Imidazo[4,5-b]pyridine derivatives as ALK and JAK modulators for the treatment of proliferative disorders

Patent metadata

Field	Value
Publication number	US-9238656-B2
Application number	US-201414446411-A
Country	US
Kind code	B2
Filing date	Jul 30, 2014
Priority date	Jan 30, 2012
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

This application relates to compounds of the Formula I

as defined herein, and/or salts thereof. This application further relates to compositions and methods of using these compounds and/or salts thereof. The compounds of Formula I are useful as ALK and JAK modulators for the treatment of proliferative disorders.

First claim

The invention claimed is:

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

and a salt thereof, wherein:
W is H and Z is selected from

or
W and Z are taken together to form

R 1 is selected from (C 6 -C 10 )aryl, aminophenyl, (C 2 -C 9 )heterocycloalkyl, (C 1 -C 9 )heteroaryl and a group of formula

wherein any of the foregoing may be optionally substituted with one or more R 6 groups;
R 2 is selected from hydrogen and halogen;
R 3 is selected from CH 2 OH and CONR 4 R 5 ;
Q is selected from CH 2 and O;
“------” is either present so as to form a double bond or is absent;
R 4 and R 5 are each independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, and (C 1 -C 6 )alkyl-OR 9 wherein any of the foregoing except for H may be optionally substituted with one or more R 7 ;
each R 6 is independently selected from (C 0 -C 4 )alkylCO 2 R 8 , (C 0 -C 4 )alkylCON(R 8 ) 2 , (C 0 -C 4 )alkylCOR 8 , (C 0 -C 4 )alkylN(R 8 ) 2 , (C 0 -C 4 )OR 9 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )alkoxy(C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 1 -C 9 )heteroaryl, (C 1 -C 6 )alkyl(C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 2 -C 6 )alkenyl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heterocycloalkyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyloxy, (C 3 -C 9 )heterocycloalkenyl, (C 6 -C 10 )aryl, cyano, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, O(C 0 -C 4 )alkylCO 2 R 8 , O(C 0 -C 4 )alkylCON(R 8 ) 2 , O(C 0 -C 4 )alkylCOR 8 , PO((C 1 -C 4 )alkyl) 2 , and O(C 0 -C 4 )alkylN(R 8 ) 2 , wherein any of the foregoing except for halogen, may be optionally substituted with one or more R 7 ;
each R 7 is independently selected from (C 0 -C 4 )alkylCO 2 R 8 , (C 0 -C 4 )alkylCON(R 8 ) 2 , (C 0 -C 4 )alkylCOR 8 , (C 0 -C 4 )OR 9 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 1 -C 9 )heteroaryl, (C 1 -C 6 )alkyl(C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heterocycloalkyl optionally substituted with (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halogen, hydroxy(C 1 -C 6 )alkyl, PO((C 1 -C 4 )alkyl) 2 , and hydroxy(C 1 -C 6 )alkyl(C 1 -C 6 )alkoxy;
each R 8 is independently selected from H, (C 1 -C 6 )alkyl, and (C 2 -C 9 )heterocycloalkyl, or two R 8 are taken together with the nitrogen atom to which they are attached to form (C 2 -C 9 )heterocycloalkyl, wherein any of the foregoing except for H, may be optionally substituted with (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, halogen, (C 0 -C 4 )alkylCO 2 R 9 , (C 0 -C 4 )alkylN(R 9 ) 2 or (C 0 -C 4 )alkylOR 9 ;
R 9 is independently selected from H and (C 1 -C 6 )alkyl; and
R 10 is independently a carbonyl or a hydroxyl group.

2. A compound according to claim 1 or a salt thereof, wherein Z is:

3. A compound according to claim 1 or a salt thereof, wherein Z is:

4. A compound according to claim 1 or a salt thereof, wherein Z is:

5. A compound according to claim 1 , or a salt thereof, wherein Z is selected from:

6. A compound according to claim 1 , or a salt thereof, wherein W and Z are taken together to form

7. A compound according to claim 5 , or a salt thereof, wherein Z is selected from:

8. A compound according to claim 7 , or a salt thereof, wherein Z is:

9. A compound according to claim 7 , or a salt thereof, wherein Z is:

10. A compound according to claim 5 , or a salt thereof, wherein Z is:

11. A compound according to claim 7 , or a salt thereof, wherein Z is

12. A compound according to claim 1 , or a salt thereof, wherein R 2 is selected from hydrogen, chlorine and bromine.

13. A compound according to claim 9 , or a salt thereof, wherein:
R 1 is selected from phenyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isoxazolyl, tetrahydroimidazopyridinyl, and aminophenyl, wherein each of the foregoing may be optionally substituted with one or more R 6 groups;
R 2 is selected from hydrogen, chlorine and bromine; and
R 4 and R 5 are each independently selected from hydrogen, methyl, isopropyl, hydroxyethyl, and cyclopropyl.

14. A compound according to claim 13 that is selected from the following:
(1S,2S,3R,4R)-3-[6-Chloro-2-(4-morpholin-4-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-[6-Chloro-2-(4-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-[6-Chloro-2-(3-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-[6-Chloro-2-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-[6-Chloro-2-(3-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-[6-Chloro-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-[6-Chloro-2-(2-methoxy-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-{6-Chloro-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4,5-b]pyridine-7-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
3-[7-((1R,2R,3S,4S)-3-Carbamoyl-bicyclo[2.2.1]hept-5-en-2-ylamino)-6-chloro-3H-imidazo[4,5-b]pyridine-2-yl]-piperidine-1-carboxylic acid tert-butyl ester;
(1S,2S,3R,4R)-3-[6-Chloro-2-(3-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide;
(1S,2S,3R,4R)-3-(6-Chloro-2-piperidin-3-yl-3H-imidazo[4,5-b]pyridin-7-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide; (1S,2S,3R,4R)-3-[6-Chloro-2-(4-piperazin-1-yl-phenyl)-3H-imidazo

Assignees

• Cephalon Inc

Inventors

• Breslin Henry J
• Curry Matthew A
• Gingrich Diane E
• Learn Keith S
• Ott Gregory R
• Wagner Jason C

Classifications

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D493/08 Primary

  Bridged systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title