Tricyclic compounds and PBK inhibitors containing the same

Patent metadata

Field	Value
Publication number	US-9453025-B2
Application number	US-201414565047-A
Country	US
Kind code	B2
Filing date	Dec 9, 2014
Priority date	Mar 29, 2010
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

Tricyclic compounds are provided. These compounds are PBK inhibitors, and are useful for the treatment of PBK related diseases, including cancer.

First claim

The invention claimed is:

1. A method for treating a PBK dependent disease in a subject, comprising administering to said subject an effective amount of a compound or a pharmaceutically acceptable salt thereof wherein the compound is represented by general formula I:

or a pharmaceutically acceptable salt thereof,
wherein R 1 , R 2 , and R 3 are each independently a group selected from the group consisting of:
hydrogen,
hydroxyl,
halogen,
cyano,
nitro,
amino,
C 1 -C 6 alkyl,
C 2 -C 6 alkenyl,
C 2 -C 6 alkynyl,
C 3 -C 10 cycloalkyl,
C 3 -C 10 cycloalkenyl,
C 1 -C 6 alkoxy,
C 6 -C 10 aryl,
indanyl,
heteroaryl,
3- to 8-membered heterocycloalkyl,
—OSO 2 CH 3 ,
—OSO 2 CF 3 ,
—CONH 2 ,
—OCONR 101 R 102 , wherein R 101 and R 102 each independently is hydrogen, C 1 -C 6 alkyl, or R 101 and R 102 taken together form morpholinyl,
—OCOR 103 , wherein R 103 represents C 1 -C 6 alkyl, and
—OCOOR 104 , wherein R 104 represents C 1 -C 6 alkyl,
wherein R 1 , R 2 , and R 3 are optionally substituted with a substituent independently selected from the group consisting of substituent A;
R 4 is selected from the group consisting of hydroxyl, halogen, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, indanyl, heteroaryl, and 3- to 8-membered heterocycloalkyl, and R 4 is optionally substituted with substituent A;
wherein substituent A is independently selected from the group consisting of:
hydroxyl;
oxo (═O);
cyano;
halogen;
C 1 -C 6 alkyl optionally substituted with substituent B;
C 3 -C 10 cycloalkyl optionally substituted with cyano or C 1 -C 6 alkyl substituted with —NR 31 R 32 , wherein R 31 and R 32 each independently represent hydrogen or C 1 -C 6 alkyl;
—NR 21 R 22 , wherein R 21 and R 22 each independently represent hydrogen; C 1 -C 6 alkyl optionally substituted with hydroxyl, amino, di(C 1 -C 6 alkyl)amino, —SO 2 (C 1 -C 6 alkyl), 3- to 8-membered heterocycloalkyl, or cyano; or a 3- to 8-membered heterocycloalkyl optionally substituted with —COOR 105 wherein R 105 represents C 1 -C 6 alkyl;
C 1 -C 6 alkoxy optionally substituted with halogen, 3- to 8-membered heterocycloalkyl optionally substituted with C 1 -C 6 alkyl, or —NR 33 R 34 wherein R 33 and R 34 each independently represent hydrogen, C 1 -C 6 alkylsulfonyl, or C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkylsulfonyl or di(C 1 -C 6 alkyl)amino;
—SO 2 NR 23 R 24 , wherein R 23 and R 24 each independently represent hydrogen; C 1 -C 6 alkyl optionally substituted with hydroxyl, C 1 -C 6 alkoxy, halogen, C 3 -C 10 cycloalkyl, heteroaryl, or —NR 35 R 36 wherein R 35 and R 36 each independently represent hydrogen or C 1 -C 6 alkyl; C 3 -C 10 cycloalkyl optionally substituted with C 1 -C 6 hydroxyalkyl; 3- to 8-membered heterocycloalkyl; or R 23 and R 24 taken together form 3- to 8-membered heterocycloalkyl optionally substituted with amino or halogen;
C 1 -C 6 alkylsulfonyl optionally substituted with hydroxyl;
—NHSO 2 (C 1 -C 6 alkyl), wherein the carbon atoms are optionally substituted with —NR 37 R 38 wherein R 37 and R 38 each independently represent hydrogen or C 1 -C 6 alkyl;
3- to 8-membered heterocycloalkyl optionally substituted with —NR 39 R 40 , wherein R 39 and R 40 each independently represent hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkylsulfonyl; C 1 -C 6 alkyl optionally substituted with —NR 41 R 42 wherein R 41 and R 42 each independently represent hydrogen or C 1 -C 6 alkyl; hydroxyl; or C 1 -C 6 alkylsulfonyl;
aryl optionally substituted with C 1 -C 6 alkyl optionally substituted with cyano or amino;
heteroaryl;
—COOR 11 , wherein represents hydrogen or C 1 -C 6 alkyl; and
—COR 12 , wherein R 12 represents C 1 -C 6 alkyl; C 3 -C 10 cycloalkyl; cyanomethyl; aminomethyl; —NR 25 R 26 wherein R 25 and R 26 each independently represent hydrogen or C 1 -C 6 alkyl optionally substituted with hydroxyl or —NR 43 R 44 , wherein R 43 and R 44 each independently represent hydrogen or C 1 -C 6 alkyl; or 3- to 8-membered heterocycloalkyl optionally substituted with C 1 -C 6 alkyl;

