US 12,258,337 B2
Bicyclic CX3CR1 receptor agonists
Paolo Pevarello, Pavia (IT); William J. Ray, Houston, TX (US); Mary Hamby, Houston, TX (US); Yaima Luzardo Lightfoot, Pearland, TX (US); Philip Jones, Houston, TX (US); Russell Thomas, Siena (IT); Chiara Liberati, Milan (IT); Domenica Torino, Praia a Mare (IT); Valentina Cusano, Naples (IT); Francesco Piscitelli, Marina di Strongoli (IT); Ali Munaim Yousif, Aversa (IT); and Silvia Bovolenta, Milan (IT)
Assigned to Board of Regents, The University of Texas System, Austin, TX (US); and Golgi Neurosciences S.R.L., Milan (IT)
Filed by Board of Regents, The University of Texas System, Austin, TX (US); and Golgi Neurosciences S.R.L., Milan (IT)
Filed on Sep. 19, 2023, as Appl. No. 18/470,029.
Application 17/481,653 is a division of application No. 16/937,005, filed on Jul. 23, 2020, granted, now 11,155,538, issued on Oct. 26, 2021.
Application 18/470,029 is a continuation of application No. 17/481,653, filed on Sep. 22, 2021, granted, now 11,958,839.
Claims priority of provisional application 62/877,660, filed on Jul. 23, 2019.
Prior Publication US 2024/0150332 A1, May 9, 2024
Int. Cl. C07D 409/14 (2006.01); C07C 233/78 (2006.01); C07D 333/78 (2006.01); C07D 409/12 (2006.01)
CPC C07D 409/14 (2013.01) [C07C 233/78 (2013.01); C07D 333/78 (2013.01); C07D 409/12 (2013.01)] 13 Claims
 
1. A process of making a compound of structural formula (I)

OG Complex Work Unit Chemistry
comprising reacting a compound of structural formula (IX)

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with a hydride in a solvent, wherein
n is an integer between 1 and 4, forming a 6-10-membered cycloalkyl;
A is chosen from phenyl and heteroaryl, optionally substituted with one or more C1-C3 alkyl substituents;
R1 is hydrogen;
R2 and R3 are independently chosen from hydrogen, phenyl, and C1-C6 alkyl; or R2 and R3 are joined together via a group Y, such that R2-Y-R3, together with the carbon to which R2 and R3 attach, forms C3-C7 cycloalkyl or C3-C7 heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, halogen, and C1-C6 alkyl; or the C3-C7 cycloalkyl or C3-C7 heterocycloalkyl is fused with a phenyl ring which is optionally substituted with one or more substituents chosen from hydroxyl, halogen, and C1-C6 alkyl;
Y is chosen from C and O;
R4 is chosen from

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R5 and R6 are each independently C1-C6 alkyl;
R7, R8, R9, and R10 are independently chosen from hydrogen and hydroxyl, or is independently chosen from C1-C6 alkyl and C1-C6 alkyloxy, either of which is optionally substituted with methoxy;
p is 1 or 2; and
X is chosen from C, O, or NR11 where R11 is hydrogen or C1-C3 alkyl;
with the proviso that if A is thiophene, n is 2 or 3, R1 is hydrogen, and R4 is

OG Complex Work Unit Chemistry
then either R5 and R6 are not both methyl, and/or R2 and R3 are not both methyl, and further provided that if A is thiophene, n is 2 or 3, R1 is hydrogen, and R4 is

OG Complex Work Unit Chemistry
then R2 and R3 are not hydrogen.