US010398693B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,398 ,693 B2 Codallos, Jr. et al. ( 45) Date of Patent : Sep . 3, 2019
(54 ) PHARMACEUTICAL COMPOSITIONS AND 8 , 114 , 865 B2 2 / 2012 Bandiera et al . DOSAGE FORMS 8 , 114 , 989 B2 2 / 2012 Wang et al. 8 , 299 ,057 B2 * 10 /2012 Lombardi Borgia ...... (71 ) Applicant: Ignyta , Inc ., San Diego , CA (US ) CO7D 231 / 56 514 /210 .21 ( 72 ) Inventors : Daniel Codallos, Jr. , San Diego , CA 8 ,372 , 858 B2 2 / 2013 Michellys et al . (US ) ; Robert Orr , San Clemente , CA 8 ,404 , 846 B2 3 / 2013 Claridge et al. (US ) ; Ching - Yuan Li, San Diego , CA 8 ,497 , 284 B2 7 / 2013 Bannen et al. 8 ,513 , 263 B2 8 / 2013 Haas et al . (US ) ; Valerie Denise Start , San Diego , 8 ,673 , 893 B2 3 /2014 Lombardi Borgia et al . CA (US ) 8 ,680 , 111 B2 3 / 2014 Bailey et al. ( 73 ) Assignee: IGNYTA , INC ., San Diego , CA (US ) 9 , 102, 662 B2 8/ 2015 Lombardi Borgia et al. 10 ,085 , 979 B2 10 / 2018 Hornby et al . ( * ) Notice : Subject to any disclaimer , the term of this 10 , 231 , 965 B23 / 2019 Lim et al . patent is extended or adjusted under 35 2004/ 0014802 A11 / 2004 Dutruc -Rosset et al. U . S . C . 154 (b ) by 0 days. 2005/ 0014829 A1 * 1/ 2005 Remenar ...... C07C 211/ 42 514 / 554 (21 ) Appl. No. : 16 /039 , 196 2009 / 0263397 A1 10 / 2009 Buck et al. 2010 /0197665 Al 8 / 2010 Bandiera et al . ( 22 ) Filed : Jul. 18 , 2018 2013 /0018036 AL 1 /2013 Lombardi Borgia et al . 2014 / 0107107 A1 4 / 2014 Gautschi et al. (65 ) Prior Publication Data 2015 / 0051222 Al 2 /2015 Barbugian et al. US 2019/ 0022089 A1 Jan . 24 , 2019 2015 /0283132 Al 10 /2015 Lim et al . 2017 / 0007599 Al 1 / 2017 Lim et al . Related U . S . Application Data 2017 /0065582 A1 3/ 2017 Hornby et al. 2018 /0177792 A1 6 / 2018 Wei ( 60 ) Provisional application No . 62 /534 ,585 , filed on Jul. 2018 /0333412 AL 11 /2018 Lim et al. 19 , 2017 . 2019 /0000840 A11 /2019 Li et al . 2019 /0022089 Al 1 / 2019 Codallos et al. (51 ) Int. CI. 2019 / 0070173 Al 3 / 2019 Hornby et al. A61K 31/ 496 ( 2006 .01 ) A61P 35 /00 ( 2006 .01 ) FOREIGN PATENT DOCUMENTS A61K 9 /20 ( 2006 . 01 ) A61K 9 / 50 ( 2006 .01 ) CN 101594862 12 / 2009 CN 101754956 6 / 2010 A6IK 31/ 194 ( 2006 .01 ) CN 102924479 A 2 / 2013 A61K 31/ 197 ( 2006 .01 ) 2002 - 275068 A 9 / 2002 A61K 47/ 02 ( 2006 .01 ) UP 2010 - 530840 A 9 / 2010 A61K 47 / 12 ( 2006 .01 ) JP 2011 - 502959 A 1 /2011 WO W09943302 * 9 / 1999 A61K 47 /26 ( 2006 .01 ) WO WO -03 /051847 A 6 / 2003 A61K 47 /38 ( 2006 . 01 ) WO WO -03 / 078403 A2 9 / 2003 A61K 9 / 16 ( 2006 .01 ) WO WO - 2004 / 007676 A1 1 / 2004 A61K 9 / 48 ( 2006 .01 ) wo WO - 2004 /022544 AL 3 / 2004 ( 52 ) U . S . CI. WO WO - 2004 /062662 A17 / 2004 CPC ...... A61K 31/ 496 ( 2013 .01 ) ; A61K 9 / 1617 WOWO - 2004 /075898 A19 / 2004 ( 2013 .01 ) ; A61K 9 / 1623 (2013 . 01) ; A61K (Continued ) 9 /2013 (2013 .01 ) ; A61K 9 /2018 (2013 .01 ); A61K 9 / 2059 ( 2013 .01 ); A61K 9 / 2086 OTHER PUBLICATIONS ( 2013 .01 ); A61K 9 /2095 ( 2013 .01 ) ; A61K 9 /485 ( 2013 .01 ) ; A6IK 9 /4858 ( 2013 . 01 ) ; U . S . Appl. No . 16 /249 ,703 , filed Jan . 16 , 2019 , Ignyta , Inc . A61K 9 /4866 ( 2013 . 01 ) ; A61K 9 /5089 ( Continued ) ( 2013 . 01 ) ; A61K 31 / 194 ( 2013 .01 ) ; A61K 31/ 197 ( 2013 .01 ) ; A61K 47 /02 ( 2013 .01 ) ; Primary Examiner — Rei Tsang Shiao A61K 47 / 12 ( 2013 . 01 ) ; A61K 47 /26 ( 2013 . 01 ) ; A61K 47/ 38 ( 2013 . 01 ) ; A61P 35 / 00 (2018 .01 ) ( 74 ) Attorney, Agent, or Firm — Foley & Lardner, LLP ( 58 ) Field of Classification Search CPC ...... A61K 31/ 035 ; A61P 35 /00 (57 ) ABSTRACT See application file for complete search history. Disclosed herein are pharmaceutical compositions and dos age forms including N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol ( 56 ) References Cited 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran U . S . PATENT DOCUMENTS 4 - ylamino ) benzamide that are useful in the treatment of subjects having cancer. The present disclosure also provides 4 , 555 , 402 A 11/ 1985 Matsuda et al. methods for preparing these pharmaceutical compositions 7 ,015 ,231 B2 3 / 2006 Lackey et al. 7 , 230 , 098 B2 6 / 2007 Cui et al. and dosage forms, and methods of treating subjects having 7 , 534 , 792 B25 / 2009 Wittman et al. cancer utilizing the pharmaceutical compositions and dos 7 ,790 , 756 B2 9 / 2010 Flynn et al. age forms provided herein . 7 , 799 , 782 B2 * 9 / 2010 Munson ...... C07D 231/ 56 514 / 234 . 5 7, 964 ,592 B2 6 / 2011 Garcia - Echeverria et al. 25 Claims, 4 Drawing Sheets US 10 ,398 ,693 B2 Page 2
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" NTRK1_ human ” , ( Jun . 24 , 2015 ) , patients using a pharmacodynamics assay for TrkA activation ” , available on the internet : http : / /www .uniprot .org /uniprot / P04629 . European Journal of Cancer , Poster Session - Molecular Targeted txt ? version = 204 ( 12 pages ) . Agents II , 2014 , 50 (6 ): 143 - 144 . Vaishnavi, A . et al ., Oncogenic and drug sensitive NTRK1 rear Nakagawara et al. ; “ Association between high levels of expression rangements in lung cancer, Nat Med . , Nov. 2013, 19 (11 ) :1469 of the Trk gene and favorable outcome in human neuroblastoma” ; 1472. N Engl J Med ; 1993 ; 328 :847 -54 . Valent, A . et al. Mapping of the tyrosine kinase receptors trkA Nakagawara , A ., Trk receptor tyrosine kinases : a bride between (NTRK1 ) , trkB (NTRK2 ) and trkC (NTRK3 ) to human chromo cancer and neural development, Cancer Letters , 2001, 169 : 107 - 114 . somes 1222 , 9q22 and 15425 by fluorescence in situ hybridization . National Comprehensive Cancer Network , NCCN Clinical Practice Eur. J . Hum . Genet ( 1997 ) , vol. 5 ( 2 ) , pp . 102 - 104 . Guidelines in Oncology : Non - small cell lung cancer, Apr. 2016 , Valentinis , B . et al. , IGF -I receptor signaling in transformation and Version 4. 2016 . 169 pp . differentiation , 2001 , Mol Pathol, 54 : 133 - 137 . US 10 ,398 ,693 B2 Page 5
( 56 ) References Cited Wolff , M . E ., Burger ' s Medicinal Chemistry and Drug Discovery , 5th Ed . vol. 1 , 1995 , pp . 975 -977 , John Wiley & Sons, Inc ., New OTHER PUBLICATIONS York , NY . Wood et al. , “ Somatic Mutations ofGUCY2F , EPHA3 , and NTRK3 Vasconcelos et al ., " Solid dispersions a strategy to improve oral in Human Cancers ” , Human Mutation in Brief # 923 , 2006 . ( 9 bioavailability of poor water soluble drug, ” Drug Discovery Today , pages ) . vol. 12 , Jan . 2012 , pp . 1068 - 1075 . Woolf , C . J . et al. , Letter to Neuroscience : Nerve growth factor Voskoglou - Nomikos, T. et al ., Clinical predictive value of the in contributes to the generation of inflammatory sensory hypersensi vitro cell line , human xenograft , and mouse allograft preclinical tivity , Neuroscience , 1994 , vol. 62 , No. 2 , pp . 327 - 331. cancer models , Clinical Cancer Research , Sep . 15 , 2003 , 9 :4227 Xalkori® (crizotinib ) capsules , for oral use , Prescribing Informa 4239 . tion , Mar. 2016 , 27 pp . Wang , Y . et al ., Insulin - like growth factor receptor - 1 as an anti Zahn , P . et al. , Effect of blockade of nerve growth factor and tumor cancer target : blocking transformation and inducing apoptosis , Curr necrosis factor on pain behaviors after plantar incision , J . Pain , vol. Cancer Drug Targets , 2002 , 2: 191 -207 . 5 No . 3 , Apr. 2004 , pp . 157 - 163 . Warner , S . et al ., Targeting aurora - 2 kinase in cancer , Molecular Zhu et al. , “ Nerve Growth Factor expression Correlates With Cancer Therapeutics, Jun . 3 , 2003 , 2 :589 -595 . Perineural Invasion and Pain in Human Pancreatic Cancer” , Journal Wei et al. , " Abstract 2136 : Entrectinib is effective against the of Clinical Oncology , 1999 ;17 : 2419 -2428 . gatekeeper and other emerging resistance mutations in NTRK - , Zhu , L ., et al. Implications of tropomyosin -related kinase B ( TrkB ) ROS1 - and ALK -rearranged cancers ” , [ abstract] , Proceedings: AACR in head and neck cancer . Anticancer Res. Sep . -Oct . 2007 ;27 (5A ) :3121 107th Annual Meeting 2016 ; Apr. 16 - 20 , 2016 : New Orleans , LA ; 6 . 2016 ; 76 ( 14 Suppl ) :Abstract nr 2136 . ZykadiaTM ( ceritinib ) capsules , for oral use , Prescribing Informa Weroha , S . J. et al . , IFG - 1 receptor inhibitors in clinical trials - early tion , Apr. 2014 , 16 pp . lessons, J . Mammary Gland Biol. Neoplasia , 2008 , vol. 13 , pp . 471- 483 . * cited by examiner U . S . Patent Sep . 3 , 2019 Sheet 11 ofof 4 4 Us 10, 398, 693 B2
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*vom*ANON Mean(nM) ROL ADORONTO ONUN SONRA STRONanterwowowowowowoOORVOOvowwww NOWOROU 500 moonwww 0 4 8 12 16 20 24 Time FIG . 4 US 10 , 398 ,693 B2 PHARMACEUTICAL COMPOSITIONS AND amide AUC values were approximately 200 % and 50 % DOSAGE FORMS higher using N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H - pyran - 4 CROSS REFERENCE TO RELATED ylamino ) -benzamide doses of 200 mg/ mº / day and 400 APPLICATIONS 5 mg/ m² / day , respectively when taken with food . Cmax values were approximately 150 % higher with food for both doses. This application claims the benefit of and priority to U . S . In addition , some patients in these studies received N - [ 5 Provisional Patent Application No. 62 /534 ,585 , filed Jul . 19 , ( 3 ,5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl -piper 2017 , the contents of which are hereby incorporated by azin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide reference herein in their entirety . and concomitant proton pump inhibitor drugs (PPIs ) , such as lansoprazole , and demonstrated variable N - [ 5 - ( 3 , 5 -difluo FIELD robenzyl) - 1H - indazol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 The present disclosure relates to pharmaceutical compo (tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide exposures . sitions and dosage forms that are useful in the treatment of 15 Moreover , dose proportionality was lost at doses higher than subjects having cancer . The present disclosure also provides 800 mg/m² / day . As such , it is an object of the present methods for preparing these pharmaceutical compositions disclosure to provide pharmaceutical compositions and dos and dosage forms, and methods of treating subjects having age forms comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - inda cancer utilizing the pharmaceutical compositions and dos zol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro - 2H age forms provided herein . 20 pyran - 4 - ylamino ) -benzamide that do not suffer from the variability in absorption in subjects , such as humans , when BACKGROUND dosed with or without food and in the presence or absence of PPIs . The compound N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - indazol- 3 yl] - 4 - (4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro - 2H -pyran - 4 - 25 SUMMARY ylamino ) - benzamide and its preparation have been disclosed in U . S . Pat. No. 8 , 299, 057, the contents of which are hereby In some embodiments are provided pharmaceutical com incorporated by reference in their entirety . N -[ 5 -( 3 , 5 -difluo - positions, comprising a weakly basic organic compound and robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - at least one acidulant. In some embodiments , the at least one ( tetrahydro - 2H - pyran - 4 - ylamino ) -benzamide is a potent 30 acidulant is an organic acidulant. In some embodiments , the inhibitor of tyrosine kinases , NTRK1/ 2 / 3 - transforming tyro - at least one acidulant is selected from tartaric acid , maleic sine kinase proteins ( TrkA , TrkB , TrkC ) , proto -oncogene acid , fumaric acid , citric acid , and betaine hydrochloride. In tyrosine -protein kinase 1 (ROS1 ) , and anaplastic lymphoma some embodiments , the at least one acidulant is fumaric kinase ( ALK ) . In various in vitro studies, N - [ 5 - ( 3 , 5 - difluo acid . In some embodiments , the at least one acidulant is robenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - 35 tartaric acid . In some embodiments, the said at least one (tetrahydro - 2H - pyran - 4 - ylamino ) -benzamide inhibited pro - acidulant is maleic acid . In some embodiments , the said at liferation of the CRC cell line KM12 , which depends upon least one acidulant is citric acid . In some embodiments , the TrkA kinase activity for proliferation and survival. It was said at least one acidulant is betaine hydrochloride . also potent in inhibiting cell proliferation of ALK -dependent In any of the embodiments described herein , the at least Anaplastic Large Cell Lymphoma cell lines . 40 one acidulant is an organic acidulant. In some embodiments , In a single - dose food effect study in dogs of N -15 -( 3 , 5 - the at least one acidulant is selected from tartaric acid , difluorobenzyl) - 1H -indazol - 3 - yl ] - 4 - (4 -methyl - piperazin - 1 - maleic acid , fumaric acid , citric acid , and betaine hydro yl) - 2 - ( tetrahydro -2H -pyran - 4 -ylamino ) -benzamide , in a for chloride. In some embodiments , the least one acidulant is mulation that did not comprise at least one acidulant, fumaric acid . In some embodiments , the at least one acidu exposure levels of N - 15 -( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - 45 lant is tartaric acid . In some embodiments , the said at least yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 - one acidulant is maleic acid . In some embodiments, the said ylamino ) -benzamide in the dogs were approximately 2 - fold at least one acidulant is citric acid . In some embodiments , higher under fed conditions compared to those observed the said at least one acidulant is betaine hydrochloride . under fasting conditions . Such food effects can cause diffi - In some embodiments are provided pharmaceutical com culty during human testing of drugs as the fed or fasted 50 positions, comprising N - [5 -( 3 ,5 - difluorobenzyl) - 1H -inda condition of the patient can cause exposure or bioavailability zol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -pyran of drugs to vary widely . 4 - ylamino ) -benzamide and at least one acidulant. In some In early clinical studies in humans, N - [ 5 - ( 3 , 5 - difluo - embodiments , the at least one acidulant is an organic acidu robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - lant. In some embodiments , the at least one acidulant is ( tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide has been 55 selected from tartaric acid , maleic acid , fumaric acid , citric shown to have antitumor effects in patients having various acid , and betaine hydrochloride . In some embodiments , the forms of cancer having at least one molecular alteration in least one acidulant is fumaric acid . In some embodiments , one or more of ALK , ROS1 , TrkA , TrkB and TrkC . In the the at least one acidulant is tartaric acid . In some embodi studies using a formulation of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - ments , the said at least one acidulant is maleic acid . In some 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra - 60 embodiments , the said at least one acidulant is citric acid . In hydro - 2H - pyran - 4 - ylamino ) -benzamide that did not com - some embodiments , the said at least one acidulant is betaine prise at least one acidulant , systemic exposure of N - [ 5 - ( 3 , hydrochloride . 5 -difluorobenzyl ) -1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - In some embodiments are provided pharmaceutical com 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda increased when co -administered with food . In particular, 65 zol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - (4 -methyl 4 - ylamino ) -benzamide and at least one acidulant, wherein piperazin - 1 -yl ) - 2 - ( tetrahydro -2H -pyran - 4 -ylamino ) - benz the molar ratio between said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H US 10 , 398 ,693 B2 indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro benzamide has been released from said tablet or capsule at pyran - 4 - ylamino ) -benzamide and said at least one acidulant about 60 minutes when tested in USP Apparatus Type I is from about 0 .5 to about 2. Basket Method at 50 rpm in 500 mL of sodium acetate buffer In some embodiments are provided pharmaceutical com at a pH of 4 .5 and at about 37° C . positions in the form of a tablet or capsule . In some 5 In some embodiments are provided pharmaceutical com embodiments are provided pharmaceutical compositions in positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda the form of a tablet . In some embodiments are provided pharmaceutical compositions in the form of a capsule . zol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran In some embodiments are provided pharmaceutical com 4 - ylamino ) -benzamide , wherein said wherein said tablet or positions, wherein said pharmaceutical composition com - 10 capsule has a dissolution profile wherein at least about 20 % prises from about 10 mg to about 1000 mg of said N -15 - ( 3 , of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - yl) - 4 - ( 4 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin methyl- piperazin - 1 -yl ) -2 - ( tetrahydro -pyran - 4 - ylamino ) 1 - yl) - 2 - tetrahydro -pyran - 4 - ylamino ) -benzamide and at benzamide has been released from said tablet or capsule at least one acidulant. about 45 minutes when tested in USP Apparatus Type I In some embodiments are provided pharmaceutical com - 15 BasBasket Method at 50 rpm in 500 mL of sodium acetate buffer positions comprising N - 15 -( 3 , 5 -difluorobenzyl ) - 1H - inda - at a pH of 4 . 5 and at about 37° C . zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - In some embodiments are provided pharmaceutical com 4 - ylamino )- benzamide and at least one acidulant, wherein positions comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H -inda less than about 2 % of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H zol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin -1 - yl) -2 - ( tetrahydro - 20 4 -ylamino )- benzamide , wherein said wherein said tablet or pyran - 4 -ylamino )- benzamide degrades in said pharmaceuti- capsule has a dissolution profile wherein at least about 15 % cal composition after said pharmaceutical composition is of said N - 15 - ( 3 ,5 - difluorobenzyl ) - 1H - indazol- 3 - y1 ] -4 - ( 4 stored for 3 months in an open container at 40° C . and 75 % methyl- piperazin - 1 -yl ) -2 - ( tetrahydro -pyran -4 - ylamino ) relative humidity . benzamide has been released from said tablet or capsule at In some embodiments are provided pharmaceutical com - 25 about 30 minutes when tested in USP Apparatus Type I positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - Basket Method at 50 rpm in 500 mL of sodium acetate buffer zol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - pyran - at a pH of 4 .5 and at about 37° C . 4 -ylamino ) -benzamide and at least acidulant, wherein more In some embodiments are provided pharmaceutical com than about 98 % of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda zol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran - 30 zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran 4 - ylamino ) - benzamide is present in said pharmaceutical 4 - ylamino ) -benzamide and at least one acidulant, wherein composition after said pharmaceutical composition is stored said pharmaceutical composition when administered to a for 3 months in an open container at 40° C . and 75 % relative subject in a fasted state provides a pharmacokinetic profile humidity . in said subject wherein the Tmax of said N - [ 5 - ( 3 , 5 - difluo In some embodiments are provided pharmaceutical com - 35 robenzyl) - 1H - indazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 positions comprising N -[ 5 - ( 3 ,5 -difluorobenzyl ) - 1H -inda - ( tetrahydro -pyran -4 -ylamino )- benzamide in the plasma of zol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - said subject is between about 2 hours and 6 hours following 4 - ylamino ) -benzamide and at least one acidulant , wherein said administration of said pharmaceutical composition to less than about 2 % of said N -15 - ( 3 , 5 -difluorobenzyl )- 1H - said subject . indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - 40 In some embodiments are provided pharmaceutical com pyran - 4 - ylamino )- benzamide degrades in said pharmaceuti - positions comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda cal composition after said pharmaceutical composition is zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran stored for 3 months in an open container at 60° C . and 75 % 4 - ylamino ) - benzamide and at least one acidulant, wherein relative humidity . said pharmaceutical composition when administered to a In some embodiments are provided pharmaceutical com - 45 subject in a fasted state at a total dose of about 800 mg of positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 zol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran - methyl -piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) 4 - ylamino ) - benzamide and at least one acidulant, wherein benzamide provides a pharmacokinetic profile in said sub said compositions are non -hygroscopic . ject wherein the Cmar of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H In some embodiments are provided pharmaceutical com - 50 indazol- 3 - yl) - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro positions comprising N - [ 5 -( 3 , 5 - difluorobenzyl) - 1H - inda - pyran - 4 - ylamino ) -benzamide in the plasma of said subject is zol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 - yl )- 2 -( tetrahydro -pyran between about 2080 nM and about 2110 nM following said 4 -ylamino )- benzamide and at least one pharmaceutically administration of said pharmaceutical composition to said acceptable excipient, wherein said pharmaceutical compo subject. sition is in the form of a tablet or capsule , and wherein said 55 In some embodiments are provided pharmaceutical com tablet or capsule has a dissolution profile wherein at least positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda about 30 % of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 4 - ylamino ) -benzamide and at least one acidulant, wherein ylamino ) -benzamide has been released from said tablet or said pharmaceutical composition when administered to a capsule at about 60 minutes when tested in USP Apparatus 60 subject in a fed state at a total dose of about 800 mg of said Type I Basket Method at 50 rpm in 500 mL of sodium N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl acetate buffer at a pH of 4 . 5 and at about 37° C . In some piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide embodiments are provided such pharmaceutical formula provides a pharmacokinetic profile in said subject wherein tions wherein at least about 40 % , or about 50 % , or about the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 60 % , or about 70 % , or about 80 % , or about 90 % , or about 65 yl] -4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro -pyran - 4 95 % of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ylamino ) -benzamide in the plasma of said subject is between ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) 80 % to 125 % of 2560 nM , based on a 90 percent confidence US 10 , 398 ,693 B2 interval following said administration of said pharmaceuti methyl- piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) cal composition to said subject. benzamide to a subject that exhibits no significant food In some embodiments are provided pharmaceutical com - effect . positions , comprising N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda In some embodiments are provided pharmaceutical com zol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - pyran - 5 positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda 4 - ylamino )- benzamide and at least one acidulant, wherein zol- 3 -yl ] - 4 - (4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro -pyran said pharmaceutical composition when administered to a 4 -ylamino ) - benzamide , wherein said pharmaceutical subiect in a fasted state at a total dose of about 800 mg of composition exhibits no food effect when administered to a subject. said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - yl )- 4 -( 4 10 In some embodiments are provided pharmaceutical com methyl- piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ). positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda benzamide provides a pharmacokinetic profile in said sub zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran ject wherein the AUC ( O to 24 ) of said N - [ 5 - ( 3 , 5 4 - ylamino ) - benzamide , wherein said pharmaceutical difluorobenzyl) - 1H -indazol - 3 -yl ] - 4 - (4 -methyl - piperazin - 1 composition exhibits no food effect when administered to a yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide in the1 15 subject and said subject is also administered one or more plasma of said subject is between about 28 , 900 nM * hr and proton pump inhibitor compounds. about 30 ,800 nM * hr following said administration of said In some embodiments are provided pharmaceutical com pharmaceutical composition to said subject . positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda In some embodiments are provided pharmaceutical com zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - 20 4 -ylamino ) -benzamide and at least one acidulant, wherein dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro said pharmaceutical composition when administered to a pyran - 4 - ylamino )- benzamide ; and (b ) means for delivering subject in a fasted state at a total dose of about 600 mg of a Cmax of said N - [5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 -yl ] said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl )- 4 -( 4 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran -4 methyl- piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) ylamino ) - benzamide in the plasma of a subject of between 25 benzamide provides a pharmacokinetic profile in said sub about 2080 nM and about 2100 nM following administration ject wherein the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H of said pharmaceutical composition to said subject in a indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro fasted state, and wherein said composition comprises a total pyran -4 -ylamino )- benzamide in the plasma of said subject is between about 2 hours and about 5 hours following said dose of about 800 mgof said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H 30 administration of said pharmaceutical composition to said indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro subject . In some embodiments , the at least one acidulant is pyran - 4 -ylamino )- benzamide . an organic acidulant. In some embodiments , the at least one In some embodiments are provided pharmaceutical com acidulant is selected from tartaric acid , maleic acid , fumaric positions, comprising (a ) N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H -in acid , citric acid , and betaine hydrochloride . In some embodi dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro . 35 ments , the least one acidulant is fumaric acid . In some pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering embodiments , the at least one acidulant is tartaric acid . In an AUC ( O to 24 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H some embodiments , the said at least one acidulant is maleic indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro acid . In some embodiments , the said at least one acidulant is pyran - 4 - ylamino ) -benzamide in the plasma of a subject of citric acid . In some embodiments, the said at least one between about 28 , 900 nM * hr and about 30 ,800 nM * hr 40 acidulant is betaine hydrochloride . following administration of said pharmaceutical composi In some embodiments are provided pharmaceutical com tion to said subject in a fasted state , and wherein said positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda composition comprises a total dose of about 800 mg of said zol- 3 -yl ) - 4 - (4 -methyl - piperazin -1 -yl ) - 2 -( tetrahydro -pyran N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- 4 -ylamino )- benzamide and at least one acidulant, wherein piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide . 45 said pharmaceutical composition when administered to a In some embodiments are provided pharmaceutical com - subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro yl) -2 - ( tetrahydro -pyran -4 - ylamino )- benzamide provides a pyran - 4 -ylamino ) - benzamide ; and ( b ) means for delivering pharmacokinetic profile in said subject wherein the Tmor of a Tmax of said N - [ 5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 50 said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl ] - 4 - ( 4 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -pyran -4 methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) ylamino ) - benzamide in the plasma of a subject of between benzamide in the plasma of said subject is between about 2 about 2 hours and about 6 hours following administration of hours and about 8 hours following said administration of said pharmaceutical composition to said subject in a fasted said pharmaceutical composition to said subject. In some state . 55 embodiments , the at least one acidulant is an organic acidu In some embodiments are provided pharmaceutical com lant. In some embodiments , the at least one acidulant is positions, comprising (a ) N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H -in - selected from tartaric acid , maleic acid , fumaric acid , citric dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro acid , and betaine hydrochloride . In some embodiments , the pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering least one acidulant is fumaric acid . In some embodiments , said N -15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - 60 the at least one acidulant is tartaric acid . In some embodi methyl- piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) - ments , the said at least one acidulant is maleic acid . In some benzamide to a subject that exhibits no food effect. embodiments , the said at least one acidulant is citric acid . In In some embodiments are provided pharmaceutical com some embodiments , the said at least one acidulant is betaine positions, comprising (a ) N - [5 -( 3 ,5 - difluorobenzyl) - 1H - in - hydrochloride . dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1- yl) -2 -( tetrahydro - 65 In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering positions comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - zol- 3 - yl) -4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran US 10 , 398 ,693 B2
4 - ylamino ) -benzamide and at least one acidulant, wherein citric acid . In some embodiments, the said at least one said pharmaceutical composition when administered to a acidulant is betaine hydrochloride . subject in a fed state at a total dose of about 600 mg of said In some embodiments are provided pharmaceutical com N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide 5 zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran provides a pharmacokinetic profile in said subject wherein 4 -ylamino ) - benzamide and at least one acidulant, wherein the Tmax of said N - [ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 - said pharmaceutical composition when administered to a yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 ylamino ) -benzamide in the plasma of said subject is between difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 about 4 hours and about 8 hours following said administra - 10 yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide provides a tion of said pharmaceutical composition to said subject. In pharmacokinetic profile in said subject wherein the Cm of some embodiments , the at least one acidulant is an organic said N - [5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 -yl ] -4 - ( 4 acidulant. In some embodiments , the at least one acidulant methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) is selected from tartaric acid , maleic acid , fumaric acid , benzamide in the plasma of said subject is between about citric acid , and betaine hydrochloride . In some embodi- 15 1200 nM and about 3500 nM , following said administration ments , the least one acidulant is fumaric acid . In some of said pharmaceutical composition to said subject. In some embodiments , the at least one acidulant is tartaric acid . In embodiments , the at least one acidulant is an organic acidu some embodiments , the said at least one acidulant is maleic lant. In some embodiments , the at least one acidulant is acid . In some embodiments, the said at least one acidulant is selected from tartaric acid , maleic acid , fumaric acid , citric citric acid . In some embodiments, the said at least one 20 acid , and betaine hydrochloride . In some embodiments , the acidulant is betaine hydrochloride . least one acidulant is fumaric acid . In some embodiments , In some embodiments are provided pharmaceutical com - the at least one acidulant is tartaric acid . In some embodi positions comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda ments , the said at least one acidulant is maleic acid . In some zol- 3 -yl ] - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran embodiments , the said at least one acidulant is citric acid . In 4 - ylamino ) -benzamide and at least one acidulant, wherein 25 some embodiments , the said at least one acidulant is betaine said pharmaceutical composition when administered to a hydrochloride . subject at a total dose of about 600 mg of said N -[ 5 - (3 , 5 - In some embodiments are provided pharmaceutical com difluorobenzyl) -1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - inda yl ) - 2 - tetrahydro - pyran - 4 - ylamino ) - benzamide provides a zol - 3 - y1 ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran pharmacokinetic profile in said subject wherein the Tor of 30 4 -ylamino ) - benzamide and at least one acidulant, wherein said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 - said pharmaceutical composition when administered to a methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino )- subject in a fed state at a total dose of about 600 mg of said benzamide in the plasma of said subject is between about 4 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl hours and about 8 hours following said administration of piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide said pharmaceutical composition to said subject. In some 35 provides a pharmacokinetic profile in said subject wherein embodiments , the at least one acidulant is an organic acidu - the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 lant. In some embodiments , the at least one acidulant is yl] -4 -( 4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro -pyran -4 selected from tartaric acid , maleic acid , fumaric acid , citric y lamino ) -benzamide in the plasma of said subject is between acid , and betaine hydrochloride . In some embodiments , the about 1500 nM and about 3500 nM following said admin least one acidulant is fumaric acid . In some embodiments , 40 istration of said pharmaceutical composition to said subject . the at least one acidulant is tartaric acid . In some embodi- In some embodiments, the at least one acidulant is an ments , the said at least one acidulant is maleic acid . In some organic acidulant. In some embodiments , the at least one embodiments , the said at least one acidulant is citric acid . In acidulant is selected from tartaric acid , maleic acid , fumaric some embodiments , the said at least one acidulant is betaine acid , citric acid , and betaine hydrochloride . In some embodi hydrochloride . 45 ments , the least one acidulant is fumaric acid . In some In some embodiments are provided pharmaceutical com - embodiments , the at least one acidulant is tartaric acid . In positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H - inda some embodiments , the said at least one acidulant is maleic zol- 3 -yl ) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - acid . In some embodiments , the said at least one acidulant is 4 - ylamino ) -benzamide and at least one acidulant, wherein citric acid . In some embodiments, the said at least one said pharmaceutical composition when administered to a 50 acidulant is betaine hydrochloride. subject in a fasted state at a total dose of about 600 mg of In some embodiments are provided pharmaceutical com said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 - positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda methyl- piperazin - 1 -yl ) - 2 - (tetrahydro -pyran -4 -ylamino ) zol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran benzamide provides a pharmacokinetic profile in said sub - 4 -ylamino ) - benzamide and at least one acidulant, wherein ject wherein the Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - 55 said pharmaceutical composition when administered to a indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro subject at a total dose of about 600 mg of said N - [ 5 -( 3 , 5 pyran - 4 - ylamino ) -benzamide in the plasma of said subject is difluorobenzyl ) -1H - indazol- 3 -yl ] -4 - (4 -methyl - piperazin - 1 between about 1200 nM and about 3500 nM , following said yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide provides a administration of said pharmaceutical composition to said pharmacokinetic profile in said subject wherein the mor of subject. In some embodiments , the at least one acidulant is 60 said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 an organic acidulant . In some embodiments , the at least one methyl - piperazin - 1 - yl) - 2 - tetrahydro -pyran - 4 - ylamino ) acidulant is selected from tartaric acid , maleic acid , fumaric benzamide in the plasma of said subject is between about acid , citric acid , and betaine hydrochloride . In some embodi- 1500 nM and about 3500 nM following said administration ments , the least one acidulant is fumaric acid . In some of said pharmaceutical composition to said subject . In some embodiments , the at least one acidulant is tartaric acid . In 65 embodiments , the at least one acidulant is an organic acidu some embodiments , the said at least one acidulant is maleic lant. In some embodiments , the at least one acidulant is acid . In some embodiments , the said at least one acidulant is selected from tartaric acid , maleic acid , fumaric acid , citric US 10 , 398 ,693 B2 10 acid , and betaine hydrochloride . In some embodiments , the pyran - 4 - ylamino ) - benzamide in the plasma of said subject is least one acidulant is fumaric acid . In some embodiments , between about 35 , 000 nM * hr and about 90 ,000 nM * hr the at least one acidulant is tartaric acid . In some embodi following said administration of said pharmaceutical com ments , the said at least one acidulant is maleic acid . In some position to said subject . In some embodiments , the at least embodiments , the said at least one acidulant is citric acid . In 5 one acidulant is an organic acidulant. In some embodiments, some embodiments , the said at least one acidulant is betaine the at least one acidulant is selected from tartaric acid , hydrochloride . maleic acid , fumaric acid , citric acid , and betaine hydro In some embodiments are provided pharmaceutical com - chloride . In some embodiments , the least one acidulant is positions, comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - fumaric acid . In some embodiments , the at least one acidu zol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 10 lant is tartaric acid . In some embodiments , the said at least 4 - ylamino ) -benzamide and at least one acidulant, wherein one acidulant is maleic acid . In some embodiments, the said said pharmaceutical composition when administered to a at least one acidulant is citric acid . In some embodiments , subject in a fasted state at a total dose of about 600 mg of the said at least one acidulant is betaine hydrochloride . said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 - In some embodiments are provided pharmaceutical com methyl- piperazin -1 -yl ) - 2 - ( tetrahydro -pyran -4 -ylamino ) - 15 positions, comprising N - [5 -( 3 ,5 - difluorobenzyl) - 1H -inda benzamide provides a pharmacokinetic profile in said sub - zol- 3 - yl) -4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran ject wherein the AUC (O to 120 ) of said N - [5 - (3 , 5 - 4 -ylamino )- benzamide and at least one acidulant, wherein difluorobenzyl) - 1H - indazol- 3 -yl ) -4 - ( 4 -methyl - piperazin - 1 - said pharmaceutical composition when administered to a yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide in the subject at a total dose of about 600 mg of said N -15 - ( 3 , 5 plasma of said subject is between about 30 ,000 nM * hr and 20 difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 about 85 , 000 nM * hr following said administration of said yl )- 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide provides a pharmaceutical composition to said subject . In some pharmacokinetic profile in said subject wherein the AUC ( O embodiments , the at least one acidulant is an organic acidu - to 120 ) of said N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol -3 -yl ] lant. In some embodiments , the at least one acidulant is 4 -( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 selected from tartaric acid , maleic acid , fumaric acid , citric 25 ylamino ) - benzamide in the plasma of said subject is between acid , and betaine hydrochloride . In some embodiments , the about 35 , 000 nM * hr and about 90 , 000 nM * hr following said least one acidulant is fumaric acid . In some embodiments , administration of said pharmaceutical composition to said the at least one acidulant is tartaric acid . In some embodi- subject. In some embodiments , the at least one acidulant is ments , the said at least one acidulant is maleic acid . In some an organic acidulant. In some embodiments , the at least one embodiments , the said at least one acidulant is citric acid . In 30 acidulant is selected from tartaric acid , maleic acid , fumaric some embodiments , the said at least one acidulant is betaine acid , citric acid , and betaine hydrochloride . In some embodi hydrochloride . ments , the least one acidulant is fumaric acid . In some In some embodiments are provided pharmaceutical com - embodiments , the at least one acidulant is tartaric acid . In positions, comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda some embodiments , the said at least one acidulant ismaleic zol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 35 acid . In some embodiments , the said at least one acidulant is 4 - ylamino ) -benzamide and at least one acidulant, wherein citric acid . In some embodiments, the said at least one said pharmaceutical composition when administered to a acidulant is betaine hydrochloride. subject state at a total dose of about 600 mg of said In some embodiments are provided pharmaceutical com N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide 40 zol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran provides a pharmacokinetic profile in said subject wherein 4 -ylamino ) -benzamide and at least one acidulant , wherein the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - said pharmaceutical composition when administered to a indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro subject in a fasted state at a total dose of about 600 mg of pyran - 4 - ylamino ) -benzamide in the plasma of said subject is said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ] - 4 - ( 4 between about 30 ,000 nM * hr and about 85 ,000 nM * hr 45 methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) following said administration of said pharmaceutical com - benzamide provides a pharmacokinetic profile in said sub position to said subject . In some embodiments , the at least j ect wherein the AUC ( infinity ) of said N - [ 5 -( 3, 5 one acidulant is an organic acidulant. In some embodiments , difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 the at least one acidulant is selected from tartaric acid , yl) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide in the maleic acid , fumaric acid , citric acid , and betaine hydro - 50 plasma of said subject is between about 30 , 000 nM * hr and chloride . In some embodiments , the least one acidulant is about 85 , 000 nM * hr following said administration of said fumaric acid . In some embodiments , the at least one acidu - pharmaceutical composition to said subject. In some lant is tartaric acid . In some embodiments , the said at least embodiments , the at least one acidulant is an organic acidu one acidulant is maleic acid . In some embodiments, the said lant. In some embodiments, the at least one acidulant is at least one acidulant is citric acid . In some embodiments , 55 selected from tartaric acid , maleic acid , fumaric acid , citric the said at least one acidulant is betaine hydrochloride . acid , and betaine hydrochloride . In some embodiments , the In some embodiments are provided pharmaceutical com - least one acidulant is fumaric acid . In some embodiments , positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - the at least one acidulant is tartaric acid . In some embodi zol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - pyran - ments , the said at least one acidulant is maleic acid . In some 4 - ylamino ) -benzamide and at least one acidulant, wherein 60 embodiments , the said at least one acidulant is citric acid . In said pharmaceutical composition when administered to a some embodiments , the said at least one acidulant is betaine subject in a fed state at a total dose of about 600 mg of said hydrochloride. N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - In some embodiments are provided pharmaceutical com piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda provides a pharmacokinetic profile in said subject wherein 65 zol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - 4 - ylamino ) -benzamide and at least one acidulant, wherein indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro said pharmaceutical composition when administered to a US 10 , 398 ,693 B2 12 subject at a total dose of about 600 mg of said N - [ 5 -( 3 , 5 In some embodiments are provided pharmaceutical com difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 . positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide provides a dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pharmacokinetic profile in said subject wherein the AUC pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering ( infinity ) of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - 5 a Cmax of said N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol -3 -yl ] yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 ylamino ) - benzamide in the plasma of said subject is between ylamino )- benzamide in the plasma of a subject of between about 30 , 000 nM * hr and about 85, 000 nM * hr following said about 1200 nM and about 3500 nM following administration administration of said pharmaceutical composition to said of said pharmaceutical composition to said subject in a subject . In some embodiments , the at least one acidulant is 10 fasted state , and wherein said composition comprises a total an organic acidulant. In some embodiments, the at least one dose of about 600 mg of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H acidulant is selected from tartaric acid , maleic acid , fumaric indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro acid , citric acid , and betaine hydrochloride . In some embodi pyran - 4 -ylamino ) -benzamide . ments , the least one acidulant is fumaric acid . In some In some embodiments are provided pharmaceutical com embodiments , the at least one acidulant is tartaric acid . In 15 positions, comprising (a ) N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - in some embodiments , the said at least one acidulant is maleic dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro acid . In some embodiments , the said at least one acidulant is pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering citric acid . In some embodiments , the said at least one a Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] acidulant is betaine hydrochloride . 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com - 20 ylamino ) - benzamide in the plasma of a subject of between positions, comprising N - [5 - ( 3 , 5 - difluorobenzyl ) - 1H - inda about 1200 nM and about 3500 nM following administration zol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - of said pharmaceutical composition to said subject , and 4 -ylamino ) -benzamide and at least one acidulant, wherein wherein said composition comprises a total dose of about said pharmaceutical composition when administered to a 600 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] subject in a fed state at a total dose of about 600 mg of said 25 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - ylamino ) -benzamide . piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide In some embodiments are provided pharmaceutical com provides a pharmacokinetic profile in said subject wherein positions, comprising (a ) N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - in the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 30 pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering pyran - 4 - ylamino ) -benzamide in the plasma of said subject is a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] between about 35 , 000 nM * hr and about 90 , 000 nM * hr 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 following said administration of said pharmaceutical com ylamino ) - benzamide in the plasma of a subject of between position to said subject. In some embodiments, the at least about 1500 nM and about 3500 nM following administration one acidulant is an organic acidulant. In some embodiments, 35 of said pharmaceutical composition to said subject in a fed the at least one acidulant is selected from tartaric acid , state , and wherein said composition comprises a total dose maleic acid , fumaric acid , citric acid , and betaine hydro - of about 600 mg of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H chloride. In some embodiments , the least one acidulant is indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro fumaric acid . In some embodiments , the at least one acidu - pyran - 4 - ylamino ) -benzamide . lant is tartaric acid . In some embodiments , the said at least 40 In some embodiments are provided pharmaceutical com one acidulant is maleic acid . In some embodiments , the said positions, comprising ( a ) N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - in at least one acidulant is citric acid . In some embodiments, dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro the said at least one acidulant is betaine hydrochloride . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com - a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - indazol- 3 -yl ] positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 45 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 zol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - ylamino ) -benzamide in the plasma of a subject of between 4 - ylamino ) -benzamide and at least one acidulant, wherein about 1500 nM and about 3500 nM following administration said pharmaceutical composition when administered to a of said pharmaceutical composition to said subject , and subject at a total dose of about 600 mg of said N -15 - ( 3 , 5 - wherein said composition comprises a total dose of about difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - 50 600 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide provides a 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran - 4 pharmacokinetic profile in said subject wherein the AUC ylamino ) -benzamide . ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 In some embodiments are provided pharmaceutical com yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 positions, comprising (a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in ylamino )- benzamide in the plasma of said subject is between 55 dazol- 3 - yl )- 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro about 35 ,000 nM * hr and about 90 ,000 nM * hr following said pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering administration of said pharmaceutical composition to said an AUC ( 0 to 120 ) of said N -[ 5 -( 3 , 5 -difluorobenzyl ) - 1H subject. In some embodiments , the at least one acidulant is indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro an organic acidulant. In some embodiments , the at least one pyran - 4 -ylamino ) - benzamide in the plasma of a subject of acidulant is selected from tartaric acid , maleic acid , fumaric 60 between about 30 , 000 nM * hr and about 85 , 000 nM * hr acid , citric acid , and betaine hydrochloride . In some embodi following administration of said pharmaceutical composi ments , the least one acidulant is fumaric acid . In some tion to said subject in a fasted state , and wherein said embodiments , the at least one acidulant is tartaric acid . In composition comprises a total dose of about 600 mg of said some embodiments , the said at least one acidulant is maleic N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl acid . In some embodiments , the said at least one acidulant is 65 piperazin - 1 -yl ) -2 -( tetrahydro -pyran -4 - ylamino ) -benzamide . citric acid . In some embodiments , the said at least one In some embodiments are provided pharmaceutical com acidulant is betaine hydrochloride . positions , comprising ( a ) N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - in US 10 , 398 ,693 B2 13 14 dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran - 4 -ylamino ) -benzamide in the plasma of a subject of pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering between about 35 , 000 nM * hr and about 90 ,000 nM * hr an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H following administration of said pharmaceutical composi indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro tion to said subject in a fed state , and wherein said compo pyran - 4 - ylamino ) -benzamide in the plasma of a subject of 5 sition comprises a total dose of about 600 mg of said between about 30 , 000 nM * hr and about 85, 000 nM * hr N -[ 5 - (3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] -4 -( 4 -methyl following administration of said pharmaceutical composi piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide. tion to said subject , and wherein said composition comprises In some embodiments are provided pharmaceutical com a total dose of about 600 mg of said N -[ 5 - (3 ,5 -difluoroben positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in zyl) - 1H - indazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetra 10 dazol -3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2- (tetrahydro hydro -pyran - 4 -ylamino ) -benzamide . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in positions, comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran - 4 - ylamino ) -benzamide in the plasma of a subject of pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering 15 between about 35, 000 nM * hr and about 90 , 000 nM * hr an AUC (0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H following administration of said pharmaceutical composi indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro tion to said subject, and wherein said composition comprises pyran - 4 - ylamino ) -benzamide in the plasma of a subject of a total dose of about 600 mg of said N - [ 5 - ( 3 ,5 - difluoroben between about 35 ,000 nM * hr and about 90 ,000 nM * hr zyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra following administration of said pharmaceutical composii - 20 hydro -pyran -4 - ylamino )- benzamide . tion to said subject in a fed state , and wherein said compo In some embodiments are provided pharmaceutical com sition comprises a total dose of about 600 mg of said positions , comprising ( a ) N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - in N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com - 25 a Tmax of said N - [ 5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol - 3 - yl] positions, comprising (a ) N - [5 - (3 ,5 -difluorobenzyl )- 1H - in 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 dazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - ylamino ) -benzamide in the plasma of a subject of between pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering about 2 hours and about 5 hours following administration of an AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 - difluorobenzyl ) - 1H - said pharmaceutical composition to said subject in a fasted indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro - 30 state , and wherein said composition comprises a total dose pyran - 4 - ylamino ) -benzamide in the plasma of a subject of of about 600 mg of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H between about 35, 000 nM * hr and about 90 ,000 nM * hr indazol- 3 -yl ] - 4 -( 4 -methyl -piperazin - 1- yl) - 2 -( tetrahydro following administration of said pharmaceutical composi- pyran - 4 - ylamino ) -benzamide . tion to said subject , and wherein said composition comprises In some embodiments are provided pharmaceutical com a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 - difluoroben - 35 positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in zyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra - dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro hydro -pyran -4 - ylamino ) -benzamide . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com a Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 dazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) -benzamide in the plasma of a subject of between pyran -4 - ylamino ) - benzamide ; and ( b ) means for delivering 40 about 2 hours and about 5 hours following administration of an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in said pharmaceutical composition to said subject, and dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - wherein said composition comprises a total dose of about pyran - 4 - ylamino ) -benzamide in the plasma of a subject of 600 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] between about 30 , 000 nM * hr and about 85, 000 nM * hr 4 -( 4 -methyl -piperazin - 1 -yl ) - 2- ( tetrahydro -pyran - 4 following administration of said pharmaceutical composi - 45 ylamino ) -benzamide . tion to said subject in a fasted state , and wherein said In some embodiments are provided pharmaceutical com composition comprises a total dose of about 600 mg of said positions, comprising ( a ) N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - in N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide . pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com - 50 a Tmax of said N - [5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] positions , comprising ( a ) N - [ 5 -( 3 , 5 -difluorobenzyl ) - 1H - in - 4 -( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject of between pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering about 4 hours and about 8 hours following administration of an AUC ( infinity ) of said N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - said pharmaceutical composition to said subject in a fed dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - ss state , and wherein said composition comprises a total dose pyran - 4 - ylamino ) -benzamide in the plasma of a subject of of about 600 mg of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H between about 30 , 000 nM * hr and about 85 ,000 nM * hr indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro following administration of said pharmaceutical composi pyran - 4 -ylamino ) -benzamide . tion to said subject , and wherein said composition comprises In some embodiments are provided pharmaceutical com a total dose of about 600 mg of said N - 15 - ( 3 , 5 - difluoroben - positions, comprising ( a ) N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - in zyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetra - 60 dazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro hydro - pyran - 4 - ylamino ) -benzamide . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com a Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H - in 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro ylamino )- benzamide in the plasma of a subject of between pyran - 4 - ylamino )- benzamide ; and (b ) means for delivering 65 about 4 hours and about 8 hours following administration of an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - said pharmaceutical composition to said subject, and dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro wherein said composition comprises a total dose of about US 10 , 398 ,693 B2 15 16 600 mg of said N - [5 - (3 , 5 -difluorobenzyl ) - 1H -indazol -3 - yl ] Hereinafter all references to N - [ 5 - ( 3 , 5 -difluorobenzyl ) 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra ylamino ) -benzamide . hydro -pyran - 4 - ylamino ) -benzamide herein include refer ences to solvates, complexes, polymorphic forms, BRIEF DESCRIPTION OF DRAWINGS 5 stereoisomers, and isotopically labeled versions thereof. FIG . 1 is a graphical illustration of the bioavailability Also included within the scope provided herein are phar (area under the curve, AUC ) of N - [5 - ( 3 , 5 -difluorobenzyl ) maceutical compositions comprising solvates, complexes, 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra polymorphic forms, stereoisomers , and isotopically labeled hydro - pyran - 4 - ylamino ) - benzamide , measured in nM * hr versions of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 mL , after administration of the F2A formulation under 10 ( 4 -methyl - piperazin - 1 - yl ) - 2 -( tetrahydro -pyran -4 - ylamino ) fasted conditions , with and without a PPI. benzamide . FIG . 2 is a graphical illustration of the effect of food on As used herein , the term “ about” means either within plus bioavailability ( area under the curve , AUC ) of N - [ 5 - ( 3 , 5 - or minus 10 % of the provided value , or rounded to the difluorobenzyl) - 1H -indazol - 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 nearest significant figure , in all cases inclusive of the pro yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) - benzamide, measured 15 vided value . Where ranges are provided , they are inclusive in nM * hr /mL . The F2A formulation was administered under of the boundary values. fed or fasted conditions without a PPI. FIG . 