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 Nos. 62 / 793,122, 62 / 793,131, and 62 / 793,160, 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, infects 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, CN, or C1-C6 alkyl; Ring A is a monocyclic heterocycloalkylene or a 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, 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 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 halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or 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 O, S, SO2, C=O, or [ka] where t is 1, 2, 3, 4, 5, or 6; 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 the C1-C8 alkylene, C3-C8 alkenylene, or C3-C8 alkynylene are optionally independently substituted with O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-cycloalkyl), NH(C=O), N-(C1-6 alkyl)(C=O), or (C=O), Ring B is a bicyclic heterocycloalkylene or bicyclic cycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic cycloalkylene 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, OH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; L is absent or a straight or branched C1-C6 alkylene, wherein up to two methylene units of the 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), wherein the C1-C6 alkylene is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, OH, NH2, COO(C1-C6 alkyl), CONH2, C1-C6 aminoalkyl, and C1-C6 hydroxyalkyl; R1 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 an amino protecting group; 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 an amino protecting group; R2 and R3 are each independently C1-C6 alkyl, halo, CN, OH, NH2, NH(C1-C6 alkyl), O(C1-C6 haloalkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, C1-C6 haloalkyl, or C1-C6 alkoxy; 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, CN, or C1-C6 alkyl; Ring A is a monocyclic heterocycloalkylene or a 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, 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 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 halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or 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 O, S, SO2, C=O, or [ka] where t is 1, 2, 3, 4, 5, or 6; 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 C1-C8 alkylene, C3-C8 alkenylene, or C3-C8 alkynylene are optionally independently substituted with 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 bicyclic heterocycloalkylene or bicyclic cycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic cycloalkylene 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, OH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; L is absent or a straight or branched 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 wherein said C1-C6 alkylene is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, OH, NH2, COO(C1-C6 alkyl), CONH2, C1-C6 aminoalkyl, and C1-C6 hydroxyalkyl; R1 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 an amino protecting group; 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 an amino protecting group; R2 and R3 are each independently C1-C6 alkyl, halo, CN, OH, NH2, NH(C1-C6 alkyl), O(C1-C6 haloalkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, C1-C6 haloalkyl, or C1-C6 alkoxy; 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, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo. (Item 4) The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4-7 membered monocyclic heterocycloalkylene optionally substituted with C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, or oxo, wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen or 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, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo, wherein the bicyclic heterocycloalkylene contains up to two nitrogen atoms. (Item 6) Ring A is [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 may be optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or OH, and wherein for each occurrence of C1-C6 alkylene, one or two methylene units of said C1-C6 alkylene may independently be optionally substituted with C=O or [ka] wherein t is 1, 2, or 3; or a pharmaceutically acceptable salt thereof. (Item 9) J is -CH2-, -CH2CH2-, [ka] [ka] 9. The compound according to item 8, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 10) R 1’ is H, NH2, NH(C1-C6 alkyl), NHCO(C1-C6 alkyl), or NH(C1-C6 alkyl-SO3 - 10. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein (Item 11) [ka] but, [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, and C1-C6 haloalkyl, and wherein m is 0, 1, or 2. (Item 13) [ka] but, [ka] [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-C 3-8 cycloalkyl), NH(C=O), N-(C 1-614. The compound according to any one of items 1 to 13, wherein the compound is substituted with (C=O) or (C=O) or a pharmaceutically acceptable salt thereof. (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) 16. The compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-12 membered fused, spiro, or bridged bicyclic heterocycloalkylene containing up to three nitrogen atoms, wherein the fused, spiro, or bridged bicyclic heterocycloalkylene is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl. (Item 17) The compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- to 12-membered fused, spiro, or bridged bicyclic cycloalkylene, optionally substituted with up to two substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, C1-C6 haloalkyl, OH, and C1-C6 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, optionally substituted with C1-C6 alkoxy, halo, CN, OH, NH2, COO(C1-C6 alkyl), or CONH2, wherein one methylene unit of said C1-C6 alkylene is O, NH, (C=O), or N-(C 1-6 19. The compound according to any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, optionally substituted with (alkyl). (Item 21) R1 is H, NH2, NH(C1-C6 alkyl), NHCO(C1-C6 alkyl), or NH(C1-C6 alkyl-SO3 - 21. The compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof, wherein (Item 22) [ka] but, [ka] [ka] 22. The compound according to any one of items 1 to 21, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 23) 22. The compound of any one of items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein 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. (Item 24) Compounds of formula I-1: [ka] 24. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH or N, or a pharmaceutically acceptable salt thereof. (Item 25) Compounds of formula I-2: [ka] 25. The compound according to any one of items 1 to 24, 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 may be optionally substituted with 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] wherein t is 1, 2, 3, or 4; each R5 is independently C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, or oxo; and q is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof. (Item 26) Compounds of formula I-3: [ka] wherein K is C1-C5 alkylene optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, or OH; each R5 is independently C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, or oxo; q is 0 or 1; each R3 is independently C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; and m is 0, 1, or 2. (Item 27) Compounds of formula I-4: [ka] 27. The compound according to any one of items 1 to 26, or a pharmaceutically acceptable salt thereof, wherein 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 one methylene unit of said C1-C4 alkylene is optionally substituted with O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl), N—(C 1-6 Alkylene-C 3-6 cycloalkyl), or (C=O), and R x , R y , R x’ and R y’ are each independently H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 28) Compounds of formula I-5: [ka] 27. The compound according to any one of items 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R 1’ is H or NH2, or a pharmaceutically acceptable salt thereof. (Item 29) Compounds of Formula IIA or IIB: [ka] 2. The compound according to item 1, wherein: Z is (C=O), J is C1-C6 alkylene, heterocycloalkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which may be optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or OH, and wherein one or two methylene units of said C1-C6 alkylene are independently optionally substituted with O, S, SO2, C=O, or [ka] may be replaced by L is absent or a straight or branched 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), Ring D is a monocyclic heterocycloalkylene or a 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, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), —COO(C-C alkyl), —COONH, and oxo; 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; R1 and R4 are each independently H or NR x’ R y’ where, for each occurrence, R x’ , and R y’ are each independently H or C1-C6 alkyl; R x and R yare each independently H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 30) Ring A is [ka] Item 31: The compound according to Item 29, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [ka] but, [ka] and R4 is H, NH2, or NH(C1-C6 alkyl). (Item 32) CR i R ii is selected from the group consisting of CH2, CH(C1-C6 alkyl), C(C1-C6 alkyl)2, CH-COO(C1-C6 alkyl) and CHCOOH, or a pharmaceutically acceptable salt thereof. (Item 33) Ring B is [ka] [ka] 33. The compound according to any one of items 29 to 32, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 34) Compounds of formula IIA-1 or IIB-1: [ka] 34. The compound according to any one of items 29 to 33, wherein: (Item 35) Compound of formula IIA-6: [ka] wherein K is C1-C4 alkylene optionally substituted with halo, C1-C6 alkoxy, or OH; each R3 is independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; and m is 0, 1, or 2. (Item 36) Compounds of Formula IIIA or IIIB: [ka] 2. The compound according to item 1, wherein: Z is (C=O), J is C1-C6 alkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which may be optionally substituted with halo, hydroxy, or C1-C6 alkoxy, wherein one or two methylene units of said C1-C6 alkylene are independently optionally selected from O, S, SO2, C=O, or [ka] may be replaced by L is absent or a straight or branched 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), Y2 is ethylene, optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein one methylene unit of said ethylene is 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 D' is a monocyclic heterocycloalkylene or a 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, halo, CN, C-C haloalkyl, phenyl, OH, NH, NH(C-C alkyl), N(C-C alkyl), -COO(C-C alkyl), -COONH, and oxo; R1 and R 4’ are each independently H or NR x’ R y’ and R x’ and R y’ are each independently H or C1-C6 alkyl; R x and R y are each independently H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 37) Ring A is [ka] Item 38: The compound according to Item 36, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [ka] but, [ka] 37. The compound according to item 36, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 39) Y2 is, [ka] 39. The compound according to any one of items 36 to 38, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 40) Ring B is [ka] [ka] 40. The compound according to any one of items 36 to 39, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (Item 41) Compounds of formula IIIA-1 or IIIB-1: [ka] 41. The compound according to any one of items 36 to 40, wherein: (Item 42) Compound of formula IIIA-5: [ka] wherein K is C1-C4 alkylene optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, or OH; each R3 is independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; and m is 0, 1, or 2. (Item 43) Compound of Formula IV: [ka] 2. The compound according to item 1, wherein: Z is (C=O), J is C1-C6 alkylene, optionally substituted with halo, hydroxy, or C1-C6 alkoxy, wherein one or two methylene units of said C1-C6 alkylene may be independently and optionally replaced with O, S, SO2, or C=O; Y3 is a straight chain C3-C8 alkylene, C3-C8 alkenylene, or C3-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 said C3-C8 alkylene, C3-C8 alkenylene, or C3-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), 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 or NR x’ R y’ where R x’ , and R y’ are each independently H or C1-C6 alkyl; R x and R y are each independently H or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 44) Ring A [ka] 44. The compound according to item 43, wherein: (Item 45) Y3, [ka] 45. The compound according to item 43 or 44, selected from the group consisting of: (Item 46) A compound selected from the compounds set forth in Table 7, Table 8, and Table 9, or a pharmaceutically acceptable salt thereof. (Item 47) A compound selected from the compounds set forth in Table 10, or a pharmaceutically acceptable salt thereof. (Item 48) Compound of Formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions defined in any one of paragraphs 1 to 45. (Item 49) A compound selected from the compounds set forth in Table 11, or a pharmaceutically acceptable salt thereof. (Item 50) Compound of Formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions defined in any one of items 1 to 45; and R v’ and R v” One of the two 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 51) A compound selected from the compounds set forth in Table 12, or a pharmaceutically acceptable salt thereof. (Item 52) 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 the preceding paragraph; 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 R6 is H or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. (Item 53) A compound selected from the compounds set forth in Table 13, or a pharmaceutically acceptable salt thereof. (Item 54) A pharmaceutical composition comprising a compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 55) 54. 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 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 54. (Item 56) 56. The method of item 55, wherein the bacterial infection is caused by bacteria including gram-positive and gram-negative bacteria. (Item 57) The bacteria include Francisella tularensis, Burkholderia mallei, Burkholderia pseudomallei, Bacillus anthracis, Yersinia pestis, Salmonella.Clostridium. The method of item 56, comprising C. difficile, Citrobacter, Enterobacter, Burkholderia cepacia, Mycobacterium, Proteus, Streptococcus, Serratia, Enterobacteriaceae, Escherichia, Klebsiella, Pseudomonas, and Acinitobacter. (Item 58) 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 59. The process, wherein m and q are as defined in any one of items 1 to 45, 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 45; Y4 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, halo, C1-C6 alkyl, or C1-C6 alkoxy; The above process, wherein R6 is H or C1-C6 alkyl, and R7 is H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, or C1-C6 alkylene-C3-C8 cycloalkyl. (Item 60) 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 45; 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, 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 10indicates 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 iThe 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 number of carbon atoms indicated. 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 functionality, and therefore, those skilled in the art will understand that the compounds may be isolated as salts in which the nitrogen of the amino functionality 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, CN, or C1-C6 alkyl; Ring A is a monocyclic heterocycloalkylene or a 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, 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 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 halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or 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 O, S, SO2, C=O, or [ka] where t is 1, 2, 3, 4, 5, or 6; 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 the C1-C8 alkylene, C3-C8 alkenylene, or C3-C8 alkynylene are optionally independently substituted with 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 bicyclic heterocycloalkylene or bicyclic cycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic cycloalkylene 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, OH, COO(C-C alkyl), CONH, and C-C hydroxyalkyl; L is absent or a straight or branched C1-C6 alkylene, wherein up to two methylene units of the 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), wherein the C1-C6 alkylene is optionally substituted with up to three substituents independently selected from the group consisting of C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, OH, NH2, COO(C1-C6 alkyl), CONH2, C1-C6 aminoalkyl, and C1-C6 hydroxyalkyl; R1 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 an amino protecting group; 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 an amino protecting group; R2 and R3 are each independently C1-C6 alkyl, halo, CN, OH, NH2, NH(C1-C6 alkyl), O(C1-C6 haloalkyl), N(C1-C6 alkyl)2, COO(C1-C6 alkyl), CONH2, C1-C6 haloalkyl, or C1-C6 alkoxy; 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, CN, or C1-C6 alkyl.

[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, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo.

[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 C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo. In another embodiment, Ring A is a 4-7 membered monocyclic heterocycloalkylene optionally substituted with C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, or oxo, wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen or oxygen. In another embodiment, Ring A is a 4-7 membered monocyclic heterocycloalkylene optionally substituted with C-C alkyl, phenyl, or oxo, wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen or oxygen. In another embodiment, ring A contains two nitrogen atoms. In another embodiment, ring A is a 6-membered monocyclic heterocycloalkylene optionally substituted with C-C alkyl, phenyl, or oxo, 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, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo. 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, halo, CN, C-C haloalkyl, phenyl, OH, NH, and oxo, wherein the bicyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen or oxygen. In another embodiment, Ring A is a 6-11-membered bicyclic heterocycloalkylene optionally substituted with up to two heteroatoms selected from nitrogen or oxygen. In another embodiment, Ring A is a 6-11 membered bicyclic heterocycloalkylene containing up to two nitrogen atoms. In another embodiment, Ring A is a 6-11 membered fused or spiro bicyclic heterocycloalkylene containing up to two nitrogen atoms.

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

[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 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. 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 alkoxy, C-C haloalkyl, NH, 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 C-C alkylene, optionally substituted with F, CF, NH, OMe, or OH, wherein one methylene unit of the optionally substituted C-C 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 C1-C6 alkylene. In another embodiment, J is 5-6 membered heterocycloalkylene.

[0074] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, J is selected from the moieties shown in Table 2: Table 2 [Table 2] .

[0075] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1’ are H, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHCO(C1-C6 alkyl), NH(C1-C6 alkyl-SO3 - ), or an amino protecting group. 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.

[0076] In another embodiment of the 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 C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, or oxo, wherein the monocyclic heterocycloalkylene contains up to two heteroatoms selected from nitrogen or oxygen; and J is C-C alkylene, heterocycloa 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 any one of the moieties shown in Table 1, J is any one 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 the moieties shown in Table 3: Table 3 [Table 3-1] [Table 3-2]

[0078] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein each R is independently selected from 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.

[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 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, or 2. In another embodiment, each R is independently C-C alkyl, halo, C-C alkoxy, or C-C haloalkyl.

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

[0083] In another embodiment, [ka] teeth, [ka] is.

[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), NH(C=O), N-(C1-6 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-C6 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 In another embodiment, Y is a straight chain C1-C4 alkylene optionally substituted with NH2, C1-C6 alkyl, COO(C1-C6 alkyl), or COOH, wherein up to two methylene units of the C1-C4 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), or (C=O).

[0085] 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 iiis CH2, CH(CH3), CH(COOEt), or CH(COOH). In another embodiment, CR i R ii is CH2.

[0086] 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), or (C=O).

[0087] In another embodiment, Y is —C(R i R j )-C(R i’ R j’ )-, which means [ka] is.

[0088] In another embodiment, Y is a straight chain C3-C8 alkylene, C3-C8 alkenylene, or C3-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 C3-C8 alkylene, C3-C8 alkenylene, or C3-C8 alkynylene are optionally, independently, O, NH, N—(C1-C6 alkyl), N—(C1-C6 hydroxyalkyl), N—(C1-C6 haloalkyl ... 1-6 Alkylene-cycloalkyl), NH(C=O), N-(C 1-6In another embodiment, Y is a C3-C8 alkylene optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein up to two single methylene units of the C3-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), or (C=O).

[0089] In another embodiment, Y is a C3-C8 alkylene, which is [ka] is.

[0090] In another embodiment, Y is selected from any moiety shown in Table 4: Table 4 [Table 4-1] [Table 4-2]

[0091] In another embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, Ring B is a bicyclic heterocycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0092] In another embodiment, Ring B is a 5-12 membered fused, spiro, or bridged bicyclic heterocycloalkylene containing up to three nitrogen atoms, wherein the fused, spiro, or bridged bicyclic heterocycloalkylene is optionally substituted with up to three substituents independently selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0093] In another embodiment, Ring B is a 6-12-membered fused bicyclic heterocycloalkylene containing up to two nitrogen atoms, wherein the fused bicyclic heterocycloalkylene is optionally substituted with C-C alkyl or C-C hydroxyalkyl. In another embodiment, Ring B is a 6-11-membered fused bicyclic heterocycloalkylene containing up to two nitrogen atoms, wherein the fused bicyclic heterocycloalkylene is optionally substituted with C-C alkyl or C-C hydroxyalkyl. In another embodiment, Ring B is a 6-membered fused bicyclic heterocycloalkylene containing one nitrogen atom, wherein the 6-membered fused bicyclic heterocycloalkylene is optionally substituted with C-C alkyl or C-C hydroxyalkyl. In another embodiment, Ring B is a 6-membered fused bicyclic heterocycloalkylene containing one nitrogen atom.

[0094] In another embodiment, Ring B is a 6-12 membered spiro bicyclic heterocycloalkylene containing up to two nitrogen atoms. In another embodiment, Ring B is a 6-11 membered spiro bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0095] In another embodiment, Ring B is a 5-10 membered bridged bicyclic heterocycloalkylene containing up to two nitrogen atoms. In another embodiment, Ring B is a 6-9 membered bridged bicyclic heterocycloalkylene containing up to two nitrogen atoms. In another embodiment, Ring B is a 6-9 membered bridged bicyclic heterocycloalkylene containing one nitrogen atom. In another embodiment, Ring B is an 8 membered bridged bicyclic heterocycloalkylene containing one nitrogen atom.

[0096] In another embodiment, Ring B is a 5-12 membered bicyclic cycloalkylene ring, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0097] In another embodiment, Ring B is a 5-12 membered fused, spiro, or bridged bicyclic cycloalkylene, optionally substituted with up to two substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0098] In another embodiment, Ring B is a 5-11 membered fused bicyclic cycloalkylene.

[0099] In another embodiment, Ring B is a 6-11 membered spiro bicyclic cycloalkylene. In another embodiment, Ring B is a 6-9 membered spiro bicyclic cycloalkylene. In another embodiment, Ring B is a 7 or 8 membered spiro bicyclic cycloalkylene.

[0100] In another embodiment, Ring B is a 5-10 membered bridged bicyclic cycloalkylene.

[0101] In another embodiment, Ring B is selected from any of the moieties shown in Table 5: Table 5 [Table 5-1] [Table 5-2]

[0102] In another embodiment of the compound of Formula I, or a pharmaceutically acceptable salt thereof, L is absent.

