WO/1987/006576 | CALCIUM INDEPENDENT cAMP PHOSPHODIESTERASE INHIBITOR ANTIDEPRESSANT |
JP4516922 | 2-iminopyrrolidine derivative |
JP2003506491 | [Title of Invention] Cell Adhesion Inhibitor |
FOX DAVID JOHN (GB)
HUNTINGTON JAMES ANDREW (GB)
TOMLINSON JAMES MICHAEL (GB)
HEAL JONATHAN RICHARD (GB)
SHERIDAN JOSEPH MICHAEL (GB)
EARL MATTHEW WILLIAM MARK (GB)
WO2020120992A1 | 2020-06-18 | |||
WO2021116707A1 | 2021-06-17 | |||
WO2021116706A1 | 2021-06-17 | |||
WO2021116709A1 | 2021-06-17 |
US5846514A | 1998-12-08 | |||
US6334997B1 | 2002-01-01 | |||
US6334997B1 | 2002-01-01 |
DATABASE Chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 27 May 2015 (2015-05-27), AURORA BUILDING BLOCKS 2: "Benzamide, 4-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl)methyl]-", XP055957432, Database accession no. 0548978358
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 29 May 2015 (2015-05-29), AURORA BUILDING BLOCKS 2: "Benzamide, 4-[(4-oxo-1(4H)-pyridinyl)methyl]-", XP055957433, Database accession no. 1011403166
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 22 May 2018 (2018-05-22), AURORA SCREENING COMPOUNDS 1 N M: "Benzamide, N,N-dimethyl-4-[(2-oxo-1-pyrrolidinyl)methyl]-", XP055957434, Database accession no. 2217316-52-2
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 17 April 2018 (2018-04-17), AURORA SCREENING COMPOUNDS 1 U-T: "Benzamide, N-[2-[(1,1-dimethylethyl)thio]ethyl]-4-[(2-oxo-1- pyrrolidinyl)methyl]-", XP055957435, Database accession no. 0793772649
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 6 March 2018 (2018-03-06), AURORA SCREENING COMPOUNDS 1 N (: "Benzamide, 4-[(2-oxo-1-pyrrolidinyl)methyl]-N,N-dipropyl-", XP055957436, Database accession no. 0864079310
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, OHIO, US; 6 March 2018 (2018-03-06), AURORA SCREENING COMPOUNDS 1 B U-N: "N-butyl-N-methyl-4-[(2-oxo-1-pyrrolidinyl)methyl]-", XP055957437, Database accession no. 1674602091
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 6 March 2018 (2018-03-06), AURORA SCREENING COMPOUNDS 1 B: "Benzamide, N-methyl-N-(2-methylpropyl)-4-[(2-oxopyrrolidin-1- yl)methyl]benzamide", XP055957438, Database accession no. 2017477042
DATABASE CHEMCATS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2 March 2018 (2018-03-02), AURORA SCREENING COMPOUNDS 1: "Benzamide, 4-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-", XP055957439, Database accession no. 2183398-52-7
DATABASE chemcats [online] 1 August 2018 (2018-08-01), AURORA SCREENING COMPOUNDS 1 N M: "Benzamide, N,N-dimethyl-4-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-", XP055957440, Database accession no. 005927393
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 9 September 2011 (2011-09-09), AURORA BUILDING BLOCKS 8: "Benzamide, 4-[(1-oxo-2(1H)-phthalazinyl)methyl]-", XP055957441, Database accession no. 2055222123
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 26 July 2002 (2002-07-26), AMBINTER SCREENING LIBRARY C H: "Benzamide, N-(3-methylbutyl)-4-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-", XP055957442, Database accession no. 2074664976
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 26 July 2002 (2002-07-26), LABNETWORK COMPOUNDS U-N: "Benzamide, N-butyl-4-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-", XP055957443, Database accession no. 0806390776
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 26 July 2002 (2002-07-26), LIFE CHEMICALS HTS COMPOUNDS: "Benzamide, N-(1-methylpropyl)-4-[(4-oxo-1,2,3-benzotriazin-3(4H)- yl)methyl]-(", XP055957444, Database accession no. 0921187268
DATABASE chemcats [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 26 July 2002 (2002-07-26), LIFE CHEMICALS HTS COMPOUNDS N H: "Benzamide, N-(1-methylethyl)-4-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-", XP055957445, Database accession no. 1763190013
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CLAIMS 1. A compound represented by the structure of Formula (I-a): or a pharmaceutically acceptable salt thereof, wherein: is a 6-membered heterocycle selected from: , A is selected from: -C(=O)N(H)(R1), -C(=O)N(R2)(R3); and 5-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, -OR11, N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, - OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, - OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2,=O and -CN; R1 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - N(R12)S(O)2(R12), -S(O)N(R12)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - S(O)2N(R12)2, -NO2, and -CN; R2 and R3 are each C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - OC(O)N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -S(O)2R13, - N(R13)S(O)2(R13), -S(O)2N(R13)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, - C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)C(O)N(R13)2, -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and R11, R12 and R13 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. 2. The compound or salt of claim 1, wherein A is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted. 3. The compound or salt of claim 1 or claim 2, wherein A is selected from oxazole, isoxazole, thiazole, isothiazole, and imidazole, any one of which is optionally substituted. 4. The compound or salt of any one of claims 1-3, wherein Formula (I-a) is represented by: . 5. The compound or salt of claim 1, wherein A is -C(=O)N(H)(R1) and R1 is C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents selected from: halogen, -OR12, -N(R12)2, - C(O)R12, -NO2, and -CN. 6. The compound or salt of claim 5, wherein Formula (I-a) is represented by: , , and 7. The compound or salt of claim 1, wherein A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents selected from: halogen, - OR13, -N(R13)2, -C(O)R13, -NO2, and -CN. 8. The compound or salt of claim 1 or claim 7, wherein R2 and R3 are each independently C1-3 alkyl optionally substituted with one or more substituents independently selected from fluoro, chloro, and bromo. 9. The compound or salt of any one of clams 1, 7, or 8, wherein Formula (I-a) is represented by: , , , and 10. The compound or salt of claim 1 or claim 7, wherein R2 and R3 are each independently C1-3 alkyl optionally substituted with C6 carbocycle optionally substituted with one or more substituents selected from fluoro, chloro, and bromo. 11. The compound or salt of claim 10, wherein the C6 carbocycle is phenyl optionally substituted with one or more substituents selected from fluoro, chloro, and bromo. 12. The compound or salt of any one of claims 1, 7, 10, or 11, wherein Formula (I-a) is represented by: and 13. A compound represented by the structure of Formula (I-b): or a pharmaceutically acceptable salt thereof, wherein: is a bicyclic heterocycle selected from B selected from -C(=O)N(H)(R4), -C(=O)N(R5)(R6), and 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, - OC(O)R21, -OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, =O, and -CN; R4 is selected from: C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, - OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, -N(R22)C(O)R22, -NO2, =O, and -CN; and C2-6 alkyl substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, - C(O)N(R22)2, -N(R22)C(O)R22, -N(R22)C(O)OR22, -N(R22)S(O)2(R22), - S(O)2N(R22)2, -NO2,=O, and -CN; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, -OC(O)N(R23)2, - C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, -N(R23)S(O)2(R23), - S(O)2N(R23)2, -NO2, and -CN; R6 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, - OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, - N(R24)C(O)OR24, -N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1- 6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; R21, R23, and R24 are each independently selected at each occurrence from hydrogen, - OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and R22 is independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. 