Substituted pyrido[3,4-d]pyrimidines and pyrido[4,3-d]pyrimidines as p70S6K inhibitors

Patent metadata

Field	Value
Publication number	US-10233160-B2
Application number	US-201815960759-A
Country	US
Kind code	B2
Filing date	Apr 24, 2018
Priority date	Nov 29, 2012
Publication date	Mar 19, 2019
Grant date	Mar 19, 2019

Abstract

Novel azaquinazoline carboxamide derivatives of formula (I)

wherein W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 and m which are defined above, are p70S6K inhibitor, and can be employed, inter alia, for the treatment of hyperproliferative disorders.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
W 1 is CH;
W 2 is CH;
W 3 is N; and
W 4 is CH; or
W 1 is CH;
W 2 is CH;
W 3 is CH; and
W 4 is N;
R 1 is Ar or Het 1 ;
each of R 2 , R 4 , and R 5 is independently Y;
R 3 is Y or —(CH 2 ) p —NR 4 R 5 ;
or R 2 and R 3 together with the atoms to which each is attached, may form —(CH 2 ) n —NY—(CH 2 ) p ;
or R 4 and R 5 together with the atoms to which each is attached, may form —(CY 2 ) q —;
each Y is independently H or A;
each A is independently unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced independently from one another by Hal;
Ar is an unsaturated or aromatic monocyclic or bicyclic carbocycle having 3-10 C atoms, which can be substituted by at least one substituent selected from the group consisting of Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO 2 Y, SO 2 NYY, NYSO 2 Y, NYY, NO 2 , OCN, SCN, SH, phenyl and Het 1 , where the phenyl is optionally substituted by Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO 2 Y, SO 2 NYY, NYSO 2 Y, NYY, NO 2 , OCN, SCN or SH;
each Het 1 is independently an unsaturated or aromatic monocyclic or bicyclic heterocycle having 2-10 C atoms and 1-4 N, O and/or S atoms, which can be substituted by at least one substituent selected from the group consisting of Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO 2 Y, SO 2 NYY, NYSO 2 Y, NYY, NO 2 , OCN, SCN, SH, phenyl and Het 2 , where the phenyl is optionally substituted by Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO 2 Y, SO 2 NYY, NYSO 2 Y, NYY, NO 2 , OCN, SCN or SH;
Het 2 is saturated, unsaturated or aromatic monocyclic 5-6-membered heterocycle having 2-5 C atoms and 1-3 N, O and/or S atoms, which is optionally substituted by Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO 2 Y, SO 2 NYY, NYSO 2 Y, NYY, NO 2 , OCN, SCN or SH;
each Hal is independently F, Cl, Br or I;
m is 0 or 1;
each of n and p is independently 0, 1, 2 or 3; and
q is 2, 3, 4, 5 or 6;
and/or a physiologically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is phenyl or pyridyl, each of which is optionally substituted.

3. The compound according to claim 2 , wherein R 1 is

4. The compound according to claim 3 , wherein R 1 is

5. The compound according to claim 1 , wherein R 3 is H or —(CH 2 ) p —NR 4 R 5 .

6. The compound according to claim 5 , wherein R 3 is H,

7. The compound according to claim 6 , wherein R 3 is H,

8. The compound according to claim 1 , wherein R 2 and R 3 together with the atoms to which each is attached, is

9. The compound according to claim 1 , which is selected from the group consisting of:
(R)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-8-carboxamide (19);
(S)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-8-carboxamide (20);
4-[(S)-1-(4-Isopropyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,4-d]pyrimidine-8-carboxylic acid amide (40); and
4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,4-d]pyrimidine-8-carboxylic acid amide (42).

10. A pharmaceutical composition comprising as active ingredient at least one compound according to claim 1 , and/or a physiologically acceptable salt thereof, together with at least one pharmaceutically tolerable excipient, and optionally in combination with one or more further active ingredients.

11. A method for inhibiting p70S6K in a system expressing p70S6K, wherein the system is contacted with at least one compound according to claim 1 , and/or a physiologically acceptable salt thereof.

12. A method for treating breast cancer, bladder cancer, pancreatic cancer, renal cancer, lung cancer or neuroblastoma in a subject, comprising administering to the subject at least one compound according to claim 1 , and/or a physiologically acceptable salt thereof.

Assignees

• Merck Patent Gmbh

Inventors

• Huck Bayard R
• Lan Ruoxi
• Potnick Justin
• Deselm Lizbeth Celeste
• Cronin Jr Mark W
• Neagu Constantin
• Chen Xiaoling
• Boivin Roch
• Johnson Theresa L
• Goutopoulos Andreas

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title