[0103] In another embodiment of the 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 one methylene unit of said C-C alkylene is O, NH, (C=O), or N—(C 1-6 In another embodiment, L is a straight chain or branched C1-C6 alkylene, optionally substituted with OH or NH2, wherein one methylene unit of the C1-C6 alkylene may be replaced with (C=O). 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 or (C=O).

[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 or NR x’ R y’ where R x’ and R y’ are each independently H, C1-C6 alkyl, C1-C6 alkyl-SO3, CO(C1-C6 alkyl), or an amino protecting group. In another embodiment, R1 is H, NH2, NH(C1-C6 alkyl), NHCO(C1-C6 alkyl), or NH(C1-C6 alkyl-SO3 - ). In another embodiment, R1 is H, NH2, or NH(C1-C6 alkyl). In another embodiment, R1 is H, NH2, or NHCH3. In another embodiment, R1 is H or NH2.

[0106] 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, L is a straight chain or branched C-C alkylene optionally substituted with OH or NH, wherein one methylene unit of the C-C alkylene may be replaced with (C=O), and R is H, NH, or NH(C-C alkyl). In another embodiment, Y is any one of the moieties shown in Table 4, Ring B is selected from any of the moieties shown in Table 5, L is absent or is CH, and R is H or NH.

[0107] 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 6: Table 6 [Table 6-1] [Table 6-2]

[0108] 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, R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, and C1-C6 haloalkyl. In another embodiment, each R3 is independently C1-C6 alkyl, halo, or C1-C6 haloalkyl; and m is 0, 1, or 2.

[0109] In another embodiment, R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, and C1-C6 haloalkyl; and m and n are each independently 0 or 1.

[0110] In another embodiment of a 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, and CF3.

[0111] In another embodiment, m and n are each independently 0, 1, or 2. In another embodiment, n is 0 and m is 1 or 2. In another embodiment, m and n are 0.

[0112] 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.

[0113] 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 may be optionally substituted with 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 substituted with [ka] where t is 1, 2, 3, or 4; each R is independently C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, OH, NH, or oxo; and q is 0, 1, 2, or 3.

[0114] 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] wherein t is 1 or 2, each R5 is independently C1-C6 alkyl, phenyl, or oxo, and q is 0, 1, or 2.

[0115] 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 , R y , q, and m are as defined herein.

[0116] 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, NH, or OH; each R is independently C-C alkyl, C-C alkoxy, halo, CN, C-C haloalkyl, phenyl, or oxo; q is 0 or 1; each R is independently C-C alkyl, halo, C-C haloalkyl, and C-C alkoxy; and m is 0, 1, or 2. In another embodiment, K is C-C alkylene optionally substituted with C-C haloalkyl, NH, or OH; each R is independently C-C alkyl, phenyl, or oxo; q is 0 or 1; each R is independently C-C alkyl, halo, C-C haloalkyl, and C-C alkoxy; and m is 0, 1, or 2.

[0117] 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 y , R x’ , and R y’ is as defined herein.

[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 ring A, ring B, L, Y, R, R, and m are as defined herein; and R 1’ is H or NH2.

[0119] In another aspect, the present disclosure provides a compound of formula IIA: [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 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; J is C1-C6 alkylene, heterocycloalkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which may be optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or OH, and wherein one or two carbons of the optionally substituted C1-C6 alkylene are optionally substituted with O, S, SO2, C=O, or [ka] where t is 1, 2, 3, 4, 5, or 6; R x and R y are each independently H or C1-C6 alkyl; X 1 and X 2 are each independently CH or N, 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; Ring B is a bicyclic heterocycloalkylene or bicyclic cycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic cycloalkylene 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, OH, —COO(C-C alkyl), —COONH, and C-C hydroxyalkyl; L is absent or a straight 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 alkyl), R1 is H or NR x’ R y’ where R x’ and R y’ are each independently H or C1-C6 alkyl; 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, and C1-C6 alkoxy; m and n are each independently 0, 1, 2, or 3.

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

[0121] In another embodiment of a compound of Formula I or IIA or a pharmaceutically acceptable salt thereof, 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.

[0122] 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.

[0123] In another embodiment, ring A is [ka] wherein Z1 and Z2 are each independently selected from the group consisting of CH, CH2, N, NH, and O; each R5 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo; and q and r are each independently 0, 1, 2, or 3.

[0124] In another embodiment, ring A is [ka] is selected from the group consisting of:

[0125] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, J is C1-C6 alkylene.

[0126] In another embodiment, one of the C1-C6 alkylene carbons of J is -(C=O)-.

[0127] In another embodiment, J is optionally substituted with up to three substituents selected from the group consisting of halo, C-C alkoxy, C-C haloalkyl, —NH, and —OH, wherein up to two carbon atoms of the optionally substituted C-C alkylene are: [ka] where t is 1, 2, 3, or 4.

[0128] In another embodiment, J is C1-C6 alkylene, optionally substituted with F, CF3, -NH2, OMe, or -OH, wherein one methylene unit of said optionally substituted C1-C6 alkylene is [ka] may be replaced by

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

[0130] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, R x and R y are each independently H or C1-C6 alkyl.

[0131] In another embodiment, R x and R y are each independently H.

[0132] In another embodiment of the compound of formula IIA or a pharmaceutically acceptable salt thereof, R x R y NJ is [ka] [ka] is selected from the group consisting of:

[0133] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0134] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, [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.

[0135] In another embodiment, [ka] teeth [ka] is.

[0136] In another embodiment, [ka] teeth [ka] is.

[0137] In another embodiment of the compound of formula IIA or a pharmaceutically acceptable salt thereof, each R3 is independently selected from the group consisting of Me, halo, and CF3, where m is 0, 1, or 2.

[0138] In another embodiment of the compound of Formula I or IIA, 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.

[0139] In another embodiment, [ka] teeth, [ka] is.

[0140] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, CR i R ii is selected from the group consisting of CH2, CH(C1-C6 alkyl), C(C1-C6 alkyl)2, CH-COO(C1-C6 alkyl) and CHCOOH.

[0141] In another embodiment, CR i R ii is selected from the group consisting of CH2, CH(CH3), CH(COOEt) and CH(COOH).

[0142] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0143] In another embodiment of a compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, Ring B is a bicyclic heterocycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0144] In another embodiment, Ring B is a fused, spiro, or bridged bicyclic heterocycloalkylene containing up to three nitrogen atoms, wherein the fused, spiro, or bridged bicyclic heterocycloalkylene is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0145] In another embodiment, Ring B is a fused bicyclic heterocycloalkylene containing up to two nitrogen atoms, wherein the fused bicyclic heterocycloalkylene is optionally substituted with C1-C6 alkyl or C1-C6 hydroxyalkyl.

[0146] In another embodiment, Ring B is a spiro bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0147] In another embodiment, Ring B is a bridged bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0148] In another embodiment, Ring B is a bicyclic cycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0149] In another embodiment, Ring B is a fused, spiro, or bridged bicyclic cycloalkylene, optionally substituted with up to two substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0150] In another embodiment, Ring B is a fused bicyclic cycloalkylene.

[0151] In another embodiment, Ring B is a spiro bicyclic cycloalkylene.

[0152] In another embodiment, Ring B is a bridged bicyclic cycloalkylene.

[0153] In another embodiment, ring B is [ka] [ka] is selected from the group consisting of:

[0154] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, L is absent.

[0155] In another embodiment, L is a straight chain or branched C1-C6 alkylene, wherein one carbon atom of the C1-C6 alkylene is O, NH, (C=O), or N—(C 1-6 It may be replaced by alkyl.

[0156] In another embodiment, L is CH2, CH(CH3), or C=O.

[0157] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, R1 is H, NH2, or NH(C1-C6 alkyl).

[0158] In another embodiment, R1 is H, NH2, or NHCH3.

[0159] In another embodiment of the compound of Formula I or IIA, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0160] In another embodiment of a compound of Formula I or IIA 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.

[0161] In another embodiment, R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, and C1-C6 haloalkyl; and m and n are each independently 0 or 1.

[0162] In another embodiment of the compound of Formula I or IIA or a pharmaceutically acceptable salt thereof, m is 1 or 2, and each R3 is independently selected from the group consisting of CH3, Cl, F, OCH3, CO2H, CO2Et, and CF3.

[0163] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, J, X 1 , X 2 , R1, R3, R i , R ii , R x , R y , and m are as defined herein.

[0164] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-2: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, J, X 1 , X 2 , R1, R3, R i , R ii , R x , R y, and m are as defined 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 1, 2, or 3.

[0165] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-3: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, X 1 , X 2 , R1, R3, R5, R i , R ii , R x , R y , q, and m are as defined herein, and K is C1-C4 alkylene, optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl, NH2, CN, or OH.

[0166] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-4: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, X 1 , X 2 , R1, R3, R5, R i , R ii , q and m are as defined herein.

[0167] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-4a or IA-4b: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, X 1 , X 2 , R1, R3, R i , R ii, and m are as defined herein.

[0168] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-5: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, R, R i , R ii , and m are as defined herein, R3 is selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy, CO2H, and CO2Et, and m is 0, 1, or 2.

[0169] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-6: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, R, R, R i , R ii , and m are as defined herein.

[0170] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-7: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, R, R i , and R ii is as defined herein.

[0171] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-8a or IIA-8b: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, R x’ , R y’ , Ri , and R ii is as defined herein.

[0172] In another embodiment, the compound of formula I or IIA is a compound of formula IIA-9: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, R i , and R ii is as defined herein.

[0173] In another aspect, the present disclosure provides a compound of formula IIB: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, X1, X2, R i , R j , Y1, ring B, L, m, and n are as defined in the preceding paragraph; Ring D is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, 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, 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.

[0174] In another embodiment, the compound of formula IIB is a compound of formula IIB-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, ring D, L, X 1 , X 2 , R1, R2, R3, R4, R i , R ii , m, and n are as defined herein.

[0175] In another embodiment of the compound of formula IIB-1 or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein Z1 and Z2 are each independently selected from the group consisting of CH, CH2, N, NH and O; each R5 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo; q is 0, 1, 2, or 3; and r is 1 or 2.

[0176] In another embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0177] In another aspect, the present disclosure provides a compound of formula IIIA: [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 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; J is C1-C6 alkylene, C1-C6 alkylene-heterocycloalkylene, or C1-C6 alkylene-cycloalkylene, any of which may be optionally substituted with halo, hydroxy, or alkoxy, and one or two carbons of the C1-C6 alkylene are optionally substituted with O, S, SO2, C=O, or [ka] where t is 1, 2, 3, or 4; R x and R y are each independently H or C1-C6 alkyl; X 1 and X 2 are each independently CH or N, Y2 is a straight chain C2 alkylene optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein one carbon atom of the C2 alkylene is 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 bicyclic heterocycloalkylene or bicyclic cycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic cycloalkylene 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, OH, —COO(C-C alkyl), —COONH, and C-C hydroxyalkyl; L is absent or a straight 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 alkyl), R1 is H or NR x’ R y’ where R x’ and R y’ are each independently H or C1-C6 alkyl; 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, and C1-C6 alkoxy; m and n are each independently 0, 1, 2, or 3.

[0178] In another embodiment of the compound of formula IIIA or a pharmaceutically acceptable salt thereof, Z is —(C═O)—.

[0179] In another embodiment of a compound of Formula I or IIIA, or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, 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.

[0180] 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.

[0181] In another embodiment, ring A is [ka] wherein each R5 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo; and q is 0, 1, 2, or 3.

[0182] In another embodiment, ring A is [ka] where R5 is C1-C6 alkyl and q is 1.

[0183] In another embodiment, ring A is [ka] is.

[0184] In another embodiment of a compound of Formula I or IIIA, or a pharmaceutically acceptable salt thereof, J is C1-C6 alkylene.

[0185] In another embodiment, one of the C1-C6 alkylene carbons of J is -(C=O)-.

[0186] In another embodiment, J is optionally substituted with -OH.

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

[0188] In another embodiment of the compound of Formula I or IIIA, or a pharmaceutically acceptable salt thereof, (R x R y )NJ- is, [ka] is selected from the group consisting of:

[0189] In another embodiment of the compound of Formula I or IIIA, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0190] In another embodiment of the compound of Formula I or IIIA or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein each R3 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, and C1-C6 haloalkyl; and m is 0 or 1.

[0191] In another embodiment, [ka] teeth [ka] is.

[0192] In another embodiment, [ka] teeth [ka] is.

[0193] In another embodiment, [ka] teeth, [ka] wherein R3 is selected from the group consisting of Me, OMe, halo, and CF3.

[0194] In another embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0195] In another embodiment of the compound of Formula I or IIIA or a pharmaceutically acceptable salt thereof, 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 C1-C6 alkyl, 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).

[0196] In another embodiment, Y2 is [ka] is selected from the group consisting of:

[0197] In another embodiment of the compound of Formula I or IIIA, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0198] In another embodiment of a compound of Formula I or IIIA or a pharmaceutically acceptable salt thereof, Ring B is a bicyclic heterocycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0199] In another embodiment, Ring B is a fused, spiro, or bridged bicyclic heterocycloalkylene containing up to three nitrogen atoms, wherein the fused, spiro, or bridged bicyclic heterocycloalkylene is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0200] In another embodiment, Ring B is a fused bicyclic heterocycloalkylene containing up to two nitrogen atoms, wherein the fused bicyclic heterocycloalkylene is optionally substituted with C1-C6 alkyl or C1-C6 hydroxyalkyl.

[0201] In another embodiment, Ring B is a spiro bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0202] In another embodiment, Ring B is a bridged bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0203] In another embodiment, Ring B is a bicyclic cycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0204] In another embodiment, Ring B is a fused, spiro, or bridged bicyclic cycloalkylene.

[0205] In another embodiment, Ring B is a fused bicyclic cycloalkylene.

[0206] In another embodiment, Ring B is a spiro bicyclic cycloalkylene.

[0207] In another embodiment, Ring B is a bridged bicyclic cycloalkylene.

[0208] In another embodiment, ring B is [ka] [ka] is selected from the group consisting of:

[0209] In another embodiment of the compound of Formula I or IIIA, or a pharmaceutically acceptable salt thereof, L is absent.

[0210] In another embodiment, L is a straight chain or branched C1-C6 alkylene, wherein one carbon atom of the C1-C6 alkylene is O, NH, (C=O), or N—(C 1-6 It may be replaced by alkyl.

[0211] In another embodiment, L is CH2, CH(CH3), CH(CH2CH3), or C=O.

[0212] In another embodiment of the compound of Formula I or IIIA or a pharmaceutically acceptable salt thereof, R 1 is H, NH 2 , or NH(C 1 -C 6 alkyl).

[0213] In another embodiment, R1 is H, NH2, NHCH3.

[0214] In another embodiment of the compound of Formula I or IIIA or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0215] In another embodiment of a compound of Formula I or IIIA 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, and C1-C6 alkoxy; and m and n are each independently 0, 1, or 2.

[0216] In another embodiment, R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, and C1-C6 alkoxy; and m and n are each independently 0 or 1.

[0217] In another embodiment of a compound of Formula I or IIIA or a pharmaceutically acceptable salt thereof, m and n are each 0 or 1, R2 is Me, and R3 is selected from the group consisting of CH3, F, OCH3, and CF3.

[0218] In another embodiment, the compound of formula I or IIIA is a compound of formula IIIA-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, J, Y2, X 1 , X 2 , R1, R3, R x , R y , and m are as defined herein.

[0219] In another embodiment, the compound of formula I or IIIA is a compound of formula IIIA-2: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, J, Y, X 1 , X 2 , R1, R3, R x , R y , and m are as defined herein; R5 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo; and q is 0, 1, or 2.

[0220] In another embodiment, the compound of formula I or IIIA is a compound of formula IIIA-3: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, X 1 , X 2 , R1, R3, R5, R x , R y , q and m are as defined herein, and K is C1-C4 alkylene, optionally substituted with hydroxy or alkoxy.

[0221] In another embodiment, the compound of formula I or IIIA is a compound of formula IIIA-4: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, X 1 , X 2, R1, R3, R5, q and m are as defined herein.

[0222] In another embodiment, the compound of formula I or IIIA is a compound of formula IIIA-4a or IIIA-4b: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, X 1 , X 2 , R1, R3, and m are as defined herein.

[0223] In another embodiment, the compound of Formula I or IIIA is a compound of Formula IIIA-5: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y2, and R1 are as defined herein; 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.

[0224] In another embodiment, the compound of formula I or IIIA is a compound of formula IIIA-6: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y2, R1, R3, and m are as defined herein.

[0225] In another embodiment, the compound of Formula I or IIIA is a compound of Formula IIIA-7: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y2, and R1 are as defined herein.

[0226] In another embodiment, the compound of formula I or IIIA is a compound of formula IIIA-8a or IIIA-8b: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, R x’ , and R y’ is as defined herein.

[0227] In another embodiment, the compound of Formula I or IIIA is a compound of Formula IIIA-9: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, and Y2 are as defined herein.

[0228] In another aspect, the present disclosure provides a compound of formula IIIB: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, X 1 , X 2 , Y2, B, L, m, and n are as defined herein; Ring D' is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, 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, NH(C-C alkyl), N(C-C alkyl), -COO(C-C alkyl), -COONH, and oxo; R 4’ is H or NR x” R y” where R x” and R y” are each independently H or C1-C6 alkyl.

[0229] In another embodiment, the compound of formula I or IIIB is a compound of formula IIIB-1: [ka] or a pharmaceutically acceptable salt thereof.

[0230] In another embodiment of the compound of formula IIIB or a pharmaceutically acceptable salt thereof, ring D' is [ka] wherein Z1 and Z2 are each independently selected from the group consisting of CH, CH2, N, NH and O; each R5 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo; q is 0, 1, 2, or 3; and r is 1 or 2.

[0231] In another embodiment, ring D is [ka] is.

[0232] In another embodiment of the compound of Formula I or IIIB, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0233] In another aspect, the present disclosure provides a compound of formula IV: [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 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; 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; X1 and X2 are each independently CH or N; Y3 is a straight chain C3-C8 alkylene, C3-C8 alkenylene, or C3-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 C3-C8 alkylene, C3-C8 alkenylene, or C3-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 bicyclic heterocycloalkylene or bicyclic cycloalkylene, wherein the bicyclic heterocycloalkylene and bicyclic cycloalkylene 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, OH, —COO(C-C alkyl), —COONH, and C-C hydroxyalkyl; L is absent or 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 alkyl), R1 is H or NR x’ R y’ where R x’ and R y’ are each independently H, C1-C6 alkyl, or a protecting group; 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, and C1-C6 alkoxy; m and n are each independently 0, 1, 2, or 3.

[0234] In another embodiment of the compound of formula IV or a pharmaceutically acceptable salt thereof, Z is —(C═O)—.

[0235] In another embodiment of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, Ring A is a monocyclic heterocycloalkylene or a bicyclic heterocycloalkylene, 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.

[0236] 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.

[0237] 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.

[0238] In another embodiment, ring A is [ka] wherein each R5 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, CN, C1-C6 haloalkyl, phenyl, OH, NH2, and oxo, and wherein q is 0, 1, 2, or 3.