3 is a graphical illustration of the effect of food on As used herein , the term “ acidulant ” means a chemical bioavailability (area under the curve, AUC ) of N - [ 5 - ( 3 , 5 compound that is acidic in nature . As used herein , the term difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 " organic acidulant” means an acidulant the chemical com yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benzamide , measured -20 position of which contains carbon . As used herein , the term in nM * hr/ mL . The F2A formulation was administered under “ inorganic acidulant” means an acidulant the composition of fed or fasted conditions with a PPI. which does not contain carbon . FIG . 4 is a graphical illustration of the mean plasma levels As used herein , the terms " administration " and " admin ( in nanomolar ) over time of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H istering ” mean the delivery of a bioactive composition or indazol- 3 - yl) - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro - 25 formulation to a subject by an administration route includ pyran - 4 - ylamino ) -benzamide after treatment with F2A . Dia ing , but not limited to , oral, intravenous, intra - arterial, monds ( * ) indicate administration of F2A under fasting intramuscular , intraperitoneal, subcutaneous, intramuscular, conditions without a PPI. Squares ( 1 ) indicate administra - topically , or combinations thereof. In some embodiments, tion of F2A under fasted conditions with a PPI. Triangles the administration to a subject is oral. ( A ) indicate administration of F2A under fed conditions 30 As used herein , the term “ admixture ” means a mixture of without a PPI. Circles ( 0 ) indicate administration of F2A one or more chemical compounds in a composition . It is under fed conditions with a PPI. understood by one having ordinary skill in the art that the pharmaceutical compositions disclosed herein comprise an DETAILED DESCRIPTION admixture of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ) - 4 The singular form “ a ," " an ,” and “ the” include plural 35 ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) references unless the context clearly dictates otherwise . For benzamide and the at least one acidulant. example , the term “ a cell” includes one or more cells , As used herein , the term “ ALK ” means anaplastic lym including mixtures thereof. “ A and /or B ” is used herein to phoma kinase receptor or CD246 (cluster of differentiation include all of the following alternatives : “ A , ” “ B , ” “ A or B , ” 246 ) , which is an enzyme that in humans is encoded by the and “ A and B ." ? 40 ALK gene and also has the UniProt identified ALK _ HU As used herein , the term “ N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - M indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro As used herein , the term " antibody ” means an immuno pyran - 4 - ylamino )- benzamide ” means a compound having globulin that specifically binds to , and is thereby defined as Chemical Abstracts Service Registry No. 1108743 -60 - 7 and complementary with , a particular spatial and polar organi having the chemical structure : 45 Zation of another molecule . The antibody can be monoclonal or polyclonal and can be prepared by techniques that are well known in the art, such as immunization of a host and collection of sera (polyclonal ) , or by preparing continuous hybrid cell lines and collecting the secreted protein (mono Z 50 clonal) , or by cloning and expressing nucleotide sequences or mutagenized versions thereof coding at least for the amino acid sequences required for specific binding of natu ral antibodies . Antibodies may include a complete immu HN noglobulin or fragment thereof, which immunoglobulins 55 include the various classes and isotypes , such as IgA , IgD , IgE , IgG1, IgG2a , IgG2b and IgG3, IgM , etc . Fragments thereof may include Fab , Fv and F ( ab ' ) 2 , Fab ', and the like . In addition , aggregates, polymers , and conjugates of immu noglobulins or their fragments can be used where appropri 60 ate so long as binding affinity for a particular target is maintained As used herein , the term “ AUC ” means the area under the curve of a plot of the concentration of a compound in the plasma of a subject versus time . 65 As used herein , the term “ betaine hydrochloride ” means HC a compound having Chemical Abstracts Service Registry No. 590 - 46 - 5 and the common names 1 - carboxy - n , n , n US 10 , 398 ,693 B2 17 18 trimethylmethanaminium chloride and ( carboxymethyl ) certain characteristic morphological features. Cancer cells trimethylammonium hydrochloride . are often in the form of a tumor, but such cells can exist As used herein , the term “biological sample, ” means a alone within an animal, or can be a non - tumorigenic cancer sample obtained from an organism that may be used in a cell , such as a leukemia cell . These terms include a solid diagnostic or monitoring assay . The sample may be of a 5 tumor , a soft tissue tumor , or a metastatic lesion . As used healthy tissue , diseased tissue or tissue suspected of being herein , the term " cancer ” includes premalignant, as well as diseased tissue . The sample may be a biopsy taken , for malignant cancers . In certain embodiments , the cancer is a example , during a surgical procedure . The sample may be solid tumor , a soft tissue tumor, or a metastatic lesion . The collected via means of fine needle aspiration , scraping or terms also refer to solid tumors named for the type of cells washing a cavity to collects cells or tissue therefrom . The 10 that form them , cancer of blood , bone marrow , or the sample may be of a tumor such as, for example , solid and lymphatic system . Examples of solid tumors include , but are hematopoietic tumors as well as of neighboring healthy not limited to , sarcomas and carcinomas. Examples of tissue . The sample may be a smear of subject cells or a tissue cancers of the blood include , but are not limited to , leuke section . The term encompasses blood and other liquid mias, lymphomas and myeloma . The terms include, but are samples of biological origin , solid tissue samples, such as a 15 not limited to , a primary cancer that originates at a specific biopsy specimen or tissue cultures or cells derived therefrom site in the body, a metastatic cancer that has spread from the and the progeny thereof. The term encompasses samples that place in which it started to other parts of the body, a have been manipulated in any way after their procurement, recurrence from the original primary cancer after remission , such as by treatment with reagents , solubilization , or enrich - and a second primary cancer that is a new primary cancer in ment for certain components. The term encompasses clinical 20 a person with a history of previous cancer of different type samples , and also includes cells in cell culture , cell super - from latter one. As used herein " cancer ” refers to any natants , cell lysates, cell extracts , cell homogenates, and malignant and / or invasive growth or tumor caused by abnor subcellular components including synthesized proteins, mal cell growth . serum , plasma, bodily and other biological fluids, and tissue As used herein , the term “ chemotherapeutic agent” , samples . The biological sample can contain compounds that 25 means a chemical substance , such as a cytotoxic or cyto are not naturally intermixed with the cell or tissue in nature static agent, that is used to treat a condition , particularly such as preservatives , anticoagulants , buffers , fixatives , cancer. nutrients , antibiotics or the like. In some embodiments , the As used herein , the terms " combination ” and “ in combi sample is preserved as a frozen sample or as formaldehyde - nation with ” mean the administration of N - [ 5 - ( 3 , 5 -difluo or paraformaldehyde - fixed paraffin - embedded (FFPE ) tissue 30 robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 preparation . For example , the sample can be embedded in a (tetrahydro -pyran - 4 - ylamino ) - benzamide together with at matrix , e . g ., an FFPE block or a frozen sample . least one additional pharmaceutical or medicinal agent ( e . g . , As used herein , the term “ biomarker ” means one or more an anti -cancer agent ), either sequentially or simultaneously . compounds whose level of nucleic acid or protein product It includes dosing simultaneously , or within minutes or has a quantitatively differential concentration or level with 35 hours of each other , or on the same day , or on alternating respect to an aspect of a biological state of a subject . The days, or dosing the pharmaceutical compositions provided term “ biomarker ” may be used herein interchangeably with herein on a daily basis , or multiple days per week , or weekly the term “ marker. ” The level of the biomarker can be basis , for example , while administering another compound measured at both the nucleic acid level as well as the such as a chemotherapeutic agent on the same day or polypeptide level . At the nucleic acid level, a nucleic acid 40 alternating days or weeks or on a periodic basis during a gene or a transcript which is transcribed from any part of the time simultaneous therewith or concurrent therewith , or at subject' s chromosomal and extrachromosomal genome, least a part of the time during which the pharmaceutical including for example the mitochondrial genome, may be compositions disclosed herein is dosed . For example , a measured . Preferably an RNA transcript, more preferably an pharmaceutical composition as provided herein that com RNA transcript includes a primary transcript, a spliced 45 prises N - 15 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 -yl ) -4 - ( 4 transcript , an alternatively spliced transcript , or an mRNA of methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) the biomarker is measured . At the polypeptide level, a benzamide could be dosed every day or several days a week pre - propeptide , a propeptide , a mature peptide or a secreted while the chemotherapeutic agent is dosed on alternating peptide of the biomarker may be measured . A biomarker can days or alternating weeks or other periods of time, such as be used either solely or in conjunction with one or more 50 every 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 or more days . other identified biomarkers so as to allow correlation to the As used herein , the term " contact ” when used in reference biological state of interest as defined herein . Specific to specificity or specific binding means two molecules are examples of biomarkers covered by the present disclosure close enough so that short range non - covalent chemical include those associated with ALK , ROS1 , TrkA , TrkB , and interactions, such as Van der Waal forces , hydrogen bonding , TrkC . 55 hydrophobic interactions , and the like , dominate the inter As used herein , the term " Cmax” means the peak concen - action of the molecule . tration that a compound achieves in the plasma of a subject As used herein , the term " cell line ” means to one or more after the compound , or a pharmaceutical composition com - generations of cells which are derived from a clonal cell. The prising the compound , has been administrated to the subject. term “ clone , ” or “ clonal cell, ” means a single cell which is In some embodiments , the compound , or a pharmaceutical 60 expanded to produce an isolated population of phenotypi composition comprising the compound , is administered cally similar cells ( i . e . a “ clonal cell population ” ) . orally to a subject to achieve a particular Cmax. As used herein , the parameters Dv10 , Dv50 , Dv90 and As used herein , the terms " cancer” or “ tumor ” may be Dv99 represent the particle size at the 10 % , 50 % , 90 % and used interchangeably. These terms mean the presence of 99 % points of the cumulative volume undersize particle size cells possessing characteristics typical of cancer - causing 65 distribution . Thus , a “ Dv10 " for a material represents a cells , such as uncontrolled proliferation , immortality , meta - particle size wherein 10 % of the volume of the material static potential, rapid growth and proliferation rate , and consists of particles having a particle size equal to the Dv10 US 10 , 398 ,693 B2 19 20 value or smaller. A “ Dv50 " for a material represents a mutations, gene amplifications, splice variants, deletions , particle size wherein 50 % of the volume of the material insertions/ deletions , gene rearrangements , single -nucleotide consists of particles having a particle size equal to the Dv50 variations (SNVs ) , insertions, and aberrant RNA / protein value or smaller. A " Dv90 " for a material represents a expression . particle size wherein 90 % of the volume of the material 5 As used herein , the term " particle size distribution ” means consists of particles having a particle size equal to the Dv90 the relative proportions of particles of a compound having a value or smaller. A " Dv99 " for a material represents a given particle size . While the particle size of a spherical particle size wherein 99 % of the volume of the material object can be unambiguously and quantitatively defined by consists of particles having a particle size equal to the Dv99 its diameter, particles comprising an active pharmaceutical value or smaller . 10 ingredient or an excipient may be non - spherical and irregu As used herein , the term “ food effect ” means a change in lar in shape . There are several methods by which those of the rate and / or extent of absorption of a compound in a ordinary skill in the art measure and express the size of subject when the compound is administered to the subject non - spherical and irregular particles, such as measuring the shortly after a meal ( fed conditions ) as compared to the rate size of such particles using laser diffractometry and express and / or extent of absorption of the compound when the 15 ing the size of such particles based on replacing a given compound is administered to the subject under fasting particle with an imaginary sphere that has one of a number conditions . As used herein , the term “ no food effect " means of properties of the particle. Such properties can be selected that there is no significant difference in the rate and / or extent from , for example , but are not limited to , the diameter of an of absorption of a compound in a subject when the com - imaginary sphere having the same volume of the particle pound is administered to the subject in fed conditions 20 being measured ( volume- based particle size ) , the diameter compared to fasting conditions. of an imaginary sphere having the same weight as the As used herein , the term “ immunohistochemistry ,” means particle being measured (weight - based particle size ), and the the process of localizing antigens (e .g . proteins ) in biologi- diameter of an imaginary sphere having the same surface cal samples , cells and /or cells of a tissue section exploiting area as the particle being measured ( area -based particle the principle of antibodies binding specifically to antigens . 25 size ) . Those having ordinary skill in the art are familiar with Immunohistochemical staining is widely used in the diag - such methods, and the manner in which the results of such nosis of abnormal cells such as those found in cancerous methods are expressed , and such methods can be applied to tumors . Specific molecular markers are characteristic of the embodiments disclosed herein without undue experi particular cellular events , such as cell proliferation or cell mentation . The particle size distribution may be represented , death . Visualizing an antibody - antigen interaction can be 30 for example , graphically as a plot. A common type of plot is accomplished in a number of ways . In the most common a cumulative undersize plot which represents the fraction instance , an antibody is conjugated to an enzyme, such as ( e . g . by number , volume or mass ) of particles that are peroxidase, that can catalyze a color -producing reaction . smaller than the stated particle size . Alternatively , the antibody can also be tagged to a fluoro As used herein , the term “ polyclonal antibody ” means a phore thus employing the principles of immunofluorescence . 35 composition of different antibody molecules which is Immunohistochemistry can also be used to evaluate tumor capable of binding to or reacting with several different content in the sample on which qPCR is carried out in order specific antigenic determinants on the same or on different to account for the fact that qPCR result will be influenced by antigens . The variability in antigen specificity of a poly the amount of tumor tissue present. clonal antibody is located in the variable regions of the As used herein , the term “micronization ” refers to a 40 subject antibodies constituting the polyclonal antibody, in process of reducing the average particle size of a solid particular in the complementarity determining regions material , typically to provide particles with a particle size of (CDRs ) . Preferably , the polyclonal antibody is prepared by a few micrometers . immunization of an animal with the target tyrosine kinases As used herein , the term “ micronized ” means a material or portions thereof. Alternatively , the polyclonal antibody that has been subjected to micronization 45 may be prepared by mixing multiple monoclonal antibodies As used herein , the terms " monoclonal antibody , " " mAb ” having desired specificity to a target tyrosine kinase . and “MAB ” mean an antibody that is an immunoglobulin As used herein , the term “ proton pump inhibitor” or “ PPI” produced by a single clone of lymphocytes which recognizes refers to a drug that reduces gastric acid production . PPIs only a single epitope on an antigen . For example , a mono - that may be used in some embodiments includes herein are , clonal antibody useful for the methods provided herein 50 but are not limited to , dexlansoprazole , esomeprazole , displays a single binding specificity and affinity for a par - ilaprazole , lansoprazole , omeprazole , pantoprazol, picopra ticular epitope of one or more tyrosine kinases . zole , rabeprazole , yenatoprazole , and timoprazole . As used herein , the term “ multiplexed assay ” means an As used herein , “ ROSI ” means the ROS1 receptor tyro assay in which multiple assay reactions, e . g . simultaneous sine - protein kinase having the UniProt designation ROS1 assays of multiple target biomarkers , are carried out in a 55 HUMAN . single reaction chamber and / or and analyzed in a single As used herein , the term “ selectively binds ” means the separation and detection format. situation in which one member of a specific intra - or As used herein , the term “ multiplex identification ” means inter - species binding pair will not show any significant the simultaneous identification of one or more target bio - binding to molecules other than its specific intra - or inter markers in a single mixture . For example , a two - plex assay 60 species binding partner ( e . g ., an affinity of about 100 - fold means the simultaneous identification , in a single reaction less ) , which means that only minimal cross - reactivity mixture , of two different target biomarkers . occurs. As used herein , the term “ one or more molecular altera As used herein in reference to the binding of two mol tions ” means any variation in the genetic or protein sequence ecules or one or more compounds and a complex of mol in one or more cells of a subject as compared to the 65 ecules , the term " specific ” means the specific recognition of corresponding wild - type genes or proteins. One or more one for the other and the formation of a stable complex , as molecular alterations include, but are not limited to , genetic compared to substantially less recognition of other mol US 10 , 398 ,693 B2 21 22 ecules and the lack of formation of stable complexes with In one aspect are provided pharmaceutical compositions such other molecules . Preferably , “ specific , ” in reference to comprising an admixture of N -[ 5 - ( 3 , 5 - difluorobenzyl) - 1H binding , means that to the extent that one or more com - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro pounds forms complexes with other molecules or com - pyran - 4 - ylamino ) -benzamide , at least one acidulant and at plexes , it forms at least fifty percent of the complexes with 5 least one pharmaceutically acceptable excipient. In some embodiments are provided pharmaceutical com the molecule or complex for which it has specificity . Gen positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda erally , the molecules or complexes have areas on their zol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran surfaces or in cavities giving rise to specific recognition 4 - ylamino ) -benzamide , at least one acidulant and at least between the two binding moieties . Exemplary of specific 10 one pharmaceutically acceptable excipient. Among the binding are antibody - antigen interactions, enzyme - substrate acidulants that may be used in the pharmaceutical compo interactions , polynucleotide hybridizations and / or formation sitions disclosed herein are organic and inorganic acidulants . of duplexes, cellular receptor- ligand interactions , and so In some embodiments , the at least one acidulant is an forth . organic acidulant. In some embodiments , the at least one As used herein , the term “ subject” means a mammal, 15 acidulant is an inorganic acidulant. In some embodiments , including , but not limited to , a human , a dog or a cat. In the at least one organic acidulant is selected from organic some embodiments , the subject is a human . In some embodi- carboxylic acids , aminium , and iminium salts . ments , the subject is a dog . In some embodiments , the In some embodiments , the acidulant is selected from subject is a cat . acetic acid , ascorbic acid , benzoic acid , benzosulfonic acid , As used herein , the term “ Tmax” means the time when the 20 betaine hydrochloride, carbonic acid , cinnamic acid , citric peak concentration of a compound in the plasma of a subject acid , ethanesulfonic acid , ethylenediaminetetraacetic acid , is reached after administration of the compound , or a phar dodecylsulfonic acid , fumaric acid , glucoronic acid , gluta maceutical composition comprising the compound , to the mic acid , glycolic acid , lactic acid , lactobionic acid , ( D ) or subject. ( L ) malic acid or a mixture thereof, maleic acid , mandelic As used herein , the term “ therapeutically effective 25 acid , malonic acid , methanesulfonic acid , mucic acid , naph amount” means that amount of the compound or com - thalenesulfonic acid , propionic acid , salicylic acid , stearic pounds, or pharmaceutically acceptable salts thereof, being acid , succinic acid , p - toluenesulfonic acid , trifluoroacetic administered to a subject which will relieve to some extent acid , ( D ) or ( L ) tartaric acid or a mixture thereof, valeric one or more of the symptoms of the disorder being treated acid , and the like . In reference to the treatment of a cancer , a therapeutically 30 In some embodiments , the at least one acidulant is effective amount means that amount which has the effect of selected from acetic acid , benzoic acid , betaine hydrochlo ( 1 ) reducing the size of a cancer tumor , ( 2 ) inhibiting (that ride , citric acid , fumaric acid , glucoronic acid , lactic acid , is , slowing to some extent, preferably stopping ) cancer ( D ) or ( L ) malic acid or a mixture thereof, maleic acid , tumor metastasis , ( 3 ) inhibiting to some extent ( that is , mandelic acid , malonic acid , salicylic acid , stearic acid , slowing to some extent, preferably stopping ) cancer tumor 35 succinic acid , p -toluenesulfonic acid , and ( D ) or ( L ) tartaric growth , and/ or , ( 4 ) relieving to some extent ( or, preferably , acid or a mixture thereof. eliminating ) one or more symptoms associated with the In some embodiments , the at least one acidulant is cancer. Seselected from benzoic acid , betaine hydrochloride , citric As used herein , the terms “ tropomyosin receptor kinase, ” acid , fumaric acid , ( D ) or ( L ) maleic acid or a mixture “ Trks ” and “ Trk ” mean the family of tropomyosin receptor 40 thereof, and (D ) or (L ) tartaric acid or a mixture thereof. kinases ( Trks ) that are activated by peptide hormones of the In some embodiments , the at least one acidulant is neurotrophin family and include , but are not limited to , selected from betaine hydrochloride , citric acid , fumaric TrkA , TrkB , and TrkC . As used herein , the term “ TrkA ” acid , maleic acid , and ( D ) or ( L ) tartaric acid or a mixture means wild - type tropomyosin receptor kinase A having the thereof. UniProt identifier NTRK1_ HUMAN . As used herein , the 45 In some embodiments , the at least one acidulant is betaine term “ TrkB ” means wild -type tropomyosin receptor kinase hydrochloride . In some embodiments , the at least one acidu B having the UniProt identifier NTRK2 HUMAN . As used lant is citric acid . In some embodiments , the at least one herein , the term “ TrkC ” means wild -type tropomyosin acidulant is fumaric acid . In some embodiments , the at least receptor kinase C having the UniProt identifier one acidulant is maleic acid . In some embodiments , the at NTRK3 _ HUMAN . TrkA , TrkB and TrkC are also referred 50 least one acidulant is ( D ) or ( L ) tartaric acid or a mixture to by those having ordinary skill in the art as Trk1, Trk2 and thereof. Trk3 , respectively . A reference to TrkA is a reference to In some embodiments are provided pharmaceutical com Trk1. A reference to TrkB is a reference to Trk2 . A reference positions, comprising N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H -inda to TrkC is a reference to Trk3 zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran As used herein , the term “ USP Apparatus Type I” means 55 4 - ylamino ) -benzamide and at least one acidulant, wherein the Apparatus 1 (Basket Apparatus or Basket Method ) and the at least one acidulant is ( D ) - tartaric acid . In some the procedures for using the apparatus that are described in embodiments are provided pharmaceutical compositions , United States Pharmacopeia (USP ) General Chapter < 711 > . comprising N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ] - 4 As used herein , the term “ USP Apparatus Type II” means ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) the Apparatus 2 (Paddle Apparatus or Paddle Method ) and 60 benzamide and at least one acidulant, wherein the at least the procedures for using the apparatus described in United one acidulant is ( L ) -tartaric acid . States Pharmacopeia (USP ) General Chapter < 711 > . . In some embodiments are provided pharmaceutical com In one aspect are provided pharmaceutical compositions positions, comprising N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - inda comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran ( 4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - ylamino ) - 65 4 -ylamino )- benzamide and at least one acidulant, wherein benzamide, at least one acidulant and at least one pharma - said pharmaceutical composition is prepared using wet ceutically acceptable excipient. granulation . US 10 , 398 ,693 B2 23 24 In some embodiments are provided pharmaceutical com - of greater than or equal to about 200° C . In some embodi positions, comprising N - [5 -( 3 , 5 - difluorobenzyl) - 1H - inda ments , the at least one acidulant has a melting point of zol- 3 - yl) - 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran greater than or equal to about 250° C . In some embodiments , 4 - ylamino )- benzamide and at least one acidulant, wherein the at least one acidulant has a melting point of greater than said pharmaceutical composition is prepared using dry 5 or equal to about 300° C . granulation . In some embodiments , inclusion of at least one In some embodiments , the at least one acidulant has a pKa acidulant in the dry granulation step of drug product manu of less than about 9 , or less than about 8 , or less than about facturing creates a low pH micro environment that enhances the solubility of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 7 , or less than about 6 , or less than about 5 , or less than about yl] - 4 -( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 10 4 , or less than about 3 , or less than about 2 . ylamino ) - benzamide . In some embodiments , the at least one acidulanthas a pKa In some embodiments are provided pharmaceutical com of from about 1 to about 9 , or from about 1 to about 8 , or positions, comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda from about 1 to about 7 , or from about 1 to about 6 , or from zol- 3 -yl ] - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran about 1 to about 5 , or from about 1 to about 4 , or from about 4 - vlamino ) - benzamide and at least one acidulant, wherein 15 1 to about 3 . 5 , or from about 1 to about 3 . 25 , or from about said pharmaceutical composition is prepared using wet 1 to about 3 , or from about 1 to about 2 .75 , or from about granulation and the at least one acidulant is selected from 1 to about 2 . 5 , or from about 1 to about 2 . 25 , or from about tartaric acid , maleic acid , fumaric acid , citric acid , and 1 to about 2 , or from about 1 to about 1. 9 , or from about 1. 5 betaine hydrochloride . In some embodiments , the least one to about 5 , or from about 1 .5 to about 4 . 5 , or from about 1 .5 acidulant is fumaric acid . In some embodiments, the at least 20 to about 4 , or from about 1 . 5 to about 3 . 5 , or from about 1 . 5 one acidulant is tartaric acid . In some embodiments, the said to about 3 . 25 , or from about 1 . 8 to about 3 . 5 . at least one acidulant is maleic acid . In some embodiments , In some embodiments are provided pharmaceutical com the said at least one acidulant is citric acid . In some positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda embodiments , the said at least one acidulant is betaine zol- 3 -yl ) -4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran hydrochloride . In some embodiments , the at least one acidu - 25 4 - ylamino ) -benzamide and at least one acidulant wherein lant is ( D ) or ( L ) tartaric acid or a mixture thereof. In some the molar ratio between said N -15 - ( 3 , 5 -difluorobenzyl ) - 1H embodiments , the at least one acidulant is (D ) tartaric acid . indazol - 3 -yl ] -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro In some embodiments , the at least one acidulant is ( L ) pyran - 4 - ylamino ) - benzamide and said at least one acidulant tartaric acid . In some embodiments , the at least one acidulate is from about 0 . 5 to about 2 , or from about 0 .75 to about is a mixture of ( D ) and ( L ) tartaric acid . 30 1 . 75 , or from about 1 to about 1. 75 , or from about 1 to about In some embodiments are provided pharmaceutical com 1. 5 , or from about 1. 25 to about 1 .75 , or from about 1 to positions, comprising N - [5 -( 3 , 5 - difluorobenzyl) - 1H - inda about 1 . 5 . zol- 3 - yl) - 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran In some embodiments are provided pharmaceutical com 4said -ylamino pharmaceutical ) -benzamide composition and at least isone prepared acidulant using, wherein dry 35 positions, comprising N - ( 3 - ( 3 , 5 - difluorobenzyl) - 1H - inda granulation and the at least one acidulant is selected from 201zol- 3 - yl] -4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran tartaric acid maleic acid . fumaric acid , citric acid , and 4 - ylamino )- benzamide and at least one acidulant wherein betaine hydrochloride . In some embodiments , the least one the molar ratio between said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H acidulant is fumaric acid . In some embodiments , the at least indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro one acidulant is tartaric acid . In some embodiments , the said 40 pyran - 4 - ylamino ) -benzamide and said at least one acidulant at least one acidulant is maleic acid . In some embodiments , is about 2 , or about 1 . 75 , or about 1 . 5 , or about 1 . 25 , or about the said at least one acidulant is citric acid . In some 1 , or about 0 . 75 , or about 0 . 5 . In some embodiments are embodiments , the said at least one acidulant is betaine provided pharmaceutical compositions , comprising N - [ 5 - ( 3 , hydrochloride. In some embodiments , the at least one acidu - 5 - difluorobenzyl) - 1H - indazol - 3 -yl ] - 4 - ( 4 -methyl - piperazin lant is ( D ) or ( L ) tartaric acid or a mixture thereof . In some 45 1 - yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide and at embodiments , the at least one acidulant is ( D ) tartaric acid . least one acidulant wherein the molar ratio between said In some embodiments , the at least one acidulant is (L ) N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H -indazol - 3 - yl) - 4 -( 4 -methyl tartaric acid . In some embodiments , the at least one acidulate piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide is a mixture of ( D ) and ( L ) tartaric acid . and said at least one acidulant is about 1 . 5 . In some embodiments , the at least one acidulant has a 50 In some embodiments are provided pharmaceutical com melting point of greater than or equal to about 15° C . In positions, comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda some embodiments , the at least one acidulant has a melting zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran point of greater than or equal to about 20° C . In some 4 - ylamino ) - benzamide and at least one acidulant , wherein embodiments , the at least one acidulant has a melting point said at least one acidulant is ( D ) tartaric acid , ( L ) tartaric of greater than or equal to about 25° C . In some embodi - 55 acid , or a mixture of ( D ) and ( L ) tartaric acid , and further ments, the at least one acidulant has a melting point of wherein the molar ratio between said N - [ 5 - ( 3 ,5 - difluoroben greater than or equal to about 30° C . In some embodiments, zyl) - 1H - indazol- 3 - yl] -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra the at least one acidulant has a melting point of greater than hydro -pyran - 4 - ylamino ) -benzamide and said at least one or equal to about 40° C . In some embodiments , the at least acidulant is about 2 , or about 1 .75 , or about 1 . 5 , or about one acidulant has a melting point of greater than or equal to 60 1 . 25 , or about 1, or about 0 .75 , or about 0 . 5 . In some about 50° C . In someembodiments , the at least one acidulant embodiments are provided pharmaceutical compositions , has a melting point of greater than or equal to about 75° C . comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl ] - 4 In some embodiments , the at least one acidulant has a ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) melting point of greater than or equal to about 100° C . In benzamide and at least one acidulant, wherein said at least some embodiments , the at least one acidulant has a melting 65 one acidulant is ( D ) tartaric acid , ( L ) tartaric acid , or a point of greater than or equal to about 150° C . In some mixture of ( D ) and ( L ) tartaric acid , and further wherein the embodiments , the at least one acidulant has a melting point molar ratio between said N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - in US 10 , 398 ,693 B2 25 26 dazol- 3 -yl ) -4 -( 4 -methyl - piperazin - 1- yl ) - 2 -( tetrahydro benzamide and betaine hydrochloride, wherein the molar pyran - 4 - ylamino ) -benzamide and said at least one acidulant ratio between said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 is about 1 .5 . yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com ylamino ) - benzamide and said betaine hydrochloride is about positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 5 2 . 5 . In some embodiments are provided pharmaceutical zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran compositions , comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - in 4 -ylamino ) -benzamide and at least one acidulant, wherein dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro the molar ratio between said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - pyran - 4 -ylamino ) -benzamide and betaine hydrochloride, indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro wherein the molar ratio between said N - 15 - ( 3 , 5 - difluoroben pyran -4 - ylamino )- benzamide and said at least one acidulant 10 zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra is from about 0 . 5 to about 5 , or from about 0 . 5 to about 4 . 5 , hydro - pyran - 4 - ylamino ) -benzamide and said betaine hydro or from about 0 . 5 to about 4 , or from about 0 .5 to about 3 . 5 , chloride is about 2 .75 . In some embodiments are provided or from about 0 . 5 to about 3 , or from about 0 . 5 to about 2 .75 , pharmaceutical compositions , comprising N -[ 5 -( 3 ,5 -difluo or from about 0 .5 to about 2 .5 , or from about 0 . 5 to about robenzyl) - 1H - indazol - 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 2 . 25 . 15 ( tetrahydro -pyran - 4 -ylamino ) -benzamide and betaine In some embodiments are provided pharmaceutical com - hydrochloride , wherein the molar ratio between said N -[ 5 positions, comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda - (3 ,5 - difluorobenzyl ) - 1H - indazol- 3 -yl )- 4 -( 4 -methyl -piper zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - azin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide and 4 - ylamino ) -benzamide and betaine hydrochloride , wherein said betaine hydrochloride is about 3 . In some embodiments the molar ratio between said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - 20 are provided pharmaceutical compositions , comprising indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl pyran - 4 - ylamino )- benzamide and said betaine hydrochlo - piperazin - 1 - yl ) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide ride is from about 0 . 5 to about 5 , or from about 0 . 5 to about and betaine hydrochloride , wherein themolar ratio between 4 . 5 , or from about 0 . 5 to about 4 , or from about 0 . 5 to about said N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - indazol- 3 -yl ) - 4 - ( 4 3 . 5 , or from about 0 . 5 to about 3 , or from about 0 . 5 to about 25 methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) 2 .75 , or from about 0 . 5 to about 2 . 5 , or from about 0 . 5 to benzamide and said betaine hydrochloride is about 3 . 5 . In about 2 . 25 . some embodiments are provided pharmaceutical composi In some embodiments are provided pharmaceutical com tions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 positions , comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 zol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran - 30 ylamino ) - benzamide and betaine hydrochloride, wherein the 4 - ylamino ) - benzamide and betaine hydrochloride , wherein molar ratio between said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in the molar ratio between said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) -benzamide and said betaine hydrochlo pyran - 4 -ylamino )- benzamide and said betaine hydrochlo - ride is about 4 . In some embodiments are provided ride is about 0 .5 . In some embodiments are provided 35 pharmaceutical compositions, comprising N -[ 5 -( 3 ,5 -difluo pharmaceutical compositions, comprising N - [ 5 - ( 3 , 5 - difluo - robenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino )- benzamide and betaine ( tetrahydro - pyran - 4 - ylamino ) -benzamide and betaine hydrochloride , wherein the molar ratio between said N - [ 5 hydrochloride , wherein the molar ratio between said N - [ 5 - ( 3 ,5 - difluorobenzyl ) - 1H - indazol- 3 -yl )- 4 -( 4 -methyl - piper ( 3, 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piper - 40 azin - 1- yl) -2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide and azin - 1 - yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide and said betaine hydrochloride is about 4 . 5 . In some embodi said betaine hydrochloride is about 1 . In some embodiments ments are provided pharmaceutical compositions, compris are provided pharmaceutical compositions , comprising ing N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide 45 benzamide and betaine hydrochloride, wherein the molar and betaine hydrochloride , wherein the molar ratio between ratio between said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 said N -15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol -3 - y11- 4 - ( 4 - y11 - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) ylamino ) - benzamide and said betaine hydrochloride is about benzamide and said betaine hydrochloride is about 1 . 5 . In some embodiments are provided pharmaceutical composi - 50 In some embodiments are provided pharmaceutical com tions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - inda yl] - 4 - (4 -methyl - piperazin - 1- yl) -2 -( tetrahydro -pyran - 4 zol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran ylamino ) -benzamide and betaine hydrochloride , wherein the 4 - ylamino ) - benzamide and at least one acidulant. In some molar ratio between said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in embodiments , the formulations comprise from about 10 mg dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 55 to about 1000 mg, or from about 25 mg to about 1000 mg, pyran - 4 - ylamino ) -benzamide and said betaine hydrochlo - or from about 50 mg to about 1000 mg, or from about 100 ride is about 2 . In some embodiments are provided mg to about 1000 mg, or from about 100 mg to about 800 pharmaceutical compositions, comprising N - [ 5 - ( 3 , 5 -difluo mg, or from about 100 mg to about 750 mg, or from about robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - 100 mg to about 500 mg, or from about 100 mg to about 300 (tetrahydro - pyran - 4 - ylamino ) -benzamide and betaine 60 mg, or from about 100 mg to about 250 mg, or from about hydrochloride , wherein the molar ratio between said N - [ 5 - 100 mg to about 200 mg, or from about 100 mg to 150 mg ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl) - 4 - ( 4 -methyl - piper - of said N - 15 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 -yl ] -4 - ( 4 azin - 1 - yl ) - 2 - (tetrahydro -pyran - 4 - ylamino )- benzamide and methyl- piperazin - 1 -yl ) - 2 -( tetrahydro -pyran -4 - ylamino ) said betaine hydrochloride is about 2 .25 . In some embodi benzamide . In some embodiments , the compositions com ments are provided pharmaceutical compositions, compris - 65 prise about 25 mg, or about 50 mg , or about 75 mg , or about ing N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, methyl- piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) or about 200 mg, or about 225 mg, or about 250 mg, or about US 10 , 398 ,693 B2 27 28 275 mg , or about 300 mg , or about 325 mg , or about 350 mg , form of a tablet. In some embodiments , the tablet is a or about 375 mg , or about 400 mg, or about 475 mg, or about multi -layer tablet . In some embodiments , the tablet is a 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, multi -layer tablet wherein one or more layers comprising or about600 mg, or about 625 mg, or about 650 mg, or aboutN - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl 700 mg , or about 750 mg, or about 800 mg, or about 850 mg, 5 piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide or about 900 mg, or about 950 mg, or about 1000 mg of said are separate from one or more layers comprising the at least N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl one acidulant. In some embodiments , the tablet is a bi- layer piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide . tablet wherein a layer comprising N - [ 5 - ( 3 , 5 -difluoroben In some embodiments , the compositions comprise about 25 zyl) - 1H - indazol- 3 -yl ) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra mg, or about 50 mg, or about 75 mg, or about 100 mg, or 10 hydro -pyran -4 -ylamino )- benzamide is separate from a layer about 125 mg, or about 150 mg, or about 175 mg, or about comprising the at least one acidulant. In some embodiments 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, any of the multi - layer tablets described herein further com or about 300 mg of said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - prise at least one pharmaceutically acceptable excipient. indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro In some embodiments , the pharmaceutical compositions pyran - 4 - ylamino )- benzamide . In some embodiments , the 15 are in the form of a tablet, wherein said tablet comprises compositions comprise about 25 mg, or about 50 mg, or N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 - methyl about 75 mg, or about 100 mg, or about 125 mg, or about piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide 150 mg, or about 175 mg, or about 200 mg of said N -[ 5 and at least one acidulant. In some embodiments , the phar ( 3 , 5 - difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piper maceutical compositions are in the form of a tablet , wherein azin - 1 - yl) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide . In 20 said tablet comprises an admixture of N - [ 5 - ( 3 , 5 - difluo some embodiments , the compositions comprise about 100 robenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 mg, or about 125 mg, or about 150 mg, or about 175 mg, or ( tetrahydro -pyran -4 -ylamino ) -benzamide and at least one about 200 mg, or about 225 mg, or about 250 mg, or about acidulant. In some embodiments any of the tablets described 275 mg, or about 300 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - herein further comprise at least one pharmaceutically 1H - indazol- 3 - yl] -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetra - 25 acceptable excipient. hydro - pyran - 4 - ylamino ) -benzamide . In some embodiments , In some embodiments , the pharmaceutical compositions the compositions comprise about 150 mg, or about 175 mg, are in the form of a tablet, wherein said tablet comprises or about 200 mg, or about 225 mg, or about 250 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl N - 15 -( 3 , 5 -difluorobenzyl ) -1H - indazol- 3 -yl ] - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro - pyran - 4 -ylamino )- benzamide , piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide . 30 at least one acidulant, and at least one filler. In another In some embodiments , the compositions comprise about 100 embodiment, the tablets further comprise at least one dis mg of said N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - integrant. In another embodiment, the tablets further com ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) . prise at least one glidant. In another embodiment, the tablets benzamide . In some embodiments , the compositions com further comprise at least one lubricant. In another embodi prise about 150 mg of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - 35 ment, the tablets further comprise at least one pore - forming indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro agent. In another embodiment, the tablets further comprise pyran - 4 - ylamino )- benzamide . In some embodiments , the at least one binder. In another embodiment, the tablets compositions comprise about 200 mg of said N - [ 5 - ( 3 , 5 - further comprise at least one gel- forming agent. difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - In some embodiments , the pharmaceutical compositions yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide . In some 40 are in the form of a tablet, wherein said tablet comprises embodiments , the compositions comprise about 250 mg of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ) - 4 - ( 4 - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide , methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) and at least one acidulant. In some embodiments , the at least benzamide. In some embodiments , the compositions com one acidulant is selected from acetic acid , benzoic acid , prise about 300 mg of said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - 45 betaine hydrochloride , citric acid , fumaric acid , glucoronic indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro acid , lactic acid , (D ) or ( L ) malic acid or a mixture thereof, pyran - 4 - ylamino ) -benzamide . In some embodiments , the maleic acid , mandelic acid , malonic acid , salicylic acid , compositions comprise about 350 mg of said N - [ 5 - ( 3 , 5 stearic acid , succinic acid , p - toluenesulfonic acid , and ( D ) or difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - ( L ) tartaric acid or a mixture thereof. In some embodiments , yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide . In some 50 the at least one acidulant is selected from benzoic acid , embodiments , the compositions comprise about 400 mg of betaine hydrochloride , citric acid , fumaric acid , (D ) or ( L ) said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - yl ] - 4 - ( 4 - maleic acid or a mixture thereof, and ( D ) or ( L ) tartaric acid methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) or a mixture thereof. In some embodiments , the at least one benzamide. In some embodiments , the compositions com acidulant is selected from betaine hydrochloride, citric acid , prise about 450 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - 55 fumaric acid , maleic acid , and ( D ) or ( L ) tartaric acid or a indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - mixture thereof. In some embodiments , the at least one pyran - 4 - ylamino ) -benzamide . In some embodiments , the acidulant is betaine hydrochloride . In some embodiments , compositions comprise about 500 mg of said N - [ 5 - ( 3 , 5 - the at least one acidulant is citric acid . In some embodi difluorobenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - ments , the at least one acidulant is fumaric acid . In some yl) - 2 - ( tetrahydro -pyran -4 - ylamino ) -benzamide . 60 embodiments , the at least one acidulant is maleic acid . In The embodiments of the pharmaceutical compositions some embodiments , the at least one acidulant is ( D ) or ( L ) provided herein are in a form suitable for oral administra - tartaric acid or a mixture thereof . tion , such as a tablet, capsule, powder, granule , sustained In some embodiments, the pharmaceutical compositions release formulations , solution suspension , suspension or are in the form of a tablet, wherein said tablet comprises emulsion . In some embodiments , the pharmaceutical com - 65 N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ] - 4 -( 4 -methyl positions are in the form of a tablet or capsule . In some piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 - ylamino ) -benzamide , embodiments , the pharmaceutical compositions are in the at least one acidulant, and magnesium stearate . In some US 10 ,398 ,693 B2 29 30 embodiments the at least one acidulant is selected from In some embodiments , the pharmaceutical compositions acetic acid , benzoic acid , betaine hydrochloride , citric acid , are in the form of a capsule , wherein said capsule comprises fumaric acid , glucoronic acid , lactic acid , ( D ) or ( L ) malic N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl acid or a mixture thereof, maleic acid , mandelic acid , piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide , malonic acid , salicylic acid , stearic acid , succinic acid , 5 at least one acidulant , and at least one filler. In another p -toluenesulfonic acid , and ( D ) or ( L ) tartaric acid or a embodiment, the capsules further comprise at least one mixture thereof. In some embodiments , the at least one disintegrant. In another embodiment, the capsules further acidulant is selected from benzoic acid , betaine hydrochlo - comprise at least one glidant. In another embodiment, the ride , citric acid , fumaric acid , ( D ) or ( L ) maleic acid or a capsules further comprise at least one lubricant. mixture thereof, and ( D ) or ( L ) tartaric acid or a mixture 10 In some embodiments, the pharmaceutical compositions thereof. In some embodiments , the at least one acidulant is are in the form of a capsule , wherein said capsule comprises selected from betaine hydrochloride , citric acid , fumaric N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl acid , maleic acid , and ( D ) or ( L ) tartaric acid or a mixture piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide , thereof. In some embodiments , the at least one acidulant is and at least one acidulant. In some embodiments , the at least betaine hydrochloride . In some embodiments, the at least 15 one acidulant is selected from acetic acid , benzoic acid , one acidulant is citric acid . In some embodiments , the at betaine hydrochloride, citric acid , fumaric acid , glucoronic least one acidulant is fumaric acid . In some embodiments , acid , lactic acid , (D ) or ( L ) malic acid or a mixture thereof, the at least one acidulant is maleic acid . In some embodi - maleic acid , mandelic acid , malonic acid , salicylic acid , ments , the at least one acidulant is ( D ) or ( L ) tartaric acid or stearic acid , succinic acid , p - toluenesulfonic acid , and ( D ) or a mixture thereof. 20 ( L ) tartaric acid or a mixture thereof. In some embodiments , In some embodiments , the pharmaceutical compositions the at least one acidulant is selected from benzoic acid , are in the form of a capsule . In some embodiments , the betaine hydrochloride , citric acid , fumaric acid , ( D ) or ( L ) capsule is a multi - layer capsule . In some embodiments, the maleic acid or a mixture thereof, and ( D ) or ( L ) tartaric acid capsule is a multi - layer capsule wherein one or more layers or a mixture thereof. In some embodiments , the at least one comprising N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - 25 acidulant is selected from betaine hydrochloride, citric acid , ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - fumaric acid , maleic acid , and ( D ) or ( L ) tartaric acid or a benzamide are separate from one or more layers comprising mixture thereof. In some embodiments , the at least acidulant the at least one acidulant. In some embodiments , the capsule is betaine hydrochloride . In some embodiments , the at least is a bi -layer capsule wherein a layer comprising N - 15 - ( 3 , 5 - one acidulant is citric acid . In some embodiments , the at difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - 30 least one acidulant is fumaric acid . In some embodiments , yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide is separate the at least one acidulant is maleic acid . In some embodi from a layer comprising the at least one acidulant. In some ments , the at least one acidulant is ( D ) or ( L ) tartaric acid or embodiments any of the multi - layer capsules described a mixture thereof. herein further comprise at least one pharmaceutically In some embodiments , the pharmaceutical compositions acceptable excipient. 35 are in the form of a capsule , wherein said capsule comprises In some embodiments , the pharmaceutical compositions N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - indazol- 3 - yl) -4 - ( 4 -methyl are in the form of a capsule , wherein said capsule comprises , piperazin - 1- yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) -benzamide , consists of, or consists essentially of intragranular compo - at least one acidulant , and magnesium stearate . In some nents and extragranular components within the capsule . In embodiments the at least one acidulant is selected from some embodiments , the intragranular components comprise 40 acetic acid , benzoic acid , betaine hydrochloride, citric acid , N - 15 -( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl - fumaric acid , glucoronic acid , lactic acid , ( D ) or ( L ) malic piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide acid or a mixture thereof, maleic acid , mandelic acid , and at least one acidulant. In some embodiments , the intra - malonic acid , salicylic acid , stearic acid , succinic acid , granular components further comprise a filler, a binder , a p - toluenesulfonic acid , and ( D ) or ( L ) tartaric acid or a disintegrant, or a lubricant, or any combination of two or 45 mixture thereof . In some embodiments , the at least one more thereof. In some embodiments , the intragranular com - acidulant is selected from benzoic acid , betaine hydrochlo ponents further comprise lactose, hypromellose, crospovi ride , citric acid , fumaric acid , ( D ) or ( L ) maleic acid or a done , or magnesium stearate , or any combination of two or mixture thereof, and ( D ) or ( L ) tartaric acid or a mixture more thereof. In some embodiments , the extragranular com thereof. In some embodiments, the at least one acidulant is ponents comprise a filler, a disintegrant, a glidant, or a 50 selected from betaine hydrochloride , citric acid , fumaric lubricant, or any combination of two or more thereof. In acid , maleic acid , and ( D ) or ( L ) tartaric acid or a mixture some embodiments , the extragranular components comprise thereof. In some embodiments , at one least acidulant is microcrystalline cellulose , crospovidone , colloidal silicon betaine hydrochloride . In some embodiments , the at least dioxide, or magnesium stearate , or any combination of two one acidulant is citric acid . In some embodiments , the at or more thereof . 55 least one acidulant is fumaric acid . In some embodiments , In some embodiments , the pharmaceutical compositions the at least one acidulant is maleic acid . In some embodi are in the form of a capsule , wherein said capsule comprises ments , the at least one acidulant is ( D ) or ( L ) tartaric acid or N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- a mixture thereof . piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benzamide In some embodiments are provided pharmaceutical com and at least one acidulant . In some embodiments , the phar - 60 positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H -inda maceutical compositions are in the form of a capsule , zol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran wherein said capsule comprises an admixture of N - [ 5 - ( 3 , 5 - 4 -ylamino ) - benzamide in an amount of about 10 mg to about difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - 2000 mg, or from about 10 mg to about 1500 mg, or from yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) - benzamide and at least about 10 mg to about 1000 mg, or from about 10 mg to about one acidulant. In some embodiments any of the capsules 65 750 mg, or from about 10 mg to about 500 mg, or from about described herein further comprise at least one pharmaceu - 25 mg to about 500 mg, or from about 50 to about 500 mg, tically acceptable excipient . or from about 100 mg to about 500 mg. Furthermore , the US 10 , 398 ,693 B2 31 32 pharmaceutical compositions provided herein may contain 1 , 1 .5 , 2 , 2 .5 , 3 , 3 . 5 , 4 , 4 .5 , or 5 % w /w , including increments N - [ 5 -( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ] - 4 -( 4 -methyl therein , and ranges between two of these values ( including piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide endpoints ) . In some embodiments , the colloidal silicon in an amount of about 50 mg, about 100 mg, about 150 mg, dioxide is present in the composition in an amount of about about 200 mg, about 250 mg, about 300 mg, about 350 mg, 5 0 . 1 % w / w to about 1 % w / w . In some embodiments , the about 400 mg, about 450 mg, or about 500 mg. In some colloidal silicon dioxide is present in the composition in an embodiments , the pharmaceutical compositions provided amount of about 0 . 1 % w /w to about 0 . 5 % w / w . herein contain N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - indazol -3 -yl ] - In some embodiments , the pharmaceutical composition 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -pyran -4 further comprises magnesium stearate . In some embodi ylamino ) -benzamide in an amount of about 100 mg to about 10 ments, the magnesium stearate is present in the composition 200 mg. In some embodiments, the pharmaceutical compo - in an amount of about 0 . 1 % w / w to about 5 % w / w . This sitions provided herein contain N - [ 5 - ( 3 , 5 - difluorobenzyl) includes about 0 . 10 , 0 . 15 , 0 .20 , 0 .25 , 0 . 3 , 0 . 35 , 0 . 4 , 0 .45 , 1H - indazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetratotra 0 .5 , 0 . 55 , 0 . 6 , 0 .65 , 0 . 7 , 0 .75 , 0 . 8 , 0 . 85 , 0 . 9 , 0 . 95 , 1 , 1 . 5 , 2 , hydro -pyran - 4 - ylamino ) -benzamide in an amount of about 2 . 5 , 3 , 3 . 5 , 4 , 4 . 5 , or 5 % w / w , including increments therein , 25 mg to about 800 mg. 15 and ranges between two of these values ( including end In some embodiments are provided pharmaceutical com - points ) . In some embodiments , the magnesium stearate is positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - present in the composition in an amount of about 0 . 5 % w / w zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - to about 2 % w / w . 4 - ylamino ) -benzamide in an amount from about 0 . 