US 10,472,364 B2Granted

Ectonucleotidase inhibitors and methods of use thereof

AssigneeCalithera Biosciences, Inc.

InventorsLijing Chen, Jim Li, Eric B. Sjogren, Roland J. Billedeau

Life of this patent

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Abstract

The invention relates to novel heterocyclic compounds having CD73 inhibitory activity and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.

Claims56

Dependent claims

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
X is O;
Y is O or S;
Z is NR19, O or S;
Het is an optionally substituted purinyl ring or an optionally substituted 5-methyl-pyrimidin-2,4-dione ring;
R1a is selected from halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
and
R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
or
R1a and R1b, together with the carbon atom to which they are attached, form a C═CH2 or C═C(H)C1-6alkyl;
R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R2b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
or
R2a and R2b, together with the carbon atom to which they are attached, form a C═CH2 or C═C(H)C1-6alkyl;
R3 is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and —(CH2)—C(O)OR9;
R4 is selected from alkyl, —C(O)OR9, —C(O)NR11R12, —S(O)2R10, —P(O)(OR11)(OR12), and —P(O)(OR11)(NR13R15);
R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and —C(O)OR9;
R6 is selected from —C(O)OR9 and —P(O)(OR11)(OR12);
each R7 and R8 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
R9 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and —(CHR13)m—Z—C(O)—R14;
each R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
and
each R11 and R12 is independently selected from H, alkyl, alkenyl, alkynyl, —S(O)2R10, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and —(CHR13)m—Z—C(O)—R14;
or
R11 and R12, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl;
and
each R13 is independently H or alkyl;
each R14 is independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;
R15 is selected from alkyl, aralkyl, —C(R16)(R17)—C(O)O—R18;
each R16 and R17 are selected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and —(CH2)C(O)OR9;
R18 is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
R19 is H or alkyl, preferably H;
and
m is 1 or 2;
provided that if R3 is H and R1a and R2a are each hydroxy, then at least one of R1b and R2b is C1-6alkyl.

32 more elements

A compound having the structure:

