Antimicrobial compounds and methods

Abstract

To provide antimicrobial compounds and methods.SOLUTION: The invention is directed to compounds that are active as antibacterial agents. The invention compounds are active against gram-positive and gram-negative bacteria and can be used to treat infections caused by gram-positive and gram-negative bacteria. Also disclosed are processes and intermediates for making the compounds. The invention provides methods of using compounds of formula I or a pharmaceutically acceptable salt thereof for the treatment of bacterial infections.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 793,216, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to compounds active as antibacterial agents. The present disclosure also relates to methods of treating bacterial infections using the compounds. [Background technology]

[0003] Antibacterial resistance is a global problem: both gram-positive and gram-negative bacteria are becoming increasingly resistant to antibiotics.

[0004] Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are resistant to most antibiotics related to penicillin. MRSA strains are typically associated with infections acquired in healthcare facilities and can cause infections in the larger community.

[0005] Gram-negative bacteria are thought to be more resistant to antibiotics than gram-positive bacteria because their cell walls are impermeable. According to the National Institutes of Health (NIH), gram-negative bacteria can cause many types of infections and spread to humans in a variety of ways. Some species, including Escherichia coli, are common causes of foodborne illness. Vibrio cholerae, the cause of cholera, is a waterborne pathogen. Gram-negative bacteria can also cause respiratory infections, such as certain types of pneumonia, and sexually transmitted diseases, including gonorrhea. Yersinia pestis, the gram-negative bacterium that causes the plague, is transmitted to people through the bite of infected insects or handling infected animals. See www.niaid.nih.gov / research / gram-negative-bacteria (last accessed January 7, 2020).

[0006] Certain types of Gram-negative bacteria are becoming increasingly resistant to available antibiotics. Some strains are now resistant to many, most, or all available treatments, resulting in increased illness and death from bacterial infections and contributing to rising healthcare costs. Examples of drug-resistant Gram-negative bacteria include E. coli, which causes the majority of urinary tract infections; Acinetobacter baumannii, which primarily causes illness in healthcare settings; Pseudomonas aeruginosa, which causes bloodstream infections and pneumonia in hospitalized patients and is a common cause of pneumonia in patients with cystic fibrosis; Klebsiella pneumoniae, which causes many types of healthcare-associated infections, including pneumonia, urinary tract infections, and bloodstream infections; and Neisseria gonorrhoeae, which causes the sexually transmitted disease gonorrhea, the second most commonly reported infection in the United States. Consequently, new drugs are needed to combat Gram-positive and Gram-negative bacterial infections. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] www.niaid.nih.gov / research / gram-negative-bacteria Summary of the Invention [Means for solving the problem]

[0008] These and other needs can be met by the present invention, which in one aspect provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is (C=O), (C=S), (C=NR z ), (S=O), or SO2, where R zis H, C1-C6 alkyl, or CN; Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, wherein the monocyclic heterocycloalkylene or bicyclic heterocycloalkylene is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), COOH, COO(C-C alkyl), -CONH, and oxo; J is absent, C1-C6 alkylene, heterocycloalkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which is optionally substituted with up to three substituents independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, and OH, wherein for each occurrence of C1-C6 alkylene, up to two methylene units of said C1-C6 alkylene are independently and optionally selected from O, S, SO2, C=O, or [ka] where t is 1, 2, 3, or 4; X 1 and X 2 are each independently CH or N, Y is a straight chain C1-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, and up to two carbon atoms of the C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently selected from O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6alkylene-cycloalkyl), N-(C 3-8 cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=O), or [ka] where t' is 1, 2, 3, or 4; Ring B is a monocyclic cycloalkylene or a monocyclic heterocycloalkylene, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, NH, C-C haloalkyl, OH, COOH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; L is absent or C1-C6 alkylene, wherein up to two methylene units of said C1-C6 alkylene are independently O, NH, (C=O), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 alkyl), R1 is H, halo, C1-C6 haloalkyl, NR x’ R y’ or monocyclic heterocycloalkyl optionally substituted with NH, NH(C-C alkyl), N(C-C alkyl), where R x’ and R y’are each independently H, C1-C6 alkyl, C3-C8 cycloalkyl, or an amino protecting group, and the C1-C6 alkyl and C3-C8 cycloalkyl optionally have up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —COO(C1-C6 alkyl), —CONH2, and oxo. or R1 is NH(C=O)-(C1-C6)alkyl, or NH-(C=NH)-NH2, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, and oxo; R 1’ is H or NR x R y where R x and R y are each independently H, C-C alkyl, C-C alkyl-SO, CO(C-C alkyl), CO—(C-C alkylene)-NH, or an amino protecting group; R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, CN, OH, NH2, O(C1-C6 haloalkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -COO(C1-C6 alkyl), -CONH2, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; m and n are each independently 0, 1, 2, or 3.

[0009] In another aspect, the present invention provides a method of using a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a bacterial infection.

[0010] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In a further aspect, the present invention provides processes for preparing compounds of Formula I, or pharmaceutically acceptable salts thereof, and for preparing compound intermediates used in the processes, as shown in the synthetic schemes. The present invention provides, for example, the following items. (Item 1) Compounds of Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is (C=O), (C=S), (C=NR z ), (S=O), or SO2, where R z is H, C1-C6 alkyl, or CN; Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, wherein the monocyclic heterocycloalkylene or bicyclic heterocycloalkylene is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), COOH, COO(C-C alkyl), CONH, and oxo; J is absent, C1-C6 alkylene, heterocycloalkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which is optionally substituted with up to three substituents independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, and OH, wherein for each occurrence of C1-C6 alkylene, up to two methylene units of said C1-C6 alkylene are independently and optionally selected from O, S, SO2, C=O, or [ka] where t is 1, 2, 3, or 4; X 1 and X 2 are each independently CH or N, Y is a straight chain C1-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkynylene, and up to two carbon atoms of said C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently selected from O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 alkylene-cycloalkyl), N-(C 3-8 cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=O), or [ka] wherein t' is 1, 2, 3, or 4; and Ring B is a monocyclic cycloalkylene or a monocyclic heterocycloalkylene, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, NH, C-C haloalkyl, OH, COOH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; L is absent or C1-C6 alkylene, wherein up to two methylene units of said C1-C6 alkylene are independently O, NH, (C=O), NH(C=O), N—(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 alkyl), R1 is H, halo, C1-C6 haloalkyl, NRx’ R y’ or monocyclic heterocycloalkyl optionally substituted with NH, NH(C-C alkyl), N(C-C alkyl), where R x’ and R y’ are each independently H, C1-C6 alkyl, C3-C8 cycloalkyl, or an amino protecting group, wherein the C1-C6 alkyl and C3-C8 cycloalkyl optionally have up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —COO(C1-C6 alkyl), —CONH2, and oxo. or R1 is NH(C=O)-(C1-C6)alkyl, or NH-(C=NH)-NH2, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, and oxo; R 1’ is H or NR x R y where R x and R y are each independently H, C-C alkyl, C-C alkyl-SO, CO(C-C alkyl), CO—(C-C alkylene)-NH, or an amino protecting group; R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, CN, OH, NH2, O(C1-C6 haloalkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -COO(C1-C6 alkyl), -CONH2, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; The compound or a pharmaceutically acceptable salt thereof, wherein m and n are each independently 0, 1, 2, or 3. (Item 2) 2. The compound according to item 1, wherein Z is —(C═O)—, or a pharmaceutically acceptable salt thereof. (Item 3) The compound according to any one of items 1 and 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4- to 8-membered monocyclic heterocycloalkylene or a 6- to 12-membered bicyclic heterocycloalkylene, wherein the monocyclic heterocycloalkylene and bicyclic heterocycloalkylene are optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, C-C haloalkyl, phenyl, OH, NH, COOH, COO(C-C alkyl), and -CONH. (Item 4) The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4- to 7-membered monocyclic heterocycloalkylene, optionally substituted with up to two substituents independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 hydroxyalkyl, phenyl, COOH, and COO(C1-C6 alkyl), wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen and oxygen. (Item 5) 4. The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-11-membered bicyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, C-C haloalkyl, phenyl, OH, NH, COOH, COO(C-C alkyl), and -CONH, wherein the bicyclic heterocycloalkylene contains up to three heteroatoms selected from nitrogen and oxygen. (Item 6) Ring A is [ka] [ka] 6. The compound according to any one of items 1 to 5, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 7) 7. The compound according to any one of items 1 to 6, wherein J is absent, or a pharmaceutically acceptable salt thereof. (Item 8) J is C1-C6 alkylene, heterocycloalkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which is optionally substituted with up to two substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, and OH, and wherein for each occurrence of C1-C6 alkylene, one or two methylene units of said C1-C6 alkylene are independently optionally selected from C=O or [ka] wherein t is 1, 2, or 3; or a pharmaceutically acceptable salt thereof. (Item 9) J is -CH2-, [ka] 9. The compound according to item 8, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 10) R 1’ 10. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is H, NH2, NH(C1-C6 alkyl), or NH(C1-C6 alkyl)2. (Item 11) [ka] but, [ka] [ka] [ka] 11. The compound according to any one of items 1 to 10, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 12) [ka] but, [ka] wherein each R3 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, O(C1-C6 haloalkyl), and C1-C6 haloalkyl, and wherein m is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. (Item 13) [ka] but, [ka] 13. The compound according to any one of items 1 to 12, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 14) Y is a straight chain C1-C8 alkylene optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, wherein up to two methylene units of said C1-C8 alkylene are optionally independently selected from O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-C3-8 cycloalkyl), N-(C 3-8 cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=O), or [ka] 14. The compound according to any one of items 1 to 13, or a pharmaceutically acceptable salt thereof, wherein t' is replaced by , wherein t' is 1 or 2. (Item 15) Y is CH2, CH(CH3), CH(COOEt), CH(COOH), [ka] 15. The compound according to any one of items 1 to 14, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 16) [ka] but, [ka] [ka] [ka] 16. The compound according to any one of items 1 to 15, selected from the group consisting of: (Item 17) 17. The compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, wherein ring B is a 4- to 7-membered monocyclic cycloalkylene or a 4- to 7-membered monocyclic heterocycloalkylene, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, NH, C-C haloalkyl, OH, COO(C-C alkyl), COOH, and C-C hydroxyalkyl. (Item 18) Ring B is [ka] [ka] 18. The compound according to any one of items 1 to 17, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 19) 19. The compound according to any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, wherein L is absent. (Item 20) L is a straight chain or branched C1-C6 alkylene, wherein up to two methylene units of said C1-C6 alkylene are optionally independently selected from O, NH, (C=O), NH(C=O), N—(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 19. The compound according to any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R is substituted with R(R) or R(R)(alkyl). (Item 21) L is absent or is CH2, CH2CH2, C(Me)2, CH(Me), CH(Et), (C=NH), [ka] 21. The compound according to any one of items 1 to 20, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 22) 22. The compound according to any one of items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of H, NH2, NH(C1-C6 alkyl), NH(C1-C6 alkyl)2, NH(C3-C6 cycloalkyl), CF3, and 4-6 membered monocyclic heterocycloalkyl optionally substituted with NH2. (Item 23) [ka] but, [ka] [ka] [ka] 23. The compound according to any one of items 1 to 22, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 24) 24. The compound of any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, O(C1-C6 haloalkyl), and C1-C6 alkoxy; and m and n are each independently 0, 1, or 2. (Item 25) 25. The compound of any one of items 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each R3 is C1-C6 alkyl, halo, C1-C6 haloalkyl, O(C1-C6 haloalkyl), or C1-C6 alkoxy; m is 0, 1, or 2; and n is 0. (Item 26) Compounds of formula I-1: [ka] 26. The compound according to any one of items 1 to 25, wherein X is 1 is CH or N, or a pharmaceutically acceptable salt thereof. (Item 27) Compounds of formula I-2: [ka] 27. The compound according to any one of items 1 to 26, or a pharmaceutically acceptable salt thereof, wherein K is C1-C5 alkylene, a 4- to 7-membered heterocycloalkylene, or a 4- to 6-membered cycloalkylene, any of which is optionally substituted with up to two substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or OH, and wherein one methylene unit of said C1-C5 alkylene is optionally [ka] where t is 1, 2, 3, or 4; each R5 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, COOH, COO(C1-C6 alkyl), CONH2, or oxo; R x and R y are each independently H, C1-C6 alkyl, C1-C6 alkyl-SO3, CO(C1-C6 alkyl), CO—(C1-C6 alkylene)-NH2, and q is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof. (Item 28) Compounds of formula I-3: [ka] wherein K is C1-C4 alkylene optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl, or OH; each R5 is independently C1-C6 alkyl, C1-C6 alkoxy, halo, C1-C6 haloalkyl, phenyl, OH, NH2, COOH, or COO(C1-C6 alkyl); and q is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. (Item 29) Compounds of formula I-4: [ka] 29. The compound according to any one of items 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Y is a straight chain C1-C4 alkylene optionally substituted with C1-C6 alkyl, COOH, COO(C1-C6 alkyl), or NH2, wherein up to two methylene units of said C1-C4 alkylene are optionally independently selected from (C=O), O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-C 3-6 cycloalkyl), N-(C 3-8 cycloalkyl), or [ka] where t' is 1 or 2, each R is independently C-C alkyl, halo, C-C haloalkyl, O(C-C haloalkyl), or C-C alkoxy, m is 0, 1, or 2, and R x and R x’ are each independently H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 30) Compounds of formula I-5: [ka] or a pharmaceutically acceptable salt thereof. (Item 31) Compounds of Formula II: [ka] 2. The compound according to item 1, wherein: Z is (C=O), Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, wherein the monocyclic heterocycloalkylene or bicyclic heterocycloalkylene is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), COO(C-C alkyl), -CONH, and oxo; J is C1-C6 alkylene, optionally substituted with halo, hydroxy, or alkoxy, wherein one or two methylene units of said C1-C6 alkylene may optionally be replaced with O, S, SO2, or C=O; R x and R y are each independently H, C1-C6 alkyl, or an amino protecting group; Y is a straight chain C1-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkynylene; and up to two carbon atoms of said C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-cycloalkyl), NH(C=O), N-(C 1-6alkyl)(C=O), or (C=O), Ring B is a monocyclic cycloalkylene or monocyclic heterocycloalkylene, which is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, OH, —COO(C-C alkyl), —CONH, and C-C hydroxyalkyl; R1 is H, halo, C1-C6 haloalkyl, or NR x’ R y’ where R x’ and R y’ are each independently H, C1-C6 alkyl, which is optionally substituted with up to three substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —COO(C1-C6 alkyl), —COONH2, and oxo, or a protecting group; or R1 is NH(C ═O)—(C1-C6)alkyl, or NH—(C═N)—NH2, any of which is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —COO(C1-C6 alkyl), —CONH2, and oxo; R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -COO(C1-C6 alkyl), -CONH2, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, or a pharmaceutically acceptable salt thereof. (Item 32) Ring A is [ka] [ka] 32. The compound according to item 31, selected from the group consisting of: (Item 33) J is -CH2-, [ka] 33. The compound according to item 31 or 32, selected from the group consisting of: (Item 34) NR x R y 34. The compound according to any one of items 31 to 33, or a pharmaceutically acceptable salt thereof, wherein is NH2, NHMe, NHEt, NHPG, N(Me)2, or N(Et)2, and PG is the amino protecting group. (Item 35) [ka] but, [ka] 35. The compound according to any one of items 31 to 34, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 36) Ring B is [ka] 36. The compound according to any one of items 31 to 35, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 37) 37. The compound according to any one of items 31 to 36, or a pharmaceutically acceptable salt thereof, wherein L is absent. (Item 38) L is a straight chain or branched C1-C6 alkylene, wherein up to two carbon atoms of said C1-C6 alkylene are O, NH, (C=O), NH(C=O), N—(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 37. The compound according to any one of items 31 to 36, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with (alkyl). (Item 39) 39. The compound according to any one of items 31 to 38, or a pharmaceutically acceptable salt thereof, wherein R1 is H, fluoro, NH2, NH(C1-C6 alkyl), or NH(C3-C6 cycloalkyl). (Item 40) 39. The compound according to any one of items 31 to 39, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; and m and n are each independently 0, 1, or 2. (Item 41) Compound of formula IIA-9: [ka] 41. The compound according to any one of items 31 to 40, or a pharmaceutically acceptable salt thereof, wherein K is C1-C4 alkylene, optionally substituted with hydroxy or alkoxy. (Item 42) Compounds of Formula III: [ka] 2. The compound according to item 1, wherein: Y is a straight chain C1-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkynylene, and up to two carbon atoms of said C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently selected from O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), or (C=O), R1 is H, halo, C1-C6 haloalkyl, or NR x’ R y’ where R x’ and R y’ are each independently H, C1-C6 alkyl, which is optionally substituted with up to three substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -COO(C1-C6 alkyl), -CONH2, and oxo, or a protecting group; or R1 is NH(C= O)—(C1-C6)alkyl, or NH—(C═N)—NH, any of which is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), —COO(C1-C6 alkyl), —CONH, and oxo; Ring D is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic heterocycloalkylene are optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), COO(C-C alkyl), CONH, and oxo; R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R4 is H or NR x” R y” where R x” and R y” are each independently H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 43) Compound of Formula IIIA: [ka] 43. The compound according to item 42, wherein: (Item 44) Ring D is [ka] [ka] 44. The compound according to item 42 or 43, selected from the group consisting of: (Item 45) A compound selected from the compounds set forth in Table 10, or a pharmaceutically acceptable salt thereof. (Item 46) A compound selected from the compounds set forth in Table 11, or a pharmaceutically acceptable salt thereof. (Item 47) Compound of Formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions defined in any one of items 1 to 44; u is H or an amino protecting group, or a pharmaceutically acceptable salt thereof. (Item 48) A compound selected from the compounds set forth in Table 12, or a pharmaceutically acceptable salt thereof. (Item 49) Compound of Formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions defined in any one of items 1 to 44; v’ and R v” One of them is H and the other is R v’ and R v” and the other is H or an amino protecting group, or a pharmaceutically acceptable salt thereof. (Item 50) A compound selected from the compounds set forth in Table 13, or a pharmaceutically acceptable salt thereof. (Item 51) Compound of Formula E: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, J, X 1 , X 2 , R 1’, R2, R3, R6, m, and n have the same definitions as in any one of items 1 to 44; and Y5 is a bond or a straight chain C1-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, wherein up to two carbon atoms of said C2-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkynylene are independently selected from O, (C=O), or [ka] wherein t' is 1, 2, 3, or 4, and R6 is H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 52) A compound selected from the compounds set forth in Table 14, or a pharmaceutically acceptable salt thereof. (Item 53) 47. A pharmaceutical composition comprising a compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 54) 53. A method for treating a bacterial infection in a patient in need of such treatment, the method comprising administering a compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 53. (Item 55) 55. The method of item 54, wherein the bacterial infection is caused by bacteria including gram-positive and gram-negative bacteria. (Item 56) The bacteria include Francisella tularensis, Burkholderia mallei, Burkholderia pseudomallei, Bacillus anthracis, Yersinia pestis, Salmonella.Clostridium. The method of item 55, comprising C. difficile, Citrobacter, Enterobacter, Burkholderia cepacia, Mycobacterium, Proteus, Streptococcus, Serratia, Enterobacteriaceae, Escherichia, Klebsiella, Pseudomonas, and Acinitobacter. (Item 57) Compounds of formula I-2: [ka] or a pharmaceutically acceptable salt thereof, comprising: The process comprising coupling a compound of formula A with a compound of formula B to obtain a compound of formula I-2: [ka] In the formula, rings B, K, L, Y, R1, R x , R y , R5, X 1 Item 58. The process, wherein m and q are as defined in any one of items 1 to 44, and PG is an amino protecting group. Compounds of formula I-6: [ka] or a pharmaceutically acceptable salt thereof, comprising: The process comprising coupling a compound of formula C with a compound of formula D under reductive amination conditions to obtain a compound of formula I-6: [ka] In the formula, ring A, ring B, J, L, R1, R 1’ , R2, R3, X 1 , X 2 , m, and n are as defined in any one of items 1 to 44; Y 5’ is a bond or a straight chain C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkynylene, and up to two carbon atoms of said C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are optionally independently selected from O, (C=O), or [ka] where t' is 1, 2, 3, or 4; R6 is H or C1-C6 alkyl; The above process, wherein R7 is H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C1-C6 alkylene-C3-C8 cycloalkyl. (Item 59) Compound of formula I-7: [ka] or a pharmaceutically acceptable salt thereof, comprising: the process comprising coupling a compound of formula E with a compound of formula F under reductive amination conditions to obtain a compound of formula I-7; [ka] In the formula, ring A, ring B, J, L, R1, R 1’ , R2, R3, X 1 , X 2 , m, and n are as defined in any one of items 1 to 44; Ring B1 is a nitrogen-containing monocyclic heterocycloalkylene, optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, OH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; Y5 is a bond or a straight chain C1-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkynylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy; The above process, wherein R6 is H or C1-C6 alkyl. DETAILED DESCRIPTION OF THE INVENTION

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein, including U.S. Patent Publication No. 2013 / 0090326, are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions thereof, will control.

[0013] As used herein, the terms "a," "an," and "the" include single member embodiments as well as multiple member embodiments.

[0014] As used herein, the term "about" means "approximately" and is used to modify a numerical value to indicate a defined range around that value. When "X" is a value, "about X" generally refers to a value between 0.95X and 1.05X. Reference to "about X" specifically refers to at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide support by the specification for a claim limitation of, for example, "0.98X." When the quantity "X" includes only integer values ​​(e.g., "X carbons"), "about X" refers to (X-1) to (X+1). In this case, as used herein, "about X" specifically refers to at least the values ​​X, X-1, and X+1.

[0015] When "about" is applied to the beginning of a numerical range, it applies to both ends of that range. Thus, "about 5 to 20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it applies to every value in that set. Thus, "about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%."

[0016] As used herein, wavy lines drawn into a structure may be used to indicate points of attachment to that structure. For example, [ka] So, " [ka] " indicates the point of attachment.

[0017] As used herein, the term "acyl" includes alkanoyl, aroyl, heterocycloyl, or heteroaroyl groups as defined herein. Examples of acyl groups include, but are not limited to, acetyl, benzoyl, and nicotinoyl.

[0018] As used herein, the term "alkanoyl" includes alkyl-C(O)- groups, where the alkyl group is as defined herein. Examples of alkanoyl groups include, but are not limited to, acetyl and propanoyl.

[0019] As used herein, the term "agent" includes a compound or mixture of compounds that, when added to a composition, tends to have a particular effect on the properties of the composition. For example, a composition that includes a thickening agent is likely to be more viscous than an otherwise identical comparative composition lacking the thickening agent.

[0020] As used herein, the term "alkyl" includes an aliphatic hydrocarbon chain that may be straight or branched. The chain may contain the indicated number of carbon atoms. For example, C1-C 10 indicates that the group can contain 1 to 10 (inclusive) carbon atoms in it. Unless otherwise specified, alkyl groups contain 1 to about 20 carbon atoms. In some embodiments, alkyl groups have 1 to about 10 carbon atoms. In some embodiments, alkyl groups ("lower alkyl") have 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain. Examples can include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1-butyl, 2-butyl, isobutyl (iBu), tert-butyl, pentyl, 2-methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, docecyl, cyclopentyl, or cyclohexyl.

[0021] The alkyl group may be an unsubstituted alkyl group or an optionally substituted alkyl group. If optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkyl group may be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, the alkyl group is an unsubstituted alkyl group or is not an optionally substituted alkyl group.

[0022] As used herein, "alkylene" includes di-substituted alkyl groups. Examples include methylene (-CH2-), propylene (-CH2CH2CH2-), and the like.

[0023] As used herein, the term "alkenyl" includes straight or branched chain hydrocarbons containing at least one carbon-carbon double bond. The chain may contain the number of carbon atoms indicated. For example, "C1-C 12 "Alkenyl" indicates that the group may have 1 to 12 (inclusive) carbon atoms and at least one carbon-carbon double bond. When the indicated number of carbon atoms is 1, C i The alkenyl is double-bonded to the carbon (i.e., the carbon corresponding to the oxo group). In certain embodiments, the chain contains 1 to 12, about 2 to 15, about 2 to 12, about 2 to 8, or about 2 to 6 carbon atoms. The alkenyl group may preferably be in one stereoisomer (i.e., cis- or, alternatively, trans-). Examples of alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, dodecenyl, cyclopentenyl, cyclohexenyl, 2-isopentenyl, allenyl, butadienyl, pentadienyl, 3-(1,4-pentadienyl), and hexadienyl.

[0024] An alkenyl group can be an unsubstituted alkenyl group or an optionally substituted alkenyl group. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkenyl group can be substituted with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, but the hydrogen atom substituent of the carbon-carbon double bond is not substituted with a hydroxy, amino, or thio group. In some embodiments, the alkenyl group is an unsubstituted alkenyl group or is not an optionally substituted alkenyl group.

[0025] As used herein, "alkenylene" includes di-substituted alkenyl groups, such as but-2-enylene (-CHCH=CHCH-).

[0026] As used herein, the term "alkynyl" includes straight-chain, branched, or cyclic hydrocarbons containing at least one carbon-carbon triple bond. Examples can include, but are not limited to, ethynyl, propargyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, or decynyl.

[0027] An alkynyl group can be an unsubstituted alkynyl group or an optionally substituted alkynyl group. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkynyl group can be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, but sp hybridized hydrogen atom substituents are not replaced with hydroxy, amino, or thio groups. In some embodiments, the alkynyl group is an unsubstituted alkynyl group or is not an optionally substituted alkynyl group.

[0028] As used herein, "alkynylene" includes di-substituted alkynyl groups, such as 2-butynylene (-CH2CCCH2-).

[0029] As used herein, the term "alkoxy" includes straight or branched chain saturated or unsaturated hydrocarbons containing at least one oxygen atom in an ether group (e.g., EtO-). The chain may contain the indicated number of carbon atoms. For example, "C1-C 12 "Alkoxy" indicates that the group may have 1 to 12 (inclusive) carbon atoms and at least one oxygen atom. 12 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexoxy.

[0030] The alkoxy group may be an unsubstituted alkoxy group or an optionally substituted alkoxy group. If optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkoxy group may be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, except that the hydrogen atom alpha to the ether oxygen is not replaced with a hydroxy, amino, or thio group. In some embodiments, the alkoxy group is an unsubstituted alkoxy group or is not an optionally substituted alkoxy group.

[0031] As used herein, the term "aryl" includes cyclic aromatic carbocyclic ring systems containing 6 to 18 carbons. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetracenyl, biphenyl, and phenanthrenyl.

[0032] As used herein, the term "cycloalkyl" includes non-aromatic saturated monocyclic or polycyclic ring systems that may contain the indicated number of carbon atoms. For example, C3-C 12 indicates that the group can have 3 to 12 (inclusive) carbon atoms in it. Unless otherwise specified, cycloalkyl groups contain from about 3 to about 20 carbon atoms. In some embodiments, cycloalkyl groups have 3 to about 12 carbon atoms in the group. In some embodiments, cycloalkyl groups have 3 to about 7 carbon atoms in the group. Examples can include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl. The term "cycloalkyl" also includes polycyclic rings, such as bicyclic cycloalkyls or tricyclic cycloalkyls, which may be in fused, bridged, or spiro configurations.

[0033] As used herein, the term "cycloalkylene" includes di-substituted cycloalkyl groups.

[0034] The terms "disorder" and "disease" are used interchangeably herein with respect to the condition of a subject. A disorder is a disturbance or disruption that affects the normal function of a subject's body. A disease is a pathological condition of an organ, body part, or system characterized by a discernible group of symptoms resulting from a variety of causes, such as infection, genetic defect, or environmental stress. A disorder or disease can also refer to a biofilm-associated disorder characterized by disease-associated bacterial growth or a disorder caused by a planktonic bacterial phenotype.

[0035] As used herein, the term "effective amount" or "effective dosage" includes an amount sufficient to achieve a desired result, and thus depends on the ingredient and the desired result, although determining the effective amount once the desired effect has been determined is within the skill of one of ordinary skill in the art.

[0036] As used herein, "fluoroalkyl" includes alkyl groups in which the alkyl group contains one or more fluoro substituents. Examples include, but are not limited to, trifluoromethyl.