[0239] In another embodiment, ring A is [ka] is.

[0240] In another embodiment of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, one of the C1-C6 alkylene carbons of J is -(C=O)-.

[0241] In another embodiment, J is optionally substituted with -OH.

[0242] In another embodiment, J is [ka] is selected from the group consisting of:

[0243] In another embodiment of the compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, R x and R y are each independently H.

[0244] In another embodiment of the compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, (R x R y)NJ is [ka] is selected from the group consisting of:

[0245] In another embodiment of the compound of Formula I or IV or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0246] In another embodiment of the compound of Formula I or IV 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.

[0247] In another embodiment, [ka] teeth [ka] is.

[0248] 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.

[0249] In another embodiment, [ka] teeth, [ka] is.

[0250] In another embodiment of a compound of Formula I or IV or a pharmaceutically acceptable salt thereof, Y3 is a straight chain C3-C8 alkylene, C3-C8 alkenylene, or C3-C8 alkynylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkynylene, wherein one carbon atom of the C3-C8 alkylene, C3-C8 alkenylene, or C3-C8 alkynylene is 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), or (C=O).

[0251] In another embodiment, Y3 is C3-C8 alkylene, or C3-C8 alkenylene, any of which is optionally substituted with OH, NH2, halo, C1-C6 alkyl, or C1-C6 alkoxy, wherein one carbon atom of the C3-C8 alkylene or C3-C8 alkenylene is 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).

[0252] In another embodiment, Y3 is [ka] [ka] is.

[0253] In another embodiment of the compound of Formula I or IV or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0254] In another embodiment of a compound of Formula I or IV or a pharmaceutically acceptable salt thereof, Ring B is a bicyclic heterocycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0255] In another embodiment, Ring B is a fused, spiro, or bridged bicyclic heterocycloalkylene containing up to three nitrogen atoms, wherein the fused, spiro, or bridged bicyclic heterocycloalkylene is optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0256] In another embodiment, Ring B is a fused bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0257] In another embodiment, Ring B is a spiro bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0258] In another embodiment, Ring B is a bridged bicyclic heterocycloalkylene containing up to two nitrogen atoms.

[0259] In another embodiment, Ring B is a bicyclic cycloalkylene, optionally substituted with up to three substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0260] In another embodiment, Ring B is a fused, spiro, or bridged bicyclic cycloalkylene, optionally substituted with up to two substituents selected from the group consisting of C-C alkyl, C-C alkoxy, halo, C-C haloalkyl, OH, and C-C hydroxyalkyl.

[0261] In another embodiment, Ring B is a fused bicyclic cycloalkylene.

[0262] In another embodiment, Ring B is a spiro bicyclic cycloalkylene.

[0263] In another embodiment, Ring B is a bridged bicyclic cycloalkylene.

[0264] In another embodiment, ring B is [ka] is.

[0265] In another embodiment of the compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, L is absent.

[0266] 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.

[0267] In another embodiment, L is -CH2-.

[0268] In another embodiment of the compound of Formula I or IV or a pharmaceutically acceptable salt thereof, R1 is H, NH2, or NH(C1-C6 alkyl).

[0269] In another embodiment, R1 is H or NH2.

[0270] In another embodiment of the compound of Formula I or IV or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0271] In another embodiment of a compound of Formula I or IV 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.

[0272] In another embodiment, R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl, halo, and C1-C6 alkoxy; and m and n are each independently 0 or 1.

[0273] In another embodiment, the compound of formula I or IV can be a compound of formula IA: or a pharmaceutically acceptable salt thereof.

[0274] In another embodiment, the compound of formula I or IV is a compound of formula IV-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, J, Y, X 1 , X 2 , R1, R3, Rx , R y , and m are as defined herein.

[0275] In another embodiment, the compound of formula I or IV is a compound of formula IV-2: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, J, Y, X 1 , X 2 , R1, R3, R x , R y , and m are as defined 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, or 2.

[0276] In another embodiment, the compound of formula I or IV is a compound of formula IV-3: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, X 1 , X 2 , R1, R3, R5, R x , R y , q and m are as defined herein, and K is C1-C4 alkylene, optionally substituted with hydroxy or alkoxy.

[0277] In another embodiment, the compound of formula I or IV is a compound of formula IV-4: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, X 1 , X 2 , R1, R3, R5, q and m are as defined herein.

[0278] In another embodiment, the compound of formula I or IV is a compound of formula IV-4a or IIIA-4b: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, X 1 , X 2 , R1, R3, and m are as defined herein.

[0279] In another embodiment, the compound of formula I or IV is a compound of formula IV-5: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y3, and R1 are as defined herein; and 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.

[0280] In another embodiment, the compound of formula I or IV is a compound of formula IV-6: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y3, R1, R3, and m are as defined herein.

[0281] In another embodiment, the compound of formula I or IV is a compound of formula IV-7: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y3, and R1 are as defined herein.

[0282] In another embodiment, the compound of formula I or IV is a compound of formula IV-8 or IV-9: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, K, Y, R x’ , and R y’ is as defined herein.

[0283] In another embodiment, the compound of formula I or IV is a compound of formula IV-10a, formula IV-10b, formula IV-10c, or formula IV-10d: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L, K, and Y3 are as defined herein; and p and r are each independently 1, 2, or 3.

[0284] In another embodiment, the compound of formula I or IV is a compound of formula IV-11: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, K, and Y3 are as defined herein.

[0285] In another embodiment, the compound of formula I or IV is a compound of formula IV-12: [ka] or a pharmaceutically acceptable salt thereof, wherein K and Y3 are as defined herein.

[0286] In another aspect, the present disclosure provides the compounds set forth in Table 7, or pharmaceutically acceptable salts thereof. Table 7 lists possible pharmaceutically acceptable salts and the free base for each compound. Table 7 Compounds of Formula I [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10]

[0287] In another aspect, the present disclosure provides the compounds set forth in Table 8, or pharmaceutically acceptable salts thereof. Table 8 lists possible pharmaceutically acceptable salts and the free base for each compound. Table 8 Compounds of Formula I (cont.) [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13]

[0288] In another aspect, the present disclosure provides the compounds set forth in Table 9, or pharmaceutically acceptable salts thereof. Table 9 lists possible pharmaceutically acceptable salts and the free base for each compound. Table 9 Compounds of Formula I (cont.) [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0289] In another aspect, the present disclosure provides the compounds set forth in Table 10, or pharmaceutically acceptable salts thereof. Table 10 lists possible pharmaceutically acceptable salts and the free base for each compound. Table 10 Compounds of Formula I (cont.) [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8]

[0290] 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 7, 8, 9, and 10.

[0291] In another embodiment, the compound of formula IIA or IIB, or a pharmaceutically acceptable salt thereof, is selected from the compounds set forth in Table 7.

[0292] In another embodiment, the compound of formula IIIA or IIIB, or a pharmaceutically acceptable salt thereof, is selected from the compounds set forth in Table 8.

[0293] In another embodiment, the compound of formula IV or a pharmaceutically acceptable salt thereof is selected from the compounds set forth in Table 9.

[0294] In another aspect, the present disclosure provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, Z, X 1, X 2 , R1, R2, R3, L, ring B, m, and n have the definitions given in the preceding paragraphs.

[0295] In another embodiment of the compound of formula V, ring A is [ka] where R5 and q have the definitions given in the preceding paragraphs.

[0296] In another embodiment, the compound of formula V is selected from the compounds shown in Table 11 below. Table 11 Compounds of Formula V [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]

[0297] In another embodiment, the compound of formula I-5 is selected from the compounds shown in Table 11.

[0298] In another aspect, the present disclosure provides a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables have the definitions disclosed herein.

[0299] In another embodiment, the compound of formula VI is selected from the compounds shown in Table 12 below. Table 12 Compounds of Formula VI [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]

[0300] 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 definitions as in the preceding paragraph; Y5 is a bond or a straight-chain C1-C7 alkylene, C2-C7 alkenylene, or C2-C7 alkenylene, 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 R6 is H or C1-C6 alkyl.

[0301] 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.

[0302] In another embodiment, the compound of formula E or a pharmaceutically acceptable salt thereof is selected from the compounds shown in Table 13 below. Table 13 Compounds of formula E [Table 13-1] [Table 13-2] [Table 13-3]

[0303] 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.

[0304] 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).

[0305] The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. In general, such preparative 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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.

[0313] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0314] 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.

[0315] 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.

[0316] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0317] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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).

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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).

[0341] 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).

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] Uses and Methods of Treatment 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.

[0349] 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.

[0350] 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).

[0351] 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 variables such as ring A, ring B, J, L, X, 1 , X 2 , Y, R1, R 1’ , R2, R3, R6, m, and n have the same definitions as in the preceding paragraph; 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; R6 is H or C1-C6 alkyl; X is halo; and P is a hydroxyl protecting group.

[0352] General synthetic scheme G-1 [ka] General synthetic scheme G-2 [ka] In step 1 of general synthetic scheme G-1, 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, which in step 2 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 give a compound of formula (b).

[0353] 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.

[0354] 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).

[0355] 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.

[0356] In steps 7a and 7b of general synthetic schemes G-1 and G-2, a compound of formula E (or g) is reacted with an amine under reductive amination conditions to give a compound of formula I (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.

[0357] 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.

[0358] 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.

[0359] In one embodiment, the process further comprises the step of removing the amino protecting group PG.

[0360] In another embodiment, the compound of formula B is selected from the compounds shown in Table 12.

[0361] 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; Y4 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, halo, C1-C6 alkyl, or C1-C6 alkoxy; 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.

[0362] In another embodiment, the compound of formula C is selected from the compounds shown in Table 13.

[0363] 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, ring A, ring B, 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, halo, C1-C6 alkyl, or C1-C6 alkoxy; R6 is H or C1-C6 alkyl.

[0364] 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.

[0365] In another embodiment, the compound of formula E is selected from the compounds set forth in Table 13. [Example]

[0366] 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.

[0367] 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.

[0368] 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 multiple vendors, including Sigma-Aldrich, Acros, Enamine, TCI America, Combi-Blocks, Alfa-Aesar, Angene, Ark Pharma, PharmaBlock, Strem Chemicals, Frontier Scientific, and AstaTech, Inc.

[0369] Liquid chromatography mass spectrometry Liquid Chromatography Mass Spectrometry A

[0370] 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.

[0371] Liquid Chromatography Mass Spectrometry B

[0372] 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.

[0373] 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 with 0.1% formic acid (pH = 2.70) / B - 0.1% formic acid in water:CH3CN (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.

[0374] Liquid Chromatography Mass Spectrometry

[0375] LC / MS-ES (+ / -): The analysis was performed using an AQUITY H-Class equipped with a PDA detector and a QDA, a C18 column (50x2.1 mm, 1.6 μm particle size), a column temperature of 35°C, a mobile phase: A - Milli-Q water with 0.1% formic acid (pH = 2.70) / B - 0.1% formic acid in water:CH3CN (10:90), a flow rate of 0.8-1.0 mL / min, a run time of 4.0 min, a gradient of t = 0 min 3% B, t = 2.7 min 98% B, t = 3.0 min 100% B, t = 3.51 min 3% B, a stop time of 4.0 min.

[0376] Liquid Chromatography Mass Spectrometry

[0377] 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: A - 0.1% formic acid in water (pH = 2.70) / B - 0.1% formic acid in water: CH3CN (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, a stop time of 9.0 min.

[0378] Liquid Chromatography Mass Spectrometry

[0379] 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 - MeOH, 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.

[0380] Liquid Chromatography Mass Spectrometry G

[0381] 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 - MeOH, 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.

[0382] Liquid Chromatography Mass Spectrometry

[0383] 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 with 0.1% formic acid (pH = 2.70) / B - 0.1% formic acid in water:CH3CN (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.

[0384] Analysis method 1H Nuclear magnetic resonance (NMR) spectroscopy was performed using one of the following instruments: Bruker Avance400 instrument equipped with probe DUAL 400MHz S1; 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) 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.

[0385] 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).

[0386] 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 / MeOH with gradient elution). Table 14. Abbreviations and names of reagents [Table 14-1] [Table 14-2] [Table 14-3]

[0387] 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: a) TFAA, CH2Cl2, 0°C to rt, 16 h b) TFA, CH2Cl2, rt, 1.5 h c) CDI, CH2Cl2, 16 h d) 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 (20.0 g, 107 mmol) in dry CHCl (100 mL) was cooled to 0 °C under N. TFAA (15.0 mL, 107 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 (1 L) and quenched with saturated NaHCO (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.

[0388] Step 2: 2,2,2-Trifluoro-1-(piperazin-1-yl)ethan-1-one trifluoroacetate. To a solution of TFA 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 TFA were removed under reduced pressure. The crude reaction mixture was triturated with EtO to give a solid precipitate. The solid was filtered and washed with EtO to give the title compound as a white solid (29.5 g, 97%).

[0389] Step 3: 1-(4-(1H-imidazole-1-carbonyl)piperazin-1-yl)-2,2,2-trifluoroethan-1-one. To a suspension of 2,2,2-trifluoro-1-(piperazin-1-yl)ethan-1-one trifluoroacetate (26.0 g, 88 mmol) in CHCl (100 mL) was added CDI (17.1 g, 105 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the crude reaction mixture was purified by column chromatography to give the desired product as a white solid (18 g, 76%).

[0390] Step 4: 3-Methyl-1-(4-(2,2,2-trifluoroacetylpiperazine-1-carbonyl)-1H-imidazol-3-ium iodide. To 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 CHCN (80 mL) was added MeI (15.0 mL, 235 mmol). The reaction was stirred at room temperature for 24 h. The solvent and excess MeI were removed under reduced pressure to give the title compound as a light yellow solid (27.6 g, 98%).

[0391] 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) HATU, DIPEA, DMF, rt, 16 h; 2) 10% Pd / C, MeOH, rt, 16 h; 3) CDI, CH2Cl2, rt, 16 h; 4) MeI, CH3CN, rt, 16 h. Step 1: Benzyl 4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxylate. To a stirred solution of 2-((t-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 reaction mixture was poured into HO (1500 mL) 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 column chromatography (20-30% hexanes: EtOAc) to afford the title compound (36.0 g, 55%) as an off-white solid. LCMS [M+H] 406.

[0392] Step 2: t-Butyl (2-methyl-1-oxo-1(piperazin-1-yl)propan-2-yl)carbamate. To a stirred solution of benzyl 4-(2-((t-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 H2 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.

[0393] Step 3: t-Butyl (1-(4-1H-imidazole-1-carbonyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of t-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, and 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.

[0394] Step 4: 1-(4-(2-((t-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 hours. 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).

[0395] Intermediate 3 [ka] 1-(4-((2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide The title compound was prepared in a similar manner to Scheme I-2 from (2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)oxazolidine-4-carboxylic acid and 1-Cbz-piperazine to give the title compound as a yellow solid.

[0396] Intermediate 4 [ka] tert-Butyl N-[exo-3-{[4-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-3-azabicyclo[3.1.0]hexan-6-yl]carbamate Scheme I-3 [ka] Reagents: Step 1) 4-Formylphenylboronic acid, TMEDA, Cu(OAc)2·H2O, MeOH:H2O, rt, 16 h. 2) tert-Butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate, NaBH(OAc)3, DCE:CH3CN, rt, 16 h. Step 1) Step 1: 4-(4-Amino-2-oxopyrimidin-1(2H)-yl)benzaldehyde: A suspension of cytosine (2.60 g, 24.0 mmol) and 4-formylphenylboronic acid (3.53 g, 24 mmol) in 4:1 MeOH:HO (25 mL) was stirred at room temperature under air. After 30 minutes, TMEDA (6.70 mL, 28.0 mmol) and Cu(OAc)2.HO (4.70 g, 24.0 mmol) were added. The reaction was stirred at room temperature under air for 16 hours. The MeOH was evaporated under reduced pressure, and ice was added to the remaining mixture, which was stirred for 10 minutes. The reaction mixture was filtered, and the solid was washed with HO to give the title compound (3.5 g, 69%) as a white solid.

[0397] Step 2: tert-Butyl (exo-3-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate: tert-Butyl N-[exo-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (2.07 g, 10.5 mmol) and AcOH (0.5 mL) were added to a suspension of 4-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)benzaldehyde (1.5 g, 6.97 mmol) in DCE (80 mL). The reaction was stirred at room temperature for 15 min, and NaBH(OAc) (3.7 g, 17.5 mmol) was added. After 2 h, the reaction was diluted with CHCl and washed with saturated NaHCO solution. The organic portion was concentrated under reduced pressure. The crude product was triturated with a mixture of EtOAc, MeOH, and cyclohexane, and the solid was filtered and dried to give the title compound (3.26 g, 85%). 1 H NMR (400MHz, DMSO-d6) δ 7.62 (d, 1H), 7.35-7.12 (m, 6H), 6.95-6.82 (m, 1H), 5.78 (d, 1H), 3.61-3.54 (m, 2H), 2.93 (d, 2H), 2.76-2.65 (m, 1H), 2.35 (d, 2H), 1.44 (br. s, 2H), 1.37 (s, 9H). LCMS [M+H] 398.4.

[0398] Intermediate 5 [ka] tert-Butyl ((exo-3-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate Scheme I-4 [ka] Reagents: Step 1) tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate, K2CO3, THF, 85 °C, 48 h. 2) Pd(dppf)Cl2, KOAc, 1,4-dioxane, 90 °C, 16 h. 3) TMEDA, Cu(OAc)2·H2O, CH3OH:H2O (4:1), O2, rt, 48 h. Step 1: t-Butyl ((exo-3-(4-bromophenethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A mixture of 1-bromo-4-(2-bromoethyl)benzene (0.9 g, 3.40 mmol), t-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (0.7 g, 3.4 mmol), and K2CO3 (1.41 mL, 10.2 mmol) in THF (10 mL) was stirred at 85 °C for 48 h. It was cooled, poured into HO (50 mL), and extracted with CHCl2 (3 × 20 mL). The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH3OH / CHCl2) to give the title compound. LCMS [M+H] 395.1.

[0399] Step 2: tert-butyl ((exo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A mixture of tert-butyl ((exo-3-(4-bromophenethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (0.85 g, 2.15 mmol), bis(pinacolato)diboron (1.1 g, 4.31 mmol), and KOAc (0.8 g, 8.62 mmol) in 1,4-dioxane (20 mL) was purged with N for 15 min. Pd(dppf)Cl (0.088 g, 0.10 mmol) was added and the mixture was stirred at 90 °C for 16 h, cooled, poured into H O (100 mL), and extracted with EtOAc (2 x 100 mL). The extracts were dried (Na SO ), filtered, and concentrated under reduced pressure to give the title compound. LCMS [M+H] 443.3.