5 w / w % In some embodiments , the pharmaceutical composition to about 95 w / w % , or from about 1 w / w % to about 95 w / w 20 further comprises lactose , hypromellose , crospovidone , % , or from about 1 w / w % to about 75 w / w % , or from about microcrystalline cellulose , colloidal silicon dioxide , or mag 5 w / w % to about 75 w / w % , or from about 10 w / w % to nesium stearate , or any combination of two ormore thereof. about 75 w / w % , or from about 10 w / w % to about 50 w / w In some embodiments , the lactose is anhydrous lactose . % . In some embodiments are provided pharmaceutical com In some embodiments , the pharmaceutical composition 25 positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda further comprises lactose . In some embodiments , the lactose zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran is present in the composition in an amount of about 15 % 4 -ylamino ) - benzamide, tartaric acid , lactose , hypromellose w / w to about 35 % w / w . This includes about 15 , 16 , 17 , 18 , (hydroxypropyl methylcellulose ) , crospovidone, and mag 19 , 20 , 21, 22 , 23 , 24 , 25 , 26 , 27, 28 , 29 , 30 , 31 , 32 , 33, 34 , nesium stearate . In some embodiments , the compositions and 35 % w / v , including increments therein , and ranges 30 comprise from about 10 mg to about 1000 mg of said between two of these values ( including endpoints ). In some N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl embodiments , the lactose is present in the composition in an piperazin - 1 -yl ) -2 -( tetrahydro -pyran -4 - ylamino ) -benzamide . amount of about 25 % w / w to about 30 % w / w . In some In some embodiments , the compositions comprise from embodiments , the lactose is anhydrous lactose . about 25 mg to about 1000 mg of said N - [ 5 - ( 3 , 5 - difluo In some embodiments , the pharmaceutical composition 35 robenzyl )- 1H -indazol - 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 further comprises hypromellose (hydroxypropyl methylcel ( tetrahydro -pyran -4 -ylamino )- benzamide . In some embodi lulose ). In some embodiments , the hypromellose is present ments , the compositions comprise from about 50 mg to in the composition in an amount of about 1 % w / w to about about 1000 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda 10 % w / w . This includes about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 % zol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran w /w , including increments therein , and ranges between two 40 4 -ylamino )- benzamide . In some embodiments , the compo of these values ( including endpoints ) . In some embodiments, sitions comprise from about 100 mg to about 1000 mg of the hypromellose is present in the composition in an amount said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 of about 3 % w / w to about 5 % w / w . methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) In some embodiments , the pharmaceutical composition benzamide . In some embodiments , the compositions com further comprises microcrystalline cellulose . In some 45 prise from about 100 mg to about 800 mg of said N -15 - ( 3 , embodiments , the microcrystalline cellulose is present in the 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin composition in an amount of about 1 % w / w to about 5 % 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) - benzamide . In some w / w . This includes about 1 , 1. 5 , 2 , 2 .5 , 3 , 3. 5 , 4, 4 .5 , or 5 % embodiments , the compositions comprise from about 100 w / w , including increments therein , and ranges between two mg to about 750 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H of these values ( including endpoints ) . In some embodiments , 50 indazol- 3 - yl )- 4 -( 4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro the microcrystalline cellulose is present in the composition pyran - 4 - ylamino ) -benzamide . In some embodiments , the in an amount of about 2 % w / w to about 4 % w / w . compositions comprise from about 100 mg to about 500 mg In some embodiments , the pharmaceutical composition of said N - [5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol - 3 -yl ) -4 - (4 further comprises crospovidone . In some embodiments , the methyl -piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) crospovidone is present in the composition in an amount of 55 benzamide . In some embodiments , the compositions com about 1 % w / w to about 10 % w / w . This includes about 1 , 1 . 5 , prise from about 100 mg to about 300 mg of said N - [ 5 - ( 3 , 2 , 2 .5 , 3, 3 .5 , 4 , 4 .5 , 5 , 5 .5 , 6 , 6 .5 , 7 , 7 .5 , 8 , 8 .5 , 9 , 9. 5 , or 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) -4 -( 4 -methyl -piperazin 10 % w / w , including increments therein , and ranges between 1 - yl) - 2 - tetrahydro - pyran - 4 - ylamino ) -benzamide . In some two of these values ( including endpoints ). In some embodi- embodiments , the compositions comprise from about 100 ments , the crospovidone is present in the composition in an 60 mg to about 250 mg of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H amount of about 4 % w / w to about 7 % w / w . indazol- 3 - yl ] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro In some embodiments , the pharmaceutical composition pyran - 4 - ylamino ) - benzamide. In some embodiments, the further comprises colloidal silicon dioxide. In some embodi compositions comprise from about 100 mg to about 200 mg ments , the colloidal silicon dioxide is present in the com - of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 position in an amount of about 0 . 5 % w /w to about 5 % w /w . 65 methyl- piperazin - 1 -yl ) -2 - ( tetrahydro -pyran -4 - ylamino ) This includes about 0 .05 , 0 . 10 , 0 . 15 , 0 . 20 , 0 .25 , 0 . 3 , 0 . 35 , benzamide . In certain embodiments , the compositions com 0 .4 , 0 .45 , 0 .5 , 0 . 55 , 0 . 6 , 0 .65 , 0 .7 , 0 .75 , 0 .8 , 0 .85 , 0 . 9 , 0 .95 , prise about 25 mg, or about 50 mg , or about 75 mg , or about US 10 , 398 ,693 B2 33 34 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 or about 200 mg , or about 225 mg, or about 250 mg, or about ylamino ) -benzamide . In some embodiments , the composi 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, tions comprise from about 100 mg to about 200 mg of said or about 375 mg, or about 400 mg, or about 475 mg, or about N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl 500 mg , or about 525 mg , or about 550 mg , or about 575 mg, 5 piperazin - 1 - yl) - 2 - (tetrahydro - pyran - 4 - ylamino ) -benzamide . or about 600 mg, or about 625 mg, or about650 mg, or about In certain embodiments, the compositions comprise about 700 mg, or about 750 mg, or about 800 mg , or about 850 mg, 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 900 mg, or about 950 mg, or about 1000 mg of said N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl or about 125 mg, or about 150 mg, or about 175 mg, or about piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide . 10 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, In some embodiments , the compositions comprise about 10 or about 300 mg, or about 325 mg, or about 350 mg, or about mg to about 100 mg of tartaric acid . This includes about 10 375 mg , or about 400 mg , or about 475 mg , or about 500 mg , mg to about 90 mg, about 10 mg to about 80 mg, about 10 or about 525 mg, or about 550 mg, or about 575 mg, or about mg to about 70 mg, about 10 mg to about 60 mg, about 20 600 mg, or about 625 mg, or about 650 mg, or about 700 mg, mg to about 100 mg, about 20 mg to aboutout 90 mgmo , aboutabout 20 1515 or aboutab 750 mg, or about 800 mg, or about 850 mg, or about mg to about 80 mg, about 20 mg to about 70 mg, about 20 900 mg, or about 950 mg, or about 1000 mg of said mg to about 60 mg, about 30 mg to about 100 mg, about 30 N - [ 5 -( 3, 5 - difluorobenzyl )- 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl mg to about 90 mg, about 30 mg to about 80 mg, about 30 piperazin - 1- yl) -2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide . mg to about 70 mg, and about 30 mg to about 60 mg. In In some embodiments , the compositions comprise about 10 some embodiments , tartaric acid is present in the composi- 20 mg to about 100 mg of tartaric acid . This includes about 10 tions in an amount of 10 , 11, 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , mg to about 90 mg, about 10 mg to about 80 mg, about 10 20 , 21, 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , mg to about 70 mg, about 10 mg to about 60 mg, about 20 36 , 37 , 38 , 39 , 40 , 41, 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , mg to about 100 mg, about 20 mg to about 90 mg, about 20 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61, 62 , 63 , 64 , 65 , 66 , 67 , mg to about 80 mg , about 20 mg to about 70 mg, about 20 68 , 69, 70 , 71 , 72 , 73, 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81, 82 , 83 , 25 mg to about 60 mg, about 30 mg to about 100 mg, about 30 84 , 85 , 86 , 87 , 88, 89 , 90 , 91, 92, 93, 94 , 95 , 96 , 97 , 98 , 99 , mg to about 90 mg, about 30 mg to about 80 mg, about 30 or 100 mg , including increments therein , or ranges between mg to about 70 mg, and about 30 mg to about 60 mg. In two of these values ( including endpoints ) . some embodiments , tartaric acid is present in the composi In some embodiments are provided pharmaceutical com tions in an amount of 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , positions , comprising, consisting of, or consisting essen - 30 20 , 21, 22 , 23, 24 , 25 , 26 , 27 , 28, 29, 30 , 31, 32, 33, 34 , 35 , tially of N -[ 5 - ( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - (4 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43, 44, 45 , 46 , 47 , 48, 49, 50 , 51, methyl -piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) . 52, 53, 54 , 55 , 56 , 57 , 58, 59 , 60 , 61, 62 , 63 , 64 , 65 , 66 , 67, benzamide , tartaric acid , lactose, hypromellose 68 , 69 , 70 , 71, 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , (hydroxypropyl methylcellulose ) , microcrystalline cellu - 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99, lose , crospovidone , colloidal silicon dioxide, and magne - 35 or 100 mg, including increments therein , or ranges between sium stearate . In some embodiments , the compositions com two of these values ( including endpoints ) . prise from about 10 mg to about 1000 mg of said N - [ 5 - ( 3 , In some embodiments are provided pharmaceutical com 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - positions, comprising, consisting essentially of, or consist 1 -yl ) -2 - ( tetrahydro -pyran - 4 - ylamino )- benzamide . In some ing of about 20 % w /w to about 60 % w / w N - 15 - ( 3 , 5 -difluo embodiments , the compositions comprise from about 25 mg 40 robenzyl) - 1H - indazol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 to about 1000 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - ( tetrahydro - pyran - 4 - ylamino ) - benzamide , about 5 % w / w to indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - about 20 % w / w tartaric acid , about 15 % w / w to about 35 % pyran -4 - ylamino )- benzamide . In some embodiments , the w /w lactose , about 1 % w /w to about 10 % w /w hypromel compositions comprise from about 50 mg to about 1000 mg lose , about 1 % w / w to about 5 % w / w microcrystalline of said N -15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - 45 cellulose , about 1 % w / w to about 10 % w / w crospovidone , methyl- piperazin - 1 -yl ) -2 - ( tetrahydro -pyran -4 -ylamino ) about 0 .05 % w / w to about 5 % w / w colloidal silicon dioxide, benzamide . In some embodiments , the compositions com - and about 0 . 1 % w / w to about 5 % w / w magnesium stearate . prise from about 100 mg to about 1000 mg of said N - [ 5 In some embodiments are provided pharmaceutical compo ( 3 ,5 -difluorobenzyl ) -1H - indazol- 3 -yl ] -4 -( 4 -methyl sitions , comprising , consisting essentially of, or consisting piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide . 50 of about 40 % w / w to about 50 % w / w N - [5 -( 3 , 5 - difluoroben In some embodiments , the compositions comprise from zyl) - 1H - indazol- 3 - yl )- 4 - (4 -methyl -piperazin - 1 - yl ) -2 -( tetra about 100 mg to about 800 mg of said N - [5 - ( 3 ,5 - difluo - hydro -pyran - 4 -ylamino ) -benzamide , about 10 % w / w to robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 about 15 % w /w tartaric acid , about 25 % w / w to about 30 % ( tetrahydro -pyran - 4 -ylamino ) -benzamide . In some embodi w / w lactose , about 3 % w / w to about 5 % w / w hypromellose , ments , the compositions comprise from about 100 mg to 55 about 2 % w / w to about 4 % w / w microcrystalline cellulose , about 750 mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - about 4 % w / w to about 7 % w / w crospovidone , about 0 . 1 % 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - w / w to about 1 % w / w colloidal silicon dioxide, and about ylamino ) -benzamide . In some embodiments , the composi 0 . 5 % w / w to about 2 % w / w magnesium stearate . tions comprise from about 100 mg to about 500 mg of said In some embodiments , a pharmaceutical compositions N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - 60 comprises, consists essentially of, or consists of N - [ 5 - ( 3 , 5 piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide . difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 In some embodiments , the compositions comprise from yl ) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide , tartaric about 100 mg to about 300 mg of said N - [ 5 - ( 3 , 5 - difluo acid , anhydrous lactose , hypromellose, microcrystalline cel robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - lulose , crospovidone , colloidal silicon dioxide , and magne ( tetrahydro - pyran - 4 - ylamino ) - benzamide. In some embodi - 65 sium stearate , wherein the composition is prepared in a ments , the compositions comprise from about 100 mg to method comprising , consisting essentially of, or consisting about 250 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - of: US 10 , 398 ,693 B2 35 36 adding N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - piperazin - 1 - yl) - 2 -( tetrahydro - pyran - 4 - ylamino )- benzamide . methyl -piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 4 In certain embodiments , the compositions comprise about ylamino )- benzamide ; anhydrous lactose ; hypromel- 25 mg, or about 50 mg , or about 75 mg, or about 100 mg, lose ; an intragranular portion of crospovidone ; and or about 125 mg, or about 150 mg, or about 175 mg, or about tartaric acid together and blending to form a first 5 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, admixture ; or about 300 mg, or about 325 mg, or about 350 mg, or about sieving the first admixture to form a sieved first admix 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, ture ; 0or about 525 mg, or about 550 mg, or about 575 mg, or about blending the sieved first admixture to form a second 600 mg, or about625 mg, or about 650 mg, or about 700 mg, admixture ; 10 or about 750 mg, or about 800 mg, or about 850 mg, or about sieving the second admixture to form a sieved second 900 mg, or about 950 mg, or about 1000 mg of said admixture ; N - [ 5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl blending the sieved second admixture to form a third piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide. admixture ; In some embodiments are provided pharmaceutical com adding an intragranular portion of magnesium stearate to 15 positions, comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda the third admixture and blending to form a fourth zol - 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran admixture ; 4 - ylamino ) -benzamide , betaine hydrochloride , isomalt , pre compacting and milling the fourth admixture to form a gelatinized starch , colloidal silicon dioxide , and magnesium fifth admixture ; stearate . In some embodiments , the compositions comprise adding microcrystalline cellulose , an extragranular por - 20 from about 10 mg to about 1000 mg of said N - 15 - ( 3 , 5 tion of crospovidone, and colloidal silicon dioxide to difluorobenzyl) - 1H -indazol - 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 the fifth admixture and blending to form a sixth admix - yl ) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide . In some ture ; and embodiments , the compositions comprise from about 25 mg adding an extragranular portion of magnesium stearate to to about 1000 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H the sixth admixture and blending to form the pharma - 25 indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ceutical composition . pyran - 4 - ylamino ) -benzamide . In some embodiments , the In some embodiments are provided pharmaceutical com - compositions comprise from about 50 mg to about 1000 mg positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda of said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - indazol- 3 -yl ] - 4 -( 4 zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) 4 - ylamino ) - benzamide , fumaric acid , mannitol, pre - 30 benzamide . In some embodiments , the compositions com gelatinized starch , colloidal silicon dioxide , and magnesium prise from about 100 mg to about 1000 mg of said N - [ 5 stearate . In some embodiments , the compositions comprise ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl from about 10 mg to about 1000 mg of said N -[ 5 - (3 , 5 - piperazin -1 - yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) -benzamide . difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl -piperazin - 1 In some embodiments , the compositions comprise from yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benzamide . In some 35 about 100 mg to about 800 mg of said N -[ 5 -( 3 ,5 -difluo embodiments , the compositions comprise from about 25 mg robenzyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 to about 1000 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - ( tetrahydro - pyran - 4 - ylamino ) - benzamide. In some embodi indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - ments, the compositions comprise from about 100 mg to pyran - 4 -ylamino ) -benzamide . In some embodiments , the about 750 mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol compositions comprise from about 50 mg to about 1000 mg 40 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - ylamino ) -benzamide . In some embodiments , the composi methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) tions comprise from about 100 mg to about 500 mg of said benzamide. In some embodiments , the compositions com N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - (4 -methyl prise from about 100 mg to about 1000 mg of said N - [ 5 piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide . ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - 45 In some embodiments , the compositions comprise from piperazin - 1- yl) - 2 - ( tetrahydro -pyran - 4 - ylamino )- benzamide . about 100 mg to about 300 mg of said N - [ 5 - ( 3 , 5 -difluo In some embodiments , the compositions comprise from robenzyl) - 1H - indazol -3 - yl ]- 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 about 100 mg to about 800 mg of said N - [ 5 - ( 3 , 5 - difluo ( tetrahydro - pyran - 4 - ylamino ) -benzamide . In some embodi robenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ments, the compositions comprise from about 100 mg to ( tetrahydro -pyran - 4 -ylamino )- benzamide . In some embodi- 50 about 250 mg of said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - indazol ments , the compositions comprise from about 100 mg to 3 -yl ) -4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 about 750 mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - ylamino ) -benzamide . In some embodiments , the composi 3 -yl ) - 4 - ( 4 -methyl - piperazin -1 -yl ) - 2 - ( tetrahydro -pyran - 4 - tions comprise from about 100 mg to about 200 mg of said ylamino ) - benzamide . In some embodiments , the composi - N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl tions comprise from about 100 mg to about 500 mg of said 55 piperazin - 1 -yl ) -2 -( tetrahydro -pyran -4 - ylamino ) -benzamide . N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - In certain embodiments , the compositions comprise about piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide . 25 mg , or about 50 mg, or about 75 mg, or about 100 mg , In some embodiments , the compositions comprise from or about 125 mg, or about 150 mg, or about 175 mg, or about about 100 mg to about 300 mg of said N - 15 - ( 3 , 5 - difluo - 200 mg, or about 225 mg, or about 250 mg, or about 275 mg , robenzyl) - 1H -indazol - 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - 60 or about 300 mg, or about 325 mg, or about 350 mg, or about ( tetrahydro -pyran - 4 - ylamino ) -benzamide . In some embodi- 375 mg, or about 400 mg, or about 475 mg , or about 500 mg, ments, the compositions comprise from about 100 mg to or about 525 mg, or about 550 mg, or about 575 mg, or about about 250 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 600 mg, or about 625 mg, or about 650 mg, or about 700 mg, 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 or about 750 mg, or about 800 mg, or about 850 mg, or about ylamino ) - benzamide . In some embodiments, the composi - 65 900 mg, or about 950 mg, or about 1000 mg of said tions comprise from about 100 mg to about 200 mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl piperazin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide . US 10 , 398 ,693 B2 37 38 In some embodiments are provided pharmaceutical com 70 % or at least about 75 % of said N - [5 - ( 3, 5 -difluorobenzyl ) positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran hydro - pyran - 4 - ylamino ) -benzamide has been released from 4 -ylamino ) -benzamide and at least one acidulant, wherein said tablet or capsule at about 45 minutes when tested in less than about 2 % of said N - 15 - (3 , 5 - difluorobenzyl) - 1H - 5 USP Apparatus Type I Basket Method at 50 rpm in 500 mL indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - of sodium acetate buffer at a pH of 4 . 5 and at about 37° C . pyran -4 - ylamino )- benzamide degrades in said pharmaceuti- In some embodiments , the pharmaceutical composition fur cal composition after said pharmaceutical composition is ther comprises at least one acidulant. stored for 3 months in an open container at 40° C . and 75 % In some embodiments are provided pharmaceutical com relative humidity . 10 positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda In some embodiments are provided pharmaceutical com - zol- 3 -yl ) -4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran positions, comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda - 4 - ylamino )- benzamide and at least one pharmaceutically zol- 3 - yl) - 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran acceptable excipient, wherein said pharmaceutical compo 4 - ylamino ) - benzamide and at least one acidulant, wherein sition is in the form of a tablet or capsule , and wherein said more than about 98 % of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - 15 tablet or capsule has a dissolution profile wherein at least indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro about 15 % , or at least about 20 % , or at least about 30 % , or pyran - 4 - ylamino ) -benzamide is present in said pharmaceu at least about 40 % , or at least about 50 % of said N - [ 5 - ( 3 , tical composition after said pharmaceutical composition is 5 -difluorobenzyl ) -1H - indazol- 3 -yl ) -4 -( 4 -methyl -piperazin stored for 3 months in an open container at 40° C . and 75 % 1 -yl ) - 2 - (tetrahydro -pyran -4 -ylamino )- benzamide has been relative humidity . 20 released from said tablet or capsule at about 30 minutes In some embodiments are provided pharmaceutical com when tested in USP Apparatus Type I Basket Method at 50 positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - rpm in 500 mL of sodium acetate buffer at a pH of 4 . 5 and zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran at about 37° C . In some embodiments , the pharmaceutical 4 - ylamino ) -benzamide and at least one acidulant, wherein composition further comprises at least one acidulant. less than about 2 % of said N - 15 - (3 , 5 - difluorobenzyl) - 1H - 25 In some embodiments are provided pharmaceutical com indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda pyran - 4 - ylamino ) -benzamide degrades in said pharmaceuti zol- 3 -yl ) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran cal composition after said pharmaceutical composition is 4 - ylamino ) -benzamide and at least one pharmaceutically stored for 3 months in an open container at 60° C . and 75 % acceptable excipient, wherein said pharmaceutical compo relative humidity . 30 sition is in the form of a tablet or capsule , and wherein said In some embodiments are provided pharmaceutical com - tablet or capsule has a dissolution profile wherein at least positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - about 10 % , or at least about 15 % , or at least about 20 % of zol- 3 - yl )- 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl )- 4 - ( 4 4 -ylamino ) -benzamide and at least one acidulant, wherein methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) more than about 98 % of said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - 35 benzamide has been released from said tablet or capsule at indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro about 15 minutes when tested in USP Apparatus Type I pyran - 4 - ylamino )- benzamide is present in said pharmaceu - Basket Method at 50 rpm in 500 mL of sodium acetate buffer tical composition after said pharmaceutical composition is at a pH of 4 . 5 and at about 37° C . In some embodiments , the stored for 3 months in an open container at 60° C . and 75 % pharmaceutical composition further comprises at least one relative humidity . 40 acidulant . In some embodiments are provided pharmaceutical com - In some embodiments are provided pharmaceutical com positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda zol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran zol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran 4 -ylamino ) -benzamide and at least one pharmaceutically 4 -ylamino ) - benzamide , at least one acidulant, and mannitol acceptable excipient , wherein said pharmaceutical compo - 45 or isomalt . In some embodiments are provided pharmaceu sition is in the form of a tablet or capsule, and wherein said tical compositions comprising mannitol. In some embodi tablet or capsule has a dissolution profile wherein at least ments are provided pharmaceutical compositions compris about 30 % , or at least about 40 % , or at least about 50 % , or ing isomalt . at least about 60 % , or at least about 70 % , or at least about In some embodiments are provided pharmaceutical com 75 % , or at least about 80 % , or at least about 85 % , or at least 50 positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - inda about 90 % of said N - 15 -( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro - pyran yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 4 - ylamino ) -benzamide , at least one acidulant, mannitol or ylamino ) - benzamide has been released from said tablet or isomalt , and starch . In some embodiments the weight to capsule at about 60 minutes when tested in USP Apparatus weight ratio of said mannitol or isomalt to said starch in said Type I Basket Method at 50 rpm in 500 mL of sodium 55 pharmaceutical composition is from about 1 to 1 to about 10 acetate buffer at a pH of 4 . 5 and at about 37° C . In some to 1 , or from about 1 to 1 to about 7 to 1 , or from about 1 embodiments , the pharmaceutical composition further com - to 1 to about 6 to 1, or from about 1 to 1 to about 5 to 1 , or prises at least one acidulant . from about 1 . 5 to 1 to about 3 to 1 , or from about 1 . 75 to 1 In some embodiments are provided pharmaceutical com - to about 3 to 1 , or from about 1 to 1 to about 2 . 5 to 1 , or from positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 60 about 1 to 1 to about 2 to 1 . zol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - In some embodiments are provided pharmaceutical com 4 - ylamino ) - benzamide and at least one pharmaceutically positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda acceptable excipient, wherein said pharmaceutical compo - zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran sition is in the form of a tablet or capsule, and wherein said 4 -ylamino ) -benzamide , at least one acidulant, mannitol or tablet or capsule has a dissolution profile wherein at least 65 isomalt , and starch . In some embodiments the weight to about 20 % , or at least about 30 % , or at least about 40 % , or weight ratio of said mannitol or isomalt to said starch in said at least about 50 % , or at least about 60 % , or at least about pharmaceutical composition is about 10 to 1 , or about 7 to US 10 , 398 ,693 B2 39 40 1 , or about 6 to 1 , or about 5 to 1 , or about 4 to 1 , or about subject in a fasted state at a total dose of about 800 mg of 3 to 1 , or about 2 to 1 , or about 1 . 8 to 1 , or about 1 . 5 to 1 , said N -15 -( 3 ,5 - difluorobenzyl) - 1H - indazol - 3 - yl] -4 - (4 or about 1 to 1 . methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) In some embodiments are provided pharmaceutical com benzamide provides a pharmacokinetic profile in said sub positions comprising N -15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 5 ject wherein the Cmax of said N -15 - ( 3 , 5 - difluorobenzyl) zol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 1H -indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 4 - ylamino ) -benzamide , at least one acidulant and at least (tetrahydro - pyran - 4 - ylamino ) -benzamide in the plasma of one pharmaceutically acceptable excipient . In some embodi - said subject is between about 2080 nM and about 2560 nM ments are provided pharmaceutical compositions wherein following said administration of said pharmaceutical com said at least one pharmaceutically acceptable excipient is 10 position to said subject. selected from diluents, lubricants , binding agents , disinte - In some embodiments are provided pharmaceutical com grating agents , effervescing mixtures , dyestuffs , sweeteners , positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda and wetting agents . zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran In some embodiments are provided pharmaceutical com - 4 - ylamino ) -benzamide and at least one acidulant, wherein positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 15 said pharmaceutical composition when administered to a zol- 3 - yl] -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran subject in a fasted state at a total dose of about 800 mg of 4 -ylamino )- benzamide and at least one acidulant, wherein said N -15 - ( 3 ,5 -difluorobenzyl ) - 1H - indazol - 3 -yl ) -4 - (4 said pharmaceutical composition when administered to a methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) subject in a fasted state provides a pharmacokinetic profile benzamide provides a pharmacokinetic profile in said sub in said subject wherein the Tmax of said N - [ 5 - ( 3 , 5 - difluo - 20 ject wherein the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 (tetrahydro -pyran - 4 - ylamino ) -benzamide in the plasma of (tetrahydro - pyran - 4 - ylamino ) -benzamide in the plasma of said subject is between about 2 hours and 6 hours following said subject is between 80 % to 125 % of 2080 nM , based on said administration of said pharmaceutical composition to a 90 percent confidence interval following said administra said subject. In some embodiments, the Tmax of said 25 tion of said pharmaceutical composition to said subject. N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- In some embodiments are provided pharmaceutical com piperazin -1 -yl ) - 2 -( tetrahydro - pyran - 4 -ylamino ) -benzamide positions, comprising N -[ 5 -( 3 , 5 -difluorobenzyl ) - 1H - inda in the plasma of said subject is about 5 hours following said zol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran administration of said pharmaceutical composition to said 4 -ylamino ) - benzamide and at least one acidulant, wherein subject. 30 said pharmaceutical composition when administered to a In some embodiments are provided pharmaceutical com - subject in a fed state at a total dose of about 800 mg of said positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl) - 4 - ( 4 -methyl zol- 3 - yl) - 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide 4 - ylamino ) - benzamide and at least one acidulant, wherein provides a pharmacokinetic profile in said subject wherein said pharmaceutical composition when administered to a 35 the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 subject in a fed state provides a pharmacokinetic profile in yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran - 4 said subject wherein the Tmax of said N -[ 5 - (3 ,5 -difluo ylamino )- benzamide in the plasma of said subject is between robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - 80 % to 125 % of 2560 nM , based on a 90 percent confidence ( tetrahydro -pyran - 4 - ylamino ) -benzamide in the plasma of interval following said administration of said pharmaceuti said subject is between about 5 hours and 12 hours following 40 cal composition to said subject . said administration of said pharmaceutical composition to In some embodiments are provided pharmaceutical com said subject. In some embodiments , the Tmax of said positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - zol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide 4 -ylamino )- benzamide and at least one acidulant, wherein in the plasma of said subject is about 8 hours following said 45 said pharmaceutical composition when administered to a administration of said pharmaceutical composition to said subject in a fasted state at a total dose of about 800 mg of subject. said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 In some embodiments are provided pharmaceutical com methyl -piperazin -1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl )- 1H - inda - benzamide provides a pharmacokinetic profile in said sub zol- 3 -yl ) -4 - (4 -methyl - piperazin -1 - yl) - 2 -( tetrahydro -pyran - 50 ject wherein the AUC ( to 24 ) of said N - [ 5 -( 3, 5 4 - ylamino ) -benzamide and at least one acidulant, wherein difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl - piperazin - 1 said pharmaceutical composition when administered to a yl ) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide in the subject in a fasted state at a total dose of about 800 mg of plasma of said subject is between about 28 , 900 nM * hr and said N -15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - y11- 4 - ( 4 - about 30 , 800 nM * hr following said administration of said methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - 55 pharmaceutical composition to said subject. benzamide provides a pharmacokinetic profile in said sub - In some embodiments are provided pharmaceutical com ject wherein the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran ( tetrahydro - pyran - 4 - ylamino ) -benzamide in the plasma of 4 - ylamino ) -benzamide and at least one acidulant, wherein said subject is between about 2080 nM and about 2110 nM 60 said pharmaceutical composition when administered to a following said administration of said pharmaceutical com - subject in a fed state at a total dose of about 800 mg of said position to said subject. N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl In some embodiments are provided pharmaceutical com piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino )- benzamide positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - provides a pharmacokinetic profile in said subject wherein zol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 65 the AUC (0 to 24 ) of said N - [5 -( 3 , 5 -difluorobenzyl ) - 1H 4 - ylamino ) -benzamide and at least one acidulant , wherein indazol- 3 - y1 ] - 4 - ( 4 -methyl -piperazin - 1 - yl ) - 2 - ( tetrahydro said pharmaceutical composition when administered to a pyran - 4 - ylamino ) -benzamide in the plasma of said subject is US 10 , 398 ,693 B2 41 about 40 ,400 nM * hr following said administration of said tion to said subject in a fasted state , and wherein said pharmaceutical composition to said subject. composition comprises a total dose of about 800 mg of said In some embodiments are provided pharmaceutical com N - [ 5 - ( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) -4 - (4 -methyl positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide . zol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 5 In some embodiments are provided pharmaceutical com 4 -ylamino )- benzamide and at least one acidulant, wherein positions, comprising (a ) N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in said pharmaceutical composition when administered to a dazol- 3 - yl] - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro subject in a fasted state at a total dose of about 800 mg of pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 -( 4 - an AUC ( 0 to 24 ) of said N - [5 -( 3 , 5 -difluorobenzyl ) - 1H methyl- piperazin -1 -yl ) - 2 - ( tetrahydro -pyran -4 -ylamino ) - 10 indazol- 3 -yl ] - 4 -( 4 -methyl -piperazin - 1- yl) - 2 -( tetrahydro benzamide provides a pharmacokinetic profile in said sub - pyran - 4 - ylamino ) -benzamide in the plasma of a subject of ject wherein the AUC ( 0 to 24 ) of said N - [ 5 - (3 , 5 - about 40 ,400 nM * hr following administration of said phar difluorobenzyl) - 1H - indazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 maceutical composition to said subject in a fed state , and yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide in the wherein said composition comprises a total dose of about plasma of said subject is within about 80 % to about 125 % 15 800 mg of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] of 30 , 800 nM * hr at a 90 % confidence interval following said 4 -( 4 -methyl - piperazin -1 -yl ) - 2 -( tetrahydro -pyran - 4 administration of said pharmaceutical composition to said ylamino ) -benzamide . subject. In some embodiments are provided pharmaceutical com In some embodiments are provided pharmaceutical com positions, comprising (a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in positions, comprising N -[ 5 - ( 3 ,5 -difluorobenzyl ) - 1H -inda - 20 dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro zol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering 4 - ylamino ) -benzamide and at least one acidulant, wherein a Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] said pharmaceutical composition when administered to a 4 -( 4 -methyl -piperazin - 1- yl) - 2 -( tetrahydro -pyran -4 subject in a fed state at a total dose of about 800 mg of said ylamino ) -benzamide in the plasma of a subject of between N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - 25 about 2 hours and about 6 hours following administration of piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide said pharmaceutical composition to said subject in a fasted provides a pharmacokinetic profile in said subject wherein state . the AUC (0 to 24 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - In some embodiments are provided pharmaceutical com indazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in pyran - 4 -ylamino ) - benzamide in the plasma of said subject is 30 dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro within about 80 % to about 125 % of 40 ,400 nM * hr at a 90 % pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering confidence interval following said administration of said a Tmax of said N - [ 5 - ( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - yl] pharmaceutical composition to said subject. 4 - ( 4 - methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 In some embodiments are provided pharmaceutical com - ylamino )- benzamide in the plasma of a subject of between positions, comprising (a ) N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - 35 about 5 hours and about 12 hours following administration dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1- yl) - 2 -( tetrahydro of said pharmaceutical composition to said subject in a fed pyran -4 - ylamino )- benzamide ; and ( b ) means for delivering state . a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ] - In some embodiments are provided pharmaceutical com 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 positions , comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in ylamino )- benzamide in the plasma of a subject of between 40 dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro about 2080 nM and about 2100 nM following administration pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering of said pharmaceutical composition to said subject in a a Cmax of said N - [5 - ( 3 , 5 -difluorobenzyl ) - 1H -indazol - 3 - yl] - fasted state , and wherein said composition comprises a total 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 dose of about 800 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H ylamino ) - benzamide in the plasma of a subject that is indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 45 between 80 % to 125 % of 2080 nM , based on a 90 percent pyran -4 -ylamino )- benzamide . confidence interval, following administration of said phar In some embodiments are provided pharmaceutical com maceutical composition to said subject in a fasted state , and positions , comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in wherein said composition comprises a total dose of about dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro 800 mg of said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - indazol- 3 - yl] pyran - 4 - ylamino )- benzamide ; and (b ) means for delivering 50 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 a Cmax of said N - [ 5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl] - ylamino ) - benzamide. 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 In some embodiments are provided pharmaceutical com ylamino ) -benzamide in the plasma of a subject of about positions, comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in 2560 nM following administration of said pharmaceutical dazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro composition to said subject in a fed state , and wherein said 55 pyran - 4 -ylamino ) -benzamide ; and (b ) means for delivering composition comprises a total dose of about 800 mg of said a Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl 4 - (4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide . ylamino ) - benzamide in the plasma of a subject that is In some embodiments are provided pharmaceutical com - between 80 % to 125 % of 2560 nM , based on a 90 percent positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - 60 confidence interval, following administration of said phar dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro maceutical composition to said subject in a fed state , and pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering wherein said composition comprises a total dose of about an AUC ( 0 to 24 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H 800 mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ] indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 pyran -4 - ylamino )- benzamide in the plasma of a subject of 65 ylamino ) -benzamide . between about 28 , 900 nM * hr and about 30 ,800 nM * hr I n some embodiments are provided pharmaceutical com following administration of said pharmaceutical composi - positions, comprising (a ) N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - in US 10 , 398 ,693 B2 43 44 dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro tion in ROS1 in a mammal. In some embodiments, the pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering medicament is for use in the treatment of abnormal cell an AUC (O to 24 ) of said N - [5 -( 3, 5 - difluorobenzyl) - 1H growth mediated by at least one molecular alteration in TrkA indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - in a mammal. In some embodiments , the medicament is for pyran - 4 - ylamino ) -benzamide in the plasma of a subject that 5 use in the treatment of abnormal cell growth mediated by at is between 80 % to 125 % of 30 , 800 nM * hr, based on a 90 least one molecular alteration in TrkB in a mammal. In some percent confidence interval, following administration of said embodiments , the medicament is for use in the treatment of pharmaceutical composition to said subject in a fasted state , abnormal cell growth mediated by at least one molecular and wherein said composition comprises a total dose of alteration in TrkC in a mammal. In some such embodiments , about 800 mg of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 10 the molecular alteration is the EML4 -ALK fusion protein . In 3 -yl ] -4 -( 4 -methyl - piperazin - 1 -yl ) -2 - (tetrahydro -pyran -4 some embodiments , the molecular alteration is the EML4 ylamino ) -benzamide . ALK fusion protein having at least one mutation . In some In some embodiments are provided pharmaceutical com embodiments , the mutation is L1196M . In some embodi positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in ments , the mutation is C1156Y. dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 15 In some embodiments are provided methods for the pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering treatment of abnormal cell growth in a mammal comprising an AUC (O to 24 ) of said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - administering to a mammal a therapeutically effective indazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro - amount of one or more pharmaceutical compositions pro pyran - 4 - ylamino ) -benzamide in the plasma of a subject that vided herein . In some embodiments , the abnormal cell is between 80 % to 125 % of 40 , 400 nM * hr, based on a 90 20 growth is mediated by at least one molecular alteration in percent confidence interval, following administration of said one or more of ALK , ROS1 , TrkA , TrkB and TrkC in a pharmaceutical composition to said subject in a fed state , mammal. In some embodiments , the abnormal cell growth is and wherein said composition comprises a total dose of mediated by at least one molecular alteration in ALK in a about 800 mg of said N - 15 - (3 , 5 - difluorobenzyl) - 1H -indazol - mammal. In some embodiments, the abnormal cell growth is 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - 25 mediated by at least one molecular alteration in ROS1 in a ylamino ) - benzamide . mammal. In some embodiments , the abnormal cell growth is In some embodiments are provided pharmaceutical com - mediated by at least one molecular alteration in TrkA in a positions , comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in mammal. In some embodiments , the abnormal cell growth is dazol- 3 - y11- 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro mediated by at least one molecular alteration in TrkB in a pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering 30 mammal. In some embodiments , the abnormal cell growth is said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 mediated by at least one molecular alteration in TrkC in a methyl- piperazin -1 -yl ) - 2 - ( tetrahydro -pyran -4 -ylamino ) mammal . In some such embodiments , the molecular altera benzamide to a subject that exhibits no food effect . tion is the EML4 -ALK fusion protein . In some embodi In some embodiments are provided pharmaceutical com ments, the molecular alteration is the EML4 - ALK fusion positions comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda - 35 protein having at least one mutation . In some embodiments , zol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - the mutation is L1196M . In some embodiments , the muta 4 - ylamino ) - benzamide , wherein said pharmaceutical tion is C1156Y . composition exhibits no food effect when administered to a In some embodiments are provided methods for the subject. treatment of abnormal cell growth in a mammal comprising It is understood by those having ordinary skill in the art 40 administering to a mammal an amount of one or more that references made to " pharmaceutical compositions pro - pharmaceutical compositions provided herein , in combina vided herein , " and the like , mean those pharmaceutical tion with an amount of an anti - tumor agent , which amounts compositions that are described as embodiments herein . By are together effective in treating said abnormal cell growth . way of example only , a method of treating a subject having In some embodiments , the anti- tumor agent is selected from cancer comprising administering to said subject a pharma- 45 the group consisting ofmitotic inhibitors , alkylating agents , ceutical composition as provided herein , means a method of anti -metabolites , intercalating antibiotics , growth factor treating a subject having cancer comprising administering to inhibitors , radiation , cell cycle inhibitors , enzymes , topoi said subject any of the compositions described herein that somerase inhibitors , biological response modifiers, antibod comprise N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - ies , cytotoxics , anti - hormones , and anti -androgens . methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - 50 In some embodiments are provided one or more pharma benzamide. ceutical compositions provided herein for use in the treat In some embodiments are provided pharmaceutical com - ment of abnormal cell growth in a mammal. In a further positions provided herein for use as a medicament. In some aspect, are disclosed the uses of one or more pharmaceutical embodiments , the medicament is for use in the treatment of compositions described herein for the treatment of abnormal abnormal cell growth in a mammal. In some embodiments , 55 cell growth in a mammal. the abnormal cell growth is cancer . In some embodiments , In yet another aspect, are disclosed uses of one or more the medicament is for use in the treatment of abnormal cell pharmaceutical compositions described herein for the prepa growth mediated by one or more of ALK , ROS1 , TrkA , ration of a medicament for the treatment of abnormal cell TrkB and TrkC in a mammal. In some embodiments , the growth . medicament is for use in the treatment of abnormal cell 60 In frequent embodiments of the methods and uses growth mediated by at least one molecular alteration in one described herein , the abnormal cell growth is cancer. In or more of ALK , ROS1, TrkA , TrkB and TrkC in a mammal . some embodiments , the cancer is selected from lung cancer, In some embodiments , the medicament is for use in the bone cancer , pancreatic cancer , skin cancer, cancer of the treatment of abnormal cell growth mediated by at least one head or neck , cutaneous or intraocular melanoma , uterine molecular alteration in ALK in a mammal. In some embodi- 65 cancer, ovarian cancer, rectal cancer, cancer of the anal ments , the medicament is for use in the treatment of abnor - region , stomach cancer, colon cancer, breast cancer , carci mal cell growth mediated by at least one molecular altera - noma of the fallopian tubes, carcinoma of the endometrium , US 10 , 398 ,693 B2 45 46 carcinoma of the cervix , carcinoma of the vagina , carcinoma In some embodiments are provided methods to treat of the vulva, Hodgkin ' s Disease , cancer of the esophagus , specific types of cancer comprising carcinoma, squamous cancer of the small intestine , cancer of the endocrine system , cell carcinoma, hematopoietic tumors of myeloid or lym cancer of the thyroid gland , cancer of the parathyroid gland , phoid lineage, tumors ofmesenchymal origin , tumors of the cancer of the adrenal gland , sarcoma of soft tissue , cancer of 5 central and peripheral nervous system , melanoma , semi the urethra, cancer of the penis , prostate cancer, chronic or noma, teratocarcinoma, osteosarcoma, xeroderma pigmen acute leukemia , lymphocytic lymphomas , cancer of the tosum , angiosarcoma, glioblastoma, holangiocarcinoma, bladder, cancer of the kidney or ureter, renal cell carcinoma , inflammatory myofibroblastic tumor, epitheloid heman carcinoma of the renal pelvis , neoplasms of the central gioendothelioma, astrocytoma, meningioma, angiosarcoma , nervous system ( CNS ), primary CNS lymphoma, spinal axis 10 epitheloid hemangiothelioma, keratocanthomas , thyroid fol tumors , brain stem glioma, pituitary adenoma, and combi- licular cancer, Kaposi ' s sarcoma, and pancreatic cancer. nations thereof. In some embodiments are provided methods to treat In some embodiments , the cancer is selected from the specific types of cancer such as , but not restricted to , breast group consisting of non - small cell lung cancer (NSCLC ), cancer, lung cancer, colorectal cancer, prostate cancer, ovar squamous cell carcinoma , hormone - refractory prostate can - 15 ian cancer, endometrial cancer , gastric cancer , clear cell cer, papillary renal cell carcinoma, colorectal adenocarci- renal cell carcinoma , invasive ductal carcinoma (breast ) , noma, neuroblastomas, anaplastic large cell lymphoma uveal melanoma, multiple myeloma, rhabdomyosarcoma, ( ALCL ) and gastric cancer. Ewing ' s sarcoma, Kaposi ' s sarcoma, pancreatic cancer , neu In some embodiments , the methods described herein roblastoma, and medulloblastoma. further comprise administering to themammal an amount of 20 In some embodiments are provided methods to treat an anti - cancer therapeutic agent or a palliative agent, which ALK + anaplastic large cell lymphomas ( ALCL ) and possi amounts are together effective in treating said abnormal cell bly other indications in which the ALK activity might play growth . In some such embodiments , one or more anti - cancera role , like neuroblastoma, rhabdomyosarcoma, glioblas therapeutic agent are selected from anti- tumor agents , anti - toma , inflammatory myofibroblastic tumor, and some kind angiogenesis agents , signal transduction inhibitors and anti- 25 of melanomas , breast carcinomas , Ewings sarcomas , retino proliferative agents , which amounts are together effective in blastomas and non -small cell lung carcinomas (NSCLC ). treating said abnormal cell growth . In some embodiments are provided methods to treat , In other embodiments , the uses described herein comprise reduce the symptoms of, ameliorate the symptoms of, delay the use of one or more pharmaceutical compositions pro the onset of, or otherwise pharmaceutically address pancre vided herein in combination with one or more substances 30 atic cancer and possibly other indications in which a defect selected from anti - tumor agents , anti - angiogenesis agents , in the modulation of ROS1 activity , or upregulation , mis signal transduction inhibitors and antiproliferative agents . regulation or deletion thereof might play a role by admin In some embodiments, the pharmaceutical compositions istering one or more pharmaceutical compositions provided described herein are adapted for use in combination with one herein . or more substances selected from anti - tumor agents , anti - 35 In some embodiments are provided methods to treat, angiogenesis agents , signal transduction inhibitors and anti - reduce the symptoms of, ameliorate the symptomsof , delay proliferative agents . the onset of, or otherwise pharmaceutically address pancre Each of the embodiments of the pharmaceutical compo - atic cancer and possibly other indications in which a defect sitions provided herein can be combined with one or more in the modulation of ALK , ROS1 , TrkA , TrkB , or TrkC other embodiments of the pharmaceutical compositions 40 activity , or a combination thereof , or upregulation , misregu described herein that is not inconsistent with the embodi- lation or deletion thereof might play a role by administering ment( s ) with which it is combined . one or more pharmaceutical compositions provided herein . In addition , each of the embodiments provided herein In some embodiments are provided methods to treat, envisions within its scope that the pharmaceutical compo - reduce the symptomsof , ameliorate the symptoms of, delay sitions described may comprise N - 15 - ( 3 ,5 - difluorobenzyl) - 45 the onset of, or otherwise pharmaceutically address pancre 1H - indazol -3 -yl ) -4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 -( tetra atic cancer and possibly other indications in which a defect hydro - 2H -pyran - 4 - ylamino ) -benzamide , or a in the modulation of ROS1 activity , or upregulation , mis pharmaceutically acceptable salt of N -[ 5 -( 3 ,5 -difluoroben - regulation or deletion thereof might play a role by admin zyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetra istering one ormore pharmaceutical compositions provided hydro - 2H -pyran - 4 -ylamino ) -benzamide . 50 herein . In some embodiments are provided methods for treating In some embodiments are provided methods to treat, diseases caused by and /or associated with deregulated pro - reduce the symptoms of, ameliorate the symptoms of, delay tein kinase activity, particularly PLK family , protein kinase the onset of, or otherwise pharmaceutically address pancre C in different isoforms, Met, PAK - 4 , PAK - 5 , ZC - 1 , STLK - 2 , atic cancer and possibly other indications in which a defect DDR - 2 , Aurora 1 , Aurora 2 , Bub - 1 , Chki , Chk2 , HER2, 55 in the modulation of ALK , ROS1 , TrkA , TrkB , or TrkC raf? , MEK1, MAPK , EGF- R , PDGF - R , FGF- R , FLT3, activity , or a combination thereof, or upregulation , misregu JAK2, IGF - R , ALK , PI3K , weel kinase , Src , Abl, Akt, lation or deletion thereofmight play a role by administering MAPK , ILK , MK - 2 , IKK - 2 , Cdc7 , Nek , Cdk /cyclin kinase one or more pharmaceutical compositions provided herein . family , more particularly Aurora 2 , IGF- 1R and ALK activ - In some embodiments , methods to treat, reduce the symp ity , and ROS1 activity , and further more particularly ALK 60 toms of, ameliorate the symptoms of, delay the onset of, or activity and / or ROS1 activity , which comprises administer - otherwise pharmaceutically address pancreatic cancer asso ing to a mammal in need thereof an effective amount of one ciated with a ROS1 down - regulation defect , for example a or more pharmaceutical compositions provided herein . null mutation such as a ROS1 deletion by identifying a In some embodiments are provided methods to treat a ROS1 down - regulation defect, for example a null mutation disease caused by and /or associated with dysregulated pro - 65 such as a ROS1 deletion in a cancer or precancerous tein kinase activity selected from the group consisting of pancreatic cell in an subject, and administering to the subject cancer and cell proliferative disorders . one or more pharmaceutical compositions provided herein . US 10 , 398 ,693 B2 47 48 In some embodiments are provided methods to treat , administering to the subject one or more of the pharmaceu reduce the symptoms of, ameliorate the symptoms of, delay tical compositions provided herein . the onset of, or otherwise pharmaceutically address pancre In some embodiments are provided methods to treat , atic cancer associated with a ALK , ROS1, TrkA , TrkB , or reduce the symptoms of, ameliorate the symptoms of, delay TrkC down - regulation defect, for example a null mutation 5 the onset of, or otherwise pharmaceutically address a con such as a ALK , ROS1 , TrkA , TrkB , or TrkC deletion by dition in a subject selected from non -small cell lung cancer, identifying a ALK , ROS1 , TrkA , TrkB , or TrkC down- papillary thyroid cancer, neuroblastoma, pancreatic cancer regulation defect, for example a null mutation such as a and colorectal cancer and possibly other indications in ALK , ROS1 , TrkA , TrkB , or TrkC deletion in a cancer or which a defect in the modulation of ROS1 , TrkA , TrkB , or precancerous pancreatic cell in an subject, and administering TrkC activity , or a combination thereof, activity , or upregu to the subject one or more pharmaceutical compositions lation , misregulation or deletion thereof might play a role by provided herein . administering to the subject one or more of the pharmaceu In some embodiments identifying a ROS1 modulation tical compositions provided herein . defect such as an upregulation defect or a down -regulation 16 In some embodiments are provided methods to treat , defect , for example a null mutation such as a ROS1 deletion reduce the symptoms of, ameliorate the symptoms of , delay or a ROS1 chimeric locus encoding a constitutively active the onset of, or otherwise pharmaceutically address a con ROS1 kinase in a cancer or precancerous pancreatic cell in dition in a subject selected from non -small cell lung cancer, an subject comprises assaying for ROS1 activity in a cell papillary thyroid cancer , neuroblastoma, pancreatic cancer extract from a pancreatic cancerous or precancerous cell 20 and colorectal cancer associated with a ROS1 down - regu population . lation defect, for example a null mutation such as a ROS1 In some embodiments are provided methods to treat, deletion by identifying a ROS1 down - regulation defect , for reduce the symptoms of, ameliorate the symptoms of, delay example a null mutation such as a ROS1 deletion in a cancer the onset of, or otherwise pharmaceutically address pancre - or precancerous cell in an subject, and administering to the atic cancer and possibly other indications in which a defect 25 subject one or more pharmaceutical compositions provided in the modulation of ALK , ROS1 , TrkA , TrkB , or TrkC herein . activity , or a combination thereof, or upregulation , misregu - In some embodiments are provided methods to treat, lation or deletion thereofmight play a role by administering reduce the symptoms of, ameliorate the symptoms of, delay one or more pharmaceutical compositions provided herein . the onset of , or otherwise pharmaceutically address a con In some embodiments are provided methods to treat, reduce 30 dition in a subject selected from non -small cell lung cancer , the symptoms of, ameliorate the symptoms of, delay the papillary thyroid cancer , neuroblastoma, pancreatic cancer onset of, or otherwise pharmaceutically address pancreatic and colorectal cancer associated with a ALK , ROS1 , TrkA , cancer and possibly other indications in which a defect in the TrkB , or TrkC down - regulation defect , for example a null modulation of ROS1 , TrkA , TrkB , or TrkC activity , or a mutation such as a ALK , ROS1 , TrkA , TrkB , or TrkC combination thereof, activity , or upregulation , misregulation 35 deletion by identifying a ALK , ROS1 , TrkA , TrkB , or TrkC or deletion thereofmight play a role by administering one or down - regulation defect , for example a null mutation such as more pharmaceutical compositions provided herein . a ALK , ROS1 , TrkA , TrkB , or TrkC deletion in a cancer or In some embodiments are provided methods to treat, precancerous cell in an subject, and administering to the reduce the symptoms of, ameliorate the symptoms of, delay subject one or more of the pharmaceutical compositions the onset of, or otherwise pharmaceutically address pancre - 40 provided herein . atic cancer in a subject, and possibly other indications in In some embodiments are provided methods to treat cell such subject in which a defect in the modulation of ROSI , proliferative disorders such as, but not restricted to , benign TrkA , TrkB , or TrkC activity, or a combination thereof, prostate hyperplasia , familial adenomatosis polyposis , activity, or upregulation , misregulation or deletion thereof neuro - fibromatosis , psoriasis , atherosclerosis and conditions might play a role by administering to the subject one or more 45 involving vascular smooth muscle proliferation or neointi of the pharmaceutical compositions provided herein . mal formation such as restenosis following angioplasty or In some embodiments are provided methods to treat, surgery , pulmonary fibrosis , arthritis , glomerulonephritis , reduce the symptoms of, ameliorate the symptoms of, delay retinopathies comprising diabetic and neonatal retinopathies the onset of, or otherwise pharmaceutically address pancre - and age related macular degeneration , graft vessel disease , atic cancer in a subject, which cancer is associated with a 50 such as can occur following vessel or organ transplantation , ALK , ROS1 , TrkA , TrkB , or TrkC down - regulation defect, acromegaly and disorders secondary to acromegaly as well for example a null mutation such as a ALK , ROS1 , TrkA , as other hypertrophic conditions in which IGF/ IGF - 1R sig TrkB , or TrkC deletion by identifying a ALK , ROS1, TrkA , naling is implicated , such as fibrotic lung disease , patholo TrkB , or TrkC down -regulation defect , for example a null gies related to chronic or acute oxidative stress or hyperoxia mutation such as a ALK , ROS1, TrkA , TrkB , or TrkC 55 induced tissue damage, and metabolic disorders in which deletion in a cancer or precancerous pancreatic cell in an elevated IGF levels or IGF- 1R activity are implicated , such subject, and administering to the subject one or more phar - as obesity . maceutical compositions provided herein . In some embodiments are provided methods of affecting In some embodiments are provided methods to treat, tumor angiogenesis and metastasis inhibition . reduce the symptoms of, ameliorate the symptoms of, delay 60 In some embodiments , the methods provided herein fur the onset of, or otherwise pharmaceutically address a con - ther comprise subjecting the mammal in need thereof to a dition in a subject selected from non - small cell lung cancer , radiation therapy or chemotherapy regimen in combination papillary thyroid cancer, neuroblastoma, pancreatic cancer with at least one cytostatic or cytotoxic agent. In some and colorectal cancer and possibly other indications in embodiments , themethods provided herein further comprise which a defect in the modulation of ALK , ROS1 , Trka , 65 inhibiting the activity ALK protein which comprises con TrkB , or TrkC activity , or a combination thereof, or upregu - tacting the said protein with an effective amount of one or lation ,misregulation or deletion thereofmight play a role by more pharmaceutical compositions provided herein . US 10 , 398 ,693 B2 49 50 In some embodiments , the methods provided herein for TrkB , or TrkC kinase ; and ( 2 ) administering to the subject an inhibiting at least one of ALK , ROS1, TrkA , TrkB , or TrkC effective amount of one or more pharmaceutical composi kinase activity , or a combination thereof, in a cell , compris - tions provided herein . ing contacting said cell with an effective amount of one or Some embodiments provide methods of treating cancer in more pharmaceutical compositions provided herein . 