[0037] As used herein, a "geminal" substitution includes two or more substituents directly attached to the same atom. An example is 3,3-dimethyl substitution on a cyclohexyl or spirocyclohexyl ring.

[0038] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

[0039] As used herein, "heterocycloalkyl" includes a non-aromatic saturated ring of about 3 to about 12 ring atoms (e.g., 5 to about 10 ring atoms, 3 to about 8 ring atoms, or 3 to about 6 ring atoms), in which one or more atoms of the ring system is an element(s) other than carbon, e.g., nitrogen, oxygen, or sulfur. A heterocycloalkyl group optionally includes at least one sp 2The heterocycloalkyl may contain a heteroatom (e.g., a ring incorporating a carbonyl, an endocyclic olefin, or an exocyclic olefin). In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl is optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Monocyclic heterocycle refers to a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain 0, 1, 2, or 3 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycloalkyls include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, and pyrazolinyl. These include, but are not limited to, pyrazolidinyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.

[0040] As used herein, the term "heterocycloalkylene" includes di-substituted heterocycloalkyl groups.

[0041] The term "heterocycloalkyl" also includes polycyclic rings, such as bicyclic or tricyclic heterocycles, which may be in fused, bridged, or spiro configurations. A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocyclic ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or by an alkenylene bridge of 2, 3, or 4 carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1.0]heptane, 3-azabicyclo[3.2.0]heptane, (3aR,6aS)-hexahydro-1H-2λ2-cyclopenta[c]pyrrole, (3aR,7aS)-octahydro-2λ2-isoindole.

[0042] Tricyclic heterocycles are exemplified by bicyclic heterocycles fused to a phenyl group, or bicyclic heterocycles fused to a monocyclic cycloalkyl, or bicyclic heterocycles fused to a monocyclic cycloalkenyl, or bicyclic heterocycles fused to a monocyclic heterocycle, or bicyclic heterocycles in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or by an alkenylene bridge of 2, 3, or 4 carbon atoms.

[0043] A heterocycloalkyl group can be an unsubstituted heterocycloalkyl group or an optionally substituted heterocycloalkyl group. If optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the group can be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, a substituted heterocyclyl group can incorporate an exocyclic or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some embodiments, the heterocycloalkyl group is an unsubstituted heterocycloalkyl group or is not an optionally substituted heterocycloalkyl group.

[0044] The monocyclic, bicyclic, and tricyclic heterocycles can be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring, and can be unsubstituted or substituted.

[0045] As used herein, the term "hydrophilic moiety" or "hydrophilic group" includes moieties or functional groups that have a strong affinity for water. Examples may include, but are not limited to, charged moieties, such as cationic or anionic moieties, or polar uncharged moieties, such as alkoxy or amine groups.

[0046] As used herein, the term "hydroxyalkyl" includes an alkyl group in which at least one hydrogen substituent is replaced with an alcohol (-OH) group. In certain embodiments, the hydroxyalkyl group has one alcohol group. In certain embodiments, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In certain embodiments, the hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples can include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0047] When any two substituents from a list of alternatives or any two instances of the same substituent are "independently selected," those groups may be the same or different. For example, R a and R b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then two R a group and two R b In a molecule having groups, all of the groups may be alkyl groups (e.g., four different alkyl groups). Alternatively, the first R a is alkyl and the second R a is fluoro and the first R b is hydroxyalkyl, and the second R b may be amino (or any other substituent from that group). Alternatively, both R a and the first R b is fluoro and the second R b may be alkyl (i.e., some pairs of substituents may be the same and other pairs may be different).

[0048] An "amino-protecting group" is a protecting group suitable for preventing undesired reactions at an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl, acyl groups such as alkanoyl groups, e.g., acetyl and trifluoroacetyl, alkoxycarbonyl groups, e.g., tert-butoxycarbonyl (Boc), arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc), arylmethyl groups, e.g., benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl.

[0049] A "hydroxyl protecting group" is a protecting group suitable for preventing undesired reactions at a hydroxyl oxygen. Representative hydroxy protecting groups include, but are not limited to, acyl groups such as alkanoyl groups, e.g., acetyl, arylmethyl groups, e.g., benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl, silyl groups, e.g., trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS), and the like.

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Examples of the salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0051] "Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness of the free base and are not biologically or otherwise objectionable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, orotic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0052] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference).

[0053] As used herein, "or" is generally intended to be interpreted non-exclusively. For example, an embodiment of "a composition comprising A or B" generally refers to a composition that includes both A and B. "Or," however, is intended to be interpreted to exclude stated embodiments that cannot be consistently combined (e.g., a composition with a pH of 9-10 or 7-8).

[0054] As used herein, "spiro bicyclic cycloalkyl" includes cycloalkyls in which geminal substituents on carbon atoms are replaced to participate in the formation of a 1,1-substituted ring. For example, but not limited to, -C(R 1 )(R 2 )-group, R 1 and R 2 But R 1 and R 2 is attached to form a cyclopropyl ring, incorporating the carbon to which it is attached, then it is a spiro bicyclic cycloalkyl group (ie, spirocyclopropyl).

[0055] As used herein, the term "spirobicyclic cycloalkylene" includes di-substituted spiro bicyclic cycloalkyl groups.

[0056] As used herein, "spiro bicyclic heterocycloalkyl" includes heterocycloalkyls in which geminal substituents on carbon atoms are replaced to participate in the formation of a 1,1-substituted ring. For example, but not limited to, -C(R 1 )(R 2 )-group, R 1 and R 2 But R 1 and R 2 is attached to form a pyrrolidine ring, incorporating the carbon to which it is attached, then this is a spiro bicyclic heterocycloalkyl group.

[0057] As used herein, the term "spirobicyclic heterocycloalkylene" embraces di-point substituted spiro bicyclic heterocycloalkyl groups.

[0058] Some compounds disclosed herein are characterized by the presence of an amino functional group, and therefore, those skilled in the art will understand that the compounds may be isolated as salts in which the nitrogen of the amino functional group has been quaternized.

[0059] As used herein, the terms "treat," "treating," or "treatment" include administering or applying a composition (e.g., a composition described herein) in an amount, manner (e.g., dosing schedule), and mode (e.g., route of administration) effective to ameliorate a disorder or its symptoms, or to prevent or slow the progression of a disorder or its symptoms. Such improvement can include, but is not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of the disease, stabilization of the condition (i.e., not worsening), delay or slowing of disease progression, improvement or palliation of the condition, reduction in disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable.

[0060] Embodiment compound In a first aspect, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is (C=O), (C=S), (C=NR z ), (S=O), or SO2, where R z is H, C1-C6 alkyl, or CN; Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, wherein the monocyclic heterocycloalkylene or bicyclic heterocycloalkylene is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), COOH, COO(C-C alkyl), -CONH, and oxo; J is absent, C1-C6 alkylene, heterocycloalkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which is optionally substituted with up to three substituents independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, and OH, wherein for each occurrence of C1-C6 alkylene, up to two methylene units of said C1-C6 alkylene are independently and optionally selected from O, S, SO2, C=O, or [ka] where t is 1, 2, 3, or 4; X 1 and X 2 are each independently CH or N, Y is a straight chain C1-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, and up to two carbon atoms of the C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently selected from O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 alkylene-cycloalkyl), N-(C 3-8cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=O), or [ka] where t' is 1, 2, 3, or 4; Ring B is a monocyclic cycloalkylene or a monocyclic heterocycloalkylene, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, NH, C-C haloalkyl, OH, COOH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; L is absent or C1-C6 alkylene, wherein up to two methylene units of said C1-C6 alkylene are independently O, NH, (C=O), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 alkyl), R1 is H, halo, C1-C6 haloalkyl, NR x’ R y’ or monocyclic heterocycloalkyl optionally substituted with NH, NH(C-C alkyl), N(C-C alkyl), where R x’ and R y’are each independently H, C1-C6 alkyl, C3-C8 cycloalkyl, or an amino protecting group, and the C1-C6 alkyl and C3-C8 cycloalkyl optionally have up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —COO(C1-C6 alkyl), —CONH2, and oxo. or R1 is NH(C=O)-(C1-C6)alkyl, or NH-(C=NH)-NH2, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, and oxo; R 1’ is H or NR x R y where R x and R y are each independently H, C-C alkyl, C-C alkyl-SO, CO(C-C alkyl), CO—(C-C alkylene)-NH, or an amino protecting group; R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, CN, OH, NH2, O(C1-C6 haloalkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -COO(C1-C6 alkyl), -CONH2, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; m and n are each independently 0, 1, 2, or 3.

[0061] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, Z is (C=S), (C=NR z ), S=O, or SO2, where R z is H, C1-C6 alkyl, or CN.

[0062] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, Z is C=NH, C=N(C1-C6 alkyl), or C=N-CN.

[0063] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, Z is —(C═O)—.

[0064] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, ring A is a 4-8 membered monocyclic heterocycloalkylene or a 6-12 membered bicyclic heterocycloalkylene, wherein the monocyclic heterocycloalkylene and bicyclic heterocycloalkylene are optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, C-C haloalkyl, phenyl, OH, NH, COOH, COO(C-C alkyl), and CONH.

[0065] In another embodiment, Ring A is a 4-7 membered monocyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of halo, C-C alkyl, C-C hydroxyalkyl, phenyl, COOH, and COO(C-C alkyl). In another embodiment, Ring A is a 4-7 membered monocyclic heterocycloalkylene optionally substituted with up to two substituents independently selected from the group consisting of halo, C-C alkyl, C-C hydroxyalkyl, phenyl, COOH, and COO(C-C alkyl), wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen and oxygen. In another embodiment, Ring A contains two nitrogen atoms. In another embodiment, Ring A is a 6-membered monocyclic heterocycloalkylene optionally substituted with halo, C-C alkyl, C-C hydroxyalkyl, phenyl, COOH, or COO(C-C alkyl), wherein the monocyclic heterocycloalkylene contains two nitrogen atoms.

[0066] In another embodiment, Ring A is a 6-12 membered bicyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, C-C haloalkyl, phenyl, OH, NH, COOH, COO(C-C alkyl), and -CONH. In another embodiment, Ring A is a 6-11 membered bicyclic heterocycloalkylene optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, halo, C-C haloalkyl, phenyl, OH, NH, COOH, COO(C-C alkyl), and -CONH, wherein the bicyclic heterocycloalkylene contains up to three heteroatoms selected from nitrogen and oxygen. In another embodiment, ring A is a 6-10 membered bicyclic heterocycloalkylene containing up to three heteroatoms selected from nitrogen and oxygen, hi another embodiment, ring A is a 6-10 membered fused, spiro, or bridged bicyclic heterocycloalkylene containing up to three heteroatoms selected from nitrogen and oxygen.

[0067] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, ring A is selected from any of the moieties shown in Table 1: Table 1 [Table 1-1] [Table 1-2]

[0068] In another embodiment of the compound of Formula I, or a pharmaceutically acceptable salt thereof, J is absent.

[0069] In another embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, J is C-C alkylene, heterocycloalkylene, C-C alkylene-heterocycloalkylene, or C-C alkylene-cycloalkylene, any of which is optionally substituted with up to two substituents independently selected from halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, NH, CN, or OH, and wherein for each occurrence of C-C alkylene, one or two methylene units of said C-C alkylene are independently and optionally selected from (C=O) or [ka] where t is 1, 2, or 3.

[0070] In another embodiment, J is C-C alkylene, C-C alkylene-heterocycloalkylene, or C-C alkylene-cycloalkylene, wherein one methylene unit of the C-C alkylene may be replaced with (C=O). In another embodiment, J is C-C alkylene, wherein one methylene unit of the C-C alkylene may be replaced with (C=O). In another embodiment, J is (C=O)-heterocycloalkylene, wherein the heterocycloalkylene is a 5- or 6-membered nitrogen-containing heterocycloalkylene, optionally substituted with up to two C-C alkyls. In another embodiment, J is (C=O)-(C-C cycloalkylene).

[0071] In another embodiment, J is C-C alkylene, optionally substituted with halo, C-C haloalkyl, or OH, wherein one methylene unit of the C-C alkylene may be replaced with (C=O). In another embodiment, J is C-C alkylene, wherein one methylene unit of the C-C alkylene may be replaced with (C=O) and another methylene unit of the C-C alkylene may be replaced with [ka] where t is 1, 2, 3, or 4. In another embodiment, t is 1 or 2.

[0072] In another embodiment, J is C1-C6 alkylene, optionally substituted with CF3 or OH, wherein one methylene unit of the optionally substituted C1-C6 alkylene may be replaced with -(C=O)-.

[0073] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, J is selected from any of the moieties shown in Table 2: Table 2 [Table 2]

[0074] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1’ is H or NR x R y where R x and R y are each independently H, C-C alkyl, C-C alkyl-SO, CO(C-C alkyl), or CO—(C-C alkylene)-NH. 1’ is H, NH, NH(C-C alkyl), NH(C-C alkyl), NH—CO(C-C alkyl), or NH—CO—(C-C alkylene)-NH. In another embodiment, R 1’ is H, NH, or NH(C-C alkyl). In another embodiment, R 1’ is H or NH. In another embodiment, R 1’ is H. In another embodiment, R 1’ is NH2.

[0075] R 1’ is H or NR x R y where Rx and R y are each independently H, C1-C6 alkyl, C1-C6 alkyl-SO3, CO(C1-C6 alkyl), CO—(C1-C6 alkylene)-NH2, or an amino protecting group.

[0076] In another embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, Z is (C=O), ring A is a 4-7 membered monocyclic heterocycloalkylene optionally substituted with up to two substituents independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 hydroxyalkyl, phenyl, COOH, and COO(C1-C6 alkyl), wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen or oxygen, and J is C1 -C6 alkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which is optionally substituted with up to two substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or OH, wherein for each occurrence of C1-C6 alkylene, one or two methylene units of said C1-C6 alkylene are independently optionally selected from C=O or [ka] where t is 1, 2, or 3; 1’ is H, NH, or NH(C-C alkyl). In another embodiment, Z is (C=O), ring A is selected from any of the moieties shown in Table 1, J is selected from any of the moieties shown in Table 2, and R 1’ is H, NH, or NH(C-C alkyl).

[0077] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, [ka] is selected from any of the moieties shown in Table 3: Table 3 [Table 3-1] [Table 3-2] [Table 3-3]

[0078] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein each R is independently C-C alkyl, halo, CN, OH, NH, NH(C-C alkyl), O(C-C haloalkyl), N(C-C alkyl), COO(C-C alkyl), CONH, C-C haloalkyl, or C-C alkoxy, where m is 0, 1, 2, or 3. In another embodiment, each R is independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, O(C-C haloalkyl), and C-C haloalkyl, where m is 0, 1, or 2.

[0079] In another embodiment, [ka] teeth [ka] is.

[0080] In another embodiment, [ka] teeth [ka] is.

[0081] In another embodiment, [ka] teeth, [ka] wherein each R3 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, O(C1-C6 haloalkyl), and C1-C6 haloalkyl, and wherein m is 0, 1, or 2.

[0082] In another embodiment, [ka] teeth [ka] wherein each R3 is independently C1-C6 alkyl, C1-C6 alkoxy, halo, O(C1-C6 haloalkyl), and C1-C6 haloalkyl, where m is 0, 1, or 2.

[0083] In another embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0084] In one embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, Y is a straight chain C1-C8 alkylene optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, wherein up to two methylene units of said C1-C8 alkylene are optionally, independently, O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C1-C6 alkoxy). 1-6 Alkylene-C 3-8 cycloalkyl), N-(C 3-8 cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=O), or [ka] where t' is 1 or 2.

[0085] In another embodiment, Y is a straight chain C1-C6 alkylene optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, wherein up to two methylene units of the C1-C8 alkylene are optionally, independently, O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-C 3-8 cycloalkyl), N-(C 3-8 cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=O), or [ka] where t' is 1 or 2.

[0086] In another embodiment, Y is a straight chain C1-C4 alkylene optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, wherein up to two methylene units of the C1-C8 alkylene are optionally, independently, O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-C3 cycloalkyl), N-(C3 cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=O), or [ka] where t' is 1 or 2.

[0087] In another embodiment, Y is CR i R ii where R i and R ii are each independently H, OH, NH, CN, halo, C-C alkyl, C-C haloalkyl, COO(C-C alkyl), COOH, CONH, or C-C alkoxy. i and R ii are each independently H, C1-C6 alkyl, COO(C1-C6 alkyl), or COOH. i R ii is CH, CH(C-C alkyl), C(C-C alkyl), CHCOO(C-C alkyl), and CHCOOH. In another embodiment, CR i R ii is CH2, CH(CH3), CH(COOEt), or CH(COOH). In another embodiment, CR i R ii is CH2.

[0088] In another embodiment, Y is —C(R i R j)-C(R i’ R j’ )-, where R i , R j , R i’ , R j’ are each independently H or C1-C6 alkyl, and C(R i R j ) and C(R i’ R j’ ) are each independently optionally selected from NH, N—(C 1-6 alkyl), N-(C1-C6 hydroxyalkyl), N-(C1-C6 haloalkyl), N-(C 1-6 Alkylene-C 3-8 cycloalkyl), N-(C 3-8 cycloalkyl), [ka] or (C=O), where t' is 1 or 2.

[0089] In another embodiment, Y is C—(R i R j )-C(R i’ R j’ )-, which means [ka] is selected from the group consisting of:

[0090] In another embodiment, Y is a straight chain C alkylene, C alkenylene, or C alkynylene, any of which is optionally substituted with OH, NH, halo, C-C alkyl, or C-C alkoxy, wherein one or two carbon atoms of the C alkylene, C alkenylene, or C alkynylene are selected from the group consisting of O, NH, N—(C-C alkyl), N—(C-C hydroxyalkyl), N—(C-C haloalkyl), N—(C 1-6 Alkylene-C 3-8 cycloalkyl), NH(C=O)-, N-(C 1-6In another embodiment, Y is a straight chain C alkylene optionally substituted with NH or C-C alkyl, wherein up to two single methylene units of the straight chain C alkylene are optionally, independently, O, NH, N—(C-C alkyl), N—(C-C hydroxyalkyl), N—(C-C haloalkyl), N—(C 1-6 Alkylene-C 3-8 cycloalkyl), or (C=O).

[0091] In another embodiment, Y is the optionally substituted and substituted straight chain C alkylene, which is [ka] is selected from the group consisting of:

[0092] In another embodiment, Y is a straight chain C alkylene, C alkenylene, or C alkynylene, any of which is optionally substituted with OH, NH, halo, C-C alkyl, or C-C alkoxy, wherein one or two carbon atoms of the C alkylene, C alkenylene, or C alkynylene are selected from the group consisting of O, NH, N—(C-C alkyl), N—(C-C hydroxyalkyl), N—(C-C haloalkyl), N—(C 1-6 Alkylene-cycloalkyl), NH(C=O)-, N-(C 1-6 In another embodiment, Y is a straight-chain C alkylene optionally substituted with NH or C-C alkyl, wherein up to two single methylene units of the straight-chain C alkylene are optionally, independently, replaced with O, NH, N—(C-C alkyl), or (C═O).

[0093] In another embodiment, Y is the optionally substituted and substituted straight chain C4 alkylene, which is [ka] is selected from the group consisting of:

[0094] In another embodiment, Y is selected from any of the moieties shown in Table 4: Table 4 [Table 4]

[0095] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0096] In another embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, Ring B is a 4- to 7-membered monocyclic cycloalkylene or a 4- to 7-membered monocyclic heterocycloalkylene, either of which is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, NH, C-C haloalkyl, OH, COO(C-C alkyl), COOH, and C-C hydroxyalkyl.

[0097] In another embodiment, Ring B is a 4-6 membered monocyclic cycloalkylene, optionally substituted with up to two substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, NH, C-C haloalkyl, OH, COO(C-C alkyl), COOH, and C-C hydroxyalkyl. In another embodiment, Ring B is a 4-6 membered monocyclic cycloalkylene.

[0098] In another embodiment, Ring B is a 4- to 7-membered monocyclic heterocycloalkylene optionally substituted with up to two substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, NH, C-C haloalkyl, OH, COO(C-C alkyl), COOH, and C-C hydroxyalkyl, wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen and oxygen. In another embodiment, Ring B is a 5- or 6-membered monocyclic heterocycloalkylene optionally substituted with up to two substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, NH, C-C haloalkyl, OH, COO(C-C alkyl), COOH, and C-C hydroxyalkyl, wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen and oxygen.

[0099] In another embodiment, Ring B is selected from any of the moieties shown in Table 5: Table 5 [Table 5]

[0100] In another embodiment of the compound of Formula I, or a pharmaceutically acceptable salt thereof, L is absent.

[0101] In another embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, L is a straight chain or branched C-C alkylene, optionally substituted with C-C alkoxy, halo, CN, OH, NH, COO(C-C alkyl), or CONH, wherein up to two methylene units of said C-C alkylene are optionally, independently, O, NH, (C=O), NH(C=O), N—(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6In another embodiment, L is a straight chain or branched C1-C6 alkylene, wherein up to two methylene units of the C1-C6 alkylene are optionally, independently, O, NH, (C=O), NH(C=O), N—(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 It can be replaced by alkyl.

[0102] In another embodiment, L is a straight chain or branched C1-C4 alkylene, wherein up to two methylene units of the C1-C4 alkylene are optionally independently NH, (C=O), NH(C=O), (C=NH), NH(C=N), or N—(C 1-6 In another embodiment, L is a straight chain or branched C1-C4 alkylene, optionally substituted with OH or NH2, wherein one methylene unit of the C1-C4 alkylene may be replaced with (C=O). In another embodiment, L is a C1-C4 alkylene.

[0103] In another embodiment, L is absent or is CH2, CH2CH2, C(Me)2, CH(Me), CH(Et), (C=NH), [ka] is.

[0104] In another embodiment, L is absent or CH2.

[0105] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is H, halo, C1-C6 haloalkyl, NR x’ R y’ or monocyclic heterocycloalkyl optionally substituted with NH, NH(C-C alkyl), N(C-C alkyl), where R x’ and R y’are each independently H, C1-C6 alkyl, C3-C8 cycloalkyl, or an amino protecting group. In another embodiment, R1 is a 4-6 membered monocyclic heterocycloalkyl optionally substituted with H, NH2, NH(C1-C6 alkyl), NH(C1-C6 alkyl)2, NH(C3-C6 cycloalkyl), CF3, or NH2. In another embodiment, R1 is H or NH2. In another embodiment, R1 is H. In another embodiment, R1 is NH2.

[0106] In another embodiment, R1 is NH(C=O)-(C1-C6)alkyl, or NH-(C=NH)-NH2, either of which is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, and oxo. In another embodiment, R1 is NH(C=O)-(C1-C6)alkyl, or NH-(C=NH)-NH2.

[0107] In another embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, Y is any one of the moieties shown in Table 4, Ring B is any one of the moieties shown in Table 5, and L is a straight chain or branched C1-C4 alkylene, wherein up to two methylene units of the C1-C4 alkylene are optionally, independently, NH, (C=O), NH(C=O), (C=NH), NH(C=N), or N-(C 1-6 In another embodiment, Y is any one of the moieties shown in Table 4, ring B is any one of the moieties shown in Table 5, L is absent or is C-C alkylene, and R is H or NH.

[0108] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, [ka] is selected from one of the moieties shown in Table 6: Table 6 [Table 6-1] [Table 6-2] [Table 6-3]

[0109] In another embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, each R2 and R3 is independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, O(C1-C6 haloalkyl), and C1-C6 alkoxy; and m and n are each independently 0, 1, or 2. In another embodiment, each R3 is C1-C6 alkyl, halo, C1-C6 haloalkyl, O(C1-C6 haloalkyl), or C1-C6 alkoxy; and m is 0, 1, or 2.

[0110] In another embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, n is 0, m is 0, 1, or 2, and each R3 is independently selected from the group consisting of CH3, Cl, F, OCH3, OCF3, and CF3.

[0111] In another embodiment, the compound of formula I is a compound of formula I-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, J, L, Y, R, R 1’ , R3, X 1 , and m are as defined herein.

[0112] In another embodiment, the compound of formula I or I-1 is a compound of formula I-2: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, Y, R, R, R x , R y , X 1 and m are as defined herein; K is C1-C5 alkylene, a 4- to 7-membered heterocycloalkylene, or a 4- to 6-membered cycloalkylene, any of which is optionally substituted with up to two substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or OH, and wherein one methylene unit of the C1-C5 alkylene is optionally [ka] where t is 1, 2, 3, or 4; each R5 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, COOH, COO(C1-C6 alkyl), CONH2, or oxo; R x and R y are each independently H, C1-C6 alkyl, C1-C6 alkyl-SO3, CO(C1-C6 alkyl), CO—(C1-C6 alkylene)-NH2, and q is 0, 1, 2, or 3.

[0113] In another embodiment of the compound of formula I-2 or a pharmaceutically acceptable salt thereof, K is C1-C5 alkylene, optionally substituted with C1-C6 haloalkyl, NH2, or OH, wherein one methylene unit of said C1-C5 alkylene is optionally [ka] where t is 1 or 2, each R is independently halo, C-C alkyl, C-C hydroxyalkyl, phenyl, COOH, and COO(C-C alkyl), and q is 0, 1, or 2.

[0114] In another embodiment, the compound of formula I, I-1, or I-2 is a compound of formula I-3: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, Y, K, R, R, R, R x , q, and m are as defined herein.

[0115] In another embodiment of a compound of formula I-3 or a pharmaceutically acceptable salt thereof, K is C-C alkylene optionally substituted with halo, C-C alkoxy, C-C haloalkyl, or OH; each R is independently C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, phenyl, OH, NH, COOH, or COO(C-C alkyl); and q is 0, 1, or 2.

[0116] In another embodiment, the compound of formula I, I-1, I-2, or I-3 is a compound of formula I-4: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, Y, K, R x , R x’ , R3, R5, q, and m are as defined herein.

[0117] In another embodiment of the compound of Formula I-4 or a pharmaceutically acceptable salt thereof, Y is a straight chain C1-C4 alkylene optionally substituted with C1-C6 alkyl, COOH, COO(C1-C6 alkyl), or NH2, wherein up to two methylene units of said C1-C4 alkylene are optionally, independently, (C=O), O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-C 3-6 cycloalkyl), N-(C 3-8 cycloalkyl), or [ka] where t' is 1 or 2, each R is independently C-C alkyl, halo, C-C haloalkyl, O(C-C haloalkyl), or C-C alkoxy, m is 0, 1, or 2, and R x and R x’ are each independently H or C1-C6 alkyl.

[0118] In another embodiment, the compound of formula I, I-1, I-2, I-3, or I-4 is a compound of formula I-5: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, Y, K, R3, R5, q, and m are as defined herein.

[0119] In another aspect, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is —(C═O)—; Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, wherein the monocyclic heterocycloalkylene or the bicyclic heterocycloalkylene is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), —COO(C-C alkyl), —COONH, and oxo; J is C1-C6 alkylene, optionally substituted with halo, hydroxy, or alkoxy, wherein one or two carbons of the C1-C6 alkylene may optionally be replaced with O, S, SO2, or C=O; R x and R y are each independently H, C1-C6 alkyl, or a protecting group; X 1 and X 2 are each independently CH or N, Y is a straight chain C1-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkynylene, wherein up to two carbon atoms of the C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently selected from O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-cycloalkyl), NH(C=O), N-(C 1-6 alkyl)(C=O), or (C=O), Ring B is a monocyclic cycloalkylene or monocyclic heterocycloalkylene, which is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, OH, —COO(C-C alkyl), —COONH, and C-C hydroxyalkyl; L is absent or C1-C6 alkylene, wherein up to two carbon atoms of said C1-C6 alkylene are O, NH, (C=O), NH(C=O), N-(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 alkyl), R1 is H, halo, haloalkyl, NR x’ R y’ where R x’ and R y’ are each independently H, C-C alkyl, which is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), —COO(C-C alkyl), —COONH, and oxo, or a protecting group, NH(C═O)—(C-C) alkyl, or NH—(C═N)—NH, which is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), —COO(C-C alkyl), —COONH, and oxo; R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -COO(C1-C6 alkyl), -COONH2, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; m and n are each independently 0, 1, 2, or 3.

[0120] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Z is —(C═O)—.