14. The compound or salt of claim 13, wherein R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, and C1-6 haloalkyl. 15. The compound or salt of claim 13 or claim 14 wherein, is represented by: . 16. The compound or salt of any one of claims 13-15, wherein B is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, and imidazole, any of which is optionally substituted. 17. The compound or salt of claim of any one of claims 13-16, wherein Formula (I-b) is represented by: . 18. The compound or salt of claim of any one of claims 13-15, wherein B is C(=O)N(H)(R4) and R4 is C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, - C(O)N(R22)2, -N(R22)C(O)R22, -NO2, and -CN. 19. The compound or salt claim 18, wherein Formula (I-b) is represented by: and O . 20. The compound or salt of any one of claims 13-15, wherein B is C(=O)N(R5)(R6) and; R5 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, and -CN; and R6 is C1 alkyl substituted with one more substituents one or more substituents independently selected from halogen, -OR24, -N(R24)2, -C(O)R24, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -NO2, and -CN. 21. The compound or salt of claim 20, wherein Formula (I-b) is represented by: , and 22. A compound represented by the structure of Formula (I-c): , or a pharmaceutically acceptable salt thereof, wherein: is a 6-membered heterocycle represented by: X is selected from (a), (b), and (c): (a) -C(=O)N(H)(R7), -C(=O)N(R8)(R9), -CH2C(=O)N(H)(C1-6 alkyl), - CH2C(=O)N(C1-6 alkyl)2 , -CHC(=O)N(H)(C1-6 alkyl), -CHC(=O)N(C1-6 alkyl)2, - S(=O)2N(H)(C1-6 alkyl), -S(=O)2N(C1-6 alkyl)2; (b) 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, -OC(O)R31, - OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, - N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -N(R31)2, -C(O)R31, - C(O)OR31, -OC(O)R31, -OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, - N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, =O, and -CN; and (c) 5- to 6-membered heterocycle with one or two oxo group and optionally substituted with one or more C1-3 alkyl; R7 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and -CN; R8 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, -CN; R9 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; or R8 and R9 can come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from: halogen, C1-6 alkyl, - OR35, -N(R35)2, -C(O)R35, -C(O)OR35, -OC(O)R35, -OC(O)N(R35)2, -C(O)N(R35)2, -N(R35)C(O)R35, -N(R35)C(O)OR35, -N(R35)S(O)2(R35), -S(O)2N(R35)2, -NO2, - CN; RA is independently selected at each occurrence from halogen and C1-6 alkyl; R`` is each independently selected from hydrogen, halogen, C1-3 alkyl, -NO2, and -CN; R31, R32, R33, R34 and R35 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and n is selected from 0, 1, 2, 3, and 4. 23. The compound or salt of claim 22, wherein each R`` is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, fluoro, chloro, and bromo. 24. The compound or salt of claim 22 or claim 23, wherein is represented by: . 25. The compound or salt of any one of claims 22-24, wherein X is 5-membered heteroaryl selected from oxazole, isoxazole, imidazole, 1,3,4-oxaziazole, and triazole, any of which is optionally substituted. 26. The compound or salt of claim 25, wherein Formula (I-c) is represented by: , and 27. The compound or salt of any one of claims 22-24, wherein X is -C(=O)N(H)(R7) and R7 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, - C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN; and C2-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN. 28. The compound or salt of claim 27, wherein Formula (I-c) is represented by: , and . 29. The compound or salt of any one of claims 22-24, wherein X is -C(=O)N(R8)(R9); and R8 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, - OC(O)N(R33)2, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -NO2, -CN; and C3- 6carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -NO2, and -CN; and R9 is selected from: C1 alkyl substituted with one or more substituents independently selected halogen, -OR34, -N(R34)2, -C(O)R34, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, - OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -NO2, and -CN; and C2-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - NO2, and -CN. 30. The compound or salt of claim 29, wherein Formula (I-c) is selected from: , , , , and 31. The compound or salt of any one of claims 22-24, wherein X is -C(=O)N(R8)(R9) and both of R8 and R9 come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from halogen, C1-3 alkyl and C1-3 haloalkyl. 32. The compound or salt of claim 31, wherein the optionally substituted 5- to 6-membered saturated heterocycle is selected from pyrrolidine, morpholine, and piperazine. 33. The compound or salt of claim 31 or claim 32, wherein Formula (I-c) is represented by: , and 34. The compound or salt of any one of claims 22-24, wherein n is selected from 0, 1, and 2. 35. The compound or salt of claim 34, wherein RA is selected from methyl, ethyl, propyl, chloro, fluoro, and bromo. 36. The compound or salt of claim 34 or claim 35, wherein Formula (I-c) is represented by: and 37. The compound or salt of any one of claims 22-24, wherein X is 5- to 6-membered heterocycle with one or two oxo group and optionally substituted with one or more C1-3 alkyl. 38. The compound or salt of claim 37, wherein Formula (I-c) is represented by: , , , , and . 39. The compound or salt of any one of claims 22-24, wherein X is selected from - CH2C(=O)N(H)(C1-6 alkyl), -CH2C(=O)N(C1-6 alkyl)2, -CHC(=O)N(H)(C1-6 alkyl), - CHC(=O)N(C1-6 alkyl)2, and -S(=O)2N(H)(C1-6 alkyl), -S(=O)2N(C1-6 alkyl)2. 40. The compound or salt of claim 39, wherein Formula (I-c) is represented by: 41. A compound represented by the structure of Formula (I-d): or a pharmaceutically acceptable salt thereof, wherein: each of R1 and R2 are independently selected from hydrogen and C1-6 alkyl; and is a represented by: and 42. The compound or salt of claim 41, wherein Formula (I-d) is represented by: and . 43. A compound represented by: , , , , , , , and 44. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or salt of any one of claims 1 to 43. 45. A method of inducing α1-antitrypsin (A1AT), the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of any one of claims 1 to 43 or a pharmaceutical composition of claim 44. 46. A method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of any one of claims 1 to 43 or a pharmaceutical composition of claim 44. 47. A method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (II) or a pharmaceutical composition of Formula (II), wherein, R1 is selected from C3-6 carbocycle and 6- to 12-membered bicyclic heteroaryl, any of which are optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and Ring is selected from a 5- to 6-membered saturated heterocycle. 48. The method of claim 47, wherein Formula (II) is represented by: , , and . 49. The method of claim 47 or claim 48, wherein the administering induces α1-antitrypsin (A1AT) in the subject in need thereof. |
