to item 28 or 29, wherein the bacterial infection is associated with A. baumannii and is preferably pneumonia, most preferably nosocomial pneumonia.

[0037] 31. A method for producing a compound according to any one of items 1 to 25, comprising the steps of: [ka] wherein X preferably represents a leaving group selected from hydroxyl, tosylate, triflate, mesylate, iodide, bromide, chloride, methoxy and ethoxy, and Pg preferably represents a protecting group selected from Boc, PMB and DMB, wherein R 11 and R 12 is R 11 and R 12 or may be any of the groups defined in any of the claims or clauses disclosed herein, preferably including a protecting group selected from the group Boc, PMB and DMB. optionally a precursor compound of formula M2a or M2b [ka] (wherein Y, Q1 and all R groups have the same meanings as defined in items 1 to 19). a first variant comprising coupling with an amine compound of formula (I) Formula M6 or M6' [ka] (In the formula, R 11 and R 12 is R 11 and R 12 or may be any of the groups defined in any of the claims or clauses disclosed herein, preferably including a protecting group selected from the group Boc, PMB and DMB. and optionally a compound of formula M7a or M7b [ka] wherein Y, Q1 and all R groups have the same meaning as defined in any one of items 1 to 23. a method selected from the second variant comprising coupling with a compound of formula (I) [Brief explanation of the drawings]

[0038] Detailed Description of the Invention BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Change in log CFU per gram of thigh in the mouse thigh model of Example 35 for the indicated dosing regimens and treatment periods following subcutaneous (SC) administration of the test article. Long horizontal lines indicate the mean and shorter horizontal lines indicate the standard deviation. [Figure 2] Change in log CFU per gram of lung in the mouse lung model of Example 35 for the indicated dosing regimens and treatment periods following subcutaneous (SC) administration of the test article. Long horizontal lines indicate the mean and shorter horizontal lines indicate the standard deviation. DETAILED DESCRIPTION OF THE INVENTION

[0039] definition The following definitions are provided to assist the reader. Unless otherwise specified, all technical terms, notations, and other scientific and medical terms or terminology used herein are intended to have the meanings commonly understood by those of ordinary skill in the chemical and medical arts. Terms having commonly understood meanings may be defined herein for the purposes of clarification and / or ease of reference, but the inclusion of such definitions herein should not be construed as representing a substantive departure from the definition of the term as commonly understood in the art.

[0040] In some embodiments, the term "about" refers to a ±10% variation from the stated value. When the term "about" is used herein in reference to a number, it should be understood that yet other embodiments of the invention encompass that number unmodified by the term "about."

[0041] "Administering" a drug or "administration of" (and grammatical equivalents of this phrase) to a patient refers to direct administration, which can be administration or self-administration by a health care professional to the patient, and / or indirect administration, which can be the act of prescribing a drug. For example, a physician who instructs a patient in self-administration of a drug or provides a patient with a prescription for a drug is administering a drug to the patient.

[0042] The terms "dose" and "dosage" refer to a specific amount of an active or therapeutic agent to be administered. Such an amount is contained in a "dosage form." Dosage form refers to physically discrete units suitable as administration units for human subjects and other mammals, each unit containing a predetermined amount of an active agent, together with suitable excipients such as one or more carriers, calculated to produce the desired onset, tolerability, and therapeutic effect.

[0043] The terms "treatment" and "therapy" as used in this patent application refer to a range of hygienic, pharmacological, surgical and / or physical measures used with the aim of improving a health problem, with the intention of curing and / or ameliorating a disease and / or symptoms. Both terms "treatment" and "therapy" are directed to maintaining and / or restoring the health of individuals and animals, and therefore encompass preventative and curative methods. The administration of suitable medicines to improve and / or cure a health problem, regardless of the origin of its symptoms, diseases and disorders, should be considered a form of treatment or therapy in the context of this application.

[0044] The term "unit dosage form" as used herein refers to a physically discrete unit of therapeutic preparation suitable for the subject to be treated. However, it will be understood that the total daily usage amount of the composition of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dose for any particular subject or organism will vary depending on various factors well known in the medical arts, such as the severity of the disorder to be treated and its treatment, the activity of the specific active agent employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the administration time and excretion rate of the specific active agent employed; the duration of treatment; drugs and / or additional therapies used in combination with or simultaneously with the specific compound employed.

[0045] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0046] The word "comprising" is used to mean "including, but not limited to." "Include" and "including, but not limited to" are used interchangeably. The word "comprise" is used synonymously with "comprise." The word "consisting of" is used to indicate that the listed elements are present, but no other unstated elements are present. The word "comprising" is used to encompass the meaning of "consisting of" as a preferred embodiment.

[0047] The term "FabI" is art-recognized and refers to a bacterial enzyme that is believed to function as an enoyl (acyl transfer protein) (ACP) reductase in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis. This enzyme is believed to be widely distributed in bacteria and plants.

[0048] The term "enzyme inhibitor" refers to any compound that prevents an enzyme from effectively performing its respective biochemical role. Thus, a "FabI inhibitor" is any compound that prevents FabI from performing its biochemical role. The amount of enzyme inhibition by any compound of this type will vary, as described herein and elsewhere.

[0049] The term "antibiotic" or "antibacterial agent" is intended to mean any drug useful for treating, preventing, or otherwise reducing the severity of any bacterial disorder or its complications (including any condition, disease, or complication resulting therefrom and / or described herein). Antibiotic agents include, for example, cephalosporins, quinolones and fluoroquinolones, penicillins and beta-lactamase inhibitors, carbapenems, monobactams, macrolides and lincosamides, glycopeptides, rifampin, oxazolidinones, tetracyclines, aminoglycosides, streptogramins, sulfonamides, and other antibacterial agents. Other antibiotic or antibacterial agents are disclosed herein and will be known to those of skill in the art. In certain embodiments, the term "antibiotic agent" does not include agents that are FabI inhibitors; therefore, in certain instances, the combinations of the invention include one agent that is a FabI inhibitor and another agent that is not a FabI inhibitor.

[0050] The term "drug" as used herein refers to any substance that falls within the scope of at least one of the definitions set out in Article 1, paragraphs 2(a), 2(b) or 3a of the November 16, 2012 version of Directive 2001 / 83 / EC of November 6, 2001, or Article 1, paragraphs 2(a) or 2(b) of the August 7, 2009 version of Directive 2001 / 82 / EC of November 6, 2001, and Article 2 of Regulation (EC) No. 726 / 2004 of March 31, 2004.

[0051] As used herein, the term "disease" refers to any illness caused by or associated with infection by an organism.

[0052] As used herein, the term "bacterial illness" refers to any illness caused by or associated with infection with bacteria.

[0053] The term "cis" is art-recognized and refers to the orientation of two atoms or groups in relation to a double bond such that the atoms or groups are on the same side of the double bond. The cis configuration is also often designated as the (Z) configuration.

[0054] The term "trans" is art-recognized and refers to the orientation of two atoms or groups relative to a double bond such that the atoms or groups are on opposite sides of the double bond. The trans configuration is also often designated as the (E) configuration.

[0055] The term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by a pharmacologically active substance. Thus, this term refers to any measurable effect in an animal or human related to the diagnosis, cure, mitigation, treatment, or prevention of disease, or the improvement of a desired physical or mental development and / or condition. The phrase "therapeutically effective amount" refers to an amount of such a substance that produces some desired local or systemic effect at a reasonable risk-benefit ratio appropriate for any treatment. The therapeutically effective amount of such a substance will vary depending on the subject and disease state being treated, the subject's weight and age, the severity of the disease state, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. For example, certain compositions of the present invention can be administered in an amount sufficient to produce a therapeutic effect at a reasonable risk-benefit ratio appropriate for such treatment.

[0056] The term "chiral" is art-recognized and refers to a molecule that has the property of not being superimposable on its mirror image counterpart, while the term "achiral" refers to a molecule that is superimposable on its mirror image counterpart. A "prochiral molecule" is a molecule that has the potential to be converted into a chiral molecule by a specific process.

[0057] The compounds of the present disclosure may contain one or more asymmetric centers and / or double bonds and therefore may exist as geometric isomers, enantiomers, or diastereomers. Enantiomers and diastereomers may be represented by the symbols "(+)," "(-)," "R," or "S," depending on the placement of substituents relative to the asymmetric carbon atom, although one of ordinary skill in the art will recognize that a structure may implicitly represent one or more asymmetric centers. Mixtures of enantiomers or diastereomers may be represented by "(±)" in nomenclature, although one of ordinary skill in the art will recognize that a structure may implicitly represent a chiral center. Geometric isomers resulting from the placement of substituents relative to a carbon-carbon double bond or relative to a cycloalkyl or heterocyclic ring may also exist in the compounds of the present invention.

[0058] symbol [ka] represents a bond which may be a single bond, double bond or triple bond as described herein.

[0059] Substituents on a carbon-carbon double bond are designated as having the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Alternatively, substituents on a carbon-carbon double bond may be designated as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond. The configuration of substituents on a carbocyclic ring may also be designated as "cis" or "trans," with "cis" referring to substituents on the same side relative to the plane of the ring and "trans" referring to substituents on opposite sides relative to the plane of the ring. Mixtures of both compounds in which the substituents are positioned on the same side and on opposite sides relative to the plane of the ring are designated "cis / trans" or "Z / E."

[0060] As used herein, the term "stereoisomer" comprises all geometric isomers, enantiomers, or diastereomers. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Conformational and rotational isomers of the disclosed compounds are also contemplated.

[0061] The term "IC50" is art-recognized and refers to the effectiveness of a substance in inhibiting a given biological or biochemical process (or a component of the process, i.e., an enzyme, a cell, a cellular receptor, or a microorganism). IC50 represents the concentration of a drug, e.g., a compound of the invention, required for 50% inhibition in vitro.

[0062] The term "MIC" is art-recognized and refers to the minimum inhibitory concentration, which is the lowest concentration of an antimicrobial that inhibits visible growth of a microorganism after overnight incubation, usually reported as mg / L or μg / mL.

[0063] The term "antimicrobial" is art-recognized and refers to the ability of the compounds disclosed herein to prevent, inhibit the growth of, or impair the function of microorganisms, such as bacteria, fungi, protozoa, and viruses.

[0064] The term "antimicrobial" is art-recognized and refers to the ability of the compounds disclosed herein to prevent the growth of, inhibit, or impair the function of bacterial microorganisms.

[0065] The term "microorganism" is art-recognized and refers to a small organism. In certain embodiments, the term microorganism applies to bacteria. In other embodiments, the term refers to pathogenic forms of small organisms.

[0066] The term "alkyl" as used herein refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group having 1 to 8 or 1 to 6 carbon atoms, referred to herein as C1-C8 alkyl or C1-C6 alkyl, respectively. The term "lower alkyl" as used herein specifically refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group having 1 to 4 or 1 to 3 carbon atoms, referred to herein as C1-C4 alkyl and C1-C3 alkyl, respectively. Exemplary alkyl and lower alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.

[0067] Furthermore, the term "alkyl" (or "lower alkyl") also includes divalent saturated straight-chain or branched hydrocarbon groups, sometimes referred to as alkanediyl or alkylene groups. It should be understood that the term "alkyl" encompasses unsubstituted as well as "substituted alkyls," i.e., optionally having one or more substituents at one or more positions. That is, it also refers to alkyl moieties having one or more (e.g., two, three, four, five, six, etc.) substituents each replacing a hydrogen on a carbon of the hydrocarbon backbone. Such substituents may include, for example, hydroxyl, carbonyl groups (where the carbonyl group has a hydrogen atom, an alkyl group, or other group as defined in this paragraph, e.g., to form a carboxyl, alkoxycarbonyl, formyl, or acyl group), thiocarbonyl-containing groups (where the carbonyl group has a hydrogen atom, an alkyl group, or other group as defined in this paragraph, e.g., to form a thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, phosphate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, cycloalkyl, heterocyclic, or aromatic or heteroaromatic moiety. In all instances where the above groups have more than one valence, the additional free valences may be saturated with hydrogen atoms, alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, or heteroaryl groups. Furthermore, those skilled in the art will understand that the moieties substituting the hydrocarbon chain can themselves be substituted, if appropriate. For example, substituents of substituted alkyl can include amino, azido, imino, amido, phosphoryl (including phosphonate, phosphinate, and phosphate), sulfonyl (including sulfate, sulfonamide, sulfamoyl, and sulfonate), and silyl groups, as well as substituted and unsubstituted forms of ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate, and ester), nitrile, and isonitrile. For the avoidance of doubt, alkyl groups bearing other alkyl groups should be considered as single branched alkyl groups, not as alkyl groups bearing other alkyl groups.

[0068] The term "alkylene" is art-recognized and refers to a group that corresponds to an alkyl group as defined above, except that it has two free valences. Alkylene groups are also sometimes referred to as alkanediyl groups.

[0069] The term "alkenyl" is recognized in the art and refers to a group equivalent to the alkyl group defined above, except that it contains one or more carbon-carbon double bonds. Of course, the total number of double bonds is limited by the number of carbon atoms in the alkenyl group, and to allow for at least one double bond, the alkenyl group must have at least two carbon atoms. Except for this difference, the definitions and characteristics of alkyl groups described above apply equally to alkenyl groups.

[0070] The term "alkynyl" is art-recognized and refers to groups equivalent to alkyl groups, as defined above, except that they contain one or more carbon-carbon triple bonds. Of course, the total number of triple bonds is limited by the number of carbon atoms in the alkynyl group, and to allow for at least one triple bond, the alkynyl group must have at least two carbon atoms. Except for this difference, the definitions and characteristics of alkyl groups described above apply equally to alkynyl groups.

[0071] The term "aryl" is art-recognized and refers to a 5- or 6-membered monocyclic aromatic group which may be a purely aromatic carbocyclic ring or which may contain 0 to 4 heteroatoms, such as, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryls" or "heteroaromatics." An aromatic ring can be unsubstituted or substituted at one or more positions on the ring with a substituent as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, phosphate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, etc. The term "aryl" also encompasses polycyclic ring systems having two or more rings, where two adjacent rings (the rings are "fused rings") share two or more carbons, and where at least one ring is aromatic as defined above, but without particular restriction as to the additional fused ring(s), which may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl.

[0072] The terms "aralkyl" or "arylalkyl" are art-recognized and refer to an alkyl group (e.g., an aromatic or heteroaromatic group) substituted with an aryl group.

[0073] The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0074] As used herein, the term "cycloalkyl" is used herein to refer to groups such as "C 3~6 cycloalkyl" or "C 4~6The term "cycloalkyl" refers to a monocyclic saturated or partially unsaturated alkyl or alkenyl group derived from a cycloalkane, e.g., having 3 to 6 or 4 to 6 carbons. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, cyclobutane, cyclopropane, or cyclopentene. The cycloalkyl group can be unsubstituted or substituted at one or more positions with one or more substituents described above.

[0075] As used herein, the term "halogen" refers to F, Cl, Br, or I. "Halide" refers to the corresponding anion of a halogen.

[0076] As used herein, "amino" refers to a group having the general structure -NR a R b and unless otherwise specified, R a and R b are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic groups, as well as any other substituents listed above with respect to the scope of substituted alkyl groups, excluding carbonyl groups, thiocarbonyl groups, imine groups, and substituents bonded to the remainder of the molecule through a heteroatom selected from N, O, S, and P. Alternatively, R a and R b may also represent hydrocarbon groups attached so as to form a heterocyclic ring together with the nitrogen atom to which they are attached.

[0077] The term "heteroaryl" as used herein refers to a monocyclic, aromatic, 5- or 6-membered ring system containing one or more heteroatoms, such as nitrogen, oxygen, and sulfur, which may be the same or different, e.g., 1 to 3 heteroatoms. Where possible, the heteroaryl ring can be attached to an adjacent group through a carbon or nitrogen atom. Examples of heteroaryl rings include, but are not limited to, furan, benzofuran, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, and pyrimidine. The heteroaryl group can be unsubstituted or substituted with one or more substituents described above for aryl groups. The term "heteroaryl" also encompasses polycyclic ring systems having two or more rings, where two adjacent rings (the rings are "fused rings") have two or more carbons or heteroatoms in common, and at least one ring is a heteroaryl as defined above, while the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aromatic rings, and / or saturated, unsaturated, or aromatic heterocyclic rings.

[0078] As used herein, the term "heterocycle" refers to a monocyclic ring containing one or more heteroatoms, e.g., 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur, which may be the same or different. The remaining ring members are composed of carbon atoms. Heterocycles typically have 4 to 8 ring members, preferably 5 or 6 ring members. Unless otherwise specified, heterocycles may be aromatic, partially saturated, or fully saturated. Unless otherwise specified, heterocycles may or may not contain permissible substituents, as defined herein.

[0079] As used herein, the term "heterocyclic spiro" refers to a spiro ring structure, e.g., a bicyclic structure, containing one or more heteroatoms, e.g., one to three heteroatoms, such as nitrogen, oxygen, and sulfur, which may be the same or different. The remaining ring members are carbon atoms. Heterocyclic spiro typically have 7 to 11 ring members, preferably 7 or 9 ring members. Unless otherwise specified, heterocyclic spiro can be partially saturated or fully saturated. Unless otherwise specified, heterocyclic spiro may or may not contain the permissible substituents defined herein.

[0080] As used herein, the terms "hydroxy" and "hydroxyl" refer to an --OH group.

[0081] The term "nitro" is art-recognized and refers to -NO; the term "sulfhydryl" is art-recognized and refers to -SH; and the term "sulfonyl" is art-recognized and refers to -SO-.

[0082] The definition of each expression, when it occurs more than one time in any construct, is intended to be independent of its definition elsewhere in the same construct.

[0083] The terms "triflyl," "tosyl," "mesyl," and "nonaflyl" are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate, p-toluenesulfonate, methanesulfonate, and nonafluorobutanesulfonate functional groups and molecules containing such groups, respectively.

[0084] The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, and methanesulfonyl, respectively. A more comprehensive list of abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is usually set out in a table entitled "Standard List of Abbreviations."

[0085] The term "prodrug" refers to a derivative of an active compound (drug) that is converted under conditions of use, such as within the body, to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active drug.

[0086] It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the valences allowed for the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as rearrangement, cyclization, elimination, or other reaction.

[0087] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described herein above in connection with, for example, substituted alkyl. The permissible substituents can be one or more in an appropriate organic compound and can be the same or different. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. In this context, the term "permissible substituents" refers to any substituent that can be attached to a core molecule without violating general principles of chemical bond formation, e.g., the maximum number of valence electrons of the atom in question, and without causing the compound to be so toxic that it is unacceptable to patients, even at the minimum dose required to achieve a therapeutic effect.

[0088] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements in CAS format, found on the inside cover of the Handbook of Chemistry and Physics, 67th Ed., 1986-87. Also for purposes of this disclosure, the term "hydrocarbon" is intended to encompass all permissible compounds having at least one hydrogen atom and one carbon atom. In a broad aspect, permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds, which may be substituted or unsubstituted.

[0089] The term "pharmaceutically acceptable salts" is art-recognized and refers to relatively non-toxic, inorganic and organic acid addition salts or inorganic or organic base addition salts of compounds, such as those contained in the compositions of the present invention and those present in other approved pharmaceuticals (which approval may be by any regulatory agency in the EU, USA, CA, JP, CN, or KR as of the effective date of this application).

[0090] The term "treatment" includes any significant effect that results in an improvement, eg, a reduction, diminishment, modulation, or elimination, of a condition, disease, disorder, or the like.

[0091] The terms "prophylactic" or "therapeutic" treatment are art-recognized and refer to the administration of one or more subject compositions to a host. If administration occurs before the onset of clinical signs of an unwanted condition (e.g., a disease or other unwanted condition in the host animal), the treatment is prophylactic, i.e., protects the host from developing the unwanted condition. Conversely, if administration occurs after the onset of an unwanted condition, the treatment is therapeutic (i.e., aimed at reducing, ameliorating, or maintaining an already occurring unwanted condition or its associated side effects).

[0092] A "patient," "subject," or "host" to be treated by a subject method can refer to either a human or a non-human animal. Non-human animals include companion animals (e.g., cats, dogs) and animals raised for consumption (e.g., food animals), such as cows, pigs, and chickens. Non-human animals are preferably mammals.

[0093] The term "mammal" is known in the art, and exemplary mammals include humans, primates, bovines, porcines, canines, felines, and rodents (eg, mice and rats).

[0094] The term "bioavailable" is art-recognized and refers to a form that allows the subject disclosure or a portion of an administered amount to be absorbed, taken up, or otherwise made physiologically available to the subject or patient to whom it is administered.

[0095] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting any subject composition or its components from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient.Some examples of materials that can act as pharmaceutically acceptable carriers include: (1) sugars, such as dextrose, lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch, as well as starch derivatives, such as cyclodextrins and modified cyclodextrins, including preferably (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin; (3) cellulose and its derivatives, such as microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (HPMC), and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; and (8) matrix-forming polymeric excipients, such as polyvinylpyrrolidone (PVP), e.g., PVP K30, acrylic polymers and copolymers, such as different grades of Eudragit, preferably Eurdragit. L100, hydroxypropyl methylcellulose acetate succinate (HPMCAS), other copolymers, e.g., polyethylene glycol-based copolymers such as Soluplus; (9) excipients, e.g., cocoa butter and suppository wax; (10) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) glycols, e.g., propylene glycol; (12) polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (13) esters, e.g., ethyl oleate, glyceryl behenate, and ethyl laurate; (14) agar; (15) buffers, e.g., magnesium hydroxide and aluminum hydroxide; (16) alginic acid; (17) pyrogen-free water; (18) isotonic saline; (19) Ringer's solution; (20) ethyl alcohol; (21) phosphate buffer; and (22) other compatible, non-toxic substances used in pharmaceutical formulations. The disclosed excipients can serve more than one function: for example, fillers and binders can also be disintegrants, flow agents, anti-adherents, lubricants, sweeteners, etc.

[0096] As used herein, the term "solvent" refers to a liquid chemical capable of dissolving a significant amount of a substance of interest (a "solute") other than itself, thereby producing a clear and homogeneous solution. The term "significant amount" refers to an amount of dissolved solute that is dependent on the intended use of the solution, such that the amount of dissolved solute is sufficient to permit its intended use. For example, if a compound of the present invention is intended to be administered in solution form by injection, the solvent must be capable of dissolving an amount of the compound that will allow for the administration of a therapeutic dose.

[0097] The terms "acid" and "base" are used to have their conventional meaning as proton donor and proton acceptor (i.e., Bronsted acid and base), respectively. A "strong base" is meant to be any base that has the basicity of t-BuOK in THF or stronger. A "weak acid" is meant to be any acid that has the acidity of 1 M H2SO4 or weaker.

[0098] Unless otherwise specified, all reactions described herein are carried out at a reaction temperature that yields the desired target compound and that provides a reasonable compromise between reaction rate and selectivity. Typical reaction temperatures for Pd-based coupling reactions and Fe-based cyclization reactions are 80°C to 90°C, while removal of protecting groups is usually accomplished at temperatures between 0°C and room temperature (25°C).

[0099] Unless otherwise specified, all statements in dependent claims in which variables are identical to those defined for compounds of formula I and specific embodiments thereof of formulae Ia and Ib should be understood to mean that the more specific meanings stated for these variables in other dependent claims are also possible and more preferred. The same applies to the explanation of the meanings of variables in the general description. It is particularly preferred to rely on a combination of meanings for different variables, with two, three or more, and ideally all, of these meanings being individually stated as preferred.

[0100] Unless otherwise specified, the term "protecting group" used herein refers to a group attached to a functional group to prevent the functional group from participating in a planned chemical reaction. The protecting group must be inert under the planned reaction conditions, but the protecting group must also be removable from the compound to prevent further transformations at other sites in the molecule. Suitable protecting groups for each functional group are described in "Greene's Protective Groups in Organic Synthesis," Peter GM Wuts, Theodora W. Greene, John Wiley & Sons, 20 December 2012.

[0101] Overview It has surprisingly been found that antibacterial activity against Gram-positive and / or Gram-negative bacteria, more particularly S. aureus, E. coli, K. pneumoniae, and / or A. baumannii, can be achieved using compounds of formula (I) described herein. It has surprisingly been found that compounds of the present invention can have low MICs with respect to Gram-positive and / or Gram-negative bacteria, more particularly S. aureus, E. coli, K. pneumoniae, and / or A. baumannii, indicating that compounds of formula (I) can not only be effective against these types of bacteria, but can also be effective at low doses, thereby minimizing side effects. Without wishing to be bound by theory, the inventors believe that the compounds of the present invention may overcome the mechanism of FabI inhibition associated with previous generation FabI inhibitor compounds and may be more potent and / or able to better penetrate the cytoplasm of such bacteria, or less likely to be effluxed from the bacteria, and / or more potent against Gram-negative bacteria such as A. baumannii, E. coli, and K. pneumoniae.

[0102] Compounds of the Invention The compounds of the present invention have the following general formula I [ka] where LHS represents the left side moiety, which is represented by LHSa and LHSb as shown below: [ka] wherein the asterisk ( * ) indicates the point of attachment of the molecule and is used in formulas Ia and Ib: [ka] The following two families of compounds are intended to be encompassed: 13 The meaning of is defined herein, for example, in the claims and in the Summary of the Invention. The compounds of the present invention may also be pharmaceutically acceptable prodrugs, salts and / or solvates of these compounds of formula (I).

[0103] Unless expressly specified otherwise, the present disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and mixtures thereof, within the scope of the present invention, provided that the carbon-carbon double bond between the pyridine ring and the amide group at the center of the molecule must be in the trans configuration as shown in the formula above. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be encompassed by the present invention.

[0104] For example, if a specific enantiomer of a compound disclosed herein is desired, it can be prepared by asymmetric synthesis or by derivatization with an asymmetric auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers so formed by fractional crystallization or chromatographic means known in the art, followed by recovery of the pure enantiomers.

[0105] Additionally, individual enantiomers and diastereomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing an asymmetric or stereogenic center, or by preparing a racemic mixture followed by resolution methods well known to those skilled in the art. Examples of such resolution methods include (1) coupling the mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and liberating the optically pure product from the auxiliary; (2) forming a salt with an optically active resolving agent; (3) directly separating the mixture of optical antipodes on a chiral liquid chromatography column; or (4) kinetic resolution using a stereoselective chemical or enzymatic reagent. Racemic mixtures can also be resolved into their constituent enantiomers by well-known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent. Stereoselective synthesis, chemical reactions, or enzymatic reactions in which a single reactant produces an unequal mixture of stereoisomers by generating new stereocenters or by transferring existing stereocenters, are well known in the art. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0106] The present invention also encompasses isotopically labeled compounds of the present invention recited herein, which differ only in that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 For example, the compounds of the present invention may have one or more H atoms replaced with deuterium.

[0107] Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with 3H and 14C) are useful in compound and / or substrate tissue distribution studies. Tritiated (i.e., 3H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. 2 Substitution with higher mass isotopes, such as H, can confer certain therapeutic advantages due to their increased metabolic stability (e.g., longer in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents, for example, following procedures similar to those disclosed in the Examples herein.

[0108] Prodrug The prodrugs of the present invention contain at least one prodrug moiety, i.e., a moiety that is cleaved under physiological conditions to release an active species. Such prodrug moieties can be attached to the compounds of the present invention at any position exhibiting sufficient reactivity, e.g., R 13 may be a prodrug moiety, or when Y is N, there may be a prodrug moiety attached to Y.

[0109] Salts, solvates, polymorphs The compounds of the present invention can be used in free form or alternatively in the form of a pharmaceutically acceptable salt. Acid addition salts are particularly suitable. Pharmaceutically acceptable salts that can be used in the present invention are well known to those skilled in the art, and are described, for example, in SM Berge et al., J. Pharm. Sci., 1977, 66, 1, 1-19; RJ Bastin, et al., Org. Proc. Res. Dev., 2000, 4, 427-435; and PH Stahl, CG Wermuth, Eds. "Pharmaceutical Salts: Properties, Selection, and Use", 2 nd Ed. Wiley-VCH, 2011. Particularly useful salts may be hydrochlorides, such as the hydrochloride or dihydrochloride salts, or fluoroacetates, such as the trifluoroacetate salts.

[0110] The prodrugs of the present invention may be provided in free form or in the form of a pharmaceutically acceptable salt, preferably a pharmaceutically acceptable salt well known to those skilled in the art, for example, as described in the documents cited above.

[0111] The compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present invention is meant to encompass both solvated and unsolvated forms.

[0112] The compounds of the present invention may exist in a single or multiple crystalline forms or polymorphs. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0113] Pharmaceutical Composition The compounds of the present invention can be contained in pharmaceutical compositions. As is well known in the art, the pharmaceutical compositions of the present disclosure can be administered by various means and can take any suitable formulation form depending on the intended use. For example, when the compositions of the present disclosure are administered orally, they can be formulated as tablets, capsules, granules, powders, or syrups. Alternatively, the compositions disclosed herein can be administered parenterally and formulated as injections / injectables (intravenous, intramuscular, intraperitoneal, or subcutaneous), drip infusion preparations, or suppositories. When applied via the ocular mucosa, the compositions disclosed herein can be formulated as eye drops or eye ointments. The compositions can contain any conventional additives, such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending aids, emulsifiers, or coating agents. Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be included in the compositions.

[0114] In the compositions of the present invention, an additive may serve more than one function, for example, a filler or binder may also be a disintegrant, a flow agent, an anti-adherent, a lubricant, a sweetener, etc.

[0115] The compositions can be prepared by any conventional means, which may depend on the type of formulation in question, e.g., tablet, injectable, etc. The compositions can include any conventional excipients and / or additives, such as one or more of those described above.

[0116] The compositions may be formulated to be suitable for oral, nasal (e.g., by inhalation by formulating a dry powder or aerosol formulation), rectal, vaginal, aerosol, and / or parenteral (e.g., by injection, e.g., intravenous, intraperitoneal, intramuscular, or subcutaneous) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. The amount of a compound disclosed herein that may be combined with an excipient, e.g., a carrier material, to produce a single dose may vary depending on the type of compound, the therapeutic subject, and the particular mode of administration.

[0117] As described above, the compositions of the present invention can be prepared by any conventional means, and the conventional means may depend on the desired form of the composition, for example, tablet, injection / injectable. The method for preparing the compositions of the present invention may include a step of bringing the composition of the present disclosure into association with a carrier and, optionally, one or more additional additive components. Generally, the compositions are prepared by uniformly and intimately bringing the compounds of the present invention into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0118] Compositions of the present invention formulated for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth gum), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions, or elixirs, syrups, or lozenges (using an inert base such as gelatin and glycerin, or sucrose and gum arabic), each containing a predetermined amount of the subject composition as an active ingredient. Compositions of the present disclosure may also be administered as a bolus, electuary, or paste.

[0119] In solid dosage forms for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), the subject compositions may be mixed with one or more of the following pharmaceutically acceptable excipients: (1) fillers or diluents, such as starch, dextrose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as cellulose (e.g., microcrystalline cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), and carboxymethylcellulose), alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; and (4) disintegrants, such as croscarmellose sodium, carboxymethyl starch sodium (sodium starch glycolate), cross-linked polyvinylpyrrolidone (crospovidone), gellan gum, xanthan gum, agar, calcium carbonate, potato, etc. starch or tapioca starch, alginic acid and sodium alginate, certain silicates, especially calcium silicate, and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) colorants; (11) complexing agents, such as cyclodextrins and modified cyclodextrins, preferably (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin; (12) matrix-forming polymeric excipients, such as polyvinylpyrrolidone (PVP), e.g., PVP. K30, acrylic polymers and copolymers such as different grades of Eudragit, preferably Eudragit L100, hydroxypropylmethylcellulose (acetate / succinate) (HPMCAS), other copolymers, such as polyethylene glycol-based copolymers such as Soluplus, (13) carriers, such as sodium citrate or dicalcium phosphate. In the case of capsules, tablets and pills, the compositions may also contain buffering agents.Similar types of solid compositions can also be used as fillers for soft and hard gelatin capsules using excipients such as lactose, i.e., milk sugar, and high molecular weight polyethylene glycols, etc. The disclosed pharmaceutical excipients can provide more than one function. For example, fillers and binders can also be disintegrants, flow agents, anti-adherents, lubricants, sweeteners, etc. Two or more excipients can be used in accordance with the present invention, and the two or more excipients can belong to the same and / or different classes. There is no limitation in this regard.

