IP Library › Granted Patent US 10,851,093

Granted Patent B2

US 10,851,093 · App. 16/424,619 · Granted Dec 1, 2020

Tyrosine kinase inhibitors

Inventors: Ihab Darwish (San Carlos, CA); Jiaxin Yu (San Carlos, CA); Rao Kolluri (Foster City, CA); Sacha Holland (San Francisco, CA)

Assignee: Rigel Pharmaceuticals, Inc.

C07D413/14 C07D417/14 C07D453/00 C07D491/107

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Quick Facts

Patent No.: US 10,851,093
App. No.: 16/424,619
Granted: Dec 1, 2020
Kind: B2

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Abstract

Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R 1 , X, Y 1 , Y 2 , Y 3 and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.

Claims (127)

1. A compound having the structure formula (I):

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,

wherein

X is selected from

wherein n is 0, 1, 2, 3 or 4;

each —R X1 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 , —CH 2 —OP(O)(OR), Cak(C 0 -C 6 alkyl), Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), wherein Cak, Ar and Hca are optionally substituted with one or two —R X2 groups,

wherein each —R X2 is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR 2 , —C(O)OR, —C(O)NR 2 , —C(O)R, —S(O)R, —S(O) 2 R, —S(O)OR, —S(O) 2 OR, —S(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O)R, —N(R)S(O) 2 R, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or Ar;

Y 1 is CH or CF;

Y 2 is N;

Y 3 is CH;

Z is C 1 -C 6 alkyl, Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), each optionally substituted by 1, 2 or 3 —R Z1 groups;

wherein each —R Z1 is independently halogen, cyano, C 1 -C 6 alkyl, Cak, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR);

each R is independently hydrogen or C 1 -C 6 alkyl; and

R 1 is hydrogen or C 1 -C 6 alkyl;

wherein

Hca is a 3-15 membered ring or ring system comprising at least one ring and 1, 2, 3, or 4 O, S, or N atoms, provided no O or S is adjacent to another O or S;

Het is a 5-15 membered aromatic ring or ring system comprising at least one ring and 1, 2, 3, or 4 O, S, or N atoms, provided no O or S is adjacent to another O or S;

Cak is a 3-8 membered non-aromatic carbocyclic ring or ring system, which may be saturated or partially unsaturated; and

Ar is a 6-16 membered aromatic ring or ring system having at least one carbocyclic aromatic ring optionally fused one or more aromatic or non-aromatic rings.

2. The compound according to claim 1 , wherein n is 1, 2, 3 or 4

wherein

each —R X1 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, oxo, —OR, Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), wherein Ar and Hca are optionally substituted with one or two —R X2 groups, or when —R X1 is Hca(C 0 -C 6 alkyl), two —R X2 groups taken together, when attached to the same carbon atom, form an Hca,

or two —R X1 groups taken together, when attached to adjacent atoms, form a Ar or Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —R X2 groups,

wherein each —R X2 is independently halogen, —OR, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or Ar; and

Z is unsubstituted C 1 -C 6 alkyl, Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl).

3. The compound according to claim 1 , wherein X is

wherein n is 0, 1, 2, 3 or 4.

4. The compound according to claim 1 , wherein X is

5. The compound according to claim 1 , wherein X is

6. The compound according to claim 1 , wherein X is

7. The compound according to claim 1 , having the structure of formula (IIa):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,

X 1 is —N═, —C(H)═;

X 2 is ═C(H)—, ═N—, —N(H)—; and

R Xa and R Xb are each hydrogen, or R Xa and R Xb combine with the atoms to which they are attached to form an Ar or Hca.

8. The compound according to claim 1 , having the structure of formula (IIc):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,

X 1 is —N═, —C(H)═; and

R Xa and R Xb are each hydrogen, or R Xa and R Xb combine with the atoms to which they are attached to form an Ar or Hca.

9. The compound according to claim 1 , having the structure of formula (IIIa):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,

X 3 is —N═ or —S—;

X 4 is ═N—, ═C(H)—; and

X 5 is —S—, ═C(H)-.

10. The compound according to claim 9 , having the structure of formula (IIIe):

11. The compound according to claim 1 , wherein

12. The compound according to claim 1 , wherein —R X1 is Hca(C 0 -C 6 alkyl).

13. The compound according to claim 1 , wherein each —R X2 is independently halogen, —OR, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

14. The compound according to claim 1 , wherein each —R X2 is independently halogen or —OR.

15. The compound according to claim 1 , wherein R 1 is C 1 -C 6 alkyl.

16. A compound that is:

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)picolinamide;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-8-phenyl-3,4-dihydro-2H-1,4-ethano-1,5-naphthyridine-6-carboxamide;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylpicolinamide;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylpyrimidine-2-carboxamide;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylquinazoline-2-carboxamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide, hydrochloric acid;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-8-phenyl-3,4-dihydro-2H-1,4-ethano-1,5-naphthyridine-6-carboxamide, hydrochloric acid;

4-(4-Hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide, trifluoroacetic acid;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide, trifluoroacetic acid;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-phenylpicolinamide;

4-(4-Hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(piperidin-1-yl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-morpholinopicolinamide;

4-(4-ethoxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(pyrrolidin-1-yl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(4-phenylpiperidin-1-yl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)picolinamide;

4-(3,3-difluoroazetidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

4-(4,4-difluoropiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

4-(4,4-dimethylpiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-(piperidin-1-yl)picolinamide;

6-(4-hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-morpholinopicolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-(pyrrolidin-1-yl)picolinamide;

6-(4,4-dimethylpiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

6-(4,4-difluoropiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

6-(4-ethoxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

6-(3,3-difluoroazetidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

4-Fluoro-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-methylpicolinamide;

4-Methoxy-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;

N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(trifluoromethyl)picolinamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;

N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;

N-(5-((7-(benzyloxy)-6-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;

N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;

N-(5-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;

2-bromo-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide;

2-(4-hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-2-phenylthiazole-4-carboxamide;

2-(4-fluorophenyl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide;

5-bromo-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-2-carboxamide;

2-(4-hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide, hydrochloric acid;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-2-(piperidin-1-yl)thiazole-4-carboxamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-5-(piperidin-1-yl)thiazole-2-carboxamide;

N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-5-phenylthiazole-2-carboxamide;

N-(5-((6,7-dimethoxyquinazolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;