, , , , , and [0091] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. [0092] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) , are intended to include all Z-, E- and tautomeric forms as well. [0093] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. [0094] The compounds or salts for Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration. [0095] In certain embodiments, compounds or salts for Formula (I-a), Formula (I-b), Formula (I- c), Formula (I-d) or Formula (II) , may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis. [0096] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) , exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non–limiting examples of tautomeric equilibrium include:
[0097] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [0098] In certain embodiments, the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [0099] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [0100] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [0101] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure. [0102] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0103] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [0104] The methods and compositions of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I- d) or Formula (II), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [0105] Compounds of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. [0106] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of compounds represented by Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II). The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [0107] In certain embodiments, compounds or salts of Formula (I-a), Formula (I-b), Formula (I- c), Formula (I-d) or Formula (II), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure. [0108] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell. [0109] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity. [0110] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. [0111] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations [0112] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) and at least one pharmaceutically acceptable excipient. [0113] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form. [0114] Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0115] Pharmaceutical compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate). The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. [0116] Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. For example, the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant. Such molecules can be present in combination in amounts that are effective for the purpose intended. [0117] A compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I- d) or Formula (II) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II)), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants. [0118] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). Methods of Treatment [0119] In some aspects, the present disclosure provides a method of inducing α 1 -antitrypsin (A1AT), the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0120] In some aspects, the present disclosure provides a method of inducing Z A1AT secretion, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0121] In some aspects, the present disclosure provides a method of treating a α 1 -antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0122] In some aspects, the present disclosure provides a method of treating low plasma levels of A1AT, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0123] In some aspects, the present disclosure provides a method of treating a α 1 -antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (II) or a pharmaceutical composition of Formula (II), wherein, R 1 is selected from C3-6 carbocycle and 6- to 12-membered bicyclic heteroaryl, any of which are optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and Ring is selected from a 5- to 6-membered saturated heterocycle. [0124] In some embodiments, Formula (II) is represented by: , , , , , and [0125] In some embodiments, the administration of a compound or salt of Formula (II) induces α1-antitrypsin (A1AT) in the subject in need thereof. [0126] In some aspects, the present disclosure provides a method of inducing Z A1AT secretion, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof. [0127] In some aspects, the present disclosure provides a method of treating a α 1 -antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof. [0128] In some aspects, the present disclosure provides a method of treating low plasma levels of A1AT, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof. EXAMPLES [0129] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way. [0130] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. [0131] Examples 1-106 show general and exemplary procedures for the preparation of the claimed compounds and Examples 107-110 provide A1AT cell secretion bioassays or mouse model data. Example 1. Synthesis of N-Ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e [0132] N-Ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e was prepared using the following sequential synthesis procedures: [0133] Step a: Synthesis of tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate
[0134] Pyrimidin-4(3H)-one (5g, 32 mmol) and caesium carbonate (50.85g, 156 mmol) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature. Tert-butyl 4- (bromomethyl)benzoate (14.11g, 52 mmol) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (30 % to 33%) to give tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate. Tlc Rf 0.21:1 Ethyl acetate/hexane. [0135] Step b: Synthesis of 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid [0136] Tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate (10g, 35 mmol) was dissolved in dichloromethane (50ml) and trifluoroacetic acid (70ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (300ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 30ml) and dried in vacuo to give 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid. [0137] Step c: Synthesis of N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e [0138] 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.11ml, 81 mmol) and ethylmethylamine (2M solution in tetrahydrofuran, 69 mmol) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give N-ethyl-N- methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide. m/z: 270.96 (calc 271.13) 1 H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.36 (4H, s), 6.44 (1H, d), 5.13 (2H, s), 3.43 (1H, br s), 3.17 (1H, br s), 2.88 (3H, br s), 1.05 (3H, br s). Example 2: 3-(4-(Pyrrolidine-1-carbonyl)benzyl)pyrimidin-4(3H)-one [0139] 3-(4-(Pyrrolidine-1-carbonyl)benzyl)pyrimidin-4(3H)-one was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using pyrrolidine instead of ethylmethylamine in step c of Example 1. m/z: 282.91 (calc 283.13) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.49 (2H, d), 7.35 (2H, d), 6.44 (1H, d), 5.13 (2H, s), 3.44 (2H, t), 3.34 (2H, t), 1.83 (4H, m). Example 3: 3-(4-(Morpholine-4-carbonyl)benzyl)pyrimidin-4(3H)-one [0140] 3-(4-(Morpholine-4-carbonyl)benzyl)pyrimidin-4(3H)-one was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using morpholine instead of ethylmethylamine in step c of Example 1. m/z: 298.97 (calc 299.13) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.38 (4H, m), 6.43 (1H, d), 5.13 (2H, s), 3.59-3.34 (8H, br m). Example 4: 3-(4-(4-Methylpiperazine-1-carbonyl)benzyl)pyrimidin-4(3H)-o ne [0141] 3-(4-(4-Methylpiperazine-1-carbonyl)benzyl)pyrimidin-4(3H)-o ne was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e using N-methylpiperazine instead of ethylmethylamine in step c. m/z: 312.18 (calc 312.16) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.36 (4H, s), 6.43 (1H, d), 5.13 (2H, s), 3.58 (2H, br), 3.33 (2H), 2.29 (4H, br m), 2.17 (3H, br s).