[0120] Compositions of the invention formulated for parenteral administration, including intravenous, intramuscular, intraperitoneal, or subcutaneous administration, may be provided in solid form in vials so that they can be diluted in a suitable solvent (e.g., oil or water, aqueous NaCl solution, e.g., 0.9% by weight NaCl solution, aqueous glucose solution, dextrose solution). The solid form may comprise a compound of formula (I) mixed with one or more excipients and / or further ingredients, for example buffers such as sodium citrate, solubilisers (co-solvents) such as ethanol, complexing agents such as cyclodextrins and modified cyclodextrins, including preferably (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin, stabilisers such as cellulose, 2-hydroxypropyl ether, polyethylene glycol 4000 cross-linked polyvinylpyrrolidone (crospovidone) and / or polyethylene glycol, osmotic agents such as glucose or sodium chloride, surfactants such as polyoxyethylene 20 sorbitan monooleate, polyoxyl castor oil and / or sodium lauryl sulphate, preservatives or bacteriostatic agents such as sodium citrate, benzyl alcohol and / or viscosity modifiers as benzyl alcohol or carboxymethylcellulose. Other pharmaceutically acceptable excipients may also be suitable for inclusion in the solid form, for example, one or more of the pharmaceutically acceptable excipients described herein above as suitable for inclusion in compositions formulated for oral administration. Selecting appropriate excipients depending on the desired properties of the solid form is well within the skill of those skilled in the art. Compositions formulated for parenteral administration may also be provided in liquid form, for example, in an infusion bag or pre-filled syringe. In this case, the same components as listed above may be present in the liquid formulation. The liquid formulation may be an aqueous formulation, an aqueous NaCl solution, for example, a 0.9% by weight NaCl solution, an aqueous glucose solution, or a dextrose solution, or an oil formulation, for example, a stabilized oil-in-water emulsion containing medium-chain triglycerides and long-chain triglycerides stabilized by phospholipids.

[0121] Further types of parenteral administration are also contemplated, including implantable medical devices or implantable antibiotics, particularly those containing a compound of the present invention in or in a coating on an implantable medical device or implantable antibiotic.

[0122] As used herein, the term "implantable medical device" refers to any indwelling (placed within a patient's body) medical device intended to replace, supplement, or enhance a biological structure. Implantable medical devices may be permanently placed, such as stents or artificial joints, or alternatively, they may be temporarily placed and removed when they are no longer needed (e.g., chemotherapy ports or orthopedic screws).

[0123] As used herein, the term "implantable antibiotic" refers to any indwelling (placed within a patient's body) medical device that is implanted in a patient for the primary purpose of treating or preventing an infection, e.g., a bacterial infection, by delivering an antibiotic. Implantable antibiotics can be permanently placed; alternatively, they can be temporarily placed and removed when they are no longer needed, e.g., when the infection has been eradicated, or they can simply dissolve over time within the body.

[0124] The compounds of the present invention may also be applied to medical devices, such as surgical instruments or sutures, which may prevent bacterial growth on the medical device. The medical device may also deliver antibiotics at the surgical site or, in the case of sutures, at the wound site.

[0125] As used herein, the term medical device refers to any tool used in a medical setting for the diagnosis or treatment of a patient, for example, surgical tools such as scalpels and forceps, scissors and sutures, etc. As used herein, the term "medical device" includes dental instruments.

[0126] Common excipients, particularly for compositions formulated for oral or intravenous (IV) administration, include the following: stabilizers A stabilizer can be advantageously used to improve the physicochemical stability of the formulation. There is no particular limitation on the stabilizer that can be used in the present invention.

[0127] The use of endotoxin-controlled PVP and / or polyvinylpyrrolidone may be preferred as a stabilizer for compositions formulated for parenteral administration.

[0128] The stabilizer may be present in a relative amount of from 0.01% to 20% by weight, preferably from 0.1% to 2% by weight, more preferably from 0.1% to 1% by weight.

[0129] buffer Buffers can be advantageously used to control the pH of parenteral formulations. There are no particular limitations on the buffers that can be used in the present invention.

[0130] The buffer used may depend on the physicochemical properties of the compound of the invention, such as stability and solubility, buffering capacity, and the desired pH. Phosphate, citrate, Tris, succinate, and / or histidine buffers may, for example, be used.

[0131] The buffering agent may be present in a relative amount of from 0.01% to 5% by weight, preferably from 0.01% to 5% by weight, more preferably from 0.01% to 3% by weight.

[0132] Solubilizers (co-solvents) A solubilizing agent (co-solvent) can be advantageously used to improve the solubility of the compound of the present invention. There is no particular limitation on the solubilizing agent (co-solvent) that can be used in the present invention.

[0133] The use of biocompatible cosolvents such as polyoxyethylene 300 or 400, ethanol, propylene glycol and / or glycerin may be preferred.

[0134] The co-solvent may be present in a relative amount of from 1% to 60% by weight, preferably from 1% to 30% by weight, more preferably from 1% to 15% by weight.

[0135] Osmotic agents An osmotic agent may be advantageously used to achieve isotonicity of the solution. There is no particular limitation on the osmotic agent that can be used in the present invention.

[0136] The use of glucose and / or sodium chloride may be preferred.

[0137] The osmotic agent may be present in a relative amount of from 0.01% to 20% by weight, preferably from 0.1% to 5% by weight, more preferably from 0.09% to 5% by weight.

[0138] preservatives Preservatives can be advantageously used to protect the compound from physicochemical degradation due to oxidation, light, temperature, etc. There is no particular limitation on the preservatives that can be used in the present invention.

[0139] The use of sodium bisulfite, sodium metabisulfite, ascorbate, sodium sulfite and / or thioglycerol may be preferred.

[0140] The preservative may be present in a relative amount of from 0.01% to 3% by weight, preferably from 0.01% to 2% by weight, more preferably from 0.01% to 0.01% by weight.

[0141] Binder The binder may be advantageously used alone or together with an excipient to increase the particle size of the active ingredient and improve handling. The binder material that can be used in the present invention is not particularly limited.

[0142] Suitable binder materials include povidone (polyvinylpyrrolidone), copovidone (poly(1-vinylpyrrolidone-co-vinyl acetate)), maltodextrin, poloxamer (block copolymer having a first poly(ethylene oxide) block, second and central poly(propylene oxide) blocks, and a third poly(ethylene oxide) block), polyethylene glycol, polyethylene oxide, magnesium aluminosilicate, gelatin, gum arabic, alginic acid, carbomer (e.g., Carbopol), dextrin, dextrates (purified mixtures of sugars obtained by controlled enzymatic hydrolysis of starch), guar gum, hydrogenated vegetable oil, liquid glucose, wax, starch (pregelatinized and raw), sodium alginate, and mixtures thereof.

[0143] It may be preferable to use povidone and / or copovidone.

[0144] The binder may be present in a relative amount of from 0.5% to 15% by weight, preferably from 1% to 12% by weight, more preferably from 4% to 10% by weight.

[0145] Diluent Diluents are advantageously used to increase the bulk of the pharmaceutical composition and to facilitate handling of the composition. There is no particular limitation on the materials of the diluents that can be used in the present invention.

[0146] Suitable diluent materials include mannitol, isomalt, histidine, lactose (including anhydrous or monohydrate forms), calcium phosphate (including dibasic and tribasic calcium phosphate), calcium carbonate, calcium sulfate, sucrose, fructose, maltose, xylitol, sorbitol, maltitol, aluminum silicate, dextrose, starch (pregelatinized and raw), glucose, dextrates (purified mixtures of sugars obtained by controlled enzymatic hydrolysis of starch), magnesium carbonate, and mixtures thereof.

[0147] It may be preferable to use mannitol, xylitol, sorbitol, isomalt and / or histidine, especially mannitol.

[0148] The relative amount of diluent present is not particularly limited, and suitable amounts may range from 2% to 85% by weight, preferably from 8% to 80% by weight, and more preferably from 10% to 50% by weight.

[0149] surfactants A surfactant can be advantageously used to enhance the wettability of the tablet and the active ingredient. The surfactant is an optional component, but is a preferred component. The surfactant material that can be used in the present invention is not particularly limited.

[0150] Suitable surfactant materials include sodium lauryl sulfate, poloxamer, sodium docusate, sorbitan esters, polyethylene oxide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (ethoxylated sorbitan esterified with a fatty acid, the number representing the number of repeating polyethylene glycol units), and mixtures thereof.

[0151] It may be preferable to use sodium lauryl sulfate.

[0152] The relative amount of surfactant present is not particularly limited, and suitable amounts can range from above 0% to 7% by weight, preferably 0.1% to 6.5% by weight, and more preferably 1% to 6% by weight.

[0153] Disintegrant Disintegrants can be used to promote disintegration of the pharmaceutical composition, thereby promoting dissolution and uptake of the active ingredient. There is no particular limitation on the materials of the disintegrants that can be used in the present invention.

[0154] Suitable disintegrant materials include cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), croscarmellose sodium, gellan gum, xanthan gum, magnesium aluminosilicate, sodium alginate, pregelatinized starch, alginic acid, guar gum, homo- and copolymers of (meth)acrylic acid and salts thereof, such as polacrilin potassium, and mixtures thereof.

[0155] It may be preferable to use crospovidone.

[0156] The relative amount of disintegrant present is not particularly limited, and suitable amounts can range from above 0% to 20% by weight, preferably from 1% to 15% by weight, and more preferably from 2% to 10% by weight.

[0157] Superplasticizer A fluidizer can be advantageously used to improve the fluidity of a pharmaceutical composition, thereby improving its handling. A fluidizer is an optional but preferred component. The fluidizer material that can be used in the present invention is not particularly limited.

[0158] Suitable flow agent materials include colloidal silicon dioxide, magnesium oxide, magnesium silicate, tricalcium phosphate and mixtures thereof.

[0159] It may be preferable to use colloidal silicon dioxide.

[0160] The relative amount of fluidizing agent present is not particularly limited, and suitable amounts may range from greater than 0% to 5% by weight, preferably 0.1% to 4% by weight, and more preferably 0.2% to 1% by weight.

[0161] lubricant Lubricants can be advantageously used to facilitate tableting, particularly by preventing tablets from sticking to tablet punches. Lubricants are optional but preferred components. The lubricant materials that can be used in the present invention are not particularly limited.

[0162] Suitable lubricant materials include magnesium stearate, sodium stearyl fumarate, talc, stearic acid, leucine, poloxamer, polyethylene glycol, glyceryl behenate, glyceryl monostearate, magnesium lauryl sulfate, sucrose esters of fatty acids, calcium stearate, aluminum stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, sodium benzoate, zinc stearate, palmitic acid, carnauba wax, sodium lauryl sulfate, polyoxyethylene monostearate, calcium silicate, and mixtures thereof.

[0163] It may be preferable to use a lubricant selected from magnesium stearate and sodium stearyl fumarate, and mixtures thereof.

[0164] The relative amount of lubricant present is not particularly limited, and suitable amounts may range from above 0% to 7% by weight, preferably 0.1% to 4% by weight, and more preferably 0.5% to 3.5% by weight.

[0165] Matrix-forming polymers and copolymers A matrix-forming polymer or copolymer may be used as an optional, but preferred, component.

[0166] Suitable matrix-forming polymers and copolymers include polyvinylpyrrolidone (PVP), acrylic polymers and copolymers such as different grades of Eudragit, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and other copolymers such as polyethylene glycol-based copolymers such as Soluplus.

[0167] Preferred matrix-forming polymers and copolymers may be HPMC AS and Soluplus.

[0168] The relative amounts of matrix-forming polymer and copolymer present are not particularly limited, and suitable amounts may range from 0.1 g to 10 g or 0.1% to 10% by weight, preferably 0.2 g to 5 g or 0.2% to 5% by weight, and more preferably 0.3 g to 4 g or 0.3% to 4% by weight.

[0169] complexing agent A complexing agent may be used as an optional but preferred component.

[0170] Suitable complexing agents include cyclodextrins and modified cyclodextrins.

[0171] Preferred complexing agents include (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin.

[0172] The relative amount of complexing agent present is not particularly limited, and suitable amounts may range from 0.1 g to 24 g or 0.1 wt % to 40 wt %, or 0.1 wt % to 30 wt %, or 0.1 wt % to 24 wt %, preferably 0.1 g to 10 g or 0.1 wt % to 10 wt %, and more preferably 0.1 g to 5 g or 0.1 wt % to 6 wt %, or 0.1 wt % to 5 wt %.

[0173] Other types of pharmaceutical excipients The compositions of the present invention may contain additional pharmaceutical excipients commonly used in the art.

[0174] Such additional pharmaceutical additives may include release rate modifiers, plasticizers, film-forming agents, colorants, anti-adherents, and / or pigments for use in coating the compositions of the present invention. Other types of pharmaceutical additives that may be present include flavoring agents, sweeteners, antioxidants, absorption enhancers, and / or bulking agents. The relative amounts of such pharmaceutical additive excipients are not particularly limited. This can be determined by one skilled in the art based on general knowledge and routine procedures.

[0175] Film-forming agents are advantageously used to provide the tablets of the invention with a cohesive coating. Suitable film-forming agents include enteric coating agents such as materials selected from the group consisting of isomalt, polyvinyl alcohol, polyethylene glycol, maltodextrin, sucrose, xylitol, maltitol, methyl acrylate-methacrylic acid copolymer, polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, sodium alginate, and zein.

[0176] Suitable plasticizers include sorbitol, triacetin, poloxamer, polyethylene glycol, glycerin, propylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, acetyl triethyl citrate, castor oil, glyceryl monostearate, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, triethyl citrate, and tributyl citrate.

[0177] For each of the above excipient classes, it is possible to use a single substance or a combination of two or more substances from the same class. Of course, it is not necessary for all components from each class to be present.

[0178] The compositions of the present invention can contain the compounds disclosed herein in the form of amorphous particles or any crystalline form. The particle size is not particularly limited. For example, the compositions can contain finely divided crystals of the disclosed compounds. Micronization can be performed on the crystals of the disclosed compounds alone, or on a mixture of the crystals with some or all of the excipients or carriers. The average particle size of the finely divided crystals of the disclosed compounds can be, for example, about 5 to about 200 microns or about 10 to about 110 microns. The compounds of the present invention can also exist in the form of a molecular dispersion in a polymer matrix. In yet another embodiment, the compounds of the present invention can be complexed with a suitable complexing agent, such as cyclodextrin.

[0179] Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be formulated using binders (e.g., gelatin, microcrystalline cellulose, or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose Na), surface active agents, or dispersing agents. Molded tablets can be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, can optionally be scored or formulated with coatings and shell layers, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. The disclosed pharmaceutical excipients can provide more than one function. For example, fillers and binders can also be disintegrants, flow agents, anti-adherents, lubricants, sweeteners, etc.

[0180] It will be understood that the disclosed compositions can include lyophilized or freeze-dried compounds disclosed herein. For example, compositions are disclosed herein that include the disclosed compounds in crystalline and / or amorphous powder form. Such forms can be reconstituted and used, for example, as aqueous compositions.

[0181] Oral liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0182] Suspensions can contain, in addition to the subject compositions, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth gum.

[0183] Compositions formulated for rectal or vaginal administration can be provided as suppositories, which can be prepared by mixing the composition of interest with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository waxes, or salicylates, which are solid at room temperature but liquid at body temperature and will melt in the body cavity to release the active agent. Compositions formulated in a form suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or sprays, containing carriers known in the art to be appropriate.

[0184] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solution formulations, and patches. The compounds of the present invention can be mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, preservatives, buffers, or propellants.

[0185] Ointments, pastes, creams, gels, and drops may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, zinc oxide, or mixtures thereof.

[0186] Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0187] Alternatively, the compositions and compounds of the present disclosure can be formulated into a form suitable for administration by aerosol. This can be achieved by preparing an aqueous aerosol, liposomal formulation, or solid particles containing the compounds of the present invention. Non-aqueous (e.g., fluorocarbon propellant) suspensions can also be used. Ultrasonic nebulizers can be used because they minimize exposure of the drug to shear, which can degrade the compounds contained in the composition.

[0188] Aqueous aerosols are usually prepared by formulating the target composition with conventional pharmaceutically acceptable carriers and stabilizers to form an aqueous solution or suspension. Carriers and stabilizers vary depending on the requirements of the specific target composition, but usually include nonionic surfactants (Tween, pluronics, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0189] It should be noted that the exemplified pharmaceutical excipients may perform more than one function. For example, fillers and binders can also be disintegrants, flow agents, anti-adherents, lubricants, sweeteners, etc. In one embodiment, the achievement of the quantity indications defined herein above for the different types of excipients is assessed for each type of excipient, taking into account the total amount of all excipients having the defined function.

[0190] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise a compound of the present invention in combination with one or more pharmaceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders. The compositions can be reconstituted into a sterile, injectable solution or dispersion immediately prior to use. The compositions may contain one or more excipients described herein above, such as antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. For example, aqueous compositions are provided herein that comprise the disclosed compounds and can further comprise, for example, dextrose (e.g., about 1 to about 10 weight percent dextrose or about 5 weight percent dextrose in water (D5W)).

[0191] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by the use of surfactants such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants.

[0192] It will be understood that contemplated compositions and dosage forms, such as oral formulations (e.g., pills or tablets) and parenteral formulations, e.g., solutions for intravenous (IV) infusion, can be formulated as sustained release formulations, e.g., immediate release formulations, delayed release formulations, or combinations thereof.

[0193] In certain embodiments, the subject compounds and compositions can be formulated as tablets, pills, capsules, or other suitable ingestible formulations (hereinafter collectively referred to as "tablets"), or as aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions for parenteral administration. The compositions of the present disclosure can be formulated so that the resulting amount of antibacterial agent, i.e., compound of the present invention, provided / administered to a patient (human or non-human mammal) is a therapeutically effective amount (therapeutic dose). The therapeutically effective amount can be divided into dosage units, e.g., multiple intravenous (iv) administrations / day, for example, over a period of 3 days to 5 weeks, e.g., 7 days to 2 weeks. The therapeutically effective amount can be an amount at which at least 50%, e.g., at least 60, 70, 80, 90, 95%, or 100%, of individuals exhibit a statistically significant reduction in infection. The amount should also take into account the toxicity of the antibacterial agent. The therapeutically effective amount can vary depending on the size, weight, age, condition, and type of the subject, the infection being treated, and the formulation, e.g., tablet type, and / or mode of administration, e.g., oral or parenteral, e.g., subcutaneous, intramuscular, or intravenous injection. It is well within the skill of one in the art to determine such therapeutically effective amounts using standard drug development techniques and methods, such as in vitro and / or in vivo experiments, e.g., determining probability of target attainment (PTA), and / or conducting dose-ranging clinical trials and toxicity / maximum tolerated dose / safety studies, e.g., in animals and / or humans.

[0194] Unit Dose When treating a patient with the pharmaceutical composition of the present invention by oral administration, a single unit dose of the pharmaceutical composition of the present invention is typically administered once, twice, or three times daily. The daily dose (total daily dose) is determined by a physician in accordance with the above guidelines, taking into account the type and severity of the infection, and the patient's sex, weight, age, and general condition. A preferred daily oral dose may be in the range of 40 to 5,000 mg, e.g., 40 to 3,000 mg, preferably 40 to 2,000 mg, e.g., 100 to 2,000 mg. The daily dose may vary depending on the intended frequency of administration, e.g., once daily or once weekly.

[0195] For parenteral administration (e.g., intravenous (iv) or intramuscular (im) or intraperitoneal (ip) or subcutaneous administration), the pharmaceutical compositions of the present invention may be administered two, three, or more times daily. A preferred daily dosage range is 40-5000 mg, with a typical unit dose being 40-3000 mg, preferably 100-1000 mg. The upper limit of the ranges specified herein is determined by feasibility. For example, for intramuscular (im) or subcutaneous administration, low solubility and the corresponding increased volume of drug solution may limit the maximum dose that can be administered in a single injection. In such cases, the maximum unit dose is limited by the maximum tolerated dose.

[0196] Combination medicines Compositions comprising one or more disclosed compounds and a second component are also contemplated herein. The second component in such compositions of the present disclosure can be another antibiotic other than the compounds disclosed herein, such as a FabI inhibitor. Additional components, including other FabI inhibitors or other antibiotics, may also be present. Contemplated treatment methods disclosed herein can, in some embodiments, further comprise administering another agent, such as another antibiotic (other than a compound disclosed herein). For example, methods are provided for treating bacterial infections, comprising administering a disclosed compound and further comprising administering another antibiotic or antibacterial agent. The compounds disclosed herein and the second component can be part of the same dosage form, or can be formulated as two separate dosage forms. When formulated as two separate dosage forms, the dosage form comprising the second component can be administered simultaneously with, before, or after the dosage form comprising the compound disclosed herein.

[0197] Medical indication The compounds and compositions of the present invention can be used to treat bacterial infections in patients. They may be particularly suitable for treating bacterial infections involving one or more of the following bacteria: Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Klebsiella pneumoniae, and / or A. baumannii. Such infections include, but are not limited to, wound infections, such as burn or surgical site infections, skin and soft tissue infections, such as bacterial folliculitis, impetigo, including localized impetigo, cellulitis, boils, furuncles, pimples, abscesses, dermatitis, including eczema; bacteremia and sepsis, meningitis, intra-abdominal infections, pleuropulmonary infections, and pneumonia, including hospital-acquired pneumonia, nosocomial pneumonia, and ventilator-associated pneumonia; infective endocarditis; infections caused by bacteria such as S. aureus or E. coli (E. coli diarrhea and food poisoning; urinary tract infections, including complicated urinary tract infections, thrombophlebitis when caused by bacteria, osteoarticular infections, e.g. septic arthritis, diabetic foot, bone and joint infections and prosthetic joint infections, infections associated with medical devices / implants, infections of the oral cavity, such as mouth ulcers, e.g. periodontal abscesses, dental infections, e.g. dental infections and gingivitis; eye infections, e.g. corneal ulcers; colonisation of the nasal cavity by S. aureus.

[0198] In particular, the compounds and compositions of the present invention may be effective in treating bacterial infections associated with A. baumannii, wherein the infection may be pneumonia, most preferably hospital-acquired pneumonia or ventilator-associated pneumonia.

[0199] Dosage Type As described above, the compounds and compositions of the present invention can be administered to patients intravenously, intramuscularly, intraperitoneally, or subcutaneously, or alternatively orally. To increase solubility and / or bioavailability, the compounds can be advantageously administered in the form of prodrugs or salts. Additional administration modes are also contemplated, for example, by implantation (e.g., as part of an implantable medical device) or inhalation.

[0200] Dosage The dosage of any disclosed compound or composition will vary depending on the condition, age, and weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject compositions can be administered in a single dose or in divided doses. The dosage of the present compositions can be easily determined by techniques known to those skilled in the art or following the teachings herein.

[0201] In certain embodiments, the dosage of the subject compound will generally be in the range of about 0.01 ng to about 10 g / kg body weight, particularly in the range of about 1 ng to about 0.1 g / kg body weight, and more particularly in the range of about 1 mg to about 0.1 g / kg body weight.

[0202] For any particular composition of the present disclosure, it may be necessary to determine any possible effects on the effective dose or amount of the composition and the timing of administration of the composition. This can be accomplished by conducting routine experiments on one or more groups of animals (preferably at least 2-5 animals per group), or, where appropriate, human trials. The effectiveness of any subject composition and therapeutic or prophylactic method can be evaluated by administering the composition, measuring one or more appropriate indicators, and comparing the values ​​of these indicators after treatment with the values ​​of the same indicators before treatment to assess the effect of administration.

[0203] The exact time and amount of administration of any particular subject composition that will provide the most effective treatment for a given patient will depend on the activity, pharmacokinetics and bioavailability of the subject composition, the physiological condition of the patient (age, sex, type and stage of disease, general physical condition, responsiveness to a given dosage and type of medication, etc.), the route of administration, etc. The guidance provided herein can be used to optimize treatment, and will require no more than routine experimentation consisting of subject monitoring and adjusting dosage and / or timing to determine, for example, the most appropriate time and / or amount for administration.

[0204] During treatment of a subject, the patient's health can be monitored by measuring one or more relevant indicators at predetermined times during the treatment period. Treatment (including composition, amount, time of administration, and formulation) can be optimized according to the results of such monitoring. Periodic reassessment can be performed by measuring the same parameters to determine the patient's improvement. Based on this reassessment, the amount of a subject composition administered and, optionally, the time of administration can also be adjusted.

[0205] Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound, and the dosage may be increased by small increments until the optimum therapeutic effect is attained.

[0206] The use of the subject drug combinations can reduce the required dosage of any individual agent included in the composition because the onset and duration of effect of the different agents are complementary.

[0207] Toxicity and therapeutic efficacy of a subject composition can be determined using standard pharmaceutical procedures, for example, using cell cultures or experimental animals.

[0208] Data obtained from cell culture tests and animal experiments can be used to formulate a range of dosages for use in humans. The dosage of any subject composition is preferably in a range that produces blood concentrations that statistically significantly reduce infection in at least 50% of individuals, e.g., at least 60, 70, 80, 90, 95%, or 100%, while exhibiting little or no toxicity. Dosages can vary within this range depending on the dosage form employed and the route of administration utilized. For compositions of the present disclosure, a therapeutically effective dose can be initially estimated from cell culture tests.

[0209] Dosage frequency The compounds and compositions disclosed herein can be administered at any suitable frequency. The frequency can depend on the subject being treated and the severity and type of infection. Administration can be, for example, once or multiple times a day. The number of administrations can also depend on the form of the composition and the subject and condition being treated, such as bacterial infection.

[0210] Treatment duration The compounds and compositions disclosed herein can be administered indefinitely. Advantageously, they are administered until the bacterial infection is completely eradicated, or at least until the patient's immune system is able to deal with any remaining pathological bacteria. A typical administration period can be 3 days to 7 weeks, e.g., 1 to 5 weeks, e.g., 7 days to 2 weeks. However, longer treatment periods may be required for some infections, such as bone infections.

[0211] Treatment method The compounds and compositions disclosed herein can be used in methods of treatment. In particular, the compounds and compositions disclosed herein can be used in a method of treating a bacterial infection, comprising administering to a patient in need thereof a disclosed compound of the present invention or a pharmaceutical composition containing a disclosed compound of the present invention. The bacterial infection can be an infection caused by Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Klebsiella pneumoniae, and / or A. baumannii.

[0212] The compounds of the invention may also be used in the manufacture of a pharmaceutical composition for use in the treatment, particularly the treatment of bacterial infections in a patient in need thereof, wherein said bacterial infection may be caused by S. aureus, E. coli, Klebsiella pneumoniae and / or A. baumannii.

[0213] Further embodiments relate to methods of treating a bacterial infection, such as a S. aureus, E. coli, Klebsiella pneumoniae and / or A. baumannii bacterial infection, in a patient in need thereof, comprising administering a compound or composition of the present invention.

[0214] Preparation of the Compounds of the Invention The compounds of the present invention can be prepared using existing organic chemistry synthesis methods and procedures and / or information as described hereinafter. The starting materials can be purchased (where commercially available) or synthesized using existing organic chemistry synthesis methods and procedures and / or information as described hereinafter.

[0215] The compounds disclosed herein have the formula M1 or M1′ [ka] (wherein X represents a leaving group, R 13 is R 13 Ga-PO3R e2 or -CH2-OPO3R e2 as defined herein except where e is a Pg group such as TMSCH2CH2 or CNCH2CH2, and Pg in M1′ represents a protecting group such as a BOC group, where R 11 and R 12 is R 11 and R 12 or preferably such a defined group, which also includes a protecting group selected from the group consisting of Boc, PMB and DMB. optionally with a precursor compound of formula M2a or M2b: [ka] (In the formula, R0~R 12 , R 14, Y and Q1 have the same meanings as defined for formula I The leaving group X can be a hydroxyl group, tosylate group, triflate group, mesylate group, iodide, bromide, chloride, methoxy, ethoxy, etc.

[0216] The coupling reaction is preferably carried out in a solvent in the presence of a coupling agent and a base. The solvent is preferably selected from DMF, 2-Me-THF, DCM, EtOAc, DMC, and CPME (preferably, when the leaving group is a hydroxyl group, the solvent is DMF). The coupling agent is preferably selected from HATU, HBTU, HCTU, TBTU, COMU, TOMBU, COMBU, PyBOP, T3P, DIC-HOBt, DCC, CDI, EDC, and EDC-HOBt (preferably, when the leaving group is a hydroxyl group, the coupling agent is HATU or T3P). The reaction is usually carried out in the presence of a base. The base is preferably selected from DIPEA, TEA, pyridine, or DMAP (preferably, when T3P is used as the coupling agent, TEA is used as the base). The protecting group of M1' can preferably be removed immediately after the coupling reaction. Meanwhile, R 13 and / or R 11 and / or R 12 Any protecting groups in are preferably removed as a final step.

[0217] An example of the reaction sequence is shown in the following Scheme 1. A similar reaction scheme is applied for the protected precursor M1', which of course requires the addition of a previous protection reaction and a subsequent deprotection reaction.

[0218] [ka] A similar reaction scheme applies for the synthesis of compounds of formula Ib, where precursor compound M2a is simply replaced by precursor compound M2b.

[0219] Preparation of the precursor for the right side The precursor compound of formula M1' may be a compound of formula M3 or M3' [ka] (wherein Pg in M1′ is a suitable protecting group such as Boc, and R 13 is R 13 Ga-PO3R e2 or -CH2-OPO3R e2 as defined herein except where e is a Pg group such as TMSCH2CH2 or CNCH2CH2, and R 11 and / or R 12 In addition to being as defined herein, may also contain a protecting group, which is preferably selected from a Boc group, a PMB group, and a DMB group. The compound C of acrylic acid 1~4 The acrylic acid can be prepared by reacting it with a carboxyl-protected acrylic acid, such as an alkyl ester (preferably tert-butyl, ethyl, or methyl ester). This coupling reaction is carried out under Heck coupling conditions, preferably in the presence of a Pd(II) salt, such as Pd(OAc)2, and a phosphine ligand, such as xantphos, XPhos, or tri-(o-tolyl)phosphine or 1,1-bis(diphenylphosphino)ferrocene (dppf). The highly efficient palladium catalyst Pd-162 in the presence of Cy2NMe2 and NBu4Cl has also been applied. The reaction is usually carried out in the presence of a solvent such as DMF, propionitrile, a combination thereof, or 1,4-dioxane, and also in the presence of a base such as DIPEA. This reaction sequence is shown in Scheme 2 below.

[0220] [ka] The coupling reaction is followed by deprotection of the carboxyl group and the introduction of an optional leaving group other than hydroxyl. The leaving group X can be hydroxyl, tosylate, triflate, mesylate, iodide, bromide, chloride, etc. Pg represents a suitable protecting group for the carboxyl function to be protected, for example, an alkyl group (Me, Et, t-Bu) for the protection of the carboxyl group. The nitrogen atom in the amide group can optionally be protected by a suitable protecting group (Pg'), for example, a BOC group or an alternatively protected prodrug group, where the Pg'' group is a group such as TMSCH2CH2 or CNCH2CH2, where R 11 and R 12 is R 11 and R 12 or preferably such a defined group, which also includes a protecting group selected from the group consisting of a Boc group, a PMB group and a DMB group.

[0221] The precursor compound M3 can be synthesized as shown in Schemes 3 and 4 described below.

