Tyrosine Kinase Inhibitors

Patent metadata

Field	Value
Publication number	US-2019382395-A1
Application number	US-201916424619-A
Country	US
Kind code	A1
Filing date	May 29, 2019
Priority date	Jun 1, 2018
Publication date	Dec 19, 2019
Grant date	—

Abstract

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R1, X, Y1, Y2, Y3 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

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 Het or Hca, wherein Het and Hca are substituted by 1, 2, 3, or 4 —R X1 groups, wherein
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 or CH;
Y 3 is N or 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, 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

provided that
(a) when Y 3 is N or Z is C 1 -C 6 alkyl, X is

and
(b) when Z is Hca(C 0 -C 6 alkyl), Y 1 is CH and Y 2 is N, X is not

2 . The compound according to claim 1 , wherein
X is Het or Hca, wherein the Het and Hca are substituted by 1, 2, 3 or 4 —R X1 groups, 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

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

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 , wherein X is

8 . (canceled)

9 . 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.

10 . 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.

11 . 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)—.

12 . The compound according to claim 11 , having the structure of formula (IIIe):

13 . 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.

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

15 . (canceled)

16 . 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.

17 . (canceled)

18 . (canceled)

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

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

21 . The compound of claim 1 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-

Assignees

• Rigel Pharmaceuticals Inc

Inventors

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

Classifications

• C07D491/107

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

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D453/00

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

• A61P35/00

  Antineoplastic agents · CPC title