Example 5: N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide [0142] N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using quinazolin-4(3H)-one instead of pyrimidin-4(3H)-one in step a and methylamine instead of ethylmethylamine in step c. m/z: 292.92 (calc 293.12) 1H NMR (400 MHz, d6 DMSO) δ 8.60 (1H, s), 8.41 (1H, br m), 8.15 (1H, dd), 7.85 (1H, m), 7.79 (2H, d), 7.71 (1H, d), 7.56 (1H, m), 7.42 (2H, d), 5.24 (2H, s), 2.75 (3H, d). Example 6: 4-((6-chloro-4-oxoquinazolin-3(4H)-yl)methyl)-N-methylbenzam ide [0143] 4-((6-chloro-4-oxoquinazolin-3(4H)-yl)methyl)-N-methylbenzam ide was prepared similarly to N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using 6- chloroquinazolin-4(3H)-one instead of quinazolin-4(3H)-one in step a of Example 1. m/z: 326.92, 329.10 (calc 327.08, 329.07) 1H NMR (400 MHz, d6 DMSO) δ 8.63 (1H, s), 8.42 (1H, br m), 8.09 (1H, d), 7.88 (1H, m), 7.79 (2H, d), 7.74 (1H, d), 7.42 (2H, d), 5.24 (2H, s), 2.75 (3H, d). Example 7: N-isopropyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benz amide [0144] N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using N,N-dimethylpropan-2- amine instead of ethylmethylamine in step c of Example 1. m/z: 285.10 (calc 285.15) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.93 (1H, br m), 7.34 (4H, s), 6.43 (1H, br m), 5.12 (2H, s), 3.75 (1H br m), 2.67-2.74 (3H), 1.10 (6H). Example 8: N-benzyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzami de [0145] N-benzyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzami dewas prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e using N-methyl benzylamine instead of ethylmethylamine in step c of Example 1. m/z: 333.13 (calc 333.15) 1H NMR (400 MHz, d6 DMSO) δ 8.60 (1H, s), 7.93 (1H, d), 7.41 (7H, m), 7.29 (3H, m), 6.42 (1H, d), 5.16 (2H, s). Example 9: N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2- trifluoroethyl)benzamide. [0146] N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2-triflu oroethyl)benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e using 2,2,2-trifluoro-N-methylethan-1-amine instead of ethylmethylamine in step c of Example 1. m/z: 325.12 (calc 325.10) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.94 (1H, d), 7.39 (4H, br s), 6.44 (1H, d), 5.13 (2H, s), 4.33 (2H, br), 3.00 (3H, br s). Example 10 : 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide. [0147] 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N-ethyl-N- methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using ammonium chloride instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 252.07 (calc 252.07) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.95 (1H, s,), 7.94 (1H, d), 7.86-7.81 (2H, m), 7.37 (1H, s), 7.40-7.34 (2H, m), 6.43 (1H, d), 5.14 (2H, s). Example 11: N,N-diethyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide. [0148] N,N-diethyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using diethylamine instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 308.14 (calc 308.14) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.94 (1H, d), 7.37-7.30 (4H, m), 6.44 (1H, d), 5.13 (2H, s), 3.48-3.37 (2H, m), 3.22-3.08 (2H, m), 1.17-1.08 (3H, m), 1.08-0.96 (3H, m). Example 12: N-isopropyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide. [0149] N-isopropyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using isopropylamine instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 294.12 (calc 294.12) 1H NMR (400 MHz, d6 DMSO) δ 8.63 (1H, s), 7.93 (1H, s), 7.79-7.73 (2H, m), 7.38-7.32 (2H, m), 6.43 (1H, d), 5.12 (2H, s), 4.04 (1H, sept.), 1.12 (6H, d). Example 13: N-(4-fluorobenzyl)-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzam ide. [0150] N-(4-fluorobenzyl)-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzam ide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e using 4- fluorobenzylamine instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 360.11 (calc 360.11) 1H NMR (400 MHz, d6 DMSO) δ 9.03 (1H, t), 8.68 (1H, s), 7.94 (1H, d), 7.88-7.83 (2H, m), 7.42-7.38 (2H, m), 7.34 (2H, dd), 7.17-7.11 (2H, m), 6.43 (1H, d), 5.15 (2H, s), 4.44 (2H, d). Example 14: 4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2-trifluoroethyl) benzamide. [0151] 4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2-trifluoroethyl) benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e using 2,2,2- trifluoroethan-1-amine instead of ethylmethylamine in step c of Example 1.m/z (M+Na): 334.08 (calc 334.08) 1H NMR (400 MHz, d6 DMSO) δ 9.07 (1H, t), 8.69 (1H, s), 7.95 (1H, d), 7.89-7.81 (2H, m), 7.47-7.36 (2H, m), 6.44 (1H, d), 5.16 (2H, s), 4.08 (2H, qd). Example 15: N-isopropyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)ben zamide [0152] N-isopropyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)ben zamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using isopropyl methylamine in step c of Example 1. m/z: 335.28 (calc 335.16) 1H NMR (400 MHz, d6 DMSO) δ 8.59 (1H, s), 8.15 (1H, d), 7.84 (1H, t), 7.70 (1H, d), 7.56 (1H, t), 7.39 (2H, m), 7.32 (2H, br), 5.22 (2H, s), 4.66 and 3.75 (1H, br), 2.86-2.66 (3H, br), 1.06 (6H, br). Example 16: N-benzyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzam ide [0153] N-benzyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzam ide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using N-methyl benzylamine in step c of Example 1. m/z: 383.19 (calc 383.16) 1H NMR (400 MHz, d6 DMSO) δ 8.58 (1H, d), 8.14 (1H, d), 7.83 (1H, t), 7.70 (1H, d), 7.75 (1H, t), 7.40-7.00 (9H, br), 5.23 (2H, s), 4.64 and 4.43 (2H, br), 2.84-2.78 (3H, br). Example 17: N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)-N-(2,2,2-trifl uoroethyl) benzamide. [0154] N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)-N-(2,2,2-trifl uoroethyl)benzamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using 2,2,2- trifluoro-N-methylethan-1-amine in step c of Example 1. m/z: 375.19 (calc 375.12) 1H NMR (400 MHz, d6 DMSO) δ 8.56 (1H, d), 8.12 (1H, d), 7.81 (1H, t), 7.67 (1H, d), 7.52 (1H, t), 7.39 (4H, br), 5.21 (2H, s), 4.29 and 4.10 (2H, br), 3.00 (3H, br). Example 18: 4-((4,5-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-N,N-dimethy lbenzamide. [0155] 4-((4,5-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-N,N-dimethy lbenzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamid e using 5,6-dimethylpyrimidin-4(3H)-one instead of pyrimidin-4(3H)-one in step a and dimethylamine instead of ethylmethylamine in step c of Example 1. m/z: 285.01 (calc 285.15) 1H NMR (400 MHz, d6 DMSO) δ 8.45 (1H, s), 7.34 (4H, ABq), 5.09 (2H, s), 3.95-2.86 (3H, br), 2.20 (3H, s), 1.93 (3H, s). Example 19: N,N-dimethyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide [0156] N,N-dimethyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide was prepared using the following sequential synthesis procedures.
