IP Library › Granted Patent US 8,501,770

Granted Patent B2

US 8,501,770 · App. 12/981,127 · Granted Aug 6, 2013

Substituted imidazopyridinyl-aminopyridine compounds

Inventors: Mark A. Ashwell (Carlisle, MA); Chris Brassard (Somerville, MA); Anton Filikov (Stoneham, MA); Jason Hill (Auburndale, MA); Steffi Koerner (Medford, MA); Jean-Marc Lapierre (Pelham, NH); Yanbin Liu (Acton, MA); Nivedita Namdev (Westford, MA); Robert Nicewonger (Tyngsboro, MA); Rocio Palma (North Andover, MA); Manish Tandon (Framingham, MA); David Vensel (Boston, MA); Akihisa Matsuda (Tokyo, JP); Shin Iimura (Tokyo, JP); Yuko Yamamoto (Tokyo, JP)

Assignee: ArQule, Inc.

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Quick Facts

Patent No.: US 8,501,770
App. No.: 12/981,127
Granted: Aug 6, 2013
Kind: B2

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Abstract

The present invention relates to substituted imidazopyridinyl-aminopyridine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted imidazopyridinyl-aminopyridine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

Claims (86)

1. A compound having formula I:

or a pharmaceutically acceptable salt or ester thereof, wherein:

X 1 is N and X 2 is CR x ;

R x , R 1 and R 3 are each independently H, hydroxyl, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

x is 0, 1, 2 or 3;

y is 0, 1, 2, 3 or 4;

each R pt is independently hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or unsubstituted or substituted amino;

each R pt is independently hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R n5 and R n6 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted amino, C(O)R 8 , C(O)OR 8 , S(O)R 8 , or S(O) 2 R 8 ;

R 8 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R is H, hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 3-, 4-, 5-, 6- or 7-member rings and 1-4 heteroatoms selected from N, O and S, or Q-T;

Q is a bond or unsubstituted or substituted C 1 -C 6 alkyl linker;

T is NR n1 R n2 , C(O)R o , S(O)R s or S(O) 2 R s ;

R n1 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R n2 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, C(O)R 4 , C(O)OR 4 , C(O)NR 4 ′R 4 , S(O)R 5 , S(O) 2 R 5 , S(O)NR 5 ′R 5 , or S(O) 2 NR 5 ′R 5 , or R n1 and R n2 , together with the nitrogen atom to which they attach, form a 4-, 5-, 6- or 7-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S;

R 4 , R 4 ′, R 5 and R 5 ′ are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R o is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, NR o1 R o2 , or OR o3 ;

R s is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or NR s1 R s2 ;

R o1 and R o2 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R o1 and R o2 , together with the nitrogen atom to which they attach, form a 4-, 5-, 6- or 7-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S;

R o3 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and

R s1 and R s2 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R s1 and R s2 , together with the nitrogen atom to which they attach, form a 4-, 5-, 6- or 7-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S.

2. The compound of claim 1 , having formula II:

or a pharmaceutically acceptable salt or ester thereof, wherein:

R 1 , R 2 and R 3 are each independently H, hydroxyl, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

x is 0, 1, 2 or 3;

y is 0, 1, 2, 3 or 4;

each R p1 is independently hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or unsubstituted or substituted amino;

each R p2 is independently hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R n5 and R n6 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted amino, C(O)R 8 , C(O)OR 8 , S(O)R 8 , or S(O) 2 R 8 ,

R N is NR 9 R 10 or C(O)R 11 ;

R 9 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, C(O)R 12 , C(O)OR 12 , C(O)NR 12 R 13 , S(O)R 12 , or S(O) 2 R 12 ;

R 11 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, OR 14 , or NR 14 R 15 ;

R 10 , R 12 , R 13 , R 14 and R 15 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and

is a 3-, 4-, 5-, 6- or 7-member carbocycle or heterocycle comprising 1-4 heteroatoms selected from N, O and S and is optionally substituted.

