US2023338429A1PendingUtilityA1

Compounds and use thereof in the expansion of stem cells and/or progenitor cells

Assignee: UNIV MONTREALPriority: Nov 3, 2017Filed: May 19, 2023Published: Oct 26, 2023
Est. expiryNov 3, 2037(~11.3 yrs left)· nominal 20-yr term from priority
A61K 35/28C07D 333/66C07D 495/04C12N 5/0607C12N 2500/30A61K 31/343A61K 31/381A61K 31/4355A61K 31/4365A61K 31/444A61K 31/4709A61K 31/4725A61K 31/501A61K 31/506C07D 333/70C07D 491/048A61K 31/519C12N 5/0647C12N 2501/999A61K 2300/00A61P 35/00A61P 37/00C07D 491/04C07D 409/12
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Claims

Abstract

The invention relates to compounds as described herein and pharmaceutical compositions containing them. Also, the invention relates to methods for expanding stem cells and/or progenitor cells and methods for treating a hematopoietic disorder/malignancy, an autoimmune disease and/or an inherited immunodeficient disease.

Claims

exact text as granted — not AI-modified
1 . A compound of formula I
                       or a pharmaceutically acceptable salt thereof, wherein   X is O or S;   V1 is N or CH;   V2 is N or CH;   W is N or C;   wherein not more than one of said V1, V2 and W is N;   R 1  is halo, alkyl, fluoroalkyl, cycloalkyl, alkynyl, alkenyl, cyano, or COORa, wherein Ra is an alkyl;   R 2  is H, alkyl or R2 is absent when W is N;   or R 1  and R 2  are attached together with the aromatic ring atoms to form a carbocyclic ring;   R 3  is an optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted fused bicyclic heteroaryl;   provided that the compound is other than:
                                                                                                                                                                                                                                                                                                                                                                                                
 . 
   
     
     
         2 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is a compound of formula la, or a pharmaceutically acceptable salt thereof
                       
     
     
         3 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is a compound of formula lb, or a pharmaceutically acceptable salt thereof
                       
     
     
         4 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is a compound of formula Ic, or a pharmaceutically acceptable salt thereof
                       
     
     
         5 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is a compound of formula Id, or a pharmaceutically acceptable salt thereof
                       
     
     
         6 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is a compound of formula le, or a pharmaceutically acceptable salt thereof
                       
     
     
         7 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein R 1  is halo, C1-6alkyl, C1-6fluoroalkyl, C3-6cycloalkyl, C2-3alkynyl, C2-3alkenyl, cyano, or COORa wherein Ra is a C1-6alkyl. 
     
     
         8 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein R 2  is H. 
     
     
         9 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein R 3  is an optionally mono or disubstituted phenyl at any of positions 3, 4 and 5 of said phenyl. 
     
     
         10 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein R 3  is an optionally monosubstituted 5- or 6-membered heteroaryl. 
     