[0157] Step a - Synthesis of tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate [0158] Pyridin-2(1H)-one (5g, 53 mmol) and caesium carbonate (50.85g, 156 mmol) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature. Tert-butyl 4-(bromomethyl) benzoate (14.11g, 52 mmol) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (30 % to 50%) to give tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate. m/z: 285.16 (calc 285.14) [0159] Step b - Synthesis of 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid [0160] Tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate (10g, 35 mmol) was dissolved in dichloromethane (50ml) and trifluoroacetic acid (70ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (300ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 30ml) and dried in vacuo to give 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid. m/z: 229.09 (calc 229.07) [0161] Step c - Synthesis of N,N-dimethyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide [0162] 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.11ml, 81 mmol) and dimethylamine (2M solution in tetrahydrofuran, 69 mmol) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give N,N-dimethyl-4-((2- oxopyridin-1(2H)-yl)methyl)benzamide. m/z: 255.96 (calc 256.12) 1 H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.43 (1H, m), 7.36 (2H, d), 7.29 (2H, d), 6.41 (1H, d), 6.25 (1H, t), 5.11 (2H, s), 2.95-2.87 (6H, br). Example 20: N-ethyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide [0163] N-ethyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamidew as prepared similarly using ethylmethylaminee instead of dimethylamine in step c of Example 19. m/z: 270.01 (calc 270.14) 1 H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.44 (1H, m), 7.41 (2H, d), 7.29 (2H, d), 6.41 (1H, d), 6.25 (1H, t), 5.11 (2H, s), 3.42-3.16 (2H, br), 2.91-2.83 (3H, br), 1.10-1.03 (3H, br). Example 21: N-isopropyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzam ide [0164] N-isopropyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzam ide was prepared similarly using isopropyl methylamine instead of dimethylamine in step c of Example 19. m/z: 284.0 (calc 284.15) 1 H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.43 (1H, m), 7.30 (2H, d), 6.42 (1H, d), 6.25 (1H, t), 4.67 and 3.76 (1H, br), 2.78-2.68 (3H, br), 1.07 (6H, br). Example 22: N-benzyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide [0165] N-benzyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide was prepared similarly using N-methylbenzylamine instead of dimethylamine in step c of Example 19. m/z: 332.18 (calc 332.15) 1 H NMR (400 MHz, d6 DMSO) δ 7.80 (1H, br), 7.42 - 7.29 (9H, br), 7.16 (1H, br), 6.41 (1H, br), 6.24 (1H, br), 5.12 (2H, br s), 2.85-2.79 (3H, br). Example 23: N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)-N-(2,2,2- trifluoroethyl)benzamide [0166] N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)-N-(2,2,2-trifluor oethyl)benzamide was prepared similarly using 2,2,2-trifluoro-N-methylethan-1-amine instead of dimethylamine in step c of Example 19. m/z: 324.07 (calc 324.11) 1 H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.46 - 7.32 (5H, m), 6.42 (1H, d), 6.25 (1H, t), 5.13 (2H, s), 4.40.4.00 (2H, br), 3.00 (3H, br s). Example 24: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dime thylbenzamide [0167] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dime thylbenzamide was prepared using the following sequential synthesis procedures. [0168] Step a - Synthesis of tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)benzoate: Uracil (5g) and caesium carbonate (50.85g) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature. Tert-butyl 4- (bromomethyl)benzoate (14.11g) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (30 % to 50%) to give tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoate (3.5g, most polar product) and tert-butyl 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoate (420mg. least polar product). [0169] Step b - Synthesis of 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid: Tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoate (3g) was dissolved in dichloromethane (20ml) and trifluoroacetic acid (30ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (100ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 30ml) and dried in vacuo to give 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid. [0170] Step c - Synthesis of 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.11ml, 81 mmol) and dimethylamine (2M solution in tetrahydrofuran, 69 mmol) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide. m/z: 273.10 1 H NMR (400 MHz, d6 DMSO) δ 11.35, (1H, s), 7.78 (1H, d), 7.38 (2H, d), 7.32 (2H, d), 5.60 (1H, d), 4.90 (2H, s), 2.96-2.86 (6H, br). Example 25: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl benzamide [0171] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl benzamide was prepared similarly using methylamine instead of dimethylamine in step c of Example 24.m/z (M+Na): 282.08 (calc 282.08) 1H NMR (400 MHz, d6 DMSO) δ 11.34 (1H, s), 8.44-8.39 (1H, m), 7.84- 7.74 (3H, m), 7.39-7.32 (2H, m), 5.61 (1H, dd), 4.91 (2H, s), 2.77 (3H, d). Example 26: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-isopro pylbenzamide [0172] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-isopro pylbenzamide was prepared similarly using isopropylamine instead of dimethylamine in step c of Example 24. m/z (M+Na): 310.12 (calc 310.12)1H NMR (400 MHz, d6 DMSO) δ 11.34 (1H, s), 8.18 (1H, d), 7.84- 7.79 (2H, m), 7.77 (1H, d), 7.39-7.30 (2H, m), 5.61 (1H, dd), 4.91 (2H, s), 4.08 (1H, sept.), 1.15 (6H, d). Example 27: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(4- fluorobenzyl)benzamide [0173] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(4-flu orobenzyl)benzamide was prepared similarly using 4-fluorobenzylamine instead of dimethylamine in step c of Example 24. m/z (M+Na): 376.11 (calc 376.11) 1H NMR (400 MHz, d6 DMSO) δ 11.27 (1H, s), 9.04 (1H, t), 7.91-7.82 (2H, m), 7.77 (1H, d), 7.42-7.30 (4H, m), 7.18-7.10 (2H, m), 5.61 (1H, s), 4.92 (2H, s), 4.45 (2H, d). Example 28: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dime thylbenzamide [0174] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dime thylbenzamide was prepared using the following sequential synthesis procedures. [0175] Step a - Synthesis of 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid: Tert-butyl 