Substituted quinazoline derivatives as DNA methyltransferase inhibitors

Patent metadata

Field	Value
Publication number	US-10450299-B2
Application number	US-201615560883-A
Country	US
Kind code	B2
Filing date	Mar 25, 2016
Priority date	Mar 25, 2015
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

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):

or a pharmaceutically acceptable salt thereof,
wherein:
represents a single bond or a double bond on the condition that the two bonds do not represent a double bond at the same time,
n1 and n2 represent, independently of each other, an integer comprised between 0 and 8,
Q represents an optionally substituted aryl or an optionally substituted nitrogen-containing heterocycle,
W represents NR 0 , a divalent monoglycosyl, a piperidinediyl, a piperazinediyl or a pyrrolidinediyl,
X 1 represents O or NR 1 ,
X 2 represents O, NR 2 or a bond,
X 3 represents:
N when X 3 represents a double bond ═X 3 , and
NR 3 when X 3 represents a single bond —X 3 ,

X 4 represents:
O or NR 4 when X 4 represents a double bond ═X 4 , and
OR 4 or NR 4 R 5 when X 4 represents a single bond —X 4 ,

Y 1 and Y 2 represent, independently of each other, a halogen atom, R 100 , OR 101 or NR 102 R 103 , provided that at least one of Y 1 and Y 2 represent a group other than H,
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, S or NR 6 and each aryl or heterocycle moiety being optionally substituted,
R 5 and R 6 represent, independently of each other, H or a (C 1 -C 6 )alkyl,
R 100 , R 101 , R 102 and R 103 represent, independently of one another, H, optionally substituted aryl, optionally substituted heterocycle, or —((C 1 -C 6 )alkyl)-X 6 -A 1 ,
with X 6 representing a bond, O, S or NR 104 and Ai representing H, (C 1 -C 6 )alkyl, optionally substituted aryl or optionally substituted heterocycle,
or, for the R 102 and R 103 groups, R 102 and R 103 form together, with the nitrogen carrying them, an optionally substituted heterocycle, and
R 104 represents H or a (C 1 -C 6 )alkyl.

2. The compound according to claim 1 , which is a compound of the following formula (I-3c) or (I-4c):

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein:
n1 and n2 represent, independently of each other, an integer comprised between 0 and 4,
X 1 represents NH and X 2 represents a bond or O, and
W represents

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

4. The compound according to claim 1 , wherein Q represents an aryl or nitrogen-containing heterocycle optionally substituted with one or several groups selected from halogen; oxo (═O); 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 ; and aryl 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 ,
with R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 to R 40 representing, independently of one another, H or (C 1 -C 6 )alkyl.

5. The compound according to claim 4 , wherein Q represents a cycle of the following formula:

wherein:
X 11 represents N or CR 41 ,
X 12 represents N or CR 42 ,
X 13 represents N or C—NR 43a R 43b ,
X 14 represents N or CR 44 ,
X 15 represents N or 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 27 R 28 , and NR 29 C(O)R 30 ; or aryl 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 N or CR 46 ,
X 17 represents N or CR 47 ,
X 18 represents N or CR 48 ,
X 19 represents N or 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 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

on the proviso that no more than three of X 11 , X 12 , X 14 , X 15 , X 16 , X 17 , X 18 and X 19 represent N.

6. The compound according to claim 5 , wherein Q represents

where R 41 , R 42 , R 46 , R 47 , R 48 and R 49 each represent, independently of each other, hydrogen, halogen, OR 11 , or NR 12 R 13 .

7. 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 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 to R 40 and R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 to R 61 representing, independently of one another, H or (C 1 -C 6 )alkyl.

8. The compound according to claim 7 , 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 se

Assignees

• Pf Medicament
• Centre Nat Rech Scient
• Sapienza Univ Di Roma

Inventors

• Halby Ludovic
• Arimondo Paola
• Mai Antonello
• Rotili Dante

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title