[0121] In another embodiment of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkyene, wherein the monocyclic heterocycloalkylene and bicyclic heterocycloalkylene are optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo.

[0122] In another embodiment, Ring A is a monocyclic heterocycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo.

[0123] In another embodiment, Ring A is a bicyclic heterocycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo.

[0124] In another embodiment, Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkyene, wherein the monocyclic heterocycloalkylene and bicyclic heterocycloalkylene are: [ka] wherein Q is N, and Q and Q are each independently selected from the group consisting of C, N, S, or O, and wherein the monocyclic heterocycloalkylene and bicyclic heterocycloalkylene are optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, —COH, —COMe, —COEt, and oxo.

[0125] In another embodiment, ring A is [ka] [ka] wherein each R5 is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo, and wherein q is 1, 2, or 3.

[0126] In another embodiment, ring A is [ka] [ka] is selected from the group consisting of:

[0127] In another embodiment of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, one of the C1-C6 alkylene carbons of J is -(C=O)-.

[0128] In another embodiment, J is optionally substituted with -OH.

[0129] In another embodiment, J is CH2, [ka] is selected from the group consisting of:

[0130] In another embodiment, J is CH2, [ka] is selected from the group consisting of:

[0131] In another embodiment, J is CH2, [ka] is selected from the group consisting of:

[0132] In another embodiment, J is [ka] is.

[0133] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, NR x R y is selected from the group consisting of NH2, NHMe, NHEt, NHPG, N(Me)2, and N(Et)2.

[0134] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, (R x R y )NJ is H2N-CH2-, [ka] is selected from the group consisting of:

[0135] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, (R x R y )NJ is H2N-CH2-, [ka] is selected from the group consisting of:

[0136] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, (R x R y )NJ is H2N-CH2-, [ka] is selected from the group consisting of:

[0137] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0138] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0139] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein each R4 is independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and m is 0, 1, or 2.

[0140] In another embodiment, [ka] teeth [ka] is.

[0141] In another embodiment, [ka] teeth [ka] wherein each R3 is independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and m is 0, 1, or 2.

[0142] In another embodiment, [ka] is selected from one of the moieties shown in Table 7: Table 7 [Table 7]

[0143] In another embodiment, [ka] teeth, [ka] is.

[0144] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Y is Y1, and Y1 is -C(R i Rj )-, where R i , and R i’ are each independently H or C-C alkyl, which may be optionally substituted with halo, or hydroxy; C(R i R j ) or C(R i’ R j’ ) is NH, N-(C 1-6 It may be replaced by (C=O), or (C=O).

[0145] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Y is Y1, and Y1 is CR i R ii which is selected from the group consisting of CH2, CH(C1-C6 alkyl), C(C1-C6 alkyl)2, CH-COO(C1-C6 alkyl) and CHCOOH.

[0146] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Y 1 is selected from the group consisting of CH 2 , CH(CH 3 ), CH(COOEt), and CH(COOH).

[0147] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Y is Y2, and Y2 is -C(R i R j )-C(R i’ R j’ )-, where R i , R j , R i’ , R j’ are each independently H or C-C alkyl, optionally substituted with OH or halo, where C(R i R j ) or C(R i’ R j’ ) is NH, N-(C 1-6 It may be replaced by (C=O), or (C=O).

[0148] In another embodiment of the compound of Formula I or II or a pharmaceutically acceptable salt thereof, Y2 is [ka] [ka] is selected from the group consisting of:

[0149] In another embodiment, Y is Y3, and Y3 is a straight chain C3 alkylene, C3 alkenylene, or C3 alkynylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein one or two carbon atoms of the C3 alkylene, C3 alkenylene, or C3 alkynylene are selected from the group consisting of O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl ... 1-6 alkylene-cycloalkyl), -NH(C=O)-, -N-(C 1-6 alkyl)(C=O)-, -O(C=O)-, or -(C=O).

[0150] In another embodiment, Y3 is a C3 alkylene or a C3 alkenylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein one or two carbon atoms of the C3 alkylene or C3 alkenylene are selected from the group consisting of O, NH, N-(C1-C6 alkyl), N-(C1-C6 hydroxyalkyl), N-(C1-C6 haloalkyl), N-(C 1-6 alkylene-cycloalkyl), -NH(C=O)-, -N-(C 1-6 alkyl)(C=O)-, -O(C=O)-, or -(C=O)-.

[0151] In another embodiment, Y3 is [ka] is selected from the group consisting of:

[0152] In another embodiment, Y3 is [ka] [ka] is selected from the group consisting of:

[0153] In another embodiment, Y is Y4, and Y4 is a straight chain C4 alkylene, C4 alkenylene, or C4 alkynylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein one or two carbon atoms of the C4 alkylene, C4 alkenylene, or C4 alkynylene are selected from the group consisting of O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl ... 1-6 alkylene-cycloalkyl), -NH(C=O)-, -N-(C 1-6 alkyl)(C=O)-, -O(C=O)-, or -(C=O)-.

[0154] In another embodiment, Y4 is C4 alkylene, or C4 alkenylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein one or two carbon atoms of the C3-C8 alkylene, C3-C8 alkenylene are selected from the group consisting of O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 alkylene-cycloalkyl), -NH(C=O)-, -N-(C 1-6 alkyl)(C=O)-, -O(C=O)-, or -(C=O)-.

[0155] In another embodiment, Y4 is [ka] is selected from the group consisting of:

[0156] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, [ka] is selected from any of the moieties shown in Table 7, and Y is selected from any of the moieties shown in Table 8: Table 8 [Table 8]

[0157] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0158] In another embodiment of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Ring B is a 4- to 7-membered monocyclic cycloalkylene or a 4- to 7-membered monocyclic heterocycloalkylene, either of which is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, OH, —COO(C-C alkyl), —COONH, and C-C hydroxyalkyl.

[0159] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Ring B is [ka] any of which is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, OH, —COO(C-C alkyl), —COONH, and C-C hydroxyalkyl.

[0160] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, Ring B is selected from any of the moieties shown in Table 9: Table 9 [Table 9]

[0161] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, L is absent.

[0162] In another embodiment, L is a straight chain or branched C1-C6 alkylene, wherein up to two carbon atoms of the C1-C6 alkylene are O, NH, (C=O), NH(C=O), N—(C 1-6 alkyl)(C=O), (C=NH), NH(C=N), or N-(C 1-6 It may be replaced by alkyl.

[0163] In another embodiment, L is -CH2-.

[0164] In another embodiment, L is -CH(Me)-.

[0165] In another embodiment, L is -CH(Et)-.

[0166] In another embodiment, L is C=O.

[0167] In another embodiment of the compound of Formula I or II or a pharmaceutically acceptable salt thereof, R1 is H, fluoro, NH2, NH(C1-C6 alkyl) NH(C3-C6 cycloalkyl), or a protecting group.

[0168] In another embodiment of a compound of Formula I or II or a pharmaceutically acceptable salt thereof, R1 is H, F, CF3, H, NH2, NHCH3, NH-cyclopropyl, NH(C=O)-C1-C6 alkyl-NH2, or NH(C=N)NH2.

[0169] In another embodiment, R1 is H or NH2.

[0170] In another embodiment of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, [ka] is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0171] In another embodiment of a compound of Formula I or II or a pharmaceutically acceptable salt thereof, R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; and m and n are each independently 0, 1, or 2.

[0172] In another embodiment, R2 and R3 are each independently selected from the group consisting of CH3, Cl, F, OCH3, CH3, and CF3; and m and n are each independently 0 or 1.

[0173] In another embodiment, the compound of formula I or II is a compound of formula IIA-1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0174] In another embodiment, the compound of formula I or II is a compound of formula IIA-2: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are described herein, R5 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo, and q is 0, 1, 2, or 3.

[0175] In another embodiment, the compound of formula I or II is a compound of formula IIA-3: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. In another embodiment, K is C1-C4 alkylene, optionally substituted with hydroxy or alkoxy.

[0176] In another embodiment, the compound of formula I or II is a compound of formula IIA-4: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0177] In another embodiment, the compound of formula I or II is a compound of formula IIA-4a or IIA-4b: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0178] In another embodiment, the compound of formula I or II is a compound of formula IIA-5: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. In another embodiment, R3 is selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy, and m is 0, 1, or 2.

[0179] In another embodiment, the compound of formula I or II is a compound of formula IIA-6: [ka] or a pharmaceutically acceptable salt thereof.

[0180] In another embodiment, the compound of formula I or II is a compound of formula IIA-7: [ka] or a pharmaceutically acceptable salt thereof.

[0181] In another embodiment, the compound of formula I or II is a compound of formula IIA-8a or IIA-8b: [ka] or a pharmaceutically acceptable salt thereof.

[0182] In another embodiment, the compound of formula I or II is a compound of formula IIA-9: [ka] or a pharmaceutically acceptable salt thereof.

[0183] In embodiments of the compound of Formula IIA-9 or a pharmaceutically acceptable salt thereof, Ring B is selected from any of the moieties shown in Table 9.

[0184] In another embodiment of the compounds of Formulae IIA-3 to IIA-9, or a pharmaceutically acceptable salt thereof, K is [ka] is selected from the group consisting of:

[0185] In other embodiments of compounds IIA-1 through IIA-9, Y is selected from any of the moieties shown in Table 8.

[0186] In another embodiment, the compound of formula I or II is a compound of formula IIA-10: [ka] or a pharmaceutically acceptable salt thereof.

[0187] In another embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0188] In another embodiment, the compound of formula I or II is a compound of formula IIA-11: [ka] or a pharmaceutically acceptable salt thereof.

[0189] In another embodiment, [ka] teeth, [ka] is.

[0190] In another embodiment, the compound of formula I or II is a compound of formula IIA-12: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring C is an optionally substituted C3-C7 cycloalkylene.

[0191] In another embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0192] In another aspect, the present disclosure provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, X 1 , X 2 , Y, ring B, L, m, and n are as defined herein; Ring D is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic heterocycloalkylene are optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), —COO(C-C alkyl), —COONH, and oxo; R4 is H or NR x” R y” where R x” and R y” are each independently H or C1-C6 alkyl.

[0193] In one embodiment, the compound of formula III is a compound of formula IIIA: [ka] or a pharmaceutically acceptable salt thereof.

[0194] In another embodiment, ring D is [ka] wherein p' and p" are each independently 0, 1, 2, 3, 4, or 5; Q1 is N; and Q2 and Q3 are independently selected from the group consisting of C, N, S, or O, wherein the monocyclic heterocycloalkylene and bicyclic heterocycloalkylene are optionally substituted with up to three substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, -CO2H, -CO2Me, -CO2Et, and oxo.

[0195] In another embodiment, ring D is [ka] [ka] wherein each R5 is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo, and wherein q is 1, 2, or 3.

[0196] In another embodiment, ring D is [ka] is selected from the group consisting of:

[0197] In another aspect, the present disclosure provides the compounds set forth in Table 10, or pharmaceutically acceptable salts thereof. Table 10 provides the free base and salt structures of compounds of the present invention. Table 10 Compounds of Formula I [Table 10-1] [Table 10-2] [Table 10-3]

Table 10-4

Table 10-5

Table 10-6

Table 10-7

Table 10-8

Table 10-9

Table 10-10

Table 10-11

Table 10-12

Table 10-13

Table 10-14

Table 10-15

Table 10-16

Table 10-17

Table 10-18

Table 10-19

Table 10-20

[0198] In another aspect, the present disclosure provides the compounds set forth in Table 11, or pharmaceutically acceptable salts thereof. Table 11 provides the free base and salt structures of compounds of the present invention. Table 11 Compounds of Formula I (cont.) [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] [Table 11-11] [Table 11-12] [Table 11-13] [Table 11-14] [Table 11-15] [Table 11-16]

[0199] In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the compounds set forth in any one of Tables 10 and 11.

[0200] In another embodiment, the compound of Formula II or III, or a pharmaceutically acceptable salt thereof, is selected from the compounds set forth in Table 10.

[0201] In another aspect, the present disclosure provides a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions as defined herein and Ru is H or an amino protecting group.

[0202] In another embodiment, the compound of formula IV is selected from the compounds shown in Table 12 below. Table 12 Compounds of Formula IV [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] [Table 12-10] [Table 12-11] [Table 12-12] [Table 12-13]

[0203] In another aspect, the present disclosure provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions herein and R v’ and R v” One of them is H and the other is R v’ and R v” The other is H or an amino protecting group.

[0204] In another embodiment, the compound of formula V is a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions disclosed herein.

[0205] In another embodiment, the compound of formula V or VI is selected from the compounds shown in Table 13 below. Table 13 Compounds of Formula VI [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8]

[0206] In another aspect, the present disclosure provides a compound of formula E: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, J, X 1 , X 2 , R 1’ , R2, R3, R6, m, and n have the same definition as in the preceding paragraph; and Y5 is a bond or a straight chain C1-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, wherein up to two carbon atoms of the C2-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkynylene are independently selected from O, (C=O), or [ka] where t' is 1, 2, 3, or 4, and R6 is H or C1-C6 alkyl.

[0207] In another embodiment of the compound of formula E or a pharmaceutically acceptable salt thereof, Y5 is a bond or a straight-chain C1-C3 alkylene optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0208] In embodiments, the compound of Formula E or a pharmaceutically acceptable salt thereof is selected from the compounds shown in Table 14 below. Table 14 Compounds of formula E [Table 14-1] [Table 14-2] [Table 14-3]

[0209] Pharmaceutical Compositions and Administration The present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0210] Pharmaceutically acceptable excipients include any solvents, diluents, or other liquid vehicles, dispersion agents, suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., depending on the particular dosage form desired. General discussions on the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0211] The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the step of bringing into association a compound of the present invention (the "active ingredient") with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multi-dosage unit.

[0212] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject, and / or a convenient fraction of such a dose, for example, one-half or one-third of such a dose.

[0213] The relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) active ingredient.

[0214] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents, and perfuming agents may also be present in the compositions.

[0215] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0216] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0217] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters, and the like. esters (e.g., polyoxyethylene sorbitan monolaurate [Tween® 20], polyoxyethylene sorbitan [Tween® 60], polyoxyethylene sorbitan monooleate [Tween® 80], sorbitan monopalmitate [Span® 40], sorbitan monostearate [Span® 60], sorbitan tristearate [Span® 65], glyceryl monooleate, sorbitan monooleate [Span® 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate,Ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0218] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0219] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0220] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0221] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0222] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0223] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0224] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0225] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesilate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.In certain embodiments, the preservative is an antioxidant.In other embodiments, the preservative is a chelating agent.

[0226] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, hydroxyapatite, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0227] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0228] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, cade oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon bark oil, cocoa butter, palm oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, ritsea cubeba oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0229] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage forms may 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, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, the oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and perfumes. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with a solubilizing agent, such as Cremophor, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0230] Injectables, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending agents. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables. Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0231] Sterile injectable compositions, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween® 80) and suspending agents. The sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending agents (e.g., synthetic monoglycerides or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersing agents. Other commonly used surfactants, such as Tween® or Span®, or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0232] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a suspension of crystalline or amorphous material that is poorly soluble in water. The rate of absorption of the drug therefore depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0233] Compositions for rectal or vaginal administration are usually suppositories, which can be prepared by mixing the conjugate of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active ingredient.

[0234] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, jasmine, and the like. They are mixed with guinea pig starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain a buffering agent.

[0235] Solid compositions of a similar type can be used as fillers for soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers for soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0236] The active ingredient may be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common, such dosage forms may contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0237] Dosage forms for topical and / or transdermal administration of the compounds of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and / or any necessary preservatives and / or buffers as needed. Furthermore, the present invention contemplates the use of transdermal patches, which often have the additional advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in a suitable medium. Alternatively or additionally, the rate can be controlled by providing a rate-limiting membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0238] Devices suitable for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices, such as those described in U.S. Patent Nos. 4,886,499, 5,190,521, 5,328,483, 5,527,288, 4,270,537, 5,015,235, 5,141,496, and 5,417,662. Intradermal compositions can be administered using devices that limit the effective penetration length of the needle into the skin, such as those described in PCT Publication WO 99 / 34850 and equivalent devices. Liquid jet injectors that create a jet that penetrates the stratum corneum and reaches the dermis and / or jet injection devices that deliver liquid vaccines to the dermis via a needle are suitable. Jet injection devices are disclosed, for example, in U.S. Patent Nos. 5,480,381, 5,599,302, 5,334,144, 5,993,412, 5,649,912, 5,569,189, 5,704,911, 5,383,851, 5,893,397, 5,466,220, 5,339, 163, 5,312,335, 5,503,627, 5,064,413, 5,520,639, 4,596,556, 4,790,824, 4,941,880, 4,940,460, and PCT Publications WO97 / 37705 and WO97 / 13537. A ballistic powder / particle delivery device that uses compressed gas to advance the vaccine in powder form through the outer layer of the skin into the dermis is suitable. Alternatively or additionally, a conventional syringe can be used in the classic Mantoux method of intradermal administration.

[0239] Pharmaceutical compositions of the invention may be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such formulations may comprise dry particles comprising the active ingredient and having a diameter of about 0.5 to about 7 nanometers or about 1 to about 6 nanometers. Such compositions are conveniently in the form of a dry powder for administration using a device comprising a dry powder reservoir capable of directing a stream of propellant to disperse the powder, and / or using a device comprising a self-propelling solvent / powder dispensing vessel, e.g., a sealed container containing the active ingredient dissolved and / or suspended in a low-boiling propellant. Such powders comprise particles in which at least 98% of the particles by weight are greater than 0.5 nanometers in diameter and at least 95% of the particles by number are less than 7 nanometers in diameter. Alternatively, at least 95% of the particles by weight are greater than 1 nanometer in diameter and at least 90% of the particles by number are less than 6 nanometers in diameter. Dry powder compositions may comprise a solid fine powder diluent, e.g., sugar, and are conveniently provided in a unit dose form.

[0240] Low-boiling propellants generally include liquid propellants having a boiling point below 65°F at atmospheric pressure. Generally, the propellant may comprise 50 to 99.9% (w / w) of the composition, and the active ingredient may comprise 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional components, such as a liquid nonionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size similar to that of the particles containing the active ingredient).

[0241] Pharmaceutical compositions of the present invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as optionally sterile aqueous and / or dilute alcoholic solutions and / or suspensions containing the active ingredient, and may be conveniently administered using any nebulizer and / or atomizer device. Such formulations may further contain one or more additional ingredients, including, but not limited to, flavoring agents, e.g., saccharin sodium, volatile oils, buffers, surfactants, and / or preservatives, e.g., methylbenzoate. The droplets provided by this administration route may have an average diameter of about 0.1 to about 200 nanometers.

[0242] The formulations described herein as useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions of the invention. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient, having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered by rapid inhalation through the nasal passages from a container of the powder held close to the nostrils.

[0243] Formulations for nasal administration may contain, for example, as little as about 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may optionally include one or more additional ingredients described herein. Pharmaceutical compositions of the invention may also be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may be in the form of, for example, tablets and / or lozenges manufactured using conventional methods and may contain, for example, 0.1 to 20% (w / w) of the active ingredient, the remainder comprising an orally dissolvable and / or disintegrable composition and, optionally, one or more additional ingredients described herein. Alternatively, formulations for buccal administration may comprise a powder and / or aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powders, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range of about 0.1 to about 200 nanometers and may further comprise one or more additional ingredients described herein.

[0244] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to any animal. Modifications to pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with routine experimentation.

[0245] The compound provided herein is usually formulated in dosage unit form for ease of administration and uniformity of dosage.However, it is understood that the total daily use amount of the composition of the present invention is determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, including the disease, disorder or condition being treated and the severity of said disorder, the activity of the specific active ingredient used, the specific composition used, the age, weight, general condition, sex and diet of said subject, the administration time, administration route and excretion rate of the specific active ingredient used, treatment period, the drug used in combination with or simultaneously with the specific active ingredient used, and similar factors well known in the medical field.

[0246] To carry out the method of the present invention, the compound or pharmaceutical composition thereof can be administered orally, parenterally, by inhalation spray, topically, rectally, bucally, vaginally, rectally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. Generally, the most appropriate administration route depends on various factors, including the properties of the drug (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0247] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general condition, the severity of any side effects or disorders, the identity of the particular compound(s), the method of administration, etc. The desired dose may be delivered three times daily, twice daily, once daily, every other day, every third day, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0248] In certain embodiments, an effective amount of a compound for administration to a 70 kg adult one or more times per day may include from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound per unit dosage form.

[0249] In certain embodiments, the compounds of the invention may be administered orally or parenterally at a dosage level sufficient to deliver about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, and more preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, once or more times per day, to obtain the desired therapeutic effect.

[0250] It will be understood that the dosage ranges provided herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent may be determined by a physician or by one of ordinary skill in the art and may be less than or the same as that administered to an adult.

[0251] It will also be understood that the compounds or compositions described herein can be administered in combination with one or more additional therapeutically active agents. The compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or alter their distribution in the body. It will also be understood that the treatments used can achieve the desired effect for the same disorder and / or they can achieve different effects.

[0252] The compound or composition can be administered simultaneously with, before, or after one or more additional therapeutically active agents. Generally, each agent is administered at a dose and / or time schedule determined for that agent. It is further understood that the additional therapeutically active agents used in this combination can be administered together in a single composition or separately in different compositions. The particular combination to be used in a regimen will take into account the compatibility of the compound of the present invention with the additional therapeutically active agents and / or the desired therapeutic effect to be achieved. Generally, additional therapeutically active agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination are lower than the levels at which they are used individually. Additional therapeutically active agents include antibiotic agents, such as antibiotics useful in the treatment of tuberculosis. Exemplary antibiotics include, but are not limited to, isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin.

[0253] Kits (e.g., pharmaceutical packs) are also included in the present invention. The provided kits may include a pharmaceutical composition or compound of the present invention and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the present invention. In some embodiments, the container and the pharmaceutical composition or compound of the present invention provided in the second container are mixed to form a single unit dosage form.

[0254] Treatment Uses and Methods In another aspect, the present invention provides a method for treating bacterial infections in a patient in need of such treatment.The method comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.In certain embodiments, the effective amount is a therapeutically effective amount.In certain other embodiments, the effective amount is a prophylactically effective amount.

[0255] In some embodiments, the compounds of the present invention may be active against a wide range of both Gram-positive and Gram-negative bacteria. In these and other embodiments, the compounds of the present invention may be used to treat infectious diseases and inhibit the growth of microorganisms. Thus, the compounds of the present invention can be used to treat humans and animals with a wide range of bacterial infections, such as impetigo, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infections, diabetic foot ulcers, gastrointestinal infections, and bacteremia. These bacterial infections may be caused by any of the following bacteria: Staphylococcus aureus, coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, enterococci, beta-hemolytic streptococci, viridans streptococci, multidrug-resistant M. tuberculosis and other atypical mycobacteria such as M. intracellulare and M. avium; and Bacillus mycobacterial infections caused by emerging gram-negative pathogens such as Chryseobacterium meningosepticum, Chryseobacterium indologense and other gram-negative pathogens such as E. coli, Klebsiella, Proteus, Serratia, Citrobacter, Pseudomonas, Burkholderia, Brucella, Yersinia, Francisella, Coxiella, Chlamydia, Salmonella, Rickettsia, Shigella, and Campylobacter.

[0256] In one embodiment, the bacterial infection is tuberculosis. In certain embodiments, the tuberculosis infection is a Mycobacterium tuberculosis infection. In certain embodiments, the tuberculosis infection is a multidrug-resistant tuberculosis (MDR-TB) infection, e.g., resistant to the first-line TB drugs rifampicin and / or isoniazid. In certain embodiments, the tuberculosis infection is an extensively drug-resistant tuberculosis (XDR-TB) infection, e.g., resistant to three or more of six classes of second-line drugs (see, e.g., Centers for Disease Control and Prevention (CDC) (2006). "Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs worldwide, 2000-2004", MMWR Morb Mortal Wkly Rep 55(11):301-5).

[0257] process In some embodiments, compounds and intermediates of the present disclosure can be prepared according to the following general synthetic schemes G-1 and G-2, in which ring A, ring B, J, L, X 1 , X 2 , Y, R1, R 1’ , R2, R3, R6, m, and n have the same definition as in the preceding paragraph; and Y5 is a bond or a straight chain C1-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, wherein up to two carbon atoms of the C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently selected from O, (C=O), or [ka] where t' is 1, 2, 3, or 4, R6 is H or C1-C6 alkyl, X is halo, and P is a hydroxy protecting group.

[0258] General synthetic scheme G-1 [ka] General synthetic scheme G-2 [ka] In step 1 of general synthetic scheme G-1, a protected alcohol (a) is reacted with a borate such as triisopropyl borate in the presence of a base such as butyllithium to give a boronate.

[0259] In steps 2a, 2b, and 2c of general synthetic schemes G-1 and G-2, this boronate or boronic acid is cross-coupled with cytosine in the presence of a base, such as a tertiary amine, and a copper reagent, such as a copper(II) reagent, to provide compounds of formula (b), (g), or (VI).

[0260] In steps 3a, 3b, and 3c of General Synthetic Schemes G-1 and G-2, a compound of Formula (b) or (VI) and an iodide (c) or (d) undergo amide coupling to provide intermediate (e) or (f), or a compound of Formula I. In a typical procedure, 1.1 to 2.0 molar equivalents of a compound of Formula (b) or (VI) are mixed with 1 molar equivalent of an iodide (c) or (d) in a suitable solvent, such as a polar aprotic solvent. Examples of polar aprotic solvents include dichloromethane, dimethylformamide, and acetonitrile. The mixture containing the polar aprotic solvent is then reacted at a temperature of about 0°C to 100°C for a sufficient period of time. Typically, the temperature is about 25°C to 95°C or about 50°C to 95°C, and the reaction time is about 1 to 24 hours, more typically about 2 to 20 hours, or about 5 to 18 hours.

[0261] In step 4 of general synthetic scheme G-1, the compound of formula (e) may be further coupled to give the compound of formula (f).

[0262] In steps 5 and 6 of general synthetic scheme G-1, a compound of formula (f) is deprotected to produce the free alcohol, which is then oxidized to the ketone, ie, a compound of formula E.

[0263] In steps 7a, 7b, and 7c of General Synthetic Schemes G-1 and G-2, a compound of Formula E (or i, or g) is reacted with an amine under reductive amination conditions to give a compound of Formula I (or j, or VI). This reductive amination can be carried out in the presence of a reducing agent and a suitable solvent. Suitable solvents include protic or aprotic solvents. Protic solvents include, but are not limited to, water and alcohols such as methanol, ethanol, and propanol. Aprotic solvents include, but are not limited to, solvents such as dichloromethane, dimethylformamide, and acetonitrile. The suitable solvent may also be a combination of two or three solvents. The reducing agent includes, but is not limited to, borohydride reagents or metal hydride reagents. Non-limiting examples include lithium borohydride, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

[0264] In step 8 of General Synthetic Scheme G-2, a compound of formula (j) is reacted with a boron reagent, such as bis(pinacolato)diboron (B2pin2), in the presence of a phosphine ligand, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), a base, and a suitable solvent to form the pinacol boronate ester of compound (j). Bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, and cesium carbonate. Suitable solvents can be aprotic solvents, such as dioxane, dichloromethane, dimethylformamide, and acetonitrile. In a typical procedure, 1.0 molar equivalent of a compound of formula (j) is mixed with 1 to 2.0 molar equivalents of a boron reagent, a base, a phosphine ligand, and a suitable solvent, such as dioxane. The mixture is then reacted at a temperature of about 0 to 150°C for a sufficient period of time. Typically, the temperature is about 25°C to 130°C or about 50°C to 125°C, and the reaction time is about 1 to 24 hours, more typically 2 to 24 hours or about 10 to 24 hours.

[0265] In one aspect, the present disclosure provides a compound of formula I-2: [ka] or a pharmaceutically acceptable salt thereof, the process comprising coupling a compound of formula A with a compound of formula B to obtain a compound of formula 1-2: [ka] In the formula, rings B, K, L, Y, R1, R x , R y , R5, X 1 , m, and q are as defined herein, where PG is an amino protecting group.

[0266] The process and conditions for carrying out the amide coupling of a compound of formula A to a compound of formula B are similar to steps 3a, 3b, and 3c of the general synthetic scheme.