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoate (2g) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (15ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (50ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 15ml) and dried in vacuo to give 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid. [0176] Step b - Synthesis of 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid (32mg) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (43mg) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.06ml) and dimethylamine (2M solution in tetrahydrofuran) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give 4-((2,6-dioxo-3,6- dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide. m/z: 273.51 (calc 273.11) 1 H NMR (400 MHz, d6 DMSO) δ 7.48 (1H, d), 7.32 (2H, d), 7.27 (2H, d), 5.61 (1H, d), 4.95 (2H, s), 2.95- 2.85 (6H, br). Example 29: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl- N- methylbenzamide [0177] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl- N-methylbenzamide was prepared similarly using methylethylamine instead of dimethylamine in step b of Example 28. m/z: 287.18 (calc 287.13) 1 H NMR (400 MHz, d6 DMSO) δ 7.49 (1H, d), 7.28 (4H, br s), 5.64 (1H, d), 4.95 (2H, d), 3.4-3.2 (2H, m), 2.95-2.85 (3H, br), 1.1-1.0 (3H, br). Example 30: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-isopro pyl-N- methylbenzamide [0178] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-isopro pyl-N-methylbenzamide was prepared similarly using methylisopropylamine instead of dimethylamine in step b of Example 28. m/z: 301.18 (calc 301.14) 1 H NMR (400 MHz, d6 DMSO) δ 11.20 (1H, s), 7.49 (1H, d), 7.28 (4H, br s), 5.65 (1H, d), 4.95 (2H, d), 3.78 (2H, br m), 2.78-2.60 (3H, br), 1.2-1.0 (6H, br). Example 31: N-benzyl-4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl) -N- methylbenzamide [0179] N-benzyl-4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl) -N-methylbenzamide was prepared similarly using N-methylbenzylamine instead of dimethylamine in step b of Example 28. m/z: 349.36 (calc 349.14) 1 H NMR (400 MHz, d6 DMSO) δ 11.20 (1H, s), 7.48 (1H, d), 7.35-7.29 (8H, br m), 7.15 (1H, br m), 5.62 (1H, br), 4.95 (2H, br), 4.64 and 4.44 (2H, br), 2.84-2.79 (3H, br). Example 32: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl -N-(2,2,2- trifluoroethyl)benzamide [0180] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl -N-(2,2,2- trifluoroethyl)benzamide was prepared similarly using 2,2,2-trifluoro-N-methylethan-1-amine instead of dimethylamine in step b of Example 28. m/z: 341.10 (calc 341.10) 1 H NMR (400 MHz, d6 DMSO) δ 11.25 (1H, s), 7.49 (1H, d), 7.36-7.31 (4H, br m), 5.65 (1H, br), 4.96 (2H, s), 4.34 and 4.11 (2H, br), 3.00 (3H, br). Example 33: 3-(4-(oxazol-2-yl)benzyl)pyrimidin-4(3H)-one [0181] 3-(4-(oxazol-2-yl)benzyl)pyrimidin-4(3H)-one was prepared using the following synthesis procedure. [0182] Pyrimidin-4(3H)-one (500mg, 5.2 mmol) and caesium carbonate (5g, 15.6 mmol) were stirred in dimethylformamide (25ml) for 10 minutes at room temperature. 2-(4- (bromomethyl)phenyl)oxazole (1.26g, 5.3 mmol) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (5 % to 95%) to give 3-(4-(oxazol-2-yl)benzyl)pyrimidin-4(3H)-one. m/z: 253.01 (calc 253.09) 1 H NMR (400 MHz, d 6 DMSO) δ 8.69 (1H, s), 8.21 (1H, s), 7.94 (3H, m), 7.45 (2H, d), 7.37 (1H, d), 6.44 (1H, d), 5.11 (2H, s). Example 34: 3-(4-(oxazol-2-yl)benzyl)quinazolin-4(3H)-one [0183] 3-(4-(oxazol-2-yl)benzyl)quinazolin-4(3H)-one was prepared similarly to Example 33 using quinazolin-4(3H)-one instead of pyrimidin-4(3H)-one. m/z: 303.07 (calc 303.10) 1 H NMR (400 MHz, d6 DMSO) δ 8.61 (1H, s), 8.20 (1H, s), 8.15 (1H, d), 7.94 (2H, d), 7.82 (1H, m), 7.70 (1H, d), 7.56 (1H, m), 7.50 (2H, d), 7.36 (1H, s), 5.26 (2H, s). Example 35: 3-(4-(oxazol-2-yl)benzyl)pyrimidine-2,4(1H,3H)-dione [0184] 3-(4-(oxazol-2-yl)benzyl)pyrimidine-2,4(1H,3H)-dione was prepared similarly to Example 33 using uracil instead of pyrimidin-4(3H)-one. m/z: 269.13 (calc 269.08) 1 H NMR (400 MHz, d 6 DMSO) δ 8.20 (1H, s), 7.91 (2H, d), 7.50 (1H, m), 7.39 (2H, d), 7.36 (1H, s), 5.60 (1H, d), 4.98 (2H, s). Scheme 1 - General Method For The Synthesis of Sulfonyl Derivatives [0185] Examples 36-53 were prepared using the following synthetic procedure. [0186] The carboxylic acid (1 equivalent), potassium hydroxide (1 equivalent) and potassium carbonate (2 equivalents) were added to water and stirred. The sulfonyl chloride (1 equivalent) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled to 0 o C and acidified with 2M hydrochloric acid to give a white precipitate. This precipitate was dried and triturated with n-pentane to give the compound of formula (1). Example 36: 1-(Quinolin-8-ylsulfonyl)piperidine-4-carboxylic acid [0187] 1-(Quinolin-8-ylsulfonyl)piperidine-4-carboxylic acid was prepared using the general method of Scheme 1 and 1-quinolin-8-ylsulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.26 (1H, s), 9.07 (1H, s), 8.54 (1H, d), 8.36 (1H, d), 8.30 (1H, d), 7.74 (1H, m), 7.70 (1H, m), 3.81 (2H, m), 2.82 (2H, m), 2.31 (1H, m), 1.82 (2H, m), 1.44 (1H, m). Example 37: 1-((2-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0188] Example 37 was prepared using the general method and 1-(2- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.38 (1H, br s), 7.97 (1H, d), 7.88 (2H, m), 7.56 (1H, m), 3.60 (2H, m), 2.83 (2H, t), 2.40 (1H, m), 1.86 (2H, m),1.48 (2H, m). Example 38: 1-((3-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0189] Example 38 was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, CDCl3) δ 7.77 (1H, s), 7.76 (1H, d), 7.63 (1H, m), 7.60 (1H, m), 3.68 (2H, m), 2.55 (2H, t), 2.37 (1H, m), 2.02 (2H, m),1.86 (2H, m). Example 39: 1-((2,3-Dichlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0190] Example 39 was prepared using the general method and 1-(2,3- dichlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.36 (1H, br s), 7.97 (2H, d), 7.59 (1H, m), 3.64 (2H, m), 2.90 (2H, t), 2.43 (1H, m), 1.80 (2H, m),1.54 (2H, m). Example 40: (S)-1-((3-Fluorophenyl)sulfonyl)piperidine-3-carboxylic acid [0191] Example 40 was prepared using the general method and 1-(3- fluorophenyl)sulfonylchloride and (S)-piperidine-3-carboxylic acid. 1 H NMR (400 MHz, CD 3 OD) δ 7.52 (2H, m), 7.48 (1H, m), 7.44 (1H, m), 3.73 (1H, d), 3.53 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.59 (1H, m), 1.50 (1H, m). Example 41: (S)-1-((3-Chlorophenyl)sulfonyl)piperidine-3-carboxylic acid [0192] Example 41 