     
         11 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is selected from Tables 1 and 2:
                          TABLE 1                                     V 1 
   V 2 
   W   R 1 
   R 2 
   R 3 
         N   CH   C   (CH 2 ) 3 
   Ph         N   CH   C   (CH 2 ) 3 
   4-F-Ph         N   CH   C   Br   H   Ph         N   CH   C   CI   H   Ph         N   CH   C   CH 3 
   CH 3 
   Ph         N   CH   C   (CH 2 ) 3 
   3-pyridinyl         N   CH   C   (CH 2 ) 3 
   2-pyridinyl         N   CH   C   CF 3 
   H   Ph         N   CH   C   CH 3 
   H   Ph         N   CH   C   F   H   Ph         N   CH   C   CI   H   4-pyridinyl         N   CH   C   Br   H   4-pyridinyl         N   CH   C   CF 3 
   H   4-pyridinyl         N   CH   C   (CH 2 ) 3 
   4-pyridinyl         N   CH   C   CF 3 
   H   3-pyridinyl         N   CH   C   CN   H   Ph         N   CH   C   CF 3 
   H   4-(CH 2 CH 2 OH)-Ph         N   CH   C   CF 3 
   H   4-(CH 2 OCH 3 )-Ph         N   CH   C   CF 3 
   H   4-(CH 2 OH)-Ph         N   CH   C   CCH   H   4-pyridinyl         N   CH   C   Et   H   4-pyridinyl         N   CH   C   CF 3 
   H   2-pyridinyl         N   CH   C   CF 3 
   H   5-CH 3 -2-thiazolyl         N   CH   C   CF 3 
   H   4-Et-Ph         CH   CH   N   CF 3 
       Ph         CH   CH   N   CF 3 
       4-pyridinyl         CH   N   C   CF 3 
   H   Ph         CH   N   C   CF 3 
   H   4-pyridinyl         N   CH   C   CF 3 
   H   6-benzothiazolyl         N   CH   C   CF 3 
   H   4-Ph-Ph         N   CH   C   CF 3 
   H   4-BnO-Ph         N   CH   C   CF 3 
   H   4-(CH 2 CO 2 Et)-Ph         N   CH   C   CF 3 
   H   (4-OCH 3 -3-Ph)-Ph         CH   CH   C   CF 3 
   H   Ph         CH   CH   C   CF 3 
   H   4-pyridinyl         N   CH   C   CF 3 
   H   3-Br-Ph         N   CH   C   CF 3 
   H   4-Br-Ph         N   CH   C   CF 3 
   H   4-(CH 2 CN)-Ph         N   CH   C   CF 3 
   H   5-isoquinolinyl         N   CH   C   CF 3 
   H   5-quinolinyl         N   CH   C   CF 3 
   H   6-quinolinyl         N   CH   C   CF 3 
   H   3-quinolinyl         N   CH   C   CF 3 
   H   4-quinolinyl         N   CH   C   CO 2 Et   H   Ph         N   CH   C   CF 3 
   H   4-Cl-Ph         N   CH   C   CF 3 
   H   4-(CH 2 CH 2 OMe)-Ph         N   CH   C   CF 3 
   H   4-CH 3 -Ph         N   CH   C   CF 3 
   H   4-OCH 3 -Ph         CH   CH   N   CF 3 
       4-Br-Ph         CH   N   C   CF 3 
   H   4-Br-Ph         CH   CH   N   CF 3 
       4-Cl-Ph         CH   CH   N   CF 3 
       4-CH 3 -Ph         CH   N   C   CF 3 
   H   4-Cl-Ph         CH   N   C   CF 3 
   H   4-CH 3 -Ph         N   CH   C   CF 3 
   H   4-(3-pyridinyl)-Ph         N   CH   C   CF 3 
   H   4-(4-pyridinyl)-Ph         N   CH   C   CF 3 
   H   3-(3-pyridinyl)-Ph         N   CH   C   CF 3 
   H   3-(4-pyridinyl)-Ph         N   CH   C   CF 3 
   H   3-Ph-Ph         N   CH   C   CF 3 
   H   4-F-Ph         N   CH   C   CF 3 
   H   4-CF3-Ph         N   CH   C   CH 3 
   H   4-Br-Ph         N   CH   C   CH 3 
   H   4-pyridinyl         CH   CH   C   CF 3 
   H   4-Br-Ph         CH   CH   C   CF 3 
   H   4-CH 3 -Ph         CH   CH   C   CF 3 
   H   4-Cl-Ph         CH   CH   C   CF 3 
   H   3-pyridinyl         N   CH   C   CH 3 
   H   4-Cl-Ph         N   CH   C   CH 3 
   H   4-CH 3 -Ph         N   CH   C   CF 3 
   H   6-CH 3 -3-pyridinyl         N   CH   C   CF 3 
   H   6-OCH 3 -3-pyridinyl         CH   N   C   CH 3 
   H   Ph         CH   N   C   CH 3 
   H   4-Cl-Ph         N   CH   C   CF 3 
   H   3-Cl-4-F-Ph         N   CH   C   CF 3 
   H   3,4-diF-Ph         N   CH   C   CF 3 
   H   3-CH 3 -4-F-Ph         N   CH   C   CF 3 
   H   3-F-Ph         N   CH   C   CF 3 
   H   3-F-4-CH 3 -Ph         N   CH   C   CF 3 
   H   3,5-diF-Ph         CH   CH   N   CF 3 
       3-OCH 3 -Ph         N   CH   C   (CH 2 ) 3 
   3-OCH 3 -Ph         N   CH   C   (CH 2 ) 3 
   4-Cl-Ph         CH   CH   C   CF 3 
   H   4-OCH 3 -Ph         N   CH   C   CF 3 
   H   4-CF 3 O-Ph         N   CH   C   CF 3 
   H   3-OCH 3 -Ph         N   CH   C   CF 3 
   H   4-OCHF 2 -Ph         N   CH   C   CF 3 
   H   3-Cl-4-OCH 3 -Ph         CH   CH   N   CF 3 
       4-F-Ph         CH   CH   C   CF 3 