[0267] In one embodiment, the process further comprises the step of removing the amino protecting group PG.

[0268] In another embodiment, the compound of formula B is selected from the compounds shown in Table 13.

[0269] In another aspect, the present disclosure provides a compound of formula I-6: [ka] or a pharmaceutically acceptable salt thereof, the process comprising coupling a compound of formula C with a compound of formula D under reductive amination conditions to obtain a compound of formula I-6: [ka] In the formula, ring A, ring B, J, L, R1, R 1’ , R2, R3, X 1 , X 2 , m, and n are as defined herein; Y 5’ is a bond or a straight chain C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, and up to two carbon atoms of the C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently O, (C=O), or [ka] where t' is 1, 2, 3, or 4; R6 is H or C1-C6 alkyl; R7 is H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, or C1-C6 alkylene-C3-C8 cycloalkyl.

[0270] In another embodiment, Y 5’ is a bond or a straight chain C1-C4 alkylene optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0271] In another embodiment, the compound of formula C is selected from the compounds shown in Table 14.

[0272] In another aspect, the present disclosure provides a compound of formula I-7: [ka] or a pharmaceutically acceptable salt thereof, the process comprising coupling a compound of formula E with a compound of formula F under reductive amination conditions to obtain a compound of formula I-7. [ka] In the formula, rings A, J, L, R1, R 1’ , R2, R3, X 1 , X 2 , m, and n are as defined herein; Ring B1 is a nitrogen-containing bicyclic heterocycloalkylene, optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, OH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; Y5 is a bond or a straight chain C1-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkynylene, any of which is optionally substituted with OH, NH2, CN, halo, C1-C6 alkyl, C1-C6 haloalkyl, COO(C1-C6 alkyl), COOH, CONH2, or C1-C6 alkoxy, and up to two carbon atoms of the C2-C8 alkylene, C2-C8 alkenylene, or C2-C8 alkynylene are independently O, (C=O), or [ka] where t' is 1, 2, 3, or 4; R6 is H or C1-C6 alkyl.

[0273] In another embodiment, Y5 is a bond or a straight chain C1-C7 alkylene optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0274] The reductive amination between a compound of formula C and a compound of formula D, or between a compound of formula E and a compound of formula F, is similar to steps 7a and 7b in the general synthetic scheme. In a typical procedure, 1.1 to 2.0 molar equivalents of a compound of formula D (or F) are mixed with 1 molar equivalent of a compound of formula C (or E) and 1.0 to 2.0 molar equivalents of a reducing agent in a suitable solvent. The mixture is then reacted at a temperature of about 0°C to 100°C for a sufficient period of time. Typically, the temperature is about 10°C to 95°C, or about 10°C to 50°C, or room temperature, and the reaction time is about 1 to 24 hours, more typically 2 to 20 hours, or about 5 to 18 hours. After optional workup and purification, a compound of formula I-6 or I-7 is obtained.

[0275] In another embodiment, the compound of formula E is selected from the compounds set forth in Table 14. [Example]

[0276] Preparation of compounds The preparation of starting materials that are commercially available, described in the literature, or readily available to those skilled in the art is not described. Those skilled in the art will understand that when compounds are described as being prepared similarly to previous examples or intermediates, the reaction time, number of equivalents of reagents, and temperature may vary for each specific reaction, and that different workup or purification techniques may be required or desirable. When reactions are carried out using microwave irradiation, the microwave oven used was either a Biotage Initiator or a CEM Discover System Model 908005. The actual power supplied during the reaction was varied to maintain a constant temperature.

[0277] General method All reactions requiring anhydrous conditions were carried out in flame-dried glassware under a positive pressure of either nitrogen or argon. Commercially available reagents were used as received; otherwise, materials were purified according to the Purification of Laboratory Chemicals. Dichloromethane (CHCl), N,N'-dimethylformamide (DMF), toluene, and tetrahydrofuran (THF) were degassed with nitrogen and passed through a solvent purification system (Innovative Technologies Pure Solv). Dry 1,4-dioxane was purchased from Acros Organics in Acros Seal™ bottles. Triethylamine (EtN) and N,N-diisopropylethylamine (DIPEA) were either distilled from CaH immediately before use, stored over 4 Å molecular sieves, or distilled over 4 Å molecular sieves before use. Microwave reactions were performed on a CEM Discover System Model 908005. Reactions were monitored by TLC, visualized with a dual short-wave / long-wave UV lamp, and / or stained with ethanolic solutions of KMnO, 12-phosphomolybdic acid, or other commonly used dyes. Flash chromatography was performed on EM Science-Merck silica gel Kieselgel 60 (230-400 mesh) using the specified HPLC-grade solvents or an automated medium-pressure column chromatography system (Teledyne ISCO CombiFlash® RF75 or CombiFlash® Rf+). Reverse-phase HPLC was performed on a Waters HPLC Semi-Prep 150B system using a Sunfire C18 Prep Column or an Atlantis T3 Prep Column, either isocratically or gradient-wise, with HO (0.1% TFA) and 10% HO:90% CH3CN (0.1% TFA) as eluents.

[0278] Melting points were measured using a Mel-Temp® capillary melting point apparatus. Infrared spectra were obtained using a Nicolet 380-FT IR spectrometer equipped with a Smart Orbit sample system. Optical rotations were obtained at ambient temperature on a Perkin Elmer Model 343 polarimeter (Na D radiation) using a 1-decimeter pathlength microcell. Mass spectra measured by LCMS were collected on a Thermo Scientific™ UltiMate™ 3000UHPLC using an electrochemical detector equipped with a fluorescence detector observing at 214 or 254 nm, or on a Waters Aquity UPLC H-Class series equipped with a photodiode array detector and a QDa mass detector. 1 H NMR spectra were recorded at 500 MHz, 400 MHz, and 300 MHz. 13 C was recorded at 125 MHz. Proton resonances were reported relative to the deuterated solvent peaks: 7.27 ppm for CDCl3, 3.31 ppm (center signal) for CD3OD, 2.50 for D6-DMSO, and 4.79 for DO using the following format: chemical shift (δ (ppm)) [multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet)]. Carbon resonances were reported as chemical shifts in parts per million (δ) relative to the center signal of the respective solvent peaks: 77.23 ppm for CDCl3 and 49.15 ppm for CD3OD. Commercially available chemicals are purchased from vendors such as Sigma-Aldrich, Acros, Enamine, TCI America, Combi-Blocks, Alfa-Aesar, Angene, Ark Pharma, PharmaBlock, Strem Chemicals, Frontier Scientific, and AstaTech, Inc.

[0279] Liquid chromatography mass spectrometry Liquid Chromatography Mass Spectrometry A

[0280] Total ion current (TIC) and DAD UV chromatographic traces, as well as MS and UV spectra associated with these peaks, were acquired on a UPLC / MS Acquity™ system. The system was equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer, operated in alternating positive and negative electrospray ionization mode. [LC / MS-ES(+ / -): Analysis was performed on an Acquity UPLC™ CSH system using a C18 column (50x2.1 mm, 1.7 μm particle size), column temperature 40°C, mobile phase: A - water + 0.1% HCOOH / B - CH3CN + 0.1% HCOOH, flow rate: 1.0 mL / min, run time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, stop time 2.0 min.] Positive ES100-1000, negative ES100-1000, UV detection DAD 210-350 nm were used.

[0281] Liquid Chromatography Mass Spectrometry B

[0282] Total ion current (TIC) and DAD UV chromatographic traces, as well as MS and UV spectra associated with these peaks, were acquired on a UPLC / MS Acquity™ system equipped with a PDA detector coupled to a Waters single quadrupole mass spectrometer operated in alternating positive and negative electrospray ionization mode. [LC / MS-ES(+ / -): Analysis was performed using an Acquity UPLC™ BEH with a C18 column (50 x 2.1 mm, 1.7 μm particle size), column temperature 40°C, mobile phase: A - 0.1% v / v aqueous ammonia (aq) solution pH 10 / B - CH3CN, flow rate: 1.0 mL / min, run time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, stop time 2.0 min.] Positive ES100-1000, negative ES100-1000, UV detection DAD 210-350 nm were used.

[0283] Liquid Chromatography Mass Spectrometry LC / MS-ES (+ / -): Analysis was performed using an AQUITY equipped with a PDA detector and QDA Performance, a C18 column (50x2.1 mm, 1.6 μm particle size), a column temperature of 35°C, mobile phase: A - Milli Q water (pH = 2.70) containing 0.1% formic acid / B - 0.1% formic acid in water:acetonitrile (10:90), flow rate: 0.8-1.0 mL / min, run time = 4.0 min, gradient: t = 0 min 3% B, t = 2.7 min 98% B, t = 3.0 min 100% B, t = 3.51 min 3% B, stop time 4.0 min.

[0284] Liquid Chromatography Mass Spectrometry

[0285] LC / MS-ES (+ / -): Analysis was performed using an AQUITY H-Class equipped with a PDA detector and QDA, a C18 column (50x2.1 mm, 1.6 μm particle size), column temperature 35 °C, mobile phase: A - Milli-Q water (pH = 2.70) containing 0.1% formic acid / B - 0.1% formic acid in water:acetonitrile (10:90), flow rate: 0.8-1.0 mL / min, run time = 4.0 min, gradient: t = 0 min 3% B, t = 2.7 min 98% B, t = 3.0 min 100% B, t = 3.51 min 3% B, stop time 4.0 min.

[0286] Liquid Chromatography Mass Spectrometry

[0287] LC / MS-ES (+ / -): Analysis was performed using an AQUITY H-Class equipped with a PDA detector and QDA, a C18 column (50x2.1 mm, 1.6 μm particle size), a column temperature of 35°C, a mobile phase of A 0.1% formic acid in water (pH=2.70) / B 0.1% formic acid in water:acetonitrile (10:90), a run time of 9.0 min, a gradient of t=0 min 1% B, t=2.5 min 50% B, t=4.5 min 97.5% B, t=6.5 min 1% B, and a stop time of 9.0 min.

[0288] Liquid Chromatography Mass Spectrometry

[0289] LC / MS-ES (+ / -): Analysis was performed using an Agilent Infinity II G6125C LCMS, C18 column (50x4.6 mm, 3.5 μm particle size), column temperature 35 °C, mobile phase: A - Milli-Q water (pH = 7.35) containing 5 mM ammonium bicarbonate / B - methanol, run time = 7.0 min, gradient: t = 0 min 8% B, t = 3.0 min 70% B, t = 3.7 min 95% B, t = 4.2 min 100% B, t = 5.21 min 8% B, stop time 7.0 min.

[0290] Liquid Chromatography Mass Spectrometry G

[0291] LC / MS-ES (+ / -): Analysis was performed using a Waters Alliance 2690 and 996 PDA detectors and a Micromass ZQ, a C18 column (150x4.6 mm, 3.5 μm particle size), a column temperature of 35°C, mobile phase: A - 5 mM ammonium acetate + 0.1% FA in water / B - methanol, run time = 17.0 min, gradient: t = 0 min 10% B, t = 7.0 min 90% B, t = 9.0 min 100% B, t = 14.01 min 10% B, stop time 17.0 min.

[0292] Liquid Chromatography Mass Spectrometry

[0293] LC / MS-ES (+ / -): Analysis was performed using an AQUITY equipped with a PDA detector and QDA Performance, a C18 column (50x2.1 mm, 1.6 μm particle size), a column temperature of 35°C, mobile phase: A - Milli Q water (pH = 2.70) containing 0.1% formic acid / B - 0.1% formic acid in water:acetonitrile (10:90), flow rate: 0.9 mL / min, run time = 3.0 min, gradient: t = 0 min 5% B, t = 1.8 min 98% B, t = 2.0 min 100% B, t = 2.51 min 5% B, stop time 17.0 min.

[0294] Analysis method 1H nuclear magnetic resonance (NMR) spectroscopy was performed using one of the following instruments: a Bruker Avance400 instrument equipped with probe DUAL 400MHz S1; a Bruker Avance400 instrument equipped with probe 6 S1 400MHz 5mm 1 H- 13 C ID equipped, Bruker Avance III 400 instrument nanobay, probe Broadband BBFO 5mm direct equipped, 400MHz Agilent Direct Drive instrument, ID AUTO-X PFG probe equipped, all operating at 400MHz, or Agilent VNMRS500 Direct Drive instrument, 5mm triple resonance 1 H{ 13 C / 15 N} Cryoprobe was equipped and operated at 500 MHz. Spectra were acquired near room temperature in the solvents indicated unless otherwise noted. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ (ppm)) are given in parts per million using conventional abbreviations for major peak names: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; dt, doublet of triplet; and br, broad.

[0295] Thin-layer chromatography (TLC) refers to silica gel TLC using silica gel F254 (Merck) plates. Column chromatography was performed using an automated column chromatography (Biotage SP1 or Isolera) system with Biotage silica gel cartridges (KP-Sil or KP-NH) or, for reversed-phase chromatography, with Biotage C18 cartridges (KP-C18).

[0296] Preparative HPLC was performed on a Shimadzu LC-20AP, Waters 2545, and Agilent 1260 Infinity. Purity was measured using a Waters Alliance e2695-PDA detector 2998 and an Agilent 1260 Infinity-II (mobile phase: 0.05% aqueous HCl / methanol with gradient elution). Table 15. Abbreviations and names of reagents [Table 15-1] [Table 15-2] [Table 15-3]

[0297] Synthesis of intermediates Intermediate 1 [ka] 3-Methyl-1-(4-(2,2,2-trifluoroacetylpiperazine-1-carbonyl)-1H-imidazol-3-ium iodide Scheme I-1 [ka] Reagents: 1) TFAA, CH2Cl2, 0°C to rt, 16 h 2) TFA, CH2Cl2, rt, 1.5 h 3) CDI, CH2Cl2, 16 h 4) MeI, CH3CN, rt, 16 h. Step 1: tert-Butyl 4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate. A solution of tert-butyl piperazine-1-carboxylate (20 g, 107 mmol) in dry CHCl (100 mL) was cooled to 0 °C under a nitrogen atmosphere. Trifluoroacetic anhydride (15.0 mL, 107 mmol) was added dropwise over 10 minutes. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with CHCl (1 L) and quenched with saturated NaHCO solution (1 L). The organic layer was separated, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (29.1 g, 96%) as a pale orange solid.

[0298] Step 2: 2,2,2-Trifluoro-1-(piperazin-1-yl)ethan-1-one trifluoroacetate. To a solution of trifluoroacetic acid in CHCl (50 mL, 1:1) was added tert-butyl 4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate (29.1 g, 103 mmol). The reaction was stirred at room temperature for 1.5 hours. The solvent and trifluoroacetic acid were removed under reduced pressure. The crude reaction mixture was triturated with diethyl ether to give a solid precipitate. The solid was filtered and washed with diethyl ether to give the title compound (29.5 g, 97%) as a white solid.

[0299] Step 3: 1-(4-(1H-imidazole-1-carbonyl)piperazin-1-yl)-2,2,2-trifluoroethan-1-one. To a round-bottom flask containing 2,2,2-trifluoro-1-(piperazin-1-yl)ethan-1-one trifluoroacetate (26.0 g, 88 mmol) was added 1,1′-carbonyldiimidazole (17.1 g, 105 mmol) and dry CHCl (100 mL) to give a suspension. This suspension was stirred at room temperature for 16 h. The solvent was then removed under reduced pressure, and the crude reaction mixture was purified by flash column chromatography to give the title compound (18 g, 76%) as a white solid.

[0300] 3-Methyl-1-(4-(2,2,2-trifluoroacetylpiperazine-1-carbonyl)-1H-imidazol-3-ium iodide. To a round-bottom flask containing a solution of 1-(4-(1H-imidazole-1-carbonyl)piperazin-1-yl)-2,2,2-trifluoroethan-1-one (10.8 g, 39.1 mmol) in dry MeCN (80 mL) was added iodomethane (15.0 mL, 235 mmol). The reaction was stirred at room temperature for 24 h. The solvent and excess iodomethane were removed under reduced pressure to afford the title compound (27.6 g, 98%) as a light yellow solid.

[0301] Intermediate 2 [ka] 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide Scheme I-2 [ka] Reagents: 1) Boc-AIB, HATU, DIPEA, DMF, rt, 16 h; 2) 10% Pd / C, MeOH, rt, 16 h; 3) CDI, DCM, rt, 16 h; 4) MeI, CH3CN, rt, 16 h. Step 1: Benzyl 4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxylate. To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (35.5 g, 174.8 mmol) in DMF (350 mL) was added DIPEA (51.24 g, 397.2 mmol) and HATU (90.62 g, 238.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 45 min. Benzyl piperazine-1-carboxylate (35 g, 158.9 mmol) was added to the reaction mixture at 0 °C and stirred at room temperature for 16 h. The resulting reaction mixture was poured into HO (1.5 L) and extracted with EtOAc (3 × 700 mL), and the combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (20-30% EtOAc:Hex) to afford the title compound (36.0 g, 55%) as an off-white solid. LCMS [M+H] 406.

[0302] Step 2: tert-Butyl (2-methyl-1-oxo-1(piperazin-1-yl)propan-2-yl)carbamate. To a stirred solution of benzyl 4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxylate (35.0 g, 86.4 mmol) in MeOH (500 mL) was added 10% Pd / C (3.5 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through Celite® and washed with MeOH (1500 mL). The filtrate was concentrated under reduced pressure and dried to give the title compound (25.0 g, quantitative) as a viscous oil. LCMS [M+H] 272.

[0303] Step 3: tert-Butyl (1-(4-1H-imidazole-1-carbonyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of tert-butyl (2-methyl-1-oxo-1(piperazin-1-yl)propan-2-yl)carbamate (25.0 g, 92.2 mmol) in CHCl (300 mL) was added CDI (17.78 g, 109.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (4-5% MeOH in CHCl) to afford the title compound (30.0 g, 89%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.04 (s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.03 (s, 1H), 3.65-3.52 (m, 4H), 3.51-3.40 (m, 4H), 1.38 (s, 6H), 1.30 (s, 9H). LCMS [M+H] 366.3.

[0304] Step 4: 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide. To a stirred solution of t-butyl (1-(4-1H-imidazole-1-carbonyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (20.0 g, 54.8 mmol) in CH3CN (250 mL) was added MeI (46.66 g, 20.8 mL, 328.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (30.0 g, quantitative) as a pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.57 9s, 1H), 8.05 (s, 1H), 7.87 (t, 1H), 7.40 (s, 1H), 3.93 (s, 3H), 3.78-3.65 (m, 4H), 3.59-3.45 (m, 4H), 1.40 (s, 6H), 1.32 (S, 9H). LCMS [M+H] 380.2 (-iodide).

[0305] Intermediate 3 [ka] tert-Butyl N-[1-(4-{[1-(4-formyl-phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]carbamoyl}piperazin-1-yl)-2-methyl-1-oxopropan-2-yl]carbamate Scheme I-3 [ka] Reagents: 1) 4-formylphenylboronic acid, TMEDA, Cu(OAc)2·H2O, 2) 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide, CH3CN, 78 °C, 22 h. Step 1: 4-(4-amino-2-oxopyrimidin-1(2H)-yl)benzaldehyde. Copper(II) acetate monohydrate (18.0 g, 90.2 mmol) and TMEDA (16.2 mL, 108 mmol) were added to a mixture of cytosine (10.0 g, 90.1 mmol) and (4-formylphenyl)boronic acid (13.5 g, 90.2 mmol) in MeOH (400 mL) and HO (100 mL), and the mixture was stirred at room temperature in air for 6 days. It was concentrated to remove MeOH, and ice and water were added (total: approximately 1 L). The precipitate was collected by vacuum filtration to give the title compound (8.84 g, 41.1 mmol) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.98 (d, 2H), 7.71 (d, 1H), 7.61 (d, 2H), 7.46 - 7.27 (m, 2H), 5.85 (d, 1H).

[0306] tert-Butyl N-[1-(4-{[1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]carbamoyl}piperazin-1-yl)-2-methyl-1-oxopropan-2-yl]carbamate. A mixture of 4-(4-amino-2-oxopyrimidin-1(2H)-yl)benzaldehyde (1.0 g, 4.67 mmol) and 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (3.57 g, 5.62 mmol) in CH3CN (35 mL) was stirred at reflux for 22 hours. The reaction mixture was cooled, diluted with EtOAc (250 mL), washed with saturated aqueous NaHCO (2 x 200 mL) and brine (200 mL), dried over NaSO, decanted, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc / MeOH) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 13.01 (br. s., 1H), 10.07 (s, 1H), 8.01 (d, 2H), 7.58 (d, 2H), 7.31 (d, 1H), 5.90 (d, 1H), 4.95-4.72 (m, 1H), 3.95-3.57 (m, 8H), 1.52 (s, 6H), 1.44 (s, 9H). LCMS [M+H] 513.1.

[0307] Intermediate 4 [ka] tert-Butyl (1-(3-ethylpiperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate Scheme I-4 [ka] Reagents: 1) TFAA, Et3N, CH2Cl2, 0°C, 16 hours 2) TFA, 1.5 hours 3) 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid, HATU, DIPEA, CH2Cl2, 16 hours 4) LiOH, THF:H2O, 2 hours. Step 1: tert-Butyl 3-ethyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate. A solution of tert-butyl 3-ethylpiperazine-1-carboxylate (500 mg, 2.4 mmol) in dry CHCl (15 mL) and NEt (0.39 mL, 2.8 mmol) was cooled to 0 °C. Trifluoroacetic anhydride (0.34 mL, 2.4 mmol) was added dropwise over 10 min. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with CHCl (50 mL) and quenched with saturated NaHCO (75 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to provide the title compound.

[0308] Step 2: 1-(2-Ethylpiperazin-1-yl)-2,2,2-trifluoroethan-1-one trifluoroacetate. tert-Butyl 3-ethyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate (700 mg, 2.2 mmol) was dissolved in a 1:1 solution of trifluoroacetic acid and CHCl (20 mL). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The crude reaction mixture was triturated with diethyl ether to give a solid precipitate, which was collected by filtration and washed with diethyl ether to give the title compound.

[0309] Step 3: tert-Butyl (1-(3-ethyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a suspension of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (144 mg, 0.71 mmol) and HATU (270 mg, 0.71 mmol) in CHCl was added DIPEA (0.31 mL, 1.8 mmol). The suspension was stirred for 10 min, and 1-(2-ethylpiperazin-1-yl)-2,2,2-trifluoroethan-1-one trifluoroacetate (250 mg, 0.71 mmol) was added. The solution was stirred at room temperature for 16 h. The reaction mixture was diluted with CHCl (75 mL) and washed with HO. The organic layer was concentrated under reduced pressure and purified by flash chromatography (EtOAc:Hex) to give the title compound.

[0310] Step 4: tert-Butyl (1-(3-ethylpiperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. tert-Butyl (1-(3-ethyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (132 mg, 0.31 mmol) and LiOH·HO (139 mg, 3.1 mmol) were suspended in THF:HO (1:1) and stirred at room temperature for 2 h. The solvent was removed under reduced pressure, diluted with HO (50 mL), and extracted with CHCl (3 × 50 mL). The organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound.

[0311] Intermediate 5 [ka] Ethyl 3-((((benzyloxy)carbonyl)amino)methyl)azetidine-3-carboxylate trifluoroacetate Scheme I-5 [ka] Reagents: 1) H2, Pd(OH)2 / C, 4.0 M HCl in dioxane, EtOH, rt, 6 days; 2) Boc2O, saturated aqueous NaHCO3, dioxane, rt, 24 hours; 3) LiAlH(Ot-Bu)3, THF, 0 °C to rt, 24 hours; 4) MsCl, Et3N, CHCl2, 0 °C to rt, 24 hours; 5) NaN3, DMF, 50 °C, 24 hours; 6) H2, Pd / C, EtOH, rt, 24 hours; 7) CbzCl, saturated aqueous NaHCO3, dioxane, rt, 4 days; 8) TFA, CHCl2, rt, 1.5 hours. Step 1: Diethyl azetidine-3,3-dicarboxylate hydrochloride. A mixture of diethyl 1-benzylazetidine-3,3-dicarboxylate (prepared according to Syn. Commun. 2003, 33, 3347) (830 mg, 2.85 mmol), 4.0 M HCl in dioxane (0.78 mL, 3.12 mmol), and 20 wt% Pd(OH) / C (173 mg) in EtOH (25 mL) was stirred under an H atmosphere for 6 days. The reaction mixture was filtered through a Celite® pad and rinsed with MeOH. The filtrate was concentrated to give the title compound.

[0312] Step 2: 1-(tert-Butyl) 3,3-diethylazetidine-1,3,3-tricarboxylate. A mixture of diethylazetidine-3,3-dicarboxylate hydrochloride (756 mg, 2.85 mmol) and BocO (0.82 mL, 4.00 mmol) in dioxane (12 mL) and saturated aqueous NaHCO was stirred at room temperature for 24 h. The reaction mixture was diluted with saturated aqueous NaHCO (100 mL) and extracted with EtOAc (2 × 75 mL). These extracts were washed with brine (75 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ 4.22-4.31 (m, 8H), 1.44 (s, 9H), 1.28 (t, 6H).

[0313] Step 3: 1-(tert-Butyl) 3-ethyl 3-(hydroxymethyl)azetidine-1,3-dicarboxylate. A solution of LiAlH(Ot-Bu) in THF (1.0 M, 4.4 mL) was added dropwise to a solution of 1-(tert-butyl) 3,3-diethylazetidine-1,3,3-tricarboxylate (604 mg, 2.01 mmol) in dry THF (20 mL) at 0 °C under N. The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was diluted with EtOAc (100 mL), washed with 1 M HCl (2 × 50 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc) to provide the title compound.

[0314] Step 4: 1-(tert-butyl) 3-ethyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1,3-dicarboxylate. MsCl (0.16 mL, 2.07 mmol) was added dropwise to a solution of 1-(tert-butyl) 3-ethyl 3-(hydroxymethyl)azetidine-1,3-dicarboxylate (452 ​​mg, 1.74 mmol) and EtN (0.34 mL, 2.44 mmol) in dry CHCl (12 mL) at 0 °C under N. The mixture was stirred for 4 h while warming to room temperature. The reaction mixture was poured into 2 M KCO (50 mL) and extracted with CHCl (3 × 35 mL). These extracts were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was carried on directly.

[0315] Step 5: 1-(tert-butyl) 3-ethyl 3-(aminomethyl)azetidine-1,3-dicarboxylate. A mixture of 1-(tert-butyl) 3-ethyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1,3-dicarboxylate (604 mg, 1.743 mmol) and NaN (351 mg, 5.40 mmol) in dry DMF (10 mL) was stirred at 50 °C under N for 24 h. It was cooled, diluted with EtO (100 mL), washed with saturated aqueous NaHCO (75 mL) and brine (2 × 75 mL), dried over NaSO, filtered, and concentrated to dryness to give the title compound.

[0316] Step 6: 1-(tert-butyl) 3-ethyl 3-(aminomethyl)azetidine-1,3-dicarboxylate. A solution of 1-(tert-butyl) 3-ethyl 3-(azidomethyl)azetidine-1,3-dicarboxylate (453 mg, 1.593 mmol) and 10% Pd (52 mg) in EtOH (20 mL) was stirred under an H atmosphere for 20 h. It was filtered through a Celite® pad, rinsed with MeOH, and the filtrate was concentrated to dryness to give the title compound.

[0317] Step 7: 1-(tert-butyl) 3-ethyl 3-((((benzyloxy)carbonyl)amino)methyl)azetidine-1,3-dicarboxylate. A mixture of 1-(tert-butyl) 3-ethyl 3-(aminomethyl)azetidine-1,3-dicarboxylate (414 mg, 1.593 mmol) and benzyl chloroformate (0.45 mL, 3.15 mmol) in dioxane (16 mL) and saturated aqueous NaHCO (16 mL) was stirred at room temperature under N for 4 days. It was diluted with EtOAc (75 mL), washed with saturated aqueous NaHCO (2 × 50 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes / EtOAc) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 7.28 -7.44 (m, 5H), 5.15 -5.26 (m, 1H), 5.11 (br.s., 2H), 4.22 (q, 2H), 4.12 (d, 2H), 3.79 (m, 2H), 3.65 -3.75 (m, 2H), 1.44 (s, 9H), 1.29 (t, 3H).

