|HAI LALA AT MATARUNUS009815847B2 AMOR A HALAMAN NATI (12 ) United States Patent ( 10 ) Patent No. : US 9 , 815 ,847 B2 Reddy et al. ( 45 ) Date of Patent : Nov . 14 , 2017 ( 54 ) PYRIMIDINE COMPOUNDS AS KINASE ( 56 ) References Cited INHIBITORS U . S . PATENT DOCUMENTS @(71 ) Applicant : Icahn School of Medicine at Mount 2004 / 0180914 AL 9 / 2004 Batchelor Sinai, New York , NY (US ) 2010 /0099691 AL 4 /2010 Boice 2013 / 0158057 A1 6 / 2013 Baker -Glenn @( 72 ) Inventors: M . V . Ramana Reddy , Blue Bell , PA 2014 /0045840 A1 2 /2014 Zhang (US ) ; E . Premkumar Reddy, Villanova , PA (US ) FOREIGN PATENT DOCUMENTS @(73 ) Assignee : Icahn School of Medicine at Mount EP 1364950 AL 11 /2003 JP 2009149618 A 7 / 2009 Sinai, New York , NY (US ) WO 98 / 33798 AL 8 / 1998 WO 01/ 55148 AL 8 / 2001 @( * ) Notice : Subject to any disclaimer , the term of this WO 0155147 A1 8 /2001 patent is extended or adjusted under 35 WO WO 2007 / 138974 * 12 / 2007 U . S . C . 154 ( b ) by 21 days . WO 2011/ 075616 AL 6 / 2011 WO 2011090666 A2 7 / 2011 WO 2012 /018540 A1 2 /2012 (21 ) Appl. No. : 14 /775 , 917 WO 2012 / 149567 AL 11 / 2012 ( 22 ) PCT Filed : Mar . 13 , 2014 OTHER PUBLICATIONS ( 86 ) PCT No .: PCT/ US2014 /026236 International Search Report for PCT/ US14 / 26236 dated Jun . 20 , $ 371 ( c ) ( 1 ) , 2014 . 3 pages . Pubchem SureCN4933440 , CID 10080432 , pp . 1 - 5 , Create Date : ( 2 ) Date : Sep . 14 , 2015 Oct. 25 , 2006 ; p . 1 ; [ retrieved on May 27 , 2014 ) . Retrieved from the Internet : , 25 /22 - 24 , 27 -29 , 90 -92 < URL : http : // pubchem .ncbi . nlm . ( 87) PCT Pub . No. : WO2014 /151682 nih .gov / summary / summary .cgi ? cid = 10080432 & loc = ec _ rcs > . Pubchem SureCN7898116 , CID 70223084 , pp . 1 - 3 , Create Date : PCT Pub . Date : Sep . 25 , 2014 Dec . 1 , 2012 ; p . 1 ; [ retrieved on May 27 , 2014 ] . Retrieved from the Internet : 25 /22 - 24 , 27 - 29 , 90 - 92 < URL : http : / /pubchem .ncbi . nlm . (65 ) Prior Publication Data nih . gov / summary / summary .cgi ? cid = 70223084 & loc = ec _ res > . Pubchem SureCN1093071, CID 53395796 , pp . 1 - 3 , Create Date : US 2016 /0122361 A1 May 5 , 2016 Oct . 30 , 2011 ; p . 1 ; [ retrieved on May 27 , 2014 ] . Retrieved from the Internet : 25 /22 - 24 , 27 - 29 , 90 - 92 < URL : http : // pubchem .ncbi .nlm . nih .gov / summary / summary .cgi ? cid = 53395796 & loc = ec _ rcs > . Related U . S . Application Data Pubchem SureCN3629522 , CID 59434107 , pp . 1 - 6 , Create Date : Aug . 20 , 2012 ; p . 1 ; [ retrieved on May 27 , 2014 ] . Retrieved from (60 ) Provisional application No .61 /785 , 754 , filed on Mar . the Internet : 25 / 22 - 24 , 27 - 29 , 90 - 92 < URL : http : // pubchem .ncbi . 14 , 2013 . nlm .nih . gov / summary / summary . cgi ? cid = 59434107 & loc = ec _ rcs > . SCIFINDER® Database Search Results Dated Dec . 19 , 2012 ; 883 (51 ) Int. Ci. pages . C07D 495 /04 ( 2006 . 01 ) SCIFINDER® Database Search Results (Structures ) Dated 2012 ; C07D 403 / 12 ( 2006 . 01 ) 27 pages. SCIFINDER® Database Search Results (References ) Dated 2012 ; CO7D 401/ 12 ( 2006 .01 ) 89 pages. C07D 239 /38 ( 2006 .01 ) Extended European Search Report dated Jul . 22 , 2016 for CO7D 239 /47 ( 2006 . 01 ) EP14770699 . 8 , 8 pages . CO7D 239/ 48 ( 2006 .01 ) COZD 401/ 14 ( 2006 . 01 ) * cited by examiner C07D 403 / 14 ( 2006 .01 ) ( 52 ) U . S . CI. Primary Examiner — Barbara P Badio CPC .. C07D 495 /04 ( 2013 . 01 ) ; C07D 239 / 38 Assistant Examiner — Sara E Townsley ( 2013 .01 ) ; C07D 239 /47 (2013 .01 ) ; C07D ( 74 ) Attorney , Agent, or Firm — Fish & Richardson P . C . 239/ 48 ( 2013 .01 ) ; C07D 401 /12 ( 2013 .01 ) ; C07D 401/ 14 ( 2013 .01 ) ; C07D 403 / 12 (57 ) ABSTRACT ( 2013. 01 ) ; CO7D 403 / 14 (2013 .01 ) This disclosure relates to compounds , methods for their (58 ) Field of Classification Search preparation , pharmaceutical compositions including these CPC .. CO7D 239 / 38 ; CO7D 239/ 47 ; CO7D 495 /04 ; compounds and methods for the treatment of cellular pro CO7D 401/ 12 ; COZD 401 / 14 ; C07D liferative disorders , including , but not limited to , cancer. 403 /12 ; C07D 403 / 14 ; CO7D 239 /48 See application file for complete search history . 23 Claims, No Drawings US 9 ,815 , 847 B2 PYRIMIDINE COMPOUNDS AS KINASE istering to the patient a therapeutically effective amount of INHIBITORS a compound of formula ( I ) or a pharmaceutically acceptable salt thereof. CROSS - REFERENCE TO RELATED A method of inducing cell death of cancer cells in a APPLICATIONS 5 patient is provided . The method includes administering to the patient a therapeutically effective amount of a compound This application is the national phase under 35 U . S . C . of formula ( I ) or a pharmaceutically acceptable salt thereof. $ 371 of PCT Application No . PCT/ US2014 /026236 , filed Amethod of inducing apoptosis of cancer cells in a patient Mar. 13 , 2014 , which claims the benefit of U . S . Provisional is provided . The method includes administering to the Application No. 61 / 785 ,754 . filed on Mar. 14 . 