IP Library › Granted Patent US 8,349,851

Granted Patent B2

US 8,349,851 · App. 12/714,323 · Granted Jan 8, 2013

JAK kinase modulating compounds and methods of use thereof

Assignee: Ambit Biosciences Corp.

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Quick Facts

Patent No.: US 8,349,851
App. No.: 12/714,323
Granted: Jan 8, 2013
Kind: B2

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Abstract

Provided herein are quinazoline compounds of formula (I): The compounds are useful for treatment of JAK kinase mediated diseases, including JAK2 kinase-, JAK3 kinase- or TYK2 kinase-mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.

Claims (182)

1. A compound having formula (I):

or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein

R 1 and R 2 are selected from (i), (ii), (iii), (iv) and (v) as follows:

(i) R 1 and R 2 together form ═O, ═S, ═NR 9 or ═CR 10 R 11 ;

(ii) R 1 and R 2 are both —OR 8 , or R 1 and R 2 , together with the carbon atom to which they are attached, form dioxacycloalkyl;

(iii) R 1 is hydrogen or halo; and R 2 is halo; and

(iv) R 1 is alkyl, alkenyl, alkynyl, cycloalkyl or aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl is optionally substituted with one or more substitutents selected from halo, cyano, alkyl, —R x OR w , —R x S(O) q R v , —R x NR y R z and —C(O)OR w ; and R 2 is halo or —OR 8 ; and

(v) R 1 is halo, deutero, —OR 12 , —NR 13 R 14 , or —S(O) q R 15 ; and R 2 is hydrogen, deutero, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl, is optionally substituted with one or more substitutents selected from halo, cyano, alkyl, —R x OR w , —R x S(O) q R v and —R x NR y R z ;

R 3 is hydrogen, halo, alkyl, cyano, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxy or alkoxy;

R 4 and R 5 are each independently hydrogen or alkyl;

each R 6 is independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, —R x OR 18 , —R x NR 19 R 20 , and —R x S(O) q R v ;

each R 7 is independently halo, alkyl, haloalkyl or —R x OR w ;

R 8 is alkyl, alkenyl or alkynyl;

R 9 is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy or amino;

R 10 is hydrogen or alkyl;

R 11 is hydrogen, alkyl, haloalkyl or —C(O)OR 8 ;

R 12 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —C(O)R v , —C(O)OR w and —C(O)NR y R z , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl are each optionally substituted with one or more substituents independently selected from halo, oxo, alkyl, hydroxy, alkoxy, amino and alkylthio;

R 13 and R 14 are selected as follows:

(i) R 13 is hydrogen or alkyl; and R 14 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, —C(O)R v , —C(O)OR w , —C(O)NR y R z and —S(O) q R v , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl are each optionally substituted with one or more substituents independently selected from halo, oxo, alkyl, hydroxy, alkoxy, amino and alkylthio; or

(ii) R 13 and R 14 , together with the nitrogen atom to which they are attached, form heterocyclyl or heteroaryl wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halo, alkyl, hydroxy, alkoxy, amino and alkylthio and wherein the heterocyclyl is also optionally substituted with oxo;

R 15 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —C(O)NR y R z or —NR y R z , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl are each optionally substituted with one or more substituents independently selected from halo, oxo, alkyl, hydroxy, alkoxy, amino and alkylthio;

R 18 is hydrogen, alkyl, haloalkyl, hydroxyC 2-6 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl; wherein R 18 is optionally substituted with 1 to 3 groups Q 1 , each Q 1 independently selected from alkyl, hydroxyl, halo, haloalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, hydroxycarbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloaryl and amino;

R 19 and R 20 are selected as follows:

(i) R 19 and R 20 are each independently hydrogen or alkyl; or

(ii) R 19 and R 20 , together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl which is optionally substituted with 1 to 2 groups each independently selected from halo, alkyl, haloalkyl, hydroxyl and alkoxy;

each R x is independently alkylene or a direct bond;

R v is hydrogen, alkyl, alkenyl or alkynyl;

R w is independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

R y and R z are selected as follows:

(i) R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or haloalkyl;

(ii) R y and R z , together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl which is optionally substituted with 1 to 2 groups each independently selected from halo, alkyl, haloalkyl, hydroxyl and alkoxy;

n is 0-4;

p is 0-5; and

each q is independently 0, 1 or 2.

2. The compound of claim 1 , wherein R 1 and R 2 together form ═O.

3. The compound of claim 1 , wherein R 1 is hydrogen or fluoro, and R 2 is fluoro.

4. The compound of claim 1 , wherein R 1 is hydroxyl, methoxy, amino or methoxycarbonylamino, and R 2 is hydrogen, phenyl or fluorophenyl.

5. The compound of claim 1 , wherein R 3 is hydrogen, alkyl or alkoxy.

6. The compound of claim 1 , wherein each R 6 is independently selected from hydrogen, halo, alkyl, hydroxyl and alkoxy.

7. The compound of claim 1 , wherein R 7 is halo.

8. The compound of claim 1 , wherein n is 0 or 1.

9. The compound of claim 1 , wherein p is 1 or 2.

10. The compound of claim 1 having formula (III) or (IIIa)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are selected from (i) and (ii) as follows:

(i) R 1 and R 2 are both alkoxy or R 1 and R 2 , together form ═O; and

(ii) R 1 is —OR 12 or —NR 13 R 14 , and R 2 is hydrogen, alkyl, aryl or haloaryl;

R 12 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —C(O)R v , —C(O)OR w and —C(O)NR y R z , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl are each optionally substituted with one or more substituents independently selected from halo, oxo, alkyl, hydroxy, alkoxy, amino and alkylthio;

R 13 and R 14 are selected as follows:

(i) R 13 is hydrogen or alkyl and R 14 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, —C(O)R v , —C(O)OR w , —C(O)NR y R z and —S(O) q R v wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl are each optionally substituted with one or more substituents independently selected from halo, oxo, alkyl, hydroxy, alkoxy, amino and alkylthio; or

R 3 is hydrogen or alkyl;

R 6 is selected from halo, alkyl, haloalkyl and —R x OR 18 ; where R 18 is hydrogen, alkyl, haloalkyl, hydroxyalkyl or heterocyclyl; wherein R 18 is optionally substituted with group Q 1 , where Q 1 is selected from hydroxyl, alkoxy, alkoxycarbonyl, hydroxycarbonyl, heterocyclyl and amino;

R 7 is halo, alkyl, haloalkyl, hydroxyl or alkoxy;

R v is hydrogen, alkyl, alkenyl or alkynyl;

R w is independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

R y and R z are selected as follows:

(i) R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or haloalkyl; or

and q is 0, 1 or 2.

11. The compound of claim 1 having formula (IV) or (IVa)