   H   4-F-Ph         N   CH   C   CH 2 =CMe   H   Ph         N   CH   C   c-Pr   H   Ph         N   CH   C   CF 3 
   H   4-OPh-Ph         N   CH   C   CF 3 
   H   3-Cl-Ph         N   CH   C   CF 3 
   H   3-CH 3 -Ph         N   CH   C   CF 3 
   H   3,4-diCl-Ph         N   CH   C   CF 3 
   H   3-CH 3 -4-Cl-Ph         N   CH   C   CF 3 
   H   3-OH-4-CI-Ph         N   CH   C   CF 3 
   H   3,4-(OCH 2 O)-Ph         N   CH   C   CF 3 
   H   3,4-(OCH 2 CH 2 O)-Ph         N   CH   C   CF 3 
   H   3-thienyl         N   CH   C   CF 3 
   H   2-CH 3 -5-benzothiazolyl         N   CH   C   CF 3 
   H   4-pyrimidinyl         N   CH   C   i-Pr   H   Ph         N   CH   C   (CH 2 ) 4 
   Ph         N   CH   C   (CH 2 ) 4 
   4-OCH 3 -Ph         N   CH   C   (CH 2 ) 4 
   4-F-Ph         N   CH   C   CF 3 
   H   2-pyrimidinyl         N   CH   C   CF 3 
   H   2-pyridazinyl         N   CH   C   CF 3 
   H   5-pyrimidinyl         N   CH   C   CF 3 
   H   5-indazolyl         N   CH   C   Allyl   H   Ph         N   CH   C   Et   H   Ph         N   CH   C   (CH 2 ) 5 
   Ph         N   CH   C   CH 3 
   H   4-OCH 3 -Ph         N   CH   C   CH 3 
   H   4-F-Ph         CH   N   C   CF 3 
   H   4-OCH 3 -Ph         CH   N   C   CF 3 
   H   4-F-Ph         CH   CH   C   CH 3 
   H   Ph         CH   CH   C   CH 3 
   H   4-OCH 3 -Ph         CH   CH   C   CH 3 
   H   4-F-Ph         N   CH   C   CF 3 
   H   3-OCH 3 -4-F-Ph         N   CH   C   CF 3 
   H   4-OEt-Ph         N   CH   C   CF 3 
   H   4-CONH 2 -Ph         N   CH   C   CF 3 
   H   4-(CONHCH 3 )-Ph         N   CH   C   CF 3 
   H   4-(CO 2 CH 3 )-Ph         N   CH   C   CF 3 
   H   4-(NMe 2 )-Ph         N   CH   C   CF 3 
   H   4-(SO 2 NH 2 )-Ph         N   CH   C   CF 3 
   H   5-F-2-pyridinyl         CH   N   C   CH 3 
   H   4-OCH 3 -Ph         CH   CH   C   CH 3 
   H   4-Cl-Ph         CH   CH   C   CH 3 
   H   4-CH 3 -Ph         CH   CH   C   CH 3 
   H   4-Br-Ph         N   CH   C   CF 3 
   H   4-SCH 3 -Ph         N   CH   C   n-Pr   H   Ph         N   CH   C   CH 3 
   H   3-Cl-4-OCH 3 -Ph         CH   CH   C   CF 3 
   H   3-Cl-4-OCH 3 -Ph         N   CH   C   CH 3 
   H   4-CF 3 -Ph         CH   CH   C   CF 3 
   H   4-CF 3 -Ph         N   CH   C   CH 3 
   H   3-Cl-Ph         N   CH   C   CH 3 
   H   3-CH 3 -Ph         N   CH   C   CH 3 
   H   3,4-(OCH 2 CH 2 O)-Ph         N   CH   C   CH 3 
   H   4-OEt-Ph         N   CH   C   CH 3 
   H   4-SCH 3 -Ph         CH   CH   C   CF 3 
   H   3-Cl-Ph         CH   CH   C   CF 3 
   H   3-CH 3 -Ph         CH   CH   C   CF 3 
   H   3,4-(OCH 2 CH 2 O)-Ph         CH   CH   C   CF 3 
   H   4-OEt-Ph         CH   CH   C   CF 3 
   H   4-SCH 3 -Ph         N   CH   C   CH 3 
   H   4-OCF 3 -Ph         N   CH   C   CH 3 
   H   3-thienyl         CH   CH   C   CH 3 
   H   4-OCF 3 -Ph         CH   CH   C   CF 3 
   H   3-thienyl                                                                                                                                                                                                    TABLE 2                                     V 1 
   V 2 
   W   R 1 
   R 2 
   R 3 
         N   CH   C   (CH 2 ) 3 
   Ph         N   CH   C   CF 3 
   H   4-F-Ph                     or a pharmaceutically acceptable salt thereof.   
     
     
         12 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is
                       .   
     
     
         13 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is
                       .   
     
     
         14 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is
                       .   
     
     
         15 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is
                       .   
     
     
         16 . The compound, or the pharmaceutically acceptable salt thereof of  claim 1 , wherein said compound is selected from:
                                                                                                                                                                                                                             .   
     
     
         17 . A pharmaceutical composition comprising the compound of  claim 1  or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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