[0222] [ka] In Scheme 3, the reaction of a suitable acid (where R 11 and / or R 12 is as defined herein and may also preferably contain a protecting group selected from a Boc group, a PMB group, and a DMB group, and Rz=H), such as ((S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid or ester (wherein Rz is C 1~4Condensation of 5-bromo-3-fluoro-2-nitropyridine with an alkyl, preferably methyl, such as methyl 3-amino-2-((2S,6R)-2,6-dimethylmorpholino)propanoate or (2S,3R)-methyl 3-amino-2-((tert-butoxycarbonyl)amino)butanoate, affords the 3-(substituted amino)propanoate or butanoate in good yield. Reduction of the nitro group at the 2-position is carried out in the presence of a reducing agent such as Fe in acetic acid or a mixture of water, ethanol, and ammonium chloride at 80°C. Cyclization is achieved using sodium hydride in DMF (Path A). This reaction sequence is shown in Scheme 3. The protecting group Rz is removed by basic hydrolysis using lithium hydroxide in a mixture of water and THF. Cyclization (Route B) using an agent such as HATU in the presence of a base such as DIPEA and in a solvent such as DMF leads to the formation of the 3-amino-8-bromo-1,2,3,5-tetrahydro-4H-pyrido[2,3-b][1,4]diazepin-4-one derivative, as shown in Scheme 3.

[0223] Precursor compounds of formula M3 may also be prepared by reaction of compounds of formula M4. [ka] Compounds of formula M4 can be synthesized as described in AFFINIUM PHARMACEUTICALS, INC., WO 2007 / 67416, 2007, A2, which is incorporated herein by reference.

[0224] [ka] Direct iodination of 3-bromo-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one in the presence of TMEDA, TMSI, and I2 in DCM resulted in the formation of the expected iodide in good yield. The iodide was then oxidized with various amines (HNR2, HNR3, HNR4) in acetonitrile at 50–80 °C in the presence of K2CO3 as a base. 12 R11 (where R 12 and R 11 can be readily converted to the corresponding amines (primary, secondary, tertiary, and heterocyclic compounds) by their treatment with (as defined above for Formula I) (e.g., azetidin-3-ol, morpholine, pyrrolidine and its derivatives, cyclopropanoamine, piperazine and its derivatives, 7-oxa-2-azaspiro[3.5]nonane, thiomorpholine 1,1-dioxide, etc.). Alternatively, reaction of the iodide with sodium azide in DMF and its subsequent reduction provides the corresponding primary amines.

[0225] Preparation of the precursor for the left part The left-hand moiety precursors M2a and M2b can be prepared by the reaction sequence shown in the following Scheme 5 for M2a and the analogous reaction scheme for M2b. Reduction of the protected carboxyl group to a hydroxymethyl group can be achieved using diisobutylaluminum hydride (DIBAL-H) ​​in THF. Subsequent oxidation to the aldehyde can be carried out using Dess-Martin periodinane in DCM. The final reaction in this sequence can be carried out by first reacting with methylamine in ethanol / THF, followed by reduction with sodium borohydride in ethanol / THF. If it is desired to obtain the protected form of precursor M2a or M2b, the resulting product, i.e., the compound shown below except with a hydrogen atom at the Pg position, can be subjected to a final step of protection of the amino group with a suitable protecting group, e.g., a carboxybenzyl (Cbz) group, by reaction with carboxybenzyl chloride in DCM in the presence of triethylamine. This optional final protection step is also shown in Scheme 5 below. [ka]

[0226] Alternatively, the left-hand moiety precursors M2a or M2b can be prepared by the reaction sequence shown in Scheme 5', where a carboxylic acid (or its alkyl ester) is converted to its corresponding amide by amidation (e.g., MeNH2.HCl, DIPEA, EDCl-HOBt, DMF or MeNH2 / EtOH, by reflux), followed by amide reduction (e.g., with BMS in THF or trifluoromethanesulfonic anhydride / NaBH4 in DCM) to give the corresponding amine. [ka]

[0227] Likewise, a similar reaction scheme applies to the preparation of precursor M2b. [ka]

[0228] Further alternatively (when Q1 is O), the left-hand moiety precursor M2a can be prepared by one of the reaction sequences shown in Scheme 5″, where: In Route A, base-catalyzed (e.g., using t-BuOK / THF) condensation of o-hydroxyphenone (i.e., the compound on the left side of Scheme 5″ where Q1 represents —OH) with 1,1-dichloroethylene in the presence of a strong base (e.g., in the presence of t-BuOK and THF), followed by further conversion under weakly acidic conditions (e.g., using 1 M H2SO4), gives intermediate carbaldehyde compounds, as shown in Scheme 5″, Route A below. These carbaldehydes can be easily converted to their corresponding amines, i.e., precursors M2a. This conversion can rely on standard methods, usually using reductive amination conditions (e.g., using 1. MeNH2 / THF; AcOH; 2. NaBH4); In Route B, compound X—CH—Y is reacted with the compound X—CH—Y in the presence of a base (e.g., KCO / DMF). 1 (wherein X is a leaving group as described above, and Y 1 is C 1~4Condensation of a substituted o-hydroxyphenone with a protected carboxyl or nitrile group, such as an alkyl ester (e.g., a carboxyl group precursor such as chloroacetonitrile), can result in the formation of a nitrile intermediate, e.g., a 2-nitrile benzofuran, followed by basic hydrolysis to yield the corresponding carboxylic acid, as shown in the center of Scheme 5″, Pathway B. The carboxylic acid can be converted to the corresponding amine. For example, using the same procedure, amines can also be prepared from o-hydroxyphenones and alkyl 2-bromoacetates (e.g., in the presence of K2CO3 and acetone in the first step, followed by cyclization and basic hydrolysis with NaOEt / EtOH). [ka]

[0229] Further alternatively (when Q is O), the left-hand moiety precursor M can be prepared by one of the reaction sequences shown in Scheme 5''', where the carboxyphenol is displaced with ethyl 2-bromopropanoate in the presence of a base such as KCO or NaOH in a solvent such as ACN or THF, followed by decarboxylative cyclization mediated by a base such as sodium acetate in acetic anhydride to give the benzofuran bicyclic ring, where the carbonyl moiety is introduced at the 3-position using dichloro(methoxy)methane in the presence of a Lewis acid catalyst such as tin(IV) chloride. [ka]

[0230] In Schemes 5, 5', 5" and 5'", Pg represents a protecting group such as a carboxybenzyl group (BOC group, PMB group, DMB group). Q1 has the same meaning as Q1 in Formula I (except for the restrictions on Q1 described for Scheme 5" above). R 1 ~R 4 (R 3a , R 3b and R 3c) may also have the same meaning as in Formula I. Alternatively, one or more of these groups may be precursor groups that are subsequently converted to the desired substituent according to Formula I. For example, a Br substituent may be used as such a precursor.

[0231] R 14 If different from CH3 (R 14 LHS a or LHS b Together with R0, R 14 is attached to form a heterocycle having 5 to 8 ring members, preferably the only heteroatom in the ring is R 14 is the N to which is attached), precursor M2a can be prepared by the reaction sequence shown in Scheme 5″″, where the lactam precursor is dihalogenated, converted to a piperidylene amine, then reacted with 1,4-benzoquinone and deaminated to give a tricyclic benzofuran intermediate, which can be further modified at the R2 position by conventional chemistry. [ka]

[0232] R 14 If different from CH3 (R 14 LHS a or LHS b Together with R0, R 14 is attached to form a heterocycle having 5 to 8 ring members, preferably the only heteroatom in the ring is R 14 is the N to which is attached), precursor M2b can be prepared by the reaction sequence shown in Scheme 5′′″, in which an amino(thio)phenol precursor is condensed with a cyclic 1,3-dione, converted to an oxime, and then subjected to a Beckmann rearrangement to reduce the amide to an amine. [ka]

[0233] Alternative Routes for the Preparation of Compounds of the Invention As an alternative to the above synthetic approach, compounds of the invention can be prepared from compounds of formula M6 or their protected form M6' [ka] to the formula M7a or M7b: [ka] (wherein Y and Q1 have the same meaning as defined for formula (I), and all R groups (R0 to R 14 ) has the same meaning as defined for formula I or can be a precursor thereof, e.g., Br as a precursor for other groups, e.g., CN, OH, esters, etc., or R 11 and / or R 12 is as defined herein and may also include a protecting group, preferably selected from a Boc group, a PMB group, and a DMB group. The compound of formula Ia can also be prepared by coupling with a compound of formula Ib, which can be carried out under Heck coupling conditions. Typically, this is carried out in the presence of a Pd(II) complex such as Pd-162 (i.e., [P(tBu)3]Pd(crotyl)Cl), tetrabutylammonium chloride, N-cyclohexyl-N-methylcyclohexanamine (DIPEA), and dioxane. It is also possible to use a Pd(II) salt such as Pd(OAc)2 in combination with a phosphine ligand, e.g., tri-o-tolylphosphine, a base such as DIPEA, and a solvent such as a mixture of DMF and propionitrile or 1,4-dioxane. The reaction is illustrated for a compound of formula Ia by the following reaction scheme: [ka]

[0234] Likewise, a similar reaction scheme applies to the preparation of compounds of formula Ib. [ka]

[0235] It is advantageous to use a protected precursor M6' in this reaction sequence, in which case the reaction sequence shown in the scheme above is followed by a deprotection step to give the reaction product shown above.

[0236] Y and Q1 have the same meaning as defined for Formula I, and R0 to R 12 has the same meaning as defined for formula (I) or can be a precursor thereof, e.g. Br as a precursor for other groups, e.g. CN, OH, esters, etc., or R 11 and / or R 12 is as defined herein and may also include a protecting group, preferably selected from a Boc group, a PMB group, and a DMB group, while R 13 is hydrogen.

[0237] Prodrugs of the compounds of the invention (e.g., where R 13 -PO3R e2 or -CH2-OPO3R e2 The preparation of each compound of the invention (where R 13 is hydrogen) to R 13 This is achieved by converting the prodrug moiety into a compound having the same structure, except that it exhibits a cleavable prodrug moiety, such as a phosphate-containing group as defined above, under physiological conditions. The prodrug moiety is preferably a methylene phosphate moiety or a phosphoramidate moiety. Suitable reaction conditions for preparing such prodrug moieties and methylene phosphate prodrugs are described in WO 2013 / 190384 A1 (methylene phosphate) and J. Med. Chem. 2000, 43, 1234-1241 (phosphoramidates).

[0238] Abbreviation The following abbreviations are used in this disclosure: CC column chromatography DCM dichloromethane N normality g grams pH Hydrogen ion potential mol mole v / v volume / volume vol volume m / z mass-to-charge ratio ℃ Celsius TEA, Et3N Triethylamine Et2O diethyl ether HPLC High Performance Liquid Chromatography Boc tert-butyloxycarbonyl h time mL milliliter eq. equivalent amount M mass MeOH Methanol AcOH acetic acid THF tetrahydrofuran DIPEA N,N-Diisopropylethylamine Pd(OAc)2 Palladium(II) Acetate EtOH ethanol DCE 1,2-dichloroethane EtOAc ethyl acetate Aq. Water-based RT,rt Room temperature Rt,tret retention time DMF Dimethylformamide ACN Acetonitrile NH4OAc Ammonium Acetate TFA trifluoroacetic acid HOBT / HOBt 1-Hydroxybenzotriazole TLC thin layer chromatography H2O Water sat. saturation sol. solution EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide NMR nuclear magnetic resonance s single line d double line t triple line m multiplet dd double double line MHz Megahertz ppm parts per million H proton J coupling constant UPLC-MS Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry DMSO dimethyl sulfoxide CDCl3 deuterated chloroform ML mother liquor SCX Strong Cation Exchange Chromatography LCMS Liquid Chromatography Mass Spectrometry HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, Hexafluorophosphate benzotriazole tetramethyluronium Cy2NCH 3, DCHMA N-cyclohexyl-N-methylcyclohexanamine PMB p-Methoxybenzyl STAB Sodium triacetoxyborohydride DMC Dimethyl Carbonate EtOAc ethyl acetate HCTU O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate TBTU 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazole-1-oxide hexafluorophosphate COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphate TOMBU N-{[1,3-dimethyl-2,4,6-trioxotetrahydropyrimidin-5(6H)-ylideneaminooxy](dimethylamino)methylene}-N-methylmethanaminium hexafluorophosphate COMBU 4-{[1,3-dimethyl-2,4,6-trioxotetrahydropyrimidin-5(6H)ylideneaminooxy](dimethylamino)methylene}morpholin-4-ium hexafluorophosphate PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate T3P 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphinane 2,4,6-trioxide DIC N,N'-diisopropylcarbodiimide DCC N,N'-dicyclohexylcarbodiimide CDI 1,1'-carbonyldiimidazole EDC 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine DMAP N,N-dimethylpyridin-4-amine DMB 3,4-dimethoxybenzyl BMS Borane-dimethyl sulfide DIAD Diisopropyl azodicarboxylate BrettPhos 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl DMP Dess-Martin Periodinane DIBAL Diisobutylaluminum hydride Pd-162 Tri-tert-butylphosphine(chloro)(crotyl)palladium(II) Pd-173 Crotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate Pd-175 Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) NBS 1-Bromo-2,5-pyrrolidinedione; N-Bromosuccinimide pTSA 4-methylbenzene-1-sulfonic acid LDA Lithium diisopropylamide BINOL 1,1'-bi-2-naphthol DMA N,N-dimethylacetamide DABCO 1,4-diazabicyclo[2.2.2]octane DPPF 1,1'-bis(diphenylphosphanyl)ferrocene Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl BuLi n-butyllithium DPPA Diphenylphosphoryl azide Mesyl methanesulfonyl

[0239] It should be understood that all features of the invention disclosed herein may be freely combined and that variations and modifications may be made without departing from the scope of the invention as defined in the claims. Where known equivalents exist for particular features, such equivalents are incorporated as if specifically set forth herein. It should further be understood that various variations and modifications to the preferred embodiments of the invention described herein will be apparent to those skilled in the art. Such variations and modifications can be made without departing from the spirit and scope of the inventive subject matter and without diminishing its intended advantages. Accordingly, such variations and modifications are intended to be covered by the appended claims. [Example]

[0240] Example The following examples are not intended to limit the scope of the present invention in any way, but are provided solely for the purpose of illustrating the compounds of the present invention and their preparation.

[0241] General Procedure All starting materials and solvents were obtained from commercial sources or prepared according to the literature. All reactions were stirred unless otherwise specified. Organic solutions were routinely dried over anhydrous magnesium sulfate or sodium sulfate.

[0242] Column chromatography was performed on prepacked silica (230-400 mesh, 40-63 μm) cartridges using the indicated eluents. SCX was purchased from Silicycle and treated with 1 M hydrochloric acid before use. Unless otherwise specified, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was directly loaded onto the SCX and washed with MeOH. The desired material was then eluted by washing with 0.7 M NH3 in MeOH.

[0243] Analysis method LCMS analysis was carried out using either the acidic or basic method as follows.

[0244] Method 1a: A Waters X-Select CSH C18, 2.5 μm, 4.6 × 30 mm column was used for gradient elution with MeCN (containing 0.1% formic acid) in water (containing 0.1% formic acid). The gradient conditions were 5% to 95% MeCN (containing 0.1% formic acid) over 0.00–3.00 min at a flow rate of 2.5 mL / min, followed by a 4.5 mL / min flush from 3.01–3.5 min. The column was re-equilibrated with 5% MeCN at 2.5 mL / min from 3.60–4.00 min. UV spectra of the eluted peaks were measured at 254 nm using an Agilent 1260 Infinity or Agilent 1200 VWD. Mass spectra were measured using an Agilent 6120 or Agilent 1956 MSD operated in positive / negative switching, or an Agilent 6100 MSD operated in either positive or negative ion mode.

[0245] Method 1b: A Waters X-Select BEH C18, 2.5 μm, 4.6 × 30 mm column was used for gradient elution with MeCN in 10 mM aqueous ammonium bicarbonate. The gradient conditions were 5% to 95% MeCN over 0.00–3.00 min at a flow rate of 2.5 mL / min, followed by a 4.5 mL / min flush from 3.01–3.5 min. The column was re-equilibrated with 5% MeCN at 2.5 mL / min from 3.60–4.00 min. UV spectra of the eluted peaks were measured at 254 nm using an Agilent 1260 Infinity or Agilent 1200 VWD. Mass spectra were measured using an Agilent 6120 or Agilent 1956 MSD, operating in positive / negative mode, or an Agilent 6100 MSD, operating in either positive or negative ion mode.

[0246] UPLC / MS analysis Alternatively, UPLC / MS analysis was performed using either the acidic or basic method as follows.

[0247] Method 2a: A Waters Acquity CSH C18, 1.7 μm, 2.1 x 30 mm column was used with a gradient elution of MeCN (containing 0.1% formic acid) in water (containing 0.1% formic acid). The gradient consisted of a starting point of 5% MeCN with a hold time of 0.0-0.11 min. The gradient conditions were 5-95% over 0.11-2.15 min, followed by a flush from 2.15-2.56 min. The column was re-equilibrated with 5% MeCN over 2.56-2.83 min. UV spectra of the eluting peaks were recorded using an Acquity PDA, and mass spectra were recorded using an Acquity QDa detector with ESI positive / negative ionization.

[0248] Method 2b: A Waters Acquity BEH C18, 1.7 μm, 2.1 x 30 mm column was used with a gradient elution of MeCN in 10 mM aqueous ammonium bicarbonate. The gradient consisted of a starting point of 5% MeCN with a hold time of 0.0–0.11 min. The gradient conditions were 5–95% over 0.11–2.15 min, followed by a flush period of 2.15–2.56 min. The column was re-equilibrated with 5% MeCN over 2.56–2.83 min. UV spectra of the eluted peaks were recorded using an Acquity PDA, and mass spectra were recorded using an Acquity QDa detector with ESI positive / negative ionization.

[0249] Analytical LCMS (other methods) Method 3. Liquid chromatography / mass spectrometry (LC / MS). HRMS data were acquired to confirm the molecular weight and analyze the purity of the product. The LC / MS instrument specifications were as follows: Water UPLC, electrospray (+) ionization, mass range 100-1000 Da, cone voltage 20 V, Acquity BEH C-18 column (2.1 x 50 mm, 1.7 μm), and gradient mobile phase consisting of 5 mM ammonium acetate in water and acetonitrile with a flow rate of 0.6 mL / min.

[0250] UPLC-MS analysis conditions: Column: Acquity HSS-T3 (2.1 x 100 mm, 1.8 μm). Mobile phase: A - 0.1% TFA in water; B - acetonitrile. Flow mode: gradient.

[0251] [Table 1]

[0252] Method 4. Method information: A: 0.1% TFA in HO, B: 0.1% TFA in ACN; Flow rate: 1.0 mL / min; Column: Atlantis dC18 (50 x 4.6 mm, 52), positive ion mode

[0253] [Table 2]

[0254] Preparative HPLC Preparative HPLC was performed using a Waters Xselect CSH C18, 5 μm, 19 × 50 mm column with either a gradient of 0.1% formic acid in MeCN in 0.1% aqueous formic acid or a gradient of MeCN in 10 mM aqueous ammonium bicarbonate; or a Waters Xbridge BEH C18, 5 μm, 19 × 50 mm column with a gradient of MeCN in 10 mM aqueous ammonium bicarbonate. Fractions were collected by single wavelength UV as measured by a variable wavelength detector on a Gilson 215 preparative HPLC or a Varian PrepStar preparative HPLC; and by single wavelength UV as measured by a dual wavelength detector on a ZQ single quadrupole mass spectrometer with positive and negative ion electrospray and a Waters FractionLynx LCMS or Manual Prep System: UV-Visible 2489 detector. HPLC system: Waters Alliance 2695 with 2998 / 2996 PDA detector. SFC Prep - Waters SFC 200q with 2545 Quaternary Gradient Pump and 2489 UV-Vis detector. Automated purification system - Waters 2767 Injector with 2545 Binary gradient pump and 2489UV / 2998 PDA detector and Agilent 1260 autopurifier with binary pump and DAD detector.

[0255] Preparative chiral high-performance liquid chromatography Method Ia: Chiralpak® IA (Daicel Ltd.) columns (2 x 25 cm), flow rate 13.5 mL min -1 Elution was performed with a 4:1 mixture of heptane + 0.2% TFA and chloroform with ethanol (% of ethanol), followed by UV detection at 254 nm. The sample was loaded onto the column via an at-column dilution pump, and chloroform (1.5 mL min ) was added during the run. -1 ) and the combined flow rate was set to 15 mL / min. -1It was decided.

[0256] Method Ib: Chiralpak® IC (Daicel Ltd.) columns (2 x 25 cm), flow rate 13.5 mL min -1 Elution was performed with a mixture of heptane and 0.2% diethylamine with ethanol (% of ethanol), followed by UV detection at 254 nm. The sample was loaded onto the column via an at-column dilution pump, and chloroform (1.5 mL min ) was used throughout the run. -1 ) and the combined flow rate was set to 15 mL / min. -1 It was decided.

[0257] Chiral high-performance liquid chromatography analysis Method IIa: Chiralpak® IA (Daicel Ltd.) column (4.6 mm x 25 mm), flow rate 1 mL min -1 Elution with a 4:1 mixture of isohexane + 0.2% TFA and chloroform with ethanol (% of ethanol), UV detection at 254 nm.

[0258] Method IIb: Chiralpak® IC (Daicel Ltd.) column (4.6 mm x 25 mm), flow rate 1 mL min -1 , elution with a mixture of isohexane + 0.2% diethylamine with ethanol (% of ethanol), UV detection at 254 nm.

[0259] 1 H NMR spectroscopy 1 1 H NMR spectra were acquired at 300 MHz or 400 MHz on a Bruker Avance III spectrometer, using residual undeuterated solvent as the reference standard.

[0260] Example 1. Synthesis of (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 8) General synthetic scheme [ka] N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 6) was prepared as described in the patents AFFINIUM PHARMACEUTICALS, INC. - WO 2007 / 67416, 2007, A2 and / or VITAS PHARMA RESEARCH PRIVATE LIMITED, WO 2013 / 42035, 2013, A1.

[0261] Step 1. (S)-3-((5-Bromo-2-nitropyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (compound 3). A mixture of (S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid 1 (0.83 g, 4.07 mmol), potassium carbonate (1.13 g, 8.15 mmol), and 5-bromo-3-fluoro-2-nitropyridine 2 (0.6 g, 2.72 mmol) in ethanol (70 mL) was heated to reflux for 2 hours. The reaction mixture was evaporated to dryness, and the residue was taken up in water (20 mL). The mixture was acidified to pH 3 by the addition of a 1 M solution of HCl. The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 3 as a yellow solid (1 g, 87%). t 1.94 minutes (method 1a) m / z 349 / 351 [M-tBu] + (ES + );403 / 405[MH] - (ES - ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 12.94(s,1H), 8.11-7.85(m,3H), 7.27(d,J=8.3Hz, 1H), 4.33-4.23(m,1H), 3.7 9(dt,J=14.1, 5.6Hz, 1H), 3.62(ddd,J=14.4Hz, 8.8Hz, 6.4Hz, 1H), 1.32(s,9H).

[0262] Step 2. (S)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (compound 4). A mixture of (S)-3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid 3 (1 g, 2.47 mmol), iron powder (0.55 g, 9.87 mmol), and ammonium chloride (1.32 g, 24.7 mmol) in a solvent mixture of ethanol (70 mL) and water (20 mL) was heated and stirred under reflux for 1 h. The reaction mixture was filtered hot through a plug of Celite®, and the filtrate was evaporated to dryness. The residue was triturated with water (30 mL). The solid was collected and dried to give the title compound 4 as a pale yellow solid (0.83 g, 85%). R t 0.75 min (method 2a) m / z 375 / 377[M+H] + (ES + );373 / 375[MH] - (ES - ).

[0263] Step 3. (S)-tert-Butyl (8-bromo-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate (Compound 5). To a solution of (S)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid 4 (0.83 g, 2.22 mmol) and DIPEA (1.16 mL, 6.65 mmol) in DMF (2 mL) was added HATU (1.27 g, 3.33 mmol). The reaction mixture was stirred at room temperature for 1 h and diluted with water (20 mL). The solid was collected and purified by silica chromatography (0-50% EtOAc / isohexane) to give the title compound 5 as a brown solid (0.41 g, 50%). t 1.18 min (method 2a) m / z 257 / 259[M+H-CO2 t Bu] + (ES + );355 / 357[MH] - (ES - ).1 H NMR (400MHz, DMSO-d6): δ, ppm 10.16(s,1H), 7.81(d,J=2.1Hz, 1H), 7.35(d,J=2.2Hz, 1H), 6.99(d,J=7.8Hz, 1H), 6.31(d,J= 6.0Hz, 1H), 4.18-4.09(m,1H), 3.46(ddd,J=11.7, 6.5, 3.7Hz, 1H), 3.34(s,1H), 1.38(s,9H).

[0264] Step 4. (S,E)-tert-butyl (8-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate (compound 7). A reaction vial was charged with N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (257 mg, 1.12 mmol), (S)-tert-butyl(8-bromo-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate 5 (400 mg, 1.12 mmol), tetrabutylammonium chloride hydrate (33 mg, 0.11 mmol), and [P(tBu)3]Pd(crotyl)Cl (Pd-162) (44 mg, 0.11 mmol). The reaction vial was flushed with nitrogen for 5 min. 1,4-Dioxane (15 mL) and N-cyclohexyl-N-methylcyclohexanamine (0.48 mL, 2.24 mmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 min. The mixture was heated to 80° C. for 1 hour. The mixture was cooled to room temperature and evaporated to dryness. The crude product was triturated with isohexane (20 mL) and the solid was collected and purified by silica chromatography (0-100% EtOAc / isohexane) to give the title compound 7 as a yellow solid (0.47 mg, 81%). t 2.92 minutes (method 1a) m / z 506[M+H] + (ES + ). 1H NMR (400MHz, DMSO-d6, 363K): δ, ppm 9.40(s,1H), 7.99(d,J=2.0Hz, 1H), 7.60-7.54(m,1H), 7.51-7.38(m,3H), 7.32-7.24(m,2H), 7.12(d,J=15.7Hz, 1H), 5.84(d,J=5.4Hz, 1H), 4 .84(s,2H), 3.57(dd,J=9.3Hz, 3.4Hz, 1H), 3.44(ddd,J=12.3Hz, 6.1Hz, 3.4Hz, 1H), 3.24-3.17(m,1H), 3.06(s,3H), 2.28(s,3H), 1.83(s,2H).

[0265] Step 5. (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 8). To a solution of (S,E)-tert-butyl (8-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate 7 (125 mg, 0.25 mmol) in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 30 min. The mixture was evaporated to dryness, and the residue was suspended in an aqueous solution of saturated sodium bicarbonate (10 mL) and sonicated for 10 minutes. The solid was collected and purified by silica chromatography (0-10% (0.7 M NH in MeOH) / DCM) to give the title compound 8 as a yellow solid (51 mg, 50%). t 1.09 min (method 2b) m / z 406[M+H] + (ES + ). 1H NMR (400MHz, DMSO-d6, 363K): δ, ppm 9.97(s,1H), 8.04(d,J=8.9Hz, 1H), 7.57(d,J=7.6Hz, 1H), 7.53-7.48(m,1H), 7.47- 7.35(m,2.4H), 7.32-7.23(m,2H), 7.09(d,J=15.4Hz, 0.6H), 6.04(d,J=7.3Hz, 1H), 4 .96(s,0.8H), 4.80(s,1.2H), 3.51(s,1H), 3.41(ddd,J=11.9Hz, 6.3Hz, 3.5Hz, 1H), 3.17(s,2.7H), 2.95(s,1.3H), 2.27(d,J=3.6Hz, 3H), 1.87(d,J=5.3Hz, 2H) (rotamer).

[0266] Example 2. Synthesis of (E)-3-((R)-3-((2S,6R)-2,6-dimethylmorpholino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 21) General synthetic scheme [ka] Step 1. 3-((tert-Butoxycarbonyl)amino)-2-hydroxypropanoic acid (compound 10). To a stirred solution of 3-amino-2-hydroxypropanoic acid 9 (0.5 g, 4.8 mmol) in 1,4-dioxane (5 mL) was added NaOH (0.2 g, 4.8 mmol) in HO (5 mL). The reaction mixture was stirred at 0 °C for 1 h, and di-tert-butyl dicarbonate (1.1 g, 5.2 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched at 0 °C by the addition of 1 M HCl solution (5 mL) to adjust the pH to about 6. The aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried (MgSO), filtered, and concentrated under reduced pressure to give crude title compound 10 as a colorless solid (0.8 g, 82%). 1H NMR (400MHz, CDCl3): δ, ppm 5.13 (s, 1H), 4.24 (t, J = 4.2Hz, 1H), 3.60-3.37 (m, 2H), 1.38 (s, 9H).

[0267] Step 2. Methyl 3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoate (Compound 11). To a stirred solution of 3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoic acid 10 (0.47 g, 2.3 mmol) in DMF (5 mL) was added KCO (0.34 g, 2.5 mmol), followed by MeI (0.16 mL, 2.5 mmol). The reaction mixture was stirred at room temperature for 72 h and quenched by the addition of water (5 mL). The aqueous phase was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with HO (3 × 5 mL) and brine (5 mL), dried (MgSO), filtered, and concentrated under reduced pressure to give the crude title compound 11 as a yellow oil (0.28 g, 56%), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ, ppm 4.86(d,J=16.3Hz, 1H), 4.20(t,J=4.5Hz, 1H), 3.74(s,3H), 3.43(ddd,J=7.3Hz, 4.7Hz, 2.7Hz, 2H), 1.37(s,9H).

[0268] Step 3. Methyl 3-((tert-butoxycarbonyl)amino)-2-(tosyloxy)propanoate (Compound 12). To a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoate 11 (0.17 g, 0.78 mmol) in DCM (3 mL) was added TEA (0.54 mL, 3.88 mmol), 4-methylbenzene-1-sulfonyl chloride (0.30 g, 1.55 mmol), and a catalytic amount of DMAP (9.5 mg, 0.08 mmol) at 0 °C. After 15 min, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched by the addition of 10% citric acid (5 mL) and then diluted with EtOAc (5 mL). The aqueous phase was extracted with EtOAc (2 × 5 mL). The combined organic layers were dried (MgSO), filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography (0-100% EtOAc / isohexane) to give the title compound 12 as a colourless oil (0.26 g, 68%). t 2.22 minutes (method 1a) m / z 274[M+H-Boc] + (ES + ). 1 H NMR (400MHz, CDCl3): δ, ppm 7.79-7.72(m,2H), 7.30-7.22(m,2H), 4.89(dt,J=14.2, 5.5Hz, 1H), 4.75(s,1H), 3.60(s,3H), 3.55(d,J=5.2Hz, 1H), 3.47-3.38(m,1H), 2.38(s,3H), 1.34(s,9H).

[0269] Step 4. Methyl 3-((tert-butoxycarbonyl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoate (compound 14). To a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)-2-(tosyloxy)propanoate 12 (0.26 g, 0.68 mmol) in MeCN (4 mL) was added (2R,6S)-2,6-dimethylmorpholine 13 (0.13 mL, 1.02 mmol), followed by KCO (0.28 g, 2.05 mmol). The reaction mixture was stirred at 50 °C overnight. LC / MS indicated an incomplete reaction, and an additional aliquot of K2CO3 (200 mg) and (2R,6S)-2,6-dimethylmorpholine 13 (0.126 mL, 1.024 mmol) was added to the reaction mixture and stirred at 50 °C for an additional 24 h. The reaction mixture was cooled to room temperature. HO (5 mL) was added, and the aqueous phase was extracted with EtOAc (2 × 5 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give the crude title compound 14 as a colorless, viscous oil (73 mg, 34%). 1 H NMR (400MHz, CDCl3): δ, ppm 4.83(s,1H), 3.68(s,4H), 3.40(m,4H), 2.47(m,3H), 1.38(s,9H), 1.08(dd,J=6.3Hz, 1.4Hz, 6H).

[0270] Step 5. Methyl 3-amino-2-((2S,6R)-2,6-dimethylmorpholino)propanoate (compound 15). To a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoate 14 (73 mg, 0.23 mmol) in DCM (1 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature, and stirred overnight. The solvent was removed under reduced pressure, and the resulting oil was taken up in MeOH (10 mL) and applied to an SCX column. The column was washed with methanol (20 mL), and the product was eluted with 10% methanolic ammonia (20 mL) to give the title compound 15 as a colorless oil (61 mg, quantitative yield). 1H NMR (400MHz, CDCl3): δ, ppm 5.34(s,1H), 3.67(s,3H), 3.66-3.51(m,2H), 3.25-3.15(m,1H), 2.95-2.89(m,2H), 2.58(ddt,J=11.2Hz, 6.9Hz , 1.9Hz, 2H), 2.31(dd,J=11.3Hz, 10.0Hz, 1H), 1.90(dd,J=11.4Hz, 10.0Hz, 1H), 1.08(dd,J=6.3Hz, 2.8Hz, 6H).

