Tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11110082-B2
Application number	US-201916575852-A
Country	US
Kind code	B2
Filing date	Sep 19, 2019
Priority date	Jul 8, 2016
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structureand 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 60 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) 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 alkyl, 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 Cak, optionally substituted by one to three —R Z1 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.

2. The compound of claim 1 , having the structure of formula (Ie):

3. The compound of claim 2 , wherein R Y1 is —OR.

4. The compound of claim 3 , 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.

5. The compound of claim 3 , 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.

6. The compound of claim 5 , having the structure of formula (If):

7. The compound of claim 5 , having the structure of formula (II):

or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvate or hydrate thereof, wherein
ring A is Hca;
a is 0 or 1; and
p is 1, 2, 3 or 4; and
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).

8. The compound of claim 7 , wherein
(a) ring A is

wherein
p is 0, 1, 2, 3 or 4;
X 1 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
X 2 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—; and
X 3 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(b) ring A is

wherein
p is 0, 1, 2, 3 or 4;
X 2 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(c) ring A is

wherein
p is 0, 1 or 2;
o is 0, 1 or 2; and
ring B is Hca or Het, each comprising a 3-8 membered ring optionally substituted with one or two —R X2 groups;
(d) ring A is

wherein
p is 0, 1 or 2;
o is 0, 1 or 2;
n is 0, 1 or 2;
m is 0, 1 or 2; and
X 4 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(e) ring A is

wherein
X 6 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—; and
X 7 is —CR—, —C(R X1 )— or —N—;
p is 0, 1 or 2;
q is 0, 1 or 2;
r is 0, 1 or 2; and
s is 0, 1 or 2.

9. The compound of claim 1 , wherein
(a) ring A is

wherein
p is 0, 1, 2, 3 or 4;
X 1 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
X 2 is —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—; and
X 3 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(b) ring A is

wherein
p is 0, 1, 2, 3 or 4;
X 2 is —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(c) ring A is

wherein
p is 0, 1 or 2;
o is 0, 1 or 2; and
ring B is Hca or Het, each comprising a 3-8 membered ring optionally substituted with one or two —R X2 groups;
(d) ring A is

wherein
p is 0, 1 or 2;
o is 0, 1 or 2;
n is 0, 1 or 2;
m is 0, 1 or 2

Assignees

• Rigel Pharmaceuticals Inc

Inventors

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

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/4545 Primary

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

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/519

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

• A61P35/00

  Antineoplastic agents · CPC title