US 9,809,616 B2
Pyrimidine nucleosides and their monophosphate prodrugs for the treatment of viral infections and cancer
Franck Amblard, Tucker, GA (US); Steven J. Coats, McDonough, GA (US); and Raymond F. Schinazi, Miami, FL (US)
Assigned to Emory University, Atlanta, GA (US); and Cocrystal Pharma, Inc., Tucker, GA (US)
Filed by Cocrystal Pharma, Inc., Tucker, GA (US); and Emory University, Atlanta, GA (US)
Filed on Oct. 29, 2013, as Appl. No. 14/66,461.
Claims priority of provisional application 61/719,696, filed on Oct. 29, 2012.
Claims priority of provisional application 61/763,534, filed on Feb. 12, 2013.
Prior Publication US 2014/0235566 A1, Aug. 21, 2014
Int. Cl. A01N 43/04 (2006.01); A61K 31/07 (2006.01); C07H 19/048 (2006.01); C07H 19/00 (2006.01); C07H 19/06 (2006.01); C07H 19/10 (2006.01); C07H 19/067 (2006.01); C07H 19/11 (2006.01); A61K 45/06 (2006.01); A61K 31/7068 (2006.01)
CPC C07H 19/06 (2013.01) [A61K 31/7068 (2013.01); A61K 45/06 (2013.01); C07H 19/067 (2013.01); C07H 19/10 (2013.01); C07H 19/11 (2013.01)] 11 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt thereof, wherein:
X1 is H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, COR1, or COOR1;
X2 is hydrogen, COR1, or COOR1
wherein each is, independently, CH2—O(CO)—X5; CH2—O(CO)O—X5, C1-20 alkyl, the carbon chain derived from a fatty alcohol, or C1-20 alkyl substituted with a C1-C6 alkyl, alkoxy, di(C1-C6 alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are selected from the group consisting of C1-6 alkyl, and substituted C1-6 alkyl, wherein the substituents are C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl,
X5 is independently, C1-20 alkyl, the carbon chain derived from a fatty alcohol, or C1-20 alkyl substituted with a C1-C6 alkyl, alkoxy, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl or substituted heteroaryl; wherein the substituents are C1-6 alkyl, or C1-6 alkyl substituted with a C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl,
each X3 and X4 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, alkylaryl, halogen, NH2, OH, SH, CN, or NO2,
and wherein sugar has the general Formula

OG Complex Work Unit Drawing
wherein:
Y is O or S;
Z is CH2,
A is O,
R4′, R5, R5′, R6, R6′, and R7 are independently selected from the group consisting of H, F, Cl, Br, I, OH, SH, NH2, NHOH, NHNH2, N3, C(O)OH, CN, CH2OH, C(O)NH2, C(S)NH2, C(O)OR, R, OR, SR, SSR, NHR, and NR2;
R5′ and R6′ can come together to form a ring

OG Complex Work Unit Drawing
provided that when A is O, R7′ cannot be OH, SH, NH2, NHOH, NHNH2, OR, SR, SSR, NHR, or NR2, and
R is independently a C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, C3-C6 cycloalkyl, aryl, alkylaryl, or arylalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl and substituted C1-6 alkyl, wherein the substituents are C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl,
R2 is OR8 where R8 is aryl, optionally substituted with one to three substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, (CH2)0-6CO2R9a, halogen, C1-6 haloalkyl, —N(R9a)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R9a)2, —SO2C1-6 alkyl, COR9b, nitro, cyano and

OG Complex Work Unit Drawing
wherein R21 is selected from the group consisting of H, C1-20 alkyl, C1-20 alkenyl, the carbon chain derived from a fatty acid, and C1-20 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, C3-10 cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl; wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, or C3-10 cycloalkyl alkyl,
and R3 is

OG Complex Work Unit Drawing
 where R10a and R10b are:
(i) independently selected from the group consisting of H, C1-10 alkyl, —(CH2)rNR9a2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)pMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)mCOR9b, aryl and aryl-C1-3 alkyl, wherein said aryl groups are optionally substituted with a group selected from the group consisting of hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro, and cyano;
(ii) R10a is H and R10b and R12 together are (CH2)2-4 to form a ring that includes the adjoining N and C atoms;
(iii) R10a and R10b together are (CH2)n to form a ring;
(iv) R10a and R10b both are C1-6 alkyl; or
(v) R10a is H and R10b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2—CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or C3-10 cycloalkyl;
p is 0 to 2;
r is 1 to 6;
n is 4 or 5;
m is 0 to 3;
R11 is H, C1-10 alkyl, or C1-10 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, C3-10 cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, or C3-10 cycloalkyl alkyl;
R12 is H or C1-3 alkyl,
or R10a.