Quinazoline derivatives and their use as DNA methyltransferase inhibitors

Patent metadata

Field	Value
Publication number	US-9951044-B2
Application number	US-201415023209-A
Country	US
Kind code	B2
Filing date	Sep 19, 2014
Priority date	Sep 19, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present invention relates to compounds of the following formula (I): and pharmaceutically acceptable salts and solvates thereof, their methods of preparation, their use as a drug, notably in the treatment of cancer, and pharmaceutical compositions containing such compounds.

First claim

The invention claimed is:

1. A compound of the following formula (I-1c) or (I-1d):

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
n1 and n2 represent, independently of each other, an integer comprised between 0 and 8, Q represents a cycle of the following formula:

wherein:
X 11 represents CR 41 ,
X 12 represents CR 42 ,
X 13 represents N or C—NR 43a R 43b ,
X 14 represents CR 44 ,
X 15 represents CR 45 ,
R 43a and R 43b each represent, independently of each other, H or (C 1 -C 6 )alkyl,
R 41 , R 42 , R 44 and R 45 each represent, independently of each other, hydrogen; halogen; OR 11 ; NR 12 R 13 ; C(O)R 14 ; CO 2 R 15 ; OC(O)R 16 ; C(O)NR 17 R 18 ; NR 19 C(O)R 20 ; (C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 21 , NR 22 R 23 , C(O)R 24 , CO 2 R 25 , OC(O)R 26 , C(O)NR 17 R 28 , and NR 29 C(O)R 30 ; or aryl or aryl-(C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 31 , NR 32 R 33 , C(O)R 34 , CO 2 R 35 , OC(O)R 36 , C(O)NR 37 R 38 , and NR 39 C(O)R 40 ; or
in the case of R 44 and R 45 , R 44 and R 45 form together a chain of the following formula:

wherein:
X 16 represents CR 46 ,
X 17 represents CR 47 ,
X 18 represents CR 48 ,
X 19 represents CR 49 , and
R 46 , R 47 , R 48 and R 49 each represent, independently of one another, hydrogen; halogen; OR 11 ; NR 12 R 13 ; C(O)R 14 ; CO 2 R 15 ; OC(O)R 16 ; C(O)NR 17 R 18 ; NR 19 C(O)R 20 ; (C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 21 , NR 22 R 23 , C(O)R 24 , CO 2 R 25 , OC(O)R 26 , C(O)NR 27 R 28 , and NR 29 C(O)R 30 ; or aryl or aryl-(C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 31 , NR 32 R 31 , C(O)R 34 , CO 2 R 35 , OC(O)R 36 , C(O)NR 37 R 38 , and NR 39 C(O)R 40 ;
W represents NR 0 , a piperidinediyl, a piperazinediyl or a pyrrolidinediyl,
X 1 represents NH,
X 2 represents O,
R 0 represents H; CHO; CO 2 —((C 1 -C 6 )alkyl); or a (C 1 -C 6 )alkyl optionally substituted with CHO, CO 2 H or CO 2 —((C 1 -C 6 )alkyl),
R 1 and R 2 represent, independently of each other, H or a (C 1 -C 6 )alkyl,
R 3 and R 4 represent, independently of each other, H, (C 1 -C 6 )alkyl, aryl, heterocycle, —((C 1 -C 6 )alkyl)-X 5 -aryl or —((C 1 -C 6 )alkyl)-X 5 -heterocycle,
with X 5 representing a bond, O or NR 6 and each aryl or heterocycle moiety being optionally substituted, and
R 5 and R 6 represent, independently of each other, H or a (C 1 -C 6 )alkyl.

2. The compound according to claim 1 , wherein it is a compound of the following formula (I-1c):

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound according to claim 1 , wherein n1 and n2 represent, independently of each other, an integer comprised between 1 and 4.

4. The compound according to claim 1 , wherein W represents NR 0 ,

the nitrogen atom being linked to (CH 2 ) n1 .