5 a subject, wherein one or more cancerous cells in said In some embodiments are provided pharmaceutical com subject express at least one of ROS1, TrkA , TrkB , or TrkC positions comprising one or more pharmaceutical composi kinase , the method comprising administering to the subject tions provided herein and a pharmaceutically acceptable an effective amount of one or more pharmaceutical compo excipient, carrier or diluent . sitions provided herein . Some embodiments provide methods of inhibiting ALK , 10 Some embodiments provide a method for treating a ROS1, TrkA , TrkB , or TrkC activity, or a combination subject having cancer, wherein tumors from said subject are thereof, in a subject , comprising administering to said sub ROS1, TrkA , TrkB , or TrkC positive , a combination thereof, ject an effective amount of one or more pharmaceutical the method comprising administering to the subject an compositions provided herein . 15 effective amount of one or more pharmaceutical composi Some embodiments provide methods of treating cancer in tions provided herein . a subject in need thereof, the method comprising inhibiting Some embodiments provide a method of treating a cancer ALK , ROS1, TrkA , TrkB , or TrkC activity , or a combination subject , comprising ( a ) acquiring knowledge of the presence thereof, in said subject, by administering to said subject an of at least one genetic alteration in at least one target gene effective amount of one or more pharmaceutical composi - 20 in the cancer subject, wherein the at least one target gene is tions provided herein . selected from ALK1, BDNF , NGF, NGFR , NTF3 , NTF4 , Some embodiments provide methods of treating non - ROS1 , SORT1 , NTRK1, NTRK2, and NTRK3 ; ( b ) selecting small cell lung cancer, papillary thyroid cancer , neuroblas one or more pharmaceutical compositions provided herein toma, pancreatic cancer or colorectal cancer in a subject, as a treatment for the cancer subject, based on the recogni comprising administering to said subject an effective amount 25 tion that said pharmaceutical composition is effective in of one or more pharmaceutical compositions provided treating cancer subjects having said at least one genetic herein . alteration in said at least one target gene ; and ( c ) adminis Some embodiments provide methods of treating tumors in tering a therapeutically effective amount of one or more of a subject, said methods comprising administering to the said pharmaceutical compositions to said cancer subject. 130 Some embodiments provide a method of treating a cancer subject an effective amount of one or more pharmaceutical 30 subject , comprising administering to said cancer subject a compositions provided herein . therapeutically effective amount of one or more pharmaceu Some embodiments provide methods wherein the tumors tical compositions provided herein , wherein prior to said are caused by the presence of non - small cell lung cancer, administration of said one or more pharmaceutical compo papillary thyroid cancer , neuroblastoma, pancreatic cancer 35 sitions said cancer subject is known to possess at least one or colorectal cancer in the subject. Some embodiments genetic alteration in at least one target gene selected from provide methods wherein one or more of the cells compris - ÄLKI. BDNE. NGE . NGER . NTF3 . NTF4 . ROS1 . SORT1 . ing the tumors in the subject test positive for the presence of NTRK1, NTRK2, and NTRK3. a gene that expresses at least one of ALK , ROS1, TrkA , Some embodiments provide a method of treating a cancer TrkB , or TrkC kinase or one or more of the cells comprising 40 subject, wherein prior to said treatment said subject is the tumors in said subject demonstrates at least one of ALK , known to possess at least one genetic alteration in at least ROS1, TrkA , TrkB , or TrkC kinase activity. one target gene , comprising administering to said cancer Some embodiments provide methods wherein one or subject a therapeutically effective amount of one or more more of the cells comprising the tumors in the subject test pharmaceutical compositions provided herein and wherein positive for at least one gene rearrangement comprising the 45 said at least one target gene is selected from ALK1, BDNF, gene , or a fragment thereof , that expresses at least one of NGF, NGFR , NTF3 , NTF4 , ROSI , SORT1, NTRK1, ALK , ROS1, TrkA , TrkB , or TrkC kinase . Some embodi- NTRK2, and NTRK3. ments provide such methods wherein the cells test positive Some embodiments provide any of the methods described for at least one of ROS1, TrkA , TrkB , or TrkC kinases. Some herein wherein the subject or subject is suffering from cancer embodiments provide methods wherein the cells test posi - 50 and the cancer is selected from at least one of non - small cell tive for ROS1 kinase . Some embodiments provide methods lung cancer, papillary thyroid cancer, neuroblastoma , pan wherein the cells test positive for at least one of TrkA , TrkB creatic cancer and colorectal cancer . and TrkC kinase . Some embodiments provide methods In one aspect, provided herein are methods for treating wherein the cells test positive for TrkA kinase . Some cancer in a subject, comprising ( a ) acquiring knowledge of embodiments provide methods wherein the cells test posi - 55 the presence of one or more molecular alterations in a tive for TrkB kinase . Some embodiments provide such biological sample from the cancer subject , wherein the one methods wherein the cells test positive for TrkC kinase . or more molecular alterations is detected by an assay com Some embodiments provide methods of treating cancer in prising one or more antibodies that bind to one or more of a subject, the method comprising : ( 1 ) testing one or more ALK , ROS1, TrkA , TrkB , and TrkC biomarkers ; ( b ) select cells comprising the tumors in the subject for the presence 60 ing a chemotherapeutic agent as a treatment for the cancer of at least one of ALK , ROS1 , TrkA , TrkB , or TrkC kinase ; subject wherein the assay detects the presence of one or and ( 2 ) administering to the subject an effective amount of more of molecular alterations, and wherein the selected one or more pharmaceutical compositions provided herein . chemotherapeutic agent is one or more of the pharmaceuti Some embodiments provide methods of treating cancer in cal compositions provided herein , or a pharmaceutically a subject, the method comprising: ( 1 ) testing one or more 65 acceptable salt thereof; and ( c ) administering a therapeuti cells comprising the tumors in the subject for the presence cally effective amount of the one or more selected chemo of at least one molecular alteration in ALK , ROS1 , TrkA , therapeutic agents to the cancer subject. US 10 , 398 ,693 B2 51 52 In another aspect , provided herein are methods for select g /kg . Additional guidance with regard to this aspect can be ing a cancer subject who is predicted to respond to the found in , for example, Remington : The Science and Practice administration of a therapeutic regimen , comprising ( a ) of Pharmacy, 21st Edition , Univ . of Sciences in Philadelphia acquiring knowledge of the presence of one or more molecu (USIP ) , Lippincott Williams & Wilkins, Philadelphia , Pa ., lar alterations in a biological sample from the cancer subject, 5 2005 . wherein the one or more molecular alterations is detected by Some embodiments include any of the methods described an assay comprising one or more antibodies that bind to one herein , wherein any of the pharmaceutical compositions or more of ALK , ROS1, TrkA , TrkB , and TrkC biomarkers ; provided herein that comprise N -[ 5 -( 3 ,5 - difluorobenzyl) and ( b ) selecting the subject as predicted to respond to the 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetra administration of a therapeutic regimen if the one or more 10 hydro - 2H -pyran - 4 - ylamino ) -benzamide are administered to molecular alterations is detected in one or more of the a subject in an amount such that the amount of N - 15 - ( 3 , 5 biomarkers , or selecting the subject as predicted to not difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 respond to the administration of a therapeutic regimen if the yl) - 2 -( tetrahydro - 2H -pyran -4 -ylamino ) -benzamide the sub one or more molecular alterations is not detected in the ject receives ranges from about 200 mg/m2 to about 1600 biomarkers . In the methods according to this aspect of the 15 mg/ m² , or from about 200 mg/m² to about 1200 mg/ m² , or disclosure , the therapeutic regiment includes administering from about 200 mg/ m² to about 1000 mg/ m² , or from about to the selected subject a therapeutically effective amount of 400 mg /m² to about 1200 mg/m² , or from about 400 mg/ m² one or more of the pharmaceutical compositions provided to about 1000 mg/ m² , or from about 800 mg/m² to about herein . 1000 mg/ m², or from about 800 mg/ m² to about 1200 It will be appreciated that the actual dosages N -[ 5 -( 3 ,5 - 20 mg /m² , or from about 800 mg/m² to about 1200 mg/ m² , or difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - from about 800 mg/ m² to about 1600 mg/ m² . yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide will vary Some embodiments include any of the methods described according the particular composition formulated , the mode herein , wherein any of the pharmaceutical compositions of administration , and the particular site , subject or subject, provided herein that comprise N - [ 5 - ( 3 , 5 - difluorobenzyl) and disease being treated . Those skilled in the art using 25 1H - indazol- 3 - yl) - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 -( tetra conventional dosage -determination tests in view of the hydro - 2H -pyran - 4 - ylamino ) -benzamide are administered to experimental data for N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - inda - a subject in an amount such that the amount of N -[ 5 -( 3 ,5 zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 4 - ylamino ) -benzamide may ascertain optimal dosages for a yl ) - 2 -( tetrahydro - 2H - pyran - 4 - ylamino ) -benzamide the sub given set of conditions . For oral administration , an exem - 30 ject receives is about 200 mg/m² , about 300 mg/m² , about plary daily dose generally employed will be from about 400 mg/ m ” , about 500 mg/ m ” , about 600 mg/ m ” , about 700 0 .001 to about 1000 mg/ kg , from about 0 . 1 mg to about 1000 mg/m² , about 800 mg/ m² , about 900 mg/m² , about 1000 mg of body weight, with courses of treatment repeated at mg/ m² , about 1100 mg/ m² , about 1200 mg/ m² , about 1300 appropriate intervals . mg/ m2 , about 1400 mg/ m² , about 1500 mg /m² , about 1600 This amount will vary depending upon a variety of 35 mg/m² , about 1700 mg/m² , about 1800 mg/m² , about 1900 factors , comprising but not limited to the characteristics of mg/m² , or about 2000 mg/ m2 . In some embodiments , the the pharmaceutical compositions and formulations provided amount of N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H -indazol - 3 -yl ) - 4 herein (comprising activity , pharmacokinetics, pharmacody - (4 -methyl -piperazin - 1 - yl) - 2 -( tetrahydro - 2H -pyran - 4 namics , and bioavailability thereof) , the physiological con ylamino ) - benzamide the subject receives is about 200 dition of the subject treated ( comprising age, sex , disease 40 mg/m² , about 300 mg/m² , about 400 mg/ m² , about 500 type and stage , general physical condition , responsiveness to mg/ m² , about 600 mg/ m² . In some embodiments , the a given dosage , and type of medication ) or cells , the nature amount of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) -4 of the pharmaceutically acceptable carrier mg/ kg or carriers (4 -methyl - piperazin -1 -yl ) - 2 - ( tetrahydro - 2H -pyran - 4 in the formulation , and the route of administration . Further, ylamino ) -benzamide the subject receives is about 200 an effective or therapeutically effective amount may vary 45 mg/ m2 . In some embodiments , the amount of N - [ 5 - ( 3 , 5 depending on whether the one or more pharmaceutical difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 compositions provided herein is administered alone or in yl) - 2 -( tetrahydro - 2H -pyran -4 -ylamino ) -benzamide the sub combination with other drug (s ), other therapy /therapies or ject receives is about 300 mg/ m² . In some embodiments , the other therapeutic method (s ) or modality /modalities . One amount of N - [ 5 -( 3 , 5 - difluorobenzyl) -1H -indazol - 3 - yl ) -4 skilled in the clinical and pharmacological arts will be able 50 ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 to determine an effective amount or therapeutically effective ylamino ) -benzamide the subject receives is about 400 amount through routine experimentation , namely by moni- mg/ m² . In some embodiments, the amount of N - [ 5 - ( 3 , 5 toring a cell' s or subjects response to administration of the difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin -1 one or more pharmaceutical compositions and formulations yl) - 2 -( tetrahydro - 2H -pyran -4 - ylamino ) -benzamide the sub provided herein and adjusting the dosage accordingly . 55 ject receives is about 500 mg/ m² . In some embodiments , the In some embodiments , a dose of N - [ 5 - ( 3 , 5 - difluoroben - amount of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 zyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 hydro -pyran - 4 - ylamino ) -benzamide may range from about ylamino ) -benzamide the subject receives is about 600 0 . 1 mg/ kg to about 100 mg/ kg or more, depending on the mg/ m² . factors mentioned above . In other alternatives , the dosage 60 Some embodiments include any of the methods described may range from about 0 . 1 mg/ kg to about 100 mg/kg ; or herein , wherein any of the pharmaceutical compositions about 1 mg/ kg to about 100 mg/ kg; or about 5 mg/ kg up to provided herein that comprise N - [ 5 - ( 3 , 5 - difluorobenzyl) about 100 mg/kg . For topical applications such as, for 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra example , treatment of various hair conditions , according to hydro - 2H -pyran - 4 - ylamino ) -benzamide are administered to some alternatives provided herein , suitable dosage may 65 a subject in an amount such that the amount of N - 15 - ( 3 , 5 range from about 1 mg/ kg to about 10 g /kg ; or about 10 difluorobenzyl) - 1H - indazol- 3 -yl ] -4 - (4 -methyl -piperazin - 1 mg/ kg to about 1 g /kg ; or about 50 mg/ kg up to about 10 yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide the sub US 10 , 398 ,693 B2 53 54 ject receives is about 200 mg, about 300 mg, about 400 mg, amount of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 about 500 mg, about 600 mg, about 700 mg, about 800 mg, ( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro - 2H -pyran - 4 about 900 mg, about 1000 mg, about 1100 mg, about 1200 ylamino )- benzamide the subject receives once per day is mg, about 1300 mg, about 1400 mg, about 1500 mg, about about 500 mg. In some embodiments, the amount of N - [ 5 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, 5 (3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piper or about 2000 mg. In some embodiments , the amount of azin - 1 - yl) - 2 - ( tetrahydro - 2H - pyran - 4 - ylamino ) -benzamide N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl the subject receives once per day is about 600 mg. In some piperazin - 1 -yl ) - 2 - ( tetrahydro -2H -pyran - 4 -ylamino ) -benz embodiments , the amount of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H amide the subject receives is about 200 mg, about 300 mg, indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro about 400 mg, about 500 mg, about 600 mg, about 700 mg, 10 2H -pyran -4 -ylamino )- benzamide the subject receives once about 800 mg, about 900 mg, or about 1000 mg. In some per day is about 700 mg . In some embodiments , the amount embodiments , the amount of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl indazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro piperazin - 1 - yl) - 2 - tetrahydro - 2H -pyran - 4 - ylamino ) -benz 2H -pyran -4 -ylamino )- benzamide the subject receives is amide the subject receives once per day is about 800 mg. In about 200 mg. In some embodiments , the amount of N -[ 5 - 15 some embodiments , the amount of N - [5 -( 3 ,5 -difluoroben ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - piper zyl) - 1H - indazol - 3 - yl] - 4 - (4 -methyl -piperazin - 1 - yl) - 2 - ( tetra azin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide hydro -2H - pyran - 4 -ylamino ) -benzamide the subject receives the subject receives is about 300 mg. In some embodiments , once per day is about 900 mg . In some embodiments , the the amount of N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) amount of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) -4 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -2H -pyran - 4 - 20 (4 -methyl - piperazin - 1- yl ) - 2 - ( tetrahydro - 2H -pyran -4 ylamino )- benzamide the subject receives is about 400 mg. In ylamino ) - benzamide the subject receives once per day is some embodiments , the amount of N - [5 - ( 3 ,5 -difluoroben - about 1000 mg. zyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetra - Those of ordinary skill in the art will understand that with hydro - 2H -pyran - 4 - ylamino ) -benzamide the subject receives respect to pharmaceutical compositions comprising N - [ 5 - ( 3 , is about 500 mg. In some embodiments , the amount of 25 5 -difluorobenzyl ) -1H - indazol- 3 -yl ] -4 -( 4 -methyl -piperazin N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide provided piperazin - 1 -yl )- 2 -( tetrahydro - 2H -pyran - 4 -ylamino )- benz herein the particular pharmaceutical composition , the dos amide the subject receives is about 600 mg. In some age , and the number of doses given per day to a mammal embodiments , the amount of N - 15 - ( 3 , 5 - difluorobenzyl ) - 1H - requiring such treatment, are all choices within the knowl indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 30 edge of one of ordinary skill in the art and can be determined 2H -pyran - 4 - ylamino ) -benzamide the subject receives is without undue experimentation . about 700 mg. In some embodiments , the amount of N - [ 5 - Accordingly, while certain dose and administration regi ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piper mens are exemplified herein , these examples in no way limit azin - 1 - yl) - 2 - (tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide the dose and administration regimen that may be provided to the subject receives is about 800 mg. In some embodiments , 35 a subject in practicing the presently disclosed methods. the amount of N - [ 5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl] - It is to be noted that dosage values may vary with the type 4 -( 4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro - 2H -pyran - 4 and severity of the condition to be alleviated , and may ylamino ) -benzamide the subject receives is about 900 mg. In include single or multiple doses . It is to be further under some embodiments , the amount of N -[ 5 -( 3 , 5 - difluoroben stood that for any particular subject, specific dosage regi zyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra - 40 mens should be adjusted over time according to the subject hydro - 2H - pyran - 4 - ylamino ) - benzamide the subject receives need and the professional judgment of the person adminis is about 1000 mg. tering or supervising the administration of the compositions, Some embodiments include any of themethods described and that dosage ranges set forth herein are exemplary only herein , wherein any of the pharmaceutical compositions and are not intended to limit the scope or practice of the provided herein that comprise N - 15 - ( 3 , 5 -difluorobenzyl ) - 45 claimed composition . For example , doses may be adjusted 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra - based on pharmacokinetic or pharmacodynamic parameters , hydro -2H -pyran - 4 -ylamino ) -benzamide are administered to which may include clinical effects such as toxic effects a subject once per day in an amount such that the amount of and / or laboratory values . The embodiments provided herein N - [ 5 -( 3 , 5 - difluorobenzyl ) - 1H - indazol- 3 -yl ] -4 - (4 -methyl - are intended to encompass intra -subject dose -escalation as piperazin - 1 -yl ) - 2 -( tetrahydro - 2H -pyran -4 -ylamino )- benz - 50 determined by the skilled artisan . Determining appropriate amide the subject receives per day is about 200 mg , about dosages and regimens for administration of the chemothera 300 mg, about 400 mg, about 500 mg, about 600 mg, about peutic agent are well -known in the relevant art and would be 700 mg, about 800 mg, about 900 mg, about 1000 mg , about understood to be encompassed by the skilled artisan once 1100 mg, about 1200 mg, about 1300 mg , about 1400 mg , provided the teachings provided herein . about 1500 mg, about 1600 mg, about 1700 mg, about 1800 55 Implementations of the methods of the present disclosure mg, about 1900 mg, or about 2000 mg. In some embodi can include one or more of the following features. In some ments , the amount of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - embodiments , the selected chemotherapeutic agent one or zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 2H more of the pharmaceutical compositions provided herein . pyran - 4 -ylamino ) -benzamide the subject receives once per In some embodiments , the assay includes one or more day is about 200 mg . In some embodiments, the amount of 60 antibodies that bind to at least two of ALK , ROS1, TrkA , N -[ 5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl TrkB and TrkC biomarkers . In some embodiments , the one piperazin - 1 -yl ) - 2 -( tetrahydro - 2H -pyran -4 -ylamino )- benz - or more molecular alterations detected in the biological amide the subject receives once per day is about 300 mg. In sample involve at least two , at least three , or at least four of some embodiments , the amount of N - 15 - ( 3 , 5 - difluoroben - the biomarkers . In some embodiments , the knowledge of the zyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra - 65 presence of the one or more molecular alterations in the hydro - 2H -pyran - 4 - ylamino )- benzamide the subject receives biological sample is acquired from an assay that includes once per day is about 400 mg. In some embodiments, the contacting the biological sample with one or more antibod US 10 , 398 ,693 B2 55 56 ies or fragments thereof specific for the biomarkers . In some Some embodiments provide a pharmaceutical composi embodiments , the specific antibodies are monoclonal anti - tion comprising one or more pharmaceutical compositions bodies . In some embodiments , the specific antibodies provided herein in combination with one or more chemo include at least one of D5F3 , D4D5® , C17F1® , and therapeutic agents or radiotherapy, such as radiotherapy as combinations thereof. In some embodiments , the biological 5 commonly administered to treat , ameliorate the symptoms sample is contacted with one or more of the specific anti - of, or prevent or delay the onset of cancer. Such agents can bodies simultaneously . In some embodiments , the biological include, but are not limited to , antihormonal agents such as sample is sequentially contacted with the specific antibodies . antiestrogens , antiandrogens and aromatase inhibitors , In some embodiments , the one or more molecular alterations topoisomerase 1 inhibitors , topoisomerase II inhibitors , results in elevated expression of one or more of the ALK , 10 agents that target microtubules , platin - based agents , alky ROS1 , TrkA , TrkB , and TrkC biomarkers . In some embodi- lating agents , DNA damaging or intercalating agents , anti ments , the knowledge of the one or more molecular altera - neoplastic antimetabolites , other kinase inhibitors , other tions is acquired from an assay wherein determining whether anti- angiogenic agents , inhibitors of kinesins , therapeutic the expression of one or more biomarker is elevated monoclonal antibodies , inhibitors of mTOR , histone includes : ( a ) determining the expression level of the one or 15 deacetylase inhibitors , farnesyl transferase inhibitors, and more biomarkers in the biological sample ; and ( b ) compar - inhibitors of hypoxic response. ing the determined expression level to a reference expres Some embodiments provide a product or kit comprising sion level. In some embodiments , the knowledge of the one one or more pharmaceutical compositions provided herein or more molecular alterations is acquired from an antibody - and one or more chemotherapeutic agents , as a combined based assay . In some embodiments , the antibody -based 20 preparation for simultaneous , separate or sequential use in assay is selected from the group consisting of ELISA , anticancer therapy . immunohistochemistry, western blotting , mass spectrom - Some embodiments provide one or more pharmaceutical etry , flow cytometry , protein -microarray , immunofluores - compositions as provided herein for use as a medicament. cence, and a multiplex detection assay . In some embodi- Some embodiments provide the use of one or more ments , the antibody - based assay includes an 25 pharmaceutical compositions as provided herein in the immunohistochemistry analysis . manufacture of a medicament with antitumor activity . In some embodiments , implementations of the methods Some embodiments include any of the methods described provided herein further include acquiring knowledge of a herein , wherein said cancer is selected from non -small cell genetic alteration in the cancer of the subject from a second lung cancer, papillary thyroid cancer, neuroblastoma , pan analytical assay prior to the administering step , wherein the 30 creatic cancer and colorectal cancer . Some embodiments are second analytical assay is selected from the group consisting any of the methods described herein wherein said cancer is of capillary electrophoresis , nucleic acid sequencing, poly - non -small cell lung cancer. Some embodiments include any peptide sequencing , restriction digestion , nucleic acid of the methods described herein , wherein said cancer is said amplification - based assays , nucleic acid hybridization assay, cancer is papillary thyroid cancer. Some embodiments comparative genomic hybridization , real - time PCR , quanti - 35 include any of the methods described herein , wherein said tative reverse transcription PCR ( QRT- PCR ) , PCR -RFLP cancer is wherein said cancer is neuroblastoma. Some assay, HPLC , mass - spectrometric genotyping, fluorescent embodiments include any of the methods described herein , in - situ hybridization ( FISH ) , next generation sequencing wherein said cancer is wherein said cancer is pancreatic (NGS ) , and a kinase activity assay. In some embodiments , cancer. Some embodiments include any of the methods the cancer is cancer is selected from the group consisting of 40 described herein , wherein said cancer is wherein said cancer anaplastic large - cell lymphoma (ALCL ) , colorectal cancer is colorectal cancer. (CRC ) , cholangiocarcinoma, gastric , glioblastomas (GBM ), The pharmaceutically acceptable carrier may comprise a leiomyosarcoma , melanoma, non - small cell lung cancer conventional pharmaceutical carrier or excipient . Suitable (NSCLC ) , squamous cell lung cancer, neuroblastoma (NB ) , pharmaceutical carriers include inert diluents or fillers, gli ovarian cancer, pancreatic cancer, prostate cancer, medullary 45 dants , lubricants , water and various organic solvents ( such thyroid cancer , breast cancer , and papillary thyroid cancer. as hydrates and solvates ) . The pharmaceutical compositions In some embodiments , the knowledge of the one or more may , if desired , contain additional ingredients such as fla molecular alterations is obtained from an assay performed vorings , binders , excipients and the like . Thus for oral simultaneously on a plurality of biological samples. In some administration , tablets containing various excipients , such as embodiments , the plurality of biological samples includes at 50 citric acid may be employed together with various disinte least 6 , 12 , 24 , 48 , 96 , 200 , 384 , 400 , 500 , 1000 , 1500 , or grants such as starch , alginic acid and certain complex 3000 samples . In some embodiments , the one or more silicates and with binding agents such as sucrose , gelatin and molecular alterations is selected from a genetic mutation , a acacia . In some embodiments , the excipient comprises pre gene amplification , a gene rearrangement, a single -nucleo gelatinized starch . In some embodiments , the pharmaceuti tide variation (SNV ) , a deletion , an insertion , an InDel 55 cal compositions comprise a glidant. In some embodiments , mutation , a single nucleotide point mutation (SNP ) , an the pharmaceutical compositions comprise colloidal silicon epigenetic alteration , a splicing variant, an RNA /protein dioxide . Additionally , lubricating agents such as magnesium overexpression , an aberrant RNA /protein expression , and stearate, sodium lauryl sulfate and talc are often useful for any combination thereof. In some embodiments , the one or tableting purposes. Solid compositions of a similar type may more molecular alterations include an insertion of a heter - 60 also be employed in soft and hard filled gelatin capsules . ologous nucleic acid sequence within a coding sequence of Non - limiting examples of materials , therefore , include lac a biomarker gene. In some embodiments , the insertion forms tose or milk sugar and high molecular weight polyethylene a chimeric nucleic acid sequence that encodes a fusion glycols . peptide . In some embodiments , the acquiring knowledge of To treat or prevent diseases or conditions mediated by the one ormore molecular alterations further includes deter - 65 ALK , ROS1, TrkA , TrkB , or TrkC , or a combination thereof, mining a nucleic acid sequence and /or an amino acid a pharmaceutical composition provided herein is adminis sequence comprising the one or more molecular alterations. tered by combining a therapeutically effective amount of US 10 , 398 ,693 B2 57 58 N - [5 - ( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - (4 -methyl etrants appropriate to the barrier to be permeated are used in piperazin - 1 -yl ) -2 - (tetrahydro -pyran -4 -ylamino ) -benzamide the formulation . Such penetrants are generally known in the and at least one acidulant. Optionally , such pharmaceutical art. compositions may comprise one or more pharmaceutically For oral administration , N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H suitable carriers , which may be selected , for example , from 5 indazol- 3 -yl )- 4 - (4 -methyl -piperazin - 1- yl) - 2 -( tetrahydro diluents , excipients and auxiliaries that facilitate processing pyran - 4 - ylamino ) -benzamide may be formulated by com of N - [5 -( 3 , 5 - difluorobenzyl) -1H - indazol - 3 - yl) - 4 - ( 4 -methyl bining it with pharmaceutically acceptable carriers known in the art . Such carriers enable N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benzamide indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro into the final pharmaceutical preparations . oblid 10 pyran -4 -ylamino ) -benzamide to be formulated as tablets , The pharmaceutical carriers employed may be either solid pills , dragees , capsules , powders , granules, liquids, gels , or liquid . Exemplary solid carriers are lactose , sucrose , talc , syrups , slurries, suspensions and the like, for oral ingestion gelatin , agar, pectin , acacia ,magnesium stearate , stearic acid by a subject to be treated . Pharmaceutical preparations for and the like . Exemplary liquid carriers are syrup , peanut oil, oral use can be obtained using a solid excipient in admixture olive oil, water and the like. Similarly , the inventivelive com - 15 with N - [5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 positions may include time- delay or time- release material methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 - ylamino ) known in the art , such as glyceryl monostearate or glyceryl benzamide, optionally grinding the resulting mixture , and distearate alone or with a wax , ethylcellulose , hydroxypro processing the mixture of granules after adding suitable pylmethylcellulose, methylmethacrylate or the like . Further auxiliaries, if desired , to obtain tablets or dragee cores. additives or excipients may be added to achieve the desired 20 Suitable excipients include : fillers such as sugars , compris formulation properties . For example , a bioavailability ing isomalt, lactose , sucrose, mannitol, or sorbitol; and enhancer , such as Labrasol, Gelucire or the like , or formu - cellulose preparations , for example , maize starch , wheat lator, such as CMC ( carboxy -methylcellulose ) , PG (propyl - starch , rice starch , potato starch , gelatin , gum , methyl cel eneglycol) , or PEG (polyethyleneglycol ) , may be added . lulose , hydroxypropylmethyl- cellulose , sodium carboxym Gelucire® , a semi- solid vehicle that protects active ingre - 25 ethylcellulose , microcrystalline cellulose or polyvinylpyr dients from light , moisture and oxidation , may be added , rolidone (PVP ) . In some embodiments, the filler is mannitol, e . g ., when preparing a capsule formulation . isomalt, hypromellose (hydroxypropylmethylcellulose ) , or If a solid carrier is used , the preparation can be tableted , microcrystalline cellulose . In some embodiments , the filler placed in a hard gelatin capsule in powder or pellet form , or is mannitol. In some embodiments , the filler is isomalt . In formed into a troche or lozenge . The amount of solid carrier 30 some embodiments , the filler is microcrystalline cellulose . may vary , but generally will be from about 25 mg to about In some embodiments , the filler is lactose . In some embodi 1 g . If a liquid carrier is used , the preparation may be in the ments , the filler is anhydrous lactose. If desired , disintegrat form of syrup , emulsion , soft gelatin capsule , sterile inject- ing agents may be added , such as crosslinked polyvinyl able solution or suspension in an ampoule or vial or non - pyrrolidone , agar, or alginic acid or a salt thereof such as aqueous liquid suspension . If a semi- solid carrier is used , the 35 sodium alginate . preparation may be in the form of hard and soft gelatin Dragee cores are provided with suitable coatings. For this capsule formulations. The inventive compositions are pre - purpose, concentrated sugar solutions may be used , which pared in unit -dosage form appropriate for the mode of may optionally contain gum arabic , polyvinyl pyrrolidone , administration , e . g . parenteral or oral administration . Carbopol gel , polyethylene glycol, and/ or titanium dioxide , To obtain a stable water -soluble dose form , N - 15 - ( 3 , 5 - 40 lacquer solutions, and suitable organic solvents or solvent difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - mixtures . Dyestuffs or pigments may be added to the tablets yl) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benzamide may be dis - or dragee coatings . solved in an aqueous solution of an organic or inorganic Pharmaceutical preparations that can be used orally acid , such as a 0 . 3 M solution of succinic acid or citric acid . include push - fit capsules made of gelatin , as well as soft , If a soluble salt form is not available , N -[ 5 - (3 ,5 -difluoroben - 45 sealed capsules made of gelatin and a plasticizer, such as zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetra - glycerol or sorbitol. The push - fit capsules can contain N - [ 5 hydro -pyran - 4 - ylamino ) -benzamide may be dissolved in a ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piper suitable co -solvent or combinations of co -solvents . azin - 1 - yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide in Examples of suitable co - solvents include alcohol, propylene admixture with fillers such as lactose , binders such as glycol , polyethylene glycol 300 , polysorbate 80 , glycerin 50 starches , and /or lubricants such as talc or magnesium stear and the like in concentrations ranging from 0 to 60 % of the ate, and , optionally , stabilizers . In soft capsules , N -15 - ( 3 , 5 total volume. In an exemplary embodiment, N - [ 5 - ( 3 , 5 - dif difluorobenzyl) - 1H - indazol- 3 -yl ] -4 - (4 -methyl - piperazin - 1 luorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) yl) - 2 - ( tetrahydro -pyran -4 -ylamino )- benzamide may be 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide is dissolved in dissolved or suspended in suitable liquids, such as fatty oils , DMSO and diluted with water. The pharmaceutical compo - 55 liquid paraffin , or liquid polyethylene glycols . In addition , sition may also be in the form of a solution of a salt form of stabilizers may be added . All formulations for oral admin N -[ 5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - istration should be in dosages suitable for such administra piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) -benzamide tion . in an appropriate aqueous vehicle such as water or isotonic For buccal administration , the compositions may take the saline or dextrose solution . 60 form of tablets or lozenges formulated in conventional Proper formulation is dependent upon the route of admin - manner . istration selected . For injection , N - [5 - (3 , 5 -difluorobenzyl ) The pharmaceutical compositions provided herein are 1H -indazol - 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra useful for the treatment of cancers comprising but not hydro - pyran - 4 - ylamino ) -benzamide may be formulated into limited to cancers of the : circulatory system , for example , aqueous solutions , preferably in physiologically compatible 65 heart ( sarcoma [ angiosarcoma, fibrosarcoma, rhabdomyo buffers such as Hanks solution , Ringer' s solution , or physi- sarcoma, liposarcoma ], myxoma, rhabdomyoma, fibroma, ological saline buffer. For transmucosal administration , pen - lipoma and teratoma) , mediastinum and pleura , and other US 10 , 398 ,693 B2 59 60 intrathoracic organs , vascular tumors and tumor- associated oral cavity and pharynx ; skin , for example , malignant mela vascular tissue; respiratory tract, for example, nasal cavity noma, cutaneous melanoma, basal cell carcinoma, squamous and middle ear , accessory sinuses , larynx , trachea , bronchus cell carcinoma, Karposi ' s sarcoma, moles dysplastic nevi , and lung such as small cell lung cancer (SCLC ) , non - small lipoma, angioma, dermatofibroma, and keloids ; adrenal cell lung cancer (NSCLC ) , bronchogenic carcinoma 5 glands : neuroblastoma ; and other tissues comprising con ( squamous cell, undifferentiated small cell , undifferentiated nective and soft tissue , retroperitoneum and peritoneum , large cell , adenocarcinoma ), alveolar (bronchiolar ) carci noma , bronchial adenoma , sarcoma, lymphoma, chon eye , intraocular melanoma, and adnexa, breast, head or /and dromatous hamartoma , mesothelioma ; gastrointestinal sys neck , anal region , thyroid , parathyroid , adrenal gland and tem , for example , esophagus ( squamous cell carcinoma, 10 other endocrine glands and related structures, secondary and adenocarcinoma, leiomyosarcoma, lymphoma) , stomach unspecified malignant neoplasm of lymph nodes , secondary ( carcinoma, lymphoma, leiomyosarcoma) , gastric , pancreas malignant neoplasm of respiratory and digestive systems ( ductal adenocarcinoma, insulinoma, glucagonoma, gastri and secondary malignant neoplasm of other sites . noma, carcinoid tumors , vipoma ), small bowel (adenocar More specifically , examples of cancer when used herein in cinoma, lymphoma, carcinoid tumors , Karposi ' s sarcoma, 155 connectioncon with pharmaceutical compositions provided leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , herein include cancer selected from lung cancer (NSCLC large bowel (adenocarcinoma , tubular adenoma, villous and SCLC ), cancer of the head or neck , ovarian cancer, adenoma, hamartoma , leiomyoma ) ; genitourinary tract, for colon cancer, rectal cancer, prostate cancer, cancer of the example , kidney ( adenocarcinoma, Wilm ' s tumor (nephro anal region , stomach cancer , breast cancer , cancer of the blastoma] , lymphoma, leukemia ), bladder and /or urethra 20 kidney or ureter, renal cell carcinoma, carcinoma of the renal ( squamous cell carcinoma, transitional cell carcinoma, pelvis , neoplasms of the central nervous system ( CNS ), adenocarcinoma ) , prostate ( adenocarcinoma, sarcoma) , tes - primary CNS lymphoma, non -Hodgkins ' s lymphoma, spinal tis ( seminoma, teratoma , embryonal carcinoma , teratocarci- axis tumors, or a combination of one or more of the noma, choriocarcinoma, sarcoma, interstitial cell carcinoma, foregoing cancers . fibroma, fibroadenoma, adenomatoid tumors , lipoma ) ; liver, 25 In some embodiments , the pharmaceutical compositions for example , hepatoma (hepatocellular carcinoma ) , cholan provided herein are useful for the treatment of cancers , giocarcinoma, hepatoblastoma, angiosarcoma, hepatocellu - comprising Spitz melanoma, perineural invasion , pulmonary lar adenoma, hemangioma, pancreatic endocrine tumors large cell neuroendocrine carcinoma , uterine carcinoma, ( such as pheochromocytoma, insulinoma, vasoactive intes juvenile breast cancer , nasopharyngeal carcinoma , adenoid tinal peptide tumor, islet cell tumor and glucagonoma ) ; 30 cystic cancer , meduallary thyroid cancer , salivary cancer, bone , for example , osteogenic sarcoma (osteosarcoma ), congenital infantile fibrosarcoma, mesoblastic nephroma, fibrosarcoma, malignant fibrous histiocytoma, chondrosar- esophageal cancer ( squamous) , diffuse large B -cell lym coma, Ewing ' s sarcoma, malignant lymphoma (reticulum phoma, papillary thyroid cancer , and mammary analogue cell sarcoma ), multiple myeloma, malignant giant cell tumor secretory carcinoma. chordoma, osteochronfroma ( osteocartilaginous exostoses ), 35 In some embodiments are provided methods for treating benign chondroma , chondroblastoma, chondromyxofi - diseases caused by and /or associated with deregulated pro broma, osteoid osteoma and giant cell tumors ; nervous tein kinase activity , particularly PLK family , protein kinase system , for example , neoplasms of the central nervous C in different isoforms, Met, PAK - 4 , PAK - 5 , ZC - 1 , STLK - 2 , system (CNS ), primary CNS lymphoma, skull cancer (os - DDR - 2 , Aurora 1 , Aurora 2 , Bub - 1 , Chk1, Chk2 , HER2 , teoma, hemangioma, granuloma, xanthoma, osteitis defor- 40 rafi , MEK1 , MAPK , EGF - R , PDGF - R , FGF - R , FLT3 , mans ) ,meninges (meningioma , meningiosarcoma, glioma JAK2, IGF - R , ALK , PI3K , weel kinase , Src , Abl, Akt, tosis ), brain cancer (astrocytoma , medulloblastoma, glioma, MAPK , ILK , MK - 2 , IKK - 2 , Cdc7, Nek , Cdk /cyclin kinase ependymoma, germinoma [ pinealoma ) , glioblastoma multi - family , more particularly Aurora 2 , IGF- 1R and ALK activ form , oligodendroglioma, schwannoma, retinoblastoma, ity , and ROS1 activity , and further more particularly ALK congenital tumors ), spinal cord neurofibroma, meningioma, 45 activity and / or ROS1 activity , which comprises administer glioma, sarcoma) ; reproductive system , for example , gyne- ing to a mammal in need thereof an effective amount of a cological, uterus (endometrial carcinoma ) , cervix ( cervical pharmaceutical composition provided herein . carcinoma, pre - tumor cervical dysplasia ), ovaries ( ovarian In some embodiments disclosed herein are directed to carcinoma [ serous cystadenocarcinoma, mucinous cystade - treat a disease caused by and / or associated with dysregulated nocarcinoma , unclassified carcinoma ) , granulosa - thecal cell 50 protein kinase activity selected from the group consisting of tumors , Sertoli - Leydig cell tumors , dysgerminoma, malig - cancer and cell proliferative disorders . nant teratoma ), vulva (squamous cell carcinoma, intraepi- In some embodiments are provided methods to treat thelial carcinoma, adenocarcinoma, fibrosarcoma, mela - specific types of cancer comprising carcinoma, squamous noma) , vagina ( clear cell carcinoma, squamous cell cell carcinoma, hematopoietic tumors of myeloid or lym carcinoma, botryoid sarcoma ( embryonal rhabdomyosar - 55 phoid lineage , tumors of mesenchymal origin , tumors of the coma) , fallopian tubes (carcinoma ) and other sites associ central and peripheral nervous system , melanoma, semi ated with female genital organs ; placenta , penis , prostate , noma, teratocarcinoma, osteosarcoma, xeroderma pigmen testis , and other sites associated with male genital organs ; tosum , angiosarcoma , glioblastoma, holangiocarcinoma, hematologic system , for example , blood (myeloid leukemia inflammatory myofibroblastic tumor, epitheloid heman facute and chronic ] , acute lymphoblastic leukemia , chronic 60 gioendothelioma , astrocytoma, meningioma, angiosarcoma, lymphocytic leukemia , myeloproliferative diseases , mul- epitheloid hemangiothelioma, keratocanthomas , thyroid fol tiple myeloma, myelodysplastic syndrome ) , Hodgkin ' s dis - licular cancer, Kaposi' s sarcoma, and pancreatic cancer. ease, non - Hodgkin 's lymphoma (malignant lymphoma) ; Some embodiments disclosed herein are directed to treat oral cavity , for example , lip , tongue, gum , floor of mouth , ing specific types of cancer such as, but not restricted to , palate , and other parts of mouth , parotid gland , and other 65 breast cancer, lung cancer , colorectal cancer, prostate cancer, parts of the salivary glands, tonsil , oropharynx , nasophar - ovarian cancer, endometrial cancer , gastric cancer, clear cell ynx , pyriform sinus , hypopharynx , and other sites in the lip , renal cell carcinoma, invasive ductal carcinoma (breast ) , US 10 , 398 ,693 B2 62 uveal melanoma, multiple myeloma, rhabdomyosarcoma, modulation of ROS1 activity , or upregulation ,misregulation Ewing ' s sarcoma, Kaposi ' s sarcoma, pancreatic cancer, and or deletion thereof might play a role by administering a medulloblastoma . pharmaceutical composition as provided herein . In some embodiments are provided methods of treating I n some embodiments are provided methods to treat , ALK + Anaplastic Large Cell Lymphomas ( ALCL ) and 5 reduce the symptoms of, ameliorate the symptoms of, delay possibly other indications in which the ALK activity might the onset of, or otherwise pharmaceutically address pancre play a role, like Neuroblastoma, Rhabdomyosarcoma , Glio atic cancer and possibly other indications in which a defect blastoma, Inflammatory Myofibroblastic Tumor, and some in the modulation of ALK , ROS1, TrkA , TrkB , or TrkC kind of Melanomas , Breast Carcinomas, Ewings sarcomas, activity, or a combination thereof , or upregulation , misregu Retinoblastomas and Non - Small Cell Lung Carcinomas 10 lation or deletion thereof might play a role by administering (NSCLC ) . pharmaceutical composition as provided herein . In some In some embodiments are provided methods to treat , embodiments are provided methods to treat , reduce the reduce the symptoms of, ameliorate the symptoms of, delay symptoms of, ameliorate the symptoms of, delay the onset the onset of, or otherwise pharmaceutically address pancre - of, or otherwise pharmaceutically address pancreatic cancer atic cancer and possibly other indications in which a defect 15 and possibly other indications in which a defect in the in the modulation of ROS1 activity , or upregulation , mis modulation of ROS1, TrkA , TrkB , or TrkC activity , or a regulation or deletion thereof might play a role by admin combination thereof, activity , or upregulation , misregulation istering a pharmaceutical composition as provided herein . or deletion thereof might play a role by administering a In some embodiments are provided methods to treat , pharmaceutical composition as provided herein . reduce the symptoms of, ameliorate the symptoms of, delay 20 In some embodiments are provided methods to treat, the onset of, or otherwise pharmaceutically address pancre - reduce the symptoms of, ameliorate the symptoms of, delay atic cancer and possibly other indications in which a defect the onset of , or otherwise pharmaceutically address pancre in the modulation of ROS1 activity , or upregulation , mis - atic cancer and possibly other indications in which a defect regulation or deletion thereof might play a role by admin in the modulation of ROS1 , TrkA , TrkB , or TrkC activity , or istering a by administering a pharmaceutical compositions 25 a combination thereof, activity , or upregulation , misregula as provided herein . In some embodiments are provided tion or deletion thereofmight play a role by administering a methods to treat, reduce the symptoms of , ameliorate the pharmaceutical composition as provided herein . In some symptoms of , delay the onset of, or otherwise pharmaceu - embodiments are provided methods to treat, reduce the tically address pancreatic cancer and possibly other indica - symptoms of, ameliorate the symptoms of, delay the onset tions in which a defect in the modulation of ROS1 activity , 30 of, or otherwise pharmaceutically address pancreatic cancer or upregulation , misregulation or deletion thereofmight play and possibly other indications in which a defect in the a role by administering a pharmaceutical composition as modulation of ROS1, TrkA , TrkB , or TrkC activity , or a provided herein . combination thereof, activity , or upregulation , misregulation In some embodiments are provided methods to treat, or deletion thereof might play a role by administering a reduce the symptoms of , ameliorate the symptoms of, delay 35 pharmaceutical composition as provided herein . In some the onset of, or otherwise pharmaceutically address pancre - embodiments are provided methods to treat, reduce the atic cancer and possibly other indications in which a defect symptoms of, ameliorate the symptoms of, delay the onset in the modulation of ALK , ROS1 , TrkA , TrkB , or TrkC of, or otherwise pharmaceutically address pancreatic cancer activity , or a combination thereof, or upregulation , misregu - and possibly other indications in which a defect in the lation or deletion thereofmight play a role by administering 40 modulation of ROS1, TrkA , TrkB , or TrkC activity , or a a pharmaceutical composition as provided herein . In some combination thereof, activity , or upregulation , misregulation embodiments are provided methods to treat, reduce the or deletion thereof might play a role by administering a symptoms of, ameliorate the symptoms of, delay the onset pharmaceutical composition as provided herein . of, or otherwise pharmaceutically address pancreatic cancer In some embodiments are provided methods to treat, and possibly other indications in which a defect in the 45 reduce the symptoms of, ameliorate the symptoms of , delay modulation of ALK , ROS1, TrkA , TrkB , or TrkC activity , or the onset of, or otherwise pharmaceutically address pancre a combination thereof, or upregulation , misregulation or atic cancer associated with a ROS1 down - regulation defect, deletion thereof might play a role by administering a phar- for example a null mutation such as a ROS1 deletion by maceutical composition as provided herein . identifying a ROS1 down - regulation defect, for example a In some embodiments are provided methods to treat , 50 null mutation such as a ROS1 deletion in a cancer or reduce the symptoms of, ameliorate the symptoms of, delay precancerous pancreatic cell in an subject, and administering the onset of, or otherwise pharmaceutically address pancre - to the subject a pharmaceutical composition as provided atic cancer and possibly other indications in which a defect herein . In some embodiments are provided methods to treat , in the modulation of ROS1 activity , or upregulation , mis reduce the symptoms of, ameliorate the symptoms of, delay regulation or deletion thereof might play a role by admin - 55 the onset of, or otherwise pharmaceutically address pancre istering a pharmaceutical composition as provided herein . In atic cancer associated with a ROS1 down - regulation defect , some embodiments are provided methods to treat, reduce the for example a null mutation such as a ROS1 deletion by symptoms of , ameliorate the symptoms of , delay the onset identifying a ROS1 down - regulation defect, for example a of, or otherwise pharmaceutically address pancreatic cancer null mutation such as a ROS1 deletion in a cancer or and possibly other indications in which a defect in the 60 precancerous pancreatic cell in an subject, and administering modulation of ROS1 activity, or upregulation , misregulation to the subject a pharmaceutical composition as provided or deletion thereof might play a role by administering a herein . In some embodiments are provided methods to treat, pharmaceutical composition as provided herein . In some reduce the symptoms of, ameliorate the symptoms of, delay embodiments are provided methods to treat, reduce the the onset of, or otherwise pharmaceutically address pancre symptoms of , ameliorate the symptoms of , delay the onset 65 atic cancer associated with a ROS1 down - regulation defect, of, or otherwise pharmaceutically address pancreatic cancer for example a null mutation such as a ROS1 deletion by and possibly other indications in which a defect in the identifying a ROS1 down -regulation defect, for example a US 10 ,398 ,693 B2 63 64 null mutation such as a ROS1 deletion in a cancer or subject comprises determining the nucleic acid sequence precancerous pancreatic cell in an subject, and administering such as the genomic deoxyribonucleic acid sequence in a to the subject a pharmaceutical composition as provided cell or cells or a cell population comprising a cell or cells herein . from a pancreatic cancerous or precancerous cell population . In some embodiments are provided methods to treat, 5 In some embodiments are provided methods to treat, reduce the symptoms of, ameliorate the symptoms of, delay reduce the symptoms of, ameliorate the symptoms of, delay the onset of, or otherwise pharmaceutically address pancre the onset of, or otherwise pharmaceutically address pancre atic cancer associated with a ALK , ROS1, TrkA , TrkB , or atic cancer and possibly other indications in which a defect TrkC down - regulation defect, for example a null mutation in the modulation of ALK , ROS1 , TrkA , TrkB , or TrkC such as a ALK , ROS1, TrkA , TrkB , or TrkC deletion by 10 activity , or a combination thereof, or upregulation , misregu identifying a ALK , ROS1, TrkA , TrkB , or TrkC down lation or deletion thereofmight play a role by administering regulation defect, for example a null mutation such as a a pharmaceutical composition as provided herein . In some ALK , ROS1 , TrkA , TrkB , or TrkC deletion in a cancer or embodiments are provided methods to treat, reduce the precancerous pancreatic cell in an subject , and administering symptoms of, ameliorate the symptoms of, delay the onset to the subject a pharmaceutical composition as provided 15 of, or otherwise pharmaceutically address pancreatic cancer herein . and possibly other indications in which a defect in the In some embodiments identifying a ROS1 modulation modulation of ROS1, TrkA , TrkB , or TrkC activity , or a defect such as an upregulation defect or a down - regulation combination thereof, activity , or upregulation , misregulation defect, for example a null mutation such as a ROS1 deletion or deletion thereof might play a role by administering a or a ROS1 chimeric locus encoding a constitutively active 20 pharmaceutical composition as provided herein . ROS1 kinase in a cancer or precancerous pancreatic cell in In some embodiments are provided methods to treat, an subject comprises assaying for ROS1 activity in a cell reduce the symptoms of, ameliorate the symptoms of, delay extract from a pancreatic cancerous or precancerous cell the onset of, or otherwise pharmaceutically address pancre population . In some embodiments identifying a ROS1 atic cancer and possibly other indications in which a defect modulation defect such as an upregulation defect or a 25 in the modulation of ROS1 , TrkA , TrkB , or TrkC activity , or down -regulation defect , for example a null mutation such as a combination thereof, activity , or upregulation , misregula a ROS1 deletion or a ROS1 chimeric locus encoding a tion or deletion thereofmight play a role by administering a constitutively active ROS1 kinase in a cancer or precancer - pharmaceutical composition as provided herein . In some ous pancreatic cell in an subject comprises assaying for embodiments are provided methods to treat, reduce the ROS1 transcript accumulation in an RNA population from a 30 symptoms of, ameliorate the symptoms of, delay the onset pancreatic cancerous or precancerous cell population . In of, or otherwise pharmaceutically address pancreatic cancer some embodiments identifying a ROS1 modulation defect and possibly other indications in which a defect in the such as an upregulation defect or a down -regulation defect, modulation of ROS1, TrkA , TrkB , or TrkC activity , or a for example a null mutation such as a ROS1 deletion or a combination thereof, activity , or upregulation ,misregulation ROS1 chimeric locus encoding a constitutively active ROS1 35 or deletion thereof might play a role by administering a kinase in a cancer or precancerous pancreatic cell in an pharmaceutical composition as provided herein . In some subject comprises determining the nucleic acid sequence embodiments are provided methods to treat, reduce the such as the genomic deoxyribonucleic acid sequence in a symptoms of, ameliorate the symptoms of , delay the onset cell or cells or a cell population comprising a cell or cells of, or otherwise pharmaceutically address pancreatic cancer from a pancreatic cancerous or precancerous cell population . 40 and possibly other indications in which a defect in the In some embodiments identifying a ALK , ROS1 , Trka , modulation of ROS1, Trka , TrkB , or TrkC activity , or a TrkB , or TrkC modulation defect such as an upregulation combination thereof, activity , or upregulation , misregulation defect or a down - regulation defect, for example a null or deletion thereof might play a role by administering a mutation such as a ALK , ROS1 , TrkA , TrkB , or TrkC pharmaceutical composition as provided herein . deletion or a ALK , ROS1 , Trka , TrkB , or TrkC chimeric 45 In some embodiments are provided methods to treat, locus encoding a constitutively active ALK , ROS1 , TrkA , reduce the symptoms of, ameliorate the symptoms of, delay TrkB , or TrkC kinase in a cancer or precancerous pancreatic the onset of, or otherwise pharmaceutically address pancre cell in an subject comprises assaying for ALK , ROS1, Trka , atic cancer associated with a ROS1 down - regulation defect , TrkB , or TrkC activity in a cell extract from a pancreatic for example a null mutation such as a ROS1 deletion by cancerous or precancerous cell population . In some embodi - 50 identifying a ROS1 down -regulation defect, for example a ments identifying a ALK , ROS1 , Trka , TrkB , or TrkC n ull mutation such as a ROS1 deletion in a cancer or modulation defect such as an upregulation defect or a precancerous pancreatic cell in an subject , and administering down -regulation defect, for example a nullmutation such as to the subject a pharmaceutical composition as provided a ALK , ROS1 , TrkA , TrkB , or TrkC deletion or a ALK , herein . In some embodiments are provided methods to treat , ROS1 , TrkA , TrkB , or TrkC chimeric locus encoding a 55 reduce the symptoms of, ameliorate the symptoms of, delay constitutively active ALK , ROS1, TrkA , TrkB , or TrkC the onset of, or otherwise pharmaceutically address pancre kinase in a cancer or precancerous pancreatic cell in an atic cancer associated with a ROS1 down - regulation defect , subject comprises assaying for ALK , ROS1 , TrkA , TrkB , or for example a null mutation such as a ROS1 deletion by TrkC transcript accumulation in an RNA population from a identifying a ROS1 down - regulation defect , for example a pancreatic cancerous or precancerous cell population . In 60 null mutation such as a ROS1 deletion in a cancer or some embodiments identifying a ALK , ROS1, TrkA , TrkB , precancerous pancreatic cell in an subject , and administering or TrkC modulation defect such as an upregulation defect or to the subject a pharmaceutical composition as provided a down - regulation defect, for example a null mutation such herein . In some embodiments are provided methods to treat, as a ALK , ROS1, TrkA , TrkB , or TrkC deletion or a ALK , reduce the symptoms of, ameliorate the symptomsof , delay ROS1, TrkA , TrkB , or TrkC chimeric locus encoding a 65 the onset of, or otherwise pharmaceutically address pancre constitutively active ALK , ROS1 , TrkA , TrkB , or TrkC a tic cancer associated with a ROS1 down - regulation defect, kinase in a cancer or precancerous pancreatic cell in an for example a null mutation such as a ROS1 deletion by US 10 , 398 ,693 B2 65 66 identifying a ROS1 down -regulation defect, for example a kinase in a cancer or precancerous pancreatic cell in an null mutation such as a ROS1 deletion in a cancer or subject comprises determining the nucleic acid sequence precancerous pancreatic cell in an subject , and administering such as the genomic deoxyribonucleic acid sequence in a to the subject a pharmaceutical composition as provided cell or cells or a cell population comprising a cell or cells herein . 