Tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10130623-B2
Application number	US-201715645775-A
Country	US
Kind code	B2
Filing date	Jul 10, 2017
Priority date	Jul 8, 2016
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

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 X, Y 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:

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

or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
X is hydrogen, Cak(C 0 -C 6 alkyl), Hca(C 0 -C 6 alkyl), Ar(C 0 -C 6 alkyl), Het(C 0 -C 6 alkyl), halogen or Hca(C 1 -C 6 alkyl)-O—, wherein Ar, Het, Cak, Hca and the alkyl group is optionally substituted by one to four —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, 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), Ar(C 0 -C 6 alkyl), Het(C 0 -C 6 alkyl), Cak(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl),
or two —R X1 groups taken together, when attached to adjacent atoms, form a Cak, Hca or Het, wherein the Cak Hca and the Het comprise a 3-8 membered ring optionally substituted with one or two —R X2 groups,
or two —R X1 groups taken together, when attached to the same carbon atom, form a Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —R X2 groups,
or two —R X1 groups taken together, when attached to non-adjacent atoms, and combined with X, form a bridged Hca 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, or C 1 -C 6 haloalkyl;

Y is Cak(C 0 -C 8 alkyl) or Hca(C 0 -C 6 alkyl), each optionally substituted by one or two —R Y1 groups;
wherein each —R Y1 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , N(R)C(NR 2 )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);

Z is C 1 -C 6 alkyl or Cak(C 0 -C 6 alkyl), each optionally substituted by one to three —R X1 groups;
wherein each —R Z1 is independently halogen, cyano, C 1 -C 6 alkyl, 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); and

each R is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, Hca(C 0 -C 6 alkyl), Cak(C 0 -C 8 alkyl), C 1 -C 6 alkyl-CN, —CH 2 C(O)NH 2 , C 1 -C 6 alkyl-OH, wherein
Hca is a 3-15 membered ring or ring system comprising at least one ring, 1-4 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 1-4 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 the compound is not
3-(butylamino)-8-chloro-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
3-(butylamino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
3-(butylamino)-8-(2,6-difluorophenyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one; or
3-(butylamino)-5-(4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one.

2. The compound of claim 1 , wherein
X is hydrogen, Cak(C 0 -C 6 alkyl), Hca(C 0 -C 6 alkyl), Ar(C 0 -C 6 alkyl) or Het(C 0 -C 6 alkyl), wherein Ar, Het, Cak, Hca and the alkyl group is optionally substituted by one to four —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, 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), Ar(C 0 -C 6 alkyl), Het(C 0 -C 6 alkyl), Cak(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl),
or two —R X1 groups taken together, when attached to adjacent atoms, form a Cak, Hca or Het, wherein the Cak Hca and the Het comprise a 3-8 membered ring optionally substituted with one or two —R X2 groups,
or two —R X1 groups taken together, when attached to the same carbon atom, form a Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —R X2 groups,
or two —R X1 groups taken together, when attached to non-adjacent atoms, and combined with X, form a bridged Hca 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, or C 1 -C 6 haloalkyl;

Y is Cak(C 0 -C 6 alkyl) optionally substituted by one or two —R Y1 groups;
wherein each —R Y1 is independently halogen, cyano, 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);

Z is C 1 -C 6 alkyl or Cak(C 0 -C 6 alkyl), each optionally substituted by one to three —R Z1 groups;
wherein each —R Z1 is independently halogen, cyano, 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); and

each R is independently hydrogen or C 1 -C 6 alkyl,
wherein
Hca is a 3-15 membered ring or ring system comprising at least one ring, 1-4 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 1-4 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.

3. The compound of claim 2 , having the structure of formula (Ie):

4. The compound of claim 3 , wherein m is 1 and R Y1 is —OH.

5. The compound of claim 1 , wherein X is hydrogen, Cak(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), wherein each Cak, Hca and alkyl group is optionally substituted by one to three —R X1 groups.

6. The compound of any of claim 1 , wherein X is hydrogen or Hca(C 0 -C 6 alkyl), wherein each Hca and alkyl group is optionally substituted by one to three —R X1 groups.

7. The compound of claim 2 , having the structure of formula (If):

8. The compound of claim 2 , having the structure of formula (II):

or a pharmaceutically acceptable salt, or N-oxide thereof, or a

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Holland Sacha
• Singh Rajinder
• Bhamidipati Somasekhar
• Ding Pingyu
• Kolluri Rao
• Darwish Ihab
• Masuda Esteban
• Yu Jiaxin

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/4545 Primary

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title