Syk inhibitors

Patent metadata

Field	Value
Publication number	US-10005774-B2
Application number	US-201615150038-A
Country	US
Kind code	B2
Filing date	May 9, 2016
Priority date	Jul 31, 2013
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

The present disclosure relates to compounds that are Syk inhibitors and to their use in the treatment of various disease states, including cancer and inflammatory conditions. In particular embodiments, the structure of the compounds is given by Formula I:

wherein X 1 , X 2 , X 3 , R 2 , R 3 , R 4 , R 5 , and Y are as described herein. The present disclosure further provides pharmaceutical compositions that include a compound of Formula I, or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by Syk.

First claim

What is claimed:

1. A method for treating a disease or condition selected from lymphoma, multiple myeloma, or leukemia in a human patient in need thereof, comprising administering to the human patient a therapeutically effective amount of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:
X 1 , X 2 and X 3 together with the atoms to which they are attached and any intervening atoms form:

R 1a is hydrogen, halo, haloalkyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, C 2-12 heteroaryl, or —N(R 20 )(R 22 ),
wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, or C 2-12 heteroaryl moieties may be optionally substituted with one, two, or three substituents independently selected from fluoro, —CH 2 F, —CHF 2 , —CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-12 cycloalkyl, and —N(R 20 )(R 22 );

R 1b is hydrogen, haloalkyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, or C 2-12 heteroaryl,
wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, or C 2-12 heteroaryl moieties may be optionally substituted with one, two, or three substituents independently selected from fluoro, —CH 2 F, —CHF 2 , —CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-12 cycloalkyl, and —N(R 20 )(R 22 );

Y is O or NH;
R 2 is hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 1-6 alkoxy, or —N(R 20 )(R 22 );
wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, or C 1-6 alkoxy moieties may be optionally substituted with one, two, or three substituents independently selected from fluoro, —CH 2 F, —CHF 2 , —CF 3 , C 1-6 alkyl, and C 1-6 alkoxy;

each R 3 and R 4 is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclyl, or C 2-6 alkenyl,
wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclyl, and C 2-6 alkenyl moieties may be optionally substituted with one, two, or three substituents independently selected from halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-12 aryl, C 2-8 heterocyclyl, C 2-12 heteroaryl, —OR 20 , and —N(R 20 )(R 22 );

R 5 is monocyclic or bicyclic C 6-12 aryl, monocyclic or bicyclic C 3-12 cycloalkyl, monocyclic or bicyclic C 2-8 heterocyclyl, or monocyclic or bicyclic C 2-12 heteroaryl having one, two, three, or four heteroatoms independently selected from O, N, and S;
wherein the monocyclic or bicyclic C 6-12 aryl, monocyclic or bicyclic C 3-12 cycloalkyl, monocyclic or bicyclic C 2-8 heterocyclyl, or monocyclic or bicyclic C 2-12 heteroaryl moiety may be optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, halo, —NO 2 , —CH 2 F, —CF 3 , —CHF 2 , —OCF 3 , C 3-6 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, C 2-12 heteroaryl, —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 22 ), —N(R 20 )(R 22 ), —N(R 20 )—S(O) 2 —R 20 , —N(R 20 )—C(O)—R 22 , —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), cyano, oxo, and —O—R 20 ;
wherein the C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, or C 2-12 heteroaryl moiety may be optionally further substituted with one, two, or three substituents independently selected from the group consisting of halo, —NO 2 , —CH 2 F, —CF 3 , —CHF 2 , —OCF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-12 aryl, C 2-8 heterocyclyl, C 2-6 heteroaryl, —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), cyano, —S(O) 2 R 20 , —S(O) 2 —N(R 20 )(R 22 ), —S(O) 2 —R 20 —N(R 20 )(R 22 ), oxo, and —O—R 20 ;
wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, and C 2-6 heteroaryl may be further optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 6-12 aryl, C 2-6 heteroaryl, C 2-8 heterocyclyl, halo, —NO 2 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), cyano, —S(O) 2 —R 20 , S(O) 2 —N(R 20 )(R 22 ), —S(O) 2 —R 20 —N(R 20 )(R 22 ), oxo, and —O—R 20 ; and