5 from a pancreatic cancerous or precancerous cell population . In some embodiments are provided methods to treat, In some embodiments are provided methods to treat , reduce the symptoms of, ameliorate the symptoms of, delay reduce the symptoms of, ameliorate the symptoms of, delay the onset of, or otherwise pharmaceutically address pancre - the onset of , or otherwise pharmaceutically address a con atic cancer associated with a ALK , ROS1 , TrkA , TrkB , or dition selected from non -small cell lung cancer , papillary TrkC down - regulation defect, for example a null mutation 10 thyroid cancer , neuroblastoma, pancreatic cancer and col such as a ALK , ROS1 , TrkA , TrkB , or TrkC deletion by orectal cancer and possibly other indications in which a identifying a ALK , ROS1, TrkA , TrkB , or TrkC down - defect in the modulation of ALK , ROS1, TrkA , TrkB , or regulation defect, for example a null mutation such as a TrkC activity , or a combination thereof, or upregulation , ALK , ROS1 , TrkA , TrkB , or TrkC deletion in a cancer or misregulation or deletion thereof might play a role by precancerous pancreatic cell in an subject , and administering 15 administering pharmaceutical composition as provided to the subject a pharmaceutical composition as provided herein . In some embodiments are provided methods to treat , herein . reduce the symptomsof , ameliorate the symptoms of, delay In some embodiments identifying a ROS1 modulation the onset of, or otherwise pharmaceutically address pancre defect such as an upregulation defect or a down -regulation atic cancer and possibly other indications in which a defect defect, for example a nullmutation such as a ROS1 deletion 20 in the modulation of ROS1, TrkA , TrkB , or TrkC activity , or or a ROS1 chimeric locus encoding a constitutively active a combination thereof, activity , or upregulation , misregula ROS1 kinase in a cancer or precancerous pancreatic cell in tion or deletion thereof might play a role by administering a an subject comprises assaying for ROS1 activity in a cell pharmaceutical composition as provided herein . extract from a pancreatic cancerous or precancerous cell In some embodiments are provided methods to treat , population . In some embodiments identifying a ROS1 25 reduce the symptoms of, ameliorate the symptoms of , delay modulation defect such as an upregulation defect or a the onset of, or otherwise pharmaceutically address a con down - regulation defect , for example a nullmutation such as dition selected from non - small cell lung cancer, papillary a ROS1 deletion or a ROS1 chimeric locus encoding a thyroid cancer , neuroblastoma, pancreatic cancer and col constitutively active ROS1 kinase in a cancer or precancer - orectal cancer and possibly other indications in which a ous pancreatic cell in an subject comprises assaying for 30 defect in the modulation of ROS1, TrkA , TrkB , or TrkC ROS1 transcript accumulation in an RNA population from a activity , or a combination thereof, activity , or upregulation , pancreatic cancerous or precancerous cell population . In misregulation or deletion thereof might play a role by some embodiments identifying a ROS1 modulation defect administering a pharmaceutical composition as provided such as an upregulation defect or a down- regulation defect, herein . In some embodiments are provided methods to treat , for example a null mutation such as a ROS1 deletion or a 35 reduce the symptoms of, ameliorate the symptoms of , delay ROS1 chimeric locus encoding a constitutively active ROS1 the onset of, or otherwise pharmaceutically address a con kinase in a cancer or precancerous pancreatic cell in an dition selected from non - small cell lung cancer , papillary subject comprises determining the nucleic acid sequence thyroid cancer , neuroblastoma, pancreatic cancer and col such as the genomic deoxyribonucleic acid sequence in a orectal cancer and possibly other indications in which a cell or cells or a cell population comprising a cell or cells 40 defect in the modulation of ROS1, TrkA , TrkB , or TrkC from a pancreatic cancerous or precancerous cell population . activity , or a combination thereof , activity, or upregulation , In some embodiments identifying a ALK , ROS1 , TrkA , misregulation or deletion thereof might play a role by TrkB , or TrkC modulation defect such as an upregulation administering a pharmaceutical composition as provided defect or a down - regulation defect , for example a null herein . In some embodiments are provided methods to treat , mutation such as a ALK , ROS1, TrkA , TrkB , or TrkC45 reduce the symptoms of, ameliorate the symptoms of, delay deletion or a ALK , ROS1, TrkA , TrkB , or TrkC chimeric the onset of, or otherwise pharmaceutically address a con locus encoding a constitutively active ALK , ROS1, TrkA , dition selected from non - small cell lung cancer, papillary TrkB , or TrkC kinase in a cancer or precancerous pancreatic thyroid cancer, neuroblastoma, pancreatic cancer and col cell in an subject comprises assaying for ALK , ROS1 , Trka , orectal cancer and possibly other indications in which a TrkB , or TrkC activity in a cell extract from a pancreatic 50 defect in the modulation of ROS1 , TrkA , TrkB , or TrkC cancerous or precancerous cell population . In some embodi- activity , or a combination thereof , activity, or upregulation , ments identifying a ALK , ROS1, TrkA , TrkB , or TrkC misregulation or deletion thereof might play a role by modulation defect such as an upregulation defect or a administering a pharmaceutical composition as provided down -regulation defect, for example a nullmutation such as herein . a ALK , ROS1 , TrkA , TrkB , or TrkC deletion or a ALK , 55 In some embodiments are provided methods to treat, ROS1, TrkA , TrkB , or TrkC chimeric locus encoding a reduce the symptoms of, ameliorate the symptoms of, delay constitutively active ALK , ROS1 , TrkA , TrkB , or TrkC the onset of , or otherwise pharmaceutically address a con kinase in a cancer or precancerous pancreatic cell in an dition selected from non - small cell lung cancer , papillary subject comprises assaying for ALK , ROS1 , TrkA , TrkB , or thyroid cancer, neuroblastoma, pancreatic cancer and col TrkC transcript accumulation in an RNA population from a 60 orectal cancer associated with a ROS1 down -regulation pancreatic cancerous or precancerous cell population . In defect, for example a null mutation such as a ROS1 deletion some embodiments identifying a ALK , ROS1, TrkA , TrkB , by identifying a ROS1 down -regulation defect, for example or TrkC modulation defect such as an upregulation defect or a null mutation such as a ROS1 deletion in a cancer or a down - regulation defect, for example a null mutation such precancerous cell in an subject, and administering to the as a ALK , ROS1, TrkA , TrkB , or TrkC deletion or a ALK , 65 subject a pharmaceutical composition as provided herein . In ROS1 , TrkA , TrkB , or TrkC chimeric locus encoding a some embodiments are provided methods to treat, reduce the constitutively active ALK , ROS1 , TrkA , TrkB , or TrkC symptoms of, ameliorate the symptoms of, delay the onset US 10 , 398 ,693 B2 67 of, or otherwise pharmaceutically address a condition as an upregulation defect or a down - regulation defect, for selected from non -small cell lung cancer, papillary thyroid example a null mutation such as a ALK , ROS1 , TrkA , TrkB , cancer, neuroblastoma, pancreatic cancer and colorectal or TrkC deletion or a ALK , ROS1, TrkA , TrkB , or TrkC cancer associated with a ROS1 down -regulation defect, for chimeric locus encoding a constitutively active ALK , ROS1, example a null mutation such as a ROS1 deletion by 5 TrkA , TrkB , or TrkC kinase in a cancer or precancerous cell identifying a ROS1 down - regulation defect, for example a in an subject comprises assaying for ALK , ROS1, TrkA , null mutation such as a ROS1 deletion in a cancer or TrkB , or TrkC transcript accumulation in an RNA popula precancerous cell in an subject, and administering to the tion from a cancerous or precancerous cell population . In subject a pharmaceutical composition as provided herein . In some embodiments identifying a ALK , ROS1 , TrkA , TrkB , some embodiments are provided methods to treat, reduce the 10 or TrkC modulation defect such as an upregulation defect or symptoms of , ameliorate the symptoms of, delay the onset a down -regulation defect, for example a null mutation such of, or otherwise pharmaceutically address a condition as a ALK , ROS1, TrkA , TrkB , or TrkC deletion or a ALK , selected from non -small cell lung cancer, papillary thyroid ROS1, TrkA , TrkB , or TrkC chimeric locus encoding a cancer , neuroblastoma, pancreatic cancer and colorectal constitutively active ALK , ROS1, TrkA , TrkB , or TrkC cancer associated with a ROS1 down - regulation defect , for 15 kinase in a cancer or precancerous cell in an subject com example a null mutation such as a ROS1 deletion by prises determining the nucleic acid sequence such as the identifying a ROS1 down - regulation defect, for example a genomic deoxyribonucleic acid sequence in a cell or cells or null mutation such as a ROS1 deletion in a cancer or a cell population comprising a cell or cells from a cancerous precancerous cell in an subject, and administering to the or precancerous cell populations . subject a pharmaceutical composition as provided herein . 20 In some embodiments are provided methods for inhibiting In some embodiments are provided methods to treat, at least one of ALK , ROS1 , TrkA , TrkB , or TrkC kinase reduce the symptoms of, ameliorate the symptoms of, delay activity , or a combination thereof, in a cell , comprising the onset of, or otherwise pharmaceutically address a con - contacting said cell with an effective amount of N - [ 5 -( 3, 5 dition selected from non - small cell lung cancer, papillary difluorobenzyl) - 1H - indazol- 3 - 411 - 4 -( 4 -methyl - piperazin - 1 thyroid cancer , neuroblastoma, pancreatic cancer and col- 25 yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide . Some orectal cancer associated with a ALK , ROS1 , TrkA , TrkB , or embodiments provide methods of inhibiting at least one of TrkC down - regulation defect, for example a null mutation ALK , ROS1 , TrkA , TrkB , or TrkC kinase activity, or a such as a ALK , ROS1, TrkA , TrkB , or TrkC deletion by combination thereof, in a cell , by contacting the cell with an identifying a ALK , ROS1 , TrkA , TrkB , or TrkC down - effective amount of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol regulation defect, for example a null mutation such as a 30 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - tetrahydro - 2H - pyran ALK , ROS1 , TrkA , TrkB , or TrkC deletion in a cancer or 4 -ylamino ) - benzamide . Some embodiments provide meth precancerous cell in an subject, and administering to the ods of inhibiting at least one of ALK , ROS1 , TrkA , TrkB , or subject a pharmaceutical composition as provided herein . TrkC kinase activity , or a combination thereof, in a cell , In some embodiments identifying a ROS1 modulation comprising contacting said cell with an effective amount of defect such as an upregulation defect or a down -regulation 35 a compound which is N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda defect, for example a null mutation such as a ROS1 deletion zol - 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H or a ROS1 chimeric locus encoding a constitutively active pyran - 4 - ylamino ) -benzamide . In some embodiments , the ROS1 kinase in a cancer or precancerous cell in an subjectN -[ 5 -( 3 ,5 - difluorobenzyl) - 1H -indazol - 3 - yl) - 4 -( 4 -methyl comprises assaying for ROS1 activity in a cell extract from piperazin - 1 - yl) - 2 - (tetrahydro - 2H -pyran - 4 -ylamino ) -benz a pancreatic cancerous or precancerous cell population . In 40 amide is delivered to the cell in the form of a pharmaceutical some embodiments identifying a ROS1 modulation defect composition as provided herein . such as an upregulation defect or a down - regulation defect , Some embodiments provide methods of inhibiting ALK , for example a null mutation such as a ROS1 deletion or a ROS1, TrkA , TrkB , or TrkC activity , or a combination ROS1 chimeric locus encoding a constitutively active ROS1 thereof , in a subject, comprising administering to said sub kinase in a cancer or precancerous cell in an subject com - 45 ject a pharmaceutical composition as provided herein that prises assaying for ROS1 transcript accumulation in an RNA comprises an effective amount of N - 15 - ( 3 , 5 - difluorobenzyl) population from a cancerous or precancerous cell popula - 1H -indazol - 3 - yl ] - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra tion . In some embodiments identifying a ROS1 modulation hydro - 2H -pyran - 4 - ylamino ) -benzamide . defect such as an upregulation defect or a down -regulation Some embodiments provide methods of treating cancer in defect, for example a null mutation such as a ROS1 deletion 50 a subject in need thereof, the method comprising inhibiting or a ROS1 chimeric locus encoding a constitutively active ALK , ROS1, TrkA , TrkB , or TrkC activity , or a combination ROS1 kinase in a cancer or precancerous cell in an subject thereof, in said subject, by administering to said subject a comprises determining the nucleic acid sequence such as the pharmaceutical composition as provided herein that com genomic deoxyribonucleic acid sequence in a cell or cells or prises an effective amount of N - [ 5 - ( 3, 5 - difluorobenzyl) - 1H a cell population comprising a cell or cells from a pancreatic 55 indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro cancerous or precancerous cell population . 2H -pyran - 4 -ylamino )- benzamide . In some embodiments identifying a ALK , ROS1 , TrkA , Some embodiments provide methods of treating non TrkB , or TrkC modulation defect such as an upregulation small cell lung cancer , papillary thyroid cancer, neuroblas defect or a down -regulation defect , for example a null toma , pancreatic cancer or colorectal cancer in a subject, mutation such as a ALK , ROS1, TrkA , TrkB , or TrkC60 comprising administering to said subject a pharmaceutical deletion or a ALK , ROS1 , Trka , TrkB , or TrkC chimeric composition as provided herein that comprises an effective locus encoding a constitutively active ALK , ROS1 , Trka , amount of N - 15 -( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 TrkB , or TrkC kinase in a cancer or precancerous cell in an (4 -methyl - piperazin - 1- yl) - 2 - ( tetrahydro - 2H -pyran -4 subject comprises assaying for ALK , ROS1 , TrkA , TrkB , or ylamino ) -benzamide . TrkC activity in a cell extract from a cancerous or precan - 65 Some embodiments provide methods of treating tumors in cerous cell population . In some embodiments identifying a a subject, said methods comprising administering to the ALK , ROS1, TrkA , TrkB , or TrkC modulation defect such subject a pharmaceutical composition as provided herein US 10 , 398 ,693 B2 69 70 that comprises an effective amount of N - [ 5 - ( 3 , 5 - difluo - tion thereof, the method comprising administering to the robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - subject a pharmaceutical composition as provided herein (tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide . that comprises an effective amount of N - [ 5 - ( 3 , 5 - difluo Some embodiments provide methods wherein the tumors robenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 are caused by the presence of non - small cell lung cancer , 5 ( tetrahydro - 2H - pyran - 4 - ylamino ) - benzamide . papillary thyroid cancer , neuroblastoma, pancreatic cancer Some embodiments provide a method for treating a or colorectal cancer in the subject . Some embodiments subject having ALK , ROS1, TrkA , TrkB , or TrkC positive provide methods wherein one or more of the cells compris - cancer, or a combination thereof, the method comprising ing the tumors in the subject test positive for the presence of administering to the subject a pharmaceutical formulation as a gene that expresses at least one of ALK , ROS1, TrkA , 10 provided herein that comprises an effective amount of TrkB , or TrkC kinase or one or more of the cells comprising N -15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl the tumors in said subject demonstrates at least one of ALK , piperazin - 1 - yl) - 2 - (tetrahydro - 2H -pyran - 4 -ylamino ) -benz ROS1, Trka , TrkB , or TrkC kinase activity. amide. Some embodiments provide methods wherein one or Some embodiments provide a method of treating a cancer more of the cells comprising the tumors in the subject test 15 subject, comprising ( a ) acquiring knowledge of the presence positive for at least one gene rearrangement comprising the of at least one genetic alteration in at least one target gene gene , or a fragment thereof, that expresses at least one of in the cancer subject, wherein the at least one target gene is ALK , ROS1, TrkA , TrkB , or TrkC kinase . Some embodi - selected from ALK1, BDNF, NGF, NGFR , NTF3 , NTF4 , ments provide such methods wherein the cells test positive ROS1, SORT1 , NTRK1, NTRK2, and NTRK3 ; and ( b ) for at least one ofROS1 , TrkA , TrkB , or TrkC kinases . Some 20 administering a pharmaceutical composition as provided embodiments provide methods wherein the cells test posi - herein to said cancer subject, said pharmaceutical compo tive for ROS1 kinase . Some embodiments provide methods sition comprising a therapeutically effective amount of N - [ 5 wherein the cells test positive for at least one of TrkA , TrkB (3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl )- 4 -( 4 -methyl -piper and TrkC kinase . Some embodiments provide methods azin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide . wherein the cells test positive for TrkA kinase . Some 25 Some embodiments provide a method of treating a cancer embodiments provide methods wherein the cells test posi - subject, comprising administering to said cancer subject a tive for TrkB kinase. Some embodiments provide such pharmaceutical composition as provided herein that com methods wherein the cells test positive for TrkC kinase . prises a therapeutically effective amount of N - [5 -( 3 , 5 - dif Some embodiments provide methods of treating cancer in luorobenzyl ) - 1H - indazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) a subject, the method comprising : ( 1 ) testing one or more 30 2 - tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide , wherein cells comprising the tumors in the subject for the presence prior to said administration of said pharmaceutical compo of at least one of ALK , ROS1 , TrkA , TrkB , or TrkC kinase ; sition , said cancer subject is known to possess at least one and ( 2 ) administering to the subject a pharmaceutical com genetic alteration in at least one target gene selected from position as provided herein that comprises an effective ALK1 , BDNF, NGF, NGFR , NTF3 , NTF4 , ROS1 , SORT1 , amount of N -15 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - y11 - 4 - 35 NTRK1, NTRK2 , and NTRK3 . ( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro - 2H -pyran -4 Some embodiments provide a method of treating cancer ylamino )- benzamide if said one or more cells tests positive in a subject, comprising administering to said cancer subject for at least one of ALK , ROS1, TrkA , TrkB , or TrkC kinase . known to possess at least one genetic alteration in at least Some embodiments provide methods of treating cancer in one target gene selected from ALK1, BDNF, NGF, NGFR , a subject, the method comprising : ( 1 ) testing one or more 40 NTF3, NTF4, ROS1 , SORT1, NTRK1, NTRK2 , and cells comprising the tumors in the subject for the presence NTRK3 a pharmaceutical composition as provided herein of at least one of ROS1 , TrkA , TrkB , or TrkC kinase ; and ( 2 ) that comprises a therapeutically effective amount of N -[ 5 administering to the subject a pharmaceutical formulation as (3 ,5 - difluorobenzyl) - 1H - indazol- 3 -yl )- 4 -( 4 -methyl -piper provided herein that comprises an effective amount of azin - 1 -yl ) - 2 -( tetrahydro - 2H -pyran - 4 -ylamino )- benzamide . N - 15 -( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 -( 4 -methyl - 45 Some embodiments provide a method of treating a cancer piperazin - 1 - yl) - 2 -( tetrahydro - 2H -pyran - 4 - ylamino ) - benz - subject, wherein said cancer subject is known to possess at amide if said one or more cells tests positive for at least one least one genetic alteration in at least one target gene , of ROS1 , TrkA , TrkB , or TrkC kinase . comprising administering to said cancer subject a pharma Some embodiments provide methods of treating cancer in ceutical compositions comprising a therapeutically effective a subject, wherein one or more cancerous cells in said 50 amount of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 subject express at least one of ROS1 , TrkA , TrkB , or TrkC ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H - pyran - 4 kinase , the method comprising administering to the subject y lamino )- benzamide , and wherein said target gene is a pharmaceutical composition as provided herein that com - selected from ALK1, BDNF, NGF, NGFR , NTF3 , NTF4 , prises an effective amount of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - ROS1, SORT1 , NTRK1, NTRK2, and NTRK3 . indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 55 Some embodiments provide a method of treating a cancer 2H -pyran - 4 - ylamino ) - benzamide , subject , wherein prior to said treatment said subject is Some embodiments provide methods of treating cancer in known to possess at least one genetic alteration in at least a subject , wherein one or more cancerous cells in said one target gene , comprising administering to said cancer subject express at least one of ROS1, TrkA , TrkB , or TrkC subject a pharmaceutical composition as provided herein kinase , the method comprising administering to the subject 60 that comprises a therapeutically effective amount of N - 15 a pharmaceutical composition as provided herein that com ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl )- 4 - ( 4 - methyl - piper prises an effective amount of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H azin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide , indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro and wherein said target gene is selected from ALK1, BDNF , 2H - pyran - 4 -ylamino )- benzamide . NGF, NGFR , NTF3, NTF4 , ROS1, SORT1 , NTRK1, Some embodiments provide a method for treating a 65 NTRK2, and NTRK3. subject having cancer, wherein tumors from said subject are Some embodiments provide a method of treating a cancer ALK , ROS1, TrkA , TrkB , or TrkC positive, or a combina- subject, comprising administering to said cancer subject a US 10 , 398 ,693 B2 72 pharmaceutical composition as provided herein that com benzamide and the combination anti -cancer agents when prises a therapeutically effective amount of N - [ 5 - ( 3 , 5 -dif taken as a whole is therapeutically effective for treating said luorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) abnormal cell growth . 2 - ( tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide , and In some embodiments , the anti - cancer agent used in wherein prior to said pharmaceutical composition being 5 conjunction with the pharmaceutical compositions described herein is an anti -angiogenesis agent (e .g ., an agent that stops administered to said subject , said subject is known to tumors from developing new blood vessels ). Examples of possess at least one genetic alteration in at least one target anti - angiogenesis agents include for example VEGF inhibi gene selected from ALK1, BDNF, NGF, NGFR , NTF3 , tors, VEGFR inhibitors , TIE - 2 inhibitors , PDGFR inhibi NTF4 , ROS1, SORT1, NTRK1, NTRK2, and NTRK3 . 10 tors , angiopoetin inhibitors , PKC -beta inhibitors , COX -2 Some embodiments provide a method for treating a 10 ( cyclooxygenase II ) inhibitors , integrins ( alpha - v /beta - 3 ) , cancer subject , comprising (a ) acquiring knowledge of the MMP - 2 (matrix -metalloproteinase 2 ) inhibitors , and presence of at least one genetic alteration in at least one MMP - 9 (matrix -metalloproteinase 9 ) inhibitors . Preferred target gene selected from ALK1, BDNF , NGF, NGFR , anti -angiogenesis agents include sunitinib ( Sutent® ) , beva NTF3, NTF4 , ROS1 , SORT1 , NTRK1, NTRK2, and 15 cizumab ( Avastin® ) , axitinib ( AG 13736 ), SU 14813 NTRK3 ; and (b ) administering to said subject a pharmaceu (Pfizer ), and AG 13958 (Pfizer ). tical composition as provided herein that comprises a thera Additional anti - angiogenesis agents include vatalanib peutically effective amount of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - (CGP 79787 ) , Sorafenib (Nexavar® ) , pegaptanib octaso 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 dium (Macugen® ), vandetanib (Zactima® ) , PF - 0337210 ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide . 20 ( Pfizer ) , SU 14843 ( Pfizer ), AZD 2171 ( AstraZeneca ) , Some embodiments provide any of the methods described ranibizumab (Lucentis® ), Neovastat® (AE 941) , tetrathio herein wherein the subject or subject is suffering from cancer molybdata (Coprexa® ) , AMG 706 (Amgen ), VEGF Trap and the cancer is selected from at least one of non -small cell (AVE 0005 ), CEP 7055 ( Sanofi - Aventis ), XL 880 (Exelixis ) , lung cancer, papillary thyroid cancer, neuroblastoma, pan - telatinib (BAY 57 -9352 ), and CP -868 ,596 (Pfizer ). creatic cancer and colorectal cancer. Some embodiments 25 Other anti- angiogenesis agents include enzastaurin (LY provide any of the methods described herein wherein the 317615 ), midostaurin ( CGP 41251) , perifosine (KRX 0401) , subject or subject is suffering from non -small cell lung teprenone ( Selbex® ) and UCN 01 (Kyowa Hakko ) . cancer . Some embodiments provide any of the methods Other examples of anti -angiogenesis agents which can be described herein wherein the subject or subject is suffering used in conjunction with one or more pharmaceutical com de 30 positions described herein include celecoxib (Celebrex® ) , from papillary thyroid cancer . Some embodiments provide 30 parecoxibp (Dynastat® ) , deracoxib (SC 59046 ) , lumiracoxib any of the methods described herein wherein the subject or ( Preige® ) , valdecoxib (Bextra® ) , rofecoxib (Vioxx® ), igu subject is suffering from neuroblastoma. Some embodiments ratimod ( Careram® ) , IP 751 ( Invedus ), SC - 58125 (Pharma provide any of the methods described herein wherein the cia ) and etoricoxib ( Arcoxia® ) . subject or subject is suffering from pancreatic cancercer:. someSome 35 Other anti- angiogenesis agents include exisulind ( Apto embodiments provide any of the methods described herein syn® ), salsalate ( Amigesic® ) , diflunisal (Dolobid® ), ibu wherein the subject or subject is suffering from colorectal profen (Motrin® ) , ketoprofen (Orudis® ) nabumetone cancer . (Relafen® ), piroxicam (Feldene® ), naproxen ( Alever , In some embodiments , the pharmaceutical compositions Naprosyn ) diclofenac ( Voltaren® ), indomethacin ( Indo provided herein may be used in combination with one or 40 cin® ) , sulindac ( Clinoril® ) , tolmetin ( Tolectin® ) , etodolac more additional anti - cancer agents which are described (Lodine® ), ketorolac ( Torado1® ), and oxaprozin (Day below . When a combination therapy is used , the one or more pro® ) . additional anti -cancer agents may be administered sequen - Other anti -angiogenesis agents include ABT 510 ( Ab tially or simultaneously with the pharmaceutical composi - bott) , apratastat ( TMI 005 ), AZD 8955 ( AstraZeneca ), tions provided herein . In some embodiments , the additional 45 incyclinide (Metastat® ) , and PCK 3145 (Procyon ). anti - cancer agent is administered to a mammal ( e. g . , a Other anti - angiogenesis agents include acitretin (Neoti human ) prior to administration of the pharmaceutical com - gason® ), plitidepsin ( Aplidine® ), cilengtide (EMD positions provided herein . In some embodiments , the addi- 121974 ), combretastatin A4 (CA4P ), fenretinide (4 HPR ), tional anti -cancer agent is administered to the mammal after halofuginone ( Tempostatin® ), Panzem® (2 -methoxyestra administration of the pharmaceutical compositions provided 50 diol) , PF - 03446962 (Pfizer ) , rebimastat (BMS 275291) , herein . In some embodiments, the additional anti- cancer catumaxomab (Removab® ) , lenalidomide (Revlimid® ) agent is administered to the mammal ( e . g . , a human ) simul- squalamine (EVIZON® ), thalidomide ( Thalomid® ) , taneously with the administration of pharmaceutical com Ukrain® (NSC 631570 ), Vitaxin® (MEDI 522 ), and zole positions provided herein . dronic acid (Zometa® ) . Some embodiments also relate to pharmaceutical compo - 55 In some embodiments , the anti- cancer agent is a so called sitions for the treatment of abnormal cell growth in a signal transduction inhibitor ( e . g ., inhibiting the means by mammal, comprising a human , which comprises an amount which regulatory molecules that govern the fundamental of one or more pharmaceutical compositions provided processes of cell growth , differentiation , and survival com herein comprising hydrates, solvates and polymorphs of municated within the cell) . Signal transduction inhibitors N - 15 -( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 -( 4 -methyl - 60 include small molecules, antibodies , and antisense mol piperazin - 1 - yl) - 2 - (tetrahydro - pyran - 4 - ylamino ) - benzamide ecules . Signal transduction inhibitors include for example in combination with one or more (preferably one to three ) kinase inhibitors (e . g ., tyrosine kinase inhibitors or serine / anti - cancer agents selected from the group consisting of threonine kinase inhibitors ) and cell cycle inhibitors . More anti - angiogenesis agents and signal transduction inhibitors specifically signal transduction inhibitors include , for and a pharmaceutically acceptable carrier, wherein the 65 example , ALK inhibitors, ROS1 inhibitors , TrkA inhibitors , amounts of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - TrkB inhibitors , TrkC inhibitors , farnesyl protein transferase ( 4 -methyl - piperazin -1 - yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) inhibitors, EGF inhibitor, ErbB - 1 (EGFR ), ErbB -2 , pan erb , US 10 , 398 ,693 B2 73 74 IGF1R inhibitors , MEK , C -Kit inhibitors, FLT- 3 inhibitors , 4227 ( Cheisi )) , Selective Estrogen -Receptor Downregula K -Ras inhibitors , P13 kinase inhibitors , JAK inhibitors , tors (SERD ' s ; such as fulvestrant ), exemestane ( Aromasin ) , STAT inhibitors , Raf kinase inhibitors , Akt inhibitors , anastrozole (Arimidex ) , atamestane, fadrozole , letrozole mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the (Femara ), gonadotropin -releasing hormone (GnRH ; also WNT pathway and so called multi- targeted kinase inhibi- 5 commonly referred to as luteinizing hormone- releasing hor tors . mone [LHRH ]) agonists such as buserelin (Suprefact ) , gos Preferred signal transduction inhibitors include gefitinib erelin (Zoladex ), leuprorelin ( Lupron ), and triptorelin ( Trel ( Iressa® ) , cetuximab ( Erbitux® ), erlotinib ( Tarceva® ) , tras star) , abarelix (Plenaxis ), bicalutamide ( Casodex ), tuzumab (Herceptin® ) , sunitinib (Sutent® ) imatinib cyproterone , flutamide ( Eulexin ) , megestrol, nilutamide (Gleevec® ) , and PD325901 (Pfizer ). 10 Additional examples of signal transduction inhibitors (Nilandron ), and osaterone , dutasteride, epristeride , finas which may be used in conjunction with one or more phar teride , Serenoa repens , PHL 00801, abarelix , goserelin , maceutical compositions provided herein include BMS leuprorelin , triptorelin , bicalutamide, tamoxifen , exemes 214662 ( Bristol- Myers Squibb ), lonafarnib ( Sarasar® ), peli tane, anastrozole, fadrozole , formestane , letrozole , and com trexol ( AG 2037 ), matuzumab (EMD 7200 ), nimotuzumab 15 binations thereof. ( TheraCIM h -R3® ) , panitumumab (Vectibix® ) , Vandetanib Other examples of classical antineoplastic agents used in ( Zactima® ), pazopanib (SB 786034 ) , ALT 110 ( Alteris combination with pharmaceutical compositions provided Therapeutics ), BMW 2992 (Boehringer Ingelheim ), and herein include , but are not limited to , suberolanilide Cervene® ( TP 38 ) . hydroxamic acid (SAHA , Merck Inc. / Aton Pharmaceuti Other examples of signal transduction inhibitor include 20 cals ) , depsipeptide (FR901228 or FK228 ) , G2M - 777 , PF - 2341066 (Pfizer ), PF - 299804 (Pfizer ) , canertinib (CI MS - 275 , pivaloyloxymethyl butyrate and PXD - 101; Onco 1033 ) , pertuzumab (Omnitarg® ), Lapatinib ( Tycerb® ), peli- nase ( ranpirnase ), PS - 341 (MLN - 341 ) , Velcade (bort tinib ( EKB 569 ), miltefosine (Miltefosin® ), BMS 599626 ezomib ) , 9 -aminocamptothecin , belotecan , BN -80915 ( Bristol-Myers Squibb ) , Lapuleucel- T (Neuvenge® ) , Neu - (Roche ), camptothecin , diflomotecan , edotecarin , exatecan Vax® (E75 cancer vaccine ), Osidem® (IDM 1 ), mubritinib 25 (Daiichi ) , gimatecan , 10 -hydroxycamptothecin , irinotecan ( TAK - 165) , CP -724 ,714 (Pfizer ) , panitumumab HCl ( Camptosar ), lurtotecan , Orathecin ( rubitecan , Super ( Vectibix® ) , lapatinib ( Tycerb® ), PF - 299804 (Pfizer ) , peli - gen ), SN - 38 , topotecan , camptothecin , 10- hydroxycamp tinib ( EKB 569 ) , and pertuzumab (Omnitarg® ). tothecin , 9 -aminocamptothecin , irinotecan , SN - 38 , edote Other examples of signal transduction inhibitors include carin , topotecan , aclarubicin , paclitaxel, amonafide , ARRY 142886 (Array Biopharm ) , everolimus ( Certican® ) , 30 amrubicin , annamycin , daunorubicin , doxorubicin , zotarolimus (Endeavor® ) , temsirolimus ( Torisel® ) , AP elsamitrucin , epirubicin , etoposide , idarubicin , galarubicin , 23573 (ARIAD ), and VX 680 (Vertex ). hydroxycarbamide, nemorubicin , novantrone (mitoxan Additionally , other signal transduction inhibitors include trone ), pirarubicin , pixantrone , procarbazine, rebeccamycin , XL 647 (Exelixis ) , sorafenib (Nexavar® ), LE - AON sobuzoxane, tafluposide, valrubicin , Zinecard (dexrazox (Georgetown University ) , and GI- 4000 (GlobeImmune ) . 35 ane ) , nitrogen mustard N -oxide , cyclophosphamide , AMD Other signal transduction inhibitors include ABT 751 473 , altretamine, AP -5280 , apaziquone, brostallicin , benda (Abbott ) , alvocidib ( flavopiridol) , BMS 387032 (Bristol mustine , busulfan , carboquone, carmustine , chlorambucil, Myers ), EM 1421 ( Erimos) , indisulam ( E 7070 ), seliciclib dacarbazine, estramustine , fotemustine, glufosfamide , ifos (CYC 200 ) , BIO 112 (One Bio ) , BMS 387032 (Bristol - famide, KW - 2170 , lomustine , mafosfamide, mechlore Myers Squibb ) , PD 0332991 (Pfizer ) , AG 024322 (Pfizer ) , 40 thamine ,melphalan , mitobronitol, mitolactol, mitomycin C , LOXO - 101 ( Loxo Oncology ) , crizotinib , and ceritinib . mitoxatrone, nimustine , ranimustine, temozolomide, thio In some embodiments , the pharmaceutical compositions tepa , and platinum -coordinated alkylating compounds such provided herein are used together with classical antineoplas- as cisplatin , Paraplatin (carboplatin ), eptaplatin , lobaplatin , tic agents . Classical antineoplastic agents include but are not nedaplatin , Eloxatin (oxaliplatin , Sanofi ) , streptozocin , limited to hormonal modulators such as hormonal, anti - 45 satrplatin , and combinations thereof. hormonal, androgen agonist, androgen antagonist and anti - In some embodiments , the pharmaceutical compositions estrogen therapeutic agents , histone deacetylase (HDAC ) provided herein are used together with dihydrofolate reduc inhibitors, gene silencing agents or gene activating agents , tase inhibitors ( such as methotrexate and NeuTrexin (trime ribonucleases , proteosomics , Topoisomerase I inhibitors , trexate ) ) , purine antagonists ( such as 6 -mercaptopurine ribo Camptothecin derivatives , Topoisomerase II inhibitors , 50 side , mercaptopurine, 6 - thioguanine, cladribine, clofarabine alkylating agents , antimetabolites , poly ( ADP -ribose ) poly - (Clolar ) , fludarabine , nelarabine , and raltitrexed ) , pyrimi merase - 1 (PARP - 1) inhibitor , microtubulin inhibitors , anti- dine antagonists (such as 5 - fluorouracil ( 5 - FU ), Alimta biotics , plant derived spindle inhibitors , platinum - coordi ( premetrexed disodium , LY231514 , MTA ) , capecitabine nated compounds, gene therapeutic agents , antisense (Xeloda® ) , cytosine arabinoside , Gemzar ( gemcitabine , oligonucleotides , vascular targeting agents (VTAS ) , and sta - 55 Eli Lilly ) , Tegafur (UFT Orzel or Uforal and including TS - 1 tins. combination of tegafur, gimestat and otostat) , doxifluridine , Examples of classical antineoplastic agents used in com - carmofur, cytarabine ( including ocfosfate , phosphate stear bination therapy with one or more pharmaceutical compo - ate , sustained release and liposomal forms) , enocitabine , sitions provided herein optionally with one or more other 5 - azacitidine ( Vidaza ), decitabine , and ethynylcytidine ) and agents include , but are not limited to , glucocorticoids , such 60 other antimetabolites such as eflornithine, hydroxyurea , leu as dexamethasone, prednisone , prednisolone, methylpredni- covorin , nolatrexed ( Thymitaq ), triapine , trimetrexate , N - ( 5 solone , hydrocortisone, and progestins such as medroxypro - [N - ( 3 , 4 - dihydro - 2 -methyl - 4 -oxoquinazolin - 6 - ylmethyl) - N gesterone, megestrol acetate (Megace ), mifepristone (RU - methylamino )- 2- thenoyl) -L -glutamic acid , AG -014699 486 ) , Selective Estrogen Receptor Modulators (SERMs ; (Pfizer Inc .) , ABT- 472 (Abbott Laboratories ), INO - 1001 such as tamoxifen , raloxifene , lasofoxifene , afimoxifene , 65 ( Inotek Pharmaceuticals ) , KU - 0687 (KuDOS Pharmaceuti arzoxifene , bazedoxifene, fispemifene , ormeloxifene , cals ) and GPI 18180 (Guilford Pharm Inc ) and combinations ospemifene , tesmilifene , toremifene , trilostane and CHF thereof . US 10 , 398 ,693 B2 75 76 Other examples of classical antineoplastic cytotoxic cetuximab (Erbitux ), clofarabine ( Clofarex ), CMD - 193 , agents used in combination therapy with one or more combretastatin , Cotara , CT- 2106 , CV -247 , decitabine (Da pharmaceutical compositions provided herein optionally cogen ), E - 7070 , E -7820 , edotecarin , EMD - 273066 , with one or more other agents include, but are not limited to , enzastaurin (LY -317615 ) epothilone B (EPO - 906 ) , erlotinib Abraxane ( Abraxis BioScience, Inc . ) , Batabulin ( Amgen ), 5 ( Tarceva ), flavopyridol, GCAN - 101 , gefitinib ( Iressa ) , EPO 906 (Novartis ) , Vinflunine (Bristol - Myers Squibb huA33 , huC242- DM4, imatinib (Gleevec ), indisulam , ING Company ), actinomycin D , bleomycin , mitomycin C , neo - 1 , irinotecan (CPT - 11, Camptosar) ISIS 2503 , ixabepilone , carzinostatin ( Zinostatin ) , vinblastine , vincristine , vin - lapatinib ( Tykerb ) , mapatumumab (HGS - ETR1) , MBT desine , vinorelbine (Navelbine ), docetaxel ( Taxotere ), 0206 , MEDI- 522 ( Abregrin ), Mitomycin , MK - 0457 (VX Ortataxel, paclitaxel ( including Taxoprexin a DHA /pacli - 10 680 ) , MLN - 8054 , NB - 1011 , NGR - TNF, NV- 1020 , taxel conjugate ) , cisplatin , carboplatin , Nedaplatin , oxali - oblimersen (Genasense , G3139) , OncoVex , ONYX 015 (CI platin ( Eloxatin ), Satraplatin , Camptosar , capecitabine (Xe - 1042 ), oxaliplatin (Eloxatin ), panitumumab ( ABX - EGF, loda ), oxaliplatin ( Eloxatin ), Taxotere alitretinoin , Vectibix ) , pelitinib (EKB -569 ) , pemetrexed ( Alimta ), Canfosfamide ( Telcyta® ) , DMXAA ( Antisoma) , ibandronic PD -325901 , PF - 0337210 , PF - 2341066 , RAD - 001 ( Everoli acid , L - asparaginase , pegaspargase (Oncaspar® ), Efaproxi- 15 mus) , RAV - 12 , Resveratrol, Rexin -G , S - 1 ( TS - 1 ), seliciclib , ral (Efaproxyn® — radiation therapy ) ) , bexarotene ( Targre - SN -38 liposome, Sodium stibogluconate (SSG ), sorafenib tin® ) , Tesmilifene (DPPE — enhances efficacy of cytotox - (Nexavar ) , SU - 14813 , sunitinib (Sutent ) , temsirolimus (CCI ics )) , Theratope® (Biomira ), Tretinoin (Vesanoid® ), 779 ), tetrathiomolybdate , thalomide, TLK -286 ( Telcyta ), tirapazamine ( Trizaone® ) , motexafin gadolinium topotecan (Hycamtin ), trabectedin ( Yondelis ) , vatalanib (Xcytrin® ) Cotara® (mAb ) , and NBI -3001 ( Protox Thera - 20 (PTK - 787 ) , vorinostat (SAHA , Zolinza ) , WX -UK1 , and peutics ) , polyglutamate -paclitaxel (Xyotax® ) and combina - ZYC300 , wherein the amounts of the active agent together tions thereof. with the amounts of the combination anticancer agents are Further examples of classical antineoplastic agents used effective in treating colorectal cancer. in combination therapy with one or more pharmaceutical Some embodiments provide methods for the treatment of compositions provided herein optionally with one or more 25 renal cell carcinoma in a human in need of such treatment, other agents include , but are not limited to , as Advexin (ING comprising administering to said human an amount of 201 ), TNFerade (GeneVec , one or more compounds which pharmaceutical compositions provided herein in combina express TNFalpha in response to radiotherapy ), RB94 (Bay - tion with one or more (preferably one to three ) anti -cancer lor College of Medicine ) , Genasense (Oblimersen , Genta ), agents selected from the group consisting of capecitabine Combretastatin A4P (CAP ) , Oxi- 4503 , AVE -8062 , 30 (Xeloda ) , interferon alpha , interleukin - 2 , bevacizumab ZD -6126 , TZT - 1027 , Atorvastatin (Lipitor , Pfizer Inc . ) , Pro (Avastin ), gemcitabine (Gemzar ), thalidomide, cetuximab vastatin (Pravachol , Bristol -Myers Squibb ) , Lovastatin (Me - (Erbitux ) , vatalanib (PTK -787 ) , Sutent, AG - 13736 , vacor, Merck Inc. ), Simvastatin (Zocor , Merck Inc . ), Fluv SU -11248 , Tarceva , Iressa , Lapatinib and Gleevec , wherein astatin (Lescol , Novartis ) , Cerivastatin (Baycol , Bayer ), the amounts of the active agent together with the amounts of Rosuvastatin (Crestor , AstraZeneca ), Lovostatin , Niacin 35 the combination anticancer agents is effective in treating ( Advicor, Kos Pharmaceuticals ) , Caduet , Lipitor, torce - renal cell carcinoma. trapib , and combinations thereof. Some embodiments provide methods for the treatment of Some embodiments relate to a method for the treatment of melanoma in a human in need of such treatment, comprising breast cancer in a human in need of such treatment. In some administering to said human an amount of pharmaceutical embodiments , the method includes , for example , adminis - 40 compositions provided herein , in combination with one or tering to said human an amount of one or more pharmaceu - more (preferably one to three ) anti - cancer agents selected tical compositions provided herein in combination with one from the group consisting of interferon alpha , interleukin - 2 , or more (preferably one to three ) anti -cancer agents selected temozolomide ( Temodar ) , docetaxel ( Taxotere ), paclitaxel , from the group consisting of trastuzumab , tamoxifen , doc - Dacarbazine (DTIC ) , carmustine (also known as BCNU ) , etaxel , paclitaxel, capecitabine, gemcitabine, vinorelbine, 45 Cisplatin , vinblastine , tamoxifen , PD - 325, 901, Axitinib , exemestane , letrozole and anastrozole . bevacizumab ( Avastin ) , thalidomide , sorafanib , vatalanib Some embodiments provide a method of treating colorec (PTK -787 ) , Sutent, CpG - 7909 , AG -13736 , Iressa , Lapatinib tal cancer in a mammal, such as a human , in need of such and Gleevec , wherein the amounts of the pharmaceutical treatment, by administering an amount of one or more compositions provided herein together with the amounts of pharmaceutical compositions provided herein in combina - 50 the combination anticancer agents is effective in treating tion with one or more (preferably one to three ) anti - cancer melanoma. agents . Examples of particular anti -cancer agents include Some embodiments provide methods for the treatment of those typically used in adjuvant chemotherapy, such as lung cancer in a human in need of such treatment, compris FOLFOX , a combination of 5 - fluorouracil ( 5 - FU ) or ing administering to said human an amount of one or more capecitabine Xeloda ), leucovorin and oxaliplatin (Eloxa - 55 pharmaceutical compositions provided herein in combina tin ) . Further examples of particular anti - cancer agents tion with one or more (preferably one to three ) anti - cancer include those typically used in chemotherapy for metastatic agents selected from the group consisting of capecitabine disease , such as FOLFOX or FOLFOX in combination with ( Xeloda ), bevacizumab ( Avastin ) , gemcitabine (Gemzar ) , bevacizumab (Avastin ); and FOLFIRI, a combination of docetaxel ( Taxotere ), paclitaxel , premetrexed disodium ( Al 5 - FU or capecitabine, leucovorin and irinotecan (Camp - 60 imta ) , Tarceva , Iressa , Vinorelbine, Irinotecan , Etoposide , tosar ) . Further examples include 17 -DMAG , ABX - EFR , Vinblastine, and Paraplatin ( carboplatin ), wherein the AMG - 706 , AMT- 2003 , ANX -510 ( CoFactor ) , aplidine amounts of the active agent together with the amounts of the (plitidepsin , Aplidin ), Aroplatin , axitinib ( AG - 13736 ) , AZD - combination anticancer agents is effective in treating lung 0530 , AZD - 2171 , bacillus Calmette -Guerin (BCG ) , bevaci cancer. zumab ( Avastin ) , BIO - 117 , BIO - 145 , BMS - 184476 , BMS - 65 The presence of at least one genetic alteration in at least 275183 , BMS - 528664, bortezomib (Velcade ), C - 1311 one target gene in a cancer subject, wherein the at least one ( Symadex ) , cantuzumab mertansine, capecitabine ( Xeloda ), target gene is selected from ALK1, BDNF, NGF, NGFR , US 10 , 398 ,693 B2 77 78 NTF3 , NTF4 , ROS1 , SORT1, NTRK1, NTRK2, and ROS1, TrkA , TrkB , or TrkC transcript accumulation in an NTRK3may be detected by use of an assay that includes one RNA population from a pancreatic cancerous or precancer or more antibodies that bind to at least two , three , four, or all ous cell population . In some instances , identifying a ALK , of ALK , ROS1 , TrkA , TrkB and TrkC biomarkers. The one ROS1, TrkA , TrkB , or TrkC modulation defect such as an or more molecular alterations detected in the biological 5 upregulation defect or a down - regulation defect, for sample may involve at least two , at least three , or at least example a null mutation such as a ALK , ROS1 , TrkA , TrkB , four of the biomarkers . The knowledge of the presence of the or TrkC deletion or a ALK , ROS1 , TrkA , TrkB , or TrkC one or more molecular alterations in the biological sample chimeric locus encoding a constitutively active ALK , ROS1, may be acquired from an assay that includes contacting the TrkA , TrkB , or TrkC kinase in a cancer or precancerous biological sample with one or more antibodies or fragments 10 pancreatic cell in an subject comprises determining the thereof that are specific for the biomarkers . In some nucleic acid sequence such as the genomic deoxyribonucleic instances, the specific antibodies are monoclonal antibodies. acid sequence in a cell or cells or a cell population com In some instances, the specific antibodies include at least one prising a cell or cells from a pancreatic cancerous or of D5F3® , D4D5® , C17F1® , and combinations thereof . In precancerous cell population . some instances, the biological sample is contacted with one 15 The term " microarray, " as used herein , means an ordered or more of the specific antibodies simultaneously . In some arrangement of array elements (for example , small samples instances, the biological sample is sequentially contacted of a biological sample from a subject such as tissue samples ) with the specific antibodies . In some instances , the one or mounted on a solid support capable of binding other mol more molecular alterations results in elevated expression of ecule species or antibodies . The array elements are arranged one or more of the ALK , ROS1, TrkA , TrkB , and TrkC 20 so that there are preferably at least one or more different biomarkers. In some instances , the knowledge of the one or array elements . more molecular alterations is acquired from an assay The term “ solid support, " as used herein , means the wherein determining whether the expression of one or more well - understood solid materials to which various compo biomarker is elevated includes: (a ) determining the expres - nents such as , for example , proteins and nucleic acids , are sion level of the one or more biomarkers in the biological 25 physically attached , thereby immobilizing the components . sample ; and ( b ) comparing the determined expression level The term “ solid support, " as used herein , means a non - liquid to a reference expression level. substance . A solid support can be , but is not limited to , a As used herein , the term " reference level” refers to known membrane, sheet, gel, glass, plastic or metal. Immobilized expression level of the target biomarker (s ) in a control components may be associated with a solid support by person or subject . In some instances , the reference expres - 30 covalent bonds and / or via non - covalent attractive forces sion level is the expression level of the target biomarker ( s ) such as hydrogen bond interactions , hydrophobic attractive in a healthy person or subject. In some instances, the forces and ionic forces , for example . reference expression level is the expression level of the In some instances, the microarrays suitable for the meth target biomarker ( s ) in a population of healthy control cells . ods provided herein have a density of at least 1 , 2 , 4 , 6 , 8 , In some instances , the reference expression level is the 35 10 spots /cm² , preferably at least 10 , 20 , 30 , 40 , 50 , 60, 70 , expression level of the target biomarker( s ) in a control 80 , 90 , 100 , 110 , 120 , 130 , 140 , 150 , 160 , 170 , 180 , 190 , person or subject that has been previously determined to 200 , more preferably at least 210 , 220 , 230 , 250 , 275 , 300 , possess one or more molecular alterations . In some 325 , 350 , 375 , 400 , 425 , 450 , 475 , 500 , 550 , 600 , 650 , 700 , instances , the reference expression level is the expression 750 , 800 , 850 , 900 , 950 , 1000 , 2000 , 3000 , 4000 , 5000 , level of the target biomarker ( s ) in a population of control 40 6000 , 7000 , 8000 or 9000 spots / cm². cells that have been previously determined to possess one or In some instances , it is contemplated that the spots on the more molecular alterations . array may each represent a different species of biomarkers or In some instances, the knowledge of the one or more that the multiple spots on the array may represent the same molecular alterations is acquired from an antibody -based species of biomarkers. In some instances , the spots each assay . The antibody -based assay can generally be any anti - 45 represent an array element of differing identity or charac body -based assay , and can be , for example , ELISA , immu - teristics . nohistochemistry , western blotting , mass spectrometry , flow In some instances , implementations of the methods cytometry , protein -microarray , immunofluorescence , and a according to this and other aspects of the present disclosure multiplex detection assay . In some instances , the antibody - further include acquiring knowledge of a genetic alteration based assay includes an immunohistochemistry analysis . 50 in the cancer of the subject from a second analytical assay In some instances , identifying a ALK , ROS1, TrkA , TrkB , prior to the administering step . The second analytical assay or TrkC modulation defect such as an upregulation defect or can generally be any analytical assay known to those having a down- regulation defect , for example a null mutation such ordinary skill in the art, and can be for example an antibody as a ALK , ROS1 , TrkA , TrkB , or TrkC deletion or a ALK , based assay , a nucleotide- based assay, or an enzymatic ROS1 , TrkA , TrkB , or TrkC chimeric locus encoding a 55 activity assay . Non - limiting examples of suitable second constitutively active ALK , ROS1, TrkA , TrkB , or TrkC analytical assays include capillary electrophoresis, nucleic kinase in a cancer or precancerous pancreatic cell in an acid sequencing, polypeptide sequencing, restriction diges subject comprises assaying for ALK , ROS1 , TrkA , TrkB , or tion , nucleic acid amplification -based assays , nucleic acid TrkC activity in a cell extract from a pancreatic cancerous or hybridization assay, comparative genomic hybridization , precancerous cell population . In some instances, identifying 60 real - time PCR , quantitative reverse transcription PCR ( QRT a ALK , ROS1, TrkA , TrkB , or TrkC modulation defect such PCR ), PCR - RFLP assay, HPLC , mass -spectrometric geno as an upregulation defect or a down -regulation defect , for typing , fluorescent in - situ hybridization (FISH ) , next gen example a null mutation such as a ALK , ROS1 , TrkA , TrkB , eration sequencing (NGS ) , and a kinase activity assay . Other or TrkC deletion or a ALK , ROS1, Trka , TrkB , or TrkC examples of suitable second analytical assays include chimeric locus encoding a constitutively active ALK , ROS1 , 65 ELISA , immunohistochemistry , Western blotting , mass TrkA , TrkB , or TrkC kinase in a cancer or precancerous spectrometry, flow cytometry , protein -microarray , immuno pancreatic cell in an subject comprises assaying for ALK , fluorescence , and multiplex detection assay . US 10 , 398 ,693 B2 79 80 In some instances, FISH analysis is used to identify the (NSCLC ) , squamous cell lung cancer , neuroblastoma (NB ) , chromosomal rearrangement resulting in the one or more ovarian cancer, pancreatic cancer, prostate cancer , medullary molecular alterations such as the fusion genes or gene thyroid cancer, breast cancer, and papillary thyroid cancer. products as described herein . For example, to perform FISH , In some instances are provided such methods, wherein the at least a first probe tagged with a first detectable label can 5 knowledge of the presence of the one or more molecular be designed to target a first gene of a fusion gene , such as in alterations is obtained from an assay performed simultane one or more exons of the gene and at least a second probe ously on a plurality of biological samples. In some instances , tagged with a second detectable label can be designed to the plurality of biological samples may be assayed in a target a second gene of the fusion gene , such as in one or multitest platform . more exons of the genes ( for example , the exons containing 10 As used herein , the term “ multitest platform ” is intended the part of the protein that includes the tyrosine kinase to encompass any suitable means to contain one or more domain ). The at least one first probe and the at least one reaction mixtures, suspensions , or detection reactions. As second probe will be closer together in a subject who carries such , the outcomes of a number of screening events can be the fusion compared to a subject who does not carry the assembled onto one surface , resulting in a “ multitest plat fusion gene or gene product . In some instances , a variation 15 form ” having , or consisting of multiple elements or parts to of a FISH assay , for example , " break - apart FISH ” , is used to do more than one experiment simultaneously . It is intended evaluate a subject selected by a method provided herein . By that the term " multitest platform " encompasses protein this method , at least one probe targeting the fusion junction chips , microtiter plates , multi -well plates , microcards, test and at least one probe targeting a subject gene of the fusion , tubes, petri plates , trays, slides, and the like . In some e . g ., at one or more exons and or introns of the gene, are 20 instances, multiplexing can further include simultaneously utilized . In normal cells, both probes will be observed ( or a conducting a plurality of screening events in each of a secondary color will be observed due to the close proximity plurality of separate biological samples. For example , the of the two genes of the gene fusion ), and only the single gene number of biological samples analyzed can be based on the probe will be observed when the translocation occurs or the number of spots on a slide and the number of tests conducted probes , having differing colors , will be separated such that 25 in each spot (as described in greater detail in Example 2 ) . In one of ordinary skill in the art observing the probes can another example, the number of biological samples analyzed determine that a relevant gene fusion or deletion is present can be based on the number of wells in a multi -well plate and in the sample . Generally , FISH assays are performed using the number of tests conducted in each well . For example , formalin - fixed , paraffin - embedded tissue sections that are 6 -well , 12 -well , 24 -well , 48 -well , 96 -well , 384 -well , 1536 placed on slides . The DNA from the tissue sample sections 30 well or 3456 -well microtiter plates can be useful in the is denatured to single - stranded form and subsequently presently disclosed methods , although it will be appreciated allowed to hybridize with the appropriate DNA probes that by those in the art , not each microtiter well need contain a can be designed and prepared using methods and techniques subject biological sample . Depending on the size of the known to those having ordinary skill in the art . Following microtiter plate and the number of the subject biological hybridization , any unbound probe may be removed by a 35 samples in each well, very high numbers of tests can be run series of washes and the nuclei of the cells are counter - simultaneously . Although multiplexing has been exempli stained with DAPI ( 4 ', 6 diamidino - 2 -phenylindole ) , a DNA - fied in Example 2 with respect to micro - slides, it will be specific stain that fluoresces blue . Hybridization of the probe understood that other formats can be used for multiplexing . or probes are viewed using a fluorescence microscope In some instances are provided such methods, wherein the equipped with appropriate excitation and emission filters , 40 plurality ofbiological samples includes at least 6 , 12 , 24 , 48 , allowing visualization of the fluorescent signals . 96 , 200 , 384 , 400 , 500 , 1000 , 1250 , 1500 , or 3000 samples . For example, a break -apart FISH assay may be used to In some instances are provided such methods, wherein the detect multiple types of rearrangements involving the ALK one or more molecular alterations is selected from a genetic gene locus . In the method , tumor cells from some subjects mutation , a gene amplification , a gene rearrangement, a having non - small cell lung cancer (NSCLC ) , display an 45 single -nucleotide variation ( SNV ) , a deletion , an insertion , ALK -positive FISH pattern as detected using single inter - an InDelmutation , a single nucleotide pointmutation ( SNP ) , ference filter sets comprising green ( FITC ) , red ( Texas red ) , an epigenetic alteration , a splicing variant, an RNA /protein and blue ( 4 ', 6 - diamidino - 2 - phenylindole ) as well as dual overexpression , and an aberrant RNA/ protein expression . In ( red / green ) and triple ( blue , red , green ) band - pass filters . A some instances are provided such methods , wherein the fusion of the ALK gene is visualized as split orange and 50 genetic alteration includes an insertion of a heterologous green signals , single orange signals , or single orange and nucleic acid sequence within a coding sequence of a bio single green signals . marker gene. In some instances are provided such methods, Relevant molecular alterations with respect to ROSI, wherein the insertion forms a chimeric nucleic acid TrkA , TrkB and TrkC in biological samples derived from sequence that encodes a fusion peptide . cancer subjects using the samemethods as described above , 55 In some instances are provided such methods, wherein the but by modifying the reagents , probes and other materials acquiring knowledge of the one or more molecular altera used in the assays in ways that are appropriate to the target tions further comprises determining a nucleic acid sequence molecular alteration and as can be readily determined by and / or an amino acid sequence comprising the one or more those having ordinary skill in the art . molecular alterations. In some instances , the nucleic acid Other variations of the FISH method known in the art are 60 sequence comprising the one or more molecular alterations suitable for evaluating a subject selected in accordance with from a selected cancer subject tumor is sequenced . In some the methods provided herein . instances, the sequence is determined by a next generation In some instances of the methods provided herein , the sequencing method . cancer is selected from the group consisting of anaplastic Some embodiments provide a pharmaceutical composi large - cell lymphoma (ALCL ) , colorectal cancer (CRC ), 65 tion comprising a therapeutically effective amount of N -[ 5 cholangiocarcinoma , gastric , glioblastomas (GBM ), leio - ( 3 , 5 - difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piper myosarcoma, melanoma, non -small cell lung cancer azin - 1 -yl ) - 2 - ( tetrahydro -2H -pyran - 4 -ylamino ) -benzamide US 10 , 398 ,693 B2 81 82 in combination with one or more chemotherapeutic agents or the said at least one acidulant is citric acid . In some radiotherapy , such as radiotherapy as commonly adminis - embodiments , the said at least one acidulant is betaine tered to treat , ameliorate the symptoms of, or prevent or hydrochloride . delay the onset of cancer. Such agents can include , but are In some embodiments are provided pharmaceutical com not limited to , antihormonal agents such as antiestrogens, 5 positions comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H -inda antiandrogens and aromatase inhibitors , topoisomerase I zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran inhibitors , topoisomerase II inhibitors, agents that target 4 - ylamino ) -benzamide and at least one acidulant, wherein said pharmaceutical composition when administered to a microtubules, platin -based agents , alkylating agents , DNA subject at a total dose of about 600 mg of said N - 15 - ( 3 , 5 damaging or intercalating agents , antineoplastic antimetabo 10 difluorobenzyl) - 1H - indazol- 3 - yl] -4 -( 4 -methyl - piperazin - 1 lites, other kinase inhibitors, other anti -angiogenic agents , yl) -2 - ( tetrahydro -pyran -4 -ylamino )- benzamide provides a inhibitors of kinesins , therapeutic monoclonal antibodies, pharmacokinetic profile in said subject wherein the Tmar of inhibitors ofmTOR , histone deacetylase inhibitors , farnesyl said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - indazol- 3 -yl ) - 4 -( 4 transferase inhibitors , and inhibitors of hypoxic response . methyl- piperazin - 1 -yl ) -2 - ( tetrahydro -pyran - 4 - ylamino ) Some embodiments provide a product or kit comprising a 15 benzamide in the plasma of said subiect is between about 2 pharmaceutical composition as provided herein comprising hours and about 5 hours , or between about 2 . 