was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and (S)-piperidine-3-carboxylic acid. 1 H NMR (400 MHz, CD 3 OD) δ 7.79 (1H, s), 7.68 (2H, m), 7.62 (1H, m), 3.72 (1H, d), 3.51 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.58 (1H, m), 1.51 (1H, m). Example 42: (R)-1-((3-Fluorophenyl)sulfonyl)piperidine-3-carboxylic acid [0193] Example 42 was prepared using the general method and 1-(3- fluorophenyl)sulfonylchloride and (R)-piperidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 7.52 (2H, m), 7.48 (1H, m), 7.44 (1H, m), 3.73 (1H, d), 3.53 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.59 (1H, m), 1.50 (1H, m). Example 43: (R)-1-((3-Chlorophenyl)sulfonyl)piperidine-3-carboxylic acid [0194] Example 43was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and (R)-piperidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 7.79 (1H, s), 7.68 (2H, m), 7.62 (1H, m), 3.73 (1H, d), 3.53 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.59 (1H, m), 1.50 (1H, m). Example 44: 1-((4-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0195] Example 44 was prepared using the general method and 1-(4- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.32 (1H, s), 7.73 (4H, m), 3.47 (2H, m), 2.44 (2H, m), 2.28 (1H, m), 1.86 (2H, m), 1.57 (2H, m). Example 45: 1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxyl ic acid [0196] Example 45 was prepared using the general method and 1-(2-(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.36 (1H, s), 8.03 (2H, m), 7.90 (2H, m), 3.61 (2H, m), 2.85 (2H, m), 2.41 (1H, m), 1.90 (2H, m), 1.55 (2H, m). Example 46: 1-((3-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxyl ic acid [0197] Example 46 was prepared using the general method and 1-(3- (trifluoromethyl)phenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.33 (1H, s), 8.13 (1H, m), 8.07 (1H, m), 7.95 (1H, m), 7.90 (1H, m), 3.53 (2H, m), 2.45 (2H, m), 2.32 (1H, m), 1.89 (2H, m), 1.57 (2H, m). Example 47: 1-((4-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxyl ic acid [0198] Example 47 was prepared using the general method and 1-(4-(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 8.00 (2H, m), 7.92 (2H, m), 3.20 (2H, m), 2.54 (2H, m), 1.70 (3H, m), 1.57 (2H, m). Example 48: 1-((2,5-Bis(trifluoromethyl)phenyl)sulfonyl)piperidine-4-car boxylic acid [0199] Example 48 was prepared using the general method and 1-(2,5-bis(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.36 (1H, s), 8.30 (2H, m), 8.24 (1H, s), 3.65 (2H, m), 2.87 (2H, m), 2.43 (1H, m), 1.89 (2H, m), 1.54 (2H, m). Example 49: 1-((2-(Trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxy lic acid [0200] Example 49 was prepared using the general method and 1-(2- (trifluoromethoxy)phenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.33 (1H, s), 7.93 (1H, m), 7.83 (1H, m), 7.62 (2H, m), 3.56 (2H, m), 2.71 (2H, m), 2.36 (1H, m), 1.87 (2H, m), 1.52 (2H, m). Example 50: (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)pyrrolidine-3-car boxylic acid [0201] Example 50 was prepared using the general method and 1-(2-(trifluoromethyl)phenyl) sulfonylchloride and (S)-pyrrolidine-3-carboxylic acid. 1 H NMR (400 MHz, d6 DMSO) δ 12.62 (1H, br s), 8.05 (2H, m), 7.90 (2H, m), 3.48 (2H, m), 3.38 (2H, m), 3.15 (1H, m), 2.11 (2H, m). Example 51: (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)pyrrolidine-3-car boxylic acid [0202] Example 51 was prepared using the general method and 1-(2- (trifluoromethyl)phenyl)sulfonylchloride and (R)-pyrrolidine-3-carboxylic acid 1 H NMR (400 MHz, d6 DMSO) δ 12.62 (1H, br s), 8.05 (2H, m), 7.90 (2H, m), 3.48 (2H, m), 3.38 (2H, m), 3.15 (1H, m), 2.11 (2H, m). Example 52: (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carb oxylic acid [0203] (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carb oxylic acid was prepared using the following synthesis procedure. [0204] (S)-Piperidine-3-carboxylic acid (1g, 7.7 mmol), potassium hydroxide (434mg, 7.7 mmol) and potassium carbonate (2.14g, 15.4 mmol) were added to water (20ml) and stirred. 2- (Trifluoromethyl)benzenesulfonyl chloride (1.89g, 7.7 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled to 0oC and acidified with 2M hydrochloric acid to give a white precipitate. This precipitate was dried and triturated with n- pentane to give (S)-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carb oxylic acid. Tlc Rf 0.370% ethyl acetate in hexane. m/z: 337.98 (calc 338.03) 1 H NMR (400 MHz, d6 DMSO) δ 12.33 (1H, s), 8.04 (2H, m), 7.90 (2H, m), 3.69 (1H, dd), 3.50 (1H, dd), 2.93 (1H, m), 2.81 (1H, m), 1.91 (1H, m), 1.72 (1H, m), 1.50 (2H, m). Example 53: (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carb oxylic acid [0205] (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carb oxylic acid was prepared in the same manner as (S)-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carb oxylic acid, but using (R)-piperidine-3-carboxylic acid. Tlc Rf 0.370% ethyl acetate in hexane. m/z: 338.03 (calc 338.03) 1H NMR (400 MHz, d6 DMSO) δ 12.53 (1H, s), 8.04 (2H, m), 7.90 (2H, m), 3.69 (1H, dd), 3.49 (1H, dd), 2.93 (1H, m), 2.81 (1H, m), 1.90 (1H, m), 1.72 (1H, m), 1.49 (2H, m). General Scheme 1 for the Synthesis of Examples 54–59 [0206] Active compounds can be made directly using an amide electrophile (Step 4) or indirectly via ester hydrolysis and then amidation (Steps 1, 2 and 3) (General Scheme 1). Those skilled in the art may select amines with a range of suitable R 1 and R 2 groups. Suitable R 8 groups include CH 3 , CH 2 CH 3 , C(CH 3 )3. Suitable R 1 and R 2 groups include H, CH 3 , CH 2 CH 3 , CH(CH 3 )2, C(CH 3 )3, CH 2 Ph. Herein DMF means dimethylformamide and CDI means carbonyldiimidazole. [0207] Electrophiles to be used in Step 1 of the General Scheme 1 below and their resulting amides formed after Steps 2 and 3 are shown in Table 1. Electrophiles to be used in Step 4 of Scheme 1 and their resulting amides formed directly are shown in Table 2.
Table 1. Structure of step 1 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound Table 2. Structure of step 4 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound General Scheme 2 for the Synthesis of Examples 60-81 [0208] Active compounds made in two steps involving for instance an alkylation to give an aryl halide intermediate followed by a palladium catalyzed C-C or C-N bond formation (General Scheme 2, Steps 1 and 2), or directly using an electrophile containing the final X-group (Scheme 1, Step 3).