[0318] Step 8: Ethyl 3-((((benzyloxy)carbonyl)amino)methyl)azetidine-3-carboxylate trifluoroacetate. A mixture of 1-(tert-butyl)3-ethyl 3-((((benzyloxy)carbonyl)amino)methyl)azetidine-1,3-dicarboxylate (101.5 mg, 0.259 mmol) and TFA (1.0 mL) in dry CHCl (3 mL) was stirred at room temperature for 1.5 h and concentrated to dryness to provide the title compound.

[0319] Intermediate 6 [ka] tert-Butyl [1,3'-biazetidin]-3-ylcarbamate Scheme I-6 [ka] Reagents: 1) tert-butyl azetidin-3-ylcarbamate, NaBH(OAc)3, AcOH, DCE, rt, 20 h 2) H2, Pd / C, EtOH, rt, 2 h. Step 1: Benzyl 3-((tert-butoxycarbonyl)amino)-[1,3′-biazetidine]-1′-carboxylate. NaBH(OAc) (1.67 g, 7.86 mmol) was added to dry DCE (25 mL) containing a mixture of benzyl 3-oxoazetidine-1-carboxylate (522 mg, 2.54 mmol), tert-butyl azetidin-3-ylcarbamate (433 mg, 2.52 mmol), and acetic acid (0.10 mL). The mixture was stirred at room temperature under N for 20 h. It was quenched with saturated aqueous NaHCO (100 mL) and extracted with CHCl (2 × 100 mL). These extracts were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc / MeOH) to give the title compound.

[0320] Step 2: tert-Butyl [1,3'-biazetidin]-3-ylcarbamate. A solution of benzyl 3-((tert-butoxycarbonyl)amino)-[1,3'-biazetidine]-1'-carboxylate (521 mg, 1.44 mmol) and 10% Pd (61 mg) in EtOH (20 mL) was stirred under an H atmosphere for 2 h. The reaction mixture was filtered through a Celite® pad, rinsed with MeOH, and the filtrate was concentrated to dryness to give the title compound.

[0321] Intermediate 7 [ka] 2,2,2-Trifluoro-N-(2-(3-hydroxyazetidin-3-yl)ethyl)acetamide trifluoroacetate Scheme I-7 [ka] Reagents: 1) Trifluoroacetic anhydride, Et3N, CH2Cl2, rt, 6 h 2) TFA, CH2Cl2, rt, 1.5 h. Step 1: tert-Butyl 3-(2-(2,2,2-trifluoroacetamido)ethyl)-3-(2,2,2-trifluoroacetoxy)azetidine-1-carboxylate. Trifluoroacetic anhydride (0.16 mL, 1.15 mL) was added dropwise to a solution of tert-butyl 3-(2-aminoethyl)-3-hydroxyazetidine-1-carboxylate (116 mg, 0.54 mmol) and EtN (0.22 mL, 1.58 mmol) in dry CHCl (5 mL), and the mixture was stirred at room temperature under N for 6 h. The mixture was poured into saturated aqueous NaHCO (50 mL) and extracted with CHCl (2 × 25 mL). These extracts were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc) to provide the title compound.

[0322] Step 2: 2,2,2-Trifluoro-N-(2-(3-hydroxyazetidin-3-yl)ethyl)acetamide. A mixture of tert-butyl 3-(2-(2,2,2-trifluoroacetamido)ethyl)-3-(2,2,2-trifluoroacetoxy)azetidine-1-carboxylate (81.1 mg, 0.199 mmol) and TFA (0.5 mL) in dry CHCl (2.0 mL) was stirred at room temperature for 1.5 h and concentrated to dryness to give the title compound.

[0323] Intermediate 8 [ka] tert-Butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate Scheme I-8 [ka] Reagents: 1) NaH, Me3SOI, DMSO 2) NH4OH, MeOH 3) Boc2O, DCM 4) HCO2NH4, Pd / C, MeOH. Step 1: 6-Benzyl-1-oxa-6-azaspiro[2.5]octane. NaH (60% oil dispersion, 121 mg, 3.16 mmol) was added to a solution of trimethylsulfoxonium iodide (640 mg, 2.91 mmol) in DMSO (2.5 mL) at 0 °C. The mixture was warmed to 10 °C, stirred for 10 min, and warmed to room temperature. After 1 h, a solution of N-benzylpiperidone (500 mg, 2.64 mmol) in DMSO (1.5 mL) was added via syringe. The mixture was stirred at room temperature for 1.5 h, diluted with EtO, and quenched with saturated aqueous NH4Cl. The layers were separated, and the organic portion was dried over Na2SO4 and concentrated under reduced pressure to give the crude epoxide (590 mg). LCMS [M+H] 204.2.

[0324] Step 2: 4-(aminomethyl)-1-benzylpiperidin-4-ol. Aqueous ammonia (28%, 7 mL) was added to a solution of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (590 mg) in MeOH (3.5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 16 hours. Volatiles were removed under reduced pressure. The residue was dissolved in DCM, and the organic portion was washed with 1 M aqueous NaOH. The aqueous portion was extracted with DCM. The combined organic portions were dried and concentrated under reduced pressure to give the crude aminol (497 mg). 1 H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 5H), 3.55 (s, 2H), 2.74-2.58 (m, 4H), 2.48-2.30 (m, 2H), 1.64-1.50 (m, 4H).

[0325] Step 3: tert-Butyl ((1-benzyl-4-hydroxypiperidin-4-yl)methyl)carbamate. Di-tert-butyl dicarbonate (226 mg, 1.04 mmol) was added to a solution of 4-(aminomethyl)-1-benzylpiperidin-4-ol (230 mg) in DCM (3 mL) and the reaction was stirred at room temperature for 1 h. Volatiles were removed under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH) to give the title compound (235 mg).1 H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 5H), 3.55 (s, 2H), 3.22-3.10 (m, 2H), 2.70-2.56 (m, 2H), 2.49-2.33 (m, 2H), 1.74-1.54 (m, 4H), 1.46 (s, 9H). LCMS [M+H] 321.4.

[0326] Step 4: tert-Butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate. Ammonium formate (276 mg, 4.78 mmol) and Pd / C (10 wt%, 24 mg) were added to a solution of tert-butyl N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]carbamate (235 mg, 0.73 mmol) in MeOH (4 mL), and the resulting mixture was refluxed for 1.5 h. Additional Pd / C was added, and stirring at reflux was extended for 1 h. The cooled mixture was filtered through a Celite® pad, and the solution was concentrated under reduced pressure to give the crude amine (163 mg), which was carried on directly to the next step. LCMS [M+H] 231.4.

[0327] Intermediate 9 cis-Benzyl N-[3-methoxypiperidin-4-yl]carbamate (racemic compound) Scheme I-9 [ka] Reagents: 1) Benzyl chloroformate, DIPEA, DCM 2) 3M HCl in MeOH, MeOH. Step 1: tert-Butyl (cis)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidine-1-carboxylate. Benzyl chloroformate (36 μL, 0.26 mmol) and DIPEA (76 μL, 0.43 mmol) were added to a solution of cis-4-(2-aminopropan-2-yl)-1-boc-piperidine (50 mg, 0.217 mmol) in DCM (4 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 h. Benzyl chloroformate (36 μL, 0.26 mmol) and DIPEA (76 μL, 0.434 mmol) were added. The mixture was stirred for 1 h, diluted with DCM, and washed with saturated aqueous NaHCO and water. The organic portion was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 80:20) to give the title compound (54 mg, 68%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 5.38-5.20 (m, 1H), 5.12 (s, 2H), 4.55-4.26 (m, 1H), 4.23-3.90 (m, 1H), 3.82-3.58 (m, 1H), 3.44-3.25 (m, 4H), 2.95-2.62 (m, 2H), 1.82-1.59 (m, 2H), 1.48 (s, 9H). LCMS [M+Na] 387.5.

[0328] Step 2: Benzyl ((-3-methoxypiperidin-4-yl)carbamate. 3 M HCl in MeOH (246 μL, 0.740 mmol) was added to a solution of cis-tert-butyl 4-(2-{[(benzyloxy)carbonyl]amino}propan-2-yl)piperidine-1-carboxylate (54 mg, 0.148 mmol) in MeOH (3 mL). After 16 h, the volatiles were removed under reduced pressure to give the title compound (40 mg). LCMS [M+H] 265.3.

[0329] Intermediate 10 [ka] Benzyl N-[(1R)-1-(piperidin-4-yl)ethyl]carbamate Scheme I-10 [ka] Reagents: 1) Benzyl chloroformate, K2CO3, THF 2) TFA, DCM. Step 1: tert-Butyl (R)-4-(1-(((benzyloxy)carbonyl)amino)ethyl)piperidine-1-carboxylate. Benzyl chloroformate (0.74 mL, 5.26 mmol) was added dropwise to a mixture of tert-butyl 4-[(1R)-1-aminoethyl]piperidine-1-carboxylate (1.0 g, 4.38 mmol) and K2CO3 (1.21 g, 8.76 mmol) in THF (20 mL). The mixture was stirred at room temperature for 16 h. Additional benzyl chloroformate (0.5 mL) was added. After 5 h, the reaction was diluted with water and extracted with EtOAc. The organic portion was concentrated under reduced pressure to give the title compound (2.30 g). LCMS [M+H] 363.4.

[0330] Step 2: Benzyl (R)-(1-(piperidin-4-yl)ethyl)carbamate. TFA (3 mL) was added to a solution of tert-butyl 4-[(1R)-1-{[(benzyloxy)carbonyl]amino}ethyl]piperidine-1-carboxylate (1 g, crude) in DCM (12 mL). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the crude residue was purified by column chromatography (MeOH, 1 M NH in MeOH) to give the title compound (610 mg). 1H NMR (400 MHz, DMSO) δ 7.41-7.27 (m, 4H), 7.12-7.05 (m, 1H), 5.00-4.97 (m, 2H), 4.17-3.99 (m, 1H), 3.43-3.23 (m, 1H), 2.91 (br.d, LCMS [M+H] 263.3.

[0331] Intermediate 11 [ka] Benzyl N-[(1S)-1-(piperidin-4-yl)ethyl]carbamate. Prepared in a similar manner to Scheme I-10 from tert-butyl 4-[(1S)-1-aminoethyl]piperidine-1-carboxylate. 1 H NMR (400 MHz, DMSO) δ 7.41-7.27 (m, 4H), 7.14-7.04 (m, 1H), 5.00 (s, 2H), 3.43-3.23 (m, 1H), 2.98-2.85 (m, 2H), 2.44-2.28 (m, 2H), 1.62-1.46 (m, 2H), 1.39-1.23 (m, 1H), 1.07-0.92 (m, 5H).

[0332] Intermediate 12 [ka] Benzyl N-[2-methyl-1-(piperidin-4-yl)propan-2-yl]carbamate Scheme I-11 [ka] Reagents: 1) Triethyl phosphonoacetate, NaH, THF 2) H2, Pd / C, EtOH 3) LDA, MeI, THF; LDA, MeI, THF 4) NaOH, EtOH-H2O 5) DPPA, TEA, DCE, BnOH 6) TFA, DCM. Step 1: tert-Butyl (E)-4-(3-ethoxy-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate. NaH (60% oil dispersion, 1.09 g, 28.5 mmol) was suspended in THF (20 mL) at 0° C. A solution of triethyl phosphonoacetate (5.6 mL, 28.5 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction was warmed to room temperature, stirred for 30 min, and cooled to 0° C. A solution of 1-Boc-piperidine-4-carboxaldehyde (5.00 g, 23.5 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction was warmed to room temperature, stirred for 16 h, cooled to 0° C., and water was added. The organic solvent was evaporated, and the aqueous portion was extracted three times with EtOAc. The combined organic portions were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (6.79 g). LCMS [M+H] 284.4.

[0333] Step 2: tert-Butyl 4-(3-ethoxy-3-oxopropyl)piperidine-1-carboxylate. A mixture of tert-butyl 4-[3-ethoxy-3-oxoprop-1-en-1-yl]piperidine-1-carboxylate (6.79 g) and Pd / C (10% by weight, 180 mg) in EtOH (60 mL) was stirred under an H atmosphere for 16 h. Additional Pd / C (10% by weight, 150 mg) was added, and stirring under an H atmosphere was extended for 16 h. The reaction was filtered through a Celite® pad. The solvent was removed under reduced pressure to give the crude title compound (6.64 g). LCMS [M+H] 286.4.

[0334] Step 3: tert-Butyl 4-(3-ethoxy-2-methyl-3-oxopropyl)piperidine-1-carboxylate. BuLi (1.6 M in hexanes, 20 mL, 32 mmol) was added dropwise to a solution of diisopropylamine (4.48 mL, 15 mmol) in THF (40 mL) at −60° C. The mixture was warmed to −20° C. and stirred for 30 min. The mixture was cooled to −60° C., and a solution of tert-butyl 4-(3-ethoxy-3-oxopropyl)piperidine-1-carboxylate (6.64 g) in THF (10 mL) was added dropwise. The mixture was stirred at −60° C. for 1 h. The mixture was stirred. A solution of MeI (6.7 mL, 108 mmol) in THF (10 mL) was added dropwise. The reaction was warmed to room temperature, stirred for 16 h, and quenched with saturated aqueous NH4Cl. The aqueous portion was extracted three times with EtOAc. The combined organic portions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc) to give the title compound (5.53 g, 85%). LCMS [M+H] 300.4.

[0335] Step 4: tert-Butyl 4-(3-ethoxy-2,2-dimethyl-3-oxopropyl)piperidine-1-carboxylate. BuLi (1.6 M in hexane, 17.3 mL, 27.8 mmol) was added dropwise to a solution of diisopropylamine (3.9 mL, 27.8 mmol) in THF (40 mL) at −60° C. The mixture was warmed to −20° C. and stirred for 30 minutes. The reaction mixture was cooled to −60° C., and a solution of tert-butyl 4-(3-ethoxy-2-methyl-3-oxopropyl)piperidine-1-carboxylate (5.53 g, 18.5 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at −60° C. for 1 hour. A solution of MeI (5.76 mL, 92.5 mmol) in THF (10 mL) was added dropwise. The reaction was allowed to warm to room temperature, stirred for 16 hours, and quenched with saturated aqueous NH4Cl. The aqueous portion was extracted three times with EtOAc. The combined organic portions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 70:30) to give the title compound (4.76 g, 82%). 1 H NMR (400 MHz, CDCl3) δ 4.13 (q, 2H), 4.08-3.94 (m, 2H), 2.76-2.59 (m, 2H), 1.62-1.41 (m, 14H), 1.27 (t, 3H), 1.20 (s, 6H), 1.18-1.05 (m, 2H). LCMS [M+H] 314.4.

[0336] Step 5: 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,2-dimethylpropanoic acid. NaOH (2.0 g, 50 mmol) was added to a solution of tert-butyl 4-(3-ethoxy-2,2-dimethyl-3-oxopropyl)piperidine-1-carboxylate (4.76 g, 15.2 mmol) in 5:1 EtOH-HO (24 mL). The reaction was refluxed for 16 h. The organic solvent was removed under reduced pressure. The aqueous portion was washed twice with EtO, acidified with 3 M HCl, and extracted with EtOAc (3x). The combined organic portions were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (2.72 g) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 4.04 (br s, 2H), 2.70 (t, 2H), 1.69-1.50 (m, 5H), 1.47 (s, 9H), 1.30-1.09 (m, 8H). LCMS [M+H] 286.4.

[0337] Step 6: Benzyl (2-methyl-1-(piperidin-4-yl)propan-2-yl)carbamate. EtN (1.23 mL, 9.26 mmol) and DPPA (1.10 mL, 5.09 mmol) were added sequentially to a solution of 3-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-2,2-dimethylpropanoic acid (1.32 g, 4.63 mmol) in DCE (20 mL). The reaction was stirred at 80° C. for 3 h. DPPA (0.50 mL, 2.31 mmol) was added, and the reaction mixture was heated for 2 h. Benzyl alcohol (0.93 mL, 9.26 mmol) was added, and the mixture was stirred at 80° C. for 1 h. Benzyl alcohol (3.2 mL, 31 mmol) was added, and the solution was stirred at 80° C. for 16 h. Saturated aqueous NaHCO3 was added and extracted with DCM (3x). The combined organic portions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 80:20) to give a mixture of the title compound and benzyl alcohol (approximately 30% by weight, 3.1 g), which was carried on to the next step without further purification. TFA (5 mL) was added to a solution of this mixture in DCM (15 mL), and the resulting solution was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure. The crude product was purified by column chromatography (MeOH, 1 M NH3 in MeOH) to give the title compound (490 mg, 36% over two steps) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 5.18-4.94 (m, 2H), 4.65 (br. s., 1H), 3.09-2.96 (m, 2H), 2.60 (td, 2H), 1.73-1.58 (m, 4H), 1.57-1.41 (m, 1H), 1.38-1.14 (m, 8H). LCMS [M+H] 291.3.

[0338] Intermediate 13 [ka] trans-tert-Butyl N-[3-(hydroxymethyl)piperidin-4-yl]carbamate (racemic compound) Scheme I-12 [ka] Reagents: 1) Boc2O, DCM, MeOH, 2) H2, Pd / C, MeOH. Step 1: tert-Butyl ((trans)-1-benzyl-3-(hydroxymethyl)piperidin-4-yl)carbamate. Di-tert-butyl dicarbonate (198 mg, 0.91 mmol) was added to a solution of trans-[4-amino-1-benzylpiperidin-3-yl]methanol (200 mg, 0.91 mmol) in 3:1 MeOH-DCM (10 mL). The reaction was stirred at room temperature for 16 hours and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM-MeOH) to give the title compound (59 mg, 20%). 1 H NMR (400 MHz, CDCl3) δ 7.38-7.22 (m, 5H), 4.52 (d, 1H), 3.79-3.62 (m, 2H), 3.59 (d, 1H), 3.52-3.43 (m, 2H), 3.01 (dd, 1H), 2.90 (d, 1H), 2.01 (td, 1H), 1.91-1.71 (m, 2H), 1.68-1.56 (m, 1H), 1.45 (s, 9H), 1.23-1.09 (m, 1H). LCMS [M+H] 321.4.

[0339] Step 2: tert-Butyl ((trans)-3-(hydroxymethyl)piperidin-4-yl)carbamate. Pd / C (10% by weight, 5 mg) was added to a solution of trans-tert-butyl N-[1-benzyl-3-(hydroxymethyl)piperidin-4-yl]carbamate (59 mg, 0.18 mmol) in EtOH (20 mL). The reaction was stirred under an atmosphere of H for 16 h and filtered through Celite®. The volatiles were removed under reduced pressure to give the title compound (34.5 mg, 83%), which was carried on directly to the next step. LCMS [M+H] 231.3.

[0340] Intermediate 14 [ka] tert-Butyl (1-(4-fluoropiperidin-4-yl)-2-methylpropan-2-yl)carbamate. Scheme I-13 [ka] Reagents: 1) LDA, EtOAc, THF, 2) DAST, DCM, 3) MeMgBr, THF, 4) AcOH, H2SO4, chloroacetonitrile, 5) AcOH, thiourea, EtOH, 6) Boc2O, DCM, 7) H2, Pd / C, MeOH. Step 1: Benzyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate. Lithium diisopropylamide (1.8 M in THF, 7 mL) was added to a solution of EtOAc (1.12 g, 12.7 mmol) in THF (20 mL) at −78° C. After 30 min, a solution of benzyl 4-oxopiperidine-1-carboxylate (2.0 g, 8.5 mmol) in THF (15 mL) was added. The mixture was warmed to −40° C. and stirred for 5 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted twice with EtOAc. The combined organic portions were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 40:60) to give the title compound (1.3 g, 47%). LCMS [M+H] 322.1.

[0341] Step 2: Benzyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate. DAST (602 mg, 3.74 mmol) was added to a solution of benzyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate (600 mg, 1.87 mmol) in DCM (20 mL). The reaction was stirred at room temperature for 16 hours and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc) to give the title compound (305 mg, 50%). LCMS [M+H] 324.1.

[0342] Step 3: Benzyl 4-fluoro-4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate. Methylmagnesium bromide (3 M in EtO, 0.78 mL) was added dropwise to a solution of benzyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (305 mg, 0.94 mmol) in THF (10 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h, warmed to 20 °C, stirred for 1 h, and quenched with saturated aqueous NH Cl. The aqueous portion was extracted twice with DCM. The combined organic portions were concentrated under reduced pressure to give the title compound (260 mg).

[0343] Step 4: Benzyl 4-(2-(2-chloroacetamido)-2-methylpropyl)-4-fluoropiperidine-1-carboxylate. AcOH (161 mg, 2.7 mmol) and H2SO4 (172 mg, 3.4 mmol) were added dropwise to a solution of benzyl 4-fluoro-4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate (260 mg) in chloroacetonitrile (4 mL) at 0 °C. The reaction was stirred at room temperature for 24 h. An aqueous solution of Na2CO3 (10%, 10 mL) and THF (15 mL) were added, and the mixture was stirred at room temperature for 20 min. Benzyl chloroformate (1 mL) was added, and the mixture was stirred for 2 h. The aqueous portion was extracted with DCM. The organic portion was concentrated under reduced pressure and purified by column chromatography (cyclohexane-EtOAc) to give the title compound (125 mg). LCMS [M+H] 385.1.

[0344] Step 5: Benzyl 4-(2-amino-2-methylpropyl)-4-fluoropiperidine-1-carboxylate. ACOH (500 μL) and thiourea (50 mg, 0.65 mmol) were added sequentially to a solution of benzyl 4-[2-(2-chloroacetamido)-2-methylpropyl]-4-fluoropiperidine-1-carboxylate (125 mg, 0.324 mmol) in EtOH (5 mL). The reaction was heated to 80 °C and stirred for 6 h. Aqueous NaHCO3 (5%, 10 mL) was added, and the mixture was extracted with DCM. The organic portion was concentrated under reduced pressure to give the title compound (78 mg, 78%). LCMS [M+H] 309.1.

[0345] Step 6: Benzyl 4-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4-fluoropiperidine-1-carboxylate. Di-tert-butyl dicarbonate (110 mg, 0.50 mmol) was added to a solution of benzyl 4-(2-amino-2-methylpropyl)-4-fluoropiperidine-1-carboxylate (78 mg, 0.253 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 16 h and quenched with saturated aqueous NH4Cl. After 1 h, the aqueous phase was extracted with DCM. The organic portion was concentrated under reduced pressure to give the crude title compound (99 mg). 1 H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 5.15 (s, 2H), 4.66-4.53 (m, 1H), 4.08-3.86 (m, 2H), 3.24-3.02 (m, 2H), 2.25-1.91 (m, 4H), 1.77-1.54 (m, 2H), 1.44 (s, 9H), 1.37 (s, 6H).

[0346] Step 7: tert-Butyl (1-(4-fluoropiperidin-4-yl)-2-methylpropan-2-yl)carbamate. Pd / C (10% by weight, 5 mg) was added to a solution of benzyl 4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl)-4-fluoropiperidine-1-carboxylate (99 mg) in MeOH (2 mL). The reaction was stirred under an atmosphere of H for 5 hours, filtered, and concentrated under reduced pressure to give the crude title compound (65 mg). LCMS [M+H] 275.3.

[0347] Intermediate 15 [ka] Benzyl 2-(piperidin-4-yl)morpholine-4-carboxylate Scheme I-14 [ka] Reagents: 1) 2-Bromoacetyl chloride, DIPEA, DCM, 2) KOtBu, dioxane, 3) BH3 . SMe2, THF, 4) benzyl chloroformate, TEA, DCM, 5) TFA, DCM. Step 1: tert-Butyl 4-(2-(2-bromoacetamido)-1-hydroxyethyl)piperidine-1-carboxylate. 2-Bromoacetyl chloride (401 mg, 2.55 mmol) was added to a solution of tert-butyl 4-(2-amino-1-hydroxyethyl)piperidine-1-carboxylate (566 mg, 2.32 mmol) and DIPEA (1.6 mL, 9.28 mmol) in DCM (15 mL) at 0° C. The reaction was stirred for 8 h. The mixture was diluted with DCM and washed with 5% aqueous citric acid. The organic portion was concentrated under reduced pressure to give the crude title compound (744 mg). LCMS [M+H] 321.1.

[0348] Step 2: tert-Butyl 4-(5-oxomorpholin-2-yl)piperidine-1-carboxylate. Potassium tert-butoxide (1.04 g, 9.28 mmol) was added to a solution of tert-butyl 4-(2-(2-bromoacetamido)-1-hydroxyethyl)piperidine-1-carboxylate (744 mg) in dioxane (15 mL), and the resulting mixture was stirred at 50 °C for 1 h. Water (20 mL) and saturated aqueous NH4Cl (15 mL) were added, and the solution was extracted twice with DCM. The combined organic portions were concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc-MeOH, 100:0 to 75:25) to give the title compound (230 mg, 35% over two steps). LCMS [M+H] 285.1.

[0349] Step 3: tert-Butyl 4-(morpholin-2-yl)piperidine-1-carboxylate. Borane dimethyl sulfide complex (2 M in EtO, 0.425 mL) was added to a solution of tert-butyl 4-(5-oxomorpholin-2-yl)piperidine-1-carboxylate (230 mg, 0.81 mmol) in THF (10 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was cooled to 0 °C, and borane dimethyl sulfide complex (2 M in EtO, 0.425 mL) was added. The mixture was warmed to room temperature and stirred for 2 h. Water (30 mL) was added, and the aqueous portion was extracted with DCM. The organic portion was concentrated under reduced pressure to give the crude title compound (95 mg), which was carried on directly to the next step. LCMS [M+H] 271.1.

[0350] Step 4: Benzyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)morpholine-4-carboxylate. Benzyl chloroformate (0.055 mL, 0.39 mmol) was added to a solution of tert-butyl 4-(morpholin-2-yl)piperidine-1-carboxylate (95 mg) and TEA (0.058 mL, 0.42 mmol) in DCM (2 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with DCM and washed with 5% aqueous citric acid. The organic portion was concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc) to give the title compound (117 mg, 36% over two steps). LCMS [M+H] 405.2.

[0351] Step 5: Benzyl 2-(piperidin-4-yl)morpholine-4-carboxylate. TFA (0.5 mL) was added to a solution of benzyl 2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}morpholine-4-carboxylate (117 mg, 0.290 mmol) in DCM (0.5 mL). The reaction was stirred at room temperature for 1 h and concentrated under reduced pressure. The crude solid was washed with a 1:1 EtO-EtOAc solution to afford the title compound as its trifluoroacetate salt (108 mg). LCMS [M+H] 305.1.

[0352] Intermediate 16 [ka] 2-Methyl-N-(4-methylazepan-4-yl)propane-2-sulfinamide Scheme I-15 [ka] Reagents: 1) 2-methyl-2-propanesulfinamide, Ti(OEt)4, THF, 70°C, 2) MeLi, AlMe3, THF, -78°C to rt, 3) TFA, DCM. Step 1: tert-Butyl (Z)-4-((tert-butylsulfinyl)imino)azepane-1-carboxylate. 2-Methyl-2-propanesulfinamide (125 mg, 1.03 mmol) and Ti(OEt) (428 mg, 1.87 mmol) were added to a solution of tert-butyl 4-oxoazepane-1-carboxylate (400 mg, 1.87 mmol) in THF (4 mL), and the mixture was stirred in a sealed vial at 70 °C for 18 h. The mixture was diluted with DCM. The organic portion was washed with water and filtered from the solids. Volatiles were removed under reduced pressure, and the crude product was purified by column chromatography (cyclohexane-EtOAc, 100:0 to 40:60) to afford the title compound (425 mg, 72%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 3.88-2.58 (m, 8H), 1.95-1.72 (m, 2H), 1.47 (s, 9H), 1.26 (s, 9H). LCMS [M+H] 317.3.

[0353] Step 2: tert-Butyl 4-((tert-butylsulfinyl)amino)-4-methylazepane-1-carboxylate. Trimethylaluminum (690 μL, 1.39 mmol) was added to a solution of tert-butyl 4-[(2-methylpropane-2-sulfinyl)imino]azepane-1-carboxylate (200 mg, 0.632 mmol) in toluene (5 mL) at −78 °C. After 20 min, methyllithium (1.7 mL of a 1.6 M solution in EtO) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction mixture was cooled to −15 °C, and methyllithium (1.4 mL, 2.21 mmol) was added. The mixture was warmed to 0 °C and stirred for an additional 16 h. Water was added. The aqueous portion was extracted twice with EtOAc. The combined organic portions were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-EtOAc) to give the title compound (12.0 mg, 6%) as a pale yellow wax. LCMS [M+H] 333.4.