5 hours and N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl about 4 . 7 hours , or between about 2 . 4 hours and about 4 . 7 piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benz - hours, or between about 2 .6 hours and about 4 . 8 hours , amide and one or more chemotherapeutic agents, as a following said administration of said pharmaceutical com combined preparation for simultaneous, separate or sequen - 20 position to said subject . In some embodiments , the at least tial use in anticancer therapy . one acidulant is an organic acidulant. In some embodiments , Some embodiments include any of the methods described the at least one acidulant is selected from tartaric acid , herein , wherein said cancer is selected from non - small cell maleic acid , fumaric acid , citric acid , and betaine hydro lung cancer, papillary thyroid cancer, neuroblastoma, pan - chloride . In some embodiments , the least one acidulant is creatic cancer and colorectal cancer. Some embodiments are 25 fumaric acid . In some embodiments , the at least one acidu any of the methods described herein wherein said cancer is lant is tartaric acid . In some embodiments , the said at least non - small cell lung cancer. Some embodiments include any one acidulant is maleic acid . In some embodiments , the said at least one acidulant is citric acid . In some embodiments , of themethods described herein , wherein said cancer is said the said at least one acidulant is betaine hydrochloride. cancer is papillary thyroid cancer. Some embodimentssaid 30 In some embodiments are provided pharmaceutical com include any of the methods described herein , wherein said 30 positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda cancer is wherein said cancer is neuroblastoma. Some zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran embodiments include any of the methods described herein , 4 -ylamino ) -benzamide and at least one acidulant, wherein wherein said cancer is wherein said cancer is pancreatic said pharmaceutical composition when administered to a cancer. 35 subject in a fed state at a total dose of about 600 mg of said Some embodiments include any of the methods described N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl] - 4 - ( 4 -methyl herein , wherein said cancer is wherein said cancer is col piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino )- benzamide orectal cancer . provides a pharmacokinetic profile in said subject wherein Some embodiments relate to any of the pharmaceutical theT o f said N -15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol -3 compositions provided herein for use as a medicament. 40 y11 - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran - 4 Some embodiments relate to the use of any of the pharma - ylamino ) -benzamide in the plasma of said subject is between ceutical compositions provided herein for the manufacture about 4 hours and about 8 hours , or between about 4 . 6 hours of a medicament for the treatment of abnormal cell growth and about 5 .4 hours , or between about 4 .5 hours and about In some embodiments are provided pharmaceutical com - 7 . 2 hours, or between about 4 . 2 hours and about 6 . 7 hours, positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 45 following said administration of said pharmaceutical com zol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - position to said subject. In some embodiments , the at least 4 - ylamino ) -benzamide and at least one acidulant, wherein one acidulant is an organic acidulant. In some embodiments , said pharmaceutical composition when administered to a the at least one acidulant is selected from tartaric acid , subject in a fasted state at a total dose of about 600 mg of maleic acid , fumaric acid , citric acid , and betaine hydro said N -15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 - 50 chloride . In some embodiments , the least one acidulant is methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ). fumaric acid . In some embodiments , the at least one acidu benzamide provides a pharmacokinetic profile in said sub - lant is tartaric acid . In some embodiments , the said at least ject wherein the Tmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - one acidulant is maleic acid . In some embodiments , the said indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro at least one acidulant is citric acid . In some embodiments , pyran - 4 -ylamino ) - benzamide in the plasma of said subject is 55 the said at least one acidulant is betaine hydrochloride. between about 2 hours and about 5 hours , or between about In some embodiments are provided pharmaceutical com 2 .5 hours and about 4 . 7 hours , or between about 2 .4 hours positions comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - inda and about 4 . 7 hours , or between about 2 .6 hours and about zol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran 4 . 8 hours , following said administration of said pharmaceu - 4 -ylamino ) - benzamide and at least one acidulant, wherein tical composition to said subject. In some embodiments , the 60 said pharmaceutical composition when administered to a at least one acidulant is an organic acidulant. In some subject at a total dose of about 600 mg of said N - 15 - ( 3 , 5 embodiments , the at least one acidulant is selected from difluorobenzyl) -1H -indazol - 3 -yl ) -4 -( 4 -methyl - piperazin - 1 tartaric acid , maleic acid , fumaric acid , citric acid , and yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) - benzamide provides a betaine hydrochloride . In some embodiments , the least one pharmacokinetic profile in said subject wherein the Top of acidulant is fumaric acid . In some embodiments , the at least 65 said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 one acidulant is tartaric acid . In some embodiments , the said methyl -piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) at least one acidulant is maleic acid . In some embodiments, benzamide in the plasma of said subject is between about 4 US 10 , 398 ,693 B2 83 84 hours and about 8 hours , or between about 4 . 6 hours and In some embodiments are provided pharmaceutical com about 5 . 4 hours , or between about 4 . 5 hours and about 7 . 2 positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda hours , or between about 4 . 2 hours and about 6 . 7 hours , zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran following said administration of said pharmaceutical com 4 - ylamino ) - benzamide and at least one acidulant, wherein position to said subject. In some embodiments , the at least 5 said pharmaceutical composition when administered to a one acidulant is an organic acidulant. In some embodiments, subject in a fed state at a total dose of about 600 mg of said the at least one acidulant is selected from tartaric acid , N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] -4 -( 4 -methyl maleic acid , fumaric acid , citric acid , and betaine hydro - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide chloride . In some embodiments , the least one acidulant is provides a pharmacokinetic profile in said subject wherein fumaric acid . In some embodiments, the at least one acidu - 10 the Cmax of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 lant is tartaric acid . In some embodiments, the said at least yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 one acidulant is maleic acid . In some embodiments , the said ylamino ) -benzamide in the plasma of said subject is between at least one acidulant is citric acid . In some embodiments , about 1500 nM and about 3500 nM , or between about 1810 the said at least one acidulant is betaine hydrochloride . nM and about 3070 nM , or between about 2210 nM and In some embodiments are provided pharmaceutical com - 15 about 2990 nM , or between about 1990 nM and about 2810 positions comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda - nM , following said administration of said pharmaceutical zol - 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - composition to said subject. In some embodiments, the at 4 -ylamino ) -benzamide and at least one acidulant, wherein least one acidulant is an organic acidulant. In some embodi said pharmaceutical composition when administered to a ments , the at least one acidulant is selected from tartaric subject in a fasted state at a total dose of about 600 mg of 20 acid , maleic acid , fumaric acid , citric acid , and betaine said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 - hydrochloride . In some embodiments, the least one acidulant methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - is fumaric acid . In some embodiments , the at least one benzamide provides a pharmacokinetic profile in said sub - acidulant is tartaric acid . In some embodiments , the said at ject wherein the Cmor of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - least one acidulant is maleic acid . In some embodiments , the indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 25 said at least one acidulant is citric acid . In some embodi pyran - 4 - ylamino ) -benzamide in the plasma of said subject is ments, the said at least one acidulant is betaine hydrochlo between about 1200 nM and about 3500 nM , or between ride . about 1500 nM and about 2800 nM , or between about 1490 In some embodiments are provided pharmaceutical com nM and about 3030 nM , or between about 1670 nM and positions comprising N - [ 5 -( 3, 5 -difluorobenzyl )- 1H - inda about 2930 nM , following said administration of said phar - 30 zol- 3 - yl) -4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran maceutical composition to said subject. In some embodi - 4 -ylamino ) - benzamide and at least one acidulant, wherein ments , the at least one acidulant is an organic acidulant. In said pharmaceutical composition when administered to a some embodiments , the at least one acidulant is selected subject at a total dose of about 600 mg of said N - 15 - ( 3 , 5 from tartaric acid , maleic acid , fumaric acid , citric acid , and difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl - piperazin - 1 betaine hydrochloride . In some embodiments , the least one 35 yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide provides a acidulant is fumaric acid . In some embodiments, the at least pharmacokinetic profile in said subject wherein the Cmor of one acidulant is tartaric acid . In some embodiments , the said said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 at least one acidulant is maleic acid . In some embodiments , methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) the said at least one acidulant is citric acid . In some benzamide in the plasma of said subject is between about embodiments , the said at least one acidulant is betaine 40 1500 nM and about 3500 nM , or between about 1810 nM hydrochloride. and about 3070 nM , or between about 2210 nM and about In some embodiments are provided pharmaceutical com - 2990 nM , or between about 1990 nM and about 2810 nM , positions comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda - following said administration of said pharmaceutical com zol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran position to said subject. In some embodiments , the at least 4 - ylamino ) -benzamide and at least one acidulant, wherein 45 one acidulant is an organic acidulant. In some embodiments , said pharmaceutical composition when administered to a the at least one acidulant is selected from tartaric acid , subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 - maleic acid , fumaric acid , citric acid , and betaine hydro difluorobenzyl) - 1H -indazol - 3 -yl ] -4 - (4 -methyl - piperazin - 1 - chloride. In some embodiments , the least one acidulant is yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide provides a fumaric acid . In some embodiments, the at least one acidu pharmacokinetic profile in said subject wherein the Cmor of 50 lant is tartaric acid . In some embodiments , the said at least said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - one acidulant is maleic acid . In some embodiments, the said methyl- piperazin -1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) , at least one acidulant is citric acid . In some embodiments , benzamide in the plasma of said subject is between about the said at least one acidulant is betaine hydrochloride . 1200 nM and about 3500 nM , or between about 1500 nM In some embodiments are provided pharmaceutical com and about 2800 nM , or between about 1490 nM and about 55 positions , comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H -inda 3030 nM , or between about 1670 nM and about 2930 nM , zol - 3 - yl ) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran following said administration of said pharmaceutical com - 4 -ylamino ) - benzamide and at least one acidulant, wherein position to said subject . In some embodiments , the at least said pharmaceutical composition when administered to a one acidulant is an organic acidulant. In some embodiments, subject in a fasted state at a total dose of about 600 mg of the at least one acidulant is selected from tartaric acid , 60 said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 maleic acid , fumaric acid , citric acid , and betaine hydro - methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) chloride. In some embodiments , the least one acidulant is benzamide provides a pharmacokinetic profile in said sub fumaric acid . In some embodiments , the at least one acidu ject wherein the AUC ( O to 120 ) of said N - [ 5 - ( 3 , 5 lant is tartaric acid . In some embodiments , the said at least difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 one acidulant is maleic acid . In some embodiments , the said 65 yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide in the at least one acidulant is citric acid . In some embodiments , plasma of said subject is between about 30 ,000 nM * hr and the said at least one acidulant is betaine hydrochloride . about 85 ,000 nM * hr, or between about 34 , 100 nM * hr and US 10 , 398 ,693 B2 85 86 about 71, 700 nM * hr, or between about 32 ,500 nM * hr and at least one acidulant is citric acid . In some embodiments , about 79 ,700 nM * hr, or between about 37 ,100 nM * hr and the said at least one acidulant is betaine hydrochloride . about 77 ,300 nM * hr, following said administration of said In some embodiments are provided pharmaceutical com pharmaceutical composition to said subject. In some positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H -inda embodiments , the at least one acidulant is an organic acidu - 5 zol - 3 - yl] - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran 4 - ylamino )- benzamide and at least one acidulant, wherein lant. In some embodiments , the at least one acidulant is said pharmaceutical composition when administered to a selected from tartaric acid , maleic acid , fumaric acid , citric subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 acid , and betaine hydrochloride. In some embodiments , the difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 least one acidulant is fumaric acid . In some embodimentsi , 10 yl) -2 - (tetrahydro -pyran -4 -ylamino ) -benzamide provides a the at least one acidulant is tartaric acid . In some embodi pharmacokinetic profile in said subject wherein the AUC ( 0 ments , the said at least one acidulant is maleic acid . In some to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl ] embodiments , the said at least one acidulant is citric acid . In 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 some embodiments , the said at least one acidulant is betaine ylamino ) -benzamide in the plasma of said subject is between hydrochloride . 15 about 35 ,000 nM * hr and about 90 , 000 nM * hr, or between In some embodiments are provided pharmaceutical com about 38 , 900 nM * hr and about 78 ,700 nM * hr, or between positions , comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda - about 58 , 900 nM * hr and about 84 ,700 nM * hr , or between zol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran about 51, 300 nM * hr and about 77 ,500 nM * hr, following 4 -ylamino ) -benzamide and at least one acidulant, wherein said administration of said pharmaceutical composition to said pharmaceutical composition when administered to a 20 said subject. In some embodiments , the at least one acidulant subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 - is an organic acidulant. In some embodiments , the at least difluorobenzyl) - 1H -indazol - 3 - yl ] - 4 - (4 -methyl - piperazin - 1 - one acidulant is selected from tartaric acid , maleic acid , yl) - 2 - ( tetrahydro -pyran -4 - ylamino )- benzamide provides a fumaric acid , citric acid , and betaine hydrochloride . In some pharmacokinetic profile in said subject wherein the AUC ( O embodiments , the least one acidulant is fumaric acid . In to 120 ) of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - yl) - 25 some embodiments , the at least one acidulant is tartaric acid . 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 In some embodiments , the said at least one acidulant is ylamino ) - benzamide in the plasma of said subject is between maleic acid . In some embodiments , the said at least one about 30 , 000 nM * hr and about 85 ,000 nM * hr, or between acidulant is citric acid . In some embodiments , the said at about 34 , 100 nM * hr and about 71, 700 nM * hr, or between least one acidulant is betaine hydrochloride . about 32 ,500 nM * hr and about 79 ,700 nM * hr, or between 30 In some embodiments are provided pharmaceutical com about 37, 100 nM * hr and about 77 ,300 nM * hr, following positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda said administration of said pharmaceutical composition to zol- 3 - yl) -4 -( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran said subject. In some embodiments , the at least one acidulant 4 -ylamino ) - benzamide and at least one acidulant, wherein is an organic acidulant. In some embodiments , the at least said pharmaceutical composition when administered to a one acidulant is selected from tartaric acid , maleic acid , 35 subject in a fasted state at a total dose of about 600 mg of fumaric acid , citric acid , and betaine hydrochloride . In some said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - (4 embodiments , the least one acidulant is fumaric acid . In methyl- piperazin -1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) some embodiments , the at least one acidulant is tartaric acid . benzamide provides a pharmacokinetic profile in said sub In some embodiments , the said at least one acidulant is ject wherein the AUC ( infinity ) of said N - 15 - ( 3 , 5 maleic acid . In some embodiments , the said at least one 40 difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 acidulant is citric acid . In some embodiments , the said at yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide in the least one acidulant is betaine hydrochloride . plasma of said subject is between about 30 ,000 nM * hr and In some embodiments are provided pharmaceutical com - about 85 ,000 nM * hr, or between about 34 , 700 nM * hr and positions , comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - about 72 , 900 nM * hr, or between about 33 ,200 nM * hr and zol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 45 about 81, 200 nM * hr, or between about 37, 800 nM * hr and 4 - ylamino ) -benzamide and at least one acidulant, wherein about 78 , 800 nM * hr , following said administration of said said pharmaceutical composition when administered to a pharmaceutical composition to said subject. In some subject in a fed state at a total dose of about 600 mg of said embodiments , the at least one acidulant is an organic acidu N - [ 5 -( 3 , 5 - difluorobenzyl ) - 1H - indazol- 3 -yl ] -4 - (4 -methyl - lant. In some embodiments , the at least one acidulant is piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide 50 selected from tartaric acid , maleic acid , fumaric acid , citric provides a pharmacokinetic profile in said subject wherein acid , and betaine hydrochloride . In some embodiments , the the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - least one acidulant is fumaric acid . In some embodiments , indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro the at least one acidulant is tartaric acid . In some embodi pyran - 4 - ylamino ) -benzamide in the plasma of said subject is ments , the said at least one acidulant is maleic acid . In some between about 35 ,000 nM * hr and about 90 , 000 nM * hr, or 55 embodiments , the said at least one acidulant is citric acid . In between about 38 , 900 nM * hr and about 78 , 700 nM * hr, or some embodiments , the said at least one acidulant is betaine between about 58 , 900 nM * hr and about 84 , 700 nM * hr, or hydrochloride . between about 51 , 300 nM * hr and about 77 ,500 nMöhr, In some embodiments are provided pharmaceutical com following said administration of said pharmaceutical com - positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda position to said subject . In some embodiments , the at least 60 zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran one acidulant is an organic acidulant. In some embodiments , 4 - ylamino ) - benzamide and at least one acidulant , wherein the at least one acidulant is selected from tartaric acid , said pharmaceutical composition when administered to a maleic acid , fumaric acid , citric acid , and betaine hydro subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 chloride . In some embodiments , the least one acidulant is difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 fumaric acid . In some embodiments , the at least one acidu - 65 yl) - 2 -( tetrahydro - pyran - 4 -ylamino )- benzamide provides a lant is tartaric acid . In some embodiments , the said at least pharmacokinetic profile in said subject wherein the AUC one acidulant is maleic acid . In some embodiments , the said infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 US 10 , 398 ,693 B2 87 88 yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 In some embodiments , the said at least one acidulant is ylamino ) - benzamide in the plasma of said subject is between maleic acid . In some embodiments , the said at least one about 30 , 000 nM * hr and about 85 , 000 nM * hr, or between acidulant is citric acid . In some embodiments, the said at about 34 ,700 nM * hr and about 72 , 900 nM * hr, or between least one acidulant is betaine hydrochloride . about 33 , 200 nM * hr and about 81 , 200 nM * hr, or between 5 In some embodiments are provided pharmaceutical com about 37 , 800 nM * hr and about 78 ,800 nM * hr, following positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda said administration of said pharmaceutical composition to zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran said subject. In some embodiments , the at least one acidulant 4 -ylamino ) - benzamide and at least one acidulant, wherein is an organic acidulant . In some embodiments , the at least said acidulant is tartaric acid , wherein said pharmaceutical one acidulant is selected from tartaric acid , maleic acid , 10 composition when administered to a subject in a fasted state fumaric acid , citric acid , and betaine hydrochloride . In some at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 -difluo embodiments , the least one acidulant is fumaric acid . In robenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 some embodiments , the at least one acidulant is tartaric acid . ( tetrahydro -pyran - 4 -ylamino ) -benzamide provides a phar In some embodiments , the said at least one acidulant is macokinetic profile in said subject wherein the Tmax of said maleic acid . In some embodiments , the said at least one 15 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl] - 4 - ( 4 -methyl acidulant is citric acid . In some embodiments , the said at piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 - ylamino ) -benzamide least one acidulant is betaine hydrochloride . in the plasma of said subject is between about 2 hours and In some embodiments are provided pharmaceutical com - about 5 hours , or between about 2 .5 hours and about 4 .7 positions , comprising N -15 -( 3 , 5 - difluorobenzyl) - 1H - inda - hours , or between about 2 . 4 hours and about 4 . 7 hours , or zol - 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 20 between about 2 .6 hours and about 4 . 8 hours , following said 4 -ylamino ) -benzamide and at least one acidulant, wherein administration of said pharmaceutical composition to said said pharmaceutical composition when administered to a subject. subject in a fed state at a total dose of about 600 mg of said In some embodiments are provided pharmaceutical com N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide 25 zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran provides a pharmacokinetic profile in said subject wherein 4 - ylamino ) - benzamide and at least one acidulant , wherein the AUC ( infinity ) of said N - 15 - ( 3 , 5 - difluorobenzyl ) - 1H - in said acidulant is tartaric acid , wherein said pharmaceutical dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro composition when administered to a subject at a total dose pyran - 4 - ylamino ) -benzamide in the plasma of said subject is of about 600 mg of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H between about 35 ,000 nM * hr and about 90 , 000 nM * hr, or 30 indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro between about 39, 100 nM * hr and about 79, 700 nM * hr, or pyran - 4 -ylamino ) -benzamide provides a pharmacokinetic between about 59 ,400 nM * hr and about 87 , 200 nM * hr, or profile in said subject wherein the Tor of said N - 15 - ( 3 , 5 between about 51, 700 nM * hr and about 79, 700 nM * hr, difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 following said administration of said pharmaceutical com - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide in the position to said subject. In some embodiments , the at least 35 plasma of said subject is between about 2 hours and about one acidulant is an organic acidulant. In some embodiments, 5 hours , or between about 2 . 5 hours and about 4 .7 hours, or the at least one acidulant is selected from tartaric acid , between about 2 .4 hours and about 4 .7 hours, or between maleic acid , fumaric acid , citric acid , and betaine hydro - about 2 . 6 hours and about 4 . 8 hours , following said admin chloride. In some embodiments , the least one acidulant is istration of said pharmaceutical composition to said subject. fumaric acid . In some embodiments, the at least one acidu - 40 In some embodiments are provided pharmaceutical com lant is tartaric acid . In some embodiments , the said at least positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda one acidulant is maleic acid . In some embodiments , the said zol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -pyran at least one acidulant is citric acid . In some embodiments , 4 - ylamino ) -benzamide and at least one acidulant, wherein the said at least one acidulant is betaine hydrochloride . said acidulant is tartaric acid , wherein said pharmaceutical In some embodiments are provided pharmaceutical com - 45 composition when administered to a subject in a fed state at positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - a total dose of about 600 mg of said N - [5 - ( 3 , 5 - difluoroben zol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - zyl) - 1H - indazol- 3 - yl] -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra 4 - ylamino ) - benzamide and at least one acidulant, wherein hydro -pyran - 4 - ylamino ) -benzamide provides a pharmacoki said pharmaceutical composition when administered to a netic profile in said subject wherein the Tmorm of said N - 15 subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 - 50 ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) - benzamide yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide provides a in the plasma of said subject is between about 4 hours and pharmacokinetic profile in said subject wherein the AUC about 8 hours, or between about 4 .6 hours and about 5 . 4 ( infinity ) of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - hours , or between about 4 . 5 hours and about 7 . 2 hours , or yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - 55 between about 4 . 2 hours and about 6 . 7 hours , following said ylamino ) - benzamide in the plasma of said subject is between administration of said pharmaceutical composition to said about 35 ,000 nM * hr and about 90 , 000 nM * hr, or between subject. about 39 , 100 nM * hr and about 79 ,700 nM * hr, or between In some embodiments are provided pharmaceutical com about 59 ,400 nM * hr and about 87 , 200 nM * hr, or between positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda about 51, 700 nM * hr and about 79 ,700 nM * hr, following 60 zol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl ) - 2 -( tetrahydro -pyran said administration of said pharmaceutical composition to 4 - ylamino ) - benzamide and at least one acidulant , wherein said subject. In some embodiments , the at least one acidulant said acidulant is tartaric acid , wherein said pharmaceutical is an organic acidulant. In some embodiments , the at least composition when administered to a subject at a total dose one acidulant is selected from tartaric acid , maleic acid , of about 600 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H fumaric acid , citric acid , and betaine hydrochloride . In some 65 indazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro embodiments , the least one acidulant is fumaric acid . In pyran - 4 - ylamino ) -benzamide provides a pharmacokinetic some embodiments, the at least one acidulant is tartaric acid profile in said subject wherein the Tmar??? of said N - [ 5 - ( 3 , 5 US 10 , 398 ,693 B2 89 90 difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide in the pyran -4 - ylamino )- benzamide provides a pharmacokinetic plasma of said subject is between about 4 hours and about profile in said subject wherein the Cmax of said N - [ 5 - ( 3 , 5 8 hours , or between about 4 . 6 hours and about 5 . 4 hours , or difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 between about 4 . 5 hours and about 7 . 2 hours , or between 5 yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide in the about 4 . 2 hours and about 6 . 7 hours, following said admin plasma of said subject is between about 1500 nM and about istration of said pharmaceutical composition to said subject. 3500 nM , or between about 1810 nM and about 3070 nM , In some embodiments are provided pharmaceutical com or between about 2210 nM and about 2990 nM , or between positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda about 1990 nM and about 2810 nM , following said admin zol - 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 10 st 4 - ylamino ) -benzamide and at least one acidulant, wherein " istration of said pharmaceutical composition to said subject . said acidulant is tartaric acid , wherein said pharmaceutical In some embodiments are provided pharmaceutical com composition when administered to a subject in a fasted state positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda at a total dose of about 600 mg of said N - 15 - ( 3 , 5 - difluo zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran 4 - ylamino ) - benzamide and at least one acidulant, wherein (tetrahydro - pyran - 4 - ylamino ) -benzamide provides a phar said acidulant is tartaric acid , wherein said pharmaceutical macokinetic profile in said subject wherein the C , of said composition when administered to a subject in a fasted state N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 - difluo piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide robenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 in the plasma of said subject is between about 1200 nM and 20 ( tetrahydro - pyran -4 -ylamino )- benzamide provides a phar about 3500 nM , or between about 1500 nM and about 2800 macokinetic profile in said subject wherein the AUC ( O to nM , or between about 1490 nM and about 3030 nM , or 120 ) of said N -15 - ( 3 , 5 - difluorobenzyl )- 1H - indazol- 3 - yl) - 4 between about 1670 nM and about 2930 nM , following said (4 -methyl - piperazin - 1- yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) administration of said pharmaceutical composition to said benzamide in the plasma of said subject is between about subject. 25 30 , 000 nM * hr and about 85 ,000 nM * hr , or between about In some embodiments are provided pharmaceutical com 34 , 100 nM * hr and about 71 ,700 nM * hr, or between about positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 32 , 500 nM * hr and about 79, 700 nM * hr, or between about zol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran - 37 , 100 nM * hr and about 77, 300 nM * hr, following said 4 - ylamino ) -benzamide and at least one acidulant, wherein administration of said pharmaceutical composition to said said acidulant is tartaric acid , wherein said pharmaceutical 30 subject. composition when administered to a subject at a total dose In some embodiments are provided pharmaceutical com of about 600 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran pyran - 4 -ylamino ) -benzamide provides a pharmacokinetic 4 - ylamino ) -benzamide and at least one acidulant, wherein profile in said subject wherein the Cmax of said N - [ 5 - ( 3 , 5 - 35 said acidulant is tartaric acid , wherein said pharmaceutical difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 composition when administered to a subject at a total dose yl) - 2 - ( tetrahydro -pyran -4 -ylamino ) -benzamide in the of about 600 mg of said N - [ 5 - ( 3, 5 - difluorobenzyl) - 1H plasma of said subject is between about 1200 nM and about indazol- 3 - yl] - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro 3500 nM , or between about 1500 nM and about 2800 nM , pyran - 4 - ylamino ) - benzamide provides a pharmacokinetic or between about 1490 nM and about 3030 nM , or between 40 profile in said subject wherein the AUC ( 0 to 120 ) of said about 1670 nM and about 2930 nM , following said admin N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl istration of said pharmaceutical composition to said subject. piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 - ylamino )- benzamide In some embodiments are provided pharmaceutical com in the plasma of said subject is between about 30 ,000 nM * hr positions comprising N -15 -( 3 , 5 - difluorobenzyl) - 1H - inda - and about 85 ,000 nM * hr, or between about 34 , 100 nM * hr zol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 45 and about 71 ,700 nM * hr, or between about 32 ,500 nM * hr 4 - ylamino ) -benzamide and at least one acidulant, wherein and about 79 ,700 nM * hr , or between about 37 , 100 nM * hr said acidulant is tartaric acid , wherein said pharmaceutical and about 77 , 300 nM * hr, following said administration of composition when administered to a subject in a fed state at said pharmaceutical composition to said subject . a total dose of about 600 mg of said N - 15 - ( 3 , 5 - difluoroben - In some embodiments are provided pharmaceutical com zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra - 50 positions, comprising N -[ 5 - (3 , 5 -difluorobenzyl ) - 1H - inda hydro - pyran - 4 - ylamino ) -benzamide provides a pharmacoki- zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran netic profile in said subject wherein the Cor2X of said N - 15 - 4 - ylamino ) -benzamide and at least one acidulant, wherein ( 3, 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl said acidulant is tartaric acid , wherein said pharmaceutical piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide composition when administered to a subject in a fed state at in the plasma of said subject is between about 1500 nM and 55 a total dose of about 600 mg of said N -15 -( 3 , 5 - difluoroben about 3500 nM , or between about 1810 nM and about 3070 zyl ) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra nM , or between about 2210 nM and about 2990 nM , or hydro -pyran -4 -ylamino ) - benzamide provides a pharmacoki between about 1990 nM and about 2810 nM , following said netic profile in said subject wherein the AUC (0 to 120 ) of administration of said pharmaceutical composition to said said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 subject. 60 methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) In some embodiments are provided pharmaceutical com benzamide in the plasma of said subject is between about positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 35 , 000 nM * hr and about 90 ,000 nM * hr, or between about zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran 38 , 900 nM * hr and about 78 ,700 nM * hr , or between about 4 - ylamino ) - benzamide and at least one acidulant, wherein 58 , 900 nM * hr and about 84 , 700 nM * hr, or between about said acidulant is tartaric acid , wherein said pharmaceutical 65 51, 300 nM * hr and about 77 ,500 nM * hr, following said composition when administered to a subject at a total dose administration of said pharmaceutical composition to said of about 600 mg of said N - [5 -( 3, 5 - difluorobenzyl) - 1H subject . US 10 , 398 ,693 B2 91 92 In some embodiments are provided pharmaceutical com - benzamide in the plasma of said subject is between about positions, comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 35 , 000 nM * hr and about 90 ,000 nM * hr, or between about zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran 39, 100 nM * hr and about 79 ,700 nM * hr, or between about 4 -ylamino ) -benzamide and at least one acidulant, wherein 59 ,400 nM * hr and about 87 ,200 nM * hr, or between about said acidulant is tartaric acid , wherein said pharmaceutical 5 51, 700 nM * hr and about 79 ,700 nM * hr, following said composition when administered to a subject at a total dose administration of said pharmaceutical composition to said of about 600 mg of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - subject. indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) -benzamide provides a pharmacokinetic positions, comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda profile in said subject wherein the AUC (0 to 120 ) of said 10 zol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - 4 - ylamino ) -benzamide and at least one acidulant, wherein piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide said acidulant is tartaric acid , wherein said pharmaceutical in the plasma of said subject is between about 35 ,000 nM * hr composition when administered to a subject at a total dose and about 90 ,000 nM * hr, or between about 38 , 900 nM * hr of about 600 mg of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H and about 78 ,700 nM * hr, or between about 58, 900 nM * hr 15 indazol- 3 -yl ] - 4 -( 4 -methyl -piperazin - 1- yl) - 2 -( tetrahydro and about 84 ,700 nM * hr, or between about 51, 300 nM * hr pyran - 4 -ylamino ) -benzamide provides a pharmacokinetic and about 77 , 500 nM * hr, following said administration of profile in said subject wherein the AUC ( infinity ) of said said pharmaceutical composition to said subject . N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl In some embodiments are provided pharmaceutical com - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 20 in the plasma of said subject is between about 35 , 000 nM * hr zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl )- 2 - (tetrahydro -pyran - and about 90 , 000 nM * hr, or between about 39 , 100 nM * hr 4 - ylamino ) -benzamide and at least one acidulant, wherein and about 79 ,700 nM * hr, or between about 59 ,400 nM * hr said acidulant is tartaric acid , wherein said pharmaceutical and about 87 , 200 nM * hr, or between about 51, 700 nM * hr composition when administered to a subject in a fasted state and about 79 ,700 nM * hr, following said administration of at a total dose of about 600 mg of said N -15 - ( 3 , 5 - difluo - 25 said pharmaceutical composition to said subject. robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - In some embodiments are provided pharmaceutical com ( tetrahydro -pyran - 4 - ylamino ) -benzamide provides a phar - positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda macokinetic profile in said subject wherein the AUC zol- 3 -yl ) - 4 - (4 -methyl - piperazin -1 -yl ) - 2 -( tetrahydro -pyran ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 4 - ylamino ) -benzamide and at least one acidulant, wherein yl] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - 30 said pharmaceutical composition when administered to a ylamino ) - benzamide in the plasma of said subject is between subject in a fasted state at a total dose of about 600 mg of about 30 ,000 nM * hr and about 85 ,000 nM * hr, or between said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 about 34 ,700 nM * hr and about 72 , 900 nM * hr, or between methyl- piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) about 33 ,200 nM * hr and about 81 , 200 nM * hr, or between benzamide provides a pharmacokinetic profile in said sub about 37 , 800 nM * hr and about 78 ,800 nMöhr, following 35 ject wherein the Thor of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H said administration of said pharmaceutical composition to indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro said subject. pyran -4 - ylamino )- benzamide in the plasma of said subject is In some embodiments are provided pharmaceutical com between about 2 hours and about 5 hours, or between about positions, comprising N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -inda - 2 .5 hours and about 4 . 7 hours , or between about 2 .4 hours zol- 3 -yl ) -4 - (4 -methyl - piperazin -1 - yl) - 2 -( tetrahydro -pyran - 40 and about 4 .7 hours , or between about 2 .6 hours and about 4 - ylamino ) -benzamide and at least one acidulant, wherein 4 . 8 hours , following said administration of said pharmaceu said acidulant is tartaric acid , wherein said pharmaceutical tical composition to said subject, wherein said pharmaceu composition when administered to a subject at a total dose tical composition is in the form of a capsule . In some of about 600 mg of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - embodiments , the at least one acidulant is an organic acidu indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - 45 lant. In some embodiments , the at least one acidulant is pyran - 4 - ylamino ) -benzamide provides a pharmacokinetic selected from tartaric acid , maleic acid , fumaric acid , citric profile in said subject wherein the AUC ( infinity ) of said acid , and betaine hydrochloride. In some embodiments , the N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl least one acidulant is fumaric acid . In some embodiments , piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide the at least one acidulant is tartaric acid . In some embodi in the plasma of said subject is between about 30 , 000 nM * hr 50 ments , the said at least one acidulant is maleic acid . In some and about 85 , 000 nM * hr, or between about 34 ,700 nM * hr embodiments , the said at least one acidulant is citric acid . In and about 72 , 900 nM * hr, or between about 33 , 200 nM * hr some embodiments , the said at least one acidulant is betaine and about 81 ,200 nM * hr, or between about 37 , 800 nM * hr hydrochloride . and about 78 , 800 nM * hr, following said administration of In some embodiments are provided pharmaceutical com said pharmaceutical composition to said subject . 55 positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda In some embodiments are provided pharmaceutical com - zol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran positions, comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 4 -ylamino ) - benzamide and at least one acidulant, wherein zol- 3 -yl ) -4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - said pharmaceutical composition when administered to a 4 - ylamino ) -benzamide and at least one acidulant, wherein subject at a total dose of about 600 mg of said N - 55 -( 3 , 5 said acidulant is tartaric acid , wherein said pharmaceutical 60 difluorobenzyl) - 1H -indazol - 3 -yl ) -4 -( 4 -methyl - piperazin - 1 composition when administered to a subject in a fed state at yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide provides a a total dose of about 600 mg of said N - 15 - ( 3 ,5 -difluoroben - pharmacokinetic profile in said subject wherein the Tmor of zyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - yl) - 4 - ( 4 hydro -pyran - 4 - ylamino ) -benzamide provides a pharmacoki- methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) netic profile in said subject wherein the AUC ( infinity ) of 65 benzamide in the plasma of said subject is between about 2 said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 hours and about 5 hours , or between about 2 . 5 hours and methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) about 4 . 7 hours, or between about 2 . 4 hours and about 4 . 7 US 10 , 398 ,693 B2 93 94 hours , or between about 2 .6 hours and about 4 . 8 hours, the said at least one acidulant is citric acid . In some following said administration of said pharmaceutical com - embodiments , the said at least one acidulant is betaine position to said subject, wherein said pharmaceutical com - hydrochloride . position is in the form of a capsule . In some embodiments , In some embodiments are provided pharmaceutical com the at least one acidulant is an organic acidulant . In some 5 positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H -inda embodiments , the at least one acidulant is selected from zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran tartaric acid , maleic acid , fumaric acid , citric acid , and 4 -ylamino ) -benzamide and at least one acidulant , wherein betaine hydrochloride . In some embodiments , the least one said pharmaceutical composition when administered to a acidulant is fumaric acid . In some embodiments, the at least subject in a fasted state at a total dose of about 600 mg of one acidulant is tartaric acid . In some embodiments , the said 10 said N - 15 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 -yl ) -4 - ( 4 at least one acidulant is maleic acid . In some embodiments, methyl- piperazin - 1 - yl) - 2 - (tetrahydro - pyran - 4 - ylamino ) the said at least one acidulant is citric acid . In some benzamide provides a pharmacokinetic profile in said sub embodiments , the said at least one acidulant is betaine ject wherein the Cmax of said N -[ 5 -( 3 ,5 - difluorobenzyl) -1H hydrochloride . indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro In some embodiments are provided pharmaceutical com - 15 pyran - 4 - ylamino ) -benzamide in the plasma of said subject is positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - between about 1200 nM and about 3500 nM , or between zol- 3 - yl ]- 4 -( 4 -methyl - piperazin - 1 - yl ) -2 - tetrahydro -pyran - about 1500 nM and about 2800 nM , or between about 1490 4 - ylamino ) -benzamide and at least one acidulant , wherein nM and about 3030 nM , or between about 1670 nM and said pharmaceutical composition when administered to a about 2930 nM , following said administration of said phar subject in a fed state at a total dose of about 600 mg of said 20 maceutical composition to said subject, wherein said phar N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- maceutical composition is in the form of a capsule . In some piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide embodiments , the at least one acidulant is an organic acidu provides a pharmacokinetic profile in said subject wherein lant. In some embodiments , the at least one acidulant is the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 selected from tartaric acid , maleic acid , fumaric acid , citric yl] -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - 25 acid , and betaine hydrochloride . In some embodiments , the ylamino ) -benzamide in the plasma of said subject is between least one acidulant is fumaric acid . In some embodiments , about 4 hours and about 8 hours , or between about 4 . 6 hours the at least one acidulant is tartaric acid . In some embodi and about 5 . 4 hours , or between about 4 . 5 hours and about ments, the said at least one acidulant is maleic acid . In some 7 . 2 hours , or between about 4 . 2 hours and about 6 .7 hours, embodiments , the said at least one acidulant is citric acid . In following said administration of said pharmaceutical com - 30 some embodiments , the said at least one acidulant is betaine position to said subject, wherein said pharmaceutical com - hydrochloride . position is in the form of a capsule . In some embodiments, In some embodiments are provided pharmaceutical com the at least one acidulant is an organic acidulant. In some positions comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda embodiments , the at least one acidulant is selected from zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran tartaric acid , maleic acid , fumaric acid , citric acid , and 35 4 - ylamino ) -benzamide and at least one acidulant , wherein betaine hydrochloride . In some embodiments , the least one said pharmaceutical composition when administered to a acidulant is fumaric acid . In some embodiments , the at least subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 one acidulant is tartaric acid . In some embodiments , the said difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 at least one acidulant is maleic acid . In some embodiments , yl) - 2 -( tetrahydro -pyran -4 -ylamino ) - benzamide provides a the said at least one acidulant is citric acid . In some 40 pharmacokinetic profile in said subject wherein the Cmor of embodiments , the said at least one acidulant is betaine said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 hydrochloride . methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) In some embodiments are provided pharmaceutical com - benzamide in the plasma of said subject is between about positions comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda 1200 nM and about 3500 nM , or between about 1500 nM zol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 45 and about 2800 nM , or between about 1490 nM and about 4 -ylamino )- benzamide and at least one acidulant, wherein 3030 nM , or between about 1670 nM and about 2930 nM , said pharmaceutical composition when administered to a following said administration of said pharmaceutical com subject at a total dose of about 600 mg of said N - [ 5 -( 3, 5 . position to said subject , wherein said pharmaceutical com difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - position is in the form of a capsule . In some embodiments , yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) - benzamide provides a 50 the at least one acidulant is an organic acidulant. In some pharmacokinetic profile in said subject wherein the Tmax of embodiments , the at least one acidulant is selected from said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 - tartaric acid , maleic acid , fumaric acid , citric acid , and methyl- piperazin - 1 -yl ) -2 - ( tetrahydro -pyran -4 -ylamino )- betaine hydrochloride. In some embodiments , the least one benzamide in the plasma of said subject is between about 4 acidulant is fumaric acid . In some embodiments , the at least hours and about 8 hours , or between about 4 . 6 hours and 55 one acidulant is tartaric acid . In some embodiments , the said about 5 . 4 hours , or between about 4 . 5 hours and about 7 . 2 at least one acidulant is maleic acid . In some embodiments , hours , or between about 4 . 2 hours and about 6 . 7 hours, the said at least one acidulant is citric acid . In some following said administration of said pharmaceutical com - embodiments , the said at least one acidulant is betaine position to said subject, wherein said pharmaceutical com - hydrochloride . position is in the form of a capsule . In some embodiments , 60 In some embodiments are provided pharmaceutical com the at least one acidulant is an organic acidulant. In some positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda embodiments , the at least one acidulant is selected from zol- 3 - yl) -4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran tartaric acid , maleic acid , fumaric acid , citric acid , and 4 -ylamino )- benzamide and at least one acidulant, wherein betaine hydrochloride . In some embodiments , the least one said pharmaceutical composition when administered to a acidulant is fumaric acid . In some embodiments, the at least 65 subject in a fed state at a total dose of about 600 mg of said one acidulant is tartaric acid . In some embodiments , the said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl at least one acidulant is maleic acid . In some embodiments , piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide US 10 , 398 ,693 B2 95 96 provides a pharmacokinetic profile in said subject wherein some embodiments , the at least one acidulant is an organic the Cmax of said N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 acidulant. In some embodiments , the at least one acidulant yl ] -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 is selected from tartaric acid , maleic acid , fumaric acid , ylamino ) - benzamide in the plasma of said subject is between citric acid , and betaine hydrochloride . In some embodi about 1500 nM and about 3500 nM , or between about 1810 5 ments, the least one acidulant is fumaric acid . In some nM and about 3070 nM , or between about 2210 nM and embodiments , the at least one acidulant is tartaric acid . In about 2990 nM , or between about 1990 nM and about 2810 some embodiments , the said at least one acidulant is maleic nM , following said administration of said pharmaceutical acid . In some embodiments , the said at least one acidulant is composition to said subject, wherein said pharmaceutical citric acid . In some embodiments, the said at least one composition is in the form of a capsule . In some embodi - 10 acidulant is betaine hydrochloride. ments , the at least one acidulant is an organic acidulant. In In some embodiments are provided pharmaceutical com some embodiments , the at least one acidulant is selected positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda from tartaric acid , maleic acid , fumaric acid , citric acid , and zol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro - pyran betaine hydrochloride . In some embodiments , the least one 4 - ylamino ) -benzamide and at least one acidulant, wherein acidulant is fumaric acid . In some embodiments , the at least 15 said pharmaceutical composition when administered to a one acidulant is tartaric acid . In some embodiments, the said subject at a total dose of about 600 mg of said N - 15 - ( 3 , 5 at least one acidulant is maleic acid . In some embodiments , difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl -piperazin - 1 the said at least one acidulant is citric acid . In some yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide provides a embodiments , the said at least one acidulant is betaine pharmacokinetic profile in said subject wherein the AUC (0 hydrochloride . 