[0271] Step 6. Methyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoate (Compound 16). To a stirred solution of 5-bromo-3-fluoro-2-nitropyridine 2 (62 mg, 0.28 mmol) in THF (4 mL) was added methyl 3-amino-2-((2S,6R)-2,6-dimethylmorpholino)propanoate 15 (61 mg, 0.28 mmol), followed by potassium carbonate (78 mg, 0.56 mmol). The reaction mixture was stirred at reflux for 2 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in HO (10 mL) and EtOAc (10 mL) was added. The aqueous phase was separated and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (10 mL), passed through a phase separator, and concentrated under reduced pressure. The crude product was purified by silica chromatography (0-100% EtOAc / isohexane) to give the title compound 16 as a yellow solid (88 mg, 75%). t 1.44 minutes (method 2a) m / z 417 / 419[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 8.20(d,J=6.8Hz, 1H), 7.99(d,J=1.9Hz, 1H), 7.90(d,J=1.9Hz, 1H), 3.70(m,3H), 3.62-3.45(m,5H), 2 .75(t,J=10.7Hz, 3H), 2.39(t,J=10.7Hz, 2H), 1.84(t,J=10.6Hz, 1H), 1.05(dd,J=11.9Hz, 6.3Hz, 6H).

[0272] Step 7. Methyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoate (Compound 17). To a stirred solution of methyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoate 16 (88 mg, 0.21 mmol) in EtOH (2 mL), acetic acid (0.24 mL, 4.22 mmol) was added, followed by iron powder (0.12 g, 2.11 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature and neutralized with solid NaHCO to pH 8. The resulting reaction mixture was diluted with HO (5 mL) and EtOAc (5 mL). The aqueous phase was separated and extracted with EtOAc (2 × 5 mL). The combined organic phases were washed with H2O (5 mL), passed through a hydrophobic frit and concentrated under reduced pressure to give the title compound 17 as a brown solid (79 mg, 96%). t 0.74 min (method 2a) m / z 387 / 389[M+H] + (ES + ).

[0273] Step 8. 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoic acid (compound 18). To a stirred solution of methyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoate 17 (79 mg, 0.20 mmol) in THF (0.5 mL) was added a solution of LiOH (24 mg, 1.02 mmol) in HO (0.5 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated to dryness to give the title compound 18 as a brown solid (80 mg, quantitative yield), which was used in the next step without further purification. t 0.33 min (method 2a) m / z 373 / 375[M+H] + (ES + ).

[0274] Step 9. 8-Bromo-3-((2S,6R)-2,6-dimethylmorpholino)-1,2,3,5-tetrahydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (Compound 19). To a stirred solution of 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoic acid 18 (76 mg, 0.20 mmol) in DMF (1 mL) was added DIPEA (0.11 mL, 0.61 mmol) followed by HATU (0.12 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 1 h. An aqueous solution of NH4Cl (2 mL) was added. The aqueous phase was separated and extracted with DCM (2 × 5 mL). The combined organic phases were washed with HO (3 x 5 mL), passed through a hydrophobic frit and concentrated under reduced pressure to give the title compound 19 as a yellow solid (47 mg, 64%), which was used in the next step without further purification. t 1.09 min (method 1a) m / z 355 / 357[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 9.87-9.77(m,1H), 7.59(d,J=2.1Hz, 1H), 7.14(d,J=2.1Hz, 1H), 6.34-6.20(m,1H), 3.60(dt,J=12.8Hz, 6.3Hz, 1H), 3.49-3.41(m,1H), 3.25 -3.12(m,2H), 3.09(d,J=6.2Hz, 1H), 2.82(d,J=10.8Hz, 1H), 1.93(d,J=10.6Hz, 1H), 1.79(t,J=10.5Hz, 1H), 0.99(dd,J=16.8Hz, 6.3Hz, 6H).

[0275] Step 10. (E)-3-(3-((2S,6R)-2,6-dimethylmorpholino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 20). A reaction vial was charged with N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (31 mg, 0.13 mmol), 8-bromo-3-((2S,6R)-2,6-dimethylmorpholino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]diazepin-4(5H)-one 19 (47 mg, 0.13 mmol), tetrabutylammonium chloride hydrate (4 mg, 0.01 mmol), and [P(tBu)3]Pd(crotyl)Cl (Pd-162) (5 mg, 0.01 mmol). The vial was flushed with nitrogen for 5 min. 1,4-Dioxane (2 mL) and N-cyclohexyl-N-methylcyclohexanamine (0.06 mL, 0.27 mmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 min. The mixture was heated to 80°C for 2 hours and cooled to room temperature. The solvent was evaporated to dryness. The residue was taken up in EtOAc (5 mL) and a solution of NH4Cl (5 mL) was added. The aqueous phase was separated and extracted with EtOAc (2 x 5 mL). The combined organic phases were passed through a phase separator and concentrated under reduced pressure. The crude product was purified by silica chromatography (0-10% MeOH / DCM) to give the title compound as a racemic mixture of 20 as a yellow solid (43 mg, 59%). R t 1.06 min (method 2a) m / z 504[M+H] + (ES + ). 1H NMR (400MHz, DMSO-d6): δ, ppm 9.83(s,1H), 7.93(d,J=7.3Hz, 1H), 7.62-7.03(m,6H), 6.03(s,1H), 4.88(d,J=62.9Hz, 2H), 3.62-3.42(m,2H), 3.30 -2.94(m,6H), 2.85(d,J=11.0Hz, 1H), 2.27(s,3H), 1.91(dt,J=36.4Hz, 10.5Hz, 2H), 0.99(dd,J=11.3Hz, 6.2Hz, 6H).

[0276] Step 11. (E)-3-((R)-3-((2S,6R)-2,6-dimethylmorpholino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 21). Chiral separation of compound 20. The enantiomers were separated by chiral preparative HPLC. The chirality of 21 was arbitrarily assigned. R t 1.66 min (method 1a) m / z 504[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 9.24(s,1H), 7.91(d,J=1.9Hz, 1H), 7.58-7.54(m,1H), 7.49-7.44(m,1H), 7.41( d,J=15.5Hz, 1H), 7.31-7.23(m,3H), 7.14-7.05(m,1H), 5.79(s,1H), 4.84(s,2H) ), 3.63-3.44(m,2H), 3.37-3.23(m,2H), 3.20(d,J=5.3Hz, 1H), 3.10(s,3H), 2.9 1-2.84(m,2H), 2.28(s,3H), 2.00(dt,J=19.6Hz, 10.6Hz, 2H), 1.03-0.99(m,6H).

[0277] Example 3 Synthesis of (S,E)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(4-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylamide (Compound 35) General synthetic scheme [ka] Step 1. 2-Methylbenzofuran-3-carbaldehyde (compound 23) To a stirred solution of dichloro(methoxy)methane (5.1 mL, 56.7 mmol) and 2-methylbenzofuran 22 (5.0 g, 37.8 mmol) in DCM (100 mL) at 0 °C, tin(IV) chloride (1 M in DCM) (60.5 mL, 60.5 mmol) was added dropwise over 30 min. After the addition was complete, the mixture was allowed to warm to room temperature over 30 min and then poured onto ice-cold saturated sodium bicarbonate solution (500 mL). The mixture was extracted with DCM (2 × 100 mL), and the organics were separated and dried. Filtration and evaporation gave the crude product, which was purified by silica chromatography (0–50% EtOAc / isohexane) to give the title compound 23 as a yellow solid (5.30 g, 86%). 1 H NMR (400MHz, CDCl3): δ, ppm 10.16 (s, 1H), 8.06-8.01 (m, 1H), 7.41-7.35 (m, 1H), 7.34-7.23 (m, 2H), 2.70 (s, 3H).

[0278] Step 2. N-benzyl-N-methyl-1-(2-methylbenzofuran-3-yl)methanamine (Compound 24) To a solution of 2-methylbenzofuran-3-carbaldehyde 23 (1.00 g, 6.24 mmol) and N-methyl-1-phenylmethanamine (0.98 mL, 7.49 mmol) in DCE (20 mL) was added sodium triacetoxyborohydride (1.99 g, 9.37 mmol), and the mixture was stirred for 72 h. The reaction mixture was washed with saturated sodium bicarbonate solution (20 mL) and dried over sodium sulfate. Filtration and evaporation gave the title compound 24 as a pale yellow oil (1.60 g, 94% yield), which was used without further purification. 1 H NMR(400MHz,DMSO-d6):δ,ppm 7.63-7.58(m,1H),7.48-7.43(m,1H),7.33(d,J=4.8Hz,4H),7.28-7.20(m,3H),3.56(s,2H),3.52(s,2H),2.42(s,3H),2.08(s,3H).

[0279] Step 3. N-methyl-1-(2-methylbenzofuran-3-yl)methanamine hydrochloride (compound 25) A mixture of N-benzyl-N-methyl-1-(2-methylbenzofuran-3-yl)methanamine 24 (1.60 g, 6.03 mmol) and Pd-C87L 5% on carbon (0.64 g, 6.03 mmol) in methanol (20 mL) was acidified to pH 1 with 1 M hydrochloric acid, hydrogenated at 5 bar, and left stirring at room temperature for 18 h. The catalyst was filtered off, and the filtrate was evaporated to dryness to give the title compound 25 as a white solid (737 mg, 56%). 1 H NMR (400MHz, DMSO-d6): δ,ppm 9.24(s,2H),7.89-7.80(m,1H),7.59-7.49(m,1H),7.34-7.23(m,2H),4.24(s,2H),2.57(s,3H),2.55(s,3H).

[0280] Step 4. N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide (Compound 26) To a suspension of N-methyl-1-(2-methylbenzofuran-3-yl)methanamine hydrochloride 25 (300 mg, 1.42 mmol) and triethylamine (600 μL, 4.25 mmol) in dry THF (10 mL) was added acryloyl chloride (154 mg, 1.70 mmol) dropwise over 15 min at room temperature. The mixture was stirred for 1 h and then poured into water (30 mL). The organic solvent was removed by rotary evaporation to give a solid. The solid was collected by filtration, washed with water (10 mL), and dried to give the title compound 26 as a colorless solid (316 mg, 95%). t 1.94 min (method 1b) m / z 230[M+H] + (ES + ).

[0281] Step 5. Methyl 3-((tert-butoxycarbonyl)amino)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoate (compound 28). To a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)-2-(tosyloxy)propanoate 12 (1 g, 2.7 mmol) in MeCN (4 mL) was added 2-oxa-6-azaspiro[3.3]heptane(hemioxalate) 27 (0.40 g, 4.0 mmol), followed by KCO (1.1 g, 8.0 mmol). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The crude product was purified by silica chromatography (0–100% EtOAc / isohexane) to afford the title compound 28 as a colorless oil (0.33 g, 42%). 1 H NMR (400MHz, CDCl3): δ, ppm 5.04(dd,J=9.5Hz, 5.4Hz, 1H), 4.75(s,3H), 3.93-3.61(m,8H), 3.53-3.41(m,1H), 3.34-3.15(m,2H), 1.42(s,9H).

[0282] Step 6. Methyl 3-amino-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoate (compound 29). To a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoate 28 (0.33 g, 1.11 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature, and stirred for 1 h. The solvent was removed under reduced pressure, and the resulting oil was taken up in MeOH (10 mL) and applied to an SCX column. The column was washed with methanol (20 mL), and the product was eluted with 10% methanolic ammonia (20 mL) to give the title compound 29 as a colorless oil (0.16 g, 72%). 1 H NMR (400MHz, CDCl3): δ, ppm 4.79-4.69(m,4H), 3.80-3.69(m,4H), 3.60-3.44(m,4H), 3.09(t,J=4.9Hz, 1H), 2.97-2.92(m,1H).

[0283] Step 7. Methyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoate (Compound 30). To a stirred solution of 5-bromo-3-fluoro-2-nitropyridine 2 (62.3 mg, 0.28 mmol) in THF (4 mL) was added methyl 3-amino-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoate 29 (0.16 g, 0.8 mmol), followed by potassium carbonate (0.22 g, 1.61 mmol). The reaction mixture was stirred at reflux for 1 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in HO (10 mL) and EtOAc (10 mL) was added. The aqueous phase was separated and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (10 mL), passed through a phase separator, and concentrated under reduced pressure. The crude product was purified by silica chromatography (0-100% EtOAc / isohexane) to give the title compound 30 as a yellow solid (0.15 g, 45%). t0.90 min (method 1a) m / z 401 / 403[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 7.98(t,J=5.2Hz, 1H), 7.94(d,J=2.0Hz, 1H), 7.91(d,J=1.8Hz, 1H), 4.63-4.58(m,4H), 3.63(s,3H), 3.55-3.41(m,7H).

[0284] Step 8. Methyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoate (Compound 31). To a stirred solution of methyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoate 30 (0.15 g, 0.36 mmol) in EtOH (3 mL), acetic acid (0.42 mL, 7.28 mmol) was added, followed by iron powder (0.20 g, 3.64 mmol). The reaction mixture was stirred at 90 °C for 30 min. The reaction mixture was cooled to room temperature and neutralized to pH 8 with solid NaHCO. The resulting reaction mixture was diluted with HO (5 mL) and EtOAc (5 mL). The aqueous phase was separated and extracted with EtOAc (2 x 5 mL). The combined organic phases were washed with HO (5 mL), passed through a hydrophobic frit and concentrated under reduced pressure to give the title compound 31 as a brown solid (0.13 g, 96%). t 0.15 min (method 2a) m / z 371 / 373[M+H] + (ES + ).

[0285] Step 9. 3-((2-amino-5-bromopyridin-3-yl)amino)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoic acid (compound 32). To a stirred solution of methyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((2S,6R)-2,6-dimethylmorpholino)propanoate 31 (0.13 g, 0.35 mmol) in THF (0.5 mL) was added a solution of LiOH (42 mg, 1.75 mmol) in HO (0.5 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated to dryness to give the title compound 32 (0.13 g, 0.35 mmol) as a white solid, which was used in the next step without further purification. t 0.15 min (method 2a) m / z 357 / 359[M+H] + (ES + ).

[0286] Step 10. 8-Bromo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (Compound 33). To a stirred solution of 3-((2-amino-5-bromopyridin-3-yl)amino)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoic acid 32 (0.13 g, 0.35 mmol) in DMF (2 mL) was added DIPEA (0.18 mL, 1.05 mmol) followed by HATU (0.2 g, 0.53 mmol). The reaction mixture was stirred at room temperature for 1 h. Water (2 mL) was added, and the aqueous phase was separated and extracted with DCM (2 × 5 mL). The combined organic phases were washed with H2O (3 x 5 mL), passed through a hydrophobic frit and concentrated under reduced pressure to give the title compound 33 as a yellow solid (0.06 g, 52%). t 0.26 min (method 2a) m / z 339 / 341[M+H] + (ES + ). 1H NMR (400MHz, DMSO-d6): δ, ppm 9.82(s,1H), 7.66(d,J=2.1Hz, 1H), 7.21(d,J=2.1Hz, 1H), 6.31(t,J=4.4Hz, 1H), 4.55(s,4H), 3.43-3 .35(m,4H), 3.29(ddd,J=12.7Hz, 5.2Hz, 2.3Hz, 1H), 3.25-3.17(m,1H), 3.12(dd,J=7.7Hz, 2.2Hz, 1H).

[0287] Step 11. (E)-N-Methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(4-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylamide (Compound 34). A reaction vial was charged with N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide 26 (42 mg, 0.18 mmol), 8-bromo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-b][1,4]diazepin-4-one 33 (0.06 g, 0.18 mmol), tetrabutylammonium chloride hydrate (5 mg, 0.02 mmol), and [P(tBu)3]Pd(crotyl)Cl (Pd-162) (7 mg, 0.02 mmol). The vial was flushed with nitrogen for 5 min. 1,4-Dioxane (3 mL) and N-cyclohexyl-N-methylcyclohexanamine (0.08 mL, 0.37 mmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 minutes. The mixture was heated to 80° C. for 1 hour and cooled to room temperature. The solvent was evaporated to dryness. The residue was taken up in EtOAc (5 mL), and HO (5 mL) was added. The aqueous phase was separated and extracted with EtOAc (2×5 mL). The combined organic phases were passed through a phase separator and concentrated under reduced pressure. The crude product was purified by silica chromatography (0-10% MeOH / DCM) to give the title compound 34 as a racemic mixture (yellow solid).

[0288] Step 12. (S,E)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(4-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylamide (Compound 35). The enantiomers were separated by chiral preparative HPLC using Method Ia. The chirality of 35 was arbitrarily assigned. The title first eluting isomer (25 mg, 26%) was isolated. R t 019 minutes (Method IIa) minutes, R t 0.85 min (method 2a) m / z 488[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 9.22(s,1H), 7.95(d,J=2.0Hz, 1H), 7.54(d,J=7.6Hz, 1H), 7.50-7.41(m,2H), 7.32(d,J=2.0Hz, 1H), 7.25-7.16(m,2H), 7.12-7.04(m,1H), 5.73(s,1H), 4.77 (s,2H), 4.56(s,4H), 3.47-3.41(m,4H), 3.35(ddd,J=12.7Hz, 4.8Hz, 2.5Hz, 1H ), 3.27-3.19(m,1H), 3.15(dd,J=7.5Hz, 2.5Hz, 1H), 3.00(s,3H), 2.88(s,3H).

[0289] Example 4. Synthesis of (E)-3-(3-acetamido-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 42) General synthetic scheme [ka] Step 1. 3-((5-Bromo-2-nitropyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (compound 37). A mixture of 3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid 36 (0.51 g, 2.49 mmol), triethylamine (1.60 mL, 11.2 mmol), and 5-bromo-3-fluoro-2-nitropyridine 2 (0.5 g, 2.26 mmol) in EtOH (50 mL) was heated to reflux for 2 h. The reaction mixture was evaporated to dryness, and the residue was taken up in water (20 mL). The mixture was acidified to pH 3 by the addition of a 1 M solution of HCl. The aqueous phase was extracted with ethyl acetate (2 × 20 mL), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 37 as a yellow solid (0.87 g, 90%). t 1.88 minutes (method 1a) m / z 403 / 405[MH] - (ES - ).

[0290] Step 2. 3-((2-Amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (compound 38). A mixture of 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid 37 (0.87 g, 2.15 mmol), iron powder (0.48 g, 8.59 mmol), and ammonium chloride (1.15 g, 21.5 mmol) in a solvent mixture of EtOH (80 mL) and water (20 mL) was heated and stirred under reflux for 1 h. The reaction mixture was filtered hot through a plug of Celite®, and the filtrate was evaporated to dryness. The residue was triturated with water (30 mL), and the resulting solid was collected and dried to give the title compound 38 as a pale yellow solid (0.44 g, 52%). t 0.83 min (method 2a) m / z 375 / 377[M+H] + (ES + ). 1H NMR (DMSO-d6): δ, ppm 12.77(s,1H), 7.33(d,J=2.1Hz, 1H), 7.14(d,J=8.7Hz, 1H), 6.73(d,J=2.1Hz, 1H) , 5.72(s,2H), 5.11(s,1H), 4.23-4.17(m,1H), 3.36(d,J=5.7Hz, 2H), 1.39(s,9H).

[0291] Step 3. tert-Butyl (8-bromo-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate (compound 39). To a solution of 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid 38 (0.44 g, 1.17 mmol) and DIPEA (0.61 mL, 3.52 mmol) in DMF (8.0 mL) was added HATU (0.54 g, 1.40 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with water (50 mL). The resulting solid was collected and purified by chromatography (0–50% EtOAc / isohexane) to give the title compound 39 as a white solid (0.37 g, 85%). t 1.79 minutes (method 1a) m / z 355 / 357[MH] - (ES - ).

[0292] Step 4. 3-Amino-8-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]diazepin-4(5H)-one 2,2,2-trifluoroacetate (compound 40). tert-Butyl (8-bromo-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate 39 (365 mg, 1.02 mmol) was dissolved in a mixture of TFA (5.0 mL) and DCM (5.0 mL) and allowed to stand at room temperature for 20 minutes. The mixture was evaporated to dryness, and the residue was triturated with acetonitrile (10 mL). The resulting solid was collected by filtration and dried under reduced pressure to give the title compound 40 as a white solid (0.31 g, 78%). t 0.95 min (method 1a) m / z 257 / 259[M+H]+ (ES + ). 1 H NMR (DMSO-d6): δ, ppm 10.67(s,1H), 8.42(s,3H), 7.82(d,J=2.1Hz, 1H), 7.37(d,J=2.1Hz, 1H), 6.68(dd,J=7.1, 1.8Hz, 1H), 4.27(dd,J=10.0, 3.0Hz, 1H), 3.60(ddd,J=12.3, 7.1, 3.1Hz, 1H), 3.44(ddd,J=11.9, 10.0, 1.7Hz, 1H).

[0293] Step 5. N-(8-Bromo-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)acetamide (Compound 41). To an ice-cooled suspension of 3-amino-8-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]diazepin-4(5H)-one 2,2,2-trifluoroacetate 40 (310 mg, 0.64 mmol) in DCM (20 mL) was added TEA (445 μL, 3.20 mmol), and a solution of acetyl chloride (45 μL, 0.64 mmol) in DCM (1.0 mL) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and then washed with water (20 mL). The organic phase was separated and dried over sodium sulfate. The crude product was purified by chromatography on silica gel (0-10% MeOH / DCM) to give the title compound 41 as a brown solid (69 mg, 33%). t 1.05 min (method 1a) m / z 299 / 301 (M+H) + (ES + );297 / 299[MH] - (ES - ). 1H NMR (DMSO-d6): δ, ppm 10.20(s,1H), 8.18(d,J=7.3Hz, 1H), 7.79(d,J=2.1Hz, 1H), 7.35(d,J=2.2Hz, 1H), 6.41(d,J=6.3Hz, 1H), 4.44(dd d,J=10.4, 7.3, 3.3Hz, 1H), 3.46(ddd,J=11.7, 6.6, 3.4Hz, 1H), 3.31(ddd,J=11.7, 10.0, 1.5Hz, 1H), 1.89(s,3H).

[0294] Step 6. (E)-3-(3-acetamido-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 42). A reaction vial was charged with N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (42 mg, 0.18 mmol), N-(8-bromo-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)acetamide 41 (55 mg, 0.18 mmol), NBuCl (5 mg, 0.02 mmol), and [P(tBu)]Pd(crotyl)Cl (Pd-162) (7 mg, 0.02 mmol), and the vial was flushed with N (5 min). Next, 1,4-dioxane (5.0 mL) and N-cyclohexyl-N-methylcyclohexanamine (79 μL, 0.37 mmol) were added, and the reaction mixture was purged again with N (5 min). The mixture was then heated to 80 °C for 1 h. The mixture was cooled to room temperature, and the precipitate was collected by filtration and washed with 1,4-dioxane (2.0 mL). The crude product was purified by chromatography (0-10% MeOH / DCM) to give the title compound 42 as a yellow solid (34 mg, 40%). t 1.71 min (method 1a) m / z 448[M+H] + (ES + ). 1H NMR (DMSO-d6, 363K): δ, ppm 9.68(s,1H), δ 8.05(d,J=1.9Hz, 1H), 7.86-7.79(m,1H), 7.56(dd,J=7.8, 1.3Hz, 1H), 7.50 -7.42(m,3H), 7.31-7.24(m,2H), 7.15(d,J=15.1Hz, 1H), 5.93(dd,J=6.5, 2. 3Hz, 1H), 4.85(s,2H), 4.50(ddd,J=10.3, 7.3, 3.5Hz, 1H), 3.56-3.50(m,1H) , 3.32(ddd,J=11.9, 9.6, 2.3Hz, 1H), 3.10(s,3H), 2.28(s,3H), 1.91(s,3H).

[0295] Example 5. Synthesis of (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 52) General synthetic scheme [ka] Step 1. (2S,3S)-Methyl 2-amino-3-hydroxybutanoate hydrochloride (compound 44). Thionyl chloride (1.9 mL, 26.4 mmol) was added dropwise to a stirred suspension of (2S,3S)-2-amino-3-hydroxybutanoic acid 43 (3 g, 25.2 mmol) in MeOH (20 mL) at 0 °C, and the reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was then heated to reflux for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was azeotroped with MTBE (50 mL), and the resulting white gummy solid 44 (4.99 g, quantitative) was used in the next step without further purification. 1 H NMR (500 MHz, DO) δ 4.36 (qd, J = 6.7, 3.4 Hz, 1H), 4.23 (d, J = 3.5 Hz, 1H), 3.88 (s, 3H), 1.32 (d, J = 6.7 Hz, 3H). No exchangeable protons were observed.

[0296] Step 2. (2S,3S)-Methyl 3-hydroxy-2-(tritylamino)butanoate (Compound 45). TEA (5.3 mL, 37.8 mmol) was added dropwise to a stirred suspension of (2S,3S)-methyl 2-amino-3-hydroxybutanoate hydrochloride 44 (4.27 g, 25.2 mmol) in DCM (30 mL) at 0 °C, and the reaction mixture was stirred for 5 min. Next, a solution of trityl chloride (7.4 g, 26.5 mmol) in DCM (30 mL) was added, and the reaction was allowed to warm to room temperature and stirred for 72 h. The reaction mixture was filtered, and the filtrate was washed with NaHCO (100 mL, saturated aqueous solution). The aqueous layer was extracted with DCM (3 × 100 mL), and the combined organic extracts were washed with brine (1 × 100 mL), dried using a phase separation cartridge, and concentrated under reduced pressure. The crude material was purified by column chromatography (0-50% EtOAc / isohexane) to give the desired product 45 as a white solid (3.55 g, 37%). R t 2.52 minutes (method 1a) m / z 398 (M+Na) + (ES + ); 1 H NMR (500MHz, DMSO-d6)δ δ 7.49-7.40(m,6H), 7.31-7.24(m,6H), 7.21-7.15(m,3H), 4.96(d,J=5.1Hz, 1H), 3.89-3.76(m, 1H), 3.11(dd,J=10.7, 4.1Hz, 1H), 3.08(s,3H), 2.89(d,J=10.7Hz, 1H), 1.07(d,J=6.4Hz, 3H).

[0297] Step 3. (2S,3R)-Methyl 3-azido-2-(tritylamino)butanoate (compound 46). A solution of DIAD (2.90 mL, 14.9 mmol) in THF (20 mL) was added dropwise to a stirred solution of (2S,3S)-methyl 3-hydroxy-2-(tritylamino)butanoate 45 (3.5 g, 9.32 mmol) and triphenylphosphine (3.67 g, 14.0 mmol) in THF (45 mL) at 0 °C, and the reaction mixture was stirred for 5 min. Next, a solution of diphenylphosphoroazidate (3.3 mL, 15.4 mmol) in THF (30 mL) was added, and the reaction was allowed to warm to room temperature and stirred for approximately 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (0–15% EtOAc / isohexane) to afford the desired product 46 as a colorless oil (2.05 g, 47%). t 2.69 min (method 1a) m / z 423(M+Na) + (ES + ); 1 H NMR (500 MHz, DMSO-d) δ 7.46-7.39 (m, 6H), 7.32-7.26 (m, 6H), 7.24-7.16 (m, 3H), 3.90 (p, J = 6.6 Hz, 1H), 3.30-3.26 (m, 1H), 3.10 (s, 3H), 1.11 (d, J = 6.2 Hz, 3H). No amine protons were observed.

[0298] Step 4. (2S,3R)-Methyl 3-azido-2-((tert-butoxycarbonyl)amino)butanoate (Compound 47). HCl (4.12 mL, 16.5 mmol, 4 M in dioxane) was added dropwise to a stirred solution of (2S,3R)-methyl 3-azido-2-(tritylamino)butanoate 46 (0.66 g, 1.65 mmol) in THF (10 mL) at 0 °C, and the reaction was stirred for 2 h. The solvent was concentrated under reduced pressure, and the resulting solid was triturated with MTBE (10 mL) and collected by filtration to give a fluffy white solid (0.35 g, quantitative). The intermediate was suspended in DCM (10 mL), and triethylamine (0.69 mL, 4.94 mmol) was added, followed by BocO (0.36 g, 1.65 mmol), and the reaction mixture was stirred for approximately 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (0-100% EtOAc / isohexane) to give the desired product 47 as a colorless oil (0.32 g, 72%). 1 H NMR (500MHz, DMSO-d6) δ 7.37(d,J=8.9Hz, 1H), 4.18(dd,J=8.9, 4.9Hz, 1H), 4.12-3.97(m,1H), 3.66(s,3H), 1.39(s,9H), 1.19(d,J=6.6Hz, 3H).

[0299] Step 5. (2S,3R)-Methyl 3-amino-2-((tert-butoxycarbonyl)amino)butanoate (Compound 48). Triphenylphosphine (0.65 g, 2.48 mmol) and water (0.09 mL, 4.96 mmol) were added to a stirred solution of (2S,3R)-methyl 3-azido-2-((tert-butoxycarbonyl)amino)butanoate 47 (0.32 g, 1.24 mmol) in THF (10 mL), and the reaction mixture was heated to 60 °C and stirred for approximately 16 h. The reaction mixture was cooled to room temperature, then NaHCO (40 mL, saturated aqueous solution) was added, and the aqueous mixture was extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (1 × 40 mL), dried over MgSO, concentrated under reduced pressure, and loaded onto an SCX column. The SCX column was washed with MeOH (30 mL) and the product was eluted with methanolic ammonia and concentrated under reduced pressure to give the desired product 48 as a colorless oil (0.24 g, 78%). 1 H NMR (500MHz, DMSO-d6)δ 6.97(d,J=8.4Hz, 1H), 3.88(dd,J=8.4, 4.6Hz, 1H), 3.62(s,3H), 3.16-3.10(m,1H), 1.52(s,2H), 1.39(s,9H), 0.97(d,J=6.6Hz, 3H).

[0300] Step 6. (2S,3R)-Methyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (Compound 49). A mixture of 5-bromo-3-fluoro-2-nitropyridine 2 (0.22 g, 0.99 mmol), (2S,3R)-methyl 3-amino-2-((tert-butoxycarbonyl)amino)butanoate 48 (0.23 g, 0.99 mmol), and triethylamine (0.55 mL, 3.96 mmol) in MeCN (5 mL) was stirred at 80 °C for 5 h and at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (0–50% EtOAc / isohexane) to give the desired product 49 as a yellow oil (0.37 g, 82%). R t1.80 minutes (method 1a) m / z 377 / 379 (M-tBu) + (ES + ); 1 H NMR (500MHz, DMSO-d6)δ 7.98(d,J=1.9Hz, 1H), 7.88(d,J=1.8Hz, 1H), 7.73(d,J=9.4Hz, 1H), 7.68(d,J=8.3Hz, 1H), 4. 44-4.35(m,1H), 4.33(dd,J=8.4, 5.2Hz, 1H), 3.59(s,3H), 1.37(s,9H), 1.23(d,J=6.5Hz, 3H).

[0301] Step 7. (2S,3R)-Methyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (Compound 50). A mixture of (2S,3R)-methyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)butanoate 49 (0.37 g, 0.85 mmol), iron powder (0.38 g, 6.83 mmol), and NHCl (0.18 g, 3.42 mmol) in a mixture of EtOH (10 mL) and HO (2.5 mL) was heated and stirred at 90 °C for 2 h. The reaction mixture was filtered through Celite®, the cake was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (0-100% EtOAc / iso-hexane) to give the desired product 50 as a brown oil (0.22 g, 52%). t 1.43 minutes (method 1a) m / z 403 / 405 (M+H) + (ES + ); 1 H NMR (500MHz, DMSO-d6)δ 7.31(d,J=2.0Hz, 1H), 7.15(d,J=9.3Hz, 1H), 6.75(d,J=2.1Hz, 1H), 5.68(s,2H), 4.53(d,J=9.7Hz, 1 H), 4.29(dd,J=9.3, 3.8Hz, 1H), 4.11-4.05(m,1H), 3.56(s,3H), 1.42(s,9H), 1.11(d,J=6.5Hz, 3H).