wherein substituent B is independently selected from the group consisting of:
halogen;
hydroxyl;
C 1 -C 6 alkoxy;
cyano;
cycloalkyl;
C 6 -C 10 aryl optionally substituted with cyano;
heteroaryl;
3- to 8-membered heterocycloalkyl optionally substituted with C 1 -C 6 alkyl, hydroxyl, amino, C 1 -C 6 aminoalkyl, or C 1 -C 6 alkyl substituted with C 2 -C 7 alkyloxycarbonylamino;
—NR 51 R 52 , wherein R 51 and R 52 each independently represent hydrogen; C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkylsulfonyl or 3- to 8-membered heterocycloalkyl optionally substituted with —COOR 53 wherein R 53 represents hydrogen or C 1 -C 6 alkyl; 3- to 8-membered heterocycloalkyl; C 1 -C 6 alkylsulfonyl; C 3 -C 10 cycloalkyl; —COR 55 wherein R 55 represents C 1 -C 6 alkyl; —COOR 56 wherein R 56 represents C 1 -C 6 alkyl; or —CONR 57 R 58 wherein R 57 and R 58 each independently represent hydrogen or C 1 -C 6 alkyl;
—COOR 54 , wherein R 54 represents hydrogen or C 1 -C 6 alkyl;
—CONH 2 ;
—SO 2 NR 106 R 107 , wherein R 106 and R 107 each independently represent hydrogen, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl;
C 1 -C 6 alkylsulfinyl; and
C 1 -C 6 alkylsulfonyl;

wherein R 5 is hydrogen or C 1 -C 6 alkyl; and
wherein

is a structure: —S—CR 7 ═CR 6 —,
wherein R 6 is selected from the group consisting of:
hydrogen,
hydroxyl,
C 1 -C 6 alkyl,
C 6 -C 10 aryl optionally substituted with hydroxyl, and
3- to 8-membered heterocycloalkyl optionally substituted with —NR 61 R 62 , wherein R 61 and R 62 each independently represent hydrogen or C 1 -C 6 alkyl;

wherein R 7 is selected from the group consisting of:
hydrogen;
halogen;
C 1 -C 6 alkyl optionally substituted with hydroxyl, —NR 71 R 72 wherein R 71 and R 72 each independently represent hydrogen; C 1 -C 6 alkyl optionally substituted with dimethylamino; C 3 -C 10 cycloalkyl optionally substituted with amino or 3- to 8-membered heterocycloalkyl; or 3- to 8-membered heterocycloalkyl optionally substituted with C 1 -C 6 aminoalkyl;
C 6 -C 10 aryl optionally substituted with hydroxyl;

C 6 -C 10 arylsulfonyl; and
—COR 73 , wherein R 73 represents 3- to 8-membered heterocycloalkyl optionally substituted with amino; or —NR 74 R 75 wherein R 74 and R 75 each independently represent hydrogen, 3- to 8-membered heterocycloalkyl, or C 3 -C 10 cycloalkyl optionally substituted with amino.

2. The method of claim 1 , wherein R 1 is hydrogen, cyano, C 1 -C 6 alkyl optionally substituted with hydroxyl or halogen, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or halogen.

3. The method of claim 1 , wherein R 2 is hydrogen, hydroxyl, halogen, C 1 -C 6 alkoxy, or C 6 -C 10 aryl optionally substituted with hydroxyl.

4. The method of claim 1 , wherein R 2 is hydrogen, hydroxyl, halogen, C 1 -C 6 alkoxy, or dihydroxyphenyl.

5. The method of claim 1 , wherein R 3 is selected from the group consisting of: hydrogen; hydroxyl; C 1 -C 6 alkyl optionally substituted with hydroxyl, halogen, or hydroxyethylamino; halogen; C 1 -C 6 alkoxy optionally substituted with dimethylamino or morpholin

Assignees

• Oncotherapy Science Inc

Inventors

• Nakamura Yusuke
• Matsuo Yo
• Hisada Shoji
• Ahmed Feryan
• Huntley Raymond
• Sajjadi-Hashemi Zohreh
• Jenkins David M
• Kargbo Robert B
• Cui Wenge
• Gauuan Polivina Jolicia F
• Walker Joel R
• Decornez Helene
• Gurram Mahender

Classifications

• C07D221/06

  Ring systems of three rings · CPC title

• C07D221/16

  containing carbocyclic rings other than six-membered · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title