20 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] In some embodiments are provided pharmaceutical com 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 positions comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - ylamino ) -benzamide in the plasma of said subject is between zol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran about 30 , 000 nM * hr and about 85, 000 nMöhr, or between 4 - ylamino ) -benzamide and at least one acidulant, wherein about 34 , 100 nM * hr and about 71 , 700 nM * hr, or between said pharmaceutical composition when administered to a 25 about 32 ,500 nM * hr and about 79 ,700 nM * hr, or between subject at a total dose of about 600 mg of said N -[ 5 - (3 , 5 - about 37 ,100 nM * hr and about 77 ,300 nM * hr, following difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - said administration of said pharmaceutical composition to yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benzamide provides a said subject, wherein said pharmaceutical composition is in pharmacokinetic profile in said subject wherein the Cmar of the form of a capsule . In some embodiments , the at least one said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - yl ] - 4 - ( 4 - 30 acidulant is an organic acidulant. In some embodiments , the methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - at least one acidulant is selected from tartaric acid , maleic benzamide in the plasma of said subject is between about acid , fumaric acid , citric acid , and betaine hydrochloride . In 1500 nM and about 3500 nM , or between about 1810 nM some embodiments , the least one acidulant is fumaric acid . and about 3070 nM , or between about 2210 nM and about In some embodiments , the at least one acidulant is tartaric 2990 nM , or between about 1990 nM and about 2810 nM , 35 acid . In some embodiments , the said at least one acidulant is following said administration of said pharmaceutical com - maleic acid . In some embodiments , the said at least one position to said subject, wherein said pharmaceutical com - acidulant is citric acid . In some embodiments , the said at position is in the form of a capsule . In some embodiments , least one acidulant is betaine hydrochloride . the at least one acidulant is an organic acidulant. In some In some embodiments are provided pharmaceutical com embodiments, the at least one acidulant is selected from 40 positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda tartaric acid , maleic acid , fumaric acid , citric acid , and zol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran betaine hydrochloride. In some embodiments , the least one 4 -ylamino ) - benzamide and at least one acidulant, wherein acidulant is fumaric acid . In some embodiments , the at least said pharmaceutical composition when administered to a one acidulant is tartaric acid . In some embodiments , the said subject in a fed state at a total dose of about 600 mg of said at least one acidulant is maleic acid . In some embodiments, 45 N -15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl the said at least one acidulant is citric acid . In some piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide embodiments , the said at least one acidulant is betaine amprovides a pharmacokinetic profile in said subject wherein hydrochloride . the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H In some embodiments are provided pharmaceutical com - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - 50 pyran - 4 - ylamino ) - benzamide in the plasma of said subject is zol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl )- 2 - (tetrahydro -pyran - between about 35 , 000 nM * hr and about 90 ,000 nM " hr, or 4 - ylamino ) -benzamide and at least one acidulant, wherein between about 38 , 900 nM * hr and about 78 ,700 nM * hr, or said pharmaceutical composition when administered to a between about 58 , 900 nM * hr and about 84 ,700 nM * hr, or subject in a fasted state at a total dose of about 600 mg of between about 51, 300 nM * hr and about 77 ,500 nM * hr, said N -15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - 55 following said administration of said pharmaceutical com methyl- piperazin - 1 -yl ) - 2 - (tetrahydro -pyran -4 -ylamino ) position to said subject, wherein said pharmaceutical com benzamide provides a pharmacokinetic profile in said sub - position is in the form of a capsule . In some embodiments , ject wherein the AUC ( O to 120 ) of said N - [ 5 - ( 3 , 5 the at least one acidulant is an organic acidulant. In some difluorobenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - embodiments , the at least one acidulant is selected from yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benzamide in the 60 tartaric acid , maleic acid , fumaric acid , citric acid , and plasma of said subject is between about 30 , 000 nM * hr and betaine hydrochloride . In some embodiments , the least one about 85 , 000 nM * hr, or between about 34 , 100 nM * hr and acidulant is fumaric acid . In some embodiments , the at least about 71, 700 nM * hr, or between about 32 ,500 nM * hr and one acidulant is tartaric acid . In some embodiments , the said about 79 , 700 nM * hr , or between about 37 , 100 nM * hr and at least one acidulant is maleic acid . In some embodiments , about 77 ,300 nM * hr, following said administration of said 65 the said at least one acidulant is citric acid . In some pharmaceutical composition to said subject, wherein said embodiments , the said at least one acidulant is betaine pharmaceutical composition is in the form of a capsule. In hydrochloride . US 10 , 398 ,693 B2 97 98 In some embodiments are provided pharmaceutical com - yl] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda - ylamino ) - benzamide in the plasma of said subject is between zol- 3 - yl )- 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran about 30 ,000 nM * hr and about 85 ,000 nM * hr, or between 4 -ylamino ) -benzamide and at least one acidulant, wherein about 34 ,700 nM * hr and about 72 ,900 nM * hr, or between said pharmaceutical composition when administered to a 5 about 33 , 200 nM * hr and about 81, 200 nM * hr, or between subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 - about 37 , 800 nM * hr and about 78 ,800 nM * hr, following difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - said administration of said pharmaceutical composition to yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide provides a said subject , wherein said pharmaceutical composition is in pharmacokinetic profile in said subject wherein the AUC (O the form of a capsule . In some embodiments , the at least one to 120 ) of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - yl ] - 10 acidulant is an organic acidulant . In some embodiments , the 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro - pyran - 4 at least one acidulant is selected from tartaric acid , maleic ylamino ) -benzamide in the plasma of said subject is between acid , fumaric acid , citric acid , and betaine hydrochloride . In about 35 , 000 nM * hr and about 90 ,000 nM * hr, or between some embodiments , the least one acidulant is fumaric acid . about 38 , 900 nM * hr and about 78 ,700 nM * hr, or between In some embodiments , the at least one acidulant is tartaric about 58 , 900 nM * hr and about 84 ,700 nM * hr, or between 15 acid . In some embodiments , the said at least one acidulant is about 51, 300 nM * hr and about 77 ,500 nM * hr, following maleic acid . In some embodiments , the said at least one said administration of said pharmaceutical composition to acidulant is citric acid . In some embodiments, the said at said subject, wherein said pharmaceutical composition is in least one acidulant is betaine hydrochloride . the form of a capsule . In some embodiments , the at least one In some embodiments are provided pharmaceutical com acidulant is an organic acidulant. In some embodiments , the 20 positions, comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda at least one acidulant is selected from tartaric acid , maleic zol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran acid , fumaric acid , citric acid , and betaine hydrochloride. In 4 -ylamino )- benzamide and at least one acidulant, wherein some embodiments , the least one acidulant is fumaric acid said pharmaceutical composition when administered to a In some embodiments , the at least one acidulant is tartaric subject in a fed state at a total dose of about 600 mg of said acid . In some embodiments, the said at least one acidulant is 25 N -15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl maleic acid . In some embodiments , the said at least one piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide acidulant is citric acid . In some embodiments , the said at provides a pharmacokinetic profile in said subject wherein least one acidulant is betaine hydrochloride . the AUC ( infinity ) of said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - in In some embodiments are provided pharmaceutical com - dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro positions , comprising N - [ 5 -( 3 , 5 - difluorobenzyl) - 1H - inda - 30 pyran - 4 -ylamino ) -benzamide in the plasma of said subject is zol- 3 - yl ]- 4 -( 4 -methyl - piperazin - 1 - yl ) -2 - (tetrahydro -pyran - between about 35 ,000 nM * hr and about 90 ,000 nM * hr, or 4 - ylamino ) -benzamide and at least one acidulant, wherein between about 39 , 100 nM * hr and about 79 ,700 nM * hr , or said pharmaceutical composition when administered to a between about 59 , 400 nM * hr and about 87 ,200 nM * hr, or subject in a fasted state at a total dose of about 600 mg of between about 51, 700 nM * hr and about 79 , 700 nM * hr, said N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 - ( 4 - 35 following said administration of said pharmaceutical com methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) position to said subject, wherein said pharmaceutical com benzamide provides a pharmacokinetic profile in said sub position is in the form of a capsule . In some embodiments , ject wherein the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - the at least one acidulant is an organic acidulant. In some difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl -piperazin - 1 - embodiments , the at least one acidulant is selected from yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide in the 40 tartaric acid , maleic acid , fumaric acid , citric acid , and plasma of said subject is between about 30 , 000 nM * hr and betaine hydrochloride . In some embodiments , the least one about 85 ,000 nM * hr, or between about 34 , 700 nM * hr and acidulant is fumaric acid . In some embodiments , the at least about 72 , 900 nM * hr, or between about 33 , 200 nM * hr and one acidulant is tartaric acid . In some embodiments , the said about 81 , 200 nM * hr , or between about 37 ,800 nM * hr and at least one acidulant is maleic acid . In some embodiments , about 78 , 800 nM * hr, following said administration of said 45 the said at least one acidulant is citric acid . In some pharmaceutical composition to said subject, wherein said embodiments, the said at least one acidulant is betaine pharmaceutical composition is in the form of a capsule . In hydrochloride . some embodiments , the at least one acidulant is an organic In some embodiments are provided pharmaceutical com acidulant. In some embodiments, the at least one acidulant positions, comprising N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - inda is selected from tartaric acid , maleic acid , fumaric acid , 50 zol- 3 -yl ) - 4 -( 4 -methyl - piperazin -1 -yl ) - 2 -( tetrahydro -pyran citric acid , and betaine hydrochloride . In some embodi 4 -ylamino ) -benzamide and at least one acidulant, wherein ments , the least one acidulant is fumaric acid . In some said pharmaceutical composition when administered to a embodiments , the at least one acidulant is tartaric acid . In subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 some embodiments , the said at least one acidulant is maleic difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 acid . In some embodiments , the said at least one acidulant is 55 yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide provides a citric acid . In some embodiments , the said at least one pharmacokinetic profile in said subject wherein the AUC acidulant is betaine hydrochloride . ( infinity ) of said N - [5 -( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 In some embodiments are provided pharmaceutical com yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 positions, comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda - ylamino ) -benzamide in the plasma of said subject is between zol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 60 about 35 ,000 nM * hr and about 90 ,000 nM * hr, or between 4 - ylamino ) -benzamide and at least one acidulant, wherein about 39 , 100 nM * hr and about 79 ,700 nM * hr , or between said pharmaceutical composition when administered to a about 59 ,400 nM * hr and about 87 , 200 nM * hr, or between subject at a total dose of about 600 mg of said N - [ 5 - ( 3 , 5 - about 51, 700 nM * hr and about 79 ,700 nM * hr, following difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - said administration of said pharmaceutical composition to yl) - 2 - (tetrahydro - pyran - 4 - ylamino ) -benzamide provides a 65 said subject , wherein said pharmaceutical composition is in pharmacokinetic profile in said subject wherein the AUC the form of a capsule . In some embodiments , the at least one ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - acidulant is an organic acidulant. In some embodiments , the US 10 , 398 ,693 B2 99 100 at least one acidulant is selected from tartaric acid , maleic nM , following administration of said pharmaceutical com acid , fumaric acid , citric acid , and betaine hydrochloride . In position to said subject in a fasted state . some embodiments , the least one acidulant is fumaric acid . In some embodiments are provided pharmaceutical com In some embodiments , the at least one acidulant is tartaric positions, comprising (a ) N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in acid . In some embodiments , the said at least one acidulant is 5 dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran - 4 -ylamino ) - benzamide; and ( b ) means for delivering maleic acid . In some embodiments , the said at least one a Cmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) acidulant is citric acid . In some embodiments , the said at 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 least one acidulant is betaine hydrochloride . ylamino )- benzamide in the plasma of a subject of between In some embodiments are provided pharmaceutical com 10 about 1200 nM and about 3500 nM , or between about 1500 positions , comprising (a ) N - [5 - (3 ,5 -difluorobenzyl )- 1H - in - 1 nM and about 2800 nM , or between about 1490 nM and dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro about 3030 nM , or between about 1670 nM and about 2930 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering nM , following administration of said pharmaceutical com a Tmax of said N - [5 -( 3 ,5 -difluorobenzyl ) - 1H -indazol - 3 -yl ] position to said subject . 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - tetrahydro -pyran - 4 15 In some embodiments are provided pharmaceutical com ylamino ) -benzamide in the plasma of a subject of between positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in about 2 hours and about 5 hours , or between about 2 . 5 hours dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1- yl ) - 2 -( tetrahydro and about 4 .7 hours , or between about 2 .4 hours and about pyran - 4 - ylamino )- benzamide; and (b ) means for delivering 4 .7 hours, or between about 2 . 6 hours and about 4 .8 hours, a Cmor of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] following administration of said pharmaceutical composi- 20 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 tion to said subject in a fasted state . ylamino ) - benzamide in the plasma of a subject of between In some embodiments are provided pharmaceutical com - about 1500 nM and about 3500 nM , or between about 1810 positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - nM and about 3070 nM , or between about 2210 nM and dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro about 2990 nM , or between about 1990 nM and about 2810 pyran - 4 -ylamino ) - benzamide ; and ( b ) means for delivering 25 nM , following administration of said pharmaceutical com a Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ] - position to said subject in a fed state . 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com ylamino ) -benzamide in the plasma of a subject of between positions, comprising (a ) N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - in about 2 hours and about 5 hours , or between about 2 . 5 hours dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro and about 4 . 7 hours , or between about 2 . 4 hours and about 30 pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering 4 . 7 hours , or between about 2 .6 hours and about 4 . 8 hours , a Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] following administration of said pharmaceutical composi 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 tion to said subject . ylamino )- benzamide in the plasma of a subject of between In some embodiments are provided pharmaceutical com about 1500 nM and about 3500 nM , or between about 1810 positions, comprising (a ) N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - 35 nM and about 3070 nM , or between about 2210 nM and dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro about 2990 nM , or between about 1990 nM and about 2810 pyran - 4 - ylamino ) - benzamide; and ( b ) means for delivering nM , following administration of said pharmaceutical com a Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - position to said subject. 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com ylamino )- benzamide in the plasma of a subject of between 40 positions, comprising (a ) N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - in about 4 hours and about 8 hours , or between about 4 .6 hours dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro and about 5 . 4 hours, or between about 4 . 5 hours and about pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering 7 . 2 hours , or between about 4 . 2 hours and about 6 . 7 hours , an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H following administration of said pharmaceutical composi indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro tion to said subject in a fed state . 45 pyran - 4 - ylamino ) -benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com - between about 30 , 000 nM * hr and about 85 ,000 nM * hr, or positions , comprising (a ) N - [5 - (3 ,5 -difluorobenzyl )- 1H - in between about 34 , 100 nM * hr and about 71, 700 nM * hr, or dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro between about 32 , 500 nM * hr and about 79, 700 nM * hr , or pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering between about 37 , 100 nM * hr and about 77, 300 nM * hr , a Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl ] - 50 following administration of said pharmaceutical composi 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -pyran -4 tion to said subject in a fasted state . ylamino ) - benzamide in the plasma of a subject of between In some embodiments are provided pharmaceutical com about 4 hours and about 8 hours, or between about 4 .6 hours positions, comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in and about 5 . 4 hours , or between about 4 . 5 hours and about dazol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro 7 .2 hours , or between about 4 . 2 hours and about 6 . 7 hours, 55 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering following administration of said pharmaceutical composi - an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H tion to said subject. indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com pyran - 4 -ylamino ) - benzamide in the plasma of a subject of positions , comprising ( a ) N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - in between about 30 , 000 nM * hr and about 85 ,000 nM * hr, or dazol- 3 - yl ] - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - 60 between about 34 , 100 nM * hr and about 71, 700 nM * hr, or pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering between about 32 ,500 nM * hr and about 79 ,700 nM * hr, or a Cmor of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - y1 ] - between about 37 , 100 nM * hr and about 77 , 300 nM * hr, 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 following administration of said pharmaceutical composi ylamino ) - benzamide in the plasma of a subject of between tion to said subject. about 1200 nM and about 3500 nM , or between about 1500 65 In some embodiments are provided pharmaceutical com nM and about 2800 nM , or between about 1490 nM and positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in about 3030 nM , or between about 1670 nM and about 2930 dazol- 3 - yl ]- 4 - ( 4 -methyl - piperazin - 1 - yl )- 2 -( tetrahydro US 10 , 398 ,693 B2 101 102 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H pyran - 4 - ylamino ) -benzamide in the plasma of a subject of indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro between about 35 , 000 nM * hr and about 90 , 000 nM * hr, or pyran - 4 -ylamino ) - benzamide in the plasma of a subject of between about 39 , 100 nM * hr and about 79 ,700 nM * hr, or between about 35 , 000 nM * hr and about 90 ,000 nM * hr, or 5 between about 59, 400 nM * hr and about 87 , 200 nM * hr, or between about 38 , 900 nM * hr and about 78 , 700 nM * hr, or between about 51, 700 nM * hr and about 79 ,700 nM * hr, between about 58 , 900 nM * hr and about 84 ,700 nM * hr, or following administration of said pharmaceutical composi between about 51 , 300 nM * hr and about 77 , 500 nM * hr, tion to said subject. following administration of said pharmaceutical composi- In some embodiments are provided pharmaceutical com tion to said subject in a fed state . 10 positions , comprising ( a ) N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - in In some embodiments are provided pharmaceutical com - dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydrorahydro a Tmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - 15 ylamino ) -benzamide in the plasma of a subject of between indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro about 2 hours and about 5 hours following administration of pyran -4 - ylamino )- benzamide in the plasma of a subject of said pharmaceutical composition to said subject in a fasted between about 35 , 000 nM * hr and about 90 ,000 nM * hr, or state . between about 38 , 900 nM * hr and about 78 ,700 nM * hr, or I n some embodiments are provided pharmaceutical com between about 58 , 900 nM * hr and about 84 ,700 nM * hr, or 20 positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in between about 51, 300 nM * hr and about 77 ,500 nM * hr, dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl )- 2 -( tetrahydro following administration of said pharmaceutical composi- pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering tion to said subject. a Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl] In some embodiments are provided pharmaceutical com - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - 25 ylamino ) -benzamide in the plasma of a subject of between dazol - 3 - yl) - 4 - (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro about 2 hours and about 5 hours following administration of pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering said pharmaceutical composition to said subject. an AUC ( infinity ) of said N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - In some embodiments are provided pharmaceutical com dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in pyran - 4 - ylamino ) -benzamide in the plasma of a subject of 30 dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro between about 30 , 000 nM * hr and about 85 , 000 nM * hr, or pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering between about 34 ,700 nM * hr and about 72 , 900 nM * hr, or a Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] between about 33 ,200 nM * hr and about 81 , 200 nM * hr, or 4 -( 4 -methyl - piperazin -1 -yl ) - 2 -( tetrahydro -pyran - 4 between about 37, 800 nM * hr and about 78 ,800 nM * hr, ylamino )- benzamide in the plasma of a subject of between following administration of said pharmaceutical composi - 35 about 4 hours and about 6 hours following administration of tion to said subject in a fasted state . said pharmaceutical composition to said subject in a fed In some embodiments are provided pharmaceutical com state . positions , comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - In some embodiments are provided pharmaceutical com dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in pyran -4 - ylamino )- benzamide ; and ( b ) means for delivering 40 dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - pyran - 4 - ylamino ) - benzamide; and ( b ) means for delivering dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - a Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] pyran -4 - ylamino )- benzamide in the plasma of a subject of 4 -( 4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro -pyran -4 between about 30 , 000 nM * hr and about 85 , 000 nM * hr, or ylamino ) -benzamide in the plasma of a subject of between between about 34 ,700 nM * hr and about 72 , 900 nM * hr, or 45 about 4 hours and about 6 hours following administration of between about 33 , 200 nM * hr and about 81, 200 nM * hr, or said pharmaceutical composition to said subject. between about 37 , 800 nM * hr and about 78 ,800 nM * hr, In some embodiments are provided pharmaceutical com following administration of said pharmaceutical composi positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in tion to said subject. dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com - 50 pyran -4 - ylamino )- benzamide ; and (b ) means for delivering positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H - in a Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl] dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering ylamino ) - benzamide in the plasma of a subject of between an AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - about 4 hours and about 8 hours following administration of indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - 55 said pharmaceutical composition to said subject in a fed pyran - 4 - ylamino ) -benzamide in the plasma of a subject of state . between about 35 ,000 nM * hr and about 90 , 000 nM * hr, or In some embodiments are provided pharmaceutical com between about 39 , 100 nM * hr and about 79 ,700 nM * hr, or positions, comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in between about 59 ,400 nM * hr and about 87 ,200 nM * hr, or dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro between about 51, 700 nM * hr and about 79, 700 nM * hr, 60 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering following administration of said pharmaceutical composi a Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] tion to said subject in a fed state . 4 -( 4 -methyl - piperazin -1 - yl) -2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com - ylamino ) -benzamide in the plasma of a subject of between positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in about 4 hours and about 8 hours following administration of dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 65 said pharmaceutical composition to said subject. pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an AUC (0 to 120 ) of said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - positions, comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in US 10 , 398 ,693 B2 103 104 dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering a Tmax of said N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) a Cmax of said N - [ 5 -( 3 ,5 - difluorobenzyl) - 1H -indazol - 3 -yl ] 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 ylamino ) - benzamide in the plasma of a subject of between 5 ylamino ) - benzamide in the plasma of a subject of between about 4 hours and about 7 hours following administration of about 1670 nM and about 2930 nM following administration said pharmaceutical composition to said subject in a fed of said pharmaceutical composition to said subject . state . In some embodiments are provided pharmaceutical com In some embodiments are provided pharmaceutical com - positions, comprising ( a ) N -15 - ( 3 , 5 - difluorobenzyl) - 1H - in positions, comprising (a ) N - [5 -( 3 ,5 -difluorobenzyl ) - 1H -in - 10 dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro dazol- 3 - y11- 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - indazol- 3 -yl ] a Tmax of said N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -pyran -4 ylamino ) -benzamide in the plasma of a subject of between ylamino ) -benzamide in the plasma of a subject of between 15 about 1810 nM and about 3070 nM following administration about 4 hours and about 7 hours following administration of of said pharmaceutical composition to said subject in a fed said pharmaceutical composition to said subject . state . In some embodiments are provided pharmaceutical com - In some embodiments are provided pharmaceutical com positions , comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro - 20 dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering pyran - 4 -ylamino ) -benzamide ; and (b ) means for delivering a Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran -4 ylamino ) -benzamide in the plasma of a subject of between ylamino ) - benzamide in the plasma of a subject of between about 1500 nM and about 2800 nM following administration 25 about 1810 nM and about 3070 nM following administration of said pharmaceutical composition to said subject in a of said pharmaceutical composition to said subject . fasted state . In some embodiments are provided pharmaceutical com In some embodiments are provided pharmaceutical com - positions , comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - in positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 30 pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering a Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro -pyran -4 ylamino ) -benzamide in the plasma of a subject of between ylamino ) - benzamide in the plasma of a subject of between about 2210 nM and about 2990 nM following administration about 1500 nM and about 2800 nM following administration 35 of said pharmaceutical composition to said subject in a fed of said pharmaceutical composition to said subject. state . In some embodiments are provided pharmaceutical com - In some embodiments are provided pharmaceutical com positions , comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering 40 pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering a Cmax of said N - [ 5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl] - a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - indazol- 3 - yl] 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro -pyran -4 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 ylamino ) -benzamide in the plasma of a subject of between ylamino ) -benzamide in the plasma of a subject of between about 1490 nM and about 3030 nM following administration about 2210 nM and about 2990 nM following administration of said pharmaceutical composition to said subject in a 45 of said pharmaceutical composition to said subject . fasted state . In some embodiments are provided pharmaceutical com In some embodiments are provided pharmaceutical com - positions, comprising ( a ) N - [5 - ( 3, 5 -difluorobenzyl ) - 1H - in positions , comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro pyran - 4 - ylamino )- benzamide ; and (b ) means for delivering pyran - 4 - ylamino )- benzamide ; and (b ) means for delivering 50 a Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - indazol- 3 - yl] a Cmax of said N - [ 5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro -pyran -4 ylamino ) - benzamide in the plasma of a subject of between ylamino )- benzamide in the plasma of a subject of between about 1990 nM and about 2810 nM following administration about 1490 nM and about 3030 nM following administration of said pharmaceutical composition to said subject in a fed of said pharmaceutical composition to said subject . 55 state . In some embodiments are provided pharmaceutical com - In some embodiments are provided pharmaceutical com positions, comprising (a ) N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H -in - positions, comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering a Cmax of said N - 15 -( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl ) - 60 a Cmax of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 ylamino ) - benzamide in the plasma of a subject of between ylamino )- benzamide in the plasma of a subject of between about 1670 nM and about 2930 nM following administration about 1990 nM and about 2810 nM following administration of said pharmaceutical composition to said subject in a of said pharmaceutical composition to said subject. fasted state. 65 In some embodiments are provided pharmaceutical com In some embodiments are provided pharmaceutical com - positions, comprising ( a ) N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - in positions, comprising (a ) N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H -in - dazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro US 10 , 398 ,693 B2 105 106 pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro pyran -4 - ylamino )- benzamide in the plasma of a subject of pyran - 4 -ylamino ) - benzamide ; and ( b ) means for delivering between about 34 , 100 nM * hr and about 71, 700 nM * hr 5 an AUC ( 0 to 120 ) of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H following administration of said pharmaceutical composi indazol- 3 - yl ] - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - (tetrahydro tion to said subject in a fasted state . pyran - 4 -ylamino ) -benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com between about 38 ,900 nM * hr and about 78, 700 nM * hr positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in following administration of said pharmaceutical composi dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro - 10 tion to said subject. pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an AUC (0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran -4 - ylamino )- benzamide in the plasma of a subject of pyran -4 - ylamino )- benzamide ; and ( b ) means for delivering between about 34 , 100 nM * hr and about 71, 700 nM * hr 15 an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H following administration of said pharmaceutical composi indazol- 3 - yl) - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro tion to said subject. pyran -4 - ylamino )- benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com between about 58, 900 nM * hr and about 84 , 700 nM * hr positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - following administration of said pharmaceutical composi dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 20 tion to said subject in a fed state . pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering In some embodiments are provided pharmaceutical com an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran - 4 - ylamino )- benzamide in the plasma of a subject of pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between about 32 , 500 nM * hr and about 79, 700 nM * hr 25 an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H following administration of said pharmaceutical composi indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 -( tetrahydro tion to said subject in a fasted state . pyran - 4 -ylamino )- benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com - between about 58, 900 nM * hr and about 84 , 700 nM * hr positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in following administration of said pharmaceutical composi dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 30 tion to said subject. pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering I n some embodiments are provided pharmaceutical com an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in indazol- 3 - yl) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran -4 - ylamino )- benzamide in the plasma of a subject of pyran - 4 -ylamino ) -benzamide ; and (b ) means for delivering between about 32, 500 nM * hr and about 79 ,700 nMähr 35 an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H following administration of said pharmaceutical composi indazol- 3 - yl ] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro tion to said subject. pyran - 4 - ylamino ) - benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com between about 51 ,300 nM * hr and about 77 ,500 nM * hr positions , comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in following administration of said pharmaceutical composi dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 40 tion to said subject in a fed state . pyran -4 - ylamino ) - benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran -4 - ylamino )- benzamide in the plasma of a subject of pyran - 4 -ylamino ) -benzamide ; and (b ) means for delivering between about 37 , 100 nM * hr and about 77 , 300 nM * hr 45 an AUC ( 0 to 120 ) of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H following administration of said pharmaceutical composi indazol- 3 - yl ] - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - (tetrahydro tion to said subject in a fasted state . pyran - 4 -ylamino )- benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com between about 51, 300 nM * hr and about 77 , 500 nM * hr positions, comprising (a ) N - [ 5 - ( 3 , 5 -difluorobenzyl )- 1H - in - following administration of said pharmaceutical composi dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro - 50 tion to said subject. pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an AUC (0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - dazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro pyran - 4 -ylamino )- benzamide in the plasma of a subject of pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering between about 37, 100 nM * hr and about 77 , 300 nMähr 55 an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in following administration of said pharmaceutical composi dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro tion to said subject . pyran - 4 - ylamino ) -benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com between about 34 ,700 nM * hr and about 72 ,900 nM * hr positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - following administration of said pharmaceutical composi dazol- 3 - yl ] - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - 60 tion to said subject in a fasted state . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering I n some embodiments are provided pharmaceutical com an AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - positions, comprising ( a ) N -15 - ( 3 , 5 - difluorobenzyl ) - 1H - in indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran - 4 - ylamino ) -benzamide in the plasma of a subject of pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between about 38 , 900 nM * hr and about 78 ,700 nM * hr 65 an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in following administration of said pharmaceutical composi- dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro tion to said subject in a fed state. pyran -4 - ylamino )- benzamide in the plasma of a subject of US 10 , 398 ,693 B2 107 108 between about 34, 700 nM * hr and about 72 , 900 nM * hr an AUC ( infinity ) of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in following administration of said pharmaceutical composi - dazol- 3 - yl ) -4 -( 4 -methyl -piperazin -1 - yl )- 2- ( tetrahydro tion to said subject. pyran - 4 - ylamino ) -benzamide in the plasma of a subject of In some embodiments are provided pharmaceutical com between about 59 ,400 nM * hr and about 87 , 200 nM * hr positions, comprising (a ) N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - in - 5 following administration of said pharmaceutical composi dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1- yl) - 2 -( tetrahydro tion to said subject in a fed state . pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - TH1H -- in - positions, comprising (a ) N -[ 5 -( 3 ,5 - difluorobenzyl) -1H - in dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pyran - 4 - ylamino ) -benzamide in the plasma of a subject of 10 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between about 33 , 200 nM * hr and about 81, 200 nM * hr following administration of said pharmaceutical composi an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in tion to said subject in a fasted state . dazol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) -benzamide in the plasma of a subject of positions , comprising ( a ) N -15 - ( 3 . 5 - difluorobenzyl) - 1H - in - 15 between about 59 , 400 nMähr and about 87 , 200 nM " hr dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro following administration of said pharmaceutical composi pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering tion to said subject. an AUC ( infinity ) of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H - in - In some embodiments are provided pharmaceutical com dazol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro - positions , comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - in pyran - 4 - ylamino ) -benzamide in the plasma of a subject of 20 dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro between about 33 , 200 nM * hr and about 81, 200 nM * hr pyran - 4 - ylamino ) - benzamide; and ( b ) means for delivering following administration of said pharmaceutical composi - an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in tion to said subject. dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) -benzamide in the plasma of a subject of positions, comprising (a ) N - [5 -( 3 ,5 -difluorobenzyl ) - 1H -in - 25 between about 51, 700 nM * hr and about 79, 700 nM * hr dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro following administration of said pharmaceutical composi pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering tion to said subject in a fed state . an AUC ( infinity ) of said N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - In some embodiments are provided pharmaceutical com dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - tetrahydro positions, comprising (a ) N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H -in pyran - 4 - ylamino ) -benzamide in the plasma of a subject of 30 dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro between about 37 , 800 nM * hr and about 78 ,800 nM * hr pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering following administration of said pharmaceutical composi - an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - in tion to said subject in a fasted state . dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) -benzamide in the plasma of a subject of positions, comprising (a ) N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - 35 between about 51, 700 nM * hr and about 79, 700 nM * hr dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1- yl) - 2 -( tetrahydro following administration of said pharmaceutical composi pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering tion to said subject . an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - In some embodiments are provided pharmaceutical com dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in pyran -4 - ylamino )- benzamide in the plasma of a subject of 40 dazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro between about 37 , 800 nM * hr and about 78 ,800 nM * hr pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering following administration of said pharmaceutical composi - an Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 tion to said subject. yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com ylamino ) - benzamide in the plasma of a subject that is positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - 45 between 80 % to 125 % of 3 . 6 hours, based on a 90 percent dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1- yl) - 2 -( tetrahydro confidence interval, following administration of said phar pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering m aceutical composition to said subject in a fasted state . an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in In some embodiments are provided pharmaceutical com dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - tetrahydro positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) -1H - in pyran -4 - ylamino )- benzamide in the plasma of a subject of 50 dazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro between about 39 , 100 nM * hr and about 79 ,700 nM * hr pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering following administration of said pharmaceutical composi - an Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 tion to said subject in a fed state . yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com ylamino ) -benzamide in the plasma of a subject that is positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - 55 between 80 % to 125 % of 3 .6 hours , based on a 90 percent dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro confidence interval , following administration of said phar pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering maceutical composition to said subject. an AUC ( infinity ) of said N - [ 5 -( 3 , 5 -difluorobenzyl ) - 1H - in In some embodiments are provided pharmaceutical com dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1- yl) -2 -( tetrahydro positions, comprising (a ) N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H -in pyran - 4 - ylamino )- benzamide in the plasma of a subject of 60 dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro between about 39 , 100 nM * hr and about 79, 700 nM * hr pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering following administration of said pharmaceutical composi - an Tmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - indazol- 3 tion to said subject. yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com - ylamino ) -benzamide in the plasma of a subject that is positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - 65 between 80 % to 125 % of 3 . 5 hours , based on a 90 percent dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - confidence interval, following administration of said phar pyran -4 - ylamino )- benzamide ; and ( b ) means for delivering m aceutical composition to said subject in a fasted state . US 10 , 398 ,693 B2 109 110 In some embodiments are provided pharmaceutical com between 80 % to 125 % of 5 .8 hours , based on a 90 percent positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H -in confidence interval , following administration of said phar dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydrorahydro maceutical composition to said subject. pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering I n some embodiments are provided pharmaceutical com an Tmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - 5 positions, comprising (a ) N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - in yl] -4 - (4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between 80 % to 125 % of 3 . 5 hours, based on a 90 percent an Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 confidence interval, following administration of said phar yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 maceutical composition to said subject. 10 ylamino ) -benzamide in the plasma of a subject that is In some embodiments are provided pharmaceutical com - between 80 % to 125 % of 5 . 4 hours, based on a 90 percent positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H -in confidence interval , following administration of said phar dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro tetrahydro maceutical composition to said subject in a fed state . pyran - 4 - ylamino ) - benzamide; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Tmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - 15 positions, comprising (a ) N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - in yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) -benzamide in the plasma of a subject that is pyran - 4 -ylamino ) -benzamide ; and (b ) means for delivering between 80 % to 125 % of 3 .7 hours, based on a 90 percent an Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 confidence interval , following administration of said phar yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 maceutical composition to said subject in a fasted state . 20 ylamino ) - benzamide in the plasma of a subject that is In some embodiments are provided pharmaceutical com - between 80 % to 125 % of 5 . 4 hours , based on a 90 percent positions , comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - confidence interval, following administration of said phar dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro maceutical composition to said subject. pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering I n some embodiments are provided pharmaceutical com an Tmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - 25 positions, comprising (a ) N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - in yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between 80 % to 125 % of 3 .7 hours , based on a 90 percent an Cmax of said N - [ 5 -( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 confidence interval, following administration of said phar yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 maceutical composition to said subject. 30 ylamino ) - benzamide in the plasma of a subject that is In some embodiments are provided pharmaceutical com between 80 % to 125 % of 2150 nM , based on a 90 percent positions, comprising (a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in confidence interval , following administration of said phar dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro maceutical composition to said subject in a fasted state . pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering I n some embodiments are provided pharmaceutical com an Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - 35 positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H - in yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino )- benzamide in the plasma of a subject that is pyran - 4 - ylamino ) - benzamide; and ( b ) means for delivering between 80 % to 125 % of 5 hours , based on a 90 percent an Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 confidence interval, following administration of said phar yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 maceutical composition to said subject in a fed state . 40 ylamino ) -benzamide in the plasma of a subject that is In some embodiments are provided pharmaceutical com - between 80 % to 125 % of 2150 nM , based on a 90 percent positions , comprising (a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - confidence interval, following administration of said phar dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydrorahydro maceutical composition to said subject . pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering I n some embodiments are provided pharmaceutical com an Tmax of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 - 45 positions, comprising (a ) N -[ 5 - (3 ,5 -difluorobenzyl ) - 1H - in yl] -4 - (4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between 80 % to 125 % of 5 hours , based on a 90 percent an Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 confidence interval, following administration of said phar- yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 maceutical composition to said subject. 50 ylamino ) -benzamide in the plasma of a subject that is In some embodiments are provided pharmaceutical com - between 80 % to 125 % of 2260 nM , based on a 90 percent positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - confidence interval , following administration of said phar dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydrorahydro maceutical composition to said subject in a fasted state . pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - 55 positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between 80 % to 125 % of 5 .8 hours, based on a 90 percent an Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 confidence interval, following administration of said phar- yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 maceutical composition to said subject in a fed state . 60 ylamino )- benzamide in the plasma of a subject that is In some embodiments are provided pharmaceutical com between 80 % to 125 % of 2260 nM , based on a 90 percent positions, comprising ( a ) N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - in - confidence interval, following administration of said phar dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro maceutical composition to said subject. pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - 65 positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino )- benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering US 10 , 398 ,693 B2 111 112 an Cmax of said N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 In some embodiments are provided pharmaceutical com yl] -4 -( 4 -methyl -piperazin -1 -yl ) - 2- ( tetrahydro -pyran - 4 - positions , comprising ( a) N - [5 - (3 ,5 -difluorobenzyl ) - 1H - in ylamino ) -benzamide in the plasma of a subject that is dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro between 80 % to 125 % of 2300 nM , based on a 90 percent pyran - 4 -ylamino ) -benzamide ; and (b ) means for delivering confidence interval, following administration of said phar- 5 an Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 maceutical composition to said subject in a fasted state . y ?] -4 -( 4 -methyl -piperazin -1 - yl )- 2 -( tetrahydro -pyran - 4 In some embodiments are provided pharmaceutical com - ylamino ) -benzamide in the plasma of a subject that is between 80 % to 125 % of 2400 nM , based on a 90 percent positions, comprising (a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in confidence interval, following administration of said phar dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro 10 maceutical composition to said subject. pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Cmax of said N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 positions, comprising (a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in yl] -4 - (4 -methyl - piperazin - 1- yl) -2 -( tetrahydro -pyran - 4 dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran -4 -ylamino )- benzamide ; and ( b ) means for delivering between 80 % to 125 % of 2300 nM , based onon aa 90 percent 15 an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H confidence interval, following administration of said phar - indazol - 3 - v11- 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro maceutical composition to said subject. pyran - 4 - ylamino ) - benzamide in the plasma of a subject that In some embodiments are provided pharmaceutical com is between 80 % to 125 % of 52 , 900 nM * hr, based on a 90 positions , comprising (a ) N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in percent confidence interval, following administration of said dazol -3 - yl )- 4 -( 4 -methyl -piperazin - 1- yl ) -2 -( tetrahydro - 20 pharmaceutical composition to said subject in a fasted state . pyran -4 - ylamino )- benzamide ; and ( b ) means for delivering I n some embodiments are provided pharmaceutical com an Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in yl] - 4 - (4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between 80 % to 125 % of 2440 nM , based on a 90 percent 25 an AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H confidence interval, following administration of said phar - indazol- 3 - yl] - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro maceutical composition to said subject in a fed state . pyran - 4 - ylamino ) - benzamide in the plasma of a subject that In some embodiments are provided pharmaceutical com - is between 80 % to 125 % of 52 , 900 nM * hr, based on a 90 positions , comprising (a ) N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in percent confidence interval , following administration of said dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 30 pharmaceutical composition to said subject. pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in yl] -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) - benzamide ; and ( b ) means for delivering between 80 % to 125 % of 2440 nM , based on a 90 percent 35 an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H confidence interval, following administration of said phar- indazol- 3 -yl )- 4 -( 4 -methyl -piperazin - 1- yl) - 2 -( tetrahydro maceutical composition to said subject. pyran - 4 - ylamino ) - benzamide in the plasma of a subject that In some embodiments are provided pharmaceutical com - is between 80 % to 125 % of 56 , 100 nM * hr, based on a 90 positions , comprising (a ) N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in percent confidence interval , following administration of said dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro - 40 pharmaceutical composition to said subject in a fasted state . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in yl] -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) - benzamide ; and ( b ) means for delivering between 80 % to 125 % of 2600 nM , based on a 90 percent 45 an AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H confidence interval, following administration of said phar - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro maceutical composition to said subject in a fed state . pyran - 4 -ylamino ) -benzamide in the plasma of a subject that In some embodiments are provided pharmaceutical com is between 80 % to 125 % of 56 , 100 nM * hr, based on a 90 positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - percent confidence interval, following administration of said dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro - 50 pharmaceutical composition to said subject . pyran - 4 - ylamino )- benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in yl] - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between 80 % to 125 % of 2600 nM , based on a 90 percent 55 an AUC ( 0 to 120 ) of said N -[ 5 -( 3 ,5 - difluorobenzyl) -1H confidence interval, following administration of said phar - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro maceutical composition to said subject . pyran - 4 - ylamino ) -benzamide in the plasma of a subject that In some embodiments are provided pharmaceutical com is between 80 % to 125 % of 57 , 200 nM * hr, based on a 90 positions , comprising (a ) N -15 -( 3 , 5 -difluorobenzyl ) - 1H - in percent confidence interval , following administration of said dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 60 pharmaceutical composition to said subject in a fasted state . pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering In some embodiments are provided pharmaceutical com an Cmax of said N - [ 5 -( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - positions, comprising ( a ) N - [ 5 - (3 , 5 - difluorobenzyl) - 1H - in yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro ylamino ) - benzamide in the plasma of a subject that is pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering between 80 % to 125 % of 2400 nM , based on a 90 percent 65 an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H confidence interval, following administration of said phar - indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro maceutical composition to said subject in a fed state . pyran - 4 -ylamino ) -benzamide in the plasma of a subject that US 10 , 398 ,693 B2 113 114 is between 80 % to 125 % of 57 ,200 nM * hr, based on a 90 an AUC ( infinity ) of said N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - in percent confidence interval, following administration of said dazol- 3 - yl ) -4 -( 4 -methyl -piperazin -1 - yl )- 2- ( tetrahydro pharmaceutical composition to said subject. pyran - 4 -ylamino ) -benzamide in the plasma of a subject that In some embodiments are provided pharmaceutical com is between 80 % to 125 % of 53 , 800 nM * hr, based on a 90 positions , comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - 5 percent confidence interval , following administration of said dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pharmaceutical composition to said subject in a fasted state . pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering In some embodiments are provided pharmaceutical com an AUC (0 to 120 ) of said N - [5 -( 3, 5 - difluorobenzyl) - The1H positions , comprising (a ) N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - in indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro pyran -4 - ylamino )- benzamide in the plasma of a subject that 10 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering is between 80 % to 125 % of 58 , 800 nM * hr, based on a 90 an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in percent confidence interval, following administration of said dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro pharmaceutical composition to said subject in a fed state . pyran - 4 - ylamino ) -benzamide in the plasma of a subject that In some embodiments are provided pharmaceutical com- in . 15 is between 80 % to 125 % of 53, 800 nM * hr, based on a 90 positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - 15 percent18 berw confidence interval, following administration of said pyrandazol - 34 - ylvlamino) - 4 - ( 4 -methyl ) - benzamide- piperazin: and - 1( -b yl) means) - 2 - ( tetrahydro for delivering pharmaceutical composition to said subject . an AUC ( 0 to 120 ) of said N -[ 5 - ( 3, 5 - difluorobenzyl) - 1H In some embodiments are provided pharmaceutical com indazol- 3 - y11- 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 -( tetrahydro - positions, comprising (a ) N - [ 5 - ( 3 , 5 - difluorobenzyl ) -1H - in pyran - 4 - ylamino ) -benzamide in the plasma of a subject that 20 dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro is between 80 % to 125 % of 58 , 800 nM * hr, based on a 90 pyran - 4 -ylamino ) -benzamide ; and ( b ) means for delivering percent confidence interval, following administration of said an AUC ( infinity ) of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - in pharmaceutical composition to said subject. dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) -benzamide in the plasma of a subject that positions, comprising (a ) N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - 25 is between 80 % to 125 % of 57, 200 nM * hr, based on a 90 dazol -3 - yl )- 4 -( 4 -methyl -piperazin - 1 - yl ) -2 -( tetrahydro - percent confidence interval, following administration of said pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering pharmaceutical composition to said subject in a fasted state . an AUC (0 to 120 ) of said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - In some embodiments are provided pharmaceutical com indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro positions , comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in pyran - 4 -ylamino ) - benzamide in the plasma of a subject that 30 dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro is between 80 % to 125 % of 71 ,800 nM * hr, based on a 90 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering percent confidence interval, following administration of said an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in pharmaceutical composition to said subject in a fed state . dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com - pyran - 4 - ylamino ) - benzamide in the plasma of a subject that positions, comprising (a ) N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - 35 is between 80 % to 125 % of 57, 200 nM * hr, based on a 90 dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro percent confidence interval, following administration of said pyran - 4 - ylamino )- benzamide ; and (b ) means for delivering pharmaceutical composition to said subject . an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - In some embodiments are provided pharmaceutical com indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in pyran -4 - ylamino )- benzamide in the plasma of a subject that 40 dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro is between 80 % to 125 % of 71, 800 nM " hr, based on a 90 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering percent confidence interval, following administration of said an AUC ( infinity ) of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H - in pharmaceutical composition to said subject. dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) - benzamide in the plasma of a subject that positions, comprising (a ) N - [5 -( 3 ,5 - difluorobenzyl) - 1H -in - 45 is between 80 % to 125 % of 58, 300 nM * hr, based on a 90 dazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro percent confidence interval, following administration of said pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering pharmaceutical composition to said subject in a fasted state . an AUC (0 to 120 ) of said N - [5 -( 3, 5 -difluorobenzyl ) - 1H - In some embodiments are provided pharmaceutical com indazol- 3 - yl] - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro - positions , comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in pyran - 4 - ylamino ) -benzamide in the plasma of a subject that 50 dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro is between 80 % to 125 % of 64 , 400 nM * hr, based on a 90 pyran - 4 - ylamino ) -benzamide ; and ( b ) means for delivering percent confidence interval, following administration of said an AUC ( infinity ) of said N - [ 5 - (3 , 5 - difluorobenzyl) - 1H - in pharmaceutical composition to said subject in a fed state . dazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com pyran - 4 - ylamino ) -benzamide in the plasma of a subject that positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - 55 is between 80 % to 125 % of 58 , 300 nM * hr, based on a 90 dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - percent confidence interval , following administration of said pyran -4 - ylamino ) - benzamide ; and ( b ) means for delivering pharmaceutical composition to said subject . an AUC (0 to 120 ) of said N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H In some embodiments are provided pharmaceutical com indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro - positions, comprising (a ) N - [5 -( 3 ,5 -difluorobenzyl ) - 1H - in pyran -4 - ylamino )- benzamide in the plasma of a subject that 60 dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro is between 80 % to 125 % of 64 , 400 nM * hr, based on a 90 pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering percent confidence interval, following administration of said an AUC ( infinity ) of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - in pharmaceutical composition to said subject . dazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro In some embodiments are provided pharmaceutical com - pyran - 4 - ylamino ) -benzamide in the plasma of a subject that positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in - 65 is between 80 % to 125 % of 59 , 400 nM * hr, based on a 90 dazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro percent confidence interval, following administration of said pyran -4 - ylamino )- benzamide ; and ( b ) means for delivering pharmaceutical composition to said subject in a fed state . US 10 , 398 ,693 B2 115 116 In some embodiments are provided pharmaceutical com - tion , all ranges provided herein also encompass any and all positions, comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H -in possible sub - ranges and combinations of sub -ranges thereof. dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro Any listed range can be easily recognized as sufficiently pyran - 4 -ylamino )- benzamide ; and ( b ) means for delivering describing and enabling the same range being broken down an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - 5 into at least equal halves, thirds, quarters , fifths, tenths , etc . dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro As a non - limiting example , each range discussed herein can pyran - 4 - ylamino )- benzamide in the plasma of a subject that be readily broken down into a lower third , middle third and is between 80 % to 125 % of 59 , 400 nM * hr, based on a 90 percent confidence interval, following administration of said upper third , etc . As will also be understood by one skilled in pharmaceutical composition to said subject . the art all language such as “ up to , " " at least, ” “ greater than , ” In some embodiments are provided pharmaceutical com 10 “ less than , ” and the like include the number recited and refer positions , comprising (a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in to ranges which can be subsequently broken down into dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro sub -ranges as discussed above . Finally , as will be under pyran - 4 - ylamino ) -benzamide ; and (b ) means for delivering stood by one skilled in the art , a range includes each subject an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H - in - 15 member. Thus, for example , a group having 1 - 3 articles dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro refers to groups having 1 , 2 , or 3 articles . Similarly, a group pyran -4 -ylamino )- benzamide in the plasma of a subject that having 1 - 5 articles refers to groups having 1 , 2 , 3 , 4 , or 5 is between 80 % to 125 % of 73 ,300 nM * hr, based on a 90 articles , and so forth . percent confidence interval , following administration of said pharmaceutical composition to said subject in a fed state . 