3. The compound of claim 2 , wherein x is 0 and y is 0.

4. The compound of claim 2 , wherein R 1 is unsubstituted or substituted phenyl.

5. The compound of claim 2 , wherein

is unsubstituted or substituted carbocycle selected from cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl, or a heterocycle selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, oxazetidinyl, thiazetidinyl, pyrrolidinyl, tetrahyrofuranyl, tetrahyrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolidinyl, oxadiazolidinyl, thiadiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, morpholinyl, oxazinanyl, thiazinanyl, azepanyl, oxepanyl, thiepanyl, diazepanyl, oxazepanyl, and thiazepanyl.

6. The compound of claim 5 , wherein

is unsubstituted or substituted cyclobutyl or unsubstituted or substituted oxetanyl.

7. The compound of claim 2 , wherein R N is NH 2 .

8. The compound of claim 1 , having formula III:

or a pharmaceutically acceptable salt or ester thereof, wherein:

x is 0, 1, 2 or 3;

y is 0, 1, 2, 3 or 4;

each R p1 is independently hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or unsubstituted or substituted amino;

R n5 and R n6 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted amino, C(O)R 8 , C(O)OR 8 , S(O)R 8 , or S(O) 2 R 8 ;

Q is a bond or unsubstituted or substituted C 1 -C 6 alkyl linker;

T is NR n1 R n2 , C(O)R o , S(O)R s or S(O) 2 R s ;

R n 1 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R n 2 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, C(O)R 4 , C(O)OR 4 , C(O)NR 4 ′R 4 , S(O)R 5 , S(O) 2 R 5 , S(O)NR 5 ′R 5 , or S(O) 2 NR 5 ′R 5 , or R n1 and R n2 , together with the nitrogen atom to which they attach, form a 4-, 5-, 6- or 7-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S;

R S is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or NR s1 R s2 ;

9. The compound of claim 8 , wherein x is 0 and y is 0.

10. The compound of claim 8 , wherein Q is a bond.

11. The compound of claim 8 , wherein Q is a methyl linker.

12. The compound of claim 8 , wherein T is NR n1 R n2 .

13. The compound of claim 12 , wherein R n1 is C(O)R 4 , C(O)OR 4 , C(O)NR 4 ′R 4 , or S(O) 2 R 5 .

14. The compound of claim 8 , wherein T is C(O)R o .

15. The compound of claim 14 , wherein R o is NR o1 R o2 .

16. The compound of claim 8 , having one of the following formulae:

wherein:

m is 0, 1, 2, 3, 4 or 5;

each R p4 is independently hydroxyl, cyano, nitro, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, C(O)R 22 , C(O)OR 22 , NR 22 ′C(O)R 22 , and NR 22 ′C(O)OR 22 ; and

R 22 and R 22 ′ are each independently H, unsubstituted or substituted C 1 -C 6 alkyl or unsubstituted or substituted C 6 -C 10 aryl.

17. The compound of claim 1 , having formula IV:

or a pharmaceutically acceptable salt or ester thereof, wherein:

x is 0, 1, 2 or 3;

y is 0, 1, 2, 3 or 4;

R p0 is H, hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted amino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

each R p1 is independently hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or unsubstituted or substituted amino;

R n5 and R n6 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted amino, C(O)R 8 , C(O)OR 8 , S(O)R 8 , or S(O) 2 R 8 ; and

18. The compound of claim 1 , selected from the group consisting of:

19. The compound of claim 18 , wherein said compound is:

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a salt, solvate, hydrate or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 18, 2011

From: ASHWELL, MARK A.; BRASSARD, CHRIS; FILIKOV, ANTON; HILL, JASON; KOERNER, STEFFI; LAPIERRE, JEAN-MARC; LIU, YANBIN; NAMDEV, NIVEDITA; NICEWONGER, ROBERT; PALMA, ROCIO; TANDON, MANISH; VENSEL, DAVID; MATSUDA, AKIHISA; IIMURA, SHIN; YAMAMOTO, YUKO

To: ARQULE, INC.

Reel/Frame 025978/0844 →

Continuity (2)

Provisional Application 61290923 · Dec 30, 2009

Related Publication 20110172203A1 · Jul 14, 2011