[0354] Step 3: 2-Methyl-N-(4-methylazepan-4-yl)propane-2-sulfinamide. TFA (400 μL) was added to a solution of tert-butyl 4-methyl-4-[(2-methylpropane-2-sulfinyl)amino]azepane-1-carboxylate (12.0 mg, 0.036 mmol) in DCM (1.6 mL), and the resulting solution was stirred at room temperature for 1.5 hours. The volatiles were removed under reduced pressure to give crude 2-methyl-N-(4-methylazepan-4-yl)propane-2-sulfinamide as the trifluoroacetate salt. LCMS [M+H] 233.3.

[0355] Intermediate 17 [ka] tert-Butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate Scheme I-16 [ka] Reagents: 1) Benzyl 1-piperazinecarboxylate, HATU, DIPEA, DMF, rt, 16 h 2) 10% Pd / C, MeOH, H2, rt, 16 h 3) CDI, DCM, rt, 16 h 4) MeI, CH3CN, rt, 16 h 5) 4-(4-amino-2-oxopyrimidin-1(2H)-yl)benzaldehyde, CH3CN, reflux, 16 h. Step 1: tert-Butyl (2R,4S)-4-(4-((benzyloxy)carbonyl)piperazine-1-carbonyl)-2-(tert-butyl)-4-methyloxazolidine-3-carboxylate. To a stirred solution of (2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carboxylic acid (0.60 g, 2.11 mmol, prepared in a manner similar to Org. Lett. 2011, 13, 5000) in DMF (10 mL) was added DIPEA (0.68 g, 5.28 mmol) and HATU (0.97 g, 2.53 mmol). After 15 min, benzyl 1-piperazinecarboxylate (0.463 g, 2.11 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured into saturated aqueous LiCl (30 mL) and stirred for 20 min. The precipitate was filtered and purified by flash chromatography (EtOAc:Hex) to afford the title compound (0.85 g, 82%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.22 (s, 1H), 5.17 (s, 2H), 4.95 (d, 1H), 3.83 (br s, 2H), 3.53 (br s, 3H) 3.31 (d, 1H), 1.61 (s, 3H), 1.51 (s, 9H), 0.89 (s, 12H).

[0356] Step 2: tert-Butyl (2R,4S)-2-(tert-butyl)-4-methyl-4-(piperazine-1-carbonyl)oxazolidine-3-carboxylate. To a stirred solution of tert-butyl (2R,4S)-4-(4-((benzyloxy)carbonyl)piperazine-1-carbonyl)-2-(tert-butyl)-4-methyloxazolidine-3-carboxylate (0.85 g, 1.73 mmol) in MeOH (20 mL) was added 10 wt% Pd / C (0.1 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours, filtered through Celite®, and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure and dried to give the title compound (0.58 g, 95%) as a viscous oil.

[0357] Step 3: tert-Butyl (2R,4S)-4-(4-(1H-imidazole-1-carbonyl)piperazine-1-carbonyl)-2-(tert-butyl)-4-methyloxazolidine-3-carboxylate. To a stirred solution of tert-butyl (2R,4S)-2-(tert-butyl)-4-methyl-4-(piperazine-1-carbonyl)oxazolidine-3-carboxylate (0.58 g, 1.64 mmol) in CHCl (20 mL) was added CDI (0.53 g, 3.27 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (0.66 g, 90%) as an off-white solid.

[0358] Step 4: 1-(4-((2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide. To a stirred solution of tert-butyl (2R,4S)-4-(4-(1H-imidazole-1-carbonyl)piperazine-1-carbonyl)-2-(tert-butyl)-4-methyloxazolidine-3-carboxylate (0.66 g, 1.47 mmol) in CH3CN (15 mL) was added MeI (20.8 mL, 14.7 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure to give the title compound (0.88 g, quantitative) as a pale yellow solid.

[0359] Step 5: tert-Butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate. A mixture of 1-(4-((2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (0.88 g, 1.50 mmol) and 4-(4-amino-2-oxopyrimidin-1(2H)-yl)benzaldehyde in CH3CN was stirred at reflux for 16 hours. The solvent was evaporated and the residue was purified by flash column chromatography to give the title compound (0.54 g, 60%) as a pale yellow solid. LCMS [M+H] 597.2.

[0360] Intermediate 18 [ka] tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate Scheme I-17 [ka] Reagents: 1) TBSCl, imidazole, DMF, rt, 16 h; 2) BuLi, THF, -78 °C, (iPrO)B, 2N HCl; 3) cytosine, TMEDA, Cu(OAc)₂·H₂O, 4:1 MeOH:H₂O, rt, 48 h; 4) 3-methyl-1-(4-(2,2,2-trifluoroacetyl)piperazine-1-carbonyl)-1H-imidazol-3-ium iodide, CH₃CN, 85 °C, 16 h; 5) K₂CO₃, MeOH, rt, 3 h; 6) Boc-AIB-OH, HATU, DIPEA, DMF, rt, 8 h; 7) TBAF, THF, 0 °C–rt, 16 h; 8) DMP, 1% CH₂Cl₂:H₂O, rt, 1 h. Step 1: (4-Bromophenethoxy)(tert-butyl)dimethylsilane. To a stirred solution of 2-(4-bromophenyl)ethan-1-ol (7.0 mL, 49.7 mmol) in DMF (50 mL) was added imidazole (5.1 g, 74.6 mmol) and tert-butyldimethylsilyl chloride (9.0 g, 60.0 mmol). The solution was stirred for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and extracted with aqueous LiCl (3 × 50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography (Hex: EtOAc) to give the title compound.

[0361] Step 2: Bisisopropyl(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)boronate. A stirred solution of (4-bromophenethoxy)(tert-butyl)dimethylsilane (9.0 g, 28.0 mmol) in THF (100 mL) was cooled to −78° C. A 2.5 M solution of BuLi in hexanes (28.0 mL, 71.4 mmol) was added dropwise over 30 min, maintaining the temperature below −60° C. After 25 min, triisopropyl borate (10.0 mL, 42.0 mmol) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. 2 N HCl (50 mL) was added and the reaction was stirred for 30 min. The biphasic mixture was separated and the aqueous layer was extracted with CHCl (2 × 50 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure to give the title compound.

[0362] Step 3: 4-Amino-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)pyrimidin-2(1H)-one. A suspension of cytosine (10.5 g, 95 mmol) and diisopropyl(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)boronate (26.6 g, 95.0 mmol) in MeOH:HO (4:1, 600 mL) was stirred at room temperature under air for 30 minutes. TMEDA (17.0 mL, 114.0 mmol) and Cu(OAc)·HO (19.0 g, 95.0 mmol) were added, and the reaction was stirred at room temperature under air for 48 hours. The reaction mixture was concentrated under reduced pressure, and cold HO (100 mL) was added. The solid was filtered and washed with H2O (5x50 mL), Et2O (3x30 mL), and H2O (2x30 mL) to give the title compound. LCMS [M+H] 346.2.

[0363] Step 4: N-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxamide. To a stirred solution of 4-amino-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)pyrimidin-2(1H)-one (2.41 g, 7.0 mmol) in CH3CN (50 mL) was added 3-methyl-1-(4-(2,2,2-trifluoroacetyl)piperazine-1-carbonyl)-1H-imidazol-3-ium iodide (3.79 g, 8.4 mmol). The vessel was flushed with nitrogen, heated to 85°C, and refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (CH2Cl2:MeOH:NH4OH) to give the title compound. LCMS [M+H] 554.3.

[0364] Step 5: N-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide. N-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxamide (4.50 g, 8.1 mmol) and KCO (3.36 g, 24.3 mmol) were dissolved in MeOH (200 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give a solid residue, which was purified by column chromatography (CHCl:MeOH:NHOH) to give the title compound.

[0365] Step 6: tert-Butyl (1-(4-((1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a solution of N-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide (3.66 g, 8.1 mmol) in DMF (30 mL) was added 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1.63 g, 8.1 mmol) followed by DIPEA (3.36 mL, 24.2 mmol). The solution was stirred for 5 min, and HATU (5.51 g, 14.5 mmol) was then added, and the solution was stirred at room temperature for an additional 8 h. The crude reaction mixture was dissolved in EtOAc (50 mL) and washed with aqueous LiCl (3 × 30 mL). The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by flash chromatography (CHCl:MeOH:NHOH) to give the desired compound. LCMS [M+H] 643.4.

[0366] Step 7: tert-Butyl (1-(4-((1-(4-(2-hydroxyethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a solution of tert-butyl (1-(4-((1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (1.0 g, 1.63 mmol) in THF (30 mL) at 0° C. was added a 2 M solution of TBAF in THF (3.27 mL) over 20 minutes. The solution was warmed to room temperature and stirred for 16 hours. The crude reaction mixture was concentrated under reduced pressure to give an oily residue, which was purified by column chromatography (CH2Cl2:MeOH) to give the desired compound. LCMS [M+H] 529.4.

[0367] Step 8: tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate. To a stirred solution of tert-butyl (1-(4-((1-(4-(2-hydroxyethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (150.0 mg, 0.28 mmol) in CHCl:HO (100:1, 10 mL) was added Dess-Martin periodinane (361.0 mg, 0.85 mmol). The solution was stirred for 1 h. The crude reaction mixture was dissolved in additional CH2Cl2 (50 mL) and washed with aqueous NaHCO3 / Na2S2O3 (1 x 50 mL). The aqueous layer was extracted with CH2Cl2 (1 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound, which was used immediately.

[0368] Intermediate 19 [ka] tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(3-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate Prepared from 2-(3-bromophenyl)ethan-1-ol in a similar manner to Scheme I-17.

[0369] Intermediate 20 [ka] tert-Butyl (2R,4S)-2-(tert-butyl)-4-methyl-4-(4-((2-oxo-1-(4-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)oxazolidine-3-carboxylate Prepared in a similar manner to Scheme I-17 using 1-(4-((2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide.

[0370] Intermediate 21 [ka] tert-Butyl (2S,4R)-2-(tert-butyl)-4-methyl-4-(4-((2-oxo-1-(4-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)oxazolidine-3-carboxylate Prepared in a similar manner to Scheme I-17 using 1-(4-((2S,4R)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide.

[0371] Intermediate 22 [ka] tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(3-oxopropyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate Prepared from 3-(4-bromophenyl)propan-1-ol in a similar manner to Scheme I-17.

[0372] Intermediate 23 [ka] tert-Butyl (2-methyl-1-(4-((1-(4-(2-methyl-1-oxopropan-2-yl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate Prepared from 2-(4-bromophenyl)-2-methylpropan-1-ol in a similar manner to Scheme I-17.

[0373] Intermediate 24 [ka] tert-Butyl (1-(4-((1-(4-(1-formylcyclopropyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate Prepared in a similar manner to Scheme I-17 from (1-(4-bromophenyl)cyclopropyl)methanol.

[0374] Intermediate 25 [ka] tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxopropyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate Scheme I-18 [ka] Reagents: 1) NaBH4, MeOH, rt, 3 h; 2) TBDMSCl, imidazole, CHCl, rt, 16 h; 3) n-BuLi, B(OiPr), THF, -78 °C to rt, 3 h; 4) cytosine, TMEDA, Cu(OAc)·HO, MeOH:HO (4:1), O, rt, 16 h; 5) 1-(4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide, MeCN, 90 °C, 16 h; 6) TBAF, THF, rt, 16 h; 7) DMP, CHCl, rt, 3 h. Step 1: 1-(4-bromophenyl)propan-2-ol. To a stirred solution of 1-(4-bromophenyl)propan-2-one (30.0 g, 141 mmol) in MeOH (150 mL) was added NaBH (13.3 g, 352 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into HO (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure to afford the title compound (29.0 g, 95%) as a colorless oil. 1 H NMR (DMSO-d6, 400 MHz) δ 7.43 (d, 2H), 7.15 (d, 2H), 4.58 (d, 1H), 3.82-3.73 (m, 1H), 2.64-2.48 (m, 2H), 1.01 (d, 3H).

[0375] Step 2: ((1-(4-Bromophenyl)propan-2-yl)oxy)(tert-butyl)dimethylsilane. To a stirred solution of 1-(4-bromophenyl)propan-2-ol (29.0 g, 134.9 mmol) in CHCl (300 mL) was added imidazole (13.8 g, 202 mmol) and t-butyldimethylsilyl chloride (24.4 g, 161.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into HO (500 mL) and extracted with CHCl (3 × 700 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (40.0 g, 90%) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.43 (d, 2H), 7.13 (d, 2H), 3.98-3.90 (m, 1H), 2.68-2.64 (m, 1H), 2.56-2.48 (m, 1H), 1.09 (d, 3H), 0.76 (s, 9H), 0.10 (s, 3H), -0.27 (s, 3H).

[0376] Step 3: Diisopropyl (4-(2-((tert-butyldimethylsilyl)oxy)propyl)phenyl)boronate. To a stirred solution of ((1-(4bromophenyl)propan-2-yl)oxy)(t-butyl)dimethylsilane (20.0 g, 60.8 mmol) in THF (300 mL) at −78 °C was added a solution of n-BuLi in THF (1.6 M, 94 mL). The reaction mixture was stirred at −78 °C for 30 min. Triisopropyl borate (21.2 mL, 91.2 mmol) was added at −78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was poured into NH4Cl solution (100 mL) and extracted with EtOAc (3 × 300 ml). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (20 g, 86%).

[0377] Step 4: 4-Amino-1-(4-(2-((tert-butyldimethylsilyl)oxy)propyl)phenyl)pyrimidin-2(1H)-one. A solution of diisopropyl(3-(2-((isopropyldimethylsilyl)oxy)ethyl)phenyl)boronate (20.0 g, 52.9 mmol) and cytosine (5.87 g, 52.9 mmol) in MeOH:HO (300 mL, 4:1) was stirred at room temperature under open air for 30 min. TMEDA (9.58 mL, 63.5 mmol) and Cu(OAc)2.HO (9.6 g, 52.9 mmol) were added, and the reaction mixture was stirred at room temperature under open air for 48 h. The reaction mixture was concentrated under reduced pressure, and cold HO (100 mL) was added to the mixture. The solid was filtered off and washed under reduced pressure with HO (5 × 100 mL) and Et2O (2 × 60 mL). The resulting solid was dried to give the title compound (9.2 g, 48%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.52 (d, 1H), 7.25-7.22 (m, 6H), 5.80 (bs, 1H), 4.00-3.99 (m, 1H), 2.70-2.65 (m, 2H), 1.10 (d, 3H), 0.79 (s, 9H), -0.55 (s, 3H), -0.178(s, 3H). LCMS [M+H] 360.3.

[0378] Step 5: tert-Butyl (1-(4-((1-(4(2-hydroxypropyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. A stirred solution of 4-amino-1-(4-(2-((t-butyldimethylsilyl)oxy)propyl)phenyl)pyrimidin-2(1H)-one (3.0 g, 8.3 mmol) and 1-(4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (6.35 g, 12.5 mmol) in CH3CN (45 mL) was heated at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by column chromatography (CHOH / CHCl) to give the title compound. LCMS [M+H] 357.2.

[0379] Step 6: tert-Butyl (1-(4-((1-(4-(2-hydroxypropyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of t-butyl (1-4-(-2-((t-butyldimethylsilyl)oxy)propyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (3.1 g, 4.72 mmol) in THF (40 mL) was added TBAF (1.0 M in THF, 18.9 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous NaHCO3 (25 mL) and extracted with 9:1 CH2Cl2:MeOH (3 x 100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (5% MeOH in CH2Cl2) to give the title compound as an off-white solid (2.4 g, 93%). LCMS [M+H] 543.2.

[0380] Step 7: tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxopropyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate. To a stirred solution of t-butyl (1-(4-((1-(4(2-hydroxypropyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (0.5 g, 0.92 mmol) in CHCl (5 mL) was added DMP (0.78 g, 1.84 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours, poured into NaHCO3 solution (20 mL), and extracted with CHCl2 (3 x 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure at low temperature (30-35 °C) to give the title compound (0.7 g, quantitative) as an off-white solid. LCMS [M+H] 541.0.

[0381] Intermediate 26 [ka] cis-Benzyl (3-(hydroxymethyl)piperidin-4-yl)carbamate Scheme I-19 [ka] Reagents: Step 1) Cbz-Cl, NaHCO3, dioxane:water, rt, 4 h. 2) 4 M HCl in dioxane, rt, 4 h. Step 1: cis-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-(hydroxymethyl)piperidine-1-carboxylate. To a stirred solution of cis-tert-butyl-4-amino-3-(hydroxymethyl)piperidine-1-carboxylate (0.2 g, 0.86 mmol) in 1:1 dioxane:water (4 mL) was added NaHCO (0.59 g, 7 mmol) and CBZ-Cl (0.25 mL, 1.73 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over NaSO, filtered, concentrated, and purified by column chromatography (EtOAc / hexanes) to afford the title compound (0.3 g, 80%) as an off-white solid. LCMS [M-Boc+H] 265.0.

[0382] Step 2: cis-Benzyl (3-(hydroxymethyl)piperidin-4-yl)carbamate. To a stirred solution of cis-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-(hydroxymethyl)piperidine-1-carboxylate (0.3 g, 0.8 mmol) in dioxane (6 mL) was added 4 M HCl in dioxane (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.2 g, quantitative) as a yellow oil. LCMS [M+H] 265.6.

[0383] Intermediate 27 [ka] tert-Butyl (3-amino-5-((tert-butyldimethylsilyl)oxy)cyclohexyl)carbamate Scheme I-20 [ka] Reagents: Boc2O, TEA, MeOH, rt, 16 h. tert-Butyl (3-amino-5-((tert-butyldimethylsilyl)oxy)cyclohexyl)carbamate. To a stirred solution of 5-((tert-butyldimethylsilyl)oxy)cyclohexane-1,3-diamine (0.5 g, 2.1 mmol), prepared according to New J. Chem., 2005, 29, 1152, was added TEA (0.6 ml, 4.1 mmol) and BocO (0.9 g, 4.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (0.7 g, quantitative) as a brown oil. LCMS [M+H] 345.4.

[0384] Intermediate 28 [ka] tert-Butyl (1-(R-pyrrolidin-3-yl)ethyl)carbamate Scheme I-21 [ka] Reagents: 1) PCC, Celite®, CH2Cl2 2) MeMgCl, THF, -78°C 3) MsCl, NEt3, CH2Cl2, 0°C 4) NaN3, DMF, 80°C 5) PPh3, THF, H2O, 45°C 6) Boc2O, NEt3, THF 7) H2Pd(OH)2 / C, MeOH. Step 1: Benzyl (R)-3-formylpyrrolidine-1-carboxylate. To a solution of benzyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.4 g, 6.0 mmol) in CHCl (50 mL) was added PCC (1.95 g, 9.0 mmol) in Celite® (500 mg). The reaction was stirred for 16 h. The solvent was removed and the crude solution was purified by column chromatography (Hex: EtOAc) to give the title compound.

[0385] Step 2: Benzyl (3R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate. A solution of (R)-3-formylpyrrolidine-1-carboxylate (590 mg, 2.5 mmol) in THF (15 mL) was cooled to −78 °C. To the mixture was added 3 M MeMgCl (1.69 mL, 5.08 mmol) over 30 min. The solution was allowed to warm to room temperature and stirred for 16 h. The organic layer was washed with aqueous citric acid (1 × 15 mL), dried over NaSO, and concentrated under reduced pressure to provide the title compound.

[0386] Step 3: Benzyl (3R)-3-(1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate. A solution of benzyl (3R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (330 mg, 1.3 mmol) in NEt (0.6 mL, 4.2 mmol) and CHCl (10 mL) was cooled to 0 °C, and MsCl (0.18 mL, 2.4 mmol) was added dropwise over 5 min. The solution was stirred for 4 h and washed with NaHCO (1 × 20 mL). The aqueous layer was extracted with CHCl (1 × 20 mL). The combined organics were dried over NaSO and concentrated under reduced pressure to provide the title compound.

[0387] Step 4: Benzyl (3R)-3-(1-azidoethyl)pyrrolidine-1-carboxylate. To a solution of benzyl (3R)-3-(1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate (1.3 mmol) in DMF (12 mL) was added NaN (430 mg, 6.6 mmol). The solution was warmed to 80 °C and stirred for 16 h. The solution was dissolved in EtOAc (50 mL) and washed with saturated LiCl (4 x 20 mL). The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by column chromatography (Hex: EtOAc) to give the title compound.

[0388] Step 5: Benzyl (3R)-3-(1-aminoethyl)pyrrolidine-1-carboxylate. To a solution of benzyl (3R)-3-(1-azidoethyl)pyrrolidine-1-carboxylate (235 mg, 0.85 mmol) in 12:1 THF:HO (8 mL) was added PPh (448 mg, 1.70 mmol). The solution was warmed to 45 °C and stirred for 16 h. The solution was concentrated under reduced pressure and purified by column chromatography (Hex:EtOAc, EtOAc:MeOH:NHOH) to provide the title compound.

[0389] Step 6: Benzyl (3R)-3-(1-((tert-butoxycarbonyl)amino)ethyl)pyrrolidine-1-carboxylate. To a solution of benzyl (3R)-3-(1-aminoethyl)pyrrolidine-1-carboxylate (200 mg, 0.80 mmol) in THF (20 mL) was added BocO (349 mg, 1.60 mmol) and NEt (0.33 mL, 2.4 mmol). The solution was stirred for 16 h. The solution was concentrated under reduced pressure and purified by column chromatography (Hex: EtOAc) to give the title compound.

[0390] Step 7: tert-Butyl (1-((R)-pyrrolidin-3-yl)ethyl)carbamate. To a N2-sparged solution of benzyl (3R)-3-(1-((tert-butoxycarbonyl)amino)ethyl)pyrrolidine-1-carboxylate (140 mg, 0.40 mmol) in MeOH (10 mL) was added Pd(OH)2 10 wt% (14 mg). The reaction was stirred under an H2 atmosphere for 16 h. The reaction mixture was filtered through a Celite® pad and washed with MeOH (5 x 20 mL). The combined organics were concentrated under reduced pressure to provide the title compound.

[0391] Intermediate 29 [ka] tert-Butyl (1-((S)-pyrrolidin-3-yl)ethyl)carbamate Prepared in a similar manner to Scheme I-21 from benzyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate.

[0392] Intermediate 30 [ka] (4-Bromo-2-(trifluoromethyl)phenethoxy)(tert-butyl)dimethylsilane Scheme I-22 [ka] Reagents: 1) BH3THF, THF 0℃~rt, 4 hours 2) CBr4, PPh3DMF, 0℃~rt, 4 hours 3) KCN, EtOH:H2O, 70℃, 3 hours. 4) LiOH, H2O, 100℃, 16 hours. 5)BH3THF, THF 0℃~rt, 4 hours 5)TBSCl, NEt3, CH2Cl2, rt, 16 hours. Step 1: (4-Bromo-2-(trifluoromethyl)phenyl)methanol. To a stirred solution of 4-bromo-2-(trifluoromethyl)benzoic acid (2.65 g, 10.0 mmol) in THF (50 mL) at 0 °C was added 1 M BH THF in THF (20.0 mL) dropwise over 15 min. The solution was allowed to warm to room temperature for 4 h. The reaction mixture was quenched by the addition of 2 N HCl, and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (2 × 50 mL), and the combined organics were dried over Na SO . The reaction mixture was purified by flash chromatography (hexane:EtOAc) to give the desired compound.

[0393] Step 2: 4-Bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene. To a stirred solution of (4-bromo-2-(trifluoromethyl)phenyl)methanol (1.35 g, 5.12 mmol) in DMF (20 mL) at 0 °C, triphenylphosphine (2.02 g, 7.70 mmol) and carbon tetrabromide (2.54 g, 7.70 mmol) were added. The solution was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated LiCl solution (3 x 100 mL). The crude reaction mixture was purified by flash chromatography (hexanes:EtOAc) to give the desired compound.

[0394] Step 3: 2-(4-Bromo-2-(trifluoromethyl)phenyl)acetonitrile. To a solution of 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene (1.84 g, 5.14 mmol) in 3:1 EtOH:HO was added KCN (366 mg, 5.61 mmol). The reaction was heated to 70 °C for 3 h. The reaction mixture was cooled and diluted with EtOAc (100 mL) and HO (50 mL). The biphasic mixture was separated and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The reaction mixture was purified by flash chromatography (hexanes:EtOAc) to give the desired compound.

[0395] Step 4: 2-(4-Bromo-2-(trifluoromethyl)phenyl)acetic acid. To a suspension of 2-(4-bromo-2-(trifluoromethyl)phenyl)acetonitrile (423 mg, 1.62 mmol) in HO (30 mL) was added LiOH (386 mg, 16.2 mmol). The reaction was heated to 100 °C and stirred for 16 h. The reaction mixture was diluted with HO (50 mL) and washed with EtO (1 × 50 mL), and the organic layer was discarded. The aqueous layer was acidified with 2 N HCl and extracted with EtOAc (3 × 50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure to give the desired compound.

[0396] Step 5: 2-(4-Bromo-2-(trifluoromethyl)phenyl)ethan-1-ol. To a solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)acetic acid (333 mg, 1.18 mmol) in THF (25 mL) stirred at 0 °C was added 1 M BH THF (2.36 mL) dropwise over 10 min. The solution was warmed and stirred at room temperature for 4 h. The reaction mixture was quenched by the addition of 2 N HCl, and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (2 × 50 mL), and the combined organics were dried over Na SO . The reaction mixture was purified by flash chromatography (hexane:EtOAc) to give the desired compound.

[0397] Step 6: The desired compound, (4-bromo-2-(trifluoromethyl)phenetoxy)(tert-butyl)dimethylsilane. To a solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)ethan-1-ol (317 g, 46.5 mmol) in CHCl (150 mL) was added imidazole (4.79 g, 70.5 mmol) and tert-butyldimethylsilyl chloride (10.6 g, 70.5 mmol). The solution was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the solid was dissolved in EtOAc (250 mL) and washed with HO (250 mL). The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by flash chromatography (hexanes:EtOAc) to provide the title compound.

[0398] Compound synthesis compound 117 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((trans-4-aminocyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Scheme C-1 [ka] Reagents: 1) N-Boc-trans-1,4-cyclohexanediamine, NaBH3CN, MeOH, rt, 3 days 2) 2M HCl in MeOH, rt, 17 hours. Step 1: tert-Butyl (trans-4-((4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)amino)cyclohexyl)carbamate. NaBHCN (379 mg, 6.03 mmol) was added to a mixture of tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (1.03 g, 2.01 mmol) and N-boc-trans-1,4-cyclohexanediamine (527 mg, 2.46 mmol) in dry MeOH (20 mL), and the mixture was stirred at room temperature for 3 days. It was dry-loaded directly onto silica and Celite®, and the residue was purified by flash chromatography (MeOH / EtOAc) to give the title compound (804 mg, 1.13 mmol) as a white solid.

[0399] Step 2: 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(((trans-4-aminocyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. A mixture of tert-butyl (trans-4-((4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)amino)cyclohexyl)carbamate (369 mg, 0.519 mmol) and 2 M HCl in MeOH (12 mL, 24 mmol) was stirred at room temperature for 17 hours. The precipitate was collected by vacuum filtration to give the title compound (270 mg, 0.435 mmol) as a white solid. 1 H NMR (500 MHz, D2O) δ 7.82 (d, 1H), 7.51 (d, 2H), 7.39 (d, 2H), 6.70 (d, 1H), 4.22 (s, 2H), 3.51-3.76 (m, 8H), 3.06-3.21 (m, 2H), 2.15-2.24 (m, 2H), 2.02-2.10 (m, 2H), 1.58 (s, 6H), 1.33-1.52 (m, 4H). LCMS [M+H] 511.4.