Table 3 – Possible electrophiles to be used in Step 3 of General Scheme 2, references for their synthesis, and the final compounds. Table 4 – Possible coupling reagents to be used in Step 2 of Scheme 1, references for their reactions, and the final compounds. General Scheme 3 for the Synthesis of Examples 82-106 [0209] Active compounds made directly by N-alkylation of a heterocyclic compound to give an amide (Step 4) or indirectly via an ester followed by hydrolysis and then amidation (Steps 1, 2 and 3) (Scheme 3). Those skilled in the art may select amines with a range of suitable R 1 and R 2 groups. Suitable R 8 groups include CH 3 , CH 2 CH 3 , C(CH 3 ) 3 . Suitable R 1 and R 2 groups include H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 Ph. Herein DMF means dimethylformamide and CDI means carbonyldiimidazole Table 5. Structure of Step 1 and Step 4 heterocyclic compounds, references for the synthesis and / or reaction of the heterocycle with related electrophiles, and the structure of the final compound
Example 107: Activity of compounds of the invention in an A1AT cell secretion assay using HEK-Z cells [0210] HEK-Z cells, a human embryonic kidney cell line stably transfected with the human Z A1AT gene, were plated into 96 well plates (3.0 x 10 5 cells/ml with 200 µl of media/well) overnight at 37˚C in a humidified atmosphere containing 5% CO 2 . Following incubation cells were washed with 200 µl serum-free media three times and media was replaced with treatments in quadruplicate using serum free media containing either vehicle, 10 µM suberanilohydroxamic acid (SAHA) or a compound of the invention (at concentrations of 10, 33, 100 and 333 nM) for 48 h in a 37˚C incubator in a final volume of 200 µl. At the end of the incubation step the supernatants were removed from the wells, centrifuged at 1000 x g at 4˚C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/α1-antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0211] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H 2 SO 4 ) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. [0212] The data in Table 6 show that compounds of Examples 1-18 and 24-32 increase secretion of Z A1AT from HEK-Z cells at 300nM. Table 6
[0213] The data in Table 7 show that compounds of Examples 19-23 and 33-35 increase secretion of Z A1AT from HEK-Z cells at 33nM. Table 7
[0214] For examples 36-53, the amount of human A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 µM was used a positive control for all in vitro A1AT secretion experiments. [0215] The data in Table 8 show that the compounds of Examples 36-53 increase the secretion of human Z A1AT from HEK-Z cells in a dose dependent manner as measured by ELISA. Table 8 Example 108: Activity of the compounds of Examples 1-18 in an A1AT cell secretion assay using HEK-M cells [0216] HEK-M cells, a human embryonic kidney cell line stably transfected with M A1AT, were plated into 96 well plates (3.0 x 10 5 cells/ml with 200 µl of media/well) overnight at 37˚C in a humidified atmosphere containing 5% CO 2 . Following incubation cells were washed with 200 µl serum-free media three times and media was replaced with serum-free media containing vehicle, 10 µM suberanilohydroxamic acid (SAHA) or a compound of Examples 36-51 in replicates of six for 48 h in a 37˚C incubator in a final volume of 200 µl. At the end of the incubation step the supernatants were removed from the wells, centrifuged at 1000 x g at 4˚C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/α 1 antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0217] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. Results [0218] The amount of human M A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 µM was used a positive control for all in vitro A1AT secretion experiments. The compounds of Examples 36, 38, 39, 45, 52 and 53 did not lead to an increase in secretion of human M A1AT from HEK-M cells at 10µM. Example 109: Activity of the compounds of Examples 36 and 52 in an A1AT cell secretion assay using HEK-Siiyama cells [0219] The rare Siiyama mutation (Ser 53 to Phe, mature A1AT numbering) was identified in a Japanese male with AATD (Seyama et al J Biol Chem (1991) 266:12627-32). Ser53 is one the conserved serpin residues and is thought to be important for the organization of the internal core of the A1AT molecule. The change from an uncharged polar to a large nonpolar amino acid on the conserved backbone of the protein affects the folding and intracellular processing of Siiyama A1AT. [0220] HEK-Siiyama cells, a human embryonic kidney cell line stably transfected with the human Siiyama A1AT gene, were plated into 96 well plates (3.0 x 10 5 cells/ml with 200 µl of media/well) overnight at 37˚C in a humidified atmosphere containing 5% CO 2 . Following incubation cells were washed with 200 µl serum-free media three times and media was replaced with serum-free media containing vehicle, 10 µM suberanilohydroxamic acid (SAHA) or a compound of Example 1 (at 1 and 10 µM) in replicates of eight for 48 h in a 37˚C incubator in a final volume of 200 µl. At the end of the incubation step the supernatants were removed from the wells, centrifuged at 1000 x g at 4˚C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/α 1 - antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0221] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed, and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed, and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed, and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. Results [0222] The amount of human Siiyama A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 µM was used a positive control for all in vitro A1AT human secretion experiments. The exemplar compounds of Example 36 and 52 did not stimulate secretion of Siiyama A1AT from HEK-Siiyama cells at 1 or 10 µM, as measured by ELISA. In contrast, the positive control 10 µM SAHA stimulated an increase in Siiyama A1AT secretion. Example 110: Activity of the compounds of Examples 36 and 52 in a mouse expressing human Z (huZ mouse) [0223] The huZ mouse (also referred to as the PiZZ mouse) is a transgenic mouse strain that contains multiple copies of the Z variant of the human A1AT gene, developed by two separate groups (Dycaico et al Science (1988) 242:1409-12) and Carlson et al J. Clin Invest (1989) 83:1183-90). HuZ mice are on a C57Bl/6 background and express the human Z A1AT protein in liver tissue. The mice used in this study are from the progeny of Carlson and colleagues (transgenic line Z11.03). HuZ mice have been used as a tool to assess the effects of an exemplar compound of the invention on either increasing the circulating levels of Z A1AT in plasma or the effects of compound on the accumulation of Z A1AT polymers in the liver and associated liver pathology. [0224] HuZ mice (n=4/group; male or female) with basal human Z A1AT plasma levels of between 200-600 µg/ml were treated with either vehicle or the compounds of Examples 26 or 52 at 5, 15 or 50 mg/kg twice a day by oral gavage for 14 consecutive days. Mice had access to food (standard mouse chow, SAFE diets) and water ad libitum. On study day 14, each mouse was dosed one hour prior to terminal procedures. Blood was taken from each mouse from the tail vein on pre- dosing days -12, -7 and -5, and dosing days 12, 13 and 14. Blood was collected into microvettes containing EDTA and plasma was prepared by centrifugation at 2700 x g at 4˚C for 10 min. Plasma was aliquoted and stored at -80˚C for bioanalysis. Plasma samples from pre-dosing days -12, -7 and -5 were used for to determine mean basal levels of human Z A1AT for each mouse. Plasma samples collected on the last three dosing days of the study (days 12, 13 and 14) were used to determine the effect of the compound of Example 26 or 52 on human Z A1AT secretion by measuring human Z A1AT levels and comparing to basal levels for each mouse. Human Z A1AT levels in mouse plasma samples were measured by ELISA (Human Serpin A1/α1 antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0225] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed, and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed, and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H 2 SO 4 ) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. Results [0226] The effect of the compound of Example 26 or 52 on circulating levels of human Z A1AT was assessed in the huZ mouse model. The compounds of Example 26 and 52 stimulated secretion of human Z A1AT compared to baseline levels in huZ mice.
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