US 11,746,106 B2
Inhibitors of VAP-1
Mark W. Orme, Seattle, WA (US); Edison S. Zuniga, Seattle, WA (US); Vladimir A. Kuksa, Seattle, WA (US); Russell Stuart Craft, Groningen (NL); Eduardo Moreno Saveedra, Groningen (NL); Johannes Wilhelm Georg Meissner, Groningen (NL); Jacobus Antonius Joseph den Hartog, Weesp (NL); and Albert Cornelis Dros, Groningen (NL)
Assigned to ACUCELA INC., Seattle, WA (US)
Appl. No. 17/279,382
Filed by ACUCELA INC., Seattle, WA (US)
PCT Filed Sep. 27, 2019, PCT No. PCT/US2019/053481
§ 371(c)(1), (2) Date Mar. 24, 2021,
PCT Pub. No. WO2020/069330, PCT Pub. Date Apr. 2, 2020.
Claims priority of provisional application 62/738,924, filed on Sep. 28, 2018.
Prior Publication US 2021/0387975 A1, Dec. 16, 2021
Int. Cl. C07D 413/12 (2006.01); C07D 235/08 (2006.01); C07D 249/18 (2006.01); C07D 261/20 (2006.01); C07D 263/56 (2006.01); C07D 263/58 (2006.01); C07D 277/64 (2006.01); C07D 277/82 (2006.01); C07D 413/04 (2006.01); C07D 491/107 (2006.01)
CPC C07D 413/12 (2013.01) [C07D 235/08 (2013.01); C07D 249/18 (2013.01); C07D 261/20 (2013.01); C07D 263/56 (2013.01); C07D 263/58 (2013.01); C07D 277/64 (2013.01); C07D 277/82 (2013.01); C07D 413/04 (2013.01); C07D 491/107 (2013.01)] 19 Claims
 
1. A compound having structural Formula (III-A):

OG Complex Work Unit Chemistry
or an alkene isomer, tautomer, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein:
X1 is —NR8—, —O—, or —S—;
Y is —O—;
W is a bond, —O—, —S—, or —NH—;
z1 and z2 are independently an integer from 0 to 3;
n1, n2, n5, n6, n7, n8, and n12 are independently an integer from 0 to 4;
m1, m2, m5, m6, m7, m8, m12, v1, v2, v5, v6, v7, v8, and v12 are independently 1 or 2;
L1 is a bond, —O—, —S—, —NR1L—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R1L is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R1 is independently hydrogen, halogen, —CX1.13, —CHX1.12, —CH2X1.1, —CN, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NR1BOR1D, —OCX1.13, —OCHX1.12, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;
R2 is hydrogen, halogen, —CX2.13, —CHX2.12, —CH2X2.1, —CN, —SOn2R2A, —SOv2NR2BR2C, —NR2BR2C, —C(O)R2D, —C(O)OR2D, —C(O)NR2BR2C, —OR2A, —OCX2.13, —OCHX2.12 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 and R4 are independently hydrogen or —F;
R5 is hydrogen, halogen, —CX5.13, —CHX5.112, —CH2X5.1, —CN, —N3, —SOn5R5A, —SOv5NR5BR5C, —NHNR5BR5C, —ONR5BR5C, —NHC(O)NHNR5BR5C, —NHC(O)NR5BR5C, —N(O)m5, —NR5BR5C, —C(O)R5D, —C(O)OR5D, —C(O)NR5BR5C, —OR5A, —NR5BSO2R5A, —NR5BC(O)R5D, —NR5BC(O)OR5D, —NR5BOR5D, —OCX5.13, —OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R6 is hydrogen, halogen, —CX6.13, —CHX6.12, —CH2X6.1, —CN, —N3, —SOn6R6A, —SOv6NR6BR6C, —NHNR6BR6C, —ONR6BR6C, —NHC(O)NHNR6BR6C, —NHC(O)NR6BR6C, —N(O)m6, —NR6BR6C, —C(O)R6D, —C(O)OR6D, —C(O)NR6BR6C, —OR6A, —NR6BSO2R6A, —NR6BC(O)R6D, —NR6BC(O)OR6D, —NR6BOR6D, —OCX6.13, —OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R7 is hydrogen, halogen, —CX7.113, —CHX7.112, —CH2X7.1, —CN, —SOn7R7A, —SOv7NR7BR7C, —NR7BR7C, —C(O)R7D, —C(O)OR7D, —C(O)NR7BR7C, —OR7A, —OCX7.13, —OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —OCX8.13, —OCHX8.12 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R12 is hydrogen, halogen, —CX12.13, —CHX12.12, —CH2X12.1, —CN, —SOn12R12A, —SOv12NR12BR12C, —NR12BR12C, —C(O)R12D, —C(O)OR12D, —C(O)NR12BR12C, —OR12A, —OCX12.13, —OCHX12.112 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R1A is hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —COOH, —CONH2, R12A-substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A-substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A-substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;
R1B is hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —COOH, —CONH2, R12B-substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B-substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;
R1C is hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —COOH, —CONH2, R12C-substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C-substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1B and R1C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R1D is hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —COOH, —CONH2, R12C-substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D-substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D-substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl;
R2A, R2B, R2C, R2D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R8A, R8B, R8C, R8D, R12A, R12B, R12C, and R12D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2B and R2C; R5B and R5C; R6B and R6C; R7B and R7C; R8B and R8C; or R12B and R12C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X, X1.1, X2.1, X5.1, X6.1, X7.1, X8.1, and X12.1 are independently —Cl, —Br, —I, or —F.