[0400] compound 112 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((azetidin-3-ylmethyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 using tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate. 1H NMR (400 MHz, D2O) δ 7.78 (d, 1H), 7.49 (d, 2H), 7.38 (d, 2H), 6.69 (d, 1H), 4.18 (s, 2H), 4.09 (t, 2H), 3.90 (t, 2H), 3.72-3.55 (m, 8H), 3.35-3.31 (m, 2H), 3.30-3.18 (m, 1H), 1.56 (s, 6H). LCMS [M+H] 483.

[0401] compound 114 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-((((1S,3R)-3-aminocyclopentyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 using tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((1R,3S)-3-aminocyclopentyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.81 (d, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.69 (d, 1H), 4.20 (s, 2H), 3.68-3.57 (m, 9H), 2.63-2.55 (m, 1H), 2.17-2.04 (m, 2H), 1.85-1.63 (m, 4H), 1.59 (s, 6H). LCMS [M+H] 497.3.

[0402] compound 44 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((3R)-3-(1-aminoethyl)pyrrolidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (1-((R)-pyrrolidin-3-yl)ethyl)carbamate. 1 H NMR (500 MHz, D2O) δ 8.07 (d, 1H), 7.70 (d, 2H), 7.58 (d, 2H), 6.82 (d, 1H), 4.52 (s, 2H), 3.85-3.64 (m, 8H), 3.64-3.35 (m, 3H), 3.24-3.03 (m, 1H), 2.99-2.70 (m, 1H), 2.67-2.51 (m, 1H), 2.48-2.21 (m, 1H), 2.18-2.01 (m, 1H), 1.72 (s, 6H), 1.35-1.28 (m, 3H) LCMS [M+H] 511.2.

[0403] compound 45 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((3S)-3-(1-aminoethyl)pyrrolidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (1-((S)-pyrrolidin-3-yl)ethyl)carbamate.1 H NMR (500 MHz, D2O) δ 8.01 (d, 1H), 7.69 (d, 2H), 7.57 (d, 2H), 6.84 (d, 1H), 4.52 (s, 2H), 3.83-3.63 (m, 8H), 3.60 (t, 1H), 3.53-3.36 (m, 2H), 3.22-3.10 (m, 1H), 2.91-2.79 (m, 1H), 2.68-2.52 (m, 1H), 2.48-2.19 (m, 1H), 2.15-2.02 (m, 1H), 1.73 (s, 6H), 1.38-1.28 (m, 3H). LCMS [M+H] 511.2.

[0404] compound 107 [ka] 4-(2-amino-2-methylpropanoyl)-N-(2-oxo-1-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)phenyl)-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and 4-(trifluoromethyl)piperidine. 1 H NMR (500 MHz, D2O) δ 7.99 (d, 1H), 7.69 (d, 2H), 7.58 (d, 2H), 6.85 (d, 1H), 4.44 (s, 2H), 3.83-3.75 (m, 4H), 3.74-3.70 (m, 4H), 3.68 (d, 2H), 3.13 (t, 2H), 2.66-2.60 (m, 1H), 2.22 (d, 2H), 1.88-1.78 (m, 2H), 1.74 (s, 6H). LCMS [M+H] 550.3.

[0405] Compound 383 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and 4,4-difluoropiperidine. 1 H NMR (500 MHz, D2O) δ 8.09 (d, 1H), 7.82 (d, 2H), 7.70 (d, 2H), 6.96 (d, 1H), 4.61 (s, 2H), 3.94-3.86 (m, 4H), 3.85-3.83 (m, 4H), 3.82-3.79 (m, 2H), 3.54-3.50 (m, 2H), 2.64-2.50 (m, 2H), 2.49-2.32 (m, 2H), 1.86 (s, 6H). LCMS [M+H] 417.3.

[0406] Compound 109 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((3-(1-aminoethyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (1-(piperidin-3-yl)ethyl)carbamate.1 H NMR (400 MHz, D2O) δ 7.98 (d, 1H), 7.71 (d, 2H), 7.59 (d, 2H), 6.87 (d, 1H), 4.48 (s, 2H), 3.79 (br. s, 2H), 3.74 (s, 6H), 3.60 LCMS [M+H] 525.3.

[0407] compound 110 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((3-(1-aminopropyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (1-(piperidin-3-yl)propyl)carbamate. 1 H NMR (400 MHz, D2O) δ 8.09 (d, 1H), 7.72 (d, 2H), 7.61 (d, 2H), 6.85 (d, 1H), 4.47 (s, 2H), 3.81 (br. s, 2H), 3.69 (br.s, 6H), 3.59 (d, 2H), 3.29-3.13 (m, 1H), 3.00 (t, 2H), 2.22 (t, 1H), 2.11 (d, 1H), 1.98 (d, 1H), 1.83-1.56 (m, 8H), 1.50-1.23 (m, 2H), 1.09-0.90 (m, 3H).LCMS [M+H] 539.2.

[0408] Compound 342 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((3-amino-5-hydroxycyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3-amino-5-((tert-butyldimethylsilyl)oxy)cyclohexyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.89 (d, 1H), 7.55 (d, 2H), 7.41 (d, 2H), 6.70 (d, 1H), 4.27 (m, 3H), 3.79-3.76 (m, 2H), 3.63-3.50 (m, 8H), 2.34-2.23 (m, 2H), 2.00-1.72 (m, 4H), 1.58 (s, 6H). LCMS [M+H] 527.3.

[0409] compound 120 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((4-aminocyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and 1-N-Boc-cis-1,4-cyclohexyldiamine. 1 H NMR (400 MHz, D2O) δ 7.77 (d, 1H), 7.53 (d, 2H), 7.39 (d, 2H), 6.72 (d, 1H), 4.25 (s, 2H), 3.68-6.55 (m, 8H), 3.47-3.40 (m, 1H), 3.34-3.28 (m, 1H), 1.99-1.92 (m, 2H), 1.85-1.65 (m, 6H), 1.58 (s, 6H). LCMS [(M+2H) / 2] 256.2.

[0410] compound 123 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((((1S,3S)-3-aminocyclopentyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate. 1H NMR (400 MHz, D2O) δ 7.79 (d, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 6.73 (d, 1H), 4.22 (s, 2H), 3.82-3.73 (m, 2H), 3.68-3.55 (m, 8H), 2.32-2.15 (m, 4H), 1.78-1.60 (m, 2H), 1.57 (s, 6H). LCMS [(M+2H / 2] 249.0.

[0411] compound 126 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-((((cis-3-aminocyclobutyl)methyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (cis-3-(aminomethyl)cyclobutyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.81 (d, 1H), 7.49 (d, 2H), 7.38 (d, 2H), 6.70 (d, 1H), 4.15 (s, 2H), 3.68-3.57 (m, 8H), 3.10-3.05 (m, 2H), 2.49-2.35 (m, 4H), 1.88-1.79 (m, 2H), 1.57 (s, 6H). LCMS [(M+2H) / 2] 249.1.

[0412] compound 100 [ka] 4-((S)-2-Amino-3-hydroxy-2-methylpropanoyl)-N-(1-(4-((4-((S)-2-aminopropanamido)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and tert-butyl (S)-(1-oxo-1-(piperidin-4-ylamino)propan-2-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 8.01 (d, 1H), 7.72 (d, 2H), 7.60 (d, 2H), 6.87 (d, 1H), 4.47 (d, 2H), 4.19 (d, 1H), 4.09-3.98 (m, 1H), 3.93 (d, 1H), 3.87-3.70 (m, 8H), 3.65 (d, 2H), 3.22 (t, 2H), 2.23 (d, 2H), 1.85-1.74 (m, 1H), 1.71 (s, 3H), 1.54 (d, 3H), 1.12 (d, 2H). LCMS [M+H] 584.4.

[0413] Compound 102 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-((4-guanidinopiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide trifluoroacetate Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(3-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and 1,2-bis(tert-butoxycarbonyl)-3-(piperidin-4-yl)guanidine. LCMS [M+H] 539.4.

[0414] compound 105 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-guanidinopiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and 1,2-bis(tert-butoxycarbonyl)-3-(piperidin-4-yl)guanidine. 1 H NMR (500 MHz, CD3OD) δ 7.75 (d, 1H), 7.71 (d, 2H), 7.57 (d, 2H), 6.65 (s, 1H), 4.43 (s, 2H), 3.76-3.65 (m, 9H), 3.60 (d, 2H), 3.16 (dd, 2H), 2.21 (d, 2H), 1.93-1.81 (m, 2H), 1.70 (s, 6H). LCMS [M+H] 539.4.

[0415] compound 362 [ka] 4-(3-amino-3-methylbutanoyl)-N-(1-(3-((4-aminopiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (4-(4-((1-(3-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-4-oxobutan-2-yl)carbamate and tert-butyl piperidin-4-ylcarbamate. 1 H NMR (400 MHz, CD3OD) δ 8.47 (d, 1H), 7.88 (s, 1H), 7.79 (t, 1H), 7.71 (d, 2H), 6.86 (d, 1H), 4.48 (s, 2H), 3.86-3.69 (m, 8H), 3.64 (d, 2H), 3.53 (t, 1H), 3.26 (t, 2H), 2.84 (s, 2H), 2.29 (d, 2H), 2.11 (q, 2H), 1.45 (s, 6H). LCMS [M+H] 511.3.

[0416] compound 363 [ka] 4-(3-amino-3-methylbutanoyl)-N-(1-(3-((4-amino-4-methylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (4-(4-((1-(3-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-4-oxobutan-2-yl)carbamate and tert-butyl (4-methylpiperidin-4-yl)carbamate. 1H NMR (400 MHz, CD3OD) δ 8.53 (d, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.71 (d, 2H), 6.89 (s, 1H), 4.55 (s, 2H), 3.89-3.63 (m, 8H), 3.54 LCMS [M+H] 525.3.

[0417] compound 350 [ka] 4-(3-amino-3-methylbutanoyl)-N-(1-(4-((4-guanidinopiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-4-oxobutan-2-yl)carbamate and 1,2-bis(tert-butoxycarbonyl)-3-(piperidin-4-yl)guanidine. 1 H NMR (400 MHz, CD3OD) δ 8.42 (d,1H), 7.86 (d, 2H), 7.68 (d, 2H), 6.89 (d, 1H), 3.96 (s, 2H), 3.90-3.64 (m, 9H), 3.58 (d, 2H), 3.25 (d, 2H), 2.84 (s, 2H), 2.28-2.16 (m, 2H), 1.95 (d, 2H), 1.48-1.38 (m, 6H). LCMS [M+H] 553.3.

[0418] Compound 351 [ka] 4-(3-amino-3-methylbutanoyl)-N-(1-(4-((4-carbamimidoylpiperazin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-4-oxobutan-2-yl)carbamate and 1-[N,N'-bis(tert-butoxycarbonyl)amidino]piperazine. 1 H NMR (400 MHz, CD3OD) δ 8.37 (d, 1H), 7.89 (d, 2H), 7.69 (d, 2H), 6.87 (d, 1H), 3.97 (s, 2H), 3.91-3.52 (m, 16H), 2.84 (s, 2H), 1.52-1.41 (m, 6H). LCMS [M+H] 539.3.

[0419] compound 133 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-((3-(aminomethyl)azetidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (azetidin-3-ylmethyl)carbamate. 1H NMR (500 MHz, CD3OD) δ 8.35 (d, 1H), 7.77 (m, 2H), 7.60-7.68 (m, 2H), 6.82 (d, 1H), 4.56 (m, 2H), 4.34-4.42 (m, 1H), 4.16-4.29 (m, LCMS [M+H] 483.3.

[0420] compound 134 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((3-(2-aminoethyl)azetidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (2-(azetidin-3-yl)ethyl)carbamate hydrochloride. 1 H NMR (500 MHz, CD3OD) δ 8.33-8.44 (m, 1H), 7.77 (m, 2H), 7.59-7.70 (m, 2H), 6.80-6.90 (m, 1H), 4.52 (m, 2H), 4.28-4.36 (m, 1H), 4.18-4.27 (m, 1H), 4.05-4.15 (m, 1H), 3.93-4.02 (m, 1H), 3.78 (m, 8H), 2.95-3.08 (m, 1H), 2.84-2.95 (m, 2H), 2.10-2.18 (m, 1H), 2.03-2.10 (m, 1H), 1.71 (s, 6H). LCMS [M+H] 497.3.

[0421] compound 374 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((azetidin-3-ylmethyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate. 1 H NMR (500 MHz, D2O) δ 7.79 (d, 1H), 7.51 (d, 2H), 7.40 (d, 2H), 6.71 (d, 1H), 4.20 (s, 2H), 4.07-4.16 (m, 2H), 3.87-3.96 (m, 2H), 3.50-3.72 (m, 8H), 3.34 (d, 2H), 3.22-3.31 (m, 1H), 1.58 (s, 6H). LCMS [M+H] 483.4.

[0422] compound 376 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((((3-hydroxyazetidin-3-yl)methyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate. 1 H NMR (500 MHz, D2O) δ 7.80 (d, 1H), 7.55 (d, 2H), 7.42 (d, 2H), 6.73 (d, 1H), 4.28 (s, 2H), 4.13 (d, 2H), 4.04 (d, 2H), 3.51-3.72 (m, 8H), 3.42 (s, 2H), 1.59 (s, 6H). LCMS [M+H] 499.4.

[0423] compound 375 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((2-(azetidin-3-yl)ethyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate. 1H NMR (500 MHz, D2O) δ 7.78 (d, 1H), 7.50 (d, 2H), 7.39 (d, 2H), 6.71 (d, 1H), 4.18 (s, 2H), 4.00 - 4.09 (m, 2H), 3.70 - 3.79 (m, LCMS [M+H] 497.3.

[0424] compound 135 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((2-(aminomethyl)morpholino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (morpholin-2-ylmethyl)carbamate. 1 H NMR (500 MHz, CD3OD) δ 8.32-8.41 (m, 1H), 7.87 (d, 2H), 7.68 (d, 2H), 6.82-6.89 (m, 1H), 4.46-4.59 (m, 2H), 4.15-4.26 (m, 2H), 3.97-4.07 (m, 1H), 3.69-3.86 (m, 8H), 3.44-3.58 (m, 2H), 3.26-3.36 (m, 1H), 3.16-3.25 (m, 1H), 3.05-3.15 (m, 1H), 2.95-3.04 (m, 1H), 1.71 (s, 6H).LCMS [M+H] 513.3.

[0425] compound 136 [ka] (S)-4-(2-amino-3-hydroxy-2-methylpropanoyl)-N-(1-(4-((3-(2-aminoethyl)azetidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and tert-butyl (2-(azetidin-3-yl)ethyl)carbamate hydrochloride. 1 H NMR (500 MHz, D2O) δ 7.44 (d, 1H), 7.33 (d, 2H), 7.22 (d, 2H), 6.28 (d, 1H), 3.45-3.76 (m, 11H), 3.41 (d, 1H), 3.28 (dd, 1H), 3.14-3.24 (m, 2H), 3.02-3.11 (m, 1H), 2.70 (dd, 1H), 2.48-2.54 (m, 1H), 2.29-2.40 (m, 1H), 1.98-2.08 (m, 1H), 1.43-1.54 (m, 1H), 1.22 (s, 3H).LCMS [M+H] 513.3.

[0426] Compound 377 [ka] 4-(2-amino-2-methylpropanoyl)-N-(2-oxo-1-(4-((3-(piperidin-4-yl)azetidin-1-yl)methyl)phenyl)-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl 4-(azetidin-3-yl)piperidine-1-carboxylate. 1 H NMR (400 MHz, D2O) δ 8.23 ​​(d, 1H), 7.67 (d, 2H), 7.60 (d, 2H), 6.82 (d, 1H), 4.46 (s, 2H), 4.29-4.43 (m, 2H), 4.42-4.04 (m, 2H), 3.83-3.76 (m, 8H), 3.45 (d, 2H), 3.01 (t, 2H), 2.83-2.75 (m, 1H), 2.04-1.84 (m, 3H), 1.74 (s, 6H), 1.39-1.28 (m, 2H). LC-MS [M+H] 537.3.

[0427] compound 288 [ka] 4-((S)-2-Amino-3-hydroxy-2-methylpropanoyl)-N-(1-(4-(((trans-4-aminocyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 using tert-butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and tert-butyl (trans-4-aminocyclohexyl)carbamate. 1H NMR (500 MHz, D2O) δ 7.94 (d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 6.83 (d, 1H), 4.34 (s, 2H), 4.14 (d, 1H), 3.87 (d, 1H), 3.76-3.69 (m, 8H), 3.32-3.21 (m, 2H), 2.32 (d, 2H), 2.19 (d, 2H), 1.66 (s, 3H), 1.62-1.48 (m, 4H). LCMS [M+H] 527.3.

[0428] compound 137 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-((3-(aminomethyl)-3-hydroxyazetidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((3-hydroxyazetidin-3-yl)methyl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.78 (d, 1H), 7.47-7.56 (m, 2H), 7.42 (d, 2H), 6.71 (d, 1H), 4.36-4.51 (m, 2H), 4.24-4.33 (m, 2H), 4.01-4.20 (m, 2H), 3.51-3.72 (m, 8H), 3.29 (s, 2H), 1.59 (s, 6H). LCMS [M+H] 499.3.

[0429] Compound 201 [ka] Ethyl 1-(4-(4-(4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-3-(aminomethyl)azetidine-3-carboxylate hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and ethyl 3-((((benzyloxy)carbonyl)amino)methyl)azetidine-3-carboxylate trifluoroacetate. 1 H NMR (500 MHz, CD3OD) δ 7.69 (d, 1H), 7.45 (d, 2H), 7.38 (d, 2H), 6.52-6.72 (m, 1H), 4.21 (q, 2H), 3.61-3.88 (m, 12H), 3.50 (d, 2H), 3.11 (s, 2H), 1.42 (s, 6H), 1.29 (t, 3H). LCMS [M+H] 555.3.

[0430] compound 380 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((3-amino-[1,3'-biazetidin]-1'-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl [1,3′-biazetidin]-3-ylcarbamate. 1H NMR (500 MHz, D2O) δ 7.60 (d, 1H), 7.29 (d, 2H), 7.24 (d, 2H), 6.54 (d, 1H), 3.46-3.73 (m, 10H), 3.34-3.44 (m, 3H), 3.21-3.33 (m, 3H), 2.93 (t, 2H), 2.69-2.80 (m, 2H), 1.32 (s, 6H). LCMS [M+H] 524.2.

[0431] compound 205 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((3-(2-aminoethyl)-3-hydroxyazetidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and 2,2,2-trifluoro-N-(2-(3-hydroxyazetidin-3-yl)ethyl)acetamide trifluoroacetate. 1 H NMR (500 MHz, D2O) δ 7.81 (d, 1H), 7.46-7.54 (m, 2H), 7.41 (d, 2H), 6.70 (d, 1H), 4.33-4.46 (m, 2H), 4.13-4.21 (m, 2H), 3.95-4.10 (m, 2H), 3.48-3.74 (m, 8H), 2.90-3.03 (m, 2H), 2.04-2.14 (m, 2H), 1.58 (s, 6H). LCMS [M+H] 513.3.

[0432] compound 369 [ka] 1-(4-(4-(4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-3-(2-aminoethyl)azetidine-3-carboxylic acid hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)azetidine-3-carboxylate. 1 H NMR (500 MHz, CD3OD) δ 7.71-7.86 (m, 1H), 7.61-7.70 (m, 2H), 7.48-7.59 (m, 2H), 5.78-5.84 (m, 1H), 4.38-4.59 (m, 4H), 4.17-4.34 LCMS [M+H] 541.4.

[0433] compound 132 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((trans-4-aminocyclohexyl)(2-hydroxyethyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (trans-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)cyclohexyl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.85 (d, 1H), 7.60 (d, 2H), 7.45 (d, 2H), 6.73 (d, 1H), 4.36-4.48 (m, 2H), 3.54-3.81 (m, 10H), 3.32-3.44 LCMS [M+H] 555.3.

[0434] compound 138 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((trans-4-aminocyclohexyl)(2-fluoroethyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (trans-4-((2-fluoroethyl)amino)cyclohexyl)carbamate. 1H NMR (500 MHz, D2O) δ 7.83-7.92 (m, 1H), 7.55-7.66 (m, 2H), 7.41-7.53 (m, 2H), 6.69-6.77 (m, 1H), 4.35-4.54 (m, 2H), 3.49-3.80 LCMS [M+H] 557.2.

[0435] Compound 319 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-ethylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3-ethylpiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.78 (d, 1H), 7.56 (d, 2H), 7.43 (d, 2H), 6.73 (d, 1H), 4.36-4.28 (m, 2H), 3.61-3.58 (m, 6H), 3.08-3.04 (m, LCMS [M+H] 525.4.

[0436] compound 297 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-methylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and cis-tert-butyl (3-methylpiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.78 (d, 1H), 7.52 (s, 2H), 7.41 (d, 2H), 6.69 (d, 1H), 4.33-4.22 (m, 2H), 3.61-3.48 (m, 11H), 3.31 (t, 2H), 3.20 (d, 1H), 3.02 (d, 1H), 2.85 (t, 1H), 2.44 (bs, 1H) 2.11 (s, 1H), 1.99 (s, 1H), 1.56 (s, 6H), 2.85 (t, 1H), 0.98 (d, 2H) 0.90 (d, 2H). LCMS [M+H] 511.3.

[0437] compound 296 [ka] trans-4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-methylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and trans-tert-butyl (3-methylpiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.8 (d, 1H), 7.55 (d, 2H), 7.44 (d, 2H), 6.73 (d, 1H), 4.35-4.26 (m, 2H), 3.64-3.59 (m, 8H), 3.5 (d, 1H), 3.40 (d, 1H), 3.24-2.98 (m, 3H), 2.81 (t, 1H), 2.22 (d, 1H) 2.04-1.98 (m, 2H), 1.86-1.65 (m, 2H) 1.55 (s, 6H), 0.96-0.88 (m, 3H). LCMS [M+H] 511.3.

[0438] compound 300 [ka] trans-4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-methoxypiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and trans-4-(Boc-amino)-3-methoxypiperidine. 1H NMR (400 MHz, D2O) δ 7.76 (d, 1H), 7.55 (d, 2H), 7.42 (d, 2H), 6.72 (d, 1H), 4.35-4.26 (m, 2H), 3.85-3.70 (m, 1H), 3.65-3.49 (m, LCMS [M+H] 527.8.

[0439] compound 336 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-fluoropiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and cis-4-(Boc-amino)-3-fluoropiperidine. 1 H NMR (400 MHz, D2O) δ 7.78 (d, 1H), 7.54 (d, 2H), 7.42 (d, 2H), 6.71 (d, 1H), 5.22 (s, 1H), 5.11 (m, 1H), 4.36 (s, 2H), 3.84 (t, 1H), 3.71-3.56 (m, 8H), 3.49-3.30 (m, 2H), 3.18-3.12 (m, 1H) 2.14-2.05 (m, 2H), 1.57 (s, 6H). LCMS [M+H] 515.3.

[0440] Compound 344 [ka] trans-4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-fluoropiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and trans-4-(Boc-amino)-3-fluoropiperidine. 1 H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.59 (d, 2H), 7.47 (d, 2H), 6.73 (d, 1H), 4.82-4.81 (m, 1H), 4.49-4.38 (m, 2H), 3.82-3.79 (m, 1H), 3.65-3.53 (m, 10H), 3.24-3.15 (m, 2H), 2.39-3.35 (m, 1H), 1.96-1.86 (m, 1H) 1.60 (s, 6H). LCMS [(M+2H) / 2] 258.3.

[0441] compound 320 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((3-aminocyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and cis-tert-butyl (3-aminocyclohexyl)carbamate. 1H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 6.72 (d, 1H), 5.75-5.55 (m, 1H), 4.25 (s, 2H), 3.75-3.59 (m, 8H), 3.33-3.19 (m, 2H), 2.51-2.40 (m, 1H), 2.13 (bs, 1H), 2.05-1.89 (m, 3H) 1.59 (s, 6H), 1.52-1.43 (m, 2H), 1.30-1.19 (m, 4H). LCMS [M+H] 511.3.

[0442] Compounds 298 and 299 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-(1-aminoethyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (1-(piperidin-4-yl)ethyl)carbamate. Before Boc deprotection, these two enantiomers were separated by chiral preparative HPLC and used separately in the final step. Isomer 1: 1H NMR (400 MHz, D2O) δ 7.76 (t, 1H), 7.52 (t, 2H), 7.42 (t, 2H), 6.71 (t, 1H), 4.25 (d, 2H), 3.61-3.56 (m, 9H), 3.5 (d, 4H), 3.16-3.14 (m, 1H), 2.91 (bs, 2H), 1.89 (bs, 2H), 1.81 (s, 1H) 1.28 (s, 2H), 1.55 (d, 5H) 1.43 (s, 2H), 1.15-1.08 (m, 4H). LCMS [M+H] 525.3. Isomer 2: 1 H NMR (400 MHz, D2O) δ 7.80 (d, 1H), 7.52 (s, 2H), 7.40 (d, 2H), 6.69 (d, 1H), 4.24 (s, 3H), 4.12-4.06 (m, 2H), 3.58-3.48 (m, 5H), 3.13 (bs, 2H), 2.92 (bs, 3H), 1.79-1.87 (m, 4H), 1.56 (s, 6H) 1.12 (s, 8H), 0.71 (s, 3H). LCMS [M+H] 525.5.

[0443] Compound 335 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((4-amino-3-methylcyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (4-amino-2-methylcyclohexyl)carbamate (prepared according to WO2012101062A1). 1H NMR (400 MHz, D2O) Diastereomeric mixture δ 7.83 (d, 1H), 7.55 (d, 2H), 7.44 (d, 2H), 6.76 (d, 1H), 4.29 (s, 2H), 3.67-3.56 (m, 8H), 3.28 (bs, 1H), 2.87 (bs, 1H), 2.26-2.14 (m, 2H), 2.12-2.10 (m, 2H), 1.70-1.76 (bs, 1H), 1.63 (s, 6H), 1.53-1.47 (m, 2H), 1.33 (d, 1H), 1.19 (d, 1H), 1.10 (d, 3H). LCMS [M+H] 525.3.

[0444] Compound 339 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((4-amino-3-methoxycyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (4-amino-2-methoxycyclohexyl)carbamate (prepared according to WO2012101062A1). 1H NMR (400 MHz, D2O) Diastereomeric mixture δ 7.84 (d, 1H), 7.54 (d, 2H), 7.41 (d, 2H), 6.71 (d, 1H), 4.26 (s, 2H), 3.63-3.50 (m, 8H), 3.34 (br s, LCMS [M+H] 541.5.

[0445] Compound 321 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((3,5-diaminocyclohexyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and cis-di-tert-butyl (5-aminocyclohexane-1,3-diyl)dicarbamate (prepared according to J. Am. Chem. Soc. 2004, 126, 4543). 1 H NMR (400 MHz, D2O) Rotamer mixture δ 7.83 (d, 1H), 7.55 (d, 2H), 7.42 (d, 2H), 6.73 (d, 1H), 4.31 (s, 2H), 3.64-3.51 (m, 8H), 3.49-3.46 (m, 1H), 3.42-3.33 (m, 2H), 3.27 (m, 1H), 2.51 (d, 2H), 2.38 (d, 1H), 1.65-1.52 (m, 9H). LCMS [M+H] 526.6.

[0446] compound 208 [ka] trans-4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-amino-3-fluoropiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((trans)-3-fluoropiperidin-4-yl)carbamate to give the title compound as the hydrochloride salt (8.8 mg, 56%). 1 H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.66 (d, 2H), 7.53 (d, 2H), 6.82 (d, 1H), 5.06-4.82 (m, 1H), 4.53 (d, 1H), 4.47 (d, 1H), 3.94-3.82 (m, 1H), 3.81-3.57 (m, 10H), 3.39-3.16 (m, 2H), 2.55-2.33 (m, 1H), 2.06-1.89 (m, 1H), 1.68 (s, 6H). LCMS [M+H] 515.5.