wherein:
R5 is:
(i) phenylC1-6alkyl or naphthylC1-6alkyl wherein phenyl and naphthyl are optionally substituted with one, two, or three substituents independently selected from —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl substituted with one to five fluoro, —OC1-6alkyl (substituted with one to five fluoro), —C1-6alkylene-CO2H, —C1-6alkylene-CO2C1-6alkyl, —C2-6alkenylene-CO2H, —OC1-6alkylene-CO2H, —OC1-6alkylene-CO2C1-6alkyl, —C1-6alkyl substituted with one or two hydroxy, —OC1-6alkyl substituted with one or two hydroxy, —C1-6alkyl substituted with one or two —OC1-6alkyl, —OC1-6alkyl (substituted with one or two —OC1-6alkyl), —CO2H, —COOC1-6alkyl, hydroxy, halo, nitro, —PO3H2, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —CONReRf (where Re and Rf are independently hydrogen, —C1-6alkyl, —C1-6alkylene-CO2H, —C1-6alkylene-CO2C1-6alkyl, or —C1-6alkylene-substituted with one or two substituents independently selected from hydroxy, NH2, —NHC1-6alkyl or —N(C1-6alkyl)2), —SO2(C1-6alkyl), —SO2NRgRh (where Rg and Rh are independently hydrogen, —C1-6alkyl, —C1-6alkylene-CO2H, or —C1-6alkylene-CO2C1-6alkyl), —SC1-6alkyl, —SOC1-6alkyl, —SO2NHCORj (where Rj is —C1-6alkyl, —NHC1-6alkyl, or —N(C1-6alkyl)2), phenyl, —C1-6alkylenephenyl, phenoxy, —OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO2H, —COOC1-6alkyl, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl (substituted with one to five fluoro), —OC1-6alkyl (substituted with one to five fluoro), —C1-6alkylene-CO2H, —C1-6alkylene-CO2C1-6alkyl, tetrazolyl, —SO2C1-6alkyl, —SO2NH2, —SO2NHC1-6alkyl, —SO2N(C1-6alkyl)2, —CONH2, —CONHC1-6alkyl, or —CON(C1-6alkyl)2], —ORi, —C1-6alkylene-Ri, —OC1-6alkylene-Ri, —SRi, —SC1-6alkylene-Ri, heterocyclyl, —C1-6alkyleneheterocyclyl, —OC1-6alkylene-heterocyclyl, —SC1-6alkyleneheterocyclyl, —CONRmC1-6alkyleneheterocyclyl, —NRmCOC1-6alkyleneNRoRp, —NRmCOheterocyclyl, —NRmCOC1-6alkyleneheterocyclyl, —COheterocyclyl, —CONRmRi, —CONRmC1-6alkylene-Ri, —OCONRmRm, —NRm—CORy, —NRm—CO—NRmRy, —NRm—SO2—Ry, —NRm—SO2—NRmRy, and —CONHSO2Rz;
or
(ii) 5-10 membered heteroarylC1-6alkyl having one to three heteroatoms independently selected from N, O, or S and 5-10 membered heteroaryl in 5-10 membered heteroarylC1-6alkyl is optionally substituted with one or two substituents independently selected from —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl substituted with one to five fluoro, —OC1-6alkyl substituted with one to five fluoro, —C1-6alkylene-CO2H, —C1-6alkylene-CO2C1-6alkyl, —C2-6alkenylene-CO2H, —C1-6alkyl substituted with one or two hydroxy, —OC1-6alkyl substituted with one or two hydroxy, —C1-6alkyl substituted with one or two —OC1-6alkyl, —OC1-6alkyl (substituted with one or two —OC1-6alkyl), —CO2H, —COOC1-6alkyl, hydroxy, halo, nitro, —PO3H2, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —CONReRf (where Re and Rf are independently hydrogen, —C1-6alkyl, —C1-6alkylene-CO2H, —C1-6alkylene-CO2C1-6alkyl, or —C1-6alkyl substituted with one or two hydroxyl, —NHC1-6alkyl or —N(C1-6alkyl)2), —SO2(C1-6alkyl), —SO2NRgRh (where Rg and Rh are independently hydrogen, —C1-6alkyl, —C1-6alkylene-CO2H, or —C1-6alkylene-CO2C1-6alkyl), —SC1-6alkyl, —SOC1-6alkyl, —SO2NHCORj (where RJ is —C1-6alkyl, —NH2, —NHC1-6alkyl, or —N(C1-6alkyl)2), phenyl, —C1-6alkylenephenyl, phenoxy, —OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO2H, —COOC1-6alkyl, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl (substituted with one to five fluoro), —OC1-6alkyl (substituted with one to five fluoro), —C1-6alkylene-CO2H, —C1-6alkylene-CO2C1-6alkyl, tetrazolyl, —SO2C1-6alkyl, —SO2NH2, —SO2NHC1-6alkyl, —SO2N(C1-6alkyl)2, —CONH2, —CONHC1-6alkyl, and —CON(C1-6alkyl)2], —ORi, —C1-6alkylene-Ri, —OC1-6alkylene-Ri, —SRi, —SC1-6alkylene-Ri, heterocyclyl, —C1-6alkyleneheterocyclyl, —OC1-6alkyleneheterocyclyl, —SC1-6alkyleneheterocyclyl, —CONRmC1-6alkyleneheterocyclyl, —NRmCOC1-6alkyleneNRoRp, —NRmCOheterocyclyl, —NRmCOC1-6alkyleneheterocyclyl, —COheterocyclyl, —CONRmRi, —CONRmalkylene-Ri, —OCONRmRm, —NRm—CORY, —NRm—CO—NRmRy, —NRm—SO2—Ry, —NRm—SO2—NRmRy, and —CONHSO2Rz;
and
the R5 5-10 membered heteroaryl ring is additionally optionally substituted with an additional substituent selected from —C1-6alkyl, —C1-6alkyl (wherein alkyl is substituted with one to five fluoro), —O—C1-6alkyl, —OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, —NH2, and hydroxy;
wherein:
each Rm is hydrogen or —C1-6alkyl;
Ro, Rp, and Ry are each independently hydrogen or —C1-6alkyl;
Rz is —C1-6alkyl, —NHC1-6alkyl, or —N(C1-6alkyl)2;
phenyl by itself or as part of —C1-6alkylenephenyl, phenoxy, or —OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO2H, —COOC1-6alkyl, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl substituted with one to five fluoro, —OC1-6alkyl (substituted with one to five fluoro), —C1-6alkylene-CO2H, —C1-6alkylene-CO2C1-6alkyl, tetrazolyl, —SO2C1-6alkyl, —SO2NH2, —SO2NHC1-6alkyl, —SO2N(C1-6alkyl)2, —CONH2, —CONHC1-6alkyl, or —CON(C1-6alkyl)2;
each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO2H, —COOC1-6alkyl, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl substituted with one to five fluoro, —OC1-6alkyl (substituted with one to five fluoro), —C1-6alkylene-CO2H, and —C1-6alkylene-CO2C1-6alky, tetrazolyl, —SO2C1-6alkyl, —SO2NH2, —SO2NHC1-6alkyl, —SO2N(C1-6alkyl)2, —CONH2, —CONHC1-6alkyl, or —CON(C1-6alkyl)21;
heterocyclyl by itself or as part of —C1-6alkyleneheterocyclyl, —OC1-6alkyleneheterocyclyl, —SC1-6alkyleneheterocyclyl, —CONRmC1-6alkyleneheterocyclyl, —NRmCOC1-6alkylene-heterocyclyl, —COheterocyclyl, or —NRmCOheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, —COOC1-6alkyl, —C1-6alkyl, —OC1-6alkyl, or —C1-6alkyl (substituted with hydroxy or —OC1-6alkyl);