[0400] Step 3: t-Butyl ((exo-3-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A mixture of tert-butyl ((exo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (1.9 g, 4.29 mmol) and cytosine (0.58 g, 5.27 mmol) in CHOH:HO (4:1, 50 mL) was stirred at room temperature in air for 30 minutes. TMEDA (0.9 mL, 6.33 mmol) and Cu(OAc) H O (0.98 g, 5.27 mmol) were added, and the mixture was stirred at room temperature in air for 48 h. It was poured into H O (150 mL) and extracted with CHCl (2 x 100 mL). The extracts were dried (NaSO), filtered, and concentrated under reduced pressure, and the residue was triturated with Et O (10 mL) to give the title compound. LCMS [M+H] 426.3.

[0401] Intermediate 6 [ka] tert-Butyl ((exo-3-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate Scheme I-5 [ka] Reagents: 1) MsCl, Et3N, CH2Cl2, 1 h; 2) tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate, K2CO3, NaI, CH3CN, reflux, 4 h; 3) B2pin2, Cl2Pd(dppf)·CH2Cl2, KOAc, dioxane, 100 °C, 16 h; 4) cytosine, Cu(OAc)2·H2O, TMEDA, MeOH, H2O, air, 72 h. Step 1: 2-(4-Bromophenoxy)ethyl methanesulfonate. MsCl (2.2 mL, 28.4 mmol) was added dropwise to a solution of 2-(4-bromophenoxy)ethanol (5.11 g, 23.6 mmol) and NEt (4.9 mL, 35.2 mmol) in CHCl (120 mL). The mixture was stirred at room temperature under N for 1 h, poured into saturated aqueous NaHCO (250 mL), and extracted with CHCl (2 × 200 mL). The extract was dried (NaSO), filtered, and concentrated under reduced pressure to provide the title compound.

[0402] Step 2: tert-Butyl ((exo-3-(2-(4-bromophenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A mixture of 2-(4-bromophenoxy)ethyl methanesulfonate (2.23 g, 7.55 mmol), tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (1.76 g, 8.27 mmol), KCO (2.10 g, 15.20 mmol), and NaI (1.22 g, 8.16 mmol) in CHCN (50 mL) was stirred at reflux under N for 4 h. It was cooled, diluted with EtOAc (250 mL), washed with saturated aqueous NaHCO (2×150 mL) followed by brine (1×150 mL), dried (NaSO), filtered, and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.

[0403] Step 3: tert-Butyl ((exo-3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A mixture of tert-butyl ((exo-3-(2-(4-bromophenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (2.99 g, 7.26 mmol), bis(pinacolato)diboron (3.69 g, 14.53 mmol), ClPd(dppf) CHCl (296 mg, 0.362 mmol), and KOAc (1.45 g, 14.74 mmol) in dry dioxane (35 mL) was placed under a N atmosphere and purged with N for 20 minutes, then stirred at 100 °C for 16 hours, cooled, diluted with EtOAc (100 mL), and filtered through Celite®, rinsing with additional EtOAc (50 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / EtOAc / hexanes) to provide the title compound.

[0404] Step 4: tert-Butyl ((exo-3-(2-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A mixture of tert-butyl ((exo-3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (3.27 g, 7.13 mmol) and cytosine (796 mg, 7.16 mmol) in MeOH (32 mL) and HO (8 mL) was stirred for 20 min. Cu(OAc) H O (1.42 g, 7.1 mmol) and TMEDA (1.28 mL, 8.54 mmol) were added, and the mixture was stirred in air for 72 h. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH. H O and ice were added to the residue, and the precipitate was collected by vacuum filtration. The solid was dissolved in CHCl and MeOH, dry-loaded onto Celite®, and purified by silica gel column chromatography (CHCl / MeOH / NHOH) to give the title compound.

[0405] Intermediate 7 [ka] tert-Butyl ((exo-3-(1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)-4-methylpentan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate Scheme I-6 [ka] Reagents: 1) DMP, CHCl, rt, 16 h; 2) i-BuMgBr, THF, −78°C, 2 h; 3) DMP, CHCl, rt, 16 h; 4) tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate, Ti(O-iPr), 70°C–rt, 16 h; NaBH, MeOH, 16 h; 5) Bpin, ClPd(dppf)·CHCl, KOAc, dioxane, 100°C, 16 h; 6) cytosine, Cu(OAc)·H2O, TMEDA, MeOH, H2O, air, 72 h. Step 1: 2-(4-Bromophenyl)acetaldehyde. To a solution of 2-(4-bromophenyl)ethan-1-ol (1.3 g, 6.47 mmol) in CHCl (100 mL) was added DMP (4.0 g, 9.43 mmol). The solution was stirred for 16 h. The crude reaction mixture was extracted with a 1:1 mixture of NaHCO and NaSO (3 x 300 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give the title compound as a yellow solid.

[0406] Step 2: 1-(4-Bromophenyl)-4-methylpentan-2-ol. A solution of 2-(4-bromophenyl)acetaldehyde (1.0 g, 5.02 mmol) in THF (50 mL) was cooled to -78 °C. To this was added isobutylmagnesium bromide (4.2 mL, 8.53 mmol) over 30 min. The solution was stirred for 2 h and then quenched with 1 N HCl (10 mL). The crude rxn mixture was partitioned between EtOAc (100 mL) and 1 N HCl (100 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (Hex: EtOAc) to give the title compound as a yellow semi-solid.

[0407] Step 3: 1-(4-Bromophenyl)-4-methylpentan-2-one. To a solution of 1-(4-bromophenyl)-4-methylpentan-2-ol (520 mg, 2.02 mmol) in CHCl (50 mL) was added DMP (1.4 g, 3.30 mmol). The solution was stirred for 16 h. The crude reaction mixture was extracted with a 1:1 mixture of NaHCO and NaSO (3 × 300 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give the title compound as a yellow solid. The product was used in the next step without further purification.

[0408] Step 4: tert-Butyl ((exo-3-(1-(4-bromophenyl)-4-methylpentan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. To a flask containing 1-(4-bromophenyl)-4-methylpentan-2-one (400 mg, 1.57 mmol) and tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (489 mg, 2.30 mmol) was added neat Ti(i-OPr) (4 mL). The rxn mixture was heated to 70 °C for 3 h, cooled to room temperature, and stirred for 16 h. NaBH (597 mg, 15.7 mmol) in MeOH (50 mL) was added in portions over 30 min. The rxn mixture was stirred for an additional 16 h, at which point the solution became a milky white slurry. 1-2 mL of HO was added, and the slurry was filtered through Celite®, rinsing with EtOAc; this step was repeated as many titanium salts precipitated upon filtration. The combined organics were concentrated under reduced pressure and partitioned between CHCl (100 mL) and 1 N NaOH (100 mL), and the aqueous layer was washed again with CHCl (2 x 50 mL). The combined organics were dried over NaSO, concentrated under reduced pressure, and purified by column chromatography (Hex:EtOAc) to give the title compound as an off-white solid.

[0409] Step 5: tert-Butyl ((exo-3-(4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A suspension of tert-butyl ((exo-3-(1-(4-bromophenyl)-4-methylpentan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (500 mg, 1.11 mmol), B2pin2 (421 mg, 1.66 mmol), Pd(dppf)Cl2(CHCl2) (27 mg, 0.03 mmol), and KOAc (271 mg, 2.78 mmol) in dioxane (50 mL) was degassed and heated to 100 °C for 16 h. The crude reaction mixture was filtered through Celite® and concentrated under reduced pressure. Purification by column chromatography (EtOAc:Hex) afforded the title compound.

[0410] Step 6: tert-butyl ((exo-3-(1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)-4-methylpentan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A suspension of cytosine (116 mg, 1.05 mmol) and tert-butyl ((exo-3-(4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (524 mg, 1.05 mmol) in 4:1 MeOH:HO (100 mL) was stirred at room temperature in air for 30 minutes. TMEDA (0.18 mL, 1.16 mmol) and Cu(OAc) H2O (208 mg, 1.05 mmol) were added, and the reaction was stirred at room temperature open to air for 72 h. The reaction mixture was concentrated under reduced pressure, and H2O (50 mL) was added. The aqueous phase was extracted with CHCl3 (4 x 15 mL), and the combined organics were concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (MeOH:CHCl3) to give the title compound.

[0411] Intermediate 8 [ka] tert-Butyl ((exo-3-(1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)-3-methylbutan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate Prepared in a similar manner to Scheme I-6 from 1-(4-bromophenyl)-3-methylbutan-2-one and tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate.

[0412] Intermediate 9 [ka] tert-Butyl ((exo-3-(1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)pentan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate Prepared in a similar manner to Scheme I-6 from 1-(4-bromophenyl)pentan-2-one and tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate.

[0413] Intermediate 10 [ka] tert-Butyl ((exo-3-(1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluorophenyl)butan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate Scheme I-7 [ka] Reagents: 1) N,O-dimethylhydroxylamine, EDCI·HCl, NEt3, DMAP, CHCl2, 16 hours; 2) EtMgBr, THF, -78°C, 4 hours; 3) tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate, NaCNBH3, MeOH, 16 hours; 4) Bpin2, Pd(dppf)2, KOAc, dioxane, 100°C, 16 hours; 5) cytosine, TMEDA, Cu(OAc)2·H2O, 4:1 MeOH:H2O, 48 hours. Step 1: 2-(4-Bromo-2-fluorophenyl)-N-methoxy-N-methylacetamide. To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (1.51 g, 6.51 mmol) in CHCl (50 mL) was added N,O-dimethylhydroxylamine (0.96 g, 9.76 mmol), EDCI·HCl (1.86 g, 9.76 mmol), NEt (3.60 mL, 26.04 mmol), and DMAP (0.10 g). The solution was stirred for 16 h. The reaction mixture was washed with saturated aqueous NaHCO (1 × 50 mL), 2 N HCl (1 × 50 mL), saturated aqueous NaHCO (1 × 50 mL), and 2 N HCl (1 × 50 mL). The organic extract was dried over NaSO, filtered, and the solvent was removed under reduced pressure to give the title compound.

[0414] Step 2: 1-(4-Bromo-2-fluorophenyl)butan-2-one. A solution of 2-(4-bromo-2-fluorophenyl)-N-methoxy-N-methylacetamide (1.60 g, 5.80 mmol) in THF (100 mL) was cooled to −78° C. EtMgBr (2.51 mL, 7.54 mmol) was added dropwise over 25 minutes. The solution was stirred for an additional 4 hours. The crude reaction mixture was quenched with HO (5 mL), and the combined solvents were removed under reduced pressure. The crude mixture was purified by column chromatography (hexanes:EtOAc) to provide the title compound.

[0415] Step 3: tert-Butyl ((exo-3-(1-(4-bromo-2-fluorophenyl)butan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. To a solution of 1-(4-bromo-2-fluorophenyl)butan-2-one (840 mg, 3.44 mmol) in MeOH (50 mL) was added tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (877 mg, 4.14 mmol), followed by NaCNBH (854 mg, 13.76 mmol). The solution was stirred for 16 h. Excess MeOH was removed, and the crude solid was partitioned between EtOAc (100 mL) and 1 N NaOH (100 mL). The aqueous layer was further washed with EtOAc (1 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography (hexanes: EtOAc) to give the title compound.

[0416] Step 4: tert-Butyl ((exo-3-(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A mixture of tert-butyl ((exo-3-(1-(4-bromo-2-fluorophenyl)butan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (380 mg, 0.87 mmol), B2pin2 (329 mg, 1.30 mmol), KOAc (212 mg, 2.17 mmol), and Pd(dppf)2 (21 mg, 0.03 mmol) was subjected to vacuum and pressure three times over 30 min under N2. Dioxane (30 mL) was added and the reaction was purged by bubbling N for 20 minutes. The reaction was heated to 100° C. and stirred overnight. The solvent was removed to give a brown ooze, which was purified by column chromatography (hexanes:EtOAc) to give the title compound.

[0417] Step 5: tert-butyl ((exo-3-(1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluorophenyl)butan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. A suspension of cytosine (70 mg, 0.63 mmol) and tert-butyl ((exo-3-(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (306 mg, 0.63 mmol) in MeOH:HO (4:1, 36 mL) was stirred at room temperature in air for 30 minutes. TMEDA (0.10 mL, 0.69 mmol) and Cu(OAc) H2O (125 mg, 0.63 mmol) were added, and the reaction was stirred at room temperature in air for 48 h. The reaction mixture was concentrated under reduced pressure, and cold H2O (100 mL) was added. The solid was filtered and washed with H2O (5 x 50 mL), Et2O (3 x 30 mL), and H2O (2 x 30 mL) to give the title compound.

[0418] Intermediate 11 [ka] 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 Scheme I-8 [ka] Reagents: 1) K2CO3, MeOH, 2) N-Boc-AIB-OH, HATU, DIPEA, CH3CN. Step 1: N-[1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide. K2CO3 (653 mg, 4.72 mmol) was added to a suspension of N-[1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]-4-(trifluoroacetyl)piperazine-1-carboxamide (1.0 g, 2.36 mmol) in MeOH (30 mL), and the resulting mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure to give the crude product, which was used directly in the next step. LCMS (Method A): m / z = 328.0 [M+H] + , 0.30 minutes.

[0419] Step 2: 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. N-Boc-α-methylalanine (576 mg, 2.83 mmol), HATU (1.35 g, 3.54 mmol), and DIPEA (822 μL, 4.72 mmol) were added sequentially to a solution of N-[1-(4-formylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide (theoretical value 2.36 mmol) in CH3CN (50 mL). The resulting mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure. The crude residue was dissolved in HO and the aqueous portion was extracted with EtOAc (2 x 50 mL). The combined organic portions were washed with brine, dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (CHCl-MeOH, 95:5) to give the title compound (650 mg, 54% over two steps). 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).

[0420] Intermediate 12 [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-9 [ka] Reagents: 1) TBSCl, imidazole, DMF, rt, 16 h; 2) n-BuLi, THF, -78 °C (iPrO)B, 2N HCl, 4 h; 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, 3 h; 6) Boc-aminoisobutyric acid, HATU, DIPEA, DMF, 8 h; 7) TBAF, THF, 0 °C to rt; 8) DMP, 100:1 CHCl₂:H₂O, 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 TBSCl (9.0 g, 60.0 mmol). The solution was stirred for 16 h. The reaction mixture was dissolved in 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 silica gel column chromatography (hexane:EtOAc) to give the title compound.

[0421] 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. n-BuLi (28.0 mL, 1 M in hexanes, 71.4 mmol) was added dropwise over 30 min, maintaining the temperature below −60 °C. After 25 min, (iPrO)B (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 mixture was separated and the aqueous layer was washed with CHCl (2×50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure to provide the title compound.

[0422] 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 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 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 reaction mixture was filtered and the solid was washed with H2O (5x50 mL), Et2O (3x30 mL), and H2O (2x30 mL) to give the title compound. LCMS [M+H] 346.2.

[0423] 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.

[0424] 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 (4.5 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 h. 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.

[0425] 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 stirred 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, HATU (5.51 g, 14.5 mmol) was added, and the solution was stirred for 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 column chromatography (CHCl:MeOH:NHOH) to give the title compound. LCMS [M+H] 643.4.

[0426] 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 stirred 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 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 title compound. LCMS [M+H] 529.4.

[0427] 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 mg, 0.28 mmol) in CHCl:HO (100:1, 10 mL) was added DMP (361 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 provide the title compound.

[0428] Intermediate 13 [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-9.

[0429] Intermediate 14 [ka] tert-Butyl (1-(4-((1-(3-fluoro-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate Prepared from 2-(4-bromo-2-fluorophenyl)ethan-1-ol in a similar manner to Scheme I-9.

[0430] Intermediate 15 [ka] tert-Butyl (2-methyl-1-(4-((1-(3-methyl-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate Prepared from 2-(4-bromo-2-methylphenyl)ethan-1-ol in a similar manner to Scheme I-9.

[0431] Intermediate 16 [ka] tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)-3-(trifluoromethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate Prepared in a similar manner to Scheme I-9 from 2-(4-bromo-2-(trifluoromethyl)phenyl)ethan-1-ol.

[0432] Intermediate 17 [ka] tert-Butyl (1-(4-((1-(3-methoxy-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate Prepared from 2-(4-bromo-2-methoxyphenyl)ethan-1-ol in a similar manner to Scheme I-9.

[0433] Intermediate 18 [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-10 [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)H0, MeOH:H0 (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, CHCN, 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, 140.8 mmol) in MeOH (150 mL) was added NaBH (13.3 g, 351.9 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).

[0434] Step 2: ((1-(4-Bromophenyl)propan-2-yl)oxy)(-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, 202.3 mmol) and TBSCl (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 afford the title compound (40.0 g, 90%) as a yellow oil. 1 H 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).

[0435] Step 3: Diisopropyl (4-(2-((t-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 1.6 M n-BuLi in THF (94 mL, 152.0 mmol). The reaction mixture was stirred at −78 °C for 30 min. B(iPrO) (21.17 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 (20.0 g, 86%).

[0436] Step 4: 4-Amino-1-(4-(2-((t-butyldimethylsilyl)oxy)propyl)phenyl)pyrimidin-2(1H)-one. A solution of diisopropyl(3-(2-((isopropyldimethylsilyl)oxy)ethyl)phenyl)boronate (20.0 g, 52.91 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, 48%) as a white solid. 1 H 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.

[0437] Step 5: 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. 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 h. 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.

[0438] Step 6: 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. 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, 18.9 mmol) 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 CH2Cl2:MeOH (9:1, 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 (4-5% MeOH in CH2Cl2) to afford the title compound (2.4 g, 93%) as an off-white solid. LCMS [M+H] 543.2.

[0439] Step 7: t-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. The reaction mixture was poured into NaHCO3 solution (20 mL) and extracted with CH2Cl2 (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.

[0440] 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 Scheme I-11 [ka] Reagents: Steps: 1) TBSCl, imidazole, CHCl, rt, 16 h. 2) n-BuLi, B(OiPr), THF, -78 °C to rt, 2 h. 3) Cytosine, TMEDA, Cu(OAc)H, MeOH:H, O, rt, 48 h. 4) CHCN, 85 °C, 16 h. 5) KCO, MeOH, rt, 3 h. 6) 2-((t-butoxycarbonyl)amino-2-methylpropanoic acid, HATU, DIPEA, DMF, rt, 16 h. 7) TBAF, THF, rt, 16 h. 8) DMP, CHCl, rt, 1 h. Step 1: (3-Bromophenethoxy)(t-butyl)dimethylsilane. To a stirred solution of 2-(3-bromophenyl)ethan-1-ol (30.0 g, 149.2 mmol) in DMF (150 mL) was added imidazole (15.24 g, 223.8 mmol) and TBSCl (26.99 g, 179.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was neutralized with saturated LiCl solution (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organics were dried over NaSO, filtered, concentrated under reduced pressure, and purified by column chromatography (5% EtOAc in hexanes) to give the title compound (45.0 g, 95%) as a colorless oil. 1 H NMR (400Mz, DMSO-d6): δ 7.46-7.36 (m, 2H), 7.25-7.21 (m, 2H), 3.75 (t, 2H), 2.73 (t, 2H), 0.80 (s, 9H), -0.08 (s, 6H).