20 Example 1 In some embodiments are provided pharmaceutical com positions , comprising ( a ) N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in A pharmaceutical composition comprising N - [5 - (3 , 5 -dif dazol- 3 -yl ) - 4 -( 4 -methyl -piperazin - 1 -yl ) -2 - (tetrahydro luorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) pyran - 4 -ylamino ) - benzamide ; and ( b ) means for delivering 2 - (tetrahydro - 2H - pyran - 4 - ylamino ) -benzamide and fumaric an AUC ( infinity ) of said N - 15 -( 3, 5 -difluorobenzyl ) - 1H - in - 25 acid was prepared as follows. dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro pyran - 4 - ylamino ) -benzamide in the plasma of a subject that Target is between 80 % to 125 % of 73 , 300 nM * hr, based on a 90 Target weight Actual percent confidence interval , following administration of said amount per per weight pharmaceutical composition to said subject . 30 dosage unit batch In some embodiments are provided pharmaceutical com - Component (mg ) % w /w ( g ) batch ( g ) positions , comprising (a ) N -15 - ( 3 ,5 -difluorobenzyl ) - 1H - in - N - 15 - (3 .5 -difluorobenzyl ) 200 . 0 44 . 44 66 .67 66 .67 dazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro 1H - indazol - 3 - yl) - 4 - ( 4 pyran - 4 -ylamino )- benzamide ; and (b ) means for delivering methyl- piperazin -1 -yl ) - 2 an AUC ( infinity ) of said N -15 - ( 3 , 5 - difluorobenzyl) - 1H - in - 35 (tetrahydro - 2H -pyran - 4 ylamino ) -benzamide dazol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro Fumaric acid 50 . 0 11 . 11 16 .67 16 .67 pyran - 4 - ylamino )- benzamide in the plasma of a subject that Isomalt 173 . 0 38 . 44 57 .67 57 .67 is between 80 % to 125 % of 65 ,700 nM * hr, based on a 90 Pregelatinized starch , NF 22. 50 5 .00 7 . 50 7 . 50 percent confidence interval , following administration of said ( Starch 1500 ) Colloidal silicon dioxide 2 . 25 0 . 50 0 . 75 0 . 7542 pharmaceutical composition to said subject in a fed state . 40 ( Cab - O - Sil® ) In some embodiments are provided pharmaceutical com Magnesium stearate , NF 2. 25 0. 50 0 . 75 0. 75 positions, comprising ( a ) N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in (HyQual ® 5712 Powder ) dazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl )- 2 -( tetrahydro pyran -4 - ylamino )- benzamide ; and ( b ) means for delivering Total 450 .00 100. 00 150 . 00 150. 01 an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H - in - 45 dazol- 3 -yl ) -4 - (4 -methyl - piperazin -1 - yl) - 2 -( tetrahydro - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl pyran -4 -ylamino )- benzamide in the plasma of a subject that p iperazin - 1- yl) -2 -( tetrahydro -2H -pyran -4 - ylamino )- benz is between 80 % to 125 % of 65, 700 nM * hr, based on a 90 amide was milled and the resulting materials were passed percent confidence interval, following administration of said through a 60 -mesh screen . The specified amount of fumaric pharmaceutical composition to said subject . 50 acid was ground using a mortar and pestle and the resulting materials were passed through a 60 -mesh screen . The EXAMPLES fumaric acid was added to a V - blender and was blended for about 30 seconds, after which the N -[ 5 -( 3 ,5 -difluoroben All numbers expressing quantities of ingredients , reaction zyl) - 1H - indazol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetra conditions, and so forth used in the specification are to be 55 hydro - 2H - pyran - 4 - ylamino ) -benzamide was added to the understood as being modified in all instances by the term blender and the resulting mixture was blended for about one " about. ” Accordingly , unless indicated to the contrary, the minute at 25 rpm . About one- half of the isomalt ( estimated numerical parameters set forth herein are approximations by sight ) , the pregelatinized starch , and the colloidal silicon that may vary depending upon the desired properties sought dioxide were added to the blender and the resulting mixture to be obtained . At the very least, and not as an attempt to 60 was blended for about 3 minutes . The remainder of the limit the application of the doctrine of equivalents to the isomalt was added along with the magnesium stearate to a scope of any claims in any application claiming priority to large weighing boat, the mixture was stirred . The resulting the present application , each numerical parameter should be mixture of isomalt and magnesium stearate was then added construed in light of the number of significant digits and to the blender and the mixture was blended for about 3 ordinary rounding approaches . 65 minutes at 25 rpm . The mixture was removed from the As will be understood by one skilled in the art, for any and blender, screened through a 40 -mesh screen and placed into all purposes , such as in terms of providing a written descrip - a plastic bag. Bisected , modified oval tablets were prepared US 10 , 398 ,693 B2 117 118 from the mixture using tooling with dimensions of 0 . 3200x The flow of the powder entering the tableting tooling was 0 .5800 . Some sticking issues were observed with this tool sensitive to the head space in the hopper. ing , so it was switched to tooling for a caplet having dimensions of 0 .25x0 .75 , which resulted in tablets that were less susceptible to sticking . Tablets were then prepared by 5 Example 3 wiping the tooling with magnesium stearate on a swab after each tableting run . Generally , the flow of the powder prior A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 - dif to tableting was somewhat poor and it required stirring, but luorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) compression of the tablets was acceptable when the tooling 2 - tetrahydro -2H -pyran - 4- ylamino )- benzamide and betaine was wiped each time with magnesium stearate . 10 hydrochloride was prepared as follows. Example 2 Target Actual Target weight weight A pharmaceutical composition comprising N - [5 - ( 3, 5 -dif amount per per per luorobenzyl) - 1H - indazol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 -yl ) dosage unit batch batch 2 - ( tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide and glycine Component (mg ) % w / w ( g ) ( g ) hydrochloride was prepared as follows. N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - 200. 0 44 . 44 66. 67 66 .67 indazol- 3 - yl ) - 4 - ( 4 -methyl 20. piperazin - 1 - yl) - 2 -( tetrahydro Target 2H -pyran - 4 -ylamino ) amount Target benzamide per weight Betaine hydrochloride 66 . 50 14 . 78 22 . 17 22 . 17 dosage per Actual 156 . 50 34 .78 52. 17 52 . 17 unit batch weight per Isomalt Component (mg ) % w / w ( g ) batch ( g ) Pregelatinized starch , NF 22 . 50 5 .00 7 .50 7 . 50 25 (Starch 1500 ) N - [ 5- (3 ,5 -difluorobenzyl ) -1H - 200. 0 44 .44 66 .67 66. 67 Colloidal silicon dioxide 2 .25 0 . 50 0 . 75 0 . 75 indazol- 3 - yl] - 4 - ( 4 -methyl (Cab - O - Sil ® ) piperazin - 1 - yl) - 2 - (tetrahydro Magnesium stearate , NF 2 . 25 0 .50 0. 75 0 . 75 2H -pyran - 4 - ylamino ) benzamide (HyQual ® 5712 Powder) Glycine hydrochloride 48. 00 10 .67 16 . 00 16 .00 30 Isomalt 175 . 0 38 . 89 58 . 33 58 . 33 Total 450 . 00 100 . 00 150 .00 150 .00 Pregelatinized starch , NF 22 . 50 5 .00 7 .50 7 . 50 (Starch 1500 ) Colloidal silicon dioxide 2 . 25 0 . 50 0 .75 0 . 7542 The betaine hydrochloride was ground in a mortar and (Cab -O - Sil ® ) Magnesium stearate , NF 2 . 25 0 .50 0 .75 0. 75 35 pepestle before use . The N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda (HyQual ® 5712 Powder) zol- 3 - yl] - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - 2H pyran - 4 - ylamino ) -benzamide was milled before use . Total 450 .00 100 . 00 150. 00 150 .00 Approximately the same volumes of isomalt and magnesium stearate were added to a weighing boat and stirred together. Glycine hydrochloride was ground in a mortar and pestle . 10 . Approximately the same volumes of isomalt and colloidal N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl ) - 4 - ( 4 -methyl silicon dioxide were added to a weighing boat and stirred piperazin - 1 - yl) - 2 - ( tetrahydro - 2H - pyran - 4 - ylamino ) -benz - together in a plastic bag. The remaining isomalt, pregelati amide was milled , but was not screened . Approximately the nized starch and betaine hydrochloride were added to a same volumes of isomalt and magnesium stearate were plastic bag and briefly mixed together . All the N - 15 - ( 3 , 5 added to a weighing boat and stirred together . Approxi- 45 difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 mately the same volumes of isomalt and colloidal silicon yl) - 2 - ( tetrahydro - 2H - pyran - 4 - ylamino ) -benzamide was dioxide were added to a weighing boat. The mixture of added to the plastic bag and the resulting mixture was mixed isomalt and colloidal silicon dioxide were added to a plastic by hand in the plastic bag for about one minute . The bag , along with the remaining isomalt , pregelatinized starch , resulting mixture in the plastic bag was screened through a and glycine hydrochloride. The resulting mixture was mixed 50 40 -mesh screen and was added to a V -blender . The mixture briefly in the plastic bag , after which time the N - [ 5 - ( 3 , 5 of magnesium stearate and isomalt from the weighing boat difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - were also added to the V - blender and the resulting mixture yl) - 2 - ( tetrahydro -2H -pyran - 4 -ylamino ) -benzamide was was blended at about 25 rpm for about 3 minutes . added to the plastic bag and the resulting mixture was mixed 55. Tablets were prepared from the above mixture using in the plastic bag by hand for about one minute. The tooling for caplets having dimensions measuring 0 .2500x resulting mixture in the plastic bag was screened through a 0 .750 . The flow of the powder in the hopper was improved 40 -mesh screen and was added to a V -blender . The mixture and wiping of the tooling with magnesium stearate was only of magnesium stearate and isomalt from the weighing boat infrequently required . were also added to the V -blender and the resulting mixture 60 was blended at about 25 rpm for about 10 minutes. Tablets were prepared from the above mixture using Example 4 tooling for caplets having dimensions measuring 0 . 2500x 0 . 7500 . Sticking and capping occurred on the first two A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 - dif tablets . The tableting tooling was cleaned and swabbed with 65 luorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) magnesium stearate , but tablet sticking was still significant 2 - ( tetrahydro -2H -pyran - 4 - ylamino ) -benzamide and betaine and the weight of the resulting tablets varied significantly . hydrochloride was prepared as follows. US 10 , 398 ,693 B2 119 120 -continued Actual Target weight Actual amount per Target per Target weight dosage unit weight per batch amount per Target per Component (mg ) % w /w batch ( g ) ( g ) dosage unit weight per batch N -[ 5 -( 3 ,5 - difluorobenzyl) 200. 0 57 .1485 .71 85 .71 Component (mg ) % w / w batch ( g ) ( g ) 1H - indazol- 3 -yl ] - 4 - ( 4 microcrystalline cellulose , 61. 00 13 .56 20 . 33 20 . 33 methyl -piperazin - 1 -yl ) - 2 NF ( tetrahydro - 2H -pyran - 4 ( Avicel ® PH - 200 LM ) ylamino ) -benzamide 10 Croscarmellose sodium 4. 50 1. 00 1 . 50 1 . 50 Betaine hydrochloride 66 . 50 19 .00 28 .50 28 . 50 (Ac - Di- Sol ® SD - 711) Isomalt 37 . 50 10 . 71 16 .07 16 . 07 Pregelatinized starch , NF 22 .50 5 .00 7 . 50 7 . 50 Microcrystalline cellulose , 24 . 90 7 . 11 10 . 67 10 .67 ( Starch 1500 ) NF Colloidal silicon dioxide 2 . 25 0 . 50 0. 75 0 . 75 ( Avicel ® PH -200 LM ) (Cab - O - Sil ® ) Pregelatinized starch , NF 17. 50 5 .00 7 . 50 7 .50 15 Magnesium stearate , NF 2 . 25 0 . 50 0 . 75 0 .75 Colloidal( Starch 1500 silicon ) dioxide 1. 80 0 .51 0 .77 0. 77 (HyQual ® 5712 Powder ) ( Cab - O - Sil® ) Total 450 . 00 100 . 00 150 . 00 150 .00 Magnesium stearate , NF 1 . 80 0 . 51 51 0 . 77 0 .77 (HyQual ® 5712 Powder) 20 . The betaine hydrochloride was ground in a mortar and Total 350. 00 100 .00 150. 00 150 .00 20 pestle before use . The N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - inda zol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - 2H The betaine hydrochloride was ground in a mortar and pyran -4 -ylamino )- benzamide was milled before use . pestle before use. The N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -inda Approximately the same volumes of isomalt and magnesium zol- 3 -yl ) -4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - 2H 25 stearate were added to a weighing boat and stirred together . pyran - 4 - ylamino ) -benzamide was milled before use . Approximately the same volumes of isomalt and magnesium Approximately the same volumes of isomalt and colloidal stearate were added to a weighing boat and stirred together. silicon dioxide were added to a weighing boat and stirred Approximately the same volumes of isomalt and colloidal together in a plastic bag. The remaining isomalt, pregelati silicon dioxide were added to a weighing boat and stirred 30 nized starch , microcrystalline cellulose , croscarmellose together in a plastic bag . The remaining isomalt , pregelati 30 sodium , and betaine hydrochloride were added to a plastic nized starch , microcrystalline cellulose and betaine hydro bag and mixed together for about one minute . All the chloride were added to a plastic bag and briefly mixed N - [ 5 -( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl together. All the N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H - pyran - 4 - ylamino ) -benz v11 - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - c amide was added to the plastic bag and the resulting mixture ylamino ) - benzamide was added to the plastic bag and the was mixed by hand in the plastic bag . The resulting mixture resulting mixture was mixed by hand in the plastic bag for in the plastic bag was screened through a 40 -mesh screen about two minutes . The resulting mixture in the plastic bag and was added to a V -blender . The mixture of magnesium was screened through a 40 -mesh screen and was added to a stearate and isomalt from the weighing boat were also added V - blender. The mixture of magnesium stearate and isomaltan to the V -blender and the resulting mixture was blended for from the weighing boat were also added to the V - blender and about 3 minutes at 25 rpm . the resulting mixture was blended for about 3 minutes at 25 Tablets were prepared from the above mixture using rpm . tooling for caplets having dimensions measuring 0 . 2500x Tablets were prepared from the above mixture using 0 . 7500 . The sticking of the powder to the tooling was an tooling for caplets having dimensions measuring 0 .2500X 45 issue and required the use of magnesium stearate for each 0 .7500 . The flow of the powder in the hopper was generally compression and the powder had to be stirred in the hopper poor and frequent stirring in the hopper was required . twice during compression ( tablets # 3 and # 29) . Example 5 Example 6 A pharmaceutical composition comprising N -[ 5 -( 3, 5 -dif - 50 A pharmaceutical composition comprising N -[ 5 -( 3 ,5 -dif luorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - luorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 methyl- - piperazin - 1 - yl) 2 -( tetrahydro - 2H - pyran - 4 - ylamino ) - benzamide and betaine 2 - ( tetrahydro - 2H - pyran - 4 -ylamino ) -benzamide and betaine hydrochloride was prepared as follows . hydrochloride was prepared as follows . 55 Actual Target Target weight amount amount per Target per per Target Actual dosage unit weight per batch dosage weight per weight per Component (mg ) % w / w batch ( g ) ( g ) 60 Component unit (mg ) % w / w batch ( g ) batch ( g ) N - [5 - ( 3 , 5 -difluorobenzyl ) 200 . 0 44 . 44 66 . 67 66 .67 N - 15 - ( 3 ,5 -difluorobenzyl ) 200 . 0 44 .44 66 .67 66 .67 1H - indazol - 3 - yl ) - 4 - ( 4 1H - indazol - 3 - yl] - 4 - ( 4 methyl - piperazin - 1 -yl ) - 2 methyl- piperazin - 1 - yl) - 2 ( tetrahydro - 2H -pyran - 4 ( tetrahydro - 2H -pyran - 4 ylamino ) -benzamide ylamino ) -benzamide Betaine hydrochloride 66 . 50 14 .78 22 . 17 22 . 17 65 Betaine hydrochloride 66 .50 14 . 78 22 .17 22 . 17 Isomalt 91. 00 20 . 22 30 . 33 30 . 33 Isomalt 94 . 00 20 . 889 31. 33 31 . 33 US 10 , 398 ,693 B2 121 122 - continued - continued Target Target amount amount per Target Actual per Target Actual dosage weight per weight per dosage weight per weight per Component unit (mg ) % w / w batch ( g ) batch ( g ) Component unit (mg ) % w / w batch ( g ) batch ( g ) microcrystalline cellulose , 62. 50 13 .89 20. 83 20. 83 Pregelatinized starch , NF 11 . 25 2 . 50 3 .75 3 .75 NF ( Starch 1500 ) ( Avicel ® PH - 200 LM ) Colloidal silicon dioxide 2 . 25 0 . 50 0 .75 0 . 75 Pregelatinized starch , NF 22. 50 5 .00 7 . 50 7. 50 10 ( Cab - o -Sil ® ) ( Starch 1500 ) Magnesium stearate , NF 2 . 25 0 . 50 0. 75 0 .75 Colloidal silicon dioxide 2 . 25 0 . 50 0 . 75 0 .75 ( HyQual ® 5712 Powder ) ( Cab - O - Sil ® ) Magnesium stearate , NF 22 . 2525 00 . 50 0 .75 0. 75 Total 292 . 88 65 .08 97. 63 97 .63 (HyQual ® 5712 Powder) Second Layer Total 450 .00 100 . 00 150. 00 150 .00 Betai chloride 66 .50 14 .78 22 . 17 22 . 17 Isomalt 78 . 25 17 . 39 26 . 08 26 . 08 Pregelatinized starch , NF 11 . 25 2 . 50 3 . 75 3 . 75 The betaine hydrochloride was ground in a mortar and ( Starch 1500) pestle before use . The N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - inda Magnesium stearate , NF 1 . 13 0 . 25 0 . 38 0 . 38 zol- 3 - yl ]- 4 -( 4 -methyl - piperazin - 1 - yl ) -2 -( tetrahydro -2H - 20 . ( HyQual ® 5712 Powder ) pyran - 4 - ylamino ) -benzamide was milled before use . Total for second layer 157 . 12 Approximately the same volumes of isomalt and magnesium stearate were added to a weighing boat and stirred together. Overall total 450 .00 100. 00 150 .00 150 .00 Approximately the same volumes of isomalt and colloidal silicon dioxide were added to a weighing boat and stirred 23 The betaine hydrochloride was ground in a mortar and together in a plastic bag . The remaining isomalt , pregelati pestle before use . The N - [5 - ( 3 , 5 - difluorobenzyl) - 1H - inda nized starch , microcrystalline cellulose , and betaine hydro - zol- 3 - yl) - 4 -( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro - 2H chloride were added to a plastic bag and mixed together for pyran - 4 -ylamino ) -benzamide was milled before use . about one minute . All the N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - 20 Approximately the same volumes of isomalt and magnesium indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro stearate were added to a weighing boat and stirred together 2H -pyran - 4 -ylamino ) -benzamide was added to the plastic for layer # 1 . Approximately the same volumes of isomalt bag and the resulting mixture was mixed by hand in the and colloidal silicon dioxide were added to a weighing boat plastic bag . The resulting mixture in the plastic bag was and stirred together for layer # 1 . screened through a 40 -mesh screen and was added to a 35 For layer # 2 , the betaine hydrochloride , isomalt , and V -blender . The mixture of magnesium stearate and isomalt pregelatinized starch were added to a plastic bag, mixed by from the weighing boat were also added to the V - blender and hand and then added to a V - blender. About the same volume the resulting mixture was blended for about 3 minutes at 25 of isomalt and magnesium were mixed together by stirring rpm . and the resulting mixture was also added to the V - blender Tablets were prepared from the above mixture using 40 and the mixture was blended for about 3 minutes at 25 rpm . tooling for caplets having dimensions measuring 0 . 2500x For layer # 1 , the mixture of colloidal silicon dioxide and 0 .7500 . The sticking of the powder to the tooling was an isomalt were added to a plastic bag and mixed by shaking . issue and required swabbing of the tooling with magnesium To the bag were added the remaining isomalt , pregelatinized stearate on every tablet compression . In addition , the weight starch and the mixture was shaken . All of the N - 15 - ( 3 , 5 of the resulting tablets was variable and required some 45 difluorobenzyl )- 1H - indazol- 3 -y1 ] - 4 -( 4 -methyl - piperazin -1 stirring of the powder in the hopper. yl) - 2 - tetrahydro - 2H -pyran - 4 - ylamino ) - benzamide was added to the bag, the bag was shaken and the resulting Example 7 mixture was added to a V -blender . The pre -mixed isomalt and magnesium stearate was added to the V -blender . The A pharmaceutical composition comprising N - 15 - ( 3 , 5 -dif - 50 resulting mixture was removed from the blender, screened luorobenzyl ) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) through a 40 -mesh screen , added back into the blender and 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) - benzamide and betaine blended for about 3 minutes at 25 rpm . hydrochloride was prepared as follows . The blends were weighed out for subject layers for each tablet using tooling measuring 0 .2500X0 .7500 : first layer Target 55 was about 292 .88 mg and the second layer was about 157 . 12 amount mg. The tablets were compressed using a Carver press with per Target Actual a force of about 400 pounds for the first layer and about 1400 dosage weight per weight per pounds for the finished tablet. Magnesium stearate was Component unit (mg ) % w / w batch ( g ) batch ( g ) dusted onto the upper and lower punches prior to loading the First Layer 60 powder into each . N - [ 5- (3 ,5 -difluorobenzyl ) - 200 . 0 44 .44 66 .67 66 .67 Example 8 1H - indazol - 3 - yl ) - 4 - ( 4 methyl- piperazin - 1 - yl) -2 ( tetrahydro - 2H -pyran - 4 A pharmaceutical composition comprising N - [5 - ( 3 ,5 - dif ylamino ) - benzamide 65 luorobenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) Isomalt 78 .25 17 . 39 26 . 08 26 .08 2 - ( tetrahydro - 2H - pyran - 4 - ylamino ) - benzamide and fumaric acid was prepared as follows. US 10 , 398 ,693 B2 123 124 - continued Amount Component per Capsule (mg ) Dissolution Parameters N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 200 . 0 Apparatus Baskets methyl -piperazin - 1 - yl )- 2 -( tetrahydro - 2H -pyran - 4 Sample volume 5 mL ylamino ) benzamide Samples Time points 15 , 30 , 45 , 60 , 120 minutes Fumaric acid 50 . 0 Detection UV at 300 nM Pre - gelatinized starch 70 . 0 Mannitol 125 . 5 Fumed silica 2 .25 Representative samples of the 200 mg capsules were Magnesium stearate 2 . 25 V tested using the conditions described above and provided the Total 450 following dissolution results that represent the average per cent drug release (based on measured amount of N -[ 5 - (3 , 5 N - [5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] -4 - (4 -methyl difluorobenzyl) - 1H -indazol - 3 -yl ) - 4 - (4 -methyl - piperazin - 1 piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - vlamino ) - benz 15 yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide amide was screened through 60 mesh sieve , the designated contained in the media compared to the total amount of amount was weighed , and was transferred to a blend con - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl tainer. The fumaric acid was milled so that it flowed through piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 - ylamino ) -benz a 60 -mesh screen , the desired amount was weighed and was amide contained in the capsules. The results below represent transferred to a blend container. The two components were 20 the average dissolution data for two capsules that were mixed for approximately 1 minute . The pre - gelatinized tested . starch , fumed silica , and a half portion of the mannitol were added to the blend container . The resulting mixture was blended for approximately 1 minute and was screened Dissolution through a 40 -mesh screen . The magnesium stearate and the 25 - ( % , Average of 2 Capsules prepared according to Example 8 ) remainder of the mannitol were added to a separate con tainer, blended for approximately 1 minute , screened Time (min ) through a 40 -mesh screen , added to the first mixture and the 0 15 30 45 60 120 combined mixture was blended for about 5 minutes . The resulting mixture was filled into # 00 capsules . All % release of N - [ 5 - ( 3 , 5 0 % 23 % 54 % 78 % 90 % 96 % capsules were filled in small - scale capsule filling trays 30 difluorobenzyl) - 1H - indazol- 3 yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) apparatus. Capsule filling was based on volumetric filling 2 - ( tetrahydro - 2H -pyran - 4 and dependent on the tap density of the blend material. The ylamino ) benzamide from 200 mg dose capsules were filled into size # 00 capsule shells 200 mg capsules prepared and required strong tapping of the apparatus to achieve the according to Example 8 final fill weight. 35 - Capsule dosage strengths of 50 mg and 100 were also prepared . The blend composition for all strengths of the Representative 200 mg capsules prepared according to capsules is the same as above , but the capsule fill weightwas Example 11 were tested under the same dissolution condi adjusted proportionally to achieve the required dosage tions as above and provided the following dissolution results strength . 10 that represent the average percent drug release ( based on The 100 mg dosage strength capsule was prepared by measured amount of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol filling the blend described above into size # 1 capsules , and 3 -yl ] - 4 -( 4 -methyl -piperazin - 1 -yl ) -2 - ( tetrahydro -2H -pyran the 50 mg dosage strength capsule was filled into size # 3 4 - ylamino ) -benzamide contained in the media compared to capsules. Packing density was greatest for the 200 mg the total amount of N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol strength in size # 00 capsules , and required correspondingly 15 3 - ] - 4 - ( 4 -methyl -piperazin - 1 -yl ) - 2 - ( tetrahydro - 2H -pyran more tapping of the powder to fill the capsules to the desired 4 - ylamino ) -benzamide contained in the capsules . The results weight. Packing density was the least for the 50 mg strength . below represent the average dissolution data for two cap sules that were tested . Packing Tapping Capsule Capsule Volume Density Required 50 Strength Dissolution Size Fill wt. (mg ) ( cc ) ( g /cc ) for Filling % , Average of 2 Capsules prepared according to Example 11 ) 200 mg # 00 450 0 . 95 474 Strong 100 mg # 1 225 0 . 5 450 Medium Time (min ) 50 mg # 3 112. 5 0 . 3 375 Slight - 55 0 15 30 45 60 120 % release of N - [ 5 - ( 3 , 5 - 0 % 6 % 9 % 13 % 16 % 18 % Representative samples of the 200 mg capsules prepared difluorobenzyl ) - 1H using the procedures above were tested for drug release indazol- 3 - yl ] - 4 - ( 4 using the USP Apparatus Type I Basket Method under the methyl- piperazin - 1 -yl ) - 2 conditions described below . ( tetrahydro - 2H -pyran - 4 60 ylamino ) -benzamide from 200 mg capsules prepared according to Dissolution Parameters Example 11 Media 0 .05M sodium acetate , adjusted to pH 4 . 5 Volume 500 mL Stirring speed 50 rpm 65 A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 - dif Bath Temperature 37° C . luorobenzyl ) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) 2 -( tetrahydro -2H -pyran -4 - ylamino )- benzamide and at least US 10 , 398 ,693 B2 125 126 one acidulant released a greater amount of N - [5 -( 3 ,5 -difluo robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 Gradient program ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide into the disso lution medium under the similar conditions and at about the Time (min ) A ( % ) B ( % ) samemeasured timepoints as a pharmaceutical composition 5 90 comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H -indazol - 3 - yl] - 4 ( 4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro -2H -pyran -4 15 ylamino ) - benzamide , but not comprising at least one acidu 15 . 10 lant. 10 The results as measured by HPLC are found below . Example 9
Most abundant Most The suitability ofmaleic acid , fumaric acid , citric acid and impurity abundant tartaric acid in admixture with N - [ 5 - ( 3 , 5 - difluorobenzyl) % UV ( relative impurity 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetra Sample Condition Purity retention ) ( area % hydro -2H -pyran - 4 - ylamino ) -benzamide was investigated . Tartaric Acid 40° C ./ 75 % RH 99 . 1 % 0 . 93 0 . 16 % Dry powder mixtures of each acid in a 1 : 1 weight ratio 60° C . Dry Heat 99 . 4 % 0 . 84 0 . 13 % Citric Acid 40° C . / 75 % RH 98 . 6 % 0 . 78 0 . 14 % with N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - 20 60° C . Dry Heat 98 . 3 % 0 .89 0 . 45 % methyl- piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 - ylamino ) Maleic Acid 40° C ./ 75 % RH 44 . 6 % 0 .83 51. 3 % benzamide were prepared . The mixtures were prepared in 60° C . Dry Heat 80 . 4 % 0 . 85 11. 4 % Fumaric Acid 40° C . /75 % RH 98 . 0 % 0 . 85 1 . 3 % duplicate for each sample , and stored in open top , 4 mL glass 60° C . Dry Heat 99 . 2 % 0 . 84 0 . 18 % vials at ( 1 ) 60° C ./ dry heat and ( 2 ) 40° C . and 75 % relative Control 40° C . / 75 % RH 99 . 2 % 0 . 84 0 . 13 % humidity (RH ) . Control samples were included which con - 25 60° C . Dry Heat 99. 3 % 0 .84 0 . 13 % tained only N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -2H -pyran - 4 The admixture of maleic acid and N - [ 5 - ( 3 , 5 - difluoroben ylamino ) - benzamide . zyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin -1 - yl) - 2 -( tetra After 13 days of storage it was observed that the admix - 30 hydro -2H -pyran - 4 - ylamino ) -benzamide showed poor tures comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - chemical stability as degradation was observed at both yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - tetrahydro - 2H - pyran - 4 storage conditions. The compatibility of N - [ 5 - ( 3 , 5 - difluo ylamino ) - benzamide and tartaric , citric , and maleic acid at robenzyl) - 1H - indazol- 3 - y11 - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 the 40° C . and 75 % RH condition had partially or com ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide and citric acid pletely liquefied . In contrast , the admixture comprising 35 showed only slight increases in impurities at both storage fumaric acid and N - [ 5 - (3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - conditions. An increase in the impurity at 0 .85 RRT was seen yl] -4 - (4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro -2H -pyran -4 for the fumaric acid sample ( 1 . 3 % vs . 0 . 13 % for the control) ylamino ) - benzamide and the control samples remained dry stored at the 40° C ./ 75 % RH condition , whereas the sample at 40° C . and 75 % RH remained dry. All admixture samples stored at 60° C . showed only slight increase in impurities and the control samples stored at the 60° C . and dry heat 40 compared to the control. The admixture of tartaric acid and condition remained as dry powders . N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl The excipient compatibility samples and controls were piperazin - 1 - yl ) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benz analyzed by high -performance liquid chromatography amide showed excellent chemical stability with no or very (HPLC ) after three months storage at both conditions to little increase in impurity levels. evaluate purity and degradation of N - 15 - ( 3 , 5 - difluoroben - 4 . zyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetra Although the admixture of N - [5 -( 3 , 5 -difluorobenzyl ) - 1H hydro - 2H - pyran - 4 - ylamino )- benzamide . The HPLC traces indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro analyses were conducted on an Agilent 1100 LC , equipped 2H -pyran - 4 - ylamino ) -benzamide and tartaric acid showed with Agilent Diode Array Detector and Chemstation Soft acceptable chemical stability , the admixture demonstrated ware using the conditions found in the table below . 50 unacceptable physical instability due to absorption of mois ture . In contrast , the admixture of N - [ 5 - ( 3 , 5 -difluoroben zyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra Column : Waters SunFire TM C18 , 3 . 5 um , 150 x 4 . 6 mm , hydro - 2H - pyran - 4 - ylamino ) - benzamide and fumaric acid part no . 186002554 , or equivalent. Column temp . : 10° C . did not demonstrate hygroscopicity and maintained and Flow rate : 1 mL /min . » maintained an acceptable level of chemical stability . Injection volume: 10 UL Detection 303 nM for and N - [5 - ( 3 , 5 wavelengths: difluorobenzyl) - 1H -indazol - 3 -yl ] -4 - (4 Example 10 methyl- piperazin - 1 - yl) - 2 - (tetrahydro - 2H pyran - 4 -ylamino ) benzamide and related substances 60 Sample storage temp. : Room temperature Hereinafter Referred to as Pharmaceutical Run time: 22 minutes Composition " F2" Mobile Phases : A : 70 % water: 30 % Acetonitrile , 0. 1 % trifluoroacetic acid ( TFA ) v / v B : 30 % water: 70 % Acetonitrile , 0 . 1 % A pharmaceutical composition comprising N - [5 - (3 , 5 -dif TFA V / v 65 luorobenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) 2 - ( tetrahydro - 2H - pyran - 4 - ylamino ) - benzamide and fumaric acid was prepared as follows. US 10 , 398 ,693 B2 127 128 The required amounts of active ingredient and excipients Amount per Amount are weighed into the warehouse dispensing area . The weight Capsule per batch of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl Component (mg ) piperazin -1 -yl ) - 2 -( tetrahydro -2H -pyran -4 - ylamino )- benz N - [5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 200 . 0 128 .00 5 amide and themannitol are adjusted according to the active (4 -methyl - piperazin - 1 -yl ) - 2- ( tetrahydro - 2H pyran - 4 -ylamino ) -benzamide desired potency of the dosage form . ( 1) Manually pre- mix Fumaric acid , NF 50 . 0 32 .00 N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 - ( 4 -methyl Pre - gelatinized starch 70 . 0 44 . 80 piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benz Mannitol 125 . 5 80 . 32 Colloidal silicon dioxide , NF 2 . 25 1 . 44 10 amide and colloidal silicon dioxide into a polyethylene (PE ) Magnesium stearate 2 . 25 1 . 44 bag . ( 2 ) The resulting mixture from step 1 is passed through a 0 .500 mm screen size sieve , along with a portion of the Total 450 288 .0 pregelatinized starch and mannitol and the resulting mate rials are collected in a blender. ( 3 ) The resulting mixture The N - [ 5 - ( 3 , 5 - difluorobenzyl) -1H -indazol - 3 - yl )- 4 -( 4 - 15 from step 2 is further mixed for about 20 minutes at 20 - 25 methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) - rpm . ( 4 ) The pregelatinized starch and magnesium stearate benzamide was screened through a 60 -mesh sieve and was and are pre -mixed together and are passed through a 0 .500 transferred to the batch mixing container. The fumaric acid mm screen size sieve. ( 5 ) The material from step 4 are mixed was milled in a ball mill at 30 revolutions per second for together with the materials from step 3 and mixed for about about 2 minutes , screened through a 60 -mesh sieve and then 20 20 minutes at 20 - 25 rpm . (6 ) The blend resulting from step transferred to the batch mixing container . The mixture of 5 is filled into hard gelatin capsules using an automatic N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl capsule filling machine. Representative formulations of cap piperazin - 1 -yl ) - 2 - ( tetrahydro -2H -pyran - 4 -ylamino )- benz sules comprising 50 mg, 100 mg or 200 mg of N - [ 5 - ( 3 , 5 amide and fumaric acid were mixed by hand for about one difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 minute , after which time the pre -gelatinized starch , colloidal 25 yl) - 2 -( tetrahydro -2H -pyran - 4 - ylamino )- benzamide are silicon dioxide and one - half of the amount of required shown below . mannitol were added to the batch container. The resulting mixture was mixed by hand for about one minute . The magnesium stearate and mannitol were pre -blended through 50 mg capsule representative batch formulation (50 mg F1 ) a 40 -mesh sieve and then combined with materials in the batch mixing container. The final mixture was blended by Batch formula Amount per hand for approximately 5 minutes . 50 mg (6 ,000 capsule The resulting mixture was filled into gelatin capsule Components Function capsules) 50 mg shells , opaque white , size # 00 . The body and cap of the 35 capsules were separated , the capsule bodies were placed into N - [ 5 - ( 3 , 5 Active 300 g 50 mg a capsule device , ensuring the top of the capsule body was difluorobenzyl) - 1H ingredient flush with the surface of the filling device by moving the indazol- 3 -yl ] -4 - (4 spacer of the device . The powder blend was poured onto the n - 1 - yl) surface of the filling device , volumetrically filling the body 40 2 -( tetrahydro - 2H -pyran of the capsules, and scraping the excess powder evenly until 4 - ylamino )- benzamide all capsule bodies are filled . The powder was firmly tamped Mannitol Filler 255. 00 g 42. 50 mg into the shells one time using a tamper . Additional powder Pregelatinized starch Filler 102. 75 og 17 .125 mg blend was added to fill the remainder of the capsule and any Colloidal silicon dioxide Glidant 10 .50 g 1 . 750 mg excess powder was scraped off . The tamping , filling , and 45 Magnesium stearate Lubricant 6 .75 g 1 .125 mg scraping procedures were repeated for each capsule until the desired capsule fill weight was achieved . The filled capsules Total 675. 00 g 112. 50 mg were collected in a 10 -mesh sieve and were de - dusted by agitating them lightly . The filled capsule weight range acceptance limits were set 50 at 93 % to 107 % . The average weight of the empty capsule shells was 119 . 4 mg. The low capsule weight limit was set 100 mg capsule representative batch formulation (100 mg F1) at ( 0 . 93x450 mg) + 119. 4 mg = 538 mg. The high capsule Batch formula Amount per weight limit was set at ( 1 .07x450 mg) + 119 . 4 mg = 601 mg . 100 mg ( 3 , 600 capsule Only those capsules meeting the weight limits were used in 55 Components Function capsules ) 100 mg the study described in Example 12 . N - 15 - ( 3 , 5 Active 360. 0 g 100 .00 mg difluorobenzyl) - 1H ingredient Example 11 indazol- 3 - yl) - 4 - 4 methyl -piperazin - 1 - yl ) 2 - ( tetrahydro - 2H -pyran Hereinafter Referred to as Pharmaceutical 4 - ylamino ) -benzamide Composition “ F1” . Mannitol Filler 306 .00 g 85 . 00 mg Pregelatinized starch Filler 123. 30 g 34. 25 mg Hard gelatin capsules comprising 50 mg, 100 mg, and 200 Colloidal silicon dioxide Glidant 12 .60 g 3 . 50 mg mg of N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 Magnesium stearate Lubricant 8 . 10 g 2 . 25 mg methyl- piperazin -1 -yl ) - 2 - ( tetrahydro - 2H -pyran - 4 -ylamino )- 65 Total 810 .00 g 225 .00 mg benzamide, but not comprising at least one acidulant, are prepared as follows. US 10 ,398 ,693 B2 129 130 In order to ensure a full panel of subjects ( up to 24 200 mg capsule representative batch formulation ( 200 mg F1) subjects in each study part ), prior to N - [ 5 - ( 3 , 5 - difluoroben Batch formula Amount per zyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetra 200 mg ( 4 , 100 capsule hydro - 2H -pyran -4 -ylamino ) -benzamide dosing on day 4 , Components Function capsules ) 200 mg 5 subjects , including standbys ( 3 replacement subjects in each N - [ 5 - ( 3 , 5 Active 820 .00 g 200 .00 mg dosing group to account for possible dropouts following the difluorobenzyl) -1H ingredient safety evaluations on day 3 ) received a dose of lansoprazole indazol- 3 - yl] - 4 - ( 4 on days 1 to 3 . Lansoprazole administration on days 1 to 9 methyl- piperazin - 1 -yl ) was conducted in the morning , approximately 1 . 5 hours 2 - ( tetrahydro -2H -pyran 10 4 - ylamino ) -benzamide prior to administration of either F1 or F2 at hour 0 on day Mannitol Filler 697. 00 g 170 . 00 mg Pregelatinized starch Filler 280 .85 g 68 . 50 mg Subjects were randomized and received 3 out of 4 treat Colloidal silicon dioxide Glidant 28. 70 09g 7 .00 mg Magnesium stearate Lubricant 18 .45 g 4 .50 mg ments in one of the following sequences : ABD or BAC ( i . e . , 15 Periods 1 and 2 were conducted as a crossover design under Total 1845. 00 g 450. 00 mg fasting conditions [ Treatments A and B ]) . In Period 3 , subjects received the same N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro Example 12 2H -pyran -4 -ylamino )- benzamide formulation as they 20 received in Period 2 , but under fed conditions [ Treatment C Comparative Pharmacokinetic Study of F1 and F2 or D ]) . Each subject received each of the 3 assigned treat Formulations ments on one occasion . Treatments A and C utilized 200 mg strength F1 capsules . A comparative pharmacokinetic study in healthy , human Treatments B and D utilized 200 mg F2 capsules . subjects was conducted comparing a 200 mg dosage strength 25 Treatments A , B , C , and D were as follows: of pharmaceutical composition F1 ( as described in Example Treatment A : 30 mg lansoprazole ( 1x30 mg capsule ) , for 11 ) with a 200 mg dosage strength pharmaceutical compo - 9 consecutive days (within 21 hour of dosing time on Day sition F2 (as described in Example 10 ) . 1) , with 800 mg F1 (4x200 mg capsules ) administered under Pharmaceutical compositions F1 and F2 , along with and fasting conditions 1 . 5 hours after administration of lanso lansoprazole , were administered orally with approximately 30 prazole on Day 4 . 240 mL of water , according to the randomization scheme. Treatment B : 30 mg lansoprazole ( 1x30 mg capsule ), for Lansoprazole was administered as 30 mg lansoprazole 9 consecutive days (within 11 hour of dosing time on Day delayed -release capsules . 1 ), with 800 mg F2 (4x200 mg capsules) administered under Subjects were randomized into two groups , A and B . 35 fasting conditions 1 . 5 hours after administration of lanso Periods 1 and 2 were conducted as a crossover design under prazole on Day 4 . fasting conditions where all subjects received F1 and F2 . In Treatment C : 30 mg lansoprazole ( 1x30 mg capsule ) , for Period 3 , subjects received the same N - 15 - ( 3 , 5 -difluoroben - 9 consecutive days (within + 1 hour of dosing time on Day zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra - 1 ) , with 800 mg F1 ( 4x200 mg capsules ) administered 30 hydro - 2H - pyran - 4 - ylamino ) - benzamide formulation as they 40 minutes after the start of a high - fat breakfast on Day 4 . On received in Period 2 , but under fed conditions. A represen Day 4 , lansoprazole was administered approximately 1 hour tative summary of Periods 1 , 2 , and 3 and the pharmaceutical prior to the start of the high - fat meal. compositions subjects in groups A and B will receive in each Treatment D : 30 mg lansoprazole ( 1x30 mg capsule ) Period is found below . following an overnight fast, for 9 days ( within + 1 hour of 45 dosing time on Day 1 ) , with 800 mg F2 ( 4x200 mg capsules ) administered 30 minutes after the start of a high - fat break Subject Group Period 1 ( fasted ) Period 2 (fasted ) Period 3 (fed ) fast on Day 4 . On Day 4 , lansoprazole was administered F1 F2 F2 approximately 1 hour prior to the start of the high - fat meal. F2 F1 For all procedures scheduled post -N - [ 5 -( 3 ,5 -difluoroben - 50 zyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra hydro - 2H - pyran - 4 - ylamino ) benzamide dosing , time points In each period , multiple oral daily doses of lansoprazole were relative to the time of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H were administered for 9 consecutive days with a single oral indazol- 3 - v11 - 4 - (4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro dose of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 - 2H -pyran - 4 - ylamino ) -benzamide dosing ( i . e ., Hour 0 on methyl- piperazin - 1- yl ) - 2 -( tetrahydro -2H -pyran - 4 - ylamino )- 55 Day 4 ). benzamide administered concomitantly on Day 4 under For all subjects , blood samples were collected in blood fasting (Periods 1 and 2 ) or fed (Period 3 ) conditions. PK collection tubes containing sodium heparin at scheduled sampling for N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 time points . Sampling time -points were relative to the time ( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro -2H -pyran -4 of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl ylamino ) - benzamide and its metabolite , M5 , was conducted 60 piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 - ylamino )- benz for 120 hours following N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - inda amide dosing ( i. e ., Hour 0 on Day 4 ) . Blood sampling for zol - 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H pharmacokinetic measurements were scheduled for the fol pyran - 4 -ylamino ) -benzamide administration . lowing times ( in hours ) ( all time points were measured as The washout period was at least 8 days between each dose relative to N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - 65 methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) piperazin - 1 -yl ) - 2 -( tetrahydro - 2H -pyran - 4 -ylamino ) -benz benzamide dosing , i . e . , hour 0 on day 4 of the study ) : 0 , 0 .5 , amide. 1 , 2 , 3 , 4 , 5 , 6 , 8 , 12 , 24 , 36 , 48 , 72 , 96 , and 120 . US 10 , 398 ,693 B2 131 132 Subject plasma samples were analyzed for the presence of Additional analysis was conducted to evaluate fixed dos N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - ing by body weight, or adjusted dosing based on body piperazin - 1 -yl ) - 2 - ( tetrahydro -2H -pyran - 4 -ylamino )- benz surface area. At 800 mg fixed dose, a total of 23 healthy amide and a metabolite of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H subjects were evaluated with body weights ranging from 55 indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 5 to 106 kg (median 74 kg ) and BSA ranging from 1. 57 to 2 .28 2H -pyran - 4 - ylamino ) - benzamide using analytical methods mg/m² (median 1. 79 mg/ m² ) . Total exposure of N - [ 5 - ( 3 , 5 known to those of ordinary skill in the art. difluorobenzyl) -1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 All subjects who received at least one dose of N -[ 5 -( 3 ,5 yl) - 2 -( tetrahydro - 2H - pyran - 4 - ylamino ) - benzamide did not difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 correlate with body weight or body surface area , suggesting yl) -2 - tetrahydro - 2H -pyran - 4 - ylamino )- benzamide and had 10 the viability of fixed dosing . evaluable PK data made up the PK Population and was used for all PK analyses . The following PK parameters were Example 13 calculated for N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro -2H -pyran - 4 ylamino ) -benzamide in plasma, as appropriate : AUC0- 13 15 Referred to Herein as “ F2A ” AUCO- int , AUC % extrap , Cmar , Tmar, t1 /2 , CL / F , and Vz / F . A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 - dif The PK parameters AUCO -4 , AUCo -inf and Cmax for N -[ 5 - luorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1 -yl ) ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piper 2 - ( tetrahydro -2H -pyran - 4 - ylamino ) -benzamide and betaine azin - 1 -yl ) - 2 - ( tetrahydro -2H - pyran - 4 -ylamino ) -benzamide hydrochloride was prepared as follows. were analyzed using analysis of variance (ANOVA ) model 20 to calculate the geometric least squares mean (LSM ) ratio using natural log - transformed data . A 90 % confidence inter Target val ( CI) was constructed around the ratio of the geometric amount per Target Actual mean for the three PK parameters for N - [ 5 - ( 3 , 5 -difluoroben dosage unit weight per weight per zyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra - 25 Component- (mg ) batch ( g ) batch ( g ) hydro - 2H - pyran - 4 - ylamino ) -benzamide . N - 15 - ( 3 , 5 - difluorobenzyl) -1H 200 . 0 222 . 22 222 . 23 indazol- 3 - yl ] - 4 - ( 4 -methyl Formulation F1 was used as the reference for all relative piperazin - 1 - yl) - 2 bioavailability analysis . Fasted dosing was used as the ( tetrahydro - 2H -pyran - 4 -ylamino ) reference for food effect analysis . The following assess benzamide ments were done : ( 1 ) the relative bioavailability of N - [ 5 - ( 3 , 30 Betaine hydrochloride 82 . 00 91. 11 91 . 11 Isomalt 124 . 00 137 . 78 137 .78 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin Pregelatinized starch , NF 35 .00 38. 89 38 . 89 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) - benzamide in two (Starch 1500 ) formulations under fasting conditions were evaluated by Colloidal silicon dioxide 4 . 50 5 .00 5 . 00 comparing Treatment B versus Treatment A ; and ( 2 ) the Magnesium stearate , NF 4 . 50 5 . 00 5 . 00 effect of food on each of the two N - [5 - (3 , 5 -difluorobenzyl ) - 35 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra Total 450. 00 500. 00 500 .01 hydro - 2H - pyran - 4 - ylamino )- benzamide formulations F1 and F2 , were evaluated by comparing (a ) for F1, Treatment The N -[ 5 -( 3 , 5 -difluorobenzyl )- 1H - indazol- 3 -yl )- 4 - (4 C versus Treatment A ( within the same treatment sequence ) , methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) and ( b ) for F2, Treatment D versus Treatment B (within the 40 benzamide was screened through a 60 -mesh sieve and was same treatment sequence ) . transferred to thebatch mixing container. The betaine hydro The results of the study are shown in the tables below . All chloride was ground with a mortar and pestle , screened values , except Tmar, are reported as themean value ( % CV ) . through a 60 -mesh sieve and then transferred to the batch The Tmax values are reported as the median value and the mixing container. The mixture of N - [ 5 - ( 3 , 5 - difluorobenzyl) range . For example , for formulation F1, the median Tmax for 45 1H - indazol - 3 - yl ] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetra 23 subjects in the fasted state was about 5 hours , with a hydro - 2H -pyran - 4 -ylamino ) -benzamide and betaine hydro range of about 2 hours to about 8 hours . chloride were mixed by hand for about one minute , after
Formulation F1 Formulation F2 Tmax * Cmax AUC0- 24 AUC . 12 Tmax* Cmax AUC0- 24 AUC . 1 /2 Period Food N ( hr ) (nM ) (nM · hr) (nM · hr) ( hr ) N (hr ) ( nM ) ( nM · hr ) ( nM · hr ) ( hr) 1 & 2 Fasted Mean 23 5 623 9390 26700 29 .7 24 5 2110 28900 5 9600 25 .2 CV % ( 2 - 8 ) 107 118 108 67 . 9 ( 2 - 6 ) 24 24 . 3 31 . 3 29. 8
Formulation F1 Formulation F2
max Cmax AUC0- 24 AUC 1 /2 Tmax Cmax AUC0- 24 AUC . 1/ 2 Period Food N ( hr ) ( M ) (nM hr ) (nM hr) ( hr ) N ( hr ) ( M ) (nMhr ) (nM hr ) (hr ) 2 Fasted Mean 11 5 637 8760 26600 33. 1 12 5 2080 30800 6 8800 29 . 2 CV % ( 2 - 8 ) 84 . 8 89 . 2 84. 6 86 . 4 (4 - 6 ) 21 . 4 21 . 7 27. 9 17 . 9 3 Fed Mean 11 8 2550 37300 8 8600 28. 1 12 8 2560 40400 102000 27 CV % ( 5 - 12 ) 35 . 5 30 32 .6 26 .8 (5 - 12 ) 20 .1 19 .5 28 .3 16 .6 US 10 , 398 ,693 B2 133 134 which time the pre - gelatinized starch , colloidal silicon diox Treatment F : 30 mg lansoprazole ( 1x30 mg capsule ) for ide and one -half of the amount of required isomalt were 8 consecutive days (within + 1 hour of dosing time on Day added to the batch container. The resulting mixture was 1 ) , with 800 mg F2A (4x200 mg capsules ) administered mixed by hand for about one minute . The magnesium under fasting conditions 1 . 5 hours after administration of stearate and the remaining isomalt were pre - blended through 5 lansoprazole on Day 4 . a 40 -mesh sieve and then combined with materials in the Treatment G : 800 mg F2A ( 4x200 mg capsules ) admin batch mixing container . The final mixture was blended by istered 30 minutes after the start of a high - fat breakfast on hand for approximately 5 minutes . Day 4 . The resulting mixture was filled into gelatin capsule Treatment H : 30 mg lansoprazole ( 1x30 mg capsule ) for shells, opaque white , size # 00 . The body and cap of the 10 9 consecutive days (within + 1 hour of dosing time on Day capsules were separated , the capsule bodies were placed into a capsule device , ensuring the top of the capsule body was 1 ), with 800 mg F2A (4x200 mg capsules ) administered 30 flush with the surface of the filling device by moving the minutes after the start of a high - fat breakfast on Day 4 . On spacer of the device . The powder blend was poured onto the Day 4 , lansoprazole is administered approximately 1 hour surface of the filling device . volumetrically filling the body 15 prior to the start of the high - fatmeal . of the capsules , and scraping the excess powder evenly until all capsule bodies are filled . The powder was firmly tamped Subject into the shells one time using a tamper. Additional powder Group Period 1 ( fasted ) Period 2 ( fasted ) Period 3 ( fed ) blend was added to fill the remainder of the capsule and any cess powder was seraned off The tamping filling and 20 E F2A no lansoprazole F2A w /lansoprazole F2A w / lansoprazole excess powder was scraped off. The tamping, filling , and 20 F F2A w / lansoprazole F2A no lansoprazole F2A no scraping procedures were repeated for each capsule until the lansoproazole desired capsule fill weightwas achieved . The filled capsules were collected in a 10 -mesh sieve and were de -dusted by agitating them lightly . In each period , up to 12 of the 24 subjects received doses The filled capsule weight range acceptance limits were set 25 of lansoprazole , which were administered to determine the at 93 % to 107 % . The average weight of the empty capsule effect of the PPI based on the above scheme with a single shells was 119 .4 mg. The low capsule weight limit was set oral dose of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - y1 ] - 4 at ( 0 .93x450 mg) + 119 . 4 mg = 538 mg. The high capsule ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 2H -pyran - 4 weight limit was set at ( 1 .07x450 mg ) + 119 . 4 mg = 601 mg. ylamino ) -benzamide administered concomitantly on Day 4 Only those capsules meeting the weight limits were used in 30 of each period either under fasting (Periods 1 and 2 ) or fed subsequent studies. (Period 3 ) conditions . Plasma pharmacokinetic sampling for N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl Example 14 piperazin - 1 -yl ) - 2 - ( tetrahydro -2H - pyran - 4 -ylamino ) - benz amide and its metabolite , M5, was conducted for 120 hours Comparative Pharmacokinetic Study of F2A 35 following N - [5 - (3 , 5 -difluorobenzyl ) -1H - indazol -3 -yl ] -4 - (4 methyl -piperazin -1 -yl ) - 2 -( tetrahydro - 2H -pyran - 4 -ylamino ) A comparative pharmacokinetic study in healthy, human benzamide administration . subjects was conducted comparing a single dose of F2A with The washout period was at least 8 days between each dose or without the PPI lansoprazole to determine the effects , if of N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 -( 4 -methyl any, of the PPI. 40 piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benz Pharmaceutical composition F2A was administered orally amide . at a dosage of 800 mg ( four 200 mg F2A capsules ) with The washout period was at least 8 days between each dose approximately 240 mL of water to healthy individuals under of N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 -( 4 -methyl fasted conditions . Subjects were randomized into two piperazin - 1 -yl ) - 2 - ( tetrahydro - 2H - pyran - 4 - ylamino ) -benz groups , E and F . Periods 1 and 2 were conducted as a 45 amide . crossover design under fasting conditions where all subjects For all procedures scheduled post- N - [5 -( 3 ,5 -difluoroben received F2A under fasted conditions , but in Period 1 Group Zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra A was administered of lansoprazole and Group B was not hydro - 2H -pyran - 4 -ylamino ) benzamide dosing, time points administered lansoprazole . In Period 2 , Group A was not were relative to the time of N - 15 - ( 3 , 5 - difluorobenzyl) - 1H administered lansoprazole and Group B was administered 50 indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro lansoprazole . In Period 3 , the subjects continued the same 2H -pyran - 4 -ylamino ) -benzamide dosing (i . e ., Hour 0 on treatment from Period 2 , but under fed conditions. A repre Day 4 ) . sentative summary of Periods 1 , 2 , and 3 and the pharma- For all subjects , 16 mg ondansetron is administered ceutical compositions subjects in groups A and B will without water on Day 4 of each period prior to N - [ 5 - ( 3 , 5 receive in each Period is found below . 55 difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl- piperazin - 1 Subjects were randomized and received 3 out of 4 treat - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) benzamide dosing , ments in one of the following sequences: EFH or FEG ( i . e ., as a prophylactic antiemetic measure . Periods 1 and 2 were conducted as a crossover design under For all subjects, blood samples were collected in blood fasting conditions [ Treatments E and F ]) . In Period 3 , collection tubes containing sodium heparin at scheduled subjects received the same N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - 60 time points . Sampling time -points were relative to the time indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro of N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl 2H - pyran - 4 - ylamino )- benzamide formulation as they piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 - ylamino )- benz received in Period 2 , but under fed conditions [ Treatment G amide dosing ( i. e. , Hour 0 on Day 4 ). Blood sampling for or H ] ) . Each subject received each of the 3 assigned treat pharmacokinetic measurements were scheduled for the fol ments on one occasion . 65 lowing times ( in hours ) (all time points were measured as Treatment E : 800 mg of F2A (4x200 mg capsules ) under relative to N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 fasting conditions on Day 4 . methyl - piperazin - 1 -yl ) - 2 -( tetrahydro - 2H - pyran - 4 - ylamino ) US 10 , 398 ,693 B2 135 136 benzamide dosing , i. e ., hour 0 on day 4 of the study ) : 0 , 0 . 5 , 1, 2 , 3 , 4 , 5 , 6, 8 , 12 , 24, 36 , 48 , 72, 96 , and 120 . % CV Average Subject plasma samples were analyzed for the presence of Comparison AUC . N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl No PPIPPI No PPIPPI piperazin - 1 - yl) - 2 -( tetrahydro - 2H - pyran - 4 - ylamino ) - benz Fasted 24 32 61600 44300 amide and a metabolite of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H Fed 32 32 82800 95800 indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro 2H -pyran - 4 - ylamino ) - benzamide using analytical methods The data indicate that when F2A is administered without known to those of ordinary skill in the art. 10 lansoprazole , the AUC . is approximately 25 % higher under All subjects who received at least one dose of N - [ 5 - ( 3 , 5 - fed conditions compared to fasted conditions . In addition , difluorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - the individual difference of AUC , was up to 2 . 5 times yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide and had greater under fed conditions compared to fasted conditions evaluable PK data made up the PK Population and was used (FIG . 2 ). for all PK analyses . The following PK parameters were 15 The effect of PPI co - administration was also evaluated for calculated for N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] the F2A formulation . Mean steady - state exposure of F2A 4 -( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -2H - pyran -4 - was approximately 40 % lower in subjects were co -admin ylamino ) - benzamide in plasma, as appropriate : AUCO- 13 istered a PPI, compared to subjects administered F2A alone . AUCo- inf , AUC % extrap , Cmax, Tmax, t1/ 2 , CL /F , and Vz/ F . , The table below summarizes the effect of co -administration The PK parameters AUCO- ,, AUCo -inf and Cmax for N - [ 5 20 of PPI on F2A exposure in healthy subjects under fasted (3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - (4 -methyl -piper conditions . azin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide were analyzed using analysis of variance (ANOVA ) model Geomean Ratio to calculate the geometric least squares mean (LSM ) ratio 25 GeoLSM ( % ) CI90 % using natural log - transformed data . A 90 % confidence inter val ( CI) was constructed around the ratio of the geometric Parameter 1 w PPI no PPI ( