US 10,519,187 B2Granted

Cyclic dinucleotides as anticancer agents

AssigneeBristol-Myers Squibb Company

InventorsBrian E. Fink, Dharmpal S. Dodd, Steven J. Walker, Libing Chen, Yufen Zhao, Zheming Ruan, Lan-Ying Qin, Peter Kinam Park, Muthoni G. Kamau, Lalgudi S. Harikrishnan

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Abstract

The present invention is directed to compounds of the formulae I, II and III as shown below wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

Claims70

Dependent claims

A compound of formula I

wherein
X is independently O or S;
X1, X2, X3 and X4 are each independently O or NH;
R1 and R2 are independently
with the proviso that one of R1 and R2 must be
Z1 is N or CRa;
Z2 is NRb;
Ra is H, halogen, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
Rb is H, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, —C(O)Ra1, —C(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
Ra1 is H, C1-3 alkyl or C3-6 cycloalkyl;
R3 is H, CH3, halogen, —NRa1Ra1 or ORa1;
R3a is H, CH3, halogen, —NRa1Ra1 or ORa1;
or
R3 and R3a may be taken together to form a 3-4 membered carbocycle;
or
R3 and R3a may be taken together to form a C═CH2 substituent;
R5 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
or two R5 groups may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
or R5 and R6 may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
R5a is H or C1-3 alkyl;
R6 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
R8 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
R9 is H, halogen or methyl;
Y is CRa or N;
m is 0, 1, 2 or 3;
n is 0 or 1;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

24 more elements

A compound of formula II

wherein
X is independently O or S;
X1, X2, X3 and X4 are each independently O or NH;
R1 and R2 are each independently
with the proviso that one of R1 and R2 must be
Z1 is N or CRa;
Z2 is NRb;
Ra is H, halogen, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
Rb is H, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, —C(O)Ra1, —C(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
Ra1 is H, C1-3 alkyl or C3-6 cycloalkyl;
R4 is H, CH3, halogen, —NRa1Ra1 or ORa1;
R4a is H, CH3, halogen, —NRa1Ra1 or ORa1;
or
R4 and R4a may be taken together to form a 3-4 membered carbocycle;
or
R4 and R4a may be taken together to form a C═CH2 substituent;
R5 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
or two R5 groups may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
or R5 and R6 may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
R5a is H or C1-3 alkyl;
R6 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
R8 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
R9 is H, halogen or methyl;
Y is CRa or N;
m is 0, 1, 2 or 3;
n is 0 or 1;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

24 more elements

The compound which is

(1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-8-{9-hydroxy-3H-imidazo[1,2-a]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione,
(1R,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-8-hydroxy-17-{9-oxo-3H,4H,9H-imidazo[1,2-a]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dione,
(1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-8-{3H-imidazo[2,1-f]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12dione,
(1R,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-3,18-dihydroxy-17-{9-oxo-3H,4H,9H-imidazo[1,2-a]purin-3-yl}-12-sulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dione,
(1S,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-hydroxy-17-{9-oxo-3H,5H,9H-imidazo[1,2-a]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione,
(1S,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-17-{9-oxo-3H,4H,9H-imidazo[1,2-a]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dione,
(1S,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-17-{3H-imidazo[2,1-f]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dione,
(1S,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-17-{3H-imidazo[2,1-f]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dione,
4-[(1R,6S,8R,9S,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dioxo-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]pyridine-2-carboxamide,
4-[(1R,6S,8R,9S,15R,17R,18S)-17-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dioxo-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]pyridine-2-carboxamide,
4-[(1R,6S,8R,9S,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-3,12-dioxo-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]pyridine-2-carboxamide,
4-[(1R,6S,8R,9S,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-12-hydroxy-3,12-dioxo-3-sulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]pyridine-2-carboxamide,
4-[(1S,7S,8R,10S,16R,17R)-17-(6-amino-9H-purin-9-yl)-4,13-dioxo-4,13-disulfanyl-3,5,12,14-tetraoxa-4λ5,13λ5-diphosphatricyclo[14.2.0.07,10]octadecan-8-yl]pyridine-2-carboxamide,
(1R,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-17-{3H-imidazo[2,1-f]purin-3-yl}-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione,
(1R,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-17-{3H-imidazo[2,1-f]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione,
(1R,6S,8R,9R,15R,17R,18R)-8-(6-chloro-9H-purin-9-yl)-18-fluoro-17-{3H-imidazo[2,1-f]purin-3-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione,
4-[(1R,6S,8R,9S,15R,17R,18R)-18-fluoro-17-{3H-imidazo[2,1-f]purin-3-yl}-3,12-dioxo-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]pyridine-2-carboxamide,
4-[(1R,6S,8R,9R,15R,17S,18R)-8-(6-amino-9H-purin-9-yl)-18-hydroxy-3,12-dioxo-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecan-17-yl]pyridine-2-carboxamide,
(1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-8-{5-oxo-5H,8H,9H-[1,2,4]triazolo[4,3-a]purin-8-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione,
(1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-8-(6-oxo-6,9-dihydro-1H-purin-9-yl)-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione,
(1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-8-{8-oxo-4H,5H,8H-[1,2,3,4]tetrazolo[1,5-a]purin-5-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

19 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/272,172Filed 11 Feb 2019 · us provisional application
Priority: 13 Feb 2018
Published: US 2019/0248828 A115 Aug 2019
Granted: 31 Dec 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07H 19/213
With the saccharide radical esterified by phosphoric or polyphosphoric acids: containing cyclic phosphate
A61P 35/00
Antineoplastic agents
C07H 21/00
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate
C07H 21/02
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of…: with…

Family

Application62/629,956Us provisional application · filed 13 Feb 2018
US 2019/0248828 A1Pre-grant publication · published 15 Aug 2019
US 10,519,187 B2This patent

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

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Abstract

A compound of formula I

wherein
X is independently O or S;
X1, X2, X3 and X4 are each independently O or NH;
R1 and R2 are independently
with the proviso that one of R1 and R2 must be
Z1 is N or CRa;
Z2 is NRb;
Ra is H, halogen, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
Rb is H, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, —C(O)Ra1, —C(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
Ra1 is H, C1-3 alkyl or C3-6 cycloalkyl;
R3 is H, CH3, halogen, —NRa1Ra1 or ORa1;
R3a is H, CH3, halogen, —NRa1Ra1 or ORa1;
or
R3 and R3a may be taken together to form a 3-4 membered carbocycle;
or
R3 and R3a may be taken together to form a C═CH2 substituent;
R5 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
or two R5 groups may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
or R5 and R6 may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
R5a is H or C1-3 alkyl;
R6 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
R8 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
R9 is H, halogen or methyl;
Y is CRa or N;
m is 0, 1, 2 or 3;
n is 0 or 1;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

24 more elements

Facts

Application

16/272,172Filed 11 Feb 2019 · us provisional application

Priority

13 Feb 2018

Published

US 2019/0248828 A115 Aug 2019

Granted

31 Dec 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07H 19/213
With the saccharide radical esterified by phosphoric or polyphosphoric acids: containing cyclic phosphate
A61P 35/00
Antineoplastic agents
C07H 21/00
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate
C07H 21/02
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of…: with…