[0441] Step 2: Diisopropyl (3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)boronate. To a stirred solution of (3-bromophenethoxy)(t-butyl)dimethylsilane (10.0 g, 31.7 mmol) in THF (100 mL) was added 2.5 M n-BuLi in hexanes (31.71 mL, 79.3 mmol) dropwise over 30 min at −78 °C. The temperature of the reaction mixture was maintained below −60 °C during the addition of n-BuLi. After 30 min, B(OiPr) (9.7 mL, 47.6 mmol) was added dropwise over 30 min at −78 °C. The reaction mixture was stirred at −78 °C for 1 h. The reaction mixture was quenched with saturated NH.sub.4Cl solution (500 mL), extracted with EtOAc (4.times.100 mL), and the combined organics were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the title compound (17.0 g) as a colorless oil.

[0442] Step 3: 4-amino-1-(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)pyrimidin-2(1H)-one. A solution of diisopropyl(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)boronate (17.0 g, 46.9 mmol) and cytosine (5.22 g, 46.9 mmol) in MeOH:HO (375 mL, 4:1) was stirred openly for 30 minutes. TMEDA (7.18 mL, 56.3 mmol) and Cu(OAc)HO (8.53 g, 46.9 mmol) were added, and the reaction was stirred openly at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and cold HO (100 mL) was added to the mixture. The resulting solid was filtered and washed with H2O (5 x 50 mL), hexane (3 x 30 mL), and again with H2O (2 x 30 mL) to give the title compound (9.0 g, 82%) as a white solid. 1 H NMR (400Mz, DMSO-d6): δ 7.55 (d, 1H), 7.33 (t, 1H), 7.21-7.15 (m, 5H), 5.76 (d, 1H), 3.77 (t, 2H), 2.77 (t, 2H), 0.82 (s, 9H), -0.036 (s, 6H). LCMS [M+H] 346.1.

[0443] Step 4: N-(1-(3-(2-((t-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-(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)pyrimidin-2(1H)-one (1.0 g, 2.9 mmol) in CH3CN (25 mL) was added 3-methyl-1-(4-(2,2,2-trifluoroacetyl)piperazine-1-carbonyl)-1H-imidazol-3-ium iodide (1.6 g, 3.7 mmol) at room temperature. The reaction mixture was heated at 85° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (2-3% MeOH:CH2Cl2) to give the title compound (2.0 g, 62%) as a brown sticky solid. LCMS [M+H] 554.03. Step 5: N-(1-(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide. To a stirred solution of N-(1-(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxamide (2.0 g, 3.6 mmol) in MeOH (50 mL) was added KCO (1.5 g, 10.8 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into HO (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.7 g, quantitative) as a brown sticky solid. 1 H NMR (400Mz, DMSO-d6): δ 7.73 (d, 1H), 7.38 (t, 1H), 7.28-7.24 (m, 3H), 6.71 (bs, 1H), 4.05-3.99 (m, 2H), 3.78 (t, 2H), 3.40-3.38 (m, 4H), 2.79 (t, 2H), 2.66-2.62 (m, 4H), 0.82 (s, 9H), -0.036 (s, 6H). LCMS [M+H] 458.21.

[0444] Step 6: t-butyl (1-(4-((1-(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of N-(1-(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide (1.7 g, 3.7 mmol) in DMF (10 mL) was added 2-((t-butoxycarbonyl)amino-2-methylpropanoic acid (0.75 g, 3.7 mmol) and DIPEA (1.44 g, 11.14 mL) at 0° C. and stirred for 10 min. HATU (2.8 g, 7.42 mL) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into HO (50 mL) and the resulting solid was filtered and dried to give the title compound (1.7 g, 70%) as a white solid. LCMS [M+H] 643.2.

[0445] Step 7: t-Butyl (1-(4-((1-(3-(2-hydroxyethyl)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-((1-(3-(2-((t-butyldimethylsilyl)oxy)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (1.7 g, 2.64 mmol) in THF (60 mL) was added TBAF (1 M in THF) (5.3 mL, 10.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.5 g, 72%) as an off-white solid. LCMS [M+H] 529.1.

[0446] Step 8: tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(3-(2-oxoethyl)phenyl)-1,2-dihydropyridin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate. To a stirred solution of t-butyl (1-(4-((1-(3-(2-hydroxyethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (0.2 g, 0.37 mmol) in DCE (20 mL) was added DMP (0.64 g, 1.51 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated NaHCO3 solution (30 mL) and extracted with DCE (2x20 mL). The combined organics were dried over Na2SO4 and filtered to give a solution of the title compound.

[0447] Intermediate 20 [ka] tert-Butyl N-(2-methyl-1-oxopropan-2-yl)carbamate. Scheme I-12 [ka] Reagents: DMP, CH2Cl2, 0℃ to rt. 1 hour Step 1: tert-Butyl N-(2-methyl-1-oxopropan-2-yl)carbamate. DMP (1.68 g, 3.97 mmol) was added portionwise to a solution of N-Boc-2-amino-2-methyl-1-propanol (500 mg, 2.64 mmol) in CHCl (16 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, warmed to room temperature, and stirred for 1 h. A 1:1 mixture of saturated NaSO:NaHCO was added, and the mixture was stirred vigorously for 20 min. The layers were separated, and the organic portion was washed twice with saturated aqueous NaHCO, dried (NaSO), filtered, and concentrated under reduced pressure to give the title compound (490 mg) as a white solid. 1H NMR (400MHz, CDCl3) δ 9.45 (s, 1H), 4.99 (br.s., 1H), 1.46 (s, 9H), 1.35 (s, 6H).

[0448] Intermediate 21 [ka] tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxobutyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate Scheme I-13 [ka] Reagents: Step 1) EDCI, TEA, DMAP, N,O-dimethylhydroxylamine HCl, CHCl, 0 °C to rt, 16 h. 2) EtMgBr, THF, -78 °C to rt, 3 h. 3) NaBH4, MeOH, 0°C to rt, 8 h; 4) TBDMSCl, imidazole, CHCl2, rt, 16 h; 5) n-BuLi, B(OiPr)3, THF, -78°C to rt, 2 h; 6) cytosine, TMEDA, Cu(OAc)2H2O, MeOH:H2O (4:1), O2, rt, 24 h; 7) 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide, CHCN, 90°C, 16 h; 8) TBAF, THF, 50°C, 16 h; 9) DMP, CHCl2, rt, 3 h. Step 1: 2-(4-Bromophenyl)-N-methoxy-N-methylacetamide. To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (17.1 g, 175.3 mmol) in CHCl (650 mL) was added TEA (23.3 mL, 175.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. 2-(4-Bromophenyl)acetic acid (25 g, 116.9 mmol), EDCI (24.63 g, 128.5 mmol), and DMAP (2.85 g, 23.4 mmol) were added to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (Hex:EtOAc, 1:1) to give the title compound (50.0 g, 83%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.49 (d, 2H), 7.19 (d, 2H), 3.72 (s, 2H), 3.68 (s, 3H), 3.10 (s, 3H). LCMS[M+H] 257.9

[0449] Step 2: 1-(4-Bromophenyl)butan-2-one. To a stirred solution of 2-(4-bromophenyl)-N-methoxy-N-methylacetamide (6.0 g, 23.4 mmol) in THF (150 mL) was added 3 M EtMgBr in EtO (77 mL, 233.5 mmol) at −78 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated NHCl solution (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organics were dried over NaSO, filtered, concentrated under reduced pressure, and purified by column chromatography (Hex:EtOAc, 85:15) to afford the title compound (2.5 g, 31%) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d6): δ 7.38-7.34 (m, 2H), 7.00 (d, 2H), 3.57 (s, 2H), 2.43-2.38 (m, 2H), 0.96 (t, 3H).

[0450] Step-3: 1-(4-Bromophenyl)butan-2-ol. To a stirred solution of 1-(4-bromophenyl)butan-2-one (13.5 g, 59.8 mmol) in MeOH (150 mL) was added NaBH (6.8 g, 179.3 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 8 h. The reaction mixture was poured into HO (50 mL) and extracted with CHCl (3 × 30 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (13.0 g, 96%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.46-7.42 (m, 2H), 7.16 (d, 2H), 4.38 (d, 1H), 3.53-3.49 (m, 1H), 2.65-2.53 (m, 1H), 1.40-1.24 (m, 2H), 0.86 (t, 3H).

[0451] Step 4: ((1-(4-Bromophenyl)butan-2-yl)oxy)(tert-butyl)dimethylsilane. To a stirred solution of 1-(4-bromophenyl)butan-2-ol (6.0 g, 26.3 mmol) in CHCl (120 mL) was added imidazole (7.16 g, 105.3 mmol) and TBSCl (15.9 g, 105.3 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 × 300 mL). The combined organics were dried over NaSO, filtered, concentrated under reduced pressure, and purified by column chromatography (Hex:EtOAc, 19:1) to afford the title compound (8.3 g, 93%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6): δ 7.45 (d, 2H), 7.14 (d, 2H), 3.78-3.75 (m, 1H), 2.71-2.54 (m, 2H), 1.41-1.36 (m, 2H), 0.86 (t, 3H), 0.72 (s, 9H), -0.07 (s, 3H), -0.26 (s, 3H).

[0452] Step 5: Diisopropyl (4-(2-((tert-butyldimethylsilyl)oxy)butyl)phenyl)boronate. To a stirred solution of ((1-(4-bromophenyl)butan-2-yl)oxy)(tert-butyl)dimethylsilane (5.0 g, 14.6 mmol) in THF (100 mL) at −78 °C was added 2.5 M n-BuLi in THF (30 mL, 73.1 mmol). The reaction mixture was stirred at −78 °C for 30 min. B(OiPr) (10.7 mL, 43.9 mmol) was added at −78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into NH4Cl solution (200 mL) and extracted with EtOAc (3 × 100 ml). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (11.0 g).

[0453] Step 6: 4-Amino-1-(4-(2-((tert-butyldimethylsilyl)oxy)butyl)phenyl)pyrimidin-2(1H)-one. A solution of diisopropyl(4-(2-((tert-butyldimethylsilyl)oxy)butyl)phenyl)boronate (11.0 g, 28.1 mmol) and cytosine (3.1 g, 28.1 mmol) in MeOH:HO (100 mL, 4:1) was stirred at room temperature under air for 30 min. TMEDA (4.2 mL, 30.9 mmol) and Cu(OAc)·HO (5.09 g, 28.1 mmol) were added, and the reaction mixture was stirred at room temperature under air for 48 h. The reaction mixture was concentrated under reduced pressure, and cold HO (50 mL) was added. The reaction was filtered and the solid was washed with H2O (5x50 mL) and hexanes (2x20 mL) to give the title compound (2.3 g, 31%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.54 (d, 1H), 7.26-7.20 (m, 6H), 5.77 (d, 1H), 3.81 (t, 1H), 2.75-2.64 (m, 2H), 1.42-1.33 (m, 2H), 0.87 (t, 3H), 0.82 (s, 9H), -0.02 (s, 3H), -0.15(s, 3H). LCMS[M+H] 374.2.

[0454] Step 7: 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-((tert-butyldimethylsilyl)oxy)butyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide. A stirred solution of 4-amino-1-(4-(2-((tert-butyldimethylsilyl)oxy)butyl)phenyl)pyrimidin-2(1H)-one (1.0 g, 2.7 mmol) and 1-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (2.0 g, 4.0 mmol) in CHCN (25 mL) was heated at 90° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (CH3CN:H2O, 80:20) to give the title compound (1.2 g, 60%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 7.61 (s, 1H), 7.31 (m, 5H), 6.92 (s, 1H), 6.32 (s, 1H), 3.95-3.8 (m, 1H), 3.57 (d, 9H), 2.81-2.70 (m, 2H), 2.53 (s, 1H), 1.61-1.44 (m, 3H), 1.38 (d, 15H), 0.91 (t, 3H), 0.86 (s, 9H), 0.01 (s, 3H), 0.10(s, 3H). LCMS[M+H] 671.2.

[0455] Step 8: tert-Butyl (1-(4-((1-(4-(2-hydroxybutyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. To a stirred solution of tert-butyl (1-(4-((1-(4-(2-((tert-butyldimethylsilyl)oxy)butyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (0.87 g, 1.3 mmol) in THF (40 mL) was added TBAF (1.0 M in THF) (1.42 mL, 1.4 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was poured into saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2:MeOH (9:1, 3 x 100 mL). The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (4-5% MeOH in CH2Cl2) to give the title compound (1.3 g, 60%) as an off-white solid. LCMS [M+H] 557.3.

[0456] Step 9: tert-Butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxobutyl)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-hydroxybutyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (0.25 g, 0.6 mmol) in CHCl (15 mL) was added DMP (3.81 g, 0.9 mmol) at 0° C. The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure at low temperature (35 °C) to give the title compound (0.22 g, 88%) as an off-white solid. LCMS [M+H] 555.

[0457] Intermediate 22 [ka] tert-Butyl ((2R)-2-(exo-3-azabicyclo[3.1.0]hexan-6-yl)-2-((tert-butylsulfinyl)amino)ethyl)carbamate. Scheme I-14 [ka] Reagents: Step 1) MsCl, EtN, CHCl, 0 °C–rt, 3 h; 2) NaN, DMF, 50 °C, 16 h; 3) PPh, THF:H0 (1:1), 60 °C, 16 h; 4) (Boc)O, TEA, CHCl, rt, 16 h; 5) 20 wt% Pd(OH), H, MeOH, rt, 16 h. Step 1: Benzyl exo-6-((1R)-1-((tert-butylsulfinyl)amino)-2-((methylsulfonyl)oxy)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of benzyl exo-6-((1R)-1-((tert-butylsulfinyl)amino)-2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.35 g, 0.92 mmol) and EtN (0.19 g, 1.84 mmol) in CHCl (15 mL) was added MsCl (0.16 g, 1.38 mmol) slowly dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with CHCl (15 mL), washed with saturated NaHCO, HO, brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the title compound (0.42 g, quantitative) as a colorless sticky solid.

[0458] Step 2: Benzyl exo-6-((1R)-2-azido-1-((tert-butylsulfinyl)amino)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of benzyl exo-6-((1R)-1-((tert-butylsulfinyl)amino)-2-((methylsulfonyl)oxy)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.42 g, 0.92 mmol) in CHCl (15 mL) was added NaN (0.15 g, 2.30 mmol) at room temperature and stirred at 60 °C for 16 h. The reaction mixture was quenched with saturated LiCl, and the compound was extracted with EtOAc (2 × 15 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (0.22 g, 60%) as a colorless solid.

[0459] Step 3: Benzyl exo-6-((1R)-2-amino-1-((tert-butylsulfinyl)amino)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of benzyl exo-6-((1R)-2-azido-1-((tert-butylsulfinyl)amino)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.22 g, 0.54 mmol) in THF:HO (2:1, 10 mL) at room temperature, PPh (0.22 g, 0.82 mmol) was added and stirred at 60 °C for 16 h. The reaction mixture was diluted with HO, and the compound was extracted with EtOAc (2 × 15 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the title compound (0.14 g, 68%) as a colorless sticky solid.

[0460] Step 4: Benzyl exo-6-((1R)-2-((tert-butoxycarbonyl)amino)-1-((tert-butylsulfinyl)amino)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of benzyl exo-6-((1R)-2-amino-1-((tert-butylsulfinyl)amino)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.14 g, 0.36 mmol) and EtN (0.11 g, 1.08 mmol) in CHCl (10 mL) at room temperature, BocO (0.12 g, 0.54 mmol) was added and stirred for 16 h. The reaction mixture was diluted with CHCl (15 mL), washed with saturated NaHCO, HO, brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (0.12 g, 70%) as a sticky solid.

[0461] Step 5: tert-Butyl ((2R)-2-(exo-3-azabicyclo[3.1.0]hexan-6-yl)-2-((tert-butylsulfinyl)amino)ethyl)carbamate. To a solution of benzyl exo-6-((1R)-2-((tert-butoxycarbonyl)amino)-1-((tert-butylsulfinyl)amino)ethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.12 g, 0.25 mmol) in degassed MeOH (15 mL) was added Pd(OH) / C (0.03 g, 20 wt%). The mixture was stirred under an H atmosphere for 16 h. The mixture was filtered through Celite®, and the filtrate was concentrated in vacuo to give the title compound (0.07 g, 82%) as a sticky solid.

[0462] Compound synthesis compound 3 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Scheme C-1 [ka] 1) 4-Formylphenylboronic acid, TMEDA, Cu(OAc)₂·H₂O, MeOH:H₂O, rt, 16 h; 2) tert-Butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate, NaBH(OAc)₃, DCE:CH₃CN, rt, 16 h; 3) 3-Methyl-1-(4-(2,2,2-trifluoroacetylpiperazine-1-carbonyl)-1H-imidazol-3-ium iodide, CH₃CN, 70 °C, 16 h; 4) K₂CO₃, MeOH, 2 h, rt; 5) Boc-α-methylalanine, HATU, DIPEA, CHCl₂, rt, 16 h; 6) HCl, MeOH, rt, 4 h. Step 1: 4-(4-Amino-2-oxopyrimidin-1(2H)-yl)benzaldehyde: A suspension of cytosine (2.60 g, 24.0 mmol) and 4-formylphenylboronic acid (3.53 g, 24.0 mmol) in MeOH:HO (4:1, 25 mL) was stirred at room temperature under air. After 30 min, TMEDA (6.70 mL, 28.0 mmol) and Cu(OAc)HO (4.70 g, 24.0 mmol) were added. The reaction was stirred at room temperature under air for 16 h. The MeOH was removed under reduced pressure, and ice was added to the remaining mixture, which was stirred for 10 min. The reaction was filtered, and the solid was washed with HO to give the title compound (3.5 g, 69%) as a white solid.

[0463] Step 2: tert-butyl (exo-3-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate: 4-(4-amino-2-oxopyrimidin-1(2H)-yl)benzaldehyde (1.00 g, 4.6 mmol) and tert-butyl ((exo)-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (1.39 g, 7.0 mmol) To a stirred suspension of (25 mL) of 1.61 mL of HCl in DCE:CHCN (1:1, 25 mL) was added DIPEA (1.61 mL, 9.20 mmol) and NaBH(OAc) (1.97 g, 9.30 mmol). The reaction was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure and the residue was dissolved in CHCl and washed with 10% NaOH. Purification by column chromatography (CHCl:MeOH) gave the title compound as a white solid (1.40 g, 76%).

