US 10,851,093 B2Granted

Tyrosine kinase inhibitors

AssigneeRigel Pharmaceuticals, Inc.

InventorsIhab Darwish, Jiaxin Yu, Rao Kolluri, Sacha Holland

Life of this patent

Estimating the term…

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 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.

Claims17

Dependent claims

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 —RX1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2, —CH2—OP(O)(OR), Cak(C0-C6alkyl), Ar(C0-C6alkyl) or Hca(C0-C6alkyl), wherein Cak, Ar and Hca are optionally substituted with one or two —RX2 groups,
wherein each —RX2 is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR2, —C(O)OR, —C(O)NR2, —C(O)R, —S(O)R, —S(O)2R, —S(O)OR, —S(O)2OR, —S(O)NR2, —S(O)2NR2, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)R, —N(R)S(O)2R, C1-C6alkyl, C1-C6haloalkyl or Ar;
Y1 is CH or CF;
Y2 is N;
Y3 is CH;
Z is C1-C6alkyl, Ar(C0-C6alkyl) or Hca(C0-C6alkyl), each optionally substituted by 1, 2 or 3 —RZ1 groups;
wherein each —RZ1 is independently halogen, cyano, C1-C6alkyl, Cak, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
each R is independently hydrogen or C1-C6alkyl;
and
R1 is hydrogen or C1-C6alkyl;
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.

17 more elements

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;
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-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;
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;
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-(pyrrolidin-1-yl)picolinamide;
N-(54(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)-6-(piperidin-1-yl)picolinamide;
N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-(pyrrolidin-1-yl)picolinamide;
6-(4,4-difluoropiperidin-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;
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;
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;
N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-2-(piperidin-1-yl)thiazole-4-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;
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof.

71 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/424,619Filed 29 May 2019 · us provisional application
Priority: 1 Jun 2018
Published: US 2019/0382395 A119 Dec 2019
Granted: 1 Dec 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
A61P 35/00
Antineoplastic agents
C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…

Family

Application62/679,095Us provisional application · filed 1 Jun 2018
US 2019/0382395 A1Pre-grant publication · published 19 Dec 2019
US 10,851,093 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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 —RX1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2, —CH2—OP(O)(OR), Cak(C0-C6alkyl), Ar(C0-C6alkyl) or Hca(C0-C6alkyl), wherein Cak, Ar and Hca are optionally substituted with one or two —RX2 groups,
wherein each —RX2 is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR2, —C(O)OR, —C(O)NR2, —C(O)R, —S(O)R, —S(O)2R, —S(O)OR, —S(O)2OR, —S(O)NR2, —S(O)2NR2, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)R, —N(R)S(O)2R, C1-C6alkyl, C1-C6haloalkyl or Ar;
Y1 is CH or CF;
Y2 is N;
Y3 is CH;
Z is C1-C6alkyl, Ar(C0-C6alkyl) or Hca(C0-C6alkyl), each optionally substituted by 1, 2 or 3 —RZ1 groups;
wherein each —RZ1 is independently halogen, cyano, C1-C6alkyl, Cak, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
each R is independently hydrogen or C1-C6alkyl;
and
R1 is hydrogen or C1-C6alkyl;
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.

17 more elements

Facts

Application

16/424,619Filed 29 May 2019 · us provisional application

Priority

1 Jun 2018

Published

US 2019/0382395 A119 Dec 2019

Granted

1 Dec 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
A61P 35/00
Antineoplastic agents
C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…