[0302] Step 8. tert-Butyl ((2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate (Compound 51). NaH (50 mg, 1.23 mmol, 60% in mineral oil) was added to a stirred solution of (2S,3R)-methyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)amino)butanoate 50 (0.17 g, 0.41 mmol) in DMF (5 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h, after which the reaction was quenched with water (50 mL). The resulting precipitate was collected by filtration to give the desired product as an off-white solid (72 mg, 47%). The aqueous filtrate was then extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (1 x 50 mL), dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (EtOAc / isohexane) to give a further portion of the desired product 51 as a white solid (36 mg, 23%). t 1.91 min (method 1a) m / z 315 / 317 (M-tBu) + (ES + ); 1 H NMR (500MHz, DMSO-d6)δ 10.29(s,1H), 7.77(d,J=2.1Hz, 1H), 7.32(d,J=2.1Hz, 1H), 6.82(d,J=7.6Hz, 1H), 6.47(d ,J=6.4Hz, 1H), 4.38-4.26(m,1H), 3.83-3.69(m,1H), 1.38(s,9H), 1.10(d,J=6.5Hz, 3H).

[0303] Step 9. (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 52). A mixture of N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (43 mg, 0.19 mmol), tert-butyl ((2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate 51 (70 g, 0.19 mmol), and Pd-116 (10 mg, 0.02 mmol) was evacuated and flushed with N three times. 1,4-Dioxane (2 mL) and DIPEA (0.10 mL, 0.57 mmol) were added, and the reaction mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, then HO (20 mL) was added, and the resulting precipitate was collected by filtration. The crude material was purified by column chromatography (0–10% MeOH / DCM) to give intermediate 52 as a yellow solid (63 mg, 63%). The solid was dissolved in DCM (2 mL), TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and NaHCO (20 mL, saturated aqueous solution) was added, and the resulting suspension was stirred for 1 h. The aqueous mixture was extracted with DCM / 10% MeOH (3 × 30 mL), and the combined organic layers were washed with brine (1 × 30 mL), dried by passing through a phase separation cartridge, and concentrated under reduced pressure. The crude material was purified by column chromatography (0-10% MeOH (0.7 M in NH) / DCM) to give the desired product 52 as a yellow solid (36 mg, 44%). t 1.31 min (method 1a) m / z 420 (M+H) + (ES + ); 1H NMR (500MHz, DMSO-d6, 363K)δ 9.53(s,1H), 7.99(d,J=2.0Hz, 1H), 7.58-7.53(m,1H), 7.48-7.38(m,3H), 7.31-7.22(m,2H), 7.11(d,J=15.5Hz, 1H), 5.80(d,J= 5.6Hz, 1H), 4.84(s,2H), 3.73-3.66(m,1H), 3.63(d,J=3.3Hz, 1H), 3.09(s,3H), 2.27(s,3H), 1.79(s,2H), 1.11(d,J=6.5Hz, 3H).

[0304] Example 6. Synthesis of (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-N-methylacrylamide (Compound 62) General synthetic scheme [ka] Step 1. 2-(2-Bromo-6-formylphenoxy)propanoic acid (compound 55) To a stirred solution of 3-bromo-2-hydroxybenzaldehyde 53 (10 g, 49.7 mmol) and ethyl 2-bromopropanoate 54 (5.9 mL, 45.2 mmol) in MeCN (80 mL), KCO (13.8 g, 99 mmol) was added in one portion, and the reaction was heated to reflux for 3 h. The reaction mixture was allowed to cool to room temperature, filtered to remove KCO, and then concentrated under reduced pressure. The resulting residue was dissolved in THF (50 mL), and NaOH solution (2 M in HO, 57 mL, 113 mmol) was added. The mixture was heated to reflux for 2 h, then cooled to room temperature and concentrated under reduced pressure. The remaining aqueous material was acidified to pH 1 by dropwise addition of concentrated hydrochloric acid, which precipitated the product. The product was collected by filtration and dried azeotropically with MeCN (2 × 50 mL) to give the desired product 55 as an orange oil. This crystallized on standing to give an off-white solid (13.5 g, 99% yield). t1.19 minutes (method 2a) m / z 273 / 275[M+H] + (ES + ). 1 H NMR(400MHz,DMSO-d6):δ,ppm 13.23(s,1H),10.41(d,J=0.8Hz,1H),7.97(dd,J=7.9,1.7Hz,1H),7.74(dd,J=7.7Hz,1 .7Hz,1H),7.25(td,J=7.8Hz,0.9Hz,1H),4.93(q,J=6.8Hz,1H),1.60(d,J=6.8Hz,3H).

[0305] Step 2. 7-Bromo-2-methylbenzofuran (compound 56) A mixture of 2-(2-bromo-6-formylphenoxy)propanoic acid 55 (13 g, 48 mmol) and sodium acetate (39 g, 48 mmol) in acetic anhydride (70 mL) was heated to reflux for 2 h. The mixture was allowed to cool to room temperature and then poured into ice-water (800 mL). The mixture was then extracted with DCM (3 × 300 mL). The combined organic layers were washed with NaOH (2 M aq, 2 × 200 mL) and then with saturated brine (200 mL). The organic layer was dried by passing through a phase separator and concentrated under reduced pressure. The crude product was purified by column chromatography (5–10% EtOAc / isohexane) to give the desired product 56 as a colorless oil (6.72 g, 66% yield). t 1.67 min (Method 2a). No m / z observed. 1 H NMR(400MHz,DMSO-d6):δ,ppm 7.53(dd,J=7.7Hz,1.0Hz,1H),7.43(dd,J=7.8Hz,1.0Hz,1H),7.13(t,J=7.8Hz,1H),6.71(q,J=1.1Hz,1H),2.48(d,J=1.1Hz,3H).

[0306] Step 3. 7-Bromo-2-methylbenzofuran-3-carbaldehyde (compound 57) To a stirred solution of dichloro(methoxy)methane (3.2 mL, 35 mmol) and 7-bromo-2-methylbenzofuran 56 (6.7 g, 32 mmol) in DCM (120 mL) at 0 °C, tin(IV) chloride (38 mL, 38 mmol, 1 M in DCM) was added dropwise over approximately 30 min. The reaction was allowed to warm to room temperature over approximately 90 min and then poured into ice-cold saturated sodium bicarbonate solution (500 mL). The organic material was separated, and the aqueous phase was again extracted with DCM (3 × 150 mL). The combined organic layers were washed with saturated brine (200 mL), dried on a phase separator cartridge, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc / hexane (1:1) to give the desired product 57 as a pale yellow solid (4.5 g, 59% yield). t 1.48 minutes (method 2a) m / z 239 / 241[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ,ppm 10.20(s,1H),7.98(dd,J=7.7Hz,1.1Hz,1H),7.59(dd,J=7.9Hz,1.1Hz,1H),7.29(t,J=7.8Hz,1H),2.84(s,3H).

[0307] Step 4. tert-Butyl ((7-bromo-2-methylbenzofuran-3-yl)methyl)(methyl)carbamate (Compound 58) To a stirred solution of 7-bromo-2-methylbenzofuran-3-carbaldehyde 57 (2.8 g, 3.7 mmol) and sodium triacetoxyborohydride (STAB) (1.9 g, 9.2 mmol) in EtOH (100 mL) at 0 °C, methanamine (33% in EtOH, 0.5 mL, 4.4 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction mixture was then concentrated under reduced pressure, and to the resulting residue were added EtOAc (100 mL) and NaHCO (aq. 100 mL). The organic material was separated, and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over MgSO, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (80 mL), and then DMAP (0.6 g, 4.6 mmol) and di-tert-butyl dicarbonate (1.6 g, 7.3 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The crude reaction mixture was concentrated under reduced pressure and purified by column chromatography (0-50% EtOAc / isohexane) to give the title compound 58 as a yellow oil, which crystallized upon standing (1.0 g, 69% yield). t 1.86 min (method 1a) m / z 376 / 378[M+Na] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 7.55 (br s, 1H), 7.46 (d, J=7.8Hz, 1H), 7.17 (br s, 1H), 4.48 (s, 2H), 2.67 (s, 3H), 2.51 (s, 3H), 1.44 (s, 9H).

[0308] Step 5. tert-Butyl ((7-((diphenylmethylene)amino)-2-methylbenzofuran-3-yl)methyl)(methyl)carbamate (Compound 60) tert-Butyl ((7-bromo-2-methylbenzofuran-3-yl)methyl)(methyl)carbamate 58 (2.0 g, 5.65 mmol), tris(dibenzylideneacetone)dipalladium (0.52 g, 0.57 mmol), CsCO (3.68 g, 11.3 mmol), and Xantphos (0.49 g, 0.85 mmol) were added to a flask, and the flask was evacuated and purged with N three times. Toluene (40 mL) was added, and N was bubbled through the reaction mixture for 10 min. Benzophenone imine 59 (1.1 mL, 6.78 mmol) was then added, and the reaction mixture was heated to reflux for approximately 24 h. The reaction mixture was allowed to cool to room temperature and stirred over the weekend before being concentrated under reduced pressure. The crude product was purified by column chromatography (DCM) to give the desired product 60 as a yellow oil. This was allowed to crystallize upon standing (1.67 g, 65%). t 3.09 minutes (method 1b); m / z 455[M+H] + (ES + ). 1 H NMR(500MHz,DMSO-d6):δ,ppm 7.76-7.65(m,2H),7.63-7.55(m,1H),7.55-7.46(m,2H),7.33-7.21(m,3H),7.16-7.04(m,3H) ,7.01-6.88(m,1H),6.49(d,J=7.6Hz,1H),4.40(s,2H),2.61(s,3H),2.37(s,3H),1.43(s,9H).

[0309] Step 6. N-((7-((diphenylmethylene)amino)-2-methylbenzofuran-3-yl)methyl)-N-methylacrylamide (Compound 61) A stirred solution of tert-butyl ((7-((diphenylmethylene)amino)-2-methylbenzofuran-3-yl)methyl)(methyl)carbamate 60 (0.8 g, 1.76 mmol) in DCM (30 mL) was added dropwise with TFA (15 mL, 195 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (30 mL), cooled to 0 °C, and TEA (5.0 mL, 35.9 mmol) was added, followed by acryloyl chloride (0.17 mL, 2.11 mmol). The reaction was allowed to warm to room temperature and stirred for approximately 16 h. The reaction mixture was quenched with water (50 mL), and the organic phase was separated. The aqueous phase was extracted again with DCM (2 × 50 mL). The combined organic layers were dried by passing through a phase separation cartridge and concentrated under reduced pressure. The crude product was purified by column chromatography (0-3% MeOH / DCM) to give impure material which was purified again by column chromatography (0-30% EtOAc / isohexane) to give the desired product 61 as a yellow oil (0.16 g, 21%, 2 steps).

[0310] Step 7. (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-N-methylacrylamide (compound 62). A mixture of N-((7-((diphenylmethylene)amino)-2-methylbenzofuran-3-yl)methyl)-N-methylacrylamide 61 (50 mg, 0.12 mmol), tert-butyl ((2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate 51 (35 mg, 0.09 mmol), and Pd-116 (5 mg, 9.4 μmol) was evacuated and purged with N three times. 1,4-Dioxane (1.5 mL) and DIPEA (0.05 mL, 0.28 mmol) were added, and the reaction mixture was heated to 90 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, and then the solvent was concentrated under reduced pressure. The resulting residue was dissolved in DCM (2 mL). TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, HCl (10 mL, 1M aqueous solution) was added, and the reaction mixture was stirred for an additional 15 min. The aqueous material was extracted with DCM (3 × 20 mL), and the combined organic layers were back-extracted with HCl (20 mL, 1M aqueous solution). The aqueous layer was then basified to approximately pH 8 with solid NaHCO3 and extracted with DCM / 10% MeOH (3 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL), dried by passing through a phase separation cartridge, and concentrated under reduced pressure. The crude material was purified by column chromatography (0–10% MeOH / DCM) to give the desired product 62 as a yellow solid (14 mg, 32%). t 0.93 min (method 1a) m / z 435 (M+H) + (ES + ); 1H NMR (500MHz, DMSO-d6, 363K)δ 9.53(s,1H), 7.98(d,J=1.9Hz, 1H), 7.45(d,J=15.4Hz, 1H), 7.40(d,J=2.0Hz, 1H), 7.09(d,J=16.3Hz, 1H), 6.87(t,J=7.7Hz, 1H), 6.74(d,J=7.8Hz, 1H), 6.53(dd,J=7. 7, 1.1Hz, 1H), 5.78(d,J=5.5Hz, 1H), 4.87(s,2H), 4.71(s,2H), 3.72-3.64(m,1H), 3 .62(d,J=3.3Hz, 1H), 2.98(s,3H), 2.47(s,3H), 1.82(s,2H), 1.10(d,J=6.5Hz, 3H).

[0311] Example 7. Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide hydrochloride (Compound 71) General synthetic scheme [ka] 5,6,7,9-Tetrahydro-8H-pyrido[2,3-b]azepin-8-one (compound 63) was prepared as described in AFFINIUM PHARMACEUTICALS, INC. - WO 2007 / 67416, 2007, A2 and / or BANYU PHARMACEUTICAL CO., LTD. - EP 1 726 590, 2006, A1.

[0312] Step 1. 7-Iodo-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (Compound 64). To a stirred solution of 5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one 63 (15 g, 0.0925 mol, 1.0 equiv) in DCM (150 mL, 10 vol), TMEDA (42.9 g, 0.3703 mol, 4.0 equiv) and TMSI (38.9 g, 0.1944 mol, 2.1 equiv) were added under a N atmosphere. The reaction mixture was stirred at 0 °C for 1 h, and iodine (35.3 g, 0.277 mol, 3.0 equiv) was added, and the mixture was stirred for an additional 1 h at 0 °C. The reaction mixture was diluted with HO (150 mL) and extracted with DCM (300 mL). The combined organic layers were washed with aqueous sodium thiosulfate (100 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was washed with MeOH to give the title compound 64 (15 g, 0.05208 mol, 56%) as a white solid. LCMS (Method 3): m / z 289.17 [M+H] + .

[0313] Step 2. 7-Azido-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (Compound 65). To a stirred solution of 7-iodo-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one 64 (14.5 g, 0.0503 mol, 1.0 equiv.) in DMF (150 mL), NaN (26.18 g, 0.4027 mol, 8.0 equiv.) was added under a N atmosphere, and the reaction was stirred at room temperature for 16 h. Subsequently, the reaction was diluted with HO (200 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (100 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by CHCl3 (eluent: n-hexane / EtOAc, 20 / 80). V / V ) to give the title compound 65 (8 g, 0.0392 mol, 78.2%) as a white solid. LCMS (Method 3): m / z 204.13 [M+H] + .

[0314] Step 3. 7-Amino-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (compound 66). To a stirred solution of 7-azido-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one 65 (7.9 g, 0.0389 mol, 1.0 equiv.) in EtOH (80 mL), 10% Pd / C (1.5 g, 50% humidity) was added, and the reaction was stirred at room temperature for 12 h under a H atmosphere (balloon) (TLC monitoring). The catalyst was filtered off through a Celite bed, the Celite cake was washed with EtOH (50 mL), and the filtrate was concentrated under reduced pressure to give the title compound 66 (6.5 g, 0.0367 mol, 95%) as a white solid. LCMS (method 3): m / z 178.17[M+H] + .

[0315] Step 4. tert-Butyl (8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 67). To a stirred solution of 7-amino-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one 66 (6.4 g, 0.0367 mol, 1.0 equiv.) in DCM (70 mL), TEA (11.12 g, 0.1101 mol, 3.0 equiv.) was added under N atmosphere, and the resulting mixture was stirred for 10 min. Subsequently, BocO (8.8 g, 0.0403 mol, 1.1 equiv.) was added, and the reaction was stirred at room temperature overnight (TLC control), then diluted with HO (100 mL) and extracted with DCM (300 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by CC (eluent: n-hexane / EtOAc, 20 / 80 V / V ) to give the title compound 67 (9 g, 0.0324 mol, 90%) as a white solid. LCMS (Method 3): m / z 278.23 [M+H] + .

[0316] Step 5. tert-Butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 68). To a stirred solution of tert-butyl (8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 67 (0.5 g, 0.0018 mol, 1.0 equiv.) in DCM (5 mL) under N atmosphere, KCO (0.74 g, 0.0054 mol, 3.0 equiv.) and Br (0.42 g, 0.0027 mol, 1.5 equiv.) were added and stirred at room temperature for 12 h (TLC control). The reaction mixture was diluted with HO (50 mL) and extracted with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by CC (eluent: n-hexane / EtOAc, 20 / 80 V / V ) to give the title compound 68 (0.3 g, 0.0008 mol, 46.87%) as a white solid. LCMS (Method 3): m / z 356.07 [M+H] + .

[0317] Step 6. tert-Butyl (E)-(3-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 69). In a 20 mL vial flask, N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (0.709 g, 0.003098 mol, 1.1 equiv.), tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (1.0 g, 0.002816 mol, 1.0 equiv.), DIPEA (2.9 g, 0.02253 mol, 8.0 equiv.), and a CH3CH2CN:DMF mixture (8:2) were added. V / V) (20 mL) were charged successively. Nitrogen was bubbled through the reaction mixture for 10 min. Pd(OAc)2 (0.063 g, 0.0002816 mol, 0.1 eq) and tri(o-tolyl)phosphine (0.176 g, 0.000563 mol, 0.2 eq) were added and nitrogen was bubbled through for an additional 5 min. The reaction vial was sealed and heated at 100 °C overnight (16 h). The crude reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (2 x 50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was purified by CC purification (eluent: DCM / MeOH, 96 / 4 V / V ) The desired molecule 69 was obtained as a yellow solid (0.9 g, 0.001783 mol, 63.4%) (racemic mixture). LCMS (Method 3): m / z 509.44 [M+H] + .

[0318] Step 7. tert-Butyl (S,E)-(3-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 70) was obtained by chiral separation of 0.9 g of racemic tert-butyl (E)-(3-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 69). The title product 70 was obtained as a yellowish solid (0.35 g, Peak 1). LCMS (method 3): m / z 505.33[M+H] + . Chiral Method Separation: Column name: Chiralpak IC (4.6 x 250) mm, 5μ. Mobile phase: 0.1% DEA in hexane / EtOH = 10 / 90 (v / v). Flow rate: 1.0 mL / min. Flow mode: isocratic. Temperature: ambient.

[0319] Step 8. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide hydrochloride (Compound 71). To a stirred solution of tert-butyl (S,E)-(3-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 70 (0.35 g, 0.00069 mol, 1.0 equiv) in DCM (5 mL) was added 2 M HCl in EtO (5 mL) dropwise at 0 °C. The reaction mixture was allowed to warm gradually from 0° C. to room temperature over 2 h, then EtO (5 mL) was added, resulting in the formation of a precipitate. The solvent was decanted, and the precipitate was triturated with diethyl ether (2×5 mL) to give the title compound 71 (0.3 g, 0.00068 mol, 98.36%) as a white solid. LCMS (Method 3): m / z 405.24 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.90 (s, 1H), 8.64-8.60 (m, 1H), 8.34-8.24 (m, 4H), 7.57-7.22 (m, 6H), 5.01-4.80 (2H), 3.86 (bs, 2H), 3.20-2.93 (m, 3H), 2.80-2.67 (m, 2H), 2.27 (s, 3H), 2.21-2.18 (m, 1H). The stereochemistry for compound 71 was arbitrarily attributed and subsequently confirmed by co-crystallization.

[0320] Example 8 Synthesis of (E)-3-((S)-7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((4-(((1r,4r)-4-aminocyclohexyl)oxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide bis(2,2,2-trifluoroacetate) (Compound 86) General synthetic scheme [ka] Step 1. tert-Butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate (Compound 73). Dioxane:water mixture (1:1 V / V To a stirred solution of (1s,4s)-4-aminocyclohexan-1-ol 72 (1.0 g, 0.0086 mol, 1.0 equiv) in HCl (20 mL) was added NaOH (1.39 g, 0.0347 mol, 4.0 equiv) at 0° C. To this, BocO (2.76 g, 0.0129 mol, 1.5 equiv) was added dropwise, and the reaction mixture was stirred from 0° C. to room temperature over 16 h (TLC monitoring). Note: The same reaction was carried out on a 1.0 g scale using (1s,4s)-4-aminocyclohexan-1-ol 72. Both batches were combined, diluted with water (100 mL), extracted with EtOAc (2×100 mL), dried (Na 2 SO 4 ), filtered and evaporated to dryness to afford the title intermediate 73 (3.5 g, 0.01627 mol, 93.8%) as an off-white solid. 1 H NMR (CDCl3, 400MHz): δ(ppm): 6.68(d,J=6.84Hz, 1H), 4.27(s,1H), 3.66(s,1H), 3.22(s,1H), 1.58-1.49(m,4H), 1.42-1.36(m,4H), 1.36(s,9H).

[0321] Step 2. (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (compound 74). To a stirred solution of tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate 73 (2.0 g, 0.093 mol, 1.0 equiv) in DCM (20 mL) was added TEA (3.74 g, 0.0372 mol, 4.0 equiv). Subsequently, mesyl chloride (1.58 g, 0.0139 mol, 1.5 equiv) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water (200 mL), extracted with DCM (2 × 100 mL), dried (NaSO), filtered, and evaporated to give crude product 74 (2.8 g) as an off-white solid, which was carried on to the next step. 1H NMR (CDCl3, 400MHz): δ (ppm): 4.88 (bs, 1H), 4.46 (bs, 1H), 3.52 (bs, 1H), 3.01 (s, 3H), 2 .06-2.02(m,2H), 1.85-1.82(m,2H), 1.76-1.69(m,2H), 1.60-1.56(m,2H), 1.44(s,9H).

[0322] Step 3. Methyl 2-(2-acetyl-3-hydroxyphenoxy)acetate (Compound 76). To a stirred solution of KCO (7.26 g, 0.052 mol, 1.6 equiv) in acetone (50 mL) was added 1-(2,6-dihydroxyphenyl)ethan-1-one 75 (5.0 g, 0.03 mol, 1 equiv). To this solution was then added methyl bromoacetate (5.03 g, 0.03 mol, 1.0 equiv), and the reaction mixture was heated at 60 °C for 0.5 h. Note: The same reaction was carried out with 20.0 g of starting material (1-(2,6-dihydroxyphenyl)ethan-1-one) 75 and both batches were mixed together with workup and purification. After completion of the reaction, it was filtered through a sintered funnel and washed with acetone (500 mL). The filtrate was concentrated under reduced pressure to give the title compound 76 as a brown oil with 86.16% purity (40 g, crude). This material was used in the next step without further purification. LCMS (Method 3): m / z 225.26 [M+H] + .

[0323] Step 4. Methyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (compound 77). To a cooled (0 °C) solution of methyl 2-(2-acetyl-3-hydroxyphenoxy)acetate 76 (36.0 g, 0.16 mol, 1.0 equiv.) in methanol (300 mL) was added MeONa (13.0 g, 0.24 mol, 1.5 equiv.). The reaction mixture was heated at 60 °C for 2 h. After completion of the reaction, it was concentrated under reduced pressure. The crude product was diluted with water (300 mL), extracted with EtOAc (500 mL), dried (Na2SO4), filtered, and evaporated to give the title compound 77 (14.0 g, 0.067 mol, 42%) as an off-white solid. LCMS (Method 3): m / z 205.02 [M−H] - .

[0324] Step 5. 4-Hydroxy-3-methylbenzofuran-2-carboxylic acid (compound 78). To a stirred solution of methyl 4-hydroxy-3-methylbenzofuran-2-carboxylate 77 (1.0 g, 0.0048 mol, 1 equiv.) in MeOH (10 mL) and HO (10 mL) was added NaOH (1.53 g, 0.038 mol, 8.0 equiv.). The reaction was stirred at room temperature for 18 h. Note: The same reaction was carried out on a 13.0 g scale of starting material (methyl 4-hydroxy-3-methylbenzofuran-2-carboxylate) 77 and both batches were mixed together with workup and purification. The reaction mixture was cooled to 10° C., the pH adjusted to about 2 with 1N HCl (20 mL), extracted with EtOAc (300 mL), dried (NaSO), filtered and evaporated to give the title compound 78 (13.0 g, 0.0677 mol, quantitative) as an off-white solid. LCMS (Method 3): m / z: 190.95 [M−H] - .

[0325] Step 6. 4-Hydroxy-N,3-dimethylbenzofuran-2-carboxamide (compound 79). To a stirred solution of 4-hydroxy-3-methylbenzofuran-2-carboxylic acid 78 (0.5 g, 0.0026 mol) in DMF (10 mL) was added EDCI (0.74 g, 0.0039 mol, 1.5 equiv.), HOBt (0.52 g, 0.0039 mol, 1.5 equiv.), DIPEA (1.0 g, 0.0078 mol, 3.0 equiv.) and methylamine . HCl (0.26 g, 0.0039 mol, 1.5 eq) was added and the reaction was heated at 60° C. overnight. Note: The same reaction was carried out with 12.5 g of starting material (4-hydroxy-3-methylbenzofuran-2-carboxylic acid) 78 and both batches were mixed together with workup and purification. The reaction mixture was diluted with water (500 mL), extracted with EtOAc (300 mL), dried (Na2SO4), filtered and evaporated to give the title compound 79 (9.3 g, 0.045 mol, 67%) as a pale yellow solid. LCMS (method 3): m / z:205.96[M+H] + .

[0326] Step 7. 3-Methyl-2-((methylamino)methyl)benzofuran-4-ol (Compound 80). To a cooled (0 °C) solution of 4-hydroxy-N,3-dimethylbenzofuran-2-carboxamide 79 (1.0 g, 0.0048 mol) in DCM (20 mL) was added TfO (2.75 g, 0.0097 mol, 2 equiv.) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. NaBH (0.72 g, 0.019 mol, 4 equiv.) was added to the reaction mixture in one portion. THF (10 mL) was added dropwise to the mixture and stirred overnight at 0 °C until room temperature. Note: The same reaction was carried out with 7.0 g of starting material (4-hydroxy-N,3-dimethylbenzofuran-2-carboxamide) 79 and both batches were mixed together with workup and purification. After the addition was complete, the reaction mixture was poured onto crushed ice (500 mL), neutralized with NaHCO, extracted with EtOAc (300 mL), dried (NaSO), filtered and evaporated to give the title compound 80 (8.0 g, crude) as a brown oil. LCMS (Method 3): m / z 161.22 [M-30] + .

[0327] Step 8. 3-Methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl acrylate (Compound 81). To a solution of 3-methyl-2-((methylamino)methyl)benzofuran-4-ol 80 (1.1 g, 0.0057 mol) in THF (5 mL) was added 3N NaOH (5 mL). The reaction mixture was cooled to 0 °C. Acryloyl chloride (0.67 g, 0.0074 mol, 1.0 equiv.) was added dropwise to the reaction mixture and allowed to stir at 0 °C for 0.5 h. After completion of the reaction, it was diluted with HO (150 mL), extracted with EtOAc (100 mL), dried (NaSO), filtered, and evaporated to give the title compound 81 (1.1 g, crude) as a brown oil. LCMS (Method 3): m / z: 300.3 [M+H] + .

[0328] Step 9. N-((4-hydroxy-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide (Compound 82). To a solution of 3-methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl acrylate 81 (1.1 g, 0.0036 mol) in THF (5 mL) was added 3N NaOH (5 mL). The reaction mixture was allowed to stir at room temperature for 1 hour. After completion of the reaction, it was diluted with HO (100 mL), extracted with EtOAc (100 mL), dried (NaSO), filtered and evaporated to give the crude product, which was purified by CC (eluent: n-hexane / EtOAc, 70 / 30). V / V ) to give the title compound 82 (0.5 g, 0.002 mol, 55%) as an off-white solid. LCMS (Method 3): m / z 246.21 [M+H] + .

[0329] Step 10. tert-Butyl ((1r,4r)-4-((3-methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl)oxy)cyclohexyl)carbamate (Compound 83). To a stirred solution of N-((4-hydroxy-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 82 (0.025 g, 0.000102 mol, 1.0 equiv.) and KCO (0.138 g, 0.00102 mol, 10.0 equiv.) in MeCN (1.0 mL), (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate 74 (0.119 g, 0.000408 mol, 4.0 equiv.) in MeCN (2 mL) was added portionwise over a period of 2 h with heating at 100 °C, and the reaction mixture was further heated at 100 °C for 16 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Note: The same reaction was carried out using 0.275 g of starting material N-((4-hydroxy-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 82. Both batches were combined and the crude mixture was purified by CC (silica gel, n-hexane / EtOAc, 80 / 20 V / V ) to give the title compound 83 (0.1 g, 0.000226 mol, 18.5%) as an off-white solid. LCMS (Method 3): m / z 443.47 [M+H] + .

[0330] Step 11. tert-Butyl ((1r,4r)-4-((2-(((E)-3-(7-((tert-butoxycarbonyl)amino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methylacrylamido)methyl)-3-methylbenzofuran-4-yl)oxy)cyclohexyl)carbamate (Compound 84). A 20 mL vial flask was charged with tert-butyl ((1r,4r)-4-((3-methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl)oxy)cyclohexyl)carbamate 83 (0.4 g, 0.000905 mol, 1.0 equiv.), tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (0.32 g, 0.000905 mol, 1.0 equiv.), DIPEA (0.929 g, 0.00724 mol, 8.0 equiv.), and a mixture of CH3CH2CN:DMF (8:2). V / V ) (10 mL) were charged sequentially. Nitrogen was bubbled through the reaction mixture for 10 min, then Pd(OAc) (0.02 g, 0.0000905 mol, 0.1 equiv) and tri(o-tolyl)phosphine (0.055 g, 0.000181 mol, 0.2 equiv) were added, and nitrogen was bubbled through for another 5 min. The reaction vial was sealed and heated at 100 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with water (25 mL), extracted with EtOAc (2 × 5 mL), dried (Na SO ), filtered, and concentrated under reduced pressure to give the crude product, which was further purified by CC (eluent: EtOAc). The title compound 84 (0.24 g, 0.000334 mol, 37%) was obtained as an off-white solid (racemic mixture). LCMS (method 3): m / z 718.71[M+H] + .

[0331] Step 12. tert-Butyl ((1r,4r)-4-((2-(((E)-3-((S)-7-((tert-butoxycarbonyl)amino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methylacrylamido)methyl)-3-methylbenzofuran-4-yl)oxy)cyclohexyl)carbamate (Compound 85) was prepared by dissolving 0.24 g of The title product 85 was obtained by chiral separation of racemic tert-butyl ((1r,4r)-4-((2-(((E)-3-(7-((tert-butoxycarbonyl)amino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methylacrylamido)methyl)-3-methylbenzofuran-4-yl)oxy)cyclohexyl)carbamate (compound 84). The title product 85 was obtained as a yellowish solid (0.075 g, peak-1). LCMS (Method 3): m / z 718.65 [M+H] + . Chiral Method Separation: Column name: Chiralpak IC (4.6 x 250) mm, 5μ. Mobile phase: 0.1% DEA in hexane / EtOH = 35 / 65 (v / v). Flow rate: 1.0 mL / min. Flow mode: isocratic. Temperature: ambient.

[0332] Step 13. (E)-3-((S)-7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((4-(((1r,4r)-4-aminocyclohexyl)oxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide bis(2,2,2-trifluoroacetate) (Compound 86). To a stirred solution of tert-butyl ((1r,4r)-4-((2-(((E)-3-((S)-7-((tert-butoxycarbonyl)amino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methylacrylamido)methyl)-3-methylbenzofuran-4-yl)oxy)cyclohexyl)carbamate 85 (0.07 g, 0.0000975 mol, 1.0 equiv) in DCM (2 mL) was added 2 M HCl in EtO (1.0 mL) dropwise at 0 °C. The reaction mixture was stirred for 16 hours (0° C. to room temperature) and then concentrated under reduced pressure to give a crude residue (0.1 g), which was purified by preparative HPLC to give the title compound 86 (0.017 g, 0.0000228 mol, 29.8%) as an off-white solid. LCMS (Method 3): m / z 518.42 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 10.93 (s, 1H), 8.65-8.60 (m, 1H), 8.24-8.13 (m,4H), 7.84-7.81(m,3H), 7.58-7.50(m,1H), 7.32-7.00(m,3H), 6.84-6.82 (m, 1H), 4.98-4.73 (2H), 4.43-4.35 (m, 1H), 3.92-3.88 (m, 1H), 3.17-2.87 (m, 5H), 2.84-2.74 (m, 2H), 2.36 (s, 3H), 2.22-1.94 (m, 5H), 1.55-1.46 (m, 4H). The stereochemistry for compound 86 was arbitrarily assigned.