[0464] Step 3: tert-butyl (exo-3-(4-(2-oxo-4-(4-(2,2,2-trifluoroacetyl)piperazine-1-carboxamido)pyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate: 3-methyl-1-(4-(2,2,2-trifluoroacetylpiperazine-1-carbonyl)-1H-imidazol-3-ium iodide (100 mg, 0.25 mmol) and tert-butyl (exo-3-(4-(4-amino-2-oxopyrimidine To a round-bottom flask containing (1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (112 mg, 0.28 mmol) was added dry CH3CN (12 mL). The reaction was heated to 85 °C for 8 h. The solvent was removed under reduced pressure, and the crude reaction mixture was partitioned between CHCl3 (50 mL) and HO (50 mL). The organic layer was separated and concentrated under reduced pressure. Purification by column chromatography (CHCl3:MeOH) afforded the title compound as an off-white solid (136 mg, 92%).

[0465] Step 4: tert-Butyl (exo-3-(4-(2-oxo-4-(piperazine-1-carboxamido)pyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate: To tert-butyl (exo-3-(4-(2-oxo-4-(4-(2,2,2-trifluoroacetyl)piperazine-1-carboxamido)pyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (135 mg, 0.23 mmol) and KCO (126 mg, 0.91 mmol) was added MeOH (5 mL) and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in HO. The aqueous phase was extracted with CHCl3 (3 x 20 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid (85 mg, 91%).

[0466] Step 5: tert-Butyl (exo-3-(4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate: To a suspension of Boc-α-methylalanine (52 mg, 0.26 mmol) in CHCl (2 mL) was added HATU (100 mg, 0.26 mmol), DIPEA (0.054 mL, 0.31 mmol). To this suspension was added solid tert-butyl (exo-3-(4-(2-oxo-4-(piperazine-1-carboxamido)pyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (85 mg, 0.26 mmol), and the mixture was stirred at room temperature for 16 h. The solution was diluted with CHCl (5 mL) and washed once with H0. The organic layer was concentrated under reduced pressure. Purification by column chromatography (CHCl:MeOH) afforded the title compound (140 mg, 80%) as a white solid.

[0467] Step 6: 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide: To tert-butyl (exo-3-(4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (100 mg, 0.14 mmol) was added a solution of HCl in MeOH (2 N, 15 mL) and stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure. Purification by column chromatography (CHCl3:MeOH:NH4OH / 8:2:0.2) afforded the title compound (65 mg, 76%) as a light yellow solid. 1 H NMR (500 MHz, CD3OD): δ 7.70 (d, 1H), 7.41 (d, 2H), 7.35 (d, 2H), 6.62 (d, 1H), 3.82 (s, 4H), 3.67 (s, 4H), 3.60 (s, 2H), 2.96 (d, 2H), 2.57 (s, 1H), 2.44 (d, 2H), 1.43 (s, 6H), 1.41-1.40 (m, 2H). LCMS[M+H] 495.3.

[0468] compound 2 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Prepared in a similar manner to Scheme C-1 from N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid. 1 H NMR (500 MHz, CD3OD): δ 8.40 (s, 1H), 7.92 (d, 2H), 7.53 (s, 1H), 7.51 (t, 1H), 6.89 (s, 1H), 4.60 (s, 2H), 3.89-3.72 (m, 12H), 2.59 (s, 3H), 2.39 (s, 2H), 1.74 (s, 6H). LCMS [M+H] 509.5.

[0469] compound 4 [ka] N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-((S)-2-amino-3-hydroxy-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride. Prepared in a similar manner to Scheme C-1 from N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and (2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carboxylic acid. 1H NMR (500 MHz, D2O) δ 8.06 (d, 1H), 7.70 (d, 2H), 7.59 (d, 2H), 6.86 (d, 1H), 4.95 (s, 2H), 4.18 (d, 1H), 3.93 (d, 1H), 3.90-3.60 (m, 12H), 2.95 (s, 1H), 2.46 (s, 2H), 1.71 (s, 3H). LCMS [M+H] 511.29.

[0470] compound 5 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-5-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Prepared in a similar manner to Scheme C-1 from N-(1-(3-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-5-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid. LCMS [M+H] 563.29.

[0471] compound 6 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Prepared in a similar manner to Scheme C-1 from tert-butyl (exo-3-(4-(2-oxo-4-(piperazine-1-carboxamido)pyrimidin-1(2H)-yl)-2-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid.

[0472] compound 9 [ka] N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(3-amino-3-methylbutanoyl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (exo-3-(4-(2-oxo-4-(piperazine-1-carboxamido)pyrimidin-1(2H)-yl)-2-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate and 3-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid. 1 H NMR (400 MHz, D2O) δ 7.91-7.61 (m, 4H), 6.71 (d, 1H), 4.53 (s, 2H), 3.74 (br. s., 2H), 3.55 (br.s, 8H), 3.46 (s, 2H), 2.93 (s, 1H), 2.70 (s, 2H), 2.33 (s, 2H), 1.27 (d, 6H). LCMS[M+H] 577.31.

[0473] compound 10 [ka] Ethyl 2-(4-(4-(4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)phenyl)-2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)acetate hydrochloride. Prepared in a similar manner to Scheme C-1 from ethyl 2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(2-oxo-4-(piperazine-1-carboxamido)pyrimidin-1(2H)-yl)phenyl)acetate and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid. 1 H NMR (500 MHz, CD3OD): δ 8.18 (s, 1H), 7.73 (d, 2H), 7.64 (d, 2H), 6.74 (s, 1H), 5.45 (s, 1H), 4.30-4.15 (m, 2H), 3.77-3.62 (m, 8H), 2.33 (s, 2H), 1.65 (s, 6H), 1.16-1.12 (m, 3H). LCMS [M+H] 567.4.

[0474] compound 12 [ka] 2-(4-(4-(4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)phenyl)-2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)acetic acid hydrochloride. Prepared in a similar manner to Scheme C-1 from ethyl 2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(2-oxo-4-(piperazine-1-carboxamido)pyrimidin-1(2H)-yl)phenyl)acetate and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid. 1H NMR (500 MHz, CD3OD): δ 8.44 (s, 1H), 7.86 (s, 2H), 7.74 (s, 2H), 6.93 (s, 1H), 5.52 (s, 1H), 3.87-3.72 (m, 8H), 3.34 (s, 5H), 2.43 (s, 2H), 1.71 (s, 6H). LCMS [M+H] 539.3.

[0475] compound 31 [ka] (R)-4-(2-amino-2-methylpropanoyl)-N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-3-methylpiperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (exo-3-(4-(4-((R)-3-methylpiperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid. 1 H NMR (400 MHz, D2O) δ 8.09 (d, 1H), 7.70 (d, 2H), 7.59 (d, 2H), 6.81 (d, 1H), 4.50 (s, 2H), 4.18 (s, 1H), 4.03 (s, 2H), 3.74 (s, LCMS [M+H]: 509.2.

[0476] compound 45 [ka] (R)-N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-((S)-2-amino-3-hydroxy-2-methylpropanoyl)-3-methylpiperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-1 from tert-butyl (exo-3-(4-(4-((R)-3-methylpiperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate and (2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4-carboxylic acid. 1 H NMR (400 MHz, D2O) δ 7.94 (d, 1H), 7.68 (d, 2H), 7.57 (d, 2H), 6.87 (d, 1H), 4.48 (s, 2H), 4.25-4.10 (m, 3H), 4.03 (s, 1H), 3.93 LCMS [M+H] 525.1.

[0477] Compound 111 [ka] N-(1-(4-(2-(5-amino-2-azaspiro[3.3]heptan-2-yl)propyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride Scheme C-2 [ka] Reagents: 1) tert-butyl (2-azaspiro[3.3]heptan-5-yl)carbamate, NaH(OAc) 3 , DIPEA, DCE, rt, 4 h 2) 2N HCl in MeOH, rt, 16 h. Step 1: t-Butyl (2-(1-(4-(4-(4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)phenyl)propan-2-yl)-2-azaspiro[3.3]heptan-5-yl)carbamate. To a stirred solution of t-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 (0.23 g, 0.42 mmol) and t-butyl (2-azaspiro[3.3]heptan-5-yl)carbamate (0.108 g, 0.51 mmol) in DCE (5.0 mL) was added DIPEA (0.2 mL, 1.27 mmol) and NaBH(OAc) (0.180 g, 0.85 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured into 1 N NaOH (2.0 mL) and extracted with CHCl (3 × 50 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (5-7% MeOH in CHCl) to give the title compound as a solid (0.12 g, 38%). Alternatively, this reaction can be carried out using NaBHCN (1.5 equiv.) in MeOH. LCMS [M+H] 736.9.

[0478] Step 2: N-(1-(4-(2-(5-amino-2-azaspiro[3.3]heptan-2-yl)propyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride. To a stirred solution of t-butyl (2-(1-(4-(4-(4-(2-((t-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)phenyl)propan-2-yl)-2-azaspiro[3.3]heptan-5-yl)carbamate (0.12 g, 0.16 mmol) in MeOH (3.0 mL) was added 4 M HCl in dioxane (8.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and triturated with EtO (10 mL). The resulting solid was purified by preparative HPLC to afford the title compound (0.027 g, 25%) as an off-white solid. 1 H NMR (400 MHz, D2O): rotamer mixture, δ 7.78-7.75 (m, 1H), 7.36-7.29 (m, 4H), 6.72-6.70 (m, 1H), 4.25-3.96 (m, 4H), 3.92-3.88 (m, 1H), 3.80-3.73 (m, 1H), 3.63-3.48 (m, 8H), 2.99-2.91 (m, 1H), 2.78-2.68 (m, 1H), 2.28-2.12 (m, 3H), 1.93-1.85 (m, 1H), 1.59 (s, 6H), 1.10-1.04 (m, 3H).LCMS [(M+2H) / 2] 269.0.

[0479] compound 112 [ka] N-(1-(4-(2-(6-amino-2-azaspiro[3.3]heptan-2-yl)propyl)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-2 from t-butyl N-(2-azaspiro[3.3]heptan-6-yl)carbamate and t-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. 1 H NMR (400 MHz, D2O): rotamer mixture, δ 7.82 (dd, 1H), 7.33-7.28 (m, 4H), 6.69 (d, 1H), 4.19-3.93 (m, 5H), 3.69-3.50 (m, 9H), 2.96-2.90 (m, 1H), 2.73-2.64 (m, 2H), 2.54-2.25 (m, 3H), 1.59 (s, 6H), 1.05-1.02 (m, 3H). LCMS [(M+2H) / 2] 269.0.

[0480] compound 98 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)propyl)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-oxopropyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl exo-3-azabicyclo[3.1.0]hexan-6-ylcarbamate. 1H NMR (400 MHz, D2O) δ 7.95 (d, 1H), 7.44-7.37 (m, 4H), 6.78 (d, 1H), 3.94 (d, 1H), 3.88 (d, 1H), 3.78-3.59 (m 10H), 3.30 (s, 1H), 2.80 (t, 2H), 2.38 (s, 2H), 1.68 (s, 7H), 1.21 (d, 3H). LCMS [M+H] 523.3.

[0481] compound 162 [ka] N-(1-(4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)propyl)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-2 using t-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride and t-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. 1H NMR (400 MHz, D2O): rotamer mixture, δ 7.76 (d, 1H), 7.33-7.31 (m, 4H), 6.71 (d, 1H), 4.63-4.34 (m, 2H), 4.32 (s, 2H), 4.20 (s, 2H), 4.19 (s, 2H), 3.63-3.57 (m, 8H), 2.97-2.92 (m, 1H), 2.75-2.70 (m, 1H), 1.59 (s, 6H), 1.06 (d, 3H). LCMS [(M+2H) / 2] 263.3.

[0482] compound 163 [ka] N-(1-(4-(2-(2,7-diazaspiro[3.5]nonan-7-yl)propyl)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-2 using t-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate and t-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. 1 H NMR (400 MHz, D2O): rotamer mixture, δ 7.72 (d, 1H), 7.32-7.26 (m, 4H), 6.70 (d, 1H), 3.94 (s, 2H), 3.83 (s, 2H), 3.62-3.56 (m, 9H), 3.44 (t, 3H), 3.19-3.15 (m, 2H), 3.01 (t, 3H), 2.78-2.72 (m, 2H), 2.27 (d, 3H), 1.96 (t, 3H), 1.58 (s, 6H), 1.09 (d, 3H). LCMS [(M+2H) / 2] 276.1.

[0483] compound 85 [ka] N-(1-(4-(2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-((S)-2-amino-3-hydroxy-2-methylpropanoyl)piperazine-1-carboxamide trifluoroacetate The title compound was prepared in a similar manner to Scheme C-2 from tert-butyl (2S,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 and tert-butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.90 (d, 1H), 7.52 (d, 2H), 7.47 (d, 2H), 6.89 (d, 1H), 4.20 (d, 1H), 4.00-3.92 (m, 3H), 3.84-3.73 (m, 8H), 3.65-3.55 (m, 4H), 3.17 (t, 2H) 2.87 (s, 1H), 2.47 (s, 2H), 1.73 (s, 3H). LCMS [M+H] 525.4.

[0484] compound 86 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-(2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-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-(3-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1H NMR (500 MHz, D2O) δ 8.05 (d, 1H), 7.63 (t, 1H), 7.52 (d, 1H), 7.46-7.42 (m, 2H), 6.88 (d, 1H), 3.99-3.94 (m, 2H), 3.86-3.75 (m, LCMS [M+H] 509.4.

[0485] compound 89 [ka] N-(1-(3-(2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-((S)-2-amino-3-hydroxy-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from tert-butyl (2S,4S)-2-(tert-butyl)-4-methyl-4-(4-((2-oxo-1-(3-(2-oxoethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)oxazolidine-3-carboxylate and tert-butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.89 (d, 1H), 7.59 (t, 1H), 7.47 (d, 1H), 7.40-7.37 (m, 2H), 6.87 (d, 1H), 4.17 (d, 1H), 3.92 (d, 3H), 3.83-3.72 (m, 10H), 3.13 (t, 4H), 2.82 (s, 1H), 2.43 (s, 2H), 1.70 (s, 3H). LCMS [M+H] 525.4.

[0486] compound 90 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(endo-6-amino-3-azabicyclo[3.1.0]hexan-3-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 tert-butyl (endo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR (500 MHz, D2O) δ 8.00 (d, 1H), 7.49 (d, 2H), 7.45 (d, 2H), 6.83 (d, 1H), 3.94 (d, 1H), 3.85-3.72 (m, 8H), 3.63-3.54 (m, 4H), 3.20-3.01 (m, 3H), 2.84 (s, 1H), 2.42 (s, 2H), 1.75 (s, 6H). LCMS [M+H] 509.3.

[0487] compound 91 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-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 tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate. 1H NMR (500 MHz, D2O) δ 7.94 (d, 1H), 7.50 (d, 2H), 7.44 (d, 2H), 6.85 (d, 1H), 3.92-3.86 (m, 1H), 3.83-3.68 (m, 8H), 3.64-3.52 (m, 2H), 3.44 (t, 2H), 3.18 (t, 2H), 3.13-2.97 (m, 2H), 2.56-2.47 (m, 2H), 2.37-2.29 (m, 2H), 2.15-2.00 (m, 2H), 1.94-1.84 (m, 2H), 1.75 (s, 6H).LCMS [M+H] 551.3.

[0488] compound 92 [ka] N-(1-(4-(2-(6-amino-2-azaspiro[3.3]heptan-2-yl)ethyl)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-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 tert-butyl (2-azaspiro[3.3]heptan-6-yl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.93 (d, 1H), 7.46 (d, 2H), 7.42 (d, 2H), 6.83 (d, 1H), 4.32 (d, 1H), 4.24-4.10 (m, 3H), 3.82-3.69 (m, 8H), 3.54 (t, 2H), 3.01 (t, 2H), 2.81-2.65 (m, 3H), 2.53-2.42 (m, 2H), 1.72 (s, 6H) LCMS [M+H] 523.4.

[0489] compound 93 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-amino-3-azabicyclo[4.1.0]heptan-3-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 tert-butyl (3-azabicyclo[4.1.0]heptan-1-yl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.89 (d, 1H), 7.46 (d, 2H), 7.40 (d, 2H), 6.81 (d, 1H), 3.79-3.65 (m, 8H), 3.64-3.49 (m, 2H), 3.45-3.34 (m, 1H), 3.19-3.08 (m, 2H), 2.93-2.84 (m, 1H), 2.63-2.41 (m, 3H), 1.85-1.78 (m, 1H), 1.71 (s, 6H) LCMS [M+H] 523.2.

[0490] compound 94 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-amino-6-azaspiro[2.5]octan-6-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 tert-butyl 6-azaspiro[2.5]octan-1-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 7.89 (d, 1H), 7.52 (d, 2H), 7.45 (d, 2H), 6.86 (d, 1H), 3.79 (s, 2H), 3.73 (s, 7H), 3.52 (t, 2H), 3.31-3.15 LCMS [M+H] 537.2.

[0491] compound 95 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-amino-7-azaspiro[3.5]nonan-7-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 2,2,2-trifluoro-N-(7-azaspiro[3.5]nonan-1-yl)acetamide trifluoroacetate. 1H NMR (400 MHz, D2O) δ 7.89 (d, 1H), 7.50 (d, 2H), 7.44 (d, 2H), 6.86 (d, 1H), 3.78 (s, 3H), 3.71 (d, 7H), 3.58 (d, 1H), 3.50-3.42 (m, 2H), 3.19 (d, 3H), 3.02 (s, 1H), 2.38 (d, 1H), 2.25-1.83 (m, 7H), 1.75 (s, 6H). LCMS [M+H] 551.2.

[0492] compound 96 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(6-amino-3-azabicyclo[3.2.0]heptan-3-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 tert-butyl 3-azabicyclo[3.2.0]heptan-6-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 8.00 (d, 1H), 7.55 (d, 2H), 7.47 (d, 2H), 6.84 (d, 1H), 4.18-3.94 (m, 2H), 3.93-3.48 (m, 12 H), 3.38-3.13 (m, 4H), 2.73 (s, 1H), 2.04-1.93 (m, 1H), 1.73 (s, 6H), 1.71 (d, 1H). LCMS [M+H] 523.2.

[0493] compound 97 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(1-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)propan-2-yl)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-(1-oxopropan-2-yl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl (endo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.95 (d, 1H), 7.53 (d, 2H), 7.46 (d, 2H), 6.82 (d, 1H), 3.82-3.69 (m, 8H), 3.68-3.48 (m, 4H), 3.44-3.23 (m, LCMS [M+H] 523.3.

[0494] compound 99 [ka] N-(1-(4-(2-(1-amino-3-azabicyclo[4.1.0]heptan-3-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-((R)-2-amino-3-hydroxy-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride. Prepared in a similar manner to Scheme C-2 from tert-butyl (2S,4R)-4-(4-((1-(4-((6-((tert-butoxycarbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-2-(tert-butyl)-4-methyloxazolidine-3-carboxylate and tert-butyl (3-azabicyclo[4.1.0]heptan-1-yl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.90 (d, 1H), 7.50 (d, 2H), 7.44 (d, 2H), 6.83 (d, 1H), 4.16 (d, 1H), 3.90 (d, 1H), 3.82-3.67 (m, 8H), 3.66-3.34 (m, 4H), 3.19 (t, 2H), 2.97-2.83 (m, 2H), 2.67-2.45 (m, 3H), 1.90-1.80 (m, 2H), 1.68 (s, 3H). LCMS [M+H] 539.2.

