Aryl- or heteroaryl-substituted benzene compounds

Patent metadata

Field	Value
Publication number	US-10155002-B2
Application number	US-201615346677-A
Country	US
Kind code	B2
Filing date	Nov 8, 2016
Priority date	Apr 13, 2011
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

The present invention relates to aryl- or heteroaryl-substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

First claim

What is claimed is:

1. A method of treating soft tissue sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein
X 1 is N or CR 11 ;
X 2 is N or CR 13 ;
Z is NR 7 R 8 , OR 7 , S(O) n R 7 , or CR 7 R 8 R 14 , in which n is 0, 1, or 2;
each of R 1 , R 5 , R 9 , and R 10 , independently, is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
each of R 2 , R 3 , and R 4 , independently, is -Q 1 -T 1 , in which Q 1 is a bond or C 1 -C 3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 1 is H, halo, hydroxyl, COOH, cyano, or R S1 , in which R S1 is C 1 -C 3 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C(O)O—C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R S1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
R 6 is C 6 -C 10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q 2 -T 2 , wherein Q 2 is a bond or C 1 -C 3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 2 is H, halo, cyano, —OR a , —NR a R b , —(NR a R b R c ) + A − , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR b C(O)R a , —NR b C(O)OR a , —S(O) 2 R a , —S(O) 2 NR a R b , or R S2 , in which each of R a , R b , and R c , independently is H or R S3 , A − is a pharmaceutically acceptable anion, each of R S2 and R S3 , independently, is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R a and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S2 , R S3 , and the 4 to 12-membered heterocycloalkyl ring formed by R a and R b , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 3 is selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR c , COOR d , —S(O) 2 R d , —NR d R e , and —C(O)NR d R e , each of R d and R e independently being H or C 1 -C 6 alkyl, or -Q 3 -T 3 is oxo; or any two neighboring -Q 2 -T 2 , together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
R 7 is -Q 4 -T 4 , in which Q 4 is a bond, C 1 -C 4 alkyl linker, or C 2 -C 4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 4 is H, halo, cyano, NR f R g , —OR f , —C(O)R f , —C(O)OR f , —C(O)NR f R g , —C(O)NR f OR g , —NR f C(O)R g , —S(O) 2 R f , or R S4 , in which each of R f and R g , independently is H or R S5 , each of R S4 and R S5 , independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R S4 and R S5 is optionally substituted with one or more -Q 5 -T 5 , wherein Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo;
each of R 8 , R 11 , R 12 , and R 13 , independently, is H, halo, hydroxyl, COOH, cyano, R S6 , OR S6 , or COOR S6 , in which R S6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C 1 -C 6 alkylamino, or di-C 1 -C 6 alkylamino, and R S6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, and di-C 1 -C 6 alkylamino; or R 7 and R 8 , together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, or R 7 and R 8 , together with the C atom to which they are attached, form C 3 -C 8 cycloalkyl or a 4 to 11-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 11-membered heterocycloalkyl rings or C 3 -C 8 cycloalkyl formed by R 7 and R 8 is optionally substituted with one or more -Q 6 -T 6 , wherein Q 6 is a bond, C(O), C(O)NR m , NR m C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R m being H or C 1 -C 6 alkyl, and T 6 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) p R p in which p is 0, 1, or 2 and R p is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 6 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 6 is H, halo, hydroxyl, or cyano; or -Q 6 -T 6 is oxo; and
R 14 is absent, H, or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.

2. The method of claim 1 , wherein:
X 1 is N or CR 11 ;
X 2 is N or CR 13 ;
Z is NR 7 R 8 , OR 7 , SR 7 , or CR 7 R 8 R 14 ;
each of R 1 , R 5 , R 9 , and R 10 , independently, is H or C 1 -C 6 alkyl opti

Assignees

• Epizyme Inc

Inventors

• Kuntz Kevin Wayne
• Chesworth Richard
• Duncan Kenneth William
• Keilhack Heike
• Warholic Natalie
• Klaus Christine
• Knutson Sarah Kathleen
• Wigle Timothy James Nelson
• Seki Masashi
• Shirotori Syuji
• Kawano Satoshi

Classifications

• A61P35/02

  specific for leukemia · 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

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title