2013 , which 10 patient a therapeutically effective amount of a compound of formula ( I) or a pharmaceutically acceptable salt thereof. is incorporated herein by reference in its entirety . A method of inducing apoptosis in a cell is provided . The method includes contacting the cell with an effective amount TECHNICAL FIELD of a compound of formula ( I ) or a pharmaceutically accept This disclosure relates to compoundsmpounds , methods for their 15 ableable salt thereof. preparation , pharmaceutical compositions including these compounds and methods for the treatment of cellular pro DETAILED DESCRIPTION liferative disorders , including , but not limited to , cancer. It is appreciated that certain features described herein , 20 which are , for clarity , described in the context of separate BACKGROUND embodiments , can also be provided in combination in a single embodiment. Conversely , various features described Cellular proliferative disorders are among the most com herein which are , for brevity , described in the context of a mon causes of death in developed countries . For diseases for single embodiment, can also be provided separately or in which treatments exist , such as cancer , the existing treat- 25 any suitable subcombination . ments have undesirable side effects and limited efficacy . Identifying new effective drugs for cellular proliferative I . Definitions disorders , including cancer, is a continuing focus of medical research . Unless defined otherwise , all technical and scientific 30 terms used herein have the same meaning as is commonly SUMMARY understood by one of ordinary skill in the art to which this disclosure belongs . In the event that there is a plurality of It has been found that certain compounds and composi- definitions for terms cited herein , those in this section tions are kinase inhibitors and are useful for the treatment of prevail unless otherwise stated . cellular proliferative disorders including , but not limited to 35 The terms “ e . g . ,” and “ such as, ” and grammatical equiva cancer. The compounds are useful, e . g . , as pharmaceuticals. lents thereof, the phrase " and without limitation ” is under The disclosure describes compounds of formula ( I ) : stood to follow unless explicitly stated otherwise . The singular forms “ a ," " an ,” and “ the” include plural referents unless the context clearly dictates otherwise . ( I ) 40 The term “ about" means “ approximately ” ( e . g . , plus or minus approximately 10 % of the indicated value ). WR The term " salt ” includes any ionic form of a compound R2A and one or more counter - ionic species ( cations and / or A NNVR3 , anions ). The term includes derivatives of the disclosed 45 compounds wherein the parent compound is modified by R3B converting an existing acid or base moiety to its salt form . Salts also include zwitterionic compounds ( i. e ., a molecule or a pharmaceutically acceptable salt thereof; wherein the containing one more cationic and anionic species, e . g . , variables are as defined below . zwitterionic amino acids ). Examples of salts include , but are A method for treating a cellular proliferative disorder in a 50 not limited to , mineral or organic acid salts of basic residues patient is provided . The method includes administering to such as amines ; alkali or organic salts of acidic residues such the patient a therapeutically effective amount of a compound as carboxylic acids ; and the like . Counter ions present in a of formula ( 1 ) , or a pharmaceutically acceptable salt thereof. salt can include any cationic , anionic , or zwitterionic spe A method of treating a neurological disorder in a patient cies . Exemplary anions include , but are not limited to , is provided . The method includes administering to the 55 chloride , bromide , iodide , nitrate , sulfate, bisulfate , sulfite , patient a therapeutically effective amount of a compound of bisulfite , phosphate , acid phosphate , perchlorate , chlorate , formula ( I ) , or a pharmaceutically acceptable salt thereof. chlorite , hypochlorite , periodate , iodate , iodite , hypoiodite , A method of inhibiting one or more kinases in a patient is carbonate , bicarbonate , isonicotinate , acetate , trichloroac provided . The method includes administering to the patient etate , trifluoroacetate , lactate , salicylate , citrate , tartrate , a therapeutically effective amount of a compound of formula 60 pantothenate , bitartrate , ascorbate , succinate , maleate , gen ( I) or a pharmaceutically acceptable salt thereof.