[0495] compound 100 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-amino-3-azabicyclo[4.1.0]heptan-3-yl)ethyl)-3-fluorophenyl)-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-(3-fluoro-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and t-butyl (3-azabicyclo[4.1.0]heptan-1-yl)carbamate. 1H NMR 7.88 (d, 1H), 7.51 (t, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 6.84 (d, 1H), 4.18-4.07 (m, 1H), 3.81-3.68 (m, 8H), 3.46-3.37 (m, 2H), 3.20 (t, 2H), 3.17-3.06 (m, 1H), 2.97-2.87 (m, 1H), 2.67-2.57 (m, 1H), 2.54-2.45 (m, 1H), 1.89-1.82 (m, 1H), 1.73 (s, 6H), 1.48 (t, 1H), 1.32-1.20 (m, 1H). LCMS [M+H] 541.3.

[0496] Compound 101 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-amino-3-azabicyclo[4.1.0]heptan-3-yl)ethyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (2-methyl-1-(4-((1-(3-methyl-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate and t-butyl (3-azabicyclo[4.1.0]heptan-1-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.98 (d, 1H), 7.37 (d, 1H), 7.29 (s, 1H), 7.24 (d, 1H), 6.77 (d, 1H), 4.21-4.08 (m, 1H), 3.86-3.58 (m, 9H), 3.44 (s, 1H), 3.30 (d, 2H), 3.18-3.07 (m, 2H), 2.96-2.82 (m, 1H), 2.60 (d, 1H), 2.55-2.40 (m, 1H), 2.36 (s, 3H), 1.89-1.79 (m, 1H), 1.70 (s, 6H), 1.46 (t, 1H), 1.22 (t, 1H). LCMS[M+H] 537.2.

[0497] Compound 102 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)-3-(trifluoromethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and t-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1H NMR (400 MHz, D2O) δ 7.90 (d, 1H), 7.84 (s, 1H), 7.70-7.60 (m, 2H), 6.81 (d, 1H), 3.88 (d, 2H), 3.74 (s, 2H), 3.69 (s, 6H), 3.48 (t, 4H), 3.30-3.21 (m, 2H), 2.96 (d, 2H), 2.00 (s, 2H), 1.70 (s, 6H), 1.40-1.32 (m, 1H). LCMS[M+H] 591.3

[0498] compound 103 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-amino-3-azabicyclo[4.1.0]heptan-3-yl)ethyl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)-3-(trifluoromethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and t-butyl (3-azabicyclo[4.1.0]heptan-1-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.87 (d, 2H), 7.70-7.61 (m, 2H), 6.83 (d, 1H), 4.15 (s, 1H), 3.74 (s, 2H), 3.69 (s, 7H), 3.32 (s, 3H), 3.15 LCMS[M+H] 591.4

[0499] Compound 104 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(endo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-methoxyphenyl)-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-(3-methoxy-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (endo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR 8.07 (d, 1H), 7.37 (d, 1H), 7.10 (s, 1H), 7.01 (d, 1H), 6.78 (d, 1H), 3.91 (d, 1H), 3.86 (s, 3H), 3.81-3.68 (m, 8H), 3.58-3.43 (m, 4H), 3.10-3.00 (m, 3H), 2.80 (s, 1H), 2.48-2.37 (m, 2H), 1.71 (s, 6H). LCMS [M+H] 539.3.

[0500] compound 116 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-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 tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1 H NMR (500 MHz, D2O) δ 8.10 (d, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 6.85 (d, 1H), 3.88 (d, 1H), 3.82-3.77 (m, 8H), 3.57-3.48 (m, 4H), 3.17 (t, 2H), 3.04-2.98 (m, 2H), 2.05 (s, 2H), 1.77 (s, 6H), 1.41-1.35 (m, 2H). LCMS[M+H] 523.28

[0501] Compound 117 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-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 tert-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1H NMR (400 MHz, D2O) δ 8.18 (d, 1H), 7.56 (d, 2H), 7.51 (d, 2H), 6.85 (d, 1H), 4.00 (d, 1H), 3.88-3.75 (m, 8H), 3.65-3.53 (m, 5H), 3.23-3.16 (m, 3H), 2.11-2.06 (m, 1H), 1.79 (s, 6H), 1.40-1.37 (m, 1H), 1.20 (t, 1H), 1.09 (t, 1H). LCMS [M+H] 523.3.

[0502] compound 118 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(1-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropan-2-yl)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-(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 and tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1 H NMR (500 MHz, D2O) δ 8.11 (d, 1H), 7.67 (d, 2H), 7.50 (d, 2H), 6.79 (d, 1H), 3.82-3.71 (m, 8H), 3.65 (s, 2H), 3.55-3.48 (m, 2H), 3.16 (d, 1H), 2.85 (t, 2H), 2.73-2.65 (m, 1H), 1.92-1.88 (m, 1H), 1.83-1.79 (m, 2H), 1.71 (s, 6H), 1.47 (s, 6H) LCMS [M+H] 551.2.

[0503] Compound 119 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(1-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropan-2-yl)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-(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 and tert-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1 H NMR (500 MHz, D2O) δ 8.03 (d, 1H), 7.67 (d, 2H), 7.49 (d, 2H), 6.82 (d, 1H), 3.81-3.65 (m, 12H), 3.57 (s, 1H), 3.45 (d, 1H), 3.21 (t, 1H), 2.98 (d, 1H), 1.84-1.78 (m, 1H), 1.71 (s, 6H), 1.48 (s, 6H) LCMS [M+H] 551.2.

[0504] compound 120 [ka] 4-((R)-2-Amino-3-hydroxy-2-methylpropanoyl)-N-(1-(4-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-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 (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 and tert-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1 H NMR (500 MHz, D2O) δ 8.08 (d, 1H), 7.48 (d, 2H), 7.44 (d, 2H), 6.79 (d, 1H), 4.14 (d, 1H), 3.96-3.87 (m, 2H), 3.82-3.70 (m, 8H), 3.59-3.45 (m, 5H), 3.17-3.09 (m, 3H), 2.04-1.99 (m, 1H), 1.67 (s, 3H), 1.34-1.31 (m, 1H), 1.14 (t, 1H), 1.02 (t, 1H) LCMS [M+H] 539.3.

[0505] compound 121 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(1-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)propan-2-yl)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-(1-oxopropan-2-yl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and tert-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1H NMR (500 MHz, D2O) δ 8.08 (d, 1H), 7.55 (d, 2H), 7.48 (d, 2H), 6.81 (d, 1H), 3.84-3.71 (m, 8H), 3.60-3.48 (m, 4H), 3.34-3.26 (m, 2H), 2.91 (d, 2H), 2.03-1.89 (m, 3H), 1.73 (s, 6H), 1.35-1.26 (m, 4H) LCMS [M+H] 537.2.

[0506] compound 123 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-fluorophenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from 4-(2-amino-2-methylpropanoyl)-N-(1-(3-fluoro-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and t-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1 H NMR 7.97 (d, 1H), 7.52 (t, 1H), 7.33 (d, 1H), 7.28 (d, 1H), 6.82 (d, 1H), 3.97 (d, 2H), 3.83 (d, 2H), 3.81-3.67 (m, 8H), 3.59-3.54 (m, 2H), 3.50 (t, 2H), 3.23-3.10 (m, 2H), 1.73 (s, 6H), 1.12 (t, 1H), 1.00 (t, 1H), 0.89 (t, 1H). LCMS [M+H] 541.3.

[0507] compound 126 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (2-methyl-1-(4-((1-(3-methyl-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate and t-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.98 (d, 1H), 7.36 (d, 1H), 7.29 (s, 1H), 7.24 (d, 1H), 6.77 (d, 1H), 3.86 (d, 2H), 3.75 (s, 2H), 3.71 (s, 6H), 3.49 (d, 2H), 3.46-3.38 (m, 2H), 3.12-3.05 (m, 2H), 2.96 (d, 2H), 2.35 (s, 3H), 2.00 (s, 2H), 1.70 (s, 6H), 1.39-1.29 (m, 1H).LCMS[M+H]537.4

[0508] compound 127 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-fluorophenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from 4-(2-amino-2-methylpropanoyl)-N-(1-(3-fluoro-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and t-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1 H NMR 7.86 (d, 1H), 7.50 (t, 1H), 7.30 (d, 1H), 7.26 (d, 1H), 6.84 (d, 1H), 3.86 (d, 2H), 3.81-3.66 (m, 8H), 3.54-3.48 (m, 4H), 3.17 (t, 2H), 3.00-2.95 (m, 2H), 2.13-1.97 (m, 2H), 1.73 (s, 6H), 1.38-1.29 (m, 1H). LCMS [M+H] 541.3.

[0509] compound 128 [ka] 4-((S)-2-Amino-3-hydroxy-2-methylpropanoyl)-N-(1-(4-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from 4-((2R,4S)-2-(t-butyl)-4-methyloxazolidine-4-carbonyl)-N-(1-(3-methyl-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and t-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1H NMR (400 MHz, d2o) δ 7.89 (d, 1H), 7.36 (d, 1H), 7.28 (s, 1H), 7.23 (d, 1H), 6.79 (d, 1H), 4.13 (d, 1H), 3.96 (d, 1H), 3.87 (d, 1H), 3.83 (d, 1H), 3.76 (s, 4H), 3.70 (s, 4H), 3.57-3.41 (m, 5H), 3.15-3.06 (m, 3H), 2.35 (s, 3H), 2.05-1.98 (m, 1H), 1.65 (s, 3H), 1.18-0.99 (m, 2H). LCMS [M+H] 553.3.

[0510] compound 129 [ka] 4-((S)-2-Amino-3-hydroxy-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from 4-((2R,4S)-2-(t-butyl)-4-methyloxazolidine-4-carbonyl)-N-(1-(3-methyl-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and t-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. LCMS [M+H] 553.1.

[0511] compound 130 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (2-methyl-1-(4-((1-(3-methyl-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate and t-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.93 (d, 1H), 7.36 (d, 1H), 7.28 (s, 1H), 7.23 (d, 1H), 6.78 (d, 1H), 3.96 (d, 1H), 3.82 (d, 1H), 3.75 (s, 2H), 3.70 (s, 6H), 3.57-3.41 (m, 5H), 3.17-3.03 (m, 3H), 2.35 (s, 3H), 2.06-1.97 (m, 1H), 1.69 (s, 6H), 1.13 (t, 1H), 1.03 (d, 1H). LCMS[M+H] 537.4.

[0512] compound 131 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (2-methyl-1-oxo-1-(4-((2-oxo-1-(4-(2-oxoethyl)-3-(trifluoromethyl)phenyl)-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)propan-2-yl)carbamate and t-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.94-7.89 (m, 1H), 7.84 (s, 1H), 7.71-7.60 (m, 2H), 6.81 (d, 1H), 3.98 (d, 1H), 3.84 (d, 1H), 3.74 (s, 2H), 3.69 (s, 6H), 3.59-3.44 (m, 5H), 3.32-3.22 (m, 3H), 3.11 (d, 1H), 2.01 (s, 1H), 1.69 (s, 6H), 1.67 (s, 1H). LCMS[M+H] 591.4.

[0513] compound 132 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-methoxyphenyl)-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-(3-methoxy-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and t-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1H NMR 8.03 (d, 1H), 7.38 (d, 1H), 7.10 (s, 1H), 7.01 (d, 1H), 6.79 (d, 1H), 3.86 (s, 3H), 3.85-3.80 (m, 2H), 3.80-3.68 (m, 8H), 3.48-3.41 (m, 3H), 3.07 (t, 2H), 2.98-2.91 (m, 3H), 2.01-1.95 (m, 2H), 1.72 (s, 6H), 1.35-1.29 (m, 1H). LCMS [M+H] 553.3.

[0514] compound 133 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)-3-methoxyphenyl)-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-(3-methoxy-4-(2-oxoethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and t-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1 H NMR 8.03 (d, 1H), 7.39 (d, 1H), 7.11 (s, 1H), 7.02 (d, 1H), 6.80 (d, 1H), 3.94 (d, 1H), 3.87 (s, 3H), 3.82-3.70 (m, 9H), 3.53-3.44 (m, 5H), 3.12-3.05 (m, 3H), 2.03-1.98 (m, 1H), 1.72 (s, 6H), 1.13 (t, 1H), 1.01 (t, 1H). LCMS [M+H] 553.3.

[0515] compound 84 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-amino-3-azabicyclo[3.1.0]hexan-3-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 tert-butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR (500 MHz, D2O) δ 7.97 (d, 1H), 7.47 (d, 2H), 7.42 (d, 2H), 6.81 (d, 1H), 3.91 (d, 2H), 3.80-3.66 (m, 8H), 3.60-3.50 (m, 4H), 3.14-3.10 (m, 2H), 2.82 (s, 1H), 2.39 (s, 2H), 1.71 (s, 6H). LCMS [M+H] 509.5.

[0516] compound 152 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-(exo-6-((S)-1-aminopropyl)-3-azabicyclo[3.1.0]hexan-3-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 tert-butyl ((S)-1-(exo-3-azabicyclo[3.1.0]hexan-6-yl)propyl)carbamate. LCMS [M+H] 551.2.

[0517] compound 158 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(3-(2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide trifluoroacetate Prepared in a similar manner to Scheme C-2 from 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 and tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. 1 H NMR (500 MHz, D2O) δ 8.02 (d, 1H), 7.61 (t, 1H), 7.51 (d, 1H), 7.44 (s, 1H), 7.41 (d, 1H), 6.85 (d, 1H), 4.14-4.02 (m, 1H), 3.86-3.71 (m, 10H), 3.66-3.38 (m, 8H), 3.19 (t, 2H), 3.09 (bs, 1H), 1.75 (s, 6H). LCMS [M+H] 523.2.

[0518] Compound 159 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-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 tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. 1 H NMR (500 MHz, D2O) δ 8.24 (d, 1H), 7.54 (d, 2H), 7.48 (d, 2H), 6.79 (d, 1H), 4.09-4.05 (m, 1H), 3.83-3.73 (m, 10H), 3.65-3.58 (m LCMS [M+H] 523.4.

[0519] compound 160 [ka] N-(1-(4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)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-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 tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. 1H NMR (500 MHz, D2O) δ 7.95 (d, 1H), 7.47 (d, 2H), 7.44 (d, 2H), 6.83 (d, 1H), 4.52 (s, 1H), 4.49 (s, 1H), 4.42-4.33 (m, 6H), 3.80-3.68 (m, 8H), 3.57 (t, 2H), 3.03 (t, 2H), 1.73 (s, 6H). LCMS [M+H] 509.3.

[0520] compound 161 [ka] N-(1-(4-(2-(2,7-diazaspiro[4.4]nonan-2-yl)ethyl)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-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 tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate. 1 H NMR (500 MHz, D2O) δ 7.98 (d, 1H), 7.50 (d, 2H), 7.44 (d, 2H), 6.82 (d, 1H), 3.87-3.69 (m, 10H), 3.64-3.57 (m, 3H), 3.52-3.45 (m, 2H), 3.43-3.35 (m, 2H), 3.21-3.12 (m, 4H), 2.37-2.12 (m, 3H), 1.73 (s, 6H). LCMS [M+H] 537.4.

[0521] compound 173 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(((3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)amino)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 t-butyl ((3-aminobicyclo[1.1.1]pentan-1-yl)methyl)carbamate. 1 H NMR (400Mz, D2O): δ 7.80 (d, 1H), 7.47 (d, 2H), 7.37 (d, 2H), 6.68 (d, 2H), 4.16 (s, 2H), 3.75-3.51 (m, 8H), 3.15 (s, 2H), 2.08 (s, 6H), 1.56 (s, 6H). LCMS [M+H] 509.2.

[0522] compound 14 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((endo-6-amino-3-azabicyclo[3.1.0]hexan-3-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 tert-butyl (endo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1H NMR (400 MHz, CD3OD) δ 8.35 (d, 1H), 7.88 (d, 2H), 7.65 (d, 2H), 6.86 (d, 1H), 4.52 (s, 2H), 3.78 (br. s, 8H), 3.75-3.63 (m, 3H), 3.37 (d, 2H), 2.36 (s, 2H), 1.72 (d 6H). 1 H NMR (500 MHz, D2O) δ 7.86 (d, 1 H), 7.55 (d, 2 H), 7.44 (d, 2 H), 6.72 (d, 1 H), 4.28 - 4.40 (m, 2 H), 3.42 - 3.84 (m, 12 H), 2.71 - 2.83 (m, 1 H), 2.24 - 2.35 (m, 2 H), 1.60 (s, 6 H). LCMS[M+H] 495.2

[0523] compound 46 [ka] N-(1-(4-((2,6-diazaspiro[3.3]heptan-2-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-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 tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. 1 H NMR (500 MHz, D2O) δ 7.96 (d, 1H), 7.63 (d, 2H), 7.56 (d, 2H), 6.84 (d, 1H), 4.53-4.48 (m, 4H), 4.45 (d, 4H), 4.37 (s, 2H), 3.82-3.68 (m, 8H), 1.73 (s, 6H). LCMS [M+H] 495.3.

[0524] compound 79 [ka] N-(1-(4-(((1S,5S)-3,6-diazabicyclo[3.2.0]heptan-3-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-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 tert-butyl (1R,5S)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate. 1 H NMR (500 MHz, D2O) δ 8.04 (d, 1H), 7.78 (d, 2H), 7.61 (d, 2H), 6.85 (d, 1H), 5.25 (t, 1H), 4.74 (d, 1H), 4.63 (d, 1H), 4.37 (t, LCMS [M+H] 495.3.

[0525] compound 80 [ka] N-(1-(4-((2,7-diazaspiro[4.4]nonan-2-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-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 tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate. 1 H NMR (500 MHz, D2O) δ 8.00 (d, 1H), 7.70 (d, 2H), 7.57 (d, 2H), 6.84 (d, 1H), 4.55 (s 2H), 3.83-3.60 (m, 8H), 3.58-3.35 (m, 6H), 2.40-2.13 (m, 4H), 1.73 (s, 6H). LCMS [M+H] 522.3.

[0526] compound 33 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((2-amino-7-azaspiro[3.5]nonan-7-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 tert-butyl 7-azaspiro[3.5]nonan-2-ylcarbamate. 1H NMR (400 MHz, D2O) δ 8.08 (d, 1H), 7.69 (d, 2H), 7.59 (d, 2H), 6.85 (d, 1H), 4.39 (s, 2H), 3.92-3.84 (m, 1H), 3.80 (s, 2H), 3.76 LCMS [M+H] 537.2.