and
Het is a group of formula (iii) or (xiv) below:
wherein:
Ru is —NH2, —NHR20, —NHCOR20, and —NR20R21;
Rw is hydrogen, halo, —NHR22, —NR22R23, —R22, —OH, or —OR22;
Ro and Rx is hydrogen, halo, haloC1-6alkyl, —NH2, —NHR24, —NR24R25, —R24, —SR24, cyano, —OH, —OR24, —SO2R24, —C1-6alkyleneNH2, —C1-6alkyleneNHR24, —C1-6alkyleneNR24R25, R24, —C1-6alkyleneSR24, —C1-6alkyleneOH, —C1-6alkyleneOR24, or —C1-6alkyleneSO2R24,
Rs is hydrogen, halo, or C1-6alkyl;
and
wherein:
R20, R21, R22, R23, R24 and R25 are independently optionally substituted C1-6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl;
or
R20 and R21, R22 and R23, and/or R24 and R25, together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl;
and further wherein, unless otherwise specified:
C1-6alkyl is unsubstituted;
C1-6alkyl of C1-6alkyloxy is unsubstituted;
haloC1-6alkyl is C1-6alkyl substituted with one to five halo atoms;
haloC1-6alkyloxy is C1-6alkyloxy substituted with one to five halo atoms;
C2-6alkenyl is unsubstituted;
C2-6alkynyl is unsubstituted;
C1-6alkylene is unsubstituted;
C2-6alkenylene is unsubstituted;
optionally substituted C1-6alkyl is optionally substituted with one or two substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
carbocyclyl is an unsubstituted saturated or partially unsaturated mono or bicyclic ring containing 3 to 10 carbon atoms;
optionally substituted carbocyclyl is optionally substituted with one, two, or three substituents independently selected from C1-6alkyl, halo, hydroxy, or C1-6alkoxy;
optionally substituted aryl is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2;
aryl is phenyl or naphthyl;
optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(unsubstituted C1-6alkyl)2];
heteroaryl is an unsubstituted five to ten membered or five to six membered aromatic ring containing one to four or one to three heteroatoms independently selected from N, O, and S;
the remaining ring atoms being carbon;
optionally substituted heteroaryl is a five to ten membered aromatic ring containing one to four heteroatoms independently selected from N, O, and S;
the remaining ring atoms being carbon, that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, unsubstituted C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2];
heterocyclyl is an unsubstituted monocyclic, saturated or partially unsaturated 4 to 8 membered ring containing one to three heteroatoms independently selected from N, O, S, SO, and SO2 and optionally contains one or two CO, the remaining atoms in the ring being carbon that is optionally fused to phenyl or 5 to 6 membered carbocyclyl or 5 or 6 heteroaryl ring;
nitrogen-containing heterocyclyl is a heterocyclyl ring that has at least a nitrogen atom;
optionally substituted heterocyclyl is heterocyclyl that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2], and heterocyclyl optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2];
optionally substituted carbocyclyl C1-6alkyl is optionally substituted carbocyclyl attached via C1-6alkyl;
optionally substituted heterocyclylC1-6alkyl is optionally substituted heterocyclyl attached via C1-6alkyl;
optionally substituted arylC1-6alkyl is optionally substituted aryl attached via C1-6alkyl;
optionally substituted heteroarylC1-6alkyl is optionally substituted heteroaryl attached via C1-6alkyl;
provided that the compound of Formula (I) is not:
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-phenoxybenzyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-phenoxybenzyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethyl)benzyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethyl)benzyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(naphthalen-2-ylmethyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(naphthalen-2-ylmethyl)malonate
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethyl)benzyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethyl)benzyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonyl)benzyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonyl)benzyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(dimethylcarbamoyl)benzyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(dimethylcarbamoyl)benzyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(thiophen-3-ylmethyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(thiophen-3-ylmethyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-aminobenzyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-aminobenzyl)malonate;
2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-hydroxybutyl)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-hydroxybutyl)malonate;
1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)ethane-1,1,2-tricarboxylic acid;
3-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-4-ethoxy-3-(ethoxycarbonyl)-4-oxobutanoic acid;
2-(((2R,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonic acid;
diethyl 2-(((2R,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate;
((R)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-methoxy-2-oxoethyl)phosphonic acid;
((S)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-methoxy-2-oxoethyl)phosphonic acid;
2-benzyl-2-(((2R,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonic acid;
diethyl 2-benzyl-2-(((2R,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate;
((R)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonic acid;
((S)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonic acid;
or a pharmaceutically acceptable salt thereof.

81 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/699,109Filed 8 Sep 2017 · us provisional application
Priority: 9 Sep 2016
Published: US 2018/0072742 A115 Mar 2018
Granted: 12 Nov 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system

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Application62/385,730Us provisional application · filed 9 Sep 2016
US 2018/0072742 A1Pre-grant publication · published 15 Mar 2018
US 10,472,364 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
X is O;
Y is O or S;
Z is NR19, O or S;
Het is an optionally substituted purinyl ring or an optionally substituted 5-methyl-pyrimidin-2,4-dione ring;
R1a is selected from halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
and
R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
or
R1a and R1b, together with the carbon atom to which they are attached, form a C═CH2 or C═C(H)C1-6alkyl;
R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R2b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
or
R2a and R2b, together with the carbon atom to which they are attached, form a C═CH2 or C═C(H)C1-6alkyl;
R3 is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and —(CH2)—C(O)OR9;
R4 is selected from alkyl, —C(O)OR9, —C(O)NR11R12, —S(O)2R10, —P(O)(OR11)(OR12), and —P(O)(OR11)(NR13R15);
R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and —C(O)OR9;
R6 is selected from —C(O)OR9 and —P(O)(OR11)(OR12);
each R7 and R8 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
R9 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and —(CHR13)m—Z—C(O)—R14;
each R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
and
each R11 and R12 is independently selected from H, alkyl, alkenyl, alkynyl, —S(O)2R10, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and —(CHR13)m—Z—C(O)—R14;
or
R11 and R12, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl;
and
each R13 is independently H or alkyl;
each R14 is independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;
R15 is selected from alkyl, aralkyl, —C(R16)(R17)—C(O)O—R18;
each R16 and R17 are selected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and —(CH2)C(O)OR9;
R18 is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
R19 is H or alkyl, preferably H;
and
m is 1 or 2;
provided that if R3 is H and R1a and R2a are each hydroxy, then at least one of R1b and R2b is C1-6alkyl.

32 more elements

Facts

Application

15/699,109Filed 8 Sep 2017 · us provisional application

Priority

9 Sep 2016

Published

US 2018/0072742 A115 Mar 2018

Granted

12 Nov 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system