Substituted carbonucleoside derivatives useful as anticancer agents

Patent metadata

Field	Value
Publication number	US-10220037-B2
Application number	US-201715612030-A
Country	US
Kind code	B2
Filing date	Jun 2, 2017
Priority date	Jun 6, 2016
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

Abstract

Compounds of the general formula):

processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, hydroxy, (C 1 -C 8 )alkoxy, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl, 3-12 membered heterocyclyl, OR 4 , SR 4 and N(R 4 ) 2 ;
R 2 is hydrogen, halogen, (C 1 -C 8 )alkyl, hydroxy, (C 1 -C 8 )alkoxy or N(R 5 ) 2 , where each R 5 is independently hydrogen or (C 1 -C 8 )alkyl, or two R 5 join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
each R 3 is independently selected from hydrogen, hydroxy, NH 2 ; (C 1 -C 8 )alkyl or heteroalkyl having 1-8 atoms, or when D is C(R 3 ) 2 , R 3 is additionally selected from fluorine, (C 1 -C 8 )alkylene or heteroalkylene bound to an atom on G to form a ring fused to G, where R 3 is optionally substituted with 1-6 R 8 ;
each R 9 is independently hydrogen or fluorine;
D is C(R 3 ) 2 , NR 3 , O, S or S(O) 1-2 ;
G is a (C 5 -C 12 )aryl ring system or a 5-12 membered heteroaryl ring system, wherein said (C 5 -C 12 )aryl ring system or a 5-12 membered heteroaryl ring system is fused to (C 3 -C 10 )cycloalkyl or heterocyclyl ring system;
each R 8 is absent or is independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, hydroxy, (C 1 -C 8 )alkoxy, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl, 3-12 membered heterocyclyl, OR 4 , SR 4 , N(R 4 ) 2 , CN, halogen and CON(R 4 ) 2 , where two R 8 optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or an alkylene bridge spanning G, and where two R 8 optionally join to form carbonyl;
each R 4 is independently A-R 14 , where A is absent, (C 1 -C 3 )alkyl, —C(O)— or —SO 2 —, and R 14 is hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl or 3-12 membered heterocyclyl, or two R 4 join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
Q is absent or is a divalent moiety selected from O, S, NH and (C 1 -C 8 )alkylene;
R 10 is independently selected from hydrogen, (C 1 -C 8 )alkyl, hydroxy, (C 1 -C 8 )alkoxy, halogen, SH, S—(C 1 -C 8 )alkyl and N(R 11 ) 2 where each R 11 is independently hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 12 )aryl or 5-12 membered heteroaryl; and
R 12 is independently selected from hydrogen, (C 1 -C 8 )alkyl, hydroxy, (C 1 -C 8 )alkoxy, fluoro, chloro, bromo, iodo, SH, S—(C 1 -C 8 )alkyl and N(R 13 ) 2 where each R 13 is independently hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 12 )aryl or 5-12 membered heteroaryl.

2. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, hydroxy, (C 1 -C 8 )alkoxy, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl, 3-12 membered heterocyclyl, OR 4 , SR 4 and N(R 4 ) 2 ;
R 2 is hydrogen, halogen, (C 1 -C 8 )alkyl, hydroxy, (C 1 -C 8 )alkoxy or N(R 5 ) 2 , where each R 5 is independently hydrogen or (C 1 -C 8 )alkyl, or two R 5 join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
each R 3 is independently selected from hydrogen, hydroxy, NH 2 ; (C 1 -C 8 )alkyl or heteroalkyl having 1-8 atoms, or when D is C(R 3 ) 2 , R 3 is additionally selected from fluorine, (C 1 -C 8 )alkylene or heteroalkylene bound to an atom on G to form a ring fused to G, where R 3 is optionally substituted with 1-6 R 8 ;
each R 9 is independently hydrogen or fluorine;
D is C(R 3 ) 2 , O, or S(O) 1-2 ;
G is a (C 5 -C 12 )aryl, or a 5-12 membered heteroaryl, ring system;
R 15 is heteroalkyl having 1-8 atoms bound to an atom on G and optionally substituted with 1-6 R 8 , or R 15 is heteroalkylene bound to an atom on G, optionally substituted with 1-6 R 8 , and bound to an adjacent atom on G;
each R 8 is absent or is independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, hydroxy, (C 1 -C 8 )alkoxy, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl, 3-12 membered heterocyclyl, OR 4 , SR 4 , N(R 4 ) 2 , CN, halogen and CON(R 4 ) 2 , where two R 8 optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or an alkylene bridge spanning G, and where two R 8 optionally join to form carbonyl;
each R 4 is independently A-R 14 , where A is absent, (C 1 -C 3 )alkyl, —C(O)— or —SO 2 —, and R 14 is hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl or 3-12 membered heterocyclyl, or two R 4 join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
Q is absent or is a divalent moiety selected from O, S, NH and (C 1 -C 8 )alkylene;
R 10 is independently selected from hydrogen, (C 1 -C 8 )alkyl, hydroxy, (C 1 -C 8 )alkoxy, halogen, SH, S—(C 1 -C 8 )alkyl and N(R 11 ) 2 where each R 11 is independently hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 12 )aryl or 5-12 membered heteroaryl; and
R 12 is independently selected from hydrogen, (C 1 -C 8 )alkyl, hydroxy, (C 1 -C 8 )alkoxy, fluoro, chloro, bromo, iodo, SH, S—(C 1 -C 8 )alkyl and N(R 13 ) 2 where each R 13 is independently hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 12 )aryl or 5-12 membered heteroaryl;
provided that D is S(O) 1-2 when G is C 10 aryl or a 10-membered heteroaryl.

3. A compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, hydroxy, (C 1 -C 8 )alkoxy, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl, 3-12 membered heterocyclyl, OR 4 , SR 4 and N(R 4 ) 2 ;
R 2 is hydrogen, halogen, (C 1 -C 8 )alkyl, hydroxy, (C 1 -C 8 )alkoxy or N(R 5 ) 2 , where each R 5 is independently hydrogen or (C 1 -C 8 )alkyl, or two R 5 join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
each R 3 is independently hydrogen, hydroxy or NH 2 ; or when D is C(R 3 ) 2 , R 3 is additionally selected from fluorine;
each R 9 is independently hydrogen or fluorine;
D is C(R 3 ) 2 , O, or S(O) 1-2 ;
E is NR 1 , CH 2 , C(R 1 ) 2 , O or —S(O) 2 ;
each R 8 is absent or is independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, hydroxy, (C 1 -C 8 )alkoxy, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl, 3-12 membered heterocyclyl, OR 4 , SR 4 , N(R 4 ) 2 , CN, halogen and CON(R 4 ) 2 , where two R 8 optionally join to form a 4-6 membered spiro-cycloalkyl ring, or a cycloalkyl fused ring, and where two R 8 optionally join to form carbonyl;
each R 4 is independently A-R 14 , where A is absent, (C 1 -C 3 )alkyl, —C(O)— or —SO 2 —, and R 14 is hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 12 )aryl, 5-12 membered heteroaryl, (C 3 -C 10 )cycloalkyl or 3-12 membered heterocyclyl, or two R 4 join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; and
Q is absent or is a divalent moiety selected from O, S, NH and (C 1 -C 8 )alkylene;
R 10 is independently selected from hydrogen, (C

Assignees

• Pfizer

Inventors

• Tatlock John Howard
• Mcalpine Indrawan James
• Tran-Dube Michelle Bich
• Rui Eugene Yuanjin
• Wythes Martin James
• Kumpf Robert Arnold
• Mctigue Michele Ann
• Patman Ryan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title