Morpholine-containing and piperazine-containing CXCR4 modulators and uses related thereto
CXCR4 antagonists and pharmaceutical formulations thereof are disclosed. The compounds and pharmaceutical formulations disclosed herein can be used to antagonize the CXCR4 pathway for mobilizing stem cells or treating a condition, disorder, or disease associated with the CXCR4 pathway. Exemplary conditions, disorders, and diseases relevant to this disclosure include HIV infections, WHIM syndrome, Waldenström macroglobulinemia, chronic neutropenia, primary immune-deficiency, aplastic anemia, hypoplastic myelodysplastic syndrome, acute respiratory distress syndrome (ARDS), ankylosing spondylitis, autoimmune diseases, and cancers.
1 . A compound of Formula I or a pharmaceutically acceptable salt thereof,
wherein W is CH 2 or O;
wherein Vis hydrogen, an optionally substituted C 1 -C 4 alkyl, or an optionally substituted C 1 -C 4 haloalkyl;
wherein:
(1) R 1 is an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 1 -C 4 haloalkyl, an optionally substituted C 1 -C 4 alkenyl, an optionally substituted C 1 -C 4 haloalkenyl, an optionally substituted carbocyclyl, or an optionally substituted halocarbocyclyl, or
(2) R 1 is an optionally substituted, bridging C 1 -C 4 alkyl, an optionally substituted, bridging C 1 -C 4 haloalkyl, an optionally substituted, bridging C 1 -C 4 alkenyl, or an optionally substituted, bridging C 1 -C 4 haloalkenyl, joining the carbon atom labeled by the “*” sign to form an optionally substituted heterocycle;
wherein the pair of R 8 and R 9 is ═O or ═S;
wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, amino, optionally substituted hydroxyl, optionally substituted alkyl, or optionally substituted haloalkyl;
optionally wherein one or more of the following pairs—R 2 and R 3 , R 4 and R 5 , and R 6 and R 7 —are independently ═O or ═S; and
optionally wherein two of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 joint together to form a bridge on the morpholine ring or a carbocycle or heterocycle that is connected to the morpholine ring in a spiro manner (i.e., the two rings are connected through a single common atom) or in a fused manner (i.e., the two rings share two adjacent atoms; in other words, the two rings share one covalent bond).
2 . The compound of claim 1 , wherein Formula I is in the following configuration.
3 . The compound of claim 1 , wherein Wis CH 2 and Vis hydrogen.
4 . The compound of claim 1 , wherein R 1 is methyl.
5 . The compound of claim 1 , wherein R 1 is —R 10 —R 11 ,
wherein R 10 is an optionally substituted, bridging C 1 -C 4 alkylene (alkyl bridge), an optionally substituted, bridging C 1 -C 4 haloalkylene (haloalkyl bridge), an optionally substituted, bridging C 1 -C 4 alkenylene (alkenyl bridge), an optionally substituted, bridging C 1 -C 4 haloalkenylene (haloalkenyl bridge), an optionally substituted, bridging carbocyclylene (carbocyclyl bridge), or an optionally substituted, bridging halocarbocyclylene (halocarbocyclyl bridge), and
wherein R 11 is hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, alkylcarbocyclyl, haloalkylcarbocyclyl, halocarbocyclyl, heterocyclyl, alkylheterocyclyl, haloalkylheterocyclyl, haloheterocyclyl, —NR a R b , —NR c [C(═O)R d ], or —OR f , wherein R a , R b , R c , R d , and R f are independently hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, alkylcarbocyclyl, haloalkylcarbocyclyl, halocarbocyclyl, heterocyclyl, alkylheterocyclyl, haloalkylheterocyclyl, haloheterocyclyl, aryl, alkylaryl, haloalkylaryl, haloaryl, heteroaryl, alkylheteroaryl, haloalkylheteroaryl, or haloheteroaryl.
6 . The compound of claim 5 , wherein R 1 is selected from the group consisting of: ethyl, propyl, isopropyl, butyl, isobutyl, —(CH 2 ) 2 OH, —(CH 2 ) 2 NH 2 , —(CH 2 ) 3 OH, —(CH 2 ) 3 NH 2 , —(CH 2 ) 4 OH, —(CH 2 ) 4 NH 2 , —(CH 2 ) 3 CF 3 ,
7 . The compound of claim 1 , wherein R 1 is an optionally substituted, bridging C 1 -C 4 alkyl, an optionally substituted, bridging C 1 -C 4 haloalkyl, an optionally substituted, bridging C 1 -C 4 alkenyl, or an optionally substituted, bridging C 1 -C 4 haloalkenyl, joining the carbon atom labeled by the “*” sign to form an optionally substituted heterocycle, wherein the optionally substituted heterocycle is five- or six-membered.
8 . The compound of claim 7 , wherein the optionally substituted heterocycle is a piperidine.
9 . The compound of claim 1 , selected from the group consisting of:
or is a pharmaceutically acceptable salt thereof.
10 . A pharmaceutical formulation, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
11 . The pharmaceutical formulation of claim 10 , wherein the pharmaceutical formulation is in the form of tablet, capsule, pill, gel, cream, granule, solution, suspension, emulsion, or nanoparticulate formulation.
12 . The pharmaceutical formulation of claim 10 , wherein the pharmaceutical formulation is an oral formulation.