[0333] Example 9. Synthesis of (E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 2,2,2-trifluoroacetate (Compound 92) General synthetic scheme [ka] Step 1. 7-Chloro-N,3-dimethylbenzofuran-2-carboxamide (Compound 88). To a stirred solution of 7-chloro-3-methylbenzofuran-2-carboxylic acid 87 (2.0 g, 9.52 mmol, 1.0 equiv) in DCM (20 mL) was added EtN (3.3 mL, 23.8 mmol, 2.5 equiv) and 2 M MeNH in THF (12 mL, 23.80 mmol, 2.5 equiv) at 0 °C. To this reaction mixture was added T3P (50 wt % in ethyl acetate) (2.3 mL, 14.28 mmol, 1.5 equiv), and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (TLC), the resulting mixture was diluted with DCM (20 mL), washed with H2O (2 x 20 mL), followed by brine solution (1 x 20 mL), then dried (Na2SO4), filtered, evaporated, and the crude residue was purified by flash CC on silica gel (PE / EtOAc, 95:5 V / V ) to give the final product 88 as a light brown solid in 76% yield (1.6 g, 7.17 mmol). 1 H NMR (400MHz, DMSO-d6)δ:8.43-8.40(m,1H), 7.72-7.70(m,1H), 7.57-7.55(m,1H), 7.36-7.32(m,1H), 2.81(s,3H), 2.52(s,3H).LCMS:m / z 224.3[M+H] + .

[0334] Step 2. 1-(7-Chloro-3-methylbenzofuran-2-yl)-N-methylmethanamine (Compound 89). 7-Chloro-N,3-dimethylbenzofuran-2-carboxamide 88 (1.6 g, 7.17 mmol, 1.0 equiv.) was suspended in dry THF (20 mL) and cooled in an ice bath. 2 M BMS complex in THF (5.38 mL, 10.76 mmol, 1.5 equiv.) was added dropwise to the reaction mixture and refluxed for 16 h. The reaction was quenched with MeOH (20 mL) while cooling and then refluxed for an additional 1 h. The crude reaction mixture was concentrated and purified by CC (silica gel, DCM / MeOH, 95:5 V / V ) to give the title compound 89 as a pale yellow solid. LCMS (Method 4): m / z 210.3 [M+H] + .

[0335] Step 3. N-((7-chloro-3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 90). To a stirred solution of 1-(7-chloro-3-methylbenzofuran-2-yl)-N-methylmethanamine 89 (200 mg, 0.9569 mmol, 1.0 equiv) in dry DCM (10 mL) was added EtN (0.154 mL, 1.148 mmol, 1.2 equiv) followed by acryloyl chloride (0.092 mL, 1.148 mmol, 1.2 equiv) under nitrogen at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction was then diluted with DCM and washed with 10% NaHCO and brine. The organic layer was separated, dried (Na2SO4), filtered and concentrated to give the crude product, which was purified by flash CC on silica using 20% ​​AcOEt / PE as eluent to give the title compound 90 as a brown gummy liquid. Yield 55% (150 mg, 0.60 mmol). LCMS (Method 4): m / z 250.2 [M+H] + .

[0336] Step 4. tert-Butyl (E)-(3-(3-(((7-chloro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 91). A stirred solution of tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (150 mg, 0.42 mmol, 1 equiv.) in dry DMF (2 mL) was degassed with nitrogen for 15 min, and then N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 90 (88 mg, 0.33 mmol, 0.8 equiv.), DIPEA (0.23 mL, 1.26 mmol, 3 equiv.), X-Phos (20 mg, 0.042 mmol, 0.1 equiv.), and Pd(OAc) (5 mg, 0.021 mmol, 0.05 equiv.) were added, and the reaction mixture was heated to 100 °C for 2 h. After completion of the reaction (TLC), the reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by column chromatography using 60-70% AcOEt in PE to give the desired product 91 as an off-white solid. Yield 18% (40 mg, 0.074 mmol). LCMS (Method 4): m / z 483.0 [M+H] + tert-butyl group cleavage mass.

[0337] Step 5. (E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 2,2,2-trifluoroacetate (compound 92). To a stirred solution of tert-butyl (E)-(3-(3-(((7-chloro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 91 (40 mg, 0.074 mmol, 1 equiv.) in dry DCM (5 mL) was added 4.5 M HCl in 1,4-dioxane (2 mL) at 0° C., and the reaction mixture was then stirred at room temperature for 2 h. After completion of the reaction (TLC), the resulting mixture was concentrated to give a crude solid, which was purified by preparative HPLC to give the title compound 92 as an off-white solid. Yield 20% (7.5 mg, 0.17 mmol). 1 H NMR (400MHz, DMSO-d6) δ:10.93(s,1H), 8.65-8.62(d,J=12Hz, 1H), 8.23-8.20(m,4H), 7.62-7.56(m,2H), 7.41-7.25(m,3H), 5.05-4.84(rotameric 3.94-3.90(m,1H), 3.24-2.97(rotamer,s,3H), 2.81-2.75(m,2H), 2.51-2.49(m,1H), 2.23(s,3H), 2.20-2.18(m,1H).LCMS (Method 4): m / z 439.3[M+H] + .

[0338] Example 10. Synthesis of (E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide hydrochloride (Compound 94) General synthetic scheme [ka] Step 1. tert-Butyl (E)-(3-(3-(methyl((2-methylbenzofuran-3-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 93). A stirred solution of tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (150 mg, 0.42 mmol, 1 equiv.) in DMF (2 mL) was degassed with nitrogen for 15 min, and then N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide 26 (77 mg, 0.33 mmol, 0.8 equiv.), DIPEA (0.23 mL, 1.26 mmol, 3 equiv.), X-Phos (20 mg, 0.042 mmol, 0.1 equiv.), and Pd(OAc) (5 mg, 0.021 mmol, 0.05 equiv.) were added, and the reaction mixture was heated to 100 °C for 2 h. After completion of the reaction (TLC analysis), the reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was purified by column chromatography using 80-90% AcOEt in PE to give the title compound 93 as an off-white solid. Yield 26% (55 mg, 0.108 mmol). LCMS (Method 4): m / z 505.2 [M+H] + .

[0339] Step 2. (E)-3-(7-Amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide hydrochloride (Compound 94). To a stirred solution of tert-butyl (E)-(3-(3-(methyl((2-methylbenzofuran-3-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 93 (55 mg, 0.108 mmol, 1 equiv.) in DCM (5 mL) was added 4.5 M HCl in 1,4-dioxane (2 mL) at 0° C., and the reaction mixture was then stirred at room temperature for 2 h. After completion of the reaction (TLC), the resulting mixture was concentrated to give a crude solid, which was dissolved in a mixture of Et2O:MeOH:DCM (8.5:0.5:1 V / V ) and then dried under reduced pressure to give the title compound 94 as a pale yellow solid. Yield 34% (15 mg, 0.03 mmol). 1 H NMR (400MHz, DMSO-d6): 10.90(s,1H), 8.65-8.63(d,J=12Hz, 1H), 8.29-8.23(m, 4H), 7.63-7.55(m,2H), 7.48-7.45(m,1H), 7.32-7.15)m, 3H), 4.94-4.73(rotamer ,s,2H), 3.86-3.85(d,J=4Hz, 1H), 3.05-2.88(rotamer,s,3H), 2.79-2.72(m,1H), 2.51-2.50(m,1H), 2.49(s,3H), 2.22-2.17(m,1H).LCMS(Method 4):m / z:405.2[M+H] + .

[0340] Example 11. Synthesis of (E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 95) General synthetic scheme [ka] Step 1. (E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 95). To a stirred solution of tert-butyl (E)-(3-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 69 (91.7 mg, 0.18 mmol, 1 equiv.) in DCM (2 mL), 2 M HCl in EtO (1 mL) was added, and the resulting mixture was stirred for approximately 4 h (TLC control). The reaction was concentrated to dryness and vacuumed for 1 h. The crude product (80 mg) was dissolved in MeOH (5 mL), TEA (0.07 mL, 0.54 mmol, 3 equiv.), paraformaldehyde (27 mg, 0.909 mmol, 5 equiv.), and MP-CNBH3 resin (30 mg) were added, and the reaction mixture was heated to 65 °C for 2 h. After completion of the reaction (TLC), the reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by CC using 2-3% MeOH in DCM to give the title compound 95 as an off-white solid. Yield 20% (16 mg, 0.036 mmol). 1 H NMR (400MHz, DMSO-d6)δ:10.13(s,1H), 8.52-8.48(d,J=16Hz, 1H), 8.15-8.13(d,J=8Hz, 1H), 7.58-7.49(m,3H), 7.29-7.22(m,3H), 5.0 1~4.80 (rotamer, s, 2H), 3.19 (s, 2H), 2.93 (s, 3H), 2.76-2.73 (m, 2H), 2.67-2.63 (m, 1H), 2.27-2.20 (m, 12H).LCMS (Method 4): m / z: 433.3 [M+H] + .

[0341] Example 12. Synthesis of (S,E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 96) General synthetic scheme [ka] Step 1. (S,E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 96). To a stirred solution of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide hydrochloride 71 (30 mg, 0.068 mmol, 1 equiv.) in MeOH (5 mL), TEA (0.03 mL, 0.20 mmol, 3 equiv.), paraformaldehyde (30 mg), and MP-CNBH3 resin (30 mg) were added, and the reaction mixture was heated to 65 °C for 2 h (TLC analysis). The reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by column chromatography using 2-3% MeOH in DCM. The title compound 96 was obtained as a pale pink solid. Yield 22% (7 mg, 0.016 mmol). 1 H NMR (400MHz, DMSO-d6)δ:10.14(s,1H), 8.52-8.49(m,1H), 8.15-8.13(m,1H), 7.58-7.48(m,3H), 7.30-7.24(m,3H), 5.01~4.80( Rotamer, s,2H), 3.19(s,2H), 2.99-2.89(m,2H), 2.77-2.67(m,2H), 2.66-2.62(m,2H), 2.49(s,12H).LCMS (Method 4): m / z:433.3[M+H] + (Note: Under the reaction conditions, the compound racemizes in a ratio of 75:25 (S:R isomers). The stereochemistry for compound 96 has been arbitrarily assigned.

[0342] Example 13 Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (Compound 98) General synthetic scheme [ka] Step 1. tert-Butyl (S,E)-(3-(3-(((7-chloro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 97). The racemic mixture of tert-butyl (E)-(3-(3-(((7-chloro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 91 (85 mg) was passed through a preparative HPLC chiral column to separate both enantiomers. 1st elution fraction (compound 97):t ret = 22.47 min was obtained as an off-white solid (15 mg, 0.02 mmol). LCMS (Method 4): m / z 541.2 [M+H] + . Note: Separation of isomers in the given method yielded pure compounds with good chiral purity. SFC and other methods for chiral separation were also tested, but unfortunately, no clear separation was obtained. Chiral method separation: Mobile phase: n-hexane:EtOH (40:60 V / V 0.1% DEA in HCl. Column: CHIRALPAK IC (250 x 4.6) mm, 5 μm. Flow rate: 1.0 mL / min.

[0343] Step 2. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (compound 98). tert-Butyl (S,E)-(3-(3-(((7-chloro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 97 (15 mg, 0.02 mmol, 1.0 equiv.) was suspended in dry 1,4-dioxane (0.2 mL), and 4 M HCl in 1,4-dioxane (0.2 mL) was added and allowed to stir for 2 hours. After completion of the reaction, the free solvent was decanted, and the crude residue was triturated with EtO to give the pure product 98. Yield 66% (8 mg, 0.018 mmol). 1 H NMR (400MHz, DMSO-d6) δ:10.93(s,1H), 8.66-8.61(m,1H), 8.26-8.22(m,4H), 7.60-7.55(m,2H), 7.36-7.01(m,3H), 5.06-4.84(rotation) Isomer, s, 2H), 3.89 (s, 1H), 3.20-2.96 (rotamer, s, 3H), 2.72-2.70 (m, 2H), 2.46-2.43 (m, 1H), 2.33 (s, 3H), 2.18 (s, 1H).LCMS (Method 4): m / z 439.2[M+H] + Chiral purity: 99.68% (t ret :83.02 min). The stereochemistry for compound 98 was arbitrarily assigned.

[0344] Example 14. Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (Compound 107) General synthetic scheme [ka] Step 1. 2-Fluorophenyl acetate (compound 100). To a solution of 2-fluorophenol 99 (25.0 g, 0.223 mol) in dry DCM (250 mL) at 0 °C, pyridine (19.39 g, 0.245 mol, 1.1 equiv.) was added. Subsequently, acetyl chloride (15.83 g, 0.223 mol, 1.2 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture was diluted with HO (400 mL), extracted with DCM (400 mL), dried (NaSO), filtered, and evaporated to give the crude product, which was purified by CC (silica gel, n-hexane / EtOAc, 95:5 V / V ) to give the title compound 100 (34.4 g, 0.22 mol, 98%) as a pale yellow oil. 1 H NMR (CDCl3, 400MHz): δ (ppm): 7.23-7.10 (m, 4H), 2.34 (s, 3H).

[0345] Step 2. 1-(3-Fluoro-2-hydroxyphenyl)ethan-1-one (Compound 101). A solution of 2-fluorophenyl acetate 100 (34.0 g, 0.2222 mol, 1.0 equiv.) in 1,2-dichlorobenzene (15 mL) was added dropwise to a solution of AlCl (32.62 g, 0.2456 mol, 1.1 equiv.) in 1,2-dichlorobenzene (30 mL). The reaction mixture was heated at 100 °C for 16 h and then cooled to room temperature. The mixture was quenched with 2 M NaOH (40 mL), extracted with DCM (500 mL), and the organic phase was washed with water (50 mL), dried (NaSO), filtered, and evaporated to give the crude material as a 1:1 mixture of regioisomers. The product was purified by CC (silica gel, n-hexane / EtOAc, 90:10 V / V ) to give the title compound 101 (10.10 g, 0.0655 mol, 29.5%) as a yellow sticky liquid. LCMS (Method 3): m / z: 153.14 [M−H] - .

[0346] Step 3. 7-Fluoro-3-methylbenzofuran-2-carbaldehyde (Compound 102). To a stirred solution of 1-(3-fluoro-2-hydroxyphenyl)ethan-1-one 101 (10 g, 0.0649 mol, 1 equiv.) in THF (100 mL) at room temperature, t-BuOK (58.2 g, 0.5197 mol, 8.0 equiv.) was added under a N atmosphere. To this, 1,1-dichloroethene (18.7 g, 0.1948 mol, 3.0 equiv.) was added at 0 °C, and the reaction mixture was stirred at room temperature for 16 h (TLC monitoring). The reaction mixture was diluted with HO (200 mL), extracted with DCM (300 mL), dried (NaSO), filtered, and evaporated to give a crude residue. The residue was further dissolved in DCM (100 mL), then 5M H2SO4 (100 mL) was added, and the reaction mixture was stirred at room temperature overnight (16 h). After completion of the reaction, the resulting mixture was diluted with H2O (200 mL), extracted with DCM (300 mL), dried (Na2SO4), filtered, and evaporated to give the crude product, which was purified by CC (silica gel, n-hexane / EtOAc, 95:5 V / V ) The title aldehyde 102 (4.5 g, 0.0252 mol, 38.9%) was isolated as a yellow solid. 1 H NMR (CDCl3, 400MHz): δ (ppm): 10.07 (s, 1H), 7.47-7.45 (m, 1H), 7.30-7.22 (m, 2H), 2.63 (s, 3H).

[0347] Step 4. 1-(7-Fluoro-3-methylbenzofuran-2-yl)-N-methylmethanamine (Compound 103). To a stirred solution of 7-fluoro-3-methylbenzofuran-2-carbaldehyde 102 (4.0 g, 0.0224 mol, 1 equiv.) in EtOH (40 mL) was slowly added 40% aqueous MeNH (40 mL) under a N atmosphere. The reaction was stirred at room temperature for 18 h, and then the solution was concentrated under reduced pressure. The resulting crude material was redissolved in EtOH (40 mL) under nitrogen, NaBH was added at 0 °C, and the mixture was stirred at room temperature for an additional 18 h (TLC monitoring). The reaction was quenched with water (200 mL), extracted with DCM (400 mL), dried (NaSO), filtered, and evaporated to give the crude product, which was purified by CC (silica gel, DCM / MeOH, 90:10 V / V ) The desired amine 103 (4.1 g, 0.0212 mol, 90.9%) was obtained as a yellow liquid. LCMS (Method 3): m / z: 194.13 [M+H] + .

[0348] Step 5. N-((7-Fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide (Compound 104). To a stirred solution of 1-(7-fluoro-3-methylbenzofuran-2-yl)-N-methylmethanamine 103 (4.3 g, 0.022 mol, 1 equiv.) in DCM (40 mL) at 0 °C was added EtN (4.48 g, 0.0445 mol, 2.0 equiv.) and acryloyl chloride (2.2 g, 0.0245 mol, 1.1 equiv.). The reaction was stirred at 0 °C for 1 h. The reaction was quenched with water (20 mL), extracted with DCM (100 mL), dried (NaSO), filtered, and evaporated to give the crude product, which was purified by CHCl3 (silica gel, n-hexane / EtOAc, 60:40 V / V ) to give the title acrylamide 104 (2.8 g, 0.0113 mol, 51.09%) as a yellow liquid. LCMS (Method 3): m / z: 248.31 [M+H] + .

[0349] Step 6. tert-Butyl (E)-(3-(3-(((7-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 105). A 20 mL vial flask was charged with N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 104 (0.156 g, 0.00067 mol, 1.2 equiv.), tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (0.19 g, 0.00056 mol, 1.0 equiv.), DIPEA (0.58 g, 0.0045 mol, 8.0 equiv.), and a mixture of CH3CH2CN:DMF (8:2). V / V ) (5 mL). Nitrogen was bubbled through the reaction mixture for 10 minutes. Pd(OAc)2 (0.013 g, 0.000056 mol, 0.1 equiv.) and tri(o-tolyl)phosphine (0.035 g, 0.00011 mol, 0.2 equiv.) were added, and nitrogen was bubbled through the mixture for another 5 minutes. The reaction vial was sealed and stirred at 100 °C for 16 hours. The resulting mixture was cooled to room temperature, filtered through a bed of Celite, and the cake was washed with EtOAc (50 mL). The filtrate was washed with water (20 mL), brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by CC (eluent: DCM / MeOH, 98 / 2 V / V ) to give the expected molecule 105 (0.1 g) as an off-white solid. This product was further separated into pure enantiomers by chiral preparative HPLC. LCMS (Method 3): m / z 523.41 [M+H] + .

[0350] Step 7. tert-Butyl (S,E)-(3-(3-(((7-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 106). The racemic mixture of tert-butyl (E)-(3-(3-(((7-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 105 (0.1 g) was subjected to chiral HPLC separation to separate both enantiomers. 1st elution fraction (compound 106):t ret = 18.03 min (0.03 g). LCMS (Method 3): m / z 523.40 [M+H] + . Chiral Method Separation: Column name: Chiralpak IC (4.6 x 250) mm, 5μ. Mobile phase: 0.1% DEA in hexane / EtOH = 40 / 60 (v / v). Flow rate: 1.0 mL / min. Flow mode: isocratic. Temperature: ambient.

[0351] Step 8. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (Compound 107). To a stirred solution of tert-butyl (S,E)-(3-(3-(((7-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 106 (0.025 g, 0.000047 mol) in DCM (0.5 mL) was added 2 M HCl in EtO (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred from 0° C. to room temperature over 1 h, then cold Et2O (5 mL) was added to precipitate the product, the solvent was decanted, and the product was dried. Title compound 107 (0.017 g, 0.000037 mol, 80%) was isolated as an off-white solid. Chiral HPLC purity: 99.72%. LCMS (Method 3): m / z 423.46 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.92 (s, 1H), 8.65-8.61 (m, 1H), 8.28-8.24 (m, 4H), 7.64-7.17 (m, 5H), 5.05-4.82 (2H), 3.88 (s, 1H), 3.22-2.94 (3H), 2.81-2.74 (m, 2H), 2.59-2.53 (m, 1H), 2.28 (s, 3H), 2.23-2.18 (s, 1H). The stereochemistry for compound 107 was arbitrarily assigned.

[0352] Example 15. Synthesis of (S,E)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methyl-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide (Compound 113) General synthetic scheme [ka] 3-Bromo-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (compound 108) was prepared as described in AFFINIUM PHARMACEUTICALS, INC. - WO2007 / 67416, 2007, A2.

[0353] Step 1. 3-Bromo-7-iodo-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (Compound 109). To a stirred solution of 3-bromo-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one 108 (4.0 g, 0.0167 mol, 1.0 equiv.) in DCM (40 mL) at 0 °C under a N atmosphere, TMEDA (8.16 g, 0.0703 mol, 4.2 equiv.) and trimethylsilyl iodide (7.4 g, 0.0368 mol, 2.2 equiv.) were added, followed by stirring at 0 °C for 1 h. Iodine (7.5 g, 0.0585 mol, 3.5 equiv.) was added. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was diluted with H2O (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with aqueous Na2S2O3 (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was washed with MeOH to give the title compound 109 (4.0 g, 0.0109 mol, 65.3%) as a white solid. LCMS (Method 3): m / z 368.94 [M+H] + .

[0354] Step 2. 3-Bromo-7-morpholino-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (compound 111). To a stirred solution of 3-bromo-7-iodo-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one 109 (0.35 g, 0.000956 mol, 1.0 equiv.) in ACN (5 mL) under a nitrogen atmosphere, KCO (0.264 g, 0.00191 mol, 2.0 equiv.) and morpholine 110 (7.4 g, 0.00114 mol, 1.2 equiv.) were added, and the reaction mixture was heated at 80 °C for 12 h. The reaction was diluted with HO (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried (NaSO), filtered, and concentrated under reduced pressure to give the crude material, which was recrystallized from a mixture of MeOH (5 mL) and DCM (5 mL) to give the expected 111 (0.13 g, 0.000398 mol, 41.8%) as an off-white solid. LCMS (method 3): m / z 328.2[M+H] + .

[0355] Step 3. (E)-N-((7-fluorobenzofuran-2-yl)methyl)-N-methyl-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide (compound 112). In a 20 mL vial flask, 3-bromo-7-morpholino-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one 111 (0.12 g, 0.000368 mol, 1.0 equiv.), N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 104 (0.1 g, 0.000404 mol, 1.1 equiv.), DIPEA (0.38 g, 0.00294 mol, 8.0 equiv.), and a mixture of propionitrile:DMF (4:1) were added. V / V) (5 mL) were charged sequentially. Dry nitrogen was bubbled through the reaction mixture for 10 min. Subsequently, Pd(OAc) (0.008 g, 0.0000368 mol, 0.1 equiv.) and tri(o-tolyl)phosphine (0.023 g, 0.0000736 mol, 0.2 equiv.) were added, and nitrogen was bubbled through for another 5 min. The reaction vial was sealed and stirred at 100 °C for 16 h. It was then cooled to room temperature, diluted with HO (50 mL), extracted with EtOAc (2 × 50 mL), dried (NaSO), filtered, and concentrated to dryness. The crude product was recrystallized from a mixture of MeOH (5 mL) and DCM (5 mL). The title compound 112 (0.05 g, 0.000101 mol, 27.6%) was obtained as an off-white solid. LCMS (method 3): m / z 493.58[M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 10.17 (bs, 1H), 8.52-8.49 (m, 1H), 8.11 (s, 1H), 7.56-7.16 (m, 5 H), 5.04-4.82(2H), 3.42-3.36(m,4H), 3.21-2.94(m,5H), 2.80-2.59(m,5H), 2.32-2.19(m,5H).

[0356] Step 4. (S,E)-N-((7-Fluoro-3-methylbenzofuran-2-yl)methyl)-N-methyl-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide (Compound 113). The racemic mixture of E)-N-((7-fluorobenzofuran-2-yl)methyl)-N-methyl-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide 112 (22 mg) was subjected to chiral separation to separate both enantiomers. The pure fraction of the second enantiomer was collected and concentrated. The product was then slurried in diethyl ether and filtered by centrifugation twice, followed by drying under reduced pressure at 25°C. The second enantiomer 113 was obtained as a white powder (m = 6.26 mg; chiral purity: 99.4%). LCMS (Method 3): m / z 493.3 [M+H]+ The stereochemistry for compound 113 was arbitrarily assigned. Chiral method separation: Apparatus: Isolera (Biotage). Column: Chiralpak IA (20 μm; glass column; 250 mm × 25 mm). Eluent: acetonitrile / THF (8 / 2). Flow rate: 40 mL / min. Temperature: 25°C. Run time: 18 min.

[0357] Example 16 Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzo[b]thiophen-2-yl)methyl)acrylamide hydrochloride (Compound 119) General synthetic scheme [ka] Step 1. N-Methyl-1-(3-methylbenzo[b]thiophen-2-yl)methanamine (Compound 115). To a mixture of 3-methylbenzo[b]thiophene-2-carbaldehyde 114 (1.0 g, 0.00568 mol, 1.0 equiv.) in MeOH (20 mL) was added 40% aqueous MeNH (20 mL) under N atmosphere. The reaction was stirred at room temperature for 16 h, and the solution was concentrated under reduced pressure. The resulting residue was redissolved in EtOH (20 mL), and NaBH was added at 0 °C under N. The mixture was stirred at room temperature for 1 h (TLC control), then quenched with ice-water (50 mL), extracted with EtOAc (2 × 50 mL), dried (NaSO), filtered, and evaporated. The crude amine was purified by CC (silica gel, DCM / MeOH, 95:5 V / V ) to give the title compound 115 (0.9 g, 0.004705 mol, 83%) as a colorless viscous oil. LCMS (Method 3): m / z: 191.93 [M+H] + .

[0358] Step 2. N-Methyl-N-((3-methylbenzo[b]thiophen-2-yl)methyl)acrylamide (Compound 116). To a stirred solution of N-methyl-1-(3-methylbenzo[b]thiophen-2-yl)methanamine 115 (0.9 g, 0.0047 mol, 1.0 equiv.) in DCM (20 mL) was added EtN (1.42 g, 0.0141 mol, 3.0 equiv.) and acryloyl chloride (0.511 g, 0.0056 mol, 1.2 equiv.) at 0 °C. The reaction was stirred and allowed to warm to room temperature over 30 min, then poured into water (50 mL), extracted with DCM (2 × 50 mL), dried (NaSO), filtered, and evaporated. The product was purified by CHCl3 (silica gel, n-hexane / EtOAc, 70:30 V / V ) The title acrylamide 116 (0.7 g, 0.00285 mol, 60.5%) was obtained as a colorless viscous oil. LCMS (Method 3): m / z: 245.96 [M+H] + .

[0359] Step 3. tert-Butyl (E)-(3-(3-(methyl((3-methylbenzo[b]thiophen-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 117). Propionitrile:DMF mixture (4:1) V / VTo a solution of N-methyl-N-((3-methylbenzo[b]thiophen-2-yl)methyl)acrylamide 116 (0.2 g, 0.000816 mol, 1.0 equiv.) and tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (0.29 g, 0.000816 mol, 1.0 equiv.) in 10 mL of HCl (HCl, 10 mL), DIPEA (0.84 g, 0.00653 mol, 8.0 equiv.) was added, and the resulting mixture was purged with N for 10 min. Subsequently, Pd(OAc) (0.018 g, 0.0000816 mol, 0.1 equiv.) and tri(o-tolyl)phosphine (0.049 g, 0.000163 mol, 0.2 equiv.) were added. The reaction was stirred and heated at 100° C. for 16 h. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure to give the crude product, which was purified by CC (silica gel, n-hexane / EtOAc, 20:80 V / V ) to give the title compound 117 (0.15 g, 0.000288 mol, 35.29%) as a white solid. LCMS (Method 3): m / z: 521.47 [M+H] + .

[0360] Step 4. tert-Butyl (S,E)-(3-(3-(methyl((3-methylbenzo[b]thiophen-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 118). The racemic mixture of tert-butyl (E)-(3-(3-(methyl((3-methylbenzo[b]thiophen-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 117 (0.15 g) was subjected to chiral HPLC separation to separate both enantiomers. The pure fractions of the first enantiomer 118 (peak-1) were collected, concentrated under reduced pressure and dried (0.05 g). ret=17.88 minutes. LCMS (method 3): m / z 521.49[M+H] + . Chiral method separation: Column name: Chiralpak IC (4.6 x 250) mm, 5 μm. Mobile phase: 0.1% DEA in hexane / EtOH = 40 / 60 ( V / V ). Flow rate: 1.0 mL / min. Flow mode: Isocratic. Temperature: Ambient.

[0361] Step 5. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzo[b]thiophen-2-yl)methyl)acrylamide hydrochloride (compound 119). To a stirred solution of enantiomerically pure tert-butyl (S,E)-(3-(3-(methyl((3-methylbenzo[b]thiophen-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 118 (0.045 g, 0.0000864 mol, 1.0 equiv) in DCM (2.0 mL) was added 2 M HCl in ether (0.5 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 1.5 h. The organic phase (DCM) was decanted, the residue was triturated with ether (2 × 5 mL), and the desired product was collected by filtration. The title target 119 (0.021 g, 0.0000459 mol, 53.8%) was produced as an off-white solid. LCMS (Method 3): m / z 421.44 [M+H] + . 1H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.91 (s, 1H), 8.63-8.62 (m, 1H), 8.30-8.23 (m, 4H), 7.87 (d, J = 7.96 Hz, 1H), 7.74 (d, J = 7.76 Hz, 1H), 7.61-7.31 (m, 4H), 5.13-4.89 (2H), 3.86 (bs, 1H), 3.17-2.94 (3H), 2.81-2.74 (m, 2H), 2.55-2.53 (m, 1H), 2.42 (s, 3H), 2.20-2.18 (m, 1H). Chiral purity: 99.92%. The stereochemistry for compound 119 was arbitrarily assigned.

[0362] Example 17. Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((4-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (Compound 130) General synthetic scheme [ka] Step 1. tert-Butyl 2-(2-acetyl-3-fluorophenoxy)acetate (Compound 122). To a solution of commercially available 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one 120 (2.7 g, 0.0175 mol, 1.0 equiv.) in DMF (30 mL) was added K2CO3 (6.03 g, 0.0437 mol, 2.5 equiv.). To this was added tert-butyl 2-bromoacetate 121 (4.1 g, 0.021 mol, 1.2 equiv.) dropwise, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (100 mL), dried (Na2SO4), filtered, and evaporated to give the crude product, which was purified by CC (silica gel, n-hexane / EtOAc, 90:10 V / V ) The desired compound 122 (4.6 g, 0.0171 mol, 94.4%) was obtained as a brown oil. LCMS (Method 3): m / z: 269.26 [M+H] + .

[0363] Step 2. tert-Butyl 4-fluoro-3-methylbenzofuran-2-carboxylate (compound 123). To a stirred solution of tert-butyl 2-(2-acetyl-3-fluorophenoxy)acetate 122 (4.5 g, 0.017 mol, 1 equiv.) in DMF (40 mL), DBU (5.16 g, 0.034 mol, 2.0 equiv.) was added at room temperature, and the reaction mixture was heated at 110 °C for 1 h. After completion of the reaction, it was diluted with HO (100 mL), extracted with EtOAc (150 mL), dried over NaSO, filtered, and evaporated to give the crude product, which was purified by CHCl3 (silica gel, n-hexane / EtOAc, 90:10 V / V ) The expected intermediate 123 (2.0 g, 0.08 mol, 46.6%) was obtained as a white solid. LCMS (Method 3): m / z: 251.27 [M+H] + .