each R 20 and R 22 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, or C 2-12 heteroaryl;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl and C 2-12 heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C 1-6 alkyl, acylamino, oxo, —NO 2 , —S(O) 2 R 26 , cyano, C 1-6 alkoxy, C 3-6 cycloalkoxy, —CH 2 F, —CF 3 , —CHF 2 , —OCF 3 , —OCH 2 CF 3 , —C(O)—NH 2 , C 6-12 aryl, C 3-6 cycloalkyl, C 2-8 heterocyclyl, and C 2-6 heteroaryl; and
wherein R 26 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, C 2-6 heteroaryl, acylamino, NH 2 , —CH 2 F, —CF 3 , or —CHF 2 .

2. The method according to claim 1 , wherein said compound is a compound of formula II, or a pharmaceutically acceptable salt thereof:

wherein:
Y is O;
R 1a is hydrogen, cyano, chloro, methyl, ethyl, propyl, or butyl;
R 2 is hydrogen or methyl;
R 3 is methyl, ethyl, propyl, or butyl;
R 4 is hydrogen; and
R 5 is phenyl or pyrazolyl, wherein the phenyl or pyrazolyl moieties may be optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoroethyl, difluoropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, piperazinyl, and morpholino;
wherein the R 5 piperazinyl group can be further substituted by 0 or 1 group selected from C 2-5 heterocyclyl, —S(O) 2 —C 1-6 alkyl, —S(O) 2 —C 3-6 cycloalkyl, —S(O) 2 —C 2-8 heterocyclyl, and —C(O)—C 1-6 alkyl.

3. The method according to claim 1 , wherein said compound is a compound of formula IIa, or a pharmaceutically acceptable salt thereof:

wherein:
R 1a is selected from hydrogen, methyl, and cyano;
R 2 is hydrogen or methyl;
R 1c is hydrogen or methoxy; and
R 1d is selected from hydrogen, C 1-4 alkyl, —C(O)—C 1-4 alkyl, —SO 2 H, —S(O) 2 —C 1-6 alkyl, —S(O) 2 —C 3-6 cycloalkyl, —S(O) 2 —C 2-8 heterocyclyl, C 3-6 cycloalkyl, and C 2-6 heterocyclyl.

4. A method for treating a disease or condition selected from lymphoma, multiple myeloma, or leukemia in a human patient in need thereof, comprising administering to the human patient a therapeutically effective amount of a compound selected from:
(R)-4-((R)-1-((6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one;
(R)-4-((R)-1-((6-(3,4-dimethoxyphenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one;
(R)-4-((R)-1-((3-methyl-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one;
(R)-4-((R)-1-((3-chloro-6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one;
(R)-4-((R)-1-((6-(3,4-dimethoxyphenyl)-2-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one;
(R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-3-methylpyrazo

Assignees

• Gilead Sciences Inc

Inventors

• Blomgren Peter A
• Chandrasekhar Jayaraman
• Currie Kevin S
• Du Zhimin
• Farand Julie
• Guerrero Juan A
• Katana Ashley A
• Kato Darryl
• Kropf Jeffrey E
• Lazerwith Scott E
• Lee Seung H
• Li Jiayao
• Link John O
• Lo Jennifer R
• Mai Nicholas
• Mitchell Scott A
• Notte Gregory
• Pyun Hyung-Jung
• Sangi Michael
• Schmitt Aaron C
• Schrier Adam J
• Stevens Kirk L
• Venkataramani Chandrasekar
• Watkins William J
• Xiong Jin-Ming
• Xu Jianjun
• Yang Zheng-Yu
• Zablocki Jeff
• Zhao Zhongdong
• Zipfel Sheila

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/06

  Antianaemics · CPC title