Tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10851093-B2
Application number	US-201916424619-A
Country	US
Kind code	B2
Filing date	May 29, 2019
Priority date	Jun 1, 2018
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

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.

First claim

What is claimed is:

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
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.

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-(

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Darwish Ihab
• Yu Jiaxin
• Kolluri Rao
• Holland Sacha

Classifications

• C07D453/00

  Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D471/18

  Bridged systems · CPC title