[0447] compound 212 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((cis)-4-amino-3-ethylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3-ethylpiperidin-4-yl)carbamate. These two isomers were separated by semi-preparative HPLC on a Gemini 5 μm C18 110A AXIA (100 × 30 mm) column using mobile phase A: 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia / B: CH3CN, flow rate: 40 mL / min, run time = 15.0 min, gradient: t = 0 min 10% B, t = 10 min 60% B, t = 10.5 min 100% B, t = 14.5 min 100% B, t = 15 min 10% B. Structural assignment was performed on the free base. 1 H NMR (D2O, 400 MHz) δ 7.90 (d, 1H), 7.66 (d, 2H), 7.53 (d, 2H), 6.81 (d, 1H), 4.51-4.30 (m, 2H), 3.81-3.43 (m, 11H), 3.26-2.90 (m, 2H), 2.38-2.00 (m, 3H), 1.68 (s, 6H), 1.54-1.30 (m, 2H), 1.00-0.72 (m, 3H). LCMS [M+H] 525.6.

[0448] compound 213 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((trans)-4-amino-3-ethylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3-ethylpiperidin-4-yl)carbamate. These two isomers were separated by semi-preparative HPLC on a Gemini 5 μm C18 110A AXIA (100 × 30 mm) column using mobile phase A: 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia / B: CH3CN, flow rate: 40 mL / min, run time = 15.0 min, gradient: t = 0 min 10% B, t = 10 min 60% B, t = 10.5 min 100% B, t = 14.5 min 100% B, t = 15 min 10% B. Structural assignment was performed on the free base. 1 H NMR (D2O, 400 MHz) δ 7.84 (d, 1H), 7.64 (d, 2H), 7.52 (d, 2H), 6.84-6.78 (m, 1H), 4.41 (d, 1H), 4.38 (d, 1H), 3.80-3.54 (m, 10H), 3.38-3.26 (m, 1H), 3.20-3.07 (m, 1H), 2.96 (t, 1H), 2.38-2.25 (m, 1H), 2.10-1.81 (m, 2H), 1.68 (s, 7H), 1.43-1.29 (m, 1H), 0.86 (t, 3H).LCMS [M+H] 525.6.

[0449] compound 365 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-aminoazepan-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl azepan-4-ylcarbamate. LCMS [M+H] 511.3.

[0450] compound 370 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-(azetidin-3-yl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl 3-(piperidin-4-yl)azetidine-1-carboxylate. LCMS [M+H] 537.4.

[0451] compound 292 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-6-methyl-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1. LCMS [M+H] 511.3.

[0452] compound 209 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-amino-3-fluoropiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((cis)-3-fluoropiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.64 (d, 2H), 7.53 (d, 2H), 6.82 (d, 1H), 5.27 (d, 1H), 4.53-4.38 (m, 2H), 4.02-3.88 (m, 1H), 3.85-3.57 (m, 10H), 3.55-3.18 (m, 2H), 2.32-2.16 (m, 2H), 1.68 (s, 6H). LCMS [M+H] 515.5.

[0453] compound 210 [ka] trans-4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-amino-3-methylpiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((trans)-3-methylpiperidin-4-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.88 (d, 1H), 7.64 (d, 2H), 7.52 (d, 2H), 6.81 (d, 1H), 4.42 (d,1H), 4.37 (d, 1H), 3.81-3.58 (m, 9H), 3.57-3.44 (m, 1H), 3.27-3.07 (m, 2H), 2.90 (t, 1H), 2.36-2.25 (m, 1H), 2.14-2.01 (m, 1H), 1.98-1.82 (m, 1H), 1.68 (s, 6H), 1.04 (d, 3H). LCMS [M+H] 511.5.

[0454] compound 211 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-amino-3-methylpiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide (racemic compound) hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((cis)-3-methylpiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.64 (d, 2H), 7.52 (d, 2H), 6.82 (d,1H), 4.49-4.30 (m, 2H), 3.81-3.54 (m, 10H), 3.48-3.37 (m, LCMS [M+H] 511.5.

[0455] compound 214 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and N,N-dimethylpiperidin-4-amine. 1 H NMR (400 MHz, D2O) δ 7.89 (d, 1H), 7.65 (d, 2H), 7.53 (d, 2H), 6.81 (d, 1H), 4.41 (s, 2H), 3.81-3.50 (m, 11H), 3.17 (br. s., 2H), 2.86 (s, 6H), 2.36 (br s, 2H), 2.05-1.86 (m, 2H), 1.69 (s, 6H). LCMS [M+H] 525.3.

[0456] compound 215 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[4-(aminomethyl)-4-hydroxypiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate. 1H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.64 (d, 2H), 7.52 (d, 2H), 6.81 (d, 1H), 4.40 (s, 2H), 3.80-3.61 (m, 8H), 3.51-3.41 (m, 2H), 3.37-3.23 (m, 2H), 3.05 (s, 2H), 2.00-1.78 (m, 4H), 1.68 (s, 6H). LCMS [M+H] 527.4.

[0457] compound 218 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-(2-aminoethyl)piperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.84 (d, 1H), 7.65-7.58 (m, 2H), 7.53-7.47 (m, 2H), 6.82 (d, 1H), 4.33 (s, 2H), 3.81-3.60 (m, 8H), 3.56-3.48 (m, 2H), 3.08-2.93 (m, 4H), 2.01-1.91 (m, 2H), 1.90-1.54 (m, 9H), 1.49-1.32 (m, 2H). LCMS [M+H] 525.4.

[0458] compound 223 [ka] 4-[(2S)-2-Amino-3-hydroxy-2-methylpropanoyl]-N-(1-{4-[(4-amino-3-methylpiperidin-1-yl)methyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and tert-butyl (3-methylpiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.80 (d, 1H), 7.56 (d, 2H), 7.44 (d, 2H), 6.73 (d, 1H), 4.39-4.21 (m, 2H), 4.02 (d, 1H), 3.77 (d, 1H), 3.73-2.81 (m, 13H), 2.56-2.24 (m, 1H), 2.22-1.92 (m, 2H), 1.55 (s, 3H), 1.09-0.87 (m, 3H). LCMS [M+H] 527.5.

[0459] compound 224 [ka] trans-4-[(2S)-2-Amino-3-hydroxy-2-methylpropanoyl]-N-(1-{4-[(4-amino-3-methylpiperidin-1-yl)methyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and tert-butyl ((trans)-3-methylpiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 6.81 (d, 1H), 4.46-4.30 (m, 2H), 4.18-3.81 (m, 2H), 3.80-3.58 (m, 8H), 3.69-3.57 (m, 1H), 3.57-3.38 (m, 1H), 3.24-3.03 (m, 2H), 2.89 (t, 1H), 2.30 (d, 1H), 2.09 (br. s., 1H), 1.90 (q, 1H), 1.63 (s, 3H), 1.16-0.83 (m, 3H). LCMS [M+H] 527.5.

[0460] compound 225 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-(2-amino-2-methylpropanoyl)piperazin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (2-methyl-1-oxo-1-(piperazin-1-yl)propan-2-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.84 (d, 1H), 7.64 (d, 2H), 7.53 (d, 2H), 6.82 (d, 1H), 4.43 (s, 2H), 3.85-3.26 (m, 16H), 1.68 (s, 6H), 1.66 (s, 6H). LCMS [M+H] 568.5.

[0461] compound 227 [ka] trans-4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-amino-3-(hydroxymethyl)piperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide (racemic compound) hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((trans)-3-(hydroxymethyl)piperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.97 (d, 1H), 7.71 (d, 2H), 7.59 (d, 2H), 6.85 (d, 1H), 4.53 (s, 2H), 3.90-3.58 (m, 13H), 3.29-3.08 (m, 2H), 2.09 (d, 2H), 1.80-1.53 ​​(m, 7H). LCMS [M+H] 527.6.

[0462] compound 237 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[(3S)-3-aminopiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (S)-piperidin-3-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 7.84 (d, 1H), 7.64 (d, 2H), 7.53 (d, 2H), 6.82 (d, 1H), 4.47 (s, 2H), 3.77-3.62 (m, 9H), 3.62-3.49 (m, 2H), 3.20-2.92 (m, 2H), 2.25-2.15 (m, 1H), 2.13-2.04 (m, 1H), 1.87-1.72 (m, 1H), 1.71-1.56 (m, 7H). LCMS [M+H] 497.4.

[0463] compound 238 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((3-amino-3-methylazetidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3-methylazetidin-3-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.62-7.57 (m, 2H), 7.54-7.48 (m, 2H), 6.81 (d, 1H), 4.57-4.50 (m, 4H), 4.32-4.25 (m, 2H), 3.76-3.62 (m, 8H), 1.71 (s, 3H), 1.68 (s, 6H). LCMS [M+H] 483.4.

[0464] compound 239 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[(3R)-3-aminopyrrolidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (R)-pyrrolidin-3-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.65 (d, 2H), 7.52 (d, 2H), 6.81 (d, 1H), 4.53 (s, 2H), 4.27-4.12 (m, 1H), 4.00-3.40 (m, 12H), 2.69-2.52 (m, 1H), 2.30-2.12 (m, 1H), 1.67 (s, 6H). LCMS [M+H] 483.4.

[0465] compound 240 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-{4-[(3-aminoazepan-1-yl)methyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl azepan-3-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.65 (d, 2H), 7.51 (d, 2H), 6.80 (d, 1H), 4.50 (d, 2H), 4.43 (d, 2H), 3.85-3.25 (m, 11H), 2.26-2.08 (m, 1H), 1.96-1.60 (m, 11H). LCMS [M+H] 511.4.

[0466] compound 241 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[(3S)-3-aminopyrrolidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (S)-pyrrolidin-3-ylcarbamate. 1H NMR (D2O, 400 MHz) δ 7.85 (d, 1H), 7.65 (d, 2H), 7.53 (d, 2H), 6.82 (d, 1H), 4.53 (s, 2H), 4.29-4.13 (m, 1H), 3.99-3.82 (m, 1H), 3.44-3.82 (m, 11H), 2.71-2.51 (m, 1H), 2.30-2.10 (m, 1H), 1.68 (s, 6H). LCMS [M+H] 483.3.

[0467] compound 242 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[(3R)-3-(aminomethyl)pyrrolidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (S)-(pyrrolidin-3-ylmethyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.64 (d, 2H), 7.51 (d, 2H), 6.86-6.79 (m, 1H), 4.51-4.43 (m, 2H), 3.84-2.21 (m, 14H), 2.05-1.63 (m, 9H). LCMS [M+H] 497.5.

[0468] compound 243 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[(3S)-3-(aminomethyl)pyrrolidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (R)-(pyrrolidin-3-ylmethyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.88 (d, 1H), 7.66 (d, 2H), 7.53 (d, 2H), 6.83 (d, 1H), 4.56-4.42 (m, 2H), 3.92-1.64 (m, 23H). LCMS [M+H] 497.4.

[0469] compound 244 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-{4-[(3-aminoazetidin-1-yl)methyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl azetidin-3-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 7.90 (d, 1H), 7.61 (d, 2H), 7.52 (d, 2H), 6.79 (d, 1H), 4.59-4.40 (m, 7H), 3.79-3.61 (m, 8H), 1.67 (s, 6H). LCMS [M+H] 469.3.

[0470] compound 245 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[4-(aminomethyl)piperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (piperidin-4-ylmethyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 6.81 (d, 1H), 4.36 (s, 2H), 3.81-3.63 (m, 8H), 3.62-3.51 (m, 2H), 3.13-2.99 (m, 2H), 2.92 (d, 2H), 2.09-1.93 (m, 3H), 1.69 (s, 6H), 1.58-1.40 (m, 2H). LCMS [M+H] 511.3.

[0471] compound 246 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-{4-[(3-amino-3-methylpiperidin-1-yl)methyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3-methylpiperidin-3-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.88 (d, 1H), 7.66 (d, 2H), 7.54 (d, 2H), 6.82 (d, 1H), 4.50 (d, 1H), 4.44 (d, 1H), 3.95-2.91 (m, 12H), 2.24-1.61 (m, 10H), 1.47 (br s, 3H). LCMS [M+H] 511.5.

[0472] compound 247 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4{[4-(1-aminoethyl)piperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (1-(piperidin-4-yl)ethyl)carbamate. LCMS [M+H] 525.4.

[0473] compound 248 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[4-(aminomethyl)-4-fluoropiperidin-1-yl)methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((4-fluoropiperidin-4-yl)methyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.65 (d, 2H), 7.53 (d, 2H), 6.82 (d, 1H), 4.43 (s, 2H), 3.82-3.62 (m, 8H), 3.61-3.50 (m, 2H), 3.42-3.24 (m, 4H), 2.35-2.17 (m, 2H), 2.13-1.86 (m, 2H), 1.69 (s, 6H). LCMS [M+H] 529.5.

[0474] compound 249 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[4-(aminomethyl)-4-methylpiperidin-1-yl)methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate. 1H NMR (400 MHz, D2O) δ 7.84 (d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 6.82 (d, 1H), 4.39 (s, 2H), 3.84-3.57 (m, 8H), 3.52-3.37 (m, 2H), 3.27-2.86 (m, 4H), 1.99-1.55 (m, 10H), 1.21-1.04 (m, 3H). LCMS [M+H] 525.4.

[0475] compound 250 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-(methylamino)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl methyl (piperidin-4-ylmethyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.63 (d, 2H), 7.52 (d, 2H), 6.81 (d, 1H), 4.39 (s, 2H), 3.78-3.57 (m, 10H), 3.49-3.34 (m, LCMS [M+H] 511.7.

[0476] compound 251 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-methylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3-methylpiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.64 (d, 2H), 7.52 (d, 2H), 6.81 (d, 1H), 4.50-4.29 (m, 2H), 3.87-2.82 (m, 13H), 2.66-1.81 (m, 3H), 1.68 (m, 6H), 1.22-0.94 (m, 3H). LCMS [M+H] 511.5.

[0477] compound 252 [ka] N-(1-(4-((4-amino-2-methylpiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (2-methylpiperidin-4-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.59-7.70 (m, 2H), 7.52 (d, 2H), 6.82 (d, 1H), 4.91-4.07 (m, 2H), 4.02-2.95 (m, 12H), 2.44-1.66 (m, 10H), 1.63-1.45 (m, 3H). LCMS [M+H] 511.5.

[0478] compound 267 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((cis-4-amino-3-hydroxypiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl ((cis)-3-hydroxypiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.63 (d, 2H), 7.52 (d, 2H), 6.82 (d, 1H), 4.45 (d, 1H), 4.37 (d, 1H), 4.29 (br. s., 1H), 3.83-3.44 (m, 11H), 3.34-3.07 (m, 2H), 2.32-2.16 (m, 1H), 2.15-2.06 (m, 1H), 1.68 (s, 6H). LCMS [M+H] 513.4.

[0479] compound 268 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((trans-4-amino-3-hydroxypiperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (trans-3-hydroxypiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.65 (d, 2H), 7.53 (d, 2H), 6.82 (d, 1H), 4.45 (s, 2H), 4.01-3.89 (m, 1H), 3.82-3.56 (m, LCMS [M+H] 513.5.

[0480] compound 254 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-{4-[(4-amino-3,3-dimethylpiperidin-1-yl)methyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (3,3-dimethylpiperidin-4-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.64 (d, 2H), 7.52 (d, 2H), 6.82 (d, 1H), 4.45 (d, 1H), 4.34 (d, 1H), 383-3.57 (m, 9H), 3.35 LCMS [M+H] 525.5.

[0481] compound 255 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-{4-[(4-amino-4-methylazepan-1-yl)methyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and 2-methyl-N-(4-methylazepan-4-yl)propane-2-sulfinamide. 1 H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 6.81 (d, 1H), 4.42 (s, 2H), 3.89-3.00 (m, 12H), 2.30-1.75 (m, 6H), 1.68 (s, 6H), 1.38 (br. s., 3H). LCMS [M+H] 525.5.

[0482] compound 236 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[(3R)-3-aminopiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (R)-piperidin-3-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 7.84 (d, 1H), 7.68-7.60 (m, 2H), 7.57-7.47 (m, 2H), 6.82 (d, 1H), 4.47 (s, 2H), 3.81-3.47 (m, 11H), 3.19-2.93 (m, 2H), 2.25-2.04 (m, 2H), 1.91-1.54 (m, 8H). LCMS [M+H] 497.4.

[0483] compound 253 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-(2-aminopropan-2-yl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Scheme C-2 [ka] Reagents: 1) Benzyl N-[2-(piperidin-4-yl)propan-2-yl]carbamate, NaBH(OAc)3, DCM 2) H2, Pd / C, MeOH 3) 3M HCl in MeOH. Step 1: Benzyl (2-(1-(4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)piperidin-4-yl)propan-2-yl)carbamate. Benzyl (2-(piperidin-4-yl)propan-2-yl)carbamate (11.5 mg, 0.054 mmol) was added to a suspension of tert-butyl N-[1-(4-{[1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]carbamoyl}piperazin-1-yl)-2-methyl-1-oxopropan-2-yl]carbamate (40 mg, 0.078 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 15 minutes, and NaBH(OAc) (195 mg, 0.090 mmol) was added. The reaction was stirred at room temperature for 7 hours. Additional NaBH(OAc) (20 mg) was added, and the reaction was stirred overnight. The reaction was diluted with DCM and washed with saturated aqueous NaHCO. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (H2O:CH3CN with 0.1% aqueous NH4OH, 20:80) and the collected fractions were purified by reverse-phase chromatography (H2O:CH3CN, 20:80) to give the title compound (12.0 mg, 33%). 1 H NMR (400 MHz, CDCl3) δ 12.94 (br s, 1H), 7.44 (d, 2H), 7.40-7.22 (m, 8H), 5.84 (d, 1H), 5.06 (s, 2H), 4.94-4.80 (m, 1H), 4.66 (s, 1H), 3.97-3.57 (m, 8H), 3.52 (s, 2H), 3.01-2.90 (m, 2H), 2.02-1.82 (m, 3H), 1.70-1.59 (m, 2H), 1.54 (s, 6H), 1.46 (s, 9H), 1.43-1.25 (m, 8H).LCMS [M+H] 773.7.

[0484] Step 2: tert-Butyl (1-(4-((1-(4-((4-(2-aminopropan-2-yl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. Pd / C Degussa type (10 wt%, 3.0 mg) was added to a solution of benzyl (2-(1-(4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)piperidin-4-yl)propan-2-yl)carbamate (12.0 mg, 0.015 mmol) in EtOAc (4 mL). The mixture was stirred under an atmosphere of H for 24 h. The reaction was filtered and concentrated under reduced pressure. The crude product was purified (EtOAc-MeOH, 90:10) to give the title compound (4.5 mg, 47%). 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H), 7.33-7.24 (m, 3H), 5.84 (d, 1H), 4.86 (br. s., 1H), 3.98-3.58 (m, 8H), 3.54 (br.s., 2H), 3.03-2.94 (m, 2H), 2.04-1.90 (m, 2H), 1.79-1.13 (m, 20H), 1.08 (s, 6H). LCMS [M+H] 639.7.

[0485] Step 3: 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-(2-aminopropan-2-yl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. A solution of tert-butyl (1-(4-((1-(4-((4-(2-aminopropan-2-yl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (4.5 mg, 0.007 mmol) in 3 M HCl in MeOH (1.5 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, dissolved in MeOH, and precipitated with EtOAc. The solid was filtered, washed with Et2O, and dried to give the title compound (3.9 mg, 86%) as a colorless wax. 1 H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.62 (d, 2H), 7.50 (d, 2H), 6.81 (d, 1H), 4.35 (s, 2H), 3.84-3.53 (m, 10H), 3.11-2.97 (m, 2H), 2.04-1.94 (m, 2H), 1.93-1.82 (m, 1H), 1.72-1.50 (m, 8H), 1.27 (s, 6H).LCMS [M+H] 539.5.

[0486] compound 217 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-amino-3-methoxypiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide (racemic compound) hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and benzyl ((cis)-3-methoxypiperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.62 (d, 2H), 7.56-7.48 (m, 3H), 7.46-7.41 (m, 1H), 4.42-4.22 (m, 2H), 3.99-2.80 (m, 17H), 2.21-2.03 (m, 2H), 1.68 (s, 3H), 1.66 (s, 3H). LCMS [M+H] 527.6.

[0487] compound 216 [ka] trans-4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-amino-3-methoxypiperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide (racemic compound) hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and benzyl ((trans)-3-methoxypiperidin-4-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.86 (d, 1H), 7.65 (d, 2H), 7.53 (d, 2H), 6.81 (d, 1H), 4.46 (s, 2H), 3.94-3.82 (m, 1H), 3.80-3.55 (m, LCMS [M+H] 527.6.

[0488] compound 219 [ka] 4-(2-Amino-2-methylpropanoyl)-N-{1-[4-({4-[(1R)-1-aminoethyl]piperidin-1-yl}methyl)phenyl]-2-oxo-1,2-dihydropyrimidin-4-yl}piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and benzyl (R)-(1-(piperidin-4-yl)ethyl)carbamate. 1 H NMR (600 MHz, D2O) δ 8.06-8.02 (m, 1H), 7.73-7.67 (m, 2H), 7.61-7.56 (m, 2H), 6.84 (d, 1H), 4.42 (s, 2H), 3.88-3.68 (m, 8H), 3.65 (d, 2H), 3.35-3.28 (m, 1H), 3.14-3.06 (m, 2H), 2.10-1.91 (m, 3H), 1.74 (s, 6H), 1.66-1.55 (m, 2H), 1.40-1.28 (m, 3H). LCMS [M+H] 525.4.

[0489] compound 220 [ka] 4-(2-Amino-2-methylpropanoyl)-N-{1-[4-({4-[(1S)-1-aminoethyl]piperidin-1-yl}methyl)phenyl]-2-oxo-1,2-dihydropyrimidin-4-yl}piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and benzyl (S)-(1-(piperidin-4-yl)ethyl)carbamate. 1 H NMR (600 MHz, D2O) δ 7.91 (d, 1H), 7.68 (d, 2H), 7.56 (d, 2H), 6.86 (d, 1H), 4.55-4.38 (m, 2H), 3.85-3.68 (m, 8H), 3.65 (d, 2H), 3.31 (quin, 1H), 3.09 (t, 2H), 2.05 (t, 2H), 2.00-1.89 (m, 1H), 1.75-1.71 (m, 6H), 1.65-1.54 (m, 2H), 1.39-1.26 (m, 3H). LCMS [M+H] 525.4.

[0490] compound 221 [ka] 4-[(2S)-2-Amino-3-hydroxy-2-methylpropanoyl]-N-{1-[4-({4-[(1S)-1-aminoethyl]piperidin-1-yl}methyl)phenyl]-2-oxo-1,2-dihydropyrimidin-4-yl}piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and benzyl (S)-(1-(piperidin-4-yl)ethyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.84 (d, 1H), 7.62 (d, 2H), 7.51 (d, 2H), 6.81 (d, 1H), 4.36 (s, 2H), 4.11 (d, 1H), 3.85 (d, 1H), 3.79-3.54 (m, 10H), 3.31-3.20 (m, 1H), 3.04 (t, 2H), 2.07-1.95 (m, 2H), 1.95-1.83 (m, 1H), 1.63 (s, 3H), 1.61-1.47 (m, 2H), 1.24 (d, 3H). LCMS [M+H] 541.3.

[0491] compound 222 [ka] 4-[(2S)-2-Amino-3-hydroxy-2-methylpropanoyl]-N-{1-[4-({4-[(1R)-1-aminoethyl]piperidin-1-yl}methyl)phenyl]-2-oxo-1,2-dihydropyrimidin-4-yl}piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (2R,4S)-2-(tert-butyl)-4-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and benzyl (R)-(1-(piperidin-4-yl)ethyl)carbamate. 1H NMR (400 MHz, D2O) δ 7.85 (d, 1H), 7.62 (d, 2H), 7.51 (d, 2H), 6.81 (d, 1H), 4.35 (s, 2H), 4.10 (d, 1H), 3.85 (d, 1H), 3.79-3.53 LCMS [M+H] 541.3.

[0492] compound 226 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[4-(2-amino-2-methylpropyl)piperidin-1-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and benzyl (2-methyl-1-(piperidin-4-yl)propan-2-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.83 (d, 1H), 7.61 (d, 2H), 7.50 (d, 2H), 6.88-6.75 (m, 1H), 4.32 (s, 2H), 3.81-3.61 (m, 8H), 3.52-3.41 (m, 2H), 3.09-2.94 (m, 2H), 2.04-1.93 (m, 2H), 1.84-1.40 (m, 11H), 1.32 (s, 6H).LCMS [M+H] 553.6.

[0493] Compound 322 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-(1-(4-((4-amino-3-(hydroxymethyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (1-(4-((1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and benzyl (cis-3-(hydroxymethyl)piperidin-4-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.88 (d, 1H), 7.62-7.59 (m, 2H), 7.48 (d, 2H), 6.75 (d, 1H), 4.41-4.39 (m, 2H), 4.27 (d, 1H), 3.84-3.81 (m, LCMS [M+H] 527.6.

[0494] compound 293 [ka] (S)-4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(4-aminoazepan-1-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and benzyl (S)-azepan-4-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 7.88 (d, 1H), 7.51-7.45 (m, 2H), 7.45-7.39 (m, 2H), 6.83 (d, 1H), 3.83-3.66 (m, 9H), 3.64-3.46 (m, 5H), 3.45-3.13 (m, 4H), 2.44-2.21 (m, 2H), 2.18-1.97 (m, 2H), 1.90-1.76 (m, 1H), 1.72 (s, 6H). LCMS [M+H] 525.4. ee>99% Chiralpak Measured on an AD-H (25x0.46cm, 5µm), mobile phase: n-hexane / EtOH:MeOH, 1:1 + 0.1% isopropylamine, 10 / 90% v / v, flow rate: 1mL / min, retention time: 27.1min.

[0495] compound 294 [ka] (R)-4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(4-aminoazepan-1-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and benzyl (R)-azepan-4-ylcarbamate. 1H NMR (400 MHz, D2O) δ 7.88 (d, 1H), 7.51-7.45 (m, 2H), 7.45-7.39 (m, 2H), 6.83 (d, 1H), 3.83-3.66 (m, 9H), 3.64-3.46 (m, 5H), 3.45-3.13 (m, 4H), 2.44-2.21 (m, 2H), 2.18-1.97 (m, 2H), 1.90-1.76 (m, 1H), 1.72 (s, 6H). LCMS [M+H] 525.4. ee=100% Chiralpak Measured on an AD-H (25x0.46cm, 5µm), mobile phase: n-hexane / EtOH:MeOH, 1:1 + 0.1% isopropylamine, 10 / 90% v / v, flow rate: 1mL / min, retention time: 30.3min.

[0496] Compound 119 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((trans-4-aminocyclohexyl)(ethyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Scheme C-3 [ka] Reagents: 1) CH3CHO, NaBH3CN, MeOH, rt, 18 h 2) 2 M HCl in MeOH, rt, 18 h. Step 1: tert-Butyl (trans-4-((4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)(ethyl)amino)cyclohexyl)carbamate. NaBHCN (96 mg, 1.53 mmol) was added to a mixture of tert-butyl (trans-4-((4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)amino)cyclohexyl)carbamate (488 mg, 0.69 mmol) and acetaldehyde (0.5 mL) in dry MeOH (8 mL), and the mixture was stirred at room temperature for 18 h. The mixture was concentrated to approximately 2 mL, added to 2 M aqueous KCO (50 mL), and extracted with DCM (3 × 50 mL). The extracts were dried over Na.sub.2SO.sub.4, decanted, concentrated, and the residue was purified by flash chromatography (MeOH / EtOAc / hexanes) to give the title compound as a white solid (365 mg, 0.494 mmol).

[0497] Step 2: 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(((trans-4-aminocyclohexyl)(ethyl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. A mixture of tert-butyl (trans-4-((4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)(ethyl)amino)cyclohexyl)carbamate (365 mg, 0.49 mmol) and 2 M HCl in MeOH (20 mL, 40 mmol) was stirred at room temperature for 18 hours and concentrated. The residue was purified by flash chromatography (DCM / MeOH / NH4OH). The product fractions were concentrated to dryness, converted to the HCl salt with 2M HCl in MeOH, and concentrated to dryness to give the title compound (264 mg, 0.407 mmol) as a white solid. 1H NMR (500 MHz, D2O) δ 7.97 (d, 1H), 7.63 (d, 2H), 7.52 (d, 2H), 6.78 (d, 1H), 4.50 (d, 1H), 4.32 (d, 1H), 3.59-3.82 (m, 8H), 3.35-3.45 (m, 1H), 3.14-3.33 (m, 3H),...

Claims

[Claim 1] The invention described in the present specification.

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