5. The compound according to claim 1 , wherein R 3 and R 4 represent, independently of each other, H, (C 1 -C 6 )alkyl, aryl, heterocycle, —((C 1 -C 6 )alkyl)-X 5 -aryl or —((C 1 -C 6 )alkyl)-X 5 -heterocycle,
each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO 2 ; OR 11 ; NR 12 R 13 ; C(O)R 14 ; CO 2 R 15 ; OC(O)R 16 ; C(O)NR 17 R 18 ; NR 19 C(O)R 20 ; S(O)R 50 ; S(O) 2 R 51 ; S(O) 2 NR 52 R 53 ; (C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 21 , NR 22 R 23 , C(O)R 24 , CO 2 R 25 , OC(O)R 26 , C(O)NR 27 R 28 , NR 29 C(O)R 30 , S(O)R 54 , S(O) 2 R 55 , and S(O) 2 NR 56 R 57 ; and aryl or aryl-(C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 31 , NR 32 R 33 , C(O)R 34 , CO 2 R 35 , OC(O)R 36 , C(O)NR 37 R 38 , NR 39 C(O)R 40 , S(O)R 58 , S(O) 2 R 59 , and S(O) 2 NR 60 R 61 ,
with R 11 to R 40 and R 50 to R 61 representing, independently of one another, H or (C 1 -C 6 )alkyl.

6. The compound according to claim 5 , wherein R 3 and R 4 represent, independently of each other, H, (C 1 -C 6 )alkyl, aryl, heterocycle, aryl-(C 1 -C 6 )alkyl, heterocycle-(C 1 -C 6 )alkyl, —((C 1 -C 6 )alkyl)-NH-aryl or —((C 1 -C 6 )alkyl)-NH-heterocycle,
each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO 2 ; OR 11 ; NR 12 R 13 ; C(O)R 14 ; S(O) 2 NR 52 R 53 ; (C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 21 , NR 22 R 23 , C(O)R 24 , and S(O) 2 NR 56 R 57 ; and aryl or aryl-(C 1 -C 6 )alkyl optionally substituted with one or several groups selected from halogen, OR 31 , NR 32 R 33 , C(O)R 34 , and S(O) 2 NR 60 R 61 .

7. A compound selected from the following compounds:

and the pharmaceutically acceptable salts and solvates thereof.

8. A pharmaceutical composition comprising at least one compound of formula (I-1c) or (I-1d) according to claim 1 and at least one pharmaceutically acceptable excipient.

9. A pharmaceutical composition comprising:
(i) at least one compound of formula (I-1c) or (I-1d) according to claim 1 , and
(ii) at least one other active ingredient,

as a combination product for simultaneous, separate or sequential use.

10. A method to prepare a compound of formula (I-1c) or (I-1d) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, in which W═NR 0 with R 0 representing a (C 1 -C 6 )alkyl optionally substituted with CHO, CO 2 H or CO 2 —((C 1 -C 6 )alkyl), comprising:
(a) reacting a compound of formula (I-1c) or (I-1d) according to claim 1 in which W═NH with:
a compound of formula R 0 -LG where R 0 represents a (C 1 -C 6 )alkyl optionally substituted with CHO, CO 2 H or CO 2 —((C 1 -C 6 )alkyl) and LG represents a leaving group to give a compound of formula (I-1c) or (I-1d) in which W═NR 0 with R 0 representing a (C 1 -C 6 )alkyl optionally substituted with CHO, CO 2 H or CO 2 —((C 1 -C 6 )alkyl),
dimethylformamide (DMF) to give a compound of formula (I-1c) or (I-1d) in which W═NR 0 with R 0 ═CHO, or
a compound of formula R 0 -A 1 where R 0 represents CO 2 —((C 1 -C 6 )alkyl) and A 1 represents a (C 1 -C 6 )alkoxy group or a halogen atom to give a compound of formula (I-1c) or (I-1d) in which W═NR 0 with R 0 representing CO 2 —((C 1 -C 6 )alkyl), and

(b) optionally salifying or solvating the compound obtained in step (a) to give a pharmaceutically acceptable salt or solvate of a compound of formula (I-1c) or (I-1d) according to claim 1 in which W═NR 0 w

Assignees

• Pf Medicament
• Centre Nat Rech Scient
• Centre Nat Rech Scient

Inventors

• Halby Ludovic
• Arimondo Paola Barbara

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title