[0364] Step 3. 4-Fluoro-3-methylbenzofuran-2-carboxylic acid (compound 124). To a stirred solution of tert-butyl 4-fluoro-3-methylbenzofuran-2-carboxylate 123 (1.98 g, 0.00792 mol, 1.0 equiv) in DCM (15 mL) at 0 °C, TFA (1.0 mL) was added dropwise, and the reaction was stirred at 0 °C to room temperature for 12 h. The crude mixture was concentrated to dryness to give the title compound 124 (1.45 g, 0.007468 mol, 94.3%) as a white solid. LCMS (Method 3): m / z: 193.2 [M−H] - .

[0365] Step 4. 4-Fluoro-N,3-dimethylbenzofuran-2-carboxamide (Compound 125). To a stirred solution of 4-fluoro-3-methylbenzofuran-2-carboxylic acid 124 (1.45 g, 0.00746 mol, 1.0 equiv.) in DMF (5 mL) was added EDCI (2.317 g, 0.0149 mol, 2.0 equiv.), HOBt (2.279 g, 0.0149 mol, 2.0 equiv.), DIPEA (0.93 g, 0.0444 mol, 6.0 equiv.), and methylamine HCl (1.01 g, 0.0149 mol, 2.0 equiv.). The reaction was heated at 60 °C overnight. The reaction mixture was then diluted with water (200 mL), extracted with EtOAc (200 mL), dried (Na2SO4), filtered and evaporated to give the crude product, which was purified by flash CC (silica gel, n-hexane / EtOAc, 70:30 V / V ) to give the title compound 125 (1.1 g, 0.053 mol, 73.3%) as a white solid. LCMS (Method 3): m / z: 208.1 [M+H] + .

[0366] Step 5. 1-(4-Fluoro-3-methylbenzofuran-2-yl)-N-methylmethanamine (Compound 126). To a stirred solution of 4-fluoro-N,3-dimethylbenzofuran-2-carboxamide 125 (1.1 g, 0.0053 mol) in THF (15 mL) at 0 °C, 1 M LAH in THF (5.3 mL, 0.0106 mol, 2.0 equiv.) was added dropwise. The reaction mixture was stirred at 0 °C for 16 h to room temperature. After completion of the reaction (TLC control), the resulting mixture was cooled to 0 °C and quenched with 2 N NaOH (5 mL). The crude mixture was filtered through a pad of Celite and washed with THF (25 mL). The filtrate was dried over Na SO , filtered, and evaporated to give the crude product, which was further purified by CC (silica gel, EtOAc). The title compound 126 (0.37 g, 0.0019 mol, 36.2%) was obtained as a colorless oil. 1H NMR (CDCl3, 400MHz): δ(ppm): 7.21-7.11(m,2H), 6.88-6.83(m,1H), 3.83(s,2H), 2.45(s,3H), 2.35(s,3H).

[0367] Step 6. N-((4-Fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide (Compound 127). To a stirred solution of 1-(4-fluoro-3-methylbenzofuran-2-yl)-N-methylmethanamine 126 (0.37 g, 0.00191 mol, 1 equiv.) in DCM (15 mL) at 0 °C was added EtN (0.578 g, 0.0057 mol, 3.0 equiv.) and acryloyl chloride (0.26 g, 0.00287 mol, 1.5 equiv.). The reaction was stirred at 0 °C for 1 h. The resulting mixture was quenched with water (20 mL), extracted with DCM (100 mL), dried (NaSO), filtered, and evaporated to give the crude product, which was purified by CHCl3 (silica gel, n-hexane / EtOAc, 50:50). V / V ) to give the title compound 127 (0.24 g, 0.00097 mol, 50%) as a colorless liquid. LCMS (Method 3): m / z: 248.28 [M+H] + .

[0368] Step 7. tert-Butyl (E)-(3-(3-(((4-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 128). In a 20 mL vial flask, N-((4-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 127 (0.12 g, 0.000485 mol, 1.2 equiv.), tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (0.171 g, 0.000485 mol, 1.0 equiv.), DIPEA (0.5 g, 0.00308 mol, 8 equiv.), and a mixture of CH3CH2CN:DMF (4:1) were added.V / V ) (5 mL) were charged successively. Nitrogen was bubbled through the reaction mixture for 10 min. Pd(OAc)2 (0.011 g, 0.0000485 mol, 0.1 eq) and tri(o-tolyl)phosphine (0.029 g, 0.000097 mol, 0.2 eq) were added to the reaction mixture, and nitrogen was bubbled through it for another 5 min. The reaction vial was sealed and heated at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered through a Celite bed, rinsed with EtOAc (50 mL), and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by CC (silica gel, EtOAc). The desired molecule 128 (0.055 g, 0.0001 mol, 21.7%) was isolated as a white solid. LCMS (Method 3): m / z 523.16 [M+H] + .

[0369] Step 8. tert-Butyl (S,E)-(3-(3-(((4-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 129). The racemic mixture of tert-butyl (E)-(3-(3-(((4-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 128 (0.064 g) was subjected to chiral HPLC separation to isolate both enantiomers. The pure fractions of the first enantiomer (compound 129, peak-1) were collected, concentrated under reduced pressure and dried (0.015 g). ret =10.56 minutes. LCMS (method 3): m / z 523.42[M+H] + . Chiral method separation: Column name: Chiralpak IC (4.6 x 250) mm, 5 μm. Mobile phase: 0.1% DEA in hexane / EtOH = 20 / 80 ( V / V). Flow rate: 1.0 mL / min. Flow mode: Isocratic. Temperature: Ambient.

[0370] Step 9. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((4-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (compound 130). To a stirred solution of tert-butyl (S,E)-(3-(3-(((4-fluoro-3-methylbenzofuran-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 129 (0.015 g, 0.0000287 mol, 1.0 equiv) in DCM (0.5 mL) was added 2 M HCl in ether (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred for 1 h (0 °C to RT), and then cold ether (10 mL) was added to precipitate the HCl salt of 130. The solid was dried under high vacuum to give the title product 130 (0.011 g, 0.00002397 mol, 83.5%) as an off-white solid. LCMS (method 3): m / z 423.17[M+H] +1 H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.92 (s, 1H), 8.64-8.61 (m, 1H), 8.28-8.18 (m, 4H), 7.59-7.01 (m, 4H), 5.01-4.79 (2H), 3.91-3.90 (m, 1H), 3.20-2.92 (3H), 2.84-2.74 (m, 2H), 2.54-2.50 (m, 1H), 2.37 (s, 3H), 2.23-2.09 (m, 1H). The stereochemistry for compound 130 was arbitrarily assigned.

[0371] Example 18. Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)-N-methylacrylamide hydrochloride (Compound 140) General synthetic scheme [ka] Step 1. Methyl 7-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (Compound 133). 1-(2,3-difluorophenyl)ethan-1-one 131 (4.5 g, 0.0288 mol, 1.0 equiv.) and methyl thioglycolate 132 (3.06 g, 0.0288 mol, 1.0 equiv.) were added to a mixture of DBU (8.76 g, 0.0576 mol, 2.0 equiv.) under a N atmosphere at 0 °C. The reaction was stirred at 0 °C for 3 h and then at room temperature for 12 h (TLC monitoring). The reaction was then quenched with water (200 mL), extracted with EtOAc (2 × 200 mL), dried (NaSO), filtered, and evaporated to give the title benzo[b]thiophene 133 (6.4 g, 0.02854 mol, 96.96%) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 7.86 (d, J = 8.0 Hz, 1H), 7.57-7.42 (m, 2H), 3.89 (s, 3H), 2.74 (s, 3H).

[0372] Step 2. (7-Fluoro-3-methylbenzo[b]thiophen-2-yl)methanol (Compound 134). To a stirred solution of methyl 7-fluoro-3-methylbenzo[b]thiophene-2-carboxylate 133 (5.0 g, 0.0223 mol, 1.0 equiv.) in THF (30 mL) at 0 °C was added 2 M LAH in THF (16.7 mL, 0.0334 mol, 1.5 equiv.) dropwise. The reaction was stirred at room temperature for 2 h (TLC), quenched with 2 M NaOH (30 mL), filtered through Celite, and the filter cake was rinsed with EtOAc (2 × 150 mL). The filtrate was washed with brine solution (100 mL), dried (NaSO), filtered, and evaporated to give the title compound 134 (4.0 g, 0.02038 mol, 91.53%) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ(ppm):7.56(d,J=7.92Hz, 1H), 7.43-7.16(m,2H), 4.75(d,J=5.44Hz, 1H), 5.69(t,J=5.56Hz, 2H), 2.31(s,3H).

[0373] Step 3. 7-Fluoro-3-methylbenzo[b]thiophene-2-carbaldehyde (compound 135). To a stirred solution of (7-fluoro-3-methylbenzo[b]thiophen-2-yl)methanol 134 (4.0 g, 0.02038 mol, 1.0 equiv.) in DCM (100 mL) was added Dess-Martin periodinane (25.9 g, 0.0611 mol, 3.0 equiv.). The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water (100 mL), extracted with DCM (2 × 100 mL), dried (NaSO), filtered, and evaporated to give the title compound 135 (3.7 g, 0.01907 mol, 93.67%) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 10.37 (s, 1H), 8.05 (d, J = 7.68Hz, 1H), 7.65-7.47 (m, 2H), 2.82 (s, 3H).

[0374] Step 4. 1-(7-Fluoro-3-methylbenzo[b]thiophen-2-yl)-N-methylmethanamine (Compound 136). To a stirred solution of 7-fluoro-3-methylbenzo[b]thiophene-2-carbaldehyde 135 (3.7 g, 0.01907 mol, 1.0 equiv.) in EtOH (40 mL) was added 40% aqueous MeNH (40 mL). The reaction mixture was stirred at room temperature overnight (18 h), and the solution was concentrated under reduced pressure. The residue was suspended in EtOH (40 mL) under N, and NaBH (3.62 g, 0.09535 mol, 5.0 equiv.) was added dropwise at 0 °C. The reaction was stirred at room temperature for 2 h (TLC control). The reaction was quenched with HO (100 mL), extracted with DCM (2 × 150 mL), dried (NaSO), filtered, and evaporated to dryness. The crude product was purified by CC (silica gel, DCM / MeOH, 96:4 V / V ) to give the desired amine 136 (3.0 g, 0.01433 mol, 75.18%) as a yellow solid. 1H NMR (DMSO-d6, 400MHz): δ (ppm): 7.42 (d, J = 7.92 Hz, 1H), 7.33-7.25 (m, 1H), 7.02-6.97 (m, 1H), 4.01 (s, 2H), 2.36 (s, 3H).

[0375] Step 5. N-((7-Fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)-N-methylacrylamide (Compound 137). To a stirred solution of 1-(7-fluoro-3-methylbenzo[b]thiophen-2-yl)-N-methylmethanamine 136 (3.0 g, 0.01433 mol, 1.0 equiv.) in DCM (30 mL) at 0 °C was added EtN (2.89 g, 0.02866 mol, 2.0 equiv.) and acryloyl chloride (1.42 g, 0.01576 mol, 1.1 equiv.). The reaction was stirred at 0 °C for 2 h, quenched with water (80 mL), extracted with DCM (2 × 100 mL), dried (NaSO), filtered, and evaporated to dryness. The crude product was purified by CHCl3 (silica gel, n-hexane / EtOAc, 75:25 V / V ) to give the title compound 137 (2.3 g, 0.0113 mol, 61%) as a yellow solid. LCMS (Method 3): m / z: 264.10 [M+H] + .

[0376] Step 6. tert-Butyl (E)-(3-(3-(((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 138). A 20 mL vial flask was charged with N-((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)-N-methylacrylamide 137 (0.57 g, 0.0021 mol, 1.1 equiv.), tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (0.7 g, 0.0019 mol, 1.0 equiv.), DIPEA (1.96 g, 0.0152 mol, 8.0 equiv.), and a CH3CH2CN:DMF mixture (8:2). V / V ) (15 mL) were charged sequentially. Nitrogen was bubbled through the reaction mixture for 10 min, and Pd(OAc)2 (0.042 g, 0.00019 mol, 0.1 equiv.) and tri(o-tolyl)phosphine (0.119 g, 0.00038 mol, 0.2 equiv.) were added, and inert gas was bubbled through for another 5 min. The reaction vial was sealed and stirred at 100 °C for 16 h. The reaction was cooled to room temperature, diluted with water (80 mL), and extracted with EtOAc (2 × 100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude product, which was purified by CC (eluent: DCM / MeOH, 95 / 5 V / V ) The title molecule 138 (0.37 g, 0.000686 mol, 34.9%) was prepared as an off-white solid. LCMS (Method 3): m / z 539.45 [M+1] + .

[0377] Step 7. tert-Butyl (S,E)-(3-(3-(((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 139). Racemic tert-butyl (E)-(3-(3-(((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 138 (0.37 g) was subjected to chiral preparative HPLC separation to isolate both enantiomers. The pure fractions of the first enantiomer (compound 139, peak-1) corresponding to the expected product were collected, concentrated under reduced pressure, and dried (0.12 g). ret =10.65 minutes. LCMS (method 3): m / z 539.23[M+H] + Chiral purity: 98.04%. Chiral method separation: Column name: Chiralpak IC (4.6 x 250) mm, 5 μm. Mobile phase: 0.1% DEA in hexane / EtOH = 20 / 80 ( V / V ). Flow rate: 1.0 mL / min. Flow mode: Isocratic. Temperature: Ambient.

[0378] Step 8. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)-N-methylacrylamide hydrochloride (compound 140). To a stirred solution of tert-butyl (S,E)-(3-(3-(((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 139 (0.12 g, 0.0002227 mol, 1.0 equiv) in DCM (2 mL) was added 2 M HCl in EtO (2 mL) dropwise at 0 °C. The reaction mixture was stirred from 0 °C to room temperature over 2 h, then cold EtO (10 mL) was added to the DCM solution and the precipitated product was filtered off, washed with ether (2 × 5 mL), and dried under high vacuum. The final target 140 (0.086 g, 0.000181 mol, 81.9%) was obtained as a white solid. LCMS (Method 3): m / z 439.12 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.92 (s, 1H), 8.63 (s, 1H), 8.26-8.23 (m, 4H), 7.63-7.20 (m, 5H), 5.17-4.90 (2H), 3.89 (bs, 1H), 3.19-2.95 (3H), 2.81-2.74 (m, 2H), 2.44 (s, 3H), 2.24-2.16 (m, 1H). Chiral purity: 95.40%. The stereochemistry for compound 140 was arbitrarily assigned.

[0379] Example 19. Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide hydrochloride (Compound 151) [ka] Step 1. 1-[5-(benzyloxy)-2-hydroxyphenyl]ethan-1-one (compound 142). To a solution of 2',5'-dihydroxyacetophenone 141 (1 equiv., 50 g, 328 mmol) in MeCN (499 mL) was added potassium carbonate (1.5 equiv., 68.1 g, 492 mmol) at room temperature. Benzyl bromide (1.1 equiv., 61.8 g, 43.2 mL, 361 mmol) was then added dropwise, and the reaction mixture was stirred at room temperature for 18 h. The crude reaction mixture was filtered through a Buchner funnel, and the mother liquor was evaporated to dryness. The residue was dissolved in EtOAc (300 mL). The organic layer was washed with water (300 mL), brine (300 mL), dried over sodium sulfate, filtered, and evaporated to dryness. Four successive triturations from diethyl ether afforded the title compound 142 (58.7 g, 74%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ(ppm) 2.63(t,3H,J=1.6Hz), 5.1(s,2H), 6.91(d,1H,J=9.0Hz), 7.25(d,1H,J=8.8Hz, 2.8Hz), 7.4(m,6H), 11.46(s,1H).

[0380] Step 2. 5-(Benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde (Compound 143). To a solution of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethan-1-one 142 (1 equiv., 30 g, 123 mmol) in THF (442 mL) was added dropwise at 0 °C t-BuOK (3.8 equiv., 52.8 g, 470 mmol) followed by 1,1-dichloroethylene (1.4 equiv., 16.8 g, 13.8 mL, 173 mmol) in succession. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was quenched with 1 M aqueous sulfuric acid (100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated to dryness. The residue was dissolved in DCM (300 mL) and 1 M aqueous HSO (70 mL) was added at room temperature. The reaction mixture is then stirred at 50° C. for 18 hours. The reaction mixture is diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers are washed with brine (150 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The residue is diluted with EtO (300 mL) and filtered through a short pad of silica. The solvent is evaporated to dryness to give title compound 143 (33 g, 100%) as a yellow solid. 1 H NMR 400MHz, CDCl3): δ(ppm)2.58(s,3H), 5.12(s,2H), 7.13(s,1H), 7.21(d,1H,J=8.8Hz), 7.38(m,6H), 9.99(s,1H).

[0381] Step 3. {[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]methyl}(methyl)amine (Compound 144). Methylamine (33% in EtOH; 4 equiv., 46.7 g, 61.7 mL, 495 mmol) was added to a solution of 5-(benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde 143 (1 equiv., 33 g, 123 mmol) in DCM (247 mL). The reaction mixture was stirred overnight at room temperature and concentrated to dryness. The residue was taken up in a mixture of DCM (302 mL) and MeOH (75.6 mL), cooled to 0 °C, and sodium borohydride (3 equiv., 14.1 g, 371 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (100 mL). The organic layer is washed with saturated aqueous NaHCO3 (200 mL), brine (200 mL), dried (Na2SO4), filtered and evaporated to dryness. The crude product is purified by chromatography (SiO2 pretreated with Et3N; DCM / MeOH, 100 / 0 to 95 / 5). V / V ) to afford the title compound 144 (14.0 g, 40%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ(ppm)2.19(s,3H), 2.44(s,3H), 3.84(s,2H), 5.1(s,2H), 6.93(dd,1H,J=8.9Hz, 2.6 Hz), 7.01(d,1H,J=2.6Hz), 7.3(d,1H,J=8.7Hz), 7.34(d,1H,J=6.8Hz), 7.4(t,2H,J=7.6Hz), 7.47(m,2H).

[0382] Step 4. 3-Methyl-2-[(methylamino)methyl]-1-benzofuran-5-ol (Compound 145). A solution of {[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]methyl}(methyl)amine 144 (1 equiv., 10.7 g, 37.9 mmol) in a mixture of MeOH (99 mL) and THF (99 mL) is purged and purged with argon (repeat twice). 10% palladium on carbon (10% w / w, 1.07 g) is added. The mixture is purged and purged with argon (repeat twice) and stirred at room temperature for 18 hours. The reaction mixture is filtered through a clarcel and diluted with THF / MeOH (1 / 1 V / V 150 mL), concentrate and dry under reduced pressure to give title compound 145 (7.26 g, 100%) as a brown solid. 1 H NMR (400MHz, DMSO-d6): δ(ppm) 2.1(s,3H), 2.24(s,3H), 3.72(s,2H), 6.71(d,1H,J=8.7Hz), 6.82(s,1H), 7.23(d,1H,J=8.7Hz).

[0383] Step 5. N-((5-hydroxy-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide (Compound 146). A mixture of THF and 2 M NaOH (10 mL, 1:1 V / V To a stirred solution of 3-methyl-2-((methylamino)methyl)benzofuran-5-ol 145 (5.76 g, 0.03012 mol, 1.0 equiv.) in HCl (HClO), acryloyl chloride (3.275 g, 0.03615 mol, 1.2 equiv.) was added dropwise at 0 °C. The reaction was stirred at the same temperature for 30 min (TLC monitoring). Then, the reaction was diluted with HO (100 mL), extracted with EtOAc (2 × 50 mL), dried (NaSO), filtered, and concentrated to dryness. The crude material was dissolved in a mixture of THF and 2 M NaOH (10 mL, 1:1). V / V) and stirred at room temperature for 20 min, then diluted with water (50 mL), extracted with EtOAc (100 mL), dried (Na2SO4), filtered and evaporated. The product was purified by CC (silica gel, DCM / MeOH, 98:2 V / V ) to give the expected acrylamide 146 (1.6 g, 0.006523 mol, 21.6%) as a yellow solid. LCMS (Method 3): m / z: 245.94 [M+H] + .

[0384] Step 6. N-methyl-N-((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide (Compound 148). A 20 mL vial flask was charged sequentially with N-((5-hydroxy-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide 146 (0.3 g, 0.001223 mol, 1.0 equiv), 3-iodopyridine 147 (0.597 g, 0.00293 mol, 2.4 equiv), CsCO (2.02 g, 0.006237 mol, 5.1 equiv), and DMF (10 mL). To this reaction mixture, 2,2,6,6-tetramethyl-3,5-heptanedione (0.224 g, 0.001223 mol, 1.0 equiv.) and CuI (0.232 g, 0.001223 mol, 1.0 equiv.) were added under an oxygen balloon, and the reaction vial was sealed and stirred at 60 °C for 16 h. The resulting mixture was cooled to room temperature, filtered through a Celite bed, diluted with water (50 mL), extracted with EtOAc (2 × 50 mL), dried (NaSO), filtered, and evaporated. The crude mixture was purified by CC (silica gel, n-hexane / EtOAc, 50:50 V / V ) to give the title compound 148 (0.17 g, 0.000527 mol, 43.1%) as a yellow solid. LCMS (Method 3): m / z 323.33 [M+H] + .

[0385] Step 7. tert-Butyl (E)-(3-(3-(methyl((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 149). A 20 mL vial flask was charged with N-methyl-N-((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide 148 (0.588 g, 0.00182 mol, 1.0 equiv.), tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (0.715 g, 0.002 mol, 1.1 equiv.), DIPEA (1.87 g, 0.0145 mol, 8.0 equiv.), and a mixture of CH3CH2CN:DMF (8:2). V / V ) (10 mL). Nitrogen was bubbled through the reaction mixture for 10 min. Then, Pd(OAc)2 (0.041 g, 0.000182 mol, 0.1 eq) and tri(o-tolyl)phosphine (0.114 g, 0.000364 mol, 0.2 eq) were added, and nitrogen was bubbled through for another 5 min. The reaction vial was sealed and heated overnight (100 °C; 16 h). The reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted with EtOAc (2 × 100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude product, which was purified by CC (eluent: n-hexane / EtOAc, 15 / 85 V / V ) and further purified by HPLC. The expected molecule 149 (0.45 g, 0.000753 mol, 41.28%) was prepared as an off-white solid. LCMS (Method 3): m / z 598.52 [M+H] + .

[0386] Step 8. tert-Butyl (S,E)-(3-(3-(methyl((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (Compound 150). Racemic tert-butyl (E)-(3-(3-(methyl((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 149 (0.45 g) was subjected to chiral HPLC separation to separate both enantiomers. The pure fractions of the second enantiomer (peak-2), corresponding to the expected product 150, were collected, concentrated under reduced pressure, and dried (0.17 g). ret =8.99 minutes. LCMS (method 3): m / z 598.31[M+H] + Chiral purity: 99.60%. Chiral method separation: Column name: Chiralpak IC (4.6 x 250) mm, 5 μm. Mobile phase: 0.1% DEA in hexane / EtOH = 20 / 80 ( V / V ). Flow rate: 1.0 mL / min. Flow mode: Isocratic. Temperature: Ambient. Note: A similar method using chiral HPLC of 107 standard compounds on an IB column confirmed peak-1 as the R-enantiomer and peak-2 as the S-enantiomer.

[0387] Step 9. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide hydrochloride (compound 151). To a stirred solution of tert-butyl (S,E)-(3-(3-(methyl((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 150 (0.105 g, 0.0001758 mol, 1.0 equiv) in DCM (1.5 mL) was added 2 M HCl in ether (1.5 mL) dropwise at 0 °C. The reaction mixture was stirred for about 2 hours (0° C. to room temperature), then cold ether (10 mL) was added to the reaction mixture, and the precipitated product was filtered off and dried under high vacuum to give title compound molecule 151 (0.069 g, 0.000129 mol, 79.31%) as a white solid. LCMS (method 3): m / z 498.12[M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ(ppm): 10.91(s,1H), 8.64-8.34(m,6H), 8.24(s,1H), 7.72-7.31(m,6H), 7.12(d,J=8. 6Hz, 1H), 5.03-4.81(2H), 3.87(bs,1H), 3.22-2.94(3H), 2.84-2.74(m,2H), 2.23-2.12(m,5H).Chiral purity: 99.34%.

[0388] Example 20 Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide dihydrochloride (Compound 167) General synthetic scheme [ka] Step 1. 4-Bromo-3-methylbenzofuran-2-carbonitrile (compound 153). To a stirred solution of KCO (29.8 g, 0.21 mol, 3.0 equiv.) in dry DMF (150 mL) was added 1-(2-bromo-6-hydroxyphenyl)ethan-1-one 152 (15.5 g, 0.072 mol, 1 equiv.). To this solution was then added chloroacetonitrile (8.15 g, 0.108 mol, 1.5 equiv.) over 5 min, and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, it was diluted with cold HO (1.0 L), extracted with EtOAc (500 mL), dried (NaSO), filtered, and evaporated to give the crude product, which was purified by CC (silica gel, n-hexane / EtOAc, 90:10 V / V ) to give the expected compound 153 (15.8 g, 0.066 mol, 92.9%) as a yellow oil. 1 H NMR (CDCl3, 400MHz): δ (ppm) 7.49-7.44 (m, 1H), 7.34-7.30 (t, J = 8Hz, 1H), 2.65 (s, 3H).

[0389] Step 2. 4-Bromo-3-methylbenzofuran-2-carboxylic acid (compound 154). To a stirred solution of 4-bromo-3-methylbenzofuran-2-carbonitrile 153 (15.7 g, 0.115 mol, 1 equiv.) in 200 mL (HO) and 100 mL (MeOH) was added NaOH (13.8 g, 0.346 mol, 3.0 equiv.). The reaction was heated at 100 °C for 72 h. The resulting mixture was cooled to 10 °C, the pH adjusted to approximately 2 with 1 N HCl (50 mL), extracted with EtOAc (250 mL), dried (NaSO), filtered, and evaporated to give the title compound 154 (15.0 g, 0.058 mol, 88%) as an off-white solid. LCMS (Method 3): m / z: 252.98 [M-2H] + .

[0390] Step 3. (4-Bromo-3-methylbenzofuran-2-yl)methanol (Compound 155). To a solution of 4-bromo-3-methylbenzofuran-2-carboxylic acid 154 (10.0 g, 0.039 mol) in dry THF (100 mL) at 0 °C, borane-methyl sulfide complex (5.88 g, 0.078 mol, 2.0 equiv.) was added. The reaction was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C, quenched with MeOH (50 mL), and evaporated under reduced pressure. The crude product was dissolved in EtOAc (200 mL), washed with water (100 mL), dried (NaSO), filtered, and evaporated to give the title compound 155 (10.0 g, crude) as an off-white solid. LCMS (Method 3): m / z 222.90 [M-OH] + .

[0391] Step 4. 4-Bromo-3-methylbenzofuran-2-carbaldehyde (compound 156). To a solution of (4-bromo-3-methylbenzofuran-2-yl)methanol 155 (9.94 g, 0.0414 mol) in dry DCM (100 mL) at 0 °C was added Dess-Martin periodinane (26.3 g, 0.0622 mol, 1.5 equiv.). The reaction was stirred at 0 °C for 24 h at room temperature. The reaction mixture was filtered through a bed of Celite and washed with DCM (200 mL). The filtrate was washed with 1 N NaHCO (200 mL), dried (NaSO), filtered, and evaporated to give the title compound 156 (10.0 g, crude) as an off-white solid. LCMS (Method 3): m / z: 241.04 [M+H] + .

[0392] Step 5. 1-(4-Bromo-3-methylbenzofuran-2-yl)-N-methylmethanamine (Compound 157). To a solution of 4-bromo-3-methylbenzofuran-2-carbaldehyde 156 (1.0 g, 0.042 mol) in EtOH (100 mL) was added 40% aqueous MeNH (100 mL). The reaction was stirred overnight at room temperature. The solution was concentrated under reduced pressure. The resulting dark yellow oil was solvated with EtOH (100 mL) under N. To the solution was added NaBH (3.2 g, 0.84 mol, 2.0 equiv.), and the mixture was stirred at the same temperature for 2 h. The solution was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (200 mL), washed with water (100 mL), dried (NaSO), filtered, and evaporated. The crude product was obtained and purified by CC (silica gel, DCM / MeOH, 95:5 V / V ) to give the expected molecule 157 (6.5 g, 0.0255 mol, 60.6%) as a brown oil. LCMS (Method 3): m / z: 253.8 [M−H] - .

[0393] Step 6. 3-Methyl-2-((methylamino)methyl)benzofuran-4-carbonitrile (Compound 158). A 20 mL vial flask was charged sequentially with 1-(4-bromo-3-methylbenzofuran-2-yl)-N-methylmethanamine 157 (2.0 g, 0.0078 mol, 1.0 equiv.), Zn(CN) (1.09 g, 0.0094 mol, 1.2 equiv.), Zn powder (0.51 g, 0.0078 mol, 1.0 equiv.), and DMA (20 mL). Nitrogen was bubbled into the reaction mixture for 10 min. Pd(dba) (0.72 g, 0.00078 mol, 0.1 equiv.) and dppf (0.21 g, 0.00039 mol, 0.05 equiv.) were added to the reaction mixture, and nitrogen was bubbled through for an additional 5 min. The reaction vial was sealed and heated at 130° C. overnight. The reaction mixture was cooled to room temperature, filtered through a bed of celite, rinsed with EtOAc (200 mL), and the filtrate was washed with water (100 mL), dried (NaSO), filtered, and evaporated to give the crude product, which was purified by CC (silica gel, DCM / MeOH, 95:5 V / V ) to give the title compound 158 (1.1 g, 0.0055 mol, 70%) as a brown oil. LCMS (Method 3): m / z: 201.12 [M+H] + .

[0394] Step 7. Benzyl ((4-cyano-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate (Compound 159). To a solution of 3-methyl-2-((methylamino)methyl)benzofuran-4-carbonitrile 158 (0.5 g, 0.0025 mol) in DCM (10 mL) at 0 °C was added TEA (0.75 g, 0.0075 mol, 3.0 equiv.). Benzyl chloroformate (Cbz chloride; 0.63 g, 0.0037 mol, 1.5 equiv.) was added dropwise and the mixture was allowed to stir at 0 °C for 2 h until room temperature. Note: The same reaction was carried out with 1.45 g of starting material (3-methyl-2-((methylamino)methyl)benzofuran-4-carbonitrile) 158 and both batches were mixed together with workup and purification. After completion of the reaction, the reaction mixture was diluted with HO (200 mL), extracted with EtOAc (200 mL), dried (NaSO), filtered and evaporated to give the crude product, which was purified by CC (eluent: n-hexane / EtOAc, 90 / 10 V / V ) to give the title compound 159 (2.5 g, 0.0074 mol, 76%) as a colorless oil. LCMS (Method 3): m / z: 335.27 [M+H] + .

[0395] Step 8. Benzyl ((4-(((tert-butoxycarbonyl)amino)methyl)-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate (compound 160). To a cooled (0 °C) solution of benzyl ((4-cyano-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate 159 (0.4 g, 0.0011 mol) in MeOH (10 mL) at 0 °C was added BocO (0.65 g, 0.0029 mol, 2.5 equiv.) and NiCl .6H2O (0.28 g, 0.0011 mol, 1.0 equiv.) was added. NaBH4 (0.091 g, 0.0023 mol, 2.0 equiv.) was added portionwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 2 h to room temperature. Note: The same reaction was carried out with 2.1 g of starting material (benzyl((4-cyano-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate) 159 and both batches were mixed together with further workup and purification. After completion of the reaction (TLC monitoring), the reaction was quenched with water, filtered through a bed of Celite, washed with EtOAc (100 mL), and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL), washed with HO (100 mL), brine (50 mL), dried (NaSO), and evaporated under reduced pressure to give the crude product. The crude material was purified by CC (eluent: n-hexane / EtOAc, 90 / 10 V / V ) to give the title compound 160 (2.5 g, 0.0057 mol, 72.4%) as a colorless oil. LCMS (Method 3): m / z: 456.2 [M+18] + .

