US 10,889,590 B2
Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
Kyriacos C. Nicolaou, Houston, TX (US); Min Lu, Houston, TX (US); Debashis Mandal, Houston, TX (US); Sanjeev Gangwar, Foster City, CA (US); Naidu S. Chowdari, Dublin, CA (US); and Yam B. Poudel, Fremont, CA (US)
Assigned to William Marsh Rice University, Houston, TX (US); The Scripps Research Institute, La Jolla, CA (US); and Bristol-Myers Squibb Company, Princeton, NJ (US)
Filed by WILLIAM MARSH RICE UNIVERSITY, Houston, TX (US); BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US); and THE SCRIPPS RESEARCH INSTITUTE, La Jolla, CA (US)
Filed on Mar. 18, 2019, as Appl. No. 16/357,109.
Application 16/357,109 is a division of application No. 15/677,959, filed on Aug. 15, 2017, granted, now 10,233,192, issued on Mar. 19, 2019.
Application 15/677,959 is a division of application No. 14/911,881, granted, now 9,777,013, issued on Oct. 3, 2017, previously published as PCT/US2014/051127, filed on Aug. 14, 2014.
Claims priority of provisional application 61/865,896, filed on Aug. 14, 2013.
Claims priority of provisional application 61/868,783, filed on Aug. 22, 2013.
Claims priority of provisional application 61/937,003, filed on Feb. 7, 2014.
Prior Publication US 2019/0382412 A1, Dec. 19, 2019
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 491/08 (2006.01); A61K 47/68 (2017.01)
CPC C07D 491/08 (2013.01) [A61K 47/6803 (2017.08); A61K 47/6851 (2017.08)] 20 Claims
 
1. A compound of the formula:

OG Complex Work Unit Drawing
wherein:
Y1 is —(CH2)mNR1R2;
wherein:
m is 1, 2, 3, 4, 5, or 6; and
R1 and R2 are each independently selected from hydrogen, hydroxy, alkyl(C1-12), substituted alkyl(C1-12), alkenyl(C2-12), substituted alkenyl(C2-12), alkynyl(C2-12), substituted alkynyl(C2-12), aryl(C6-12), substituted aryl(C6-12), aralkyl(C7-12), substituted aralkyl(C7-12), heteroaryl(C1-12), substituted heteroaryl(C1-12), heterocycloalkyl(C2-12), substituted heterocycloalkyl(C2-12), acyl(C1-12), substituted acyl(C1-12), acyloxy(C1-12), substituted acyloxy(C1-12), alkylamino(C1-12), substituted alkylamino(C1-12); a monovalent amine protecting group; or
R1 and R2 are taken together and are divalent amine protecting group, alkanediyl(C1-12), alkylaminodiyl(C1-8); alkoxydiyl(C1-8); or a substituted version of either of these groups; or
Z1 is absent or hydrogen;
Z2 is hydrogen;
o is 1, 2, or 3;
R3 is hydrogen, hydroxy, halo, amino, cyano, nitro, phosphate, or mercapto, or alkyl(C1-12), alkenyl(C2-12), alkynyl(C2-12), aryl(C6-12), aralkyl(C7-12), heterocycloalkyl(C2-12), acyl(C1-12), alkoxy(C1-12), acyloxy(C1-12), alkylamino(C1-12), dialkylamino(C2-12), amido(C1-12), or a substituted version of any of these groups;
R4 is hydrogen, alkyl(C1-12), a monovalent amine protecting group, or substituted alkyl(C1-12);
R5, R6, and R7 are each independently hydrogen, hydroxy, amino, mercapto, —OX1, —NX2X3, or —SX4; or
alkyl(C1-12), alkoxy(C1-12), acyloxy(C1-12), alkylamino(C1-12), dialkylamino(C2-12), alkylthio(C1-12), amido(C1-12), or a substituted version of any of these groups;
wherein:
X1 is a hydroxy protecting group;
X2 and X3 are independently selected from hydrogen, a monovalent amine protecting group, or when X2 and X3 are taken together form a divalent amine protecting group; and
X4 is a thiol protecting group;
R8 is hydroxy, amino, or mercapto; or
alkoxy(C1-12), acyloxy(C1-12), alkylamino(C1-12), dialkylamino(C2-12), alkylthio(C1-12), amido(C1-12), or a substituted version of any of these groups; or
a pharmaceutically acceptable salt thereof.