US 2018/0002366 A1 · 4'-SUBSTITUTED NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Abstract

The present invention is directed to 4′-substituted nucleoside derivatives of Formula I and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.

Claims9

Dependent claims

1-65. (canceled)

A pharmaceutical composition comprising an effective amount of a compound that is:

1) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
2) (2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
3) (2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
4) (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
5) (2R,3S,5R)-5-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
6) (2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
7) (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
8) (2R,3S,5R)-5-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
9) (2R,3S,5R)-5-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
10) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;
11) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
12) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;
13) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
14) ((2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
15) ((2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
16) ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
17) ((2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
18) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-cyano-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
19) ((2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
20) ((2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
21) ((2R,3S,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
22) (2R,3S,5R)-5-(4-aminoimidazo[2, 1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
or
23) (2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
or a pharmaceutically acceptable salt thereof, and an effective amount of one or more HIV antiviral agent selected from:
abacavir, abacavir sulfate, abacavir+lamivudine, abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirine, darunavir, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, efavirenz+emtricitabine+tenofovir disoproxil fumarate, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine, emvirine, enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lamivudine+zidovudine, lopinavir, lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir mesylate, stavudine, tipranavir or vicriviroc,
and a pharmaceutically acceptable carrier.

24 more elements

A method for the treatment of infection by HIV or for the treatment or delay in the onset of AIDS in a human subject in need thereof which comprises administering to the subject an effective amount of a compound that is:

1) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
2) (2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
3) (2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
4) (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
5) (2R,3S,5R)-5-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
6) (2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
7) (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
8) (2R,3S,5R)-5-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
9) (2R,3S,5R)-5-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
10) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;
11) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
12) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;
13) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
14) ((2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
15) ((2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
16) ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
17) ((2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
18) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-cyano-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
19) ((2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
20) ((2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
21) ((2R,3S,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;
22) (2R,3S,5R)-5-(4-aminoimidazo[2, 1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
or
23) (2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;
or a pharmaceutically acceptable salt thereof,
and an effective amount of one or more HIV antiviral agent selected from:
abacavir, abacavir sulfate, abacavir+lamivudine, abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirine, darunavir, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, efavirenz+emtricitabine+tenofovir disoproxil fumarate, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine, emvirine, enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lamivudine+zidovudine, lopinavir, lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir mesylate, stavudine, tipranavir or vicriviroc.

24 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/685,824Filed 24 Aug 2017

Priority

CN PCT/CN2014/07429428 Mar 2014

Published

4 Jan 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07H 19/14
Heterocyclic radicals containing only nitrogen atoms as ring hetero atom: pyrrolo-pyrimidine radicals
A61K 31/7064
Containing six-membered rings with nitrogen as a ring hetero atom: containing condensed or non-condensed pyrimidines
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

4'-substituted nucleoside reverse transcriptase inhibitors

Life of this patent

Abstract

Claims9

4'-substituted nucleoside reverse transcriptase inhibitors

Life of this patent

Abstract

Claims9