[0527] compound 34 [ka] N-(1-(4-((6-amino-2-azaspiro[3.3]heptan-2-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-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 tert-butyl 2-azaspiro[3.3]heptan-6-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 8.02 (d, 1H), 7.64 (d, 2H), 7.58 (d, 2H), 6.86 (d, 1H), 4.46 (s, 2H), 4.32 (d, 4H), 4.22 (d, 1H), 3.88-3.62 (m, 8H), 2.87-2.69 (m, 2H), 2.58-2.47 (m, 2H), 1.75 (s, 6H). LCMS [M+H] 509.1.

[0528] compound 38 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((1-amino-7-azaspiro[3.5]nonan-7-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 tert-butyl (7-azaspiro[3.5]nonan-1-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 7.90 (d, 3H), 7.68 (d, 2H), 7.57 (d, 2H), 6.89 (d, , 1H), 4.41 (s, 2H), 3.78 (s, 2H), 3.71 (s, 6H), 3.65-3.45 (m, 2H), 3.26-3.16 (m, 1H), 3.11-3.01 (m, 1H), 2.45-2.34 (m, 1H), 2.24 (s, 1H), 2.21-1.78 (m, 7H), 1.74 (d, 6H). LCMS [M+H] 537.2.

[0529] compound 39 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((1-amino-6-azaspiro[2.5]octan-6-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 tert-butyl 6-azaspiro[2.5]octan-1-ylcarbamate. 1H NMR (400 MHz, D2O) δ 7.96 (d, 1H), 7.71 (d, 2H), 7.59 (d, 2H), 6.86 (d, 1H), 4.46 (s, 2H), 3.79 (s, 2H), 3.73 (s, 6H), 3.59 (d, 1H), 3.37-3.16 (m, 2H), 2.72 (d, 1H), 2.33-2.16 (m, 1H), 1.74 (d, 6H), 1.34 (m, 4H), 1.15-1.07 (m, 1H), 0.97-0.92 (m, 1H). LCMS [M+H] 523.2.

[0530] compound 42 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((6-amino-3-azabicyclo[3.2.0]heptan-3-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 tert-butyl 3-azabicyclo[3.2.0]heptan-6-ylcarbamate. 1 H NMR (400 MHz, D2O) δ 8.00 (d, 1H), 7.76 (d, 2H), 7.59 (d, 2H), 6.85 (d, 1H), 4.62 (s, 2H), 4.08 (q, 1H), 3.98-3.55 (m, 11H), 3.40 (s, 1H), 3.28 (s, 1H), 2.71 (s, 1H), 1.99 (s, 1H), 1.73 (s, 6H), 1.71 (d, 1H). LCMS [M+H] 509.3.

[0531] compound 57 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(6-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyridin-3-yl)-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-(6-formylpyridin-3-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate and tert-butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 8.54 (d, 1H), 7.86-7.81 (m, 1H), 7.71 (d, 1H), 7.50 (d, 1H), 6.70 (d, 1H), 4.45 (s, 2H), 3.68 (s, 2H), 3.64-3.47 (m, 10H), 2.80 (s, 1H), 2.28 (s, 2H), 1.53 (s, 6H). LCMS[M+H] 496.2.

[0532] compound 58 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((exo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (1-(4-((1-(4-((exo-3-((t-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. 1H NMR (400 MHz, D 2 O) δ 8.15 (d, 1H), 7.74 (d, 2H), 7.61 (d, 2H), 6.85 (d, 1H), 4.36 (s,2H), 4.11 (br s, 2H), 3.82-3.75 (m, 11H), 2.66-2.57 (m, 4H), 2.26-2.20 (m, 4H), 1.74 (s, 6H). LCMS [M+H] 523.4.

[0533] compound 59 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-((endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-butyl (1-(4-((1-(4-((endo-3-((t-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 8.08 (d, 1H), 7.75 (d, 2H), 7.61 (d, 2H), 6.85 (d, 1H), 4.35 (s,2H), 4.18 (br s, 2H), 3.83-3.74 (m, 11H), 2.56-2.51 (m, 2H), 2.34-2.28 (m, 2H), 2.17 (d, 2H), 2.07 (t, 2H), 1.74 (s, 6H). LCMS [M+H] 523.4.

[0534] compound 60 [ka] N-(1-(4-((5-amino-2-azaspiro[3.3]heptan-2-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-2 from 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 and tert-butyl (2-azaspiro[3.3]heptan-5-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 8.17 (d, 1H), 7.67 (d, 2H), 7.59 (d, 2H), 6.82 (d, 1H), 4.49 (s,2H), 4.38 (d, 2H), 4.28 (d, 2H), 4.02-4.00 LCMS [M+H] 509.2.

[0535] compound 76 [ka] N-(1-{4-[(cis)-octahydropyrrolo[3,4-c]pyrrol-2-ylmethyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride Step 1: tert-Butyl (cis)-5-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate. Prepared in a similar manner to Scheme C-2 from 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 (50.0 mg, 0.098 mmol) and tert-butyl (cis)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (25.0 mg, 0.118 mmol) to give the desired product (52.0 mg, 74%). LCMS [M+H] 709.7.

[0536] Step 2: N-(1-{4-[(cis)-octahydropyrrolo[3,4-c]pyrrol-2-ylmethyl]phenyl}-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride. Prepared from tert-butyl (cis)-5-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (52.0 mg, 0.074 mmol) to afford the title compound (38.6 mg, 84%) as a white solid. 1 H NMR (400 MHz, D2O) δ 7.84 (d, 1 H), 7.63 (d, 2 H), 7.51 (d, 2 H), 6.81 (d, 1 H), 4.47 (s, 2 H), 3.76-3.62 (m, 8 H), 3.97-2.96 (m, 10 H), 1.68 (s, 6 H). LCMS[M+H] 509.4.

[0537] compound 16 [ka] 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Step 1: tert-Butyl N-[(7R)-5-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-5-azaspiro[2.4]heptan-7-yl]carbamate. In a similar manner to Scheme C-2, 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 (43.0 mg, 0.084 mmol) and tert-butyl N-[(7R)-5-azaspiro[2.4]heptan-7-yl]carbamate (26.7 mg, 0.126 mmol) was used to prepare the title compound (43.0 mg, 72%). 1 H NMR (400MHz, CDCl3) δ 12.94 (br. s., 1H), 7.45 (d, 2H), 7.34-7.24 (m, 3H), 5.84 (d, 1H), 5.04-4.44 (m, 2H), 3.98-3.54 (m, 11H), 3.03-2.86 (m, 1H), 2.71 (d, 2H), 2.37 (d, 1H), 1.54 (s, 6H), 1.46 (s, 9H), 1.45 (s, 9H), 0.89-0.70 (m, 2H), 0.67-0.59 (m, 1H), 0.52-0.44 (m, 1H).LCMS [M+H] 709.7.

[0538] Step 2: 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride. Prepared from tert-butyl N-{[(7R)-1-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}pyrrolidin-3-yl]methyl}carbamate (43.0 mg, 0.06 mmol) to afford the title compound (30.0 mg, 81%) as a pale yellow solid. 1 H NMR (400MHz, D2O) δ 7.86 (d, 1H), 7.66 (d, 2H), 7.52 (d, 2H), 6.81 (d, 1H), 4.61 (d, 1H), 4.54 (d, 1H), 4.32-4.16 (m, 1H), 3.91-3.54 (m, 11H), 3.32-3.19 (m, 1H), 1.68 (s, 6H), 1.18-1.05 (m, 1H), 1.03-0.85 (m, 3H). LCMS [M+H] 509.4.

[0539] compound 19 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Step 1: tert-Butyl N-[(7S)-5-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-5-azaspiro[2.4]heptan-7-yl]carbamate. In a similar manner to Scheme C-2, the title compound was obtained from 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 (50.0 mg, 0.098 mmol) and tert-butyl N-[(7S)-5-azaspiro[2.4]heptan-7-yl]carbamate (26.7 mg, 0.147 mmol) (54.0 mg, 78%). 1 H NMR (400MHz, CDCl3) δ 12.95 (br. s., 1H), 7.45 (d, 2H), 7.34-7.24 (m, 3H), 5.84 (d, 1H), 4.98-4.44 (m, 2H), 4.00-3.53 (m, 11H), 3.04-2.88 (m, 1H), 2.76-2.54 (m, 2H), 2.37 (d, 1H), 1.54 (s, 6H), 1.46 (s, 9H), 1.45 (s, 9H), 0.88-0.70 (m, 2H), 0.66-0.56 (m, 1H), 0.52-0.44 (m, 1H).LCMS [M+H] 709.7.

[0540] Step 2: 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride. Prepared from tert-butyl N-{[(7S)-1-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}pyrrolidin-3-yl]methyl}carbamate (54.0 mg, 0.076 mmol) to afford the title compound as its hydrochloride salt (41.3 mg, 88%) as a yellow solid. 1 H NMR (400MHz, D2O) δ 7.86 (d, 1H), 7.65 (d, 2H), 7.51 (d, 2H), 6.80 (d, 1H), 4.60 (d, 1H), 4.53 (d, 1H), 4.29-4.11 (m, 1H), 3.87-3.50 (m, 11H), 3.30-3.19 (m, 1H), 1.67 (s, 6H), 1.17-1.05 (m, 1H), 1.01-0.88 (m, 3H). LCMS [M+H] 509.4.

[0541] compound 68 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[(exo)-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Step 1: tert-Butyl N-{[(exo)-3-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-3-azabicyclo[3.1.0]hexan-6-yl]methyl}carbamate. In a similar manner to Scheme C-2, the title compound was obtained from 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 (50.0 mg, 0.098 mmol) and tert-butyl N-[exo-3-azabicyclo[3.1.0]hexan-6-ylmethyl]carbamate (31.1 mg, 0.147 mmol) (53.0 mg, 76%). 1 H NMR (400MHz, CDCl3) δ 12.94 (br. s., 1H), 7.38 (d, 2H), 7.31-7.25 (m, 3H), 5.83 (d, 1H), 4.87 (br. s., 1H), 4.58 (br. s., 1H), 3.95-3.52 (m, 10H), 3.05-2.94 (m, 4H), 2.36 (d, 2H), 1.54 (s, 6H), 1.50-1.38 (m, 19H), 1.33-1.25 (m, 2H). LCMS [M+H] 709.7.

[0542] Step 2: 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[(exo)-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride. Prepared from tert-butyl N-{[exo-3-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-3-azabicyclo[3.1.0]hexan-6-yl]methyl}carbamate (53.0 mg, 0.075 mmol) to give the title compound (40.4 mg, 87%) as a pale yellow solid. 1 H NMR (400MHz, D2O) δ 7.86 (d, 1H), 7.67-7.55 (m, 2H), 7.50 (d, 2H), 6.81 (d, 1H), 4.47-4.28 (m, 2H), 3.99-3.49 (m, 12H), 3.06-2.87 (m, 2H), 2.07-1.93 (m, 2H), 1.69 (s, 6H), 1.41-1.28 (m, 1H). LCMS [M+H] 509.4.

[0543] compound 77 [ka] 4-(2-Amino-2-methylpropanoyl)-N-(1-(4-(((3aS,7aR)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Step 1: tert-Butyl (3aS,7aR)-rel-5-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate. Prepared in a similar manner to Scheme C-2 from 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 (50.0 mg, 0.098 mmol) and cis-1-N-Boc-octahydropyrrolo[3,2-c]pyridine (33.1 mg, 0.147 mmol) to give the title compound (44.0 mg, 62%). 1 H NMR (400MHz, CDCl3) δ 12.95 (br. s., 1H), 7.45 (d, 2H), 7.34-7.24 (m, 3H), 5.84 (d, 1H), 4.97-4.46 (m, 1H), 4.03-3.19 (m, 14H), 2.85-2.58 (m, 2H), 2.45-2.15 (m, 3H), 2.14-1.91 (m, 2H), 1.87-1.59 (m, 1H), 1.53 (s, 6H), 1.47 (s, 9H), 1.46 (s, 9H). LCMS [M+H] 723.8.

[0544] Step 2: N-4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((3aS,7aR)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride. Prepared from tert-butyl (3aS,7aR)-rel-5-{[4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropanoyl)piperazine-1-carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)phenyl]methyl}-octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (44.0 mg, 0.061 mmol) to give the title compound (33.2 mg, 86%) as a pale yellow solid. 1 H NMR (400MHz, D2O) δ 7.91 (d, 1H), 7.70 (d, 2H), 7.57 (d, 2H), 6.87 (d, 1H), 4.47 (br. s., 2H), 4.14-3.07 (m, 15H), 2.92-2.76 (m, 1H), 2.51-1.81 (m, 4H), 1.73 (s, 6H). LCMS [M+H] 523.4.

[0545] compound 71 [ka] 4-(2-Amino-2-methylpropanoyl)-N-[1-(4-{[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride Step 1: tert-Butyl (1-(4-((1-(4-((1-(((tert-butoxycarbonyl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)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 C-2 from 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 (30.0 mg, 0.058 mmol) and tert-butyl N-{3-azabicyclo[3.1.0]hexan-1-ylmethyl}carbamate (15.0 mg, 0.070 mmol) (9.0 mg, 29%). LCMS [M+H] 709.7.

[0546] Step 2: 4-(2-amino-2-methylpropanoyl)-N-[1-(4-{[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl}phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl]piperazine-1-carboxamide hydrochloride. Prepared from tert-butyl (1-(4-((1-(4-((1-(((tert-butoxycarbonyl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (9.0 mg, 0.017 mmol) to give the title compound (4.2 mg, 40%) as a colorless wax. 1H NMR (400MHz, D2O) δ 7.88 (d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 6.81 (d, 1H), 4.45 (br. s., 2H), 3.85-3.51 (m, 12H), 3.49-3.39 (m, 1H), 3.15-3.00 (m, 1H), 2.05-1.92 (m, 1H), 1.68 (s, 6H), 1.15-0.95 (m, 2H). LCMS [M+H] 509.5.

[0547] compound 74 [ka] exo-3-(4-(4-(4-(2-amino-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from t-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 exo-3-azabicyclo[3.1.0]hexane-6-carboxamide. 1 H NMR (400 MHz, D2O) δ 8.08 (d, 1H), 7.69 (d, 2H), 7.56 (d, 2H), 6.81 (d, 1H), 4.48 (s, 2H), 3.90-3.59 (m, 12H), 2.30 (s, 2H), 1.90 (d, 1H), 1.72 (s, 6H). LCMS[M+H] 523.2.

[0548] compound 81 [ka] N-(1-(4-((2,7-diazaspiro[3.5]nonan-2-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-2 from tert-butyl 2-(4-(4-(4-(2-((tert-butoxycarbonyl)amino)-2-methylpropanoyl)piperazine-1-carboxamido)-2-oxopyrimidin-1(2H)-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate. 1 H NMR (500 MHz, D2O) δ 8.08 (d, 1H), 7.77 (d, 2H), 7.68 (d, 2H), 6.95 (d, 1H), 4.65 (s,2H), 4.31-4.25 (m, 4H), 3.94-3.88 (m, 4H), 3.87-3.80 (m, 4H), 3.36 (t, 2H), 3.32 (t, 2H), 2.30-2.25 (m, 4H), 1.85 (s, 6H). LCMS [M+H] 523.3.

[0549] compound 168 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((4-aminobicyclo[2.2.1]heptan-1-yl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 using t-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 t-butyl (4-aminobicyclo[2.2.1]heptan-1-yl)carbamate. LCMS [(M+2H) / 2] 262.0.

[0550] compound 167 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((4-aminobicyclo[2.2.2]octan-1-yl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 using t-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 t-butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate. 1 H NMR (400 MHz, D2O) δ 8.00 (d, 1H), 7.66 (d, 2H), 7.56 (d, 2H), 6.88 (d, 1H), 4.32 (s, 2H), 3.89-3.58 (m, 8H), 2.25-2.05 (m, 12H), 1.76 (s, 6H). LCMS [M+H] 537.2.

[0551] Compound 171 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(4-(((3-aminobicyclo[1.1.1]pentan-1-yl)amino)methyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 using t-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 t-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate. 1H NMR (400 MHz, D2O) δ 7.71 (d, 1H), 7.44 (d, 2H), 7.33 (d, 2H), 6.71 (m, 1H), 4.06 (s, 2H), 3.68-3.55 (m, 8H), 2.27 (s, 6H), 1.56 (s, 6H). LCMS [M+H] 495.1.

[0552] compound 1 [ka] N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-((S)-2-amino-3-hydroxy-2-methylpropanoyl)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-formyl-3-methylphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)piperazine-1-carbonyl)-4-methyloxazolidine-3-carboxylate and tert-butyl (exo-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. 1 H NMR (500 MHz, CD3OD): δ 7.72 (d, 1H), 7.62 (d, 1H), 7.38 (s 1H), 7.34 (d, 1H), 6.61 (s, 1H), 4.43 (s, 2H), 4.07 (d, 1H), 3.70 (d, 1H), 3.74-3.67 (m, 12H), 3.12 (s, 1H), 2.49 (s, 3H), 2.32 (s, 2H), 1.61 (s, 3H). LCMS [M+H] 525.3.

[0553] compound 11 [ka] N-(1-(4-((exo-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-((S)-2-amino-3-hydroxy-2-methylpropanoyl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 from 4-((2S,4S)-2-(tert-butyl)-4-methyloxazolidine-4-carbonyl)-N-(1-(4-formyl-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide and tert-butyl exo-3-azabicyclo[3.1.0]hexan-6-ylcarbamate.

[0554] compound 142 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-(2-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 using 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 and t-butyl ((3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate. 1H NMR (400 MHz, D2O) δ 7.82 (d, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.25-7.22 (m, 2H), 6.69 (d, 1H), 3.78 (d, 1H), 3.66-3.58 (m, 10H), 3.43-3.31 (m, 5H), 3.00-2.95 (m, 2H), 1.90-1.84 (m, 1H), 1.58 (s, 6H), 0.98 (t, 1H), 0.87-0.84 (m, 1H). LCMS [(M+2H) / 2] 262.1.

[0555] compound 143 [ka] 4-(2-amino-2-methylpropanoyl)-N-(1-(3-(2-(exo-6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 using 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 and exo-t-butyl ((3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. 1 H NMR (400 MHz, D2O);δ 7.79 (d, 1H), 7.42 (t, 1H), 7.31 (d, 1H), 7.28-7.20 (m, 2H), 6.70 (d, 1H), 3.69-3.57 (m, 10H), 3.39-3.32 LCMS [M+H] 523.0.

[0556] compound 144 [ka] cis-4-(2-amino-2-methylpropanoyl)-N-(1-(3-(2-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)phenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxamide hydrochloride Prepared in a similar manner to Scheme C-2 using 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 and cis-t-butyl (3-azabicyclo[3.1.0]hexan-1-yl)carbamate. 1 H NMR (400 MHz, D2O): δ 7.80 (d, 1H), 7.43 (t, 1H), 7.39-7.31 (m, 1H), 7.29-7.22 (m, 2H), 6.70 (d, 1H), 4.10-3.91 ...

Claims

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

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