[0396] Step 9. tert-Butyl ((3-methyl-2-((methylamino)methyl)benzofuran-4-yl)methyl)carbamate (Compound 161). To a stirred solution of benzyl ((4-(((tert-butoxycarbonyl)amino)methyl)-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate 160 (0.7 g, 0.0015 mol) in MeOH (20 mL) was added 10% Pd / C (50% wet) (0.35 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a bed of Celite, washed with MeOH (100 mL), and the filtrate was concentrated under reduced pressure to give the title compound 161 (0.5 g, 0.0016 mol, quantitative) as an off-white solid. LCMS (Method 3): m / z: 305.28 [M+H] + .

[0397] Step 10. tert-Butyl ((3-methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl)methyl)carbamate (Compound 162). To a solution of tert-butyl ((3-methyl-2-((methylamino)methyl)benzofuran-4-yl)methyl)carbamate 161 (0.5 g, 0.0016 mol) in DCM (10 mL) at 0 °C, TEA (0.49 g, 0.0049 mol, 3.0 equiv.) was added. Acryloyl chloride (0.22 g, 0.0024 mol, 1.5 equiv.) was added dropwise and allowed to stir at 0 °C for 1 h. The reaction was diluted with HO (100 mL), extracted with EtOAc (100 mL), dried (NaSO), filtered, and evaporated to dryness. The crude product was purified by CC (silica gel, DCM / MeOH, 98:2 V / V ) to give the title compound 162 (0.3 g, 0.00083 mol, 66%) as an off-white solid. LCMS (Method 3): m / z: 359.35 [M+H] + .

[0398] Step 11. N-((4-(aminomethyl)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (compound 163). To a stirred solution of tert-butyl ((3-methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl)methyl)carbamate 162 (0.3 g, 0.000836 mol, 1.0 equiv.) in DCM (5 mL) was added 4 M HCl in dioxane (1 mL) dropwise at 0° C. The reaction mixture was stirred from 0° C. to room temperature over 2 h and then concentrated under reduced pressure to give crude product 163 (0.23 g, approximately 3:2 ratio of A and B mixture) as an off-white solid. LCMS (Method 3): m / z 259.15 [M+H] + . Note: LCMS analysis showed 56.46% of the desired product in the mixture, and this crude material was used in the next step without further purification (inseparable mixture of desired salt A and adduct B).

[0399] Step 12. N-Methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide (Compound 164). A 20 mL sealed tube was charged with a mixture of N-((4-(aminomethyl)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride salt 163 (A and B) (0.01 g, 0.0000339 mol, 1.0 equiv.), 3-iodopyridine 147 (0.008 g, 0.00004 mol, 1.2 equiv.), CsCO (0.066 g, 0.0002 mol, 6.0 equiv.), and DMF (0.5 mL). The reaction mixture was purged with nitrogen for 10 min, and then 1,1-binaphthol (0.002 g, 0.0000067 mol, 1.0 equiv.), Cu (0.00021 g, 0.00000339 mol, 0.1 equiv.), and CuI (0.0006 g, 0.00000339 mol, 0.1 equiv.) were added sequentially. Nitrogen was bubbled through the resulting mixture for an additional 5 min. The reaction vial was sealed and stirred at 100 °C for 16 h. Note: The same reaction was carried out on a 0.2 g scale of N-((4-(aminomethyl)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride 163 (A and B) and both batches were mixed together (workup and purification). The reaction mixture was cooled to room temperature and filtered through a bed of celite, the filtrate was diluted with HO (50 mL) and extracted with EtOAc (2 x 50 mL), the organic phase was dried (NaSO), filtered and evaporated. The crude material was purified by CC (silica gel, DCM / MeOH, 95:5 V / V ) to afford the title intermediate 164 (0.155 g, inseparable mixture of products) as a brown oil. LCMS (Method 3): m / z 336.39 [M+H] + . Note: LCMS analysis showed 21.08% of the desired product in the isolated mixture, which was used in the next step without further purification.

[0400] Step 13. tert-Butyl (E)-(3-(3-(methyl((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 165). In a 20 mL vial flask, N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide 164 (0.2 g, 0.000596 mol, 1.0 equiv.), tert-butyl (3-bromo-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 68 (0.212 g, 0.000596 mol, 1.0 equiv.), DIPEA (0.615 g, 0.004768 mol, 8.0 equiv.), and a mixture of CH3CH2CN:DMF (8:2) were added. V / V ) (10 mL). Nitrogen was bubbled through the reaction mixture for 10 minutes, and Pd(OAc) (0.026 g, 0.0001192 mol, 0.2 equiv.) and tri(o-tolyl)phosphine (0.072 g, 0.0002385 mol, 0.4 equiv.) were added, followed by an additional 5 minutes of nitrogen bubble. The reaction vial was sealed and heated at 100 °C for 16 hours. Note: A second batch was performed with 0.14 g of starting material N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide 164 and both batches were mixed together for further workup and purification. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product, which was purified by CC (eluent: n-hexane / EtOAc, 20 / 80 V / V ) was further purified by HPLC. The title compound 165 (0.17 g, 0.000278 mol, 29.3%) was prepared as an off-white solid. LCMS (Method 3): m / z 611.37 [M+1] + .

[0401] Step 14. Synthesis of tert-butyl (S,E)-(3-(3-(methyl((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (compound 166). Racemic compound 165 (0.17 g) was subjected to chiral HPLC separation to isolate both enantiomers. The pure fractions of the first enantiomer (peak-1), corresponding to the expected product 166, were collected, concentrated under reduced pressure, and dried (0.055 g). ret =13.34 minutes. LCMS (method 3): m / z 611.41[M+H] + Chiral purity: 99.34%. Chiral method separation: Column name: Chiralpak IC (4.6 x 250) mm, 5 μm. Mobile phase: 0.1% DEA in hexane / EtOH = 10 / 90 ( V / V ). Flow rate: 1.0 mL / min. Flow mode: Isocratic. Temperature: Ambient.

[0402] Step 15. (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide dihydrochloride (compound 167). To a stirred solution of tert-butyl (S,E)-(3-(3-(methyl((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate 166 (0.05 g, 0.0000818 mol, 1.0 equiv) in DCM (2 mL) was added 2 M HCl in EtO (1.0 mL) dropwise at 0 °C. The reaction mixture was stirred for 30 min (0 °C → rt), and the DCM was evaporated under reduced pressure to give the crude product, which was precipitated from DCM (1 mL) and EtO (5 mL). The title compound 167 (0.032 g, 0.0000548 mol, 68%) was isolated as a white solid. LCMS (Method 3): m / z 511.53 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ(ppm): 10.92(s,1H), 8.66-8.61(m,1H), 8.35-8.24(m,4H), 8.14(s,1H), 8.06(s,1H), 7.78-7.72(m,2H), 7.59-7.54(m, 2H), 7.49-7.44(m,1H), 7.35-7.14(m,3H), 5.02-4.74(m,4H), 3.86(bs, 1H), 3.21-2.93(3H), 2.82-2.72(m,3H), 2.41(s,3H), 2.23-2.18(m,1H). The stereochemistry for compound 167 was arbitrarily assigned.

[0403] Example 21. Synthesis of ((S,E)-3-(7-(3-hydroxyazetidin-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 171) General synthetic scheme [ka] Step 1. 3-Bromo-7-(3-hydroxyazetidin-1-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (compound 169). To a suspension of 3-bromo-7-iodo-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 109 (200 mg, 0.54 mmol) and KCO (200 mg, 0.54 mmol) in acetonitrile (2 mL) was added azetidin-3-ol HCl salt 168 (50 mg, 0.46 mmol), and the reaction was heated to 50 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with 10% MeOH in DCM (10 mL), and pre-absorbed onto silica. Purification by chromatography (0-10% MeOH in DCM) afforded the title compound 169 (129 mg, 65% yield) as a white foam. t 0.27 min (method 1a); m / z 312 / 314[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 10.60(s,1H), 8.43(d,J=2.4Hz, 1H), 8.03(d,J=2.4Hz, 1H), 5.66(s,1H), 4.33-4.21(m,1H), 3.95(s,1H), 3.82(s,1H) , 3.42(s,1H), 3.17(d,J=4.5Hz, 1H), 2.80(dd,J=13.9, 6.4Hz, 1H), 2.72-2.61(m,1H), 2.46-2.32(m,1H), 1.92(s,2H).

[0404] Step 2. (E)-3-(7-(3-hydroxyazetidin-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 170). A reaction vial was charged with N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (95 mg, 0.41 mmol), 3-bromo-7-(3-hydroxyazetidin-1-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 169 (130 mg, 0.41 mmol), tetrabutylammonium chloride hydrate (12 mg, 0.04 mmol), and [P(tBu)3]Pd(crotyl)Cl (Pd-162) (16 mg, 0.04 mmol). The vial was flushed with nitrogen for 5 min, then 1,4-dioxane (3 mL) and N-cyclohexyl-N-methylcyclohexanamine (0.18 mL, 0.83 mmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 min. The mixture was heated to 80° C. for 1 h and cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by silica chromatography (0-10% MeOH in DCM) to give the title compound 170 (93 mg, 49% yield) as a white solid. t 1.40 minutes (method 1a); m / z 461[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 9.65(1H,s), 8.46(1H,d,J=2.3Hz), 7.98(1H,d,J=2.3Hz), 7.62-7.41(3H,m), 7.34-7.17(3H,m), 4.87(2H,s), 4.84(1H,d,J=6.4Hz), 4.11 1H,q,J=6.1Hz), 3.51(1H,t,J=6.6Hz), 3.44(1H,t,J=6.7Hz), 3.12(3H,s), 2.96(1H,dd ,J=5.2, 2.4Hz), 2.82-2.67(4H,m), 2.28(3H,s), 2.26-2.17(1H,m), 1.94-1.84(1H,m).

[0405] Step 3. (S,E)-3-(7-(3-hydroxyazetidin-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 171). The racemic mixture 170 was separated by chiral HPLC using a chiralpak IC column—30% EtOH, 16% CHCl, 64% i-hexane, 0.2% diethylamine. Pure fractions of the second-eluting isomer, corresponding to the expected product 171, were collected, concentrated under reduced pressure, and dried. t 1.40 minutes (method 1a) m / z 461[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 9.65(1H,s), 8.46(1H,d,J=2.3Hz), 7.98(1H,d,J=2.3Hz), 7.62-7.41(3H,m), 7 .34-7.17(3H,m), 4.87(2H,s), 4.84(1H,d,J=6.4Hz), 4.11(1H,q,J=6.1Hz),3. 51 (1H, t, J = 6.6 Hz), 3.44 (1H, t, J = 6.7 Hz), 3.12 (3H, s), 2.96 (1H, dd, J = 5.2 Hz, 2.4 Hz), 2.82-2.67 (4H, m), 2.28 (3H, s), 2.26-2.17 (1H, m), 1.94-1.84 (1H, m). The chirality for compound 171 was arbitrarily assigned.

[0406] Example 22. Synthesis of (E)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide (Compound 173) General synthetic scheme [ka] Step 1. 3-Bromo-7-morpholino-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one (Compound 172). To a solution of 3-bromo-7-iodo-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 109 (1.0 g, 2.7 mmol) in acetonitrile (15 mL) under nitrogen, potassium carbonate (0.75 g, 5.5 mmol) and morpholine 110 (0.29 mL, 3.3 mmol) were added. The reaction mixture was stirred at 80 °C for 18 h. After cooling to room temperature, the reaction mixture was partitioned between water (150 mL) and ethyl acetate (150 mL). The aqueous phase was extracted with ethyl acetate (150 mL). The combined organic phase was washed with brine (50 mL), dried (MgSO), and concentrated under reduced pressure. The residue was triturated from MTBE to give the title compound 172 (395 mg, 43% yield) as an off-white solid. t 0.33 min (method 1a); m / z 326 / 328[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 10.12(s,1H), 8.32(d,J=2.4Hz, 1H), 7.92(d,J=2.5Hz, 1H), 3.41(t,J=4.7Hz, 4H), 3.17(d,J=5.2Hz, 0H), 2.99(dd,J=9 .6, 7.0Hz, 1H), 2.79(ddd,J=13.8, 7.4, 3.7Hz, 1H), 2.65-2.52(m,3H), 2.46(dd,J=11.1, 4.8Hz, 2H), 2.33-2.10(m,2H).

[0407] Step 2. (E)-N-Methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide (Compound 173). A reaction vial was charged with N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide 26 (50 mg, 0.2 mmol), 3-bromo-7-morpholino-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 172 (71 mg, 0.2 mmol), tetrabutylammonium chloride hydrate (6.5 mg, 0.022 mmol), and [P(tBu)3]Pd(crotyl)Cl (Pd-162) (8.7 mg, 0.02 mmol). The tube was flushed with nitrogen for 5 minutes, then 1,4-dioxane (3 mL) and N-cyclohexyl-N-methylcyclohexanamine (93 μL, 0.44 mmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 minutes. The mixture was heated to 80° C. for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure, and the crude residue was purified by chromatography (0-10% MeOH in DCM) to give the title compound 173 (17 mg, 16% yield) as a white solid. R t 1.41 min (method 1a); m / z 475[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6, 373K): δ, ppm 9.68(s,1H), 8.46(d,J=2.3Hz, 1H), 7.98(d,J=2.3Hz, 1H), 7.56(d,J=15.5Hz, 2H), 7.45(dt,J=8.3, 0.8Hz, 1H), 7.30-7.13(m,3H), 4.79(s, 2H), 3.48-3.35(m,4H), 3.13-3.01(m,1H), 2.95(d,J=1.3Hz, 0H), 2.83(ddd,J=14.3, 7.5, 4.6Hz, 1H), 2.76-2.50(m,4H), 2.34-2.14(m,2H).

[0408] Example 23 Synthesis of (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide (Compound 176) General synthetic scheme [ka] Step 1. 3-Bromo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (compound 175). To a suspension of 3-bromo-7-iodo-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 109 (200 mg, 0.55 mmol) and K2CO3 (230 mg, 1.64 mmol) in acetonitrile (4 mL) was added 7-oxa-2-azaspiro[3.5]nonane (hemioxalate salt) 174 (110 mg, 0.65 mmol), and the reaction was heated at 50 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with 10% MeOH in DCM (10 mL), and preabsorbed onto silica. Purification by chromatography (0-10% MeOH in DCM) afforded the title compound 175 (218 mg, quantitative yield) as a yellow solid. t 0.51 min (method 1a); m / z 366 / 368[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 10.05(s,1H), 8.31(d,J=2.4Hz, 1H), 7.91(d,J=2.4Hz, 1H), 3.50(t,J=5.3Hz, 4H), 3.01(dd,J=9.7, 6.7Hz, 1H), 2 .85-2.72(m,1H), 2.64-2.52(m,2H), 2.50-2.41(m,3H), 2.38-2.23(m,1H), 2.22-2.09(m,1H), 1.36-1.27(m,4H).

[0409] Step 2. (E)-N-Methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide (Compound 176). A reaction vial was charged with N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (140 mg, 0.59 mmol), 3-bromo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 175 (220 mg, 0.59 mmol), tetrabutylammonium chloride hydrate (18 mg, 0.06 mmol), and [P(tBu)3]Pd(crotyl)Cl (Pd-162) (24 mg, 0.06 mmol). The vial was flushed with nitrogen for 5 minutes. 1,4-Dioxane (3 mL) and N-cyclohexyl-N-methylcyclohexanamine (0.25 mL, 1.2 mmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 minutes. The mixture was heated to 80° C. for 1 h and cooled to room temperature. The solvent was removed under reduced pressure. The crude residue was taken up in EtOAc (2 mL) and isohexane (1 mL) was added. The resulting suspension was filtered and the solid was washed twice with isohexane (2×3 mL). The crude product was purified by column chromatography (0-10% MeOH in DCM) to afford the title compound 176 (243 mg, 78% yield) as a white solid. R t 1.45 minutes (method 1a); m / z 515[M+H] + (ES + ). 1H NMR (400MHz, DMSO-d6): δ, ppm 9.63(s,1H), 8.43(d,J=2.3Hz, 1H), 7.96(d,J=2.3Hz, 1H), 7.58-7.54(m,1H), 7.52(d,J=15.5 Hz, 1H), 7.49-7.43(m,1H), 7.32-7.21(m,3H), 4.87(s,2H), 3.46-3.40(m,4H), 3.12(s,3H), 3. 04(dd,J=7.9, 6.8Hz, 1H), 2.95(d,J=6.4Hz, 2H), 2.89(d,J=6.4Hz, 2H), 2.81-2.66(m,2H), 2. 28(s,3H), 2.22(ddd,J=13.9, 6.9, 1.8Hz, 1H), 1.90(dt,J=7.7, 5.8Hz, 1H), 1.55-1.50(m,4H).

[0410] Example 24 Synthesis of (E)-3-(7-(1,1-dioxidothiomorpholino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 179) General synthetic scheme [ka] Step 1. 3-Bromo-7-(1,1-dioxidethiomorpholino)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound 178). To a stirred suspension of 3-bromo-7-iodo-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 109 (0.2 g, 0.55 mmol) in MeCN (4 mL) was added thiomorpholine 1,1-dioxide 177 (0.074 g, 0.55 mmol), followed by K2CO3 (0.23 g, 1.64 mmol). The reaction mixture was stirred at 50 °C for 24 h and then at 80 °C for 24 h. The reaction mixture was cooled to room temperature, and then glacial AcOH (AcOH) was added dropwise until no solid K2CO3 was visible. The solution was diluted with 10% MeOH in DCM (50 mL) and pre-absorbed onto silica. The crude product was purified by chromatography (0-10% MeOH in DCM), but this did not separate the product from the by-product. The product was purified again by chromatography (0-100% EtOAc in isohexane) to give the desired product 178 as an off-white solid (0.06 g, 29%). t 0.85 min (method 2a); m / z 374 / 376[M+H] + (ES + ). 1 H NMR (400MHz, DMSO-d6): δ, ppm 10.19(s,1H), 8.35(d,J=2.4Hz, 1H), 7.97(d,J=2.4Hz, 1H), 3.40(dd,J=11.6, 7.4Hz, 1H), 3.28-3.21(m,2H), 3. 19-3.07(m,2H), 2.98-2.95(m,4H), 2.82-2.75(m,1H), 2.63-2.55(m,1H), 2.41-2.31(m,1H), 2.20-2.14(m,1H).

[0411] Step 2. (E)-3-(7-(1,1-dioxidothiomorpholino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (Compound 179). A microwave tube was flushed with N2 and then charged with N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 6 (0.037 g, 0.16 mmol), 3-bromo-7-(1,1-dioxidothiomorpholino)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one 178 (0.06 g, 0.16 mmol), tetrabutylammonium chloride hydrate (5 mg, 0.016 mmol), and [P( t Bu)3]Pd(crotyl)Cl(Pd-162) (5 mg, 0.011 mmol) was added. The tube was flushed with N2 for an additional 5 min, then 1,4-dioxane (1.5 mL) and N-cyclohexyl-N-methylcyclohexanamine (0.069 mL, 0.32 mmol) were added. The reaction mixture was heated to 80 °C under an atmosphere of N2 and stirred for 2...

Claims

1. A compound represented by formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof. 【Chemistry 1】 (In the formula, LHS is LHSa and LHSb 【Chemistry 2】 wherein the asterisk ( ＊ ) indicates the point of attachment; Y is CH ２ , N.H. and N.R. ｄ selected from the group consisting of: Q １ is O, S, NH and N-C １～４ selected from the group consisting of alkyl; R ０ is CH ３ and Cl, or alternatively, R ０ is R １４ Together with R １４ forms a heterocycle having 5 to 8 ring members; R １ are H, F, Cl, Br, I, C １～４ Alkyl, OR ５ , C.N., N.R. ５ R ６ , CO-NR ５ R ６ , C １～４ Alkylene -NR ５ R ６ , C １～４ Alkylene-OR ５ , NH-CO-C １～４ Alkylene-R ５ , NH-CO-NR ５ R ６ , NH-COOR ５ , N.H.S.O. ２ -C １～４ Alkylene-R ５ , C ３～６ selected from the group consisting of cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S; R ２ are H, F, Cl, Br, I, C １～４ Alkyl, OR ５ , C １～４ Alkylene-OR ５ , C.N., N.R. ５ R ６ , CO-NR ５ R ６ , C １～４ Alkylene -NR ５ R ６ , C ３～６ selected from the group consisting of cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S; R ３ are H, F, Cl, Br, I, CN, and C １～４ Alkyl, O-C １～４ Alkyl, OH, NH ２ , N.H.C. １～４ Alkyl and S-C １～４ selected from the group consisting of alkyl; R ３ａ , R ３ｂ and R ３ｃ are H, F, Cl, Br, I, CN, and C １～４ Alkyl, O-C １～４ Alkyl, OH, NH ２ , N.H.C. １～４ Alkyl and S-C １～４ independently selected from the group consisting of alkyl; R ４ are H, F, Cl, Br, I, C １～４ Alkyl, OR ５ , C.N., C.O.R. １０ , phenyl, OH, NH ２ , S.C. １～４ Alkyl, NR ５ R ６ and heterocyclic groups having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S; R ５ and R ６ , H, COR １０ , C １～４ Alkyl, C ３～６ Cycloalkyl, SO ２ R ７ phenyl and heterocyclic groups having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S; R ７ are H, F, I, Br, Cl, O, C １～４ Alkyl, CONH ２ , O.H., N.H. ２ , O-C １～４ Alkyl, NH-C １～４ Alkyl, N(C １～４ Alkyl) ２ , C １～４ Alkylene-OH and C １～４ Alkylene-NH ２ , NO ２ , C.N., C. ２～４ Alkenyl, C ２～４ Alkynyl, C ２～４ Alkynylene-OH,C ２～４ Alkynylene-NH ２ , S.O. ２ CH ３ and O-C １～４ alkylene-OH; R ８ and R ９ is H, C １～４ Alkyl, C １～４ Alkyl-F, CN, OH, NH ２ , O.C. １～４ Alkyl, NH-C １～４ Alkyl, N(C １～４ Alkyl) ２ , C １～４ Alkylene-OH and C １～４ Alkylene-NH ２ are independently selected from the group consisting of: R １０ is H, C １～４ Alkyl, C １～４ Alkyl-F,C １～４ Alkylene-OH and C １～４ Alkylene-NH ２ selected from the group consisting of: R １１ and R １２ H, R ｄ , C １～４ Alkyl, CO-C １～４ Alkyl, SO ２ (C １～４ Alkyl) １ , C １～４ Alkyl-F,C １～４ Alkylene-OH and C １～４ Alkylene-NH ２ or alternatively, R １１ and R １２ form together with the N to which they are attached a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S; R １３ is H or R ｄ selected from the group consisting of: R １４ is CH ３ or alternatively, R １４ is LHS ａ Or LHS ｂ R ０ Together with R １４ forms a heterocycle having 5 to 8 ring members; and R ｄ Is -PO ３ R ｅ２ , -CH ２ -OPO ３ R ｅ２ R ｅ is selected from the group consisting of H and a cation suitable for forming a pharma- ceutically acceptable salt.

2. The compound of claim 1, wherein the LHS is LHSa.

3. The compound of claim 1, wherein LHS is LHSb.

4. Q １ is selected from the group consisting of O and S.

5. R ０ is CH ３ and R １４ is CH ３ The compound according to any one of claims 1 to 4,

6. R ０ is R １４ Together with R １４ The compound according to any one of claims 1 to 4, comprising an N to which is attached and forms a heterocycle having 5 to 8 ring members.

7. R １ is H, F, Cl, Br, C １～４ Alkyl, OR ５ , C.N., N.R. ５ R ６ , C １～４ Alkylene -NR ５ R ６ , C １～４ Alkylene-OR ５ , NH-CO-C １～４ Alkylene-R ５ , NH-CO-NR ５ R ６ , NH-COOR ５ , N.H.S.O. ２ -C １～４ Alkylene-R ５ , C ３～６ cycloalkyl, phenyl, and heterocyclic groups having 5 or 6 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, and S, where R 5, R ６ and R ７ The compound according to any one of claims 1 to 6, wherein

8. R ２ is H, F, Cl, Br, C １～４ Alkyl, OR ５ , C １～４ Alkylene-OR ５ , C.N., N.R. ５ R ６ , C １～４ Alkylene -NR ５ R ６ , C ３～６ cycloalkyl, where R 5, R ６ and R ７ The compound according to any one of claims 1 to 7, wherein

9. R ３ is H, F, Cl, Br, OH, NH ２ and N.H.C. １～４ The compound according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of alkyl.

10. R ３ａ , R ３ｂ and R ３ｃ is H, F, Cl, Br, OH, NH ２ and N.H.C. １～４ The compound of any one of claims 1 to 9, independently selected from the group consisting of alkyl.

11. R ４ is H, F, Cl, Br, OR ５ , C.O.R. １０ , O.H., N.H. ２ and N.R. ５ R ６ R 5, R ６ and R １０ The compound according to any one of claims 1 to 10, wherein

12. R ７ is H, F, C １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, OH, NH ２ , O-C １～４ Alkyl, NH-C １～４ Alkyl, N(C １～４ Alkyl) ２ , C １～４ Alkylene-OH,C １～４ Alkylene-NH ２ and O-C １～４ Alkylene-OH,C ２～４ Alkynylene-OH and C ２～４ Alkynylene-NH ２ The compound according to any one of claims 1 to 11, selected from the group consisting of:

13. R ８ and R ９ is H, C １～４ Alkyl, C １～４ Alkyl-F, O-C １～４ The compound of any one of claims 1 to 12, independently selected from the group consisting of alkyl.

14. R １０ is H, C １～４ Alkyl, C １～４ The compound according to any one of claims 1 to 13, selected from the group consisting of alkyl-F.

15. R １１ and R １２ H, R ｄ , C １～４ Alkyl, C １～４ Alkyl-F,C １～４ Alkylene-OH and C １～４ Alkylene-NH ２ or alternatively, R １１ and R １２ together with the N to which they are attached form a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S; R 7 and R ｄ The compound according to any one of claims 1 to 14, wherein

16. R １ is H, F, Cl, Br, C １～４ Alkyl, OR ５ , N.R. ５ R ６ , C １～４ Alkylene -NR ５ R ６ , C １～４ Alkylene-OR ５ , NH-CO-C １～４ Alkylene-R ５ , NH-CO-NR ５ R ６ , NH-COOR ５ , N.H.S.O. ２ -C １～４ Alkylene-R ５ , C ３～６ cycloalkyl; R ２ is H, F, Cl, Br, C １～４ Alkyl, OR ５ , C １～４ Alkylene-OR ５ , C.N., N.R. ５ R ６ , C １～４ Alkylene -NR ５ R ６ , C ３～６ cycloalkyl; R ３ is H, F, Cl, Br, OH, NH ２ and N.H.C. １～４ selected from the group consisting of alkyl; R ３ａ , R ３ｂ and R ３ｃ is H, F, Cl, Br, OH, NH ２ and N.H.C. １～４ independently selected from the group consisting of alkyl; R ４ is H, F, Cl, Br, OR ５ , C.O.R. １０ , O.H., N.H. ２ and N.R. ５ R ６ selected from the group consisting of: R ７ is H, F, C １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, OH, NH ２ , O.C. １～４ Alkyl, NH-C １～４ Alkyl, N(C １～４ Alkyl) ２ , C １～４ Alkylene-OH and C １～４ Alkylene-NH ２ , O.C. １～４ Alkylene-OH,C ２～４ Alkynylene-OH and C ２～４ Alkynylene-NH ２ selected from the group consisting of: R ８ and R ９ is H, C １～４ Alkyl, C １～４ Alkyl-F and O-C １～４ independently selected from the group consisting of alkyl; R １０ is H, C １～４ Alkyl and C １～４ alkyl-F; and R １１ and R １２ H, R ｄ , C １～４ Alkyl, C １～４ Alkyl-F,C １～４ Alkylene-OH and C １～４ Alkylene-NH ２ or alternatively, R １１ and R １２ form together with the N to which they are attached a heterocyclic group having 4 to 9 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, or form a heterocyclic spiro group having 7 to 11 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S; R ５ , R ６ and R ｄ The compound according to any one of claims 1 to 15, wherein 17. The method of claim 1, wherein R 8 and R 9 are independently selected from the group consisting of H and C 1-4 alkyl.

17. A compound according to claim 13 or 16.

18. The compound according to claim 1, wherein R 10 is selected from the group consisting of H and C 1-4 alkyl.

17. A compound according to claim 14 or 16.

19. The compound according to claim 1, wherein R 11 and R 12 are independently selected from the group consisting of H, R d and C 1-4 alkyl.

17. A compound according to claim 15 or 16.

20. Y is CH ２ The compound according to any one of claims 1 to 19,

21. 21. The compound of claim 1 or 20, wherein Y is NH.

22. (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-N-methylacrylamide, (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (E)-3-(3-acetamido-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(4-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylamide, (E)-3-((R)-3-((2S,6R)-2,6-dimethylmorpholino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide and (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-l)methyl)acrylamide, (E)-3- (7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(7-(dimethylamino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide 3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-chloro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, so-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzo[b]thiophen-2-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((4-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3 -yl)-N-((7-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-5-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide, (E)-3-((S)-7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-((4-(((1r,4r)-4-aminocyclohexyl)oxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide, (S,E)-N-((7-fluoro-3-methylbenzofuran-2-yl)methyl)-N-methyl-3-(7-morpholino-8-oxo-6,7 ,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (E)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)-3-(7-morpholino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3 -b]azepin-3-yl)acrylamide, (E)-3-(7-(1,1-dioxidothiomorpholino)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (E)- N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-(4-(methylsulfonyl)piperazin-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (S,E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(8-oxo-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, ((S,E)-3-(7-(3-hydroxyazetidin-1-yl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-N-methyl-3-(8-oxo-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide, (S,E)-N-((7-amino-2-methylbenzofuran-3-yl)methyl)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine The compound according to claim 1, which is selected from the group consisting of (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-(pyridin-3-yloxy)benzofuran-2-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide, and a pharma- ceutically acceptable salt and / or solvate of any one of them.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22.

24. A composition comprising a compound according to any one of claims 1 to 22 for use in a method of treatment.

25. The method of treatment, wherein the method is a method of treating a bacterial infection.

25. A composition for use in a method of treatment according to claim 24.

26. The method of claim 25, wherein the bacterial infection is associated with one or more of the bacteria selected from the group consisting of S. aureus, E. coli, Klebsiella pneumoniae, and A. baumannii.

26. A composition for use in a method of treatment according to claim 25.

27. The method of claim 20, wherein the bacterial infection is associated with A. baumannii.

27. A composition for use in a method of treatment according to claim 25 or 26.

28. The bacterial infection is pneumonia or hospital-acquired pneumonia. A composition for use in a method of treatment according to any one of claims 24 to 27.

29. A process for preparing a compound according to any one of claims 1 to 22, comprising the formula M1 or M1' 【Chemistry 3】 (wherein X represents a leaving group and Pg represents a protecting group; R １１ and / or R １２ is as defined in claims 1 to 22, or additionally includes protecting groups. optionally with a precursor compound of formula M2a or M2b 【Chemistry 4】 (Wherein, Y, Q １ and all R groups have the same meaning as defined in claims 1 to 22. a first variant comprising a step of coupling with an amine compound of formula (I) Formula M6 or M6′ 【Chemistry 5】 and optionally a compound of formula M7a or M7b 【Chemistry 6】 (In the formula, Pg represents a protecting group, Y and Q １ and all R groups have the same meaning as defined in claims 1 to 22, R １１ and R １２ is a radical as defined in any one of claims 1 to 22 or such a defined radical, including protecting groups. The method selected from the second variant comprising coupling with a compound of formula (I).

30. X is selected from hydroxyl, tosylate, triflate, mesylate, iodide, bromide, chloride, methoxy and ethoxy.

30. A method for producing a compound of claim 29.

31. Pg is selected from a Boc group, a PMB group, and a DMB group, or R 11 and R 12 are selected from a Boc group, a PMB group, and a DMB group; 31. A process for preparing a compound according to claim 29 or 30.

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