Substituted quinazoline derivatives as DNA methyltransferase inhibitors

• US 10,450,299 B2
• Filed: 03/25/2016
• Issued: 10/22/2019
• Est. Priority Date: 03/25/2015
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Pierre Fabre Medicament (Fondation Pierre Fabre), Sapienza Università di Roma
• Original Assignee: Centre National De La Recherche Scientifique
• Inventors: Halby, Ludovic, Arimondo, Paola, Mai, Antonello, Rotili, Dante
• Primary Examiner(s): Coleman, Brenda L
• Application Number:
  US15/560,883
• Publication Number:
  US 20180118717A1
• Time in Patent Office: 1,306 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

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.

Claims

1. A compound of the following formula (I):

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

3. The compound according to claim 1, wherein:

n1 and n2 represent, independently of each other, an integer comprised between 0 and 4,

X₁ represents NH and X₂ represents a bond or O, and

W represents

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);

OR₁₁;

NR₁₂R₁₃;

C(O)R₁₄;

CO₂R₁₅;

OC(O)R₁₆;

C(O)NR₁₇R₁₈;

NR₁₉C(O)R₂₀;

(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; and

aryl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀,

with R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉ to R₄₀ representing, independently of one another, H or (C₁-C₆)alkyl.

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

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

7. The compound according to claim 1, wherein R₃ and R₄ represent, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —

((C₁-C₆)alkyl)-X₅-aryl or —

((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen;

oxo (═

O);

NO₂;

OR₁₁;

NR₁₂R₁₃;

C(O)R₁₄;

CO₂R₁₅;

OC(O)R₁₆;

C(O)NR₁₇R₁₈;

NR₁₉C(O)R₂₀;

S(O)R₅₀;

S(O)₂R₅₁;

S(O)₂NR₅₂R₅₃;

(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅, and S(O)₂NR₅₆R₅₇; and

aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, NR₃₉C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁,

with R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉ to R₄₀ and R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, R₅₈, R₅₉, R₆₀ to R₆₁ representing, independently of one another, H or (C₁-C₆)alkyl.

8. The compound according to claim 7, wherein R₃ and R₄ represent, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —

((C₁-C₆)alkyl)-X₅-aryl or —

((C₁-C₆)alkyl)-X₅-heterocycle

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen;

OR₁₁;

NR₁₂R₁₃;

(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁ and NR₂₂R₂₃; and

aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁ and NR₃₂R₃₃.

9. The compound according to claim 1, wherein Y₁ and Y₂ represent, independently of each other, H, a halogen atom, OR₁₀₁ or NR₁₀₂R₁₀₃, provided that at least one of Y₁ and Y₂ represent a group other than H,

where R₁₀₁, R₁₀₂ and R₁₀₃ represent, independently of one another, H, optionally substituted aryl, optionally substituted heterocycle, or —

((C₁-C₆)alkyl)-X₆-A₁,

with X₆ representing a bond, O or NR₁₀₄, and A₁ representing H, (C₁-C₆)alkyl, optionally substituted aryl or optionally substituted heterocycle,

or, for the R₁₀₂ and R₁₀₃ groups, R₁₀₂ and R₁₀₃ form together, with the nitrogen carrying them, an optionally substituted heterocycle, and

where the optionally substituted aryl and optionally substituted heterocycle are optionally substituted with one or several groups selected from halogen;

oxo (═

O);

NO₂;

OR₁₁;

NR₁₂R₁₃;

C(O)R₁₄;

CO₂R₁₅;

OC(O)R₁₆;

C(O)NR₁₇R₁₈;

NR₁₉C(O)R₂₀;

S(O)R₅₀;

S(O)₂R₅₁;

S(O)₂NR₅₂R₅₃;

(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅, and S(O)₂NR₅₆R₅₇; and

aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, NR₃₉C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁,

with R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉ to R₄₀ and R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, R₅₈, R₅₉, R₆₀ to R₆₁ representing, independently of one another, H or (C₁-C₆)alkyl.

10. The compound according to claim 9, wherein Y₁ represents H, a halogen atom or NR₁₀₂R₁₀₃, and Y₂ represents H or OR₁₀₁, provided that at least one of Y₁ and Y₂ represent a group other than H, with

R₁₀₁ representing H, (C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)alkyl or (C₁-C₆)alkyl-aryl, and

R₁₀₂ and R₁₀₃ representing, independently of one another, H, (C₁-C₆)alkyl, aryl, heterocycle, aryl-(C₁-C₆)alkyl, heterocycle-(C₁-C₆)alkyl or —

((C₁-C₆)alkyl)-NR₁₀₄-A₁, with A₁ representing H, (C₁-C₆)alkyl, aryl or heterocycle,

or R₁₀₂ and R₁₀₃ forming together, with the nitrogen carrying them, a heterocycle, and where each aryl and heterocycle moiety is optionally substituted with one or several groups selected from halogen, oxo (═

O), (C₁-C₆)alkyl, aryl, and aryl-(C₁-C₆)alkyl.

11. The compound according to claim 1, which is selected from the following compounds:

12. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 and at least one pharmaceutically acceptable excipient.

13. A method to prepare a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, in which W represents NR₀, a divalent monoglycosyl,

14. A method to prepare a compound of formula (I) according to claim 1, in which at least one of Y₁ and Y₂ represents a OR₁₀₁ or NR₁₀₂R₁₀₃ group, or a pharmaceutically acceptable salt thereof, comprising:

(i) reacting a compound of the following formula (XI);

15. The compound according to claim 3, wherein:

n1 and n2 represent, independently of each other, 1 or 2,

X₂ represents O, and

W represents

16. The compound according to claim 5, wherein:

X₁₁ represents CR₄₁,

X₁₂ represents CR₄₂,

X₁₃ represents N or C—

NR_43aR_43b,

X₁₄ represents CR₄₄,

X₁₅ represents CR₄₅,

R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each other, hydrogen;

halogen;

OR₁₁;

NR₁₂R₁₃;

(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, and NR₂₂R₂₃;

or aryl optionally substituted with one or several groups selected from halogen, OR₃₁, and NR₃₂R₃₃, or

in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of the following formula;

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

18. The compound according to claim 8, wherein R₃ and R₄ represent, independently of each other, aryl, heterocycle, aryl-(C₁-C₆)alkyl, heterocycle-(C₁-C₆)alkyl, —

((C₁-C₆)alkyl)-NH-aryl or —

((C₁-C₆)alkyl)-NH-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen;

OR₁₁;

NR₁₂R₁₃;

(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁ and NR₂₂R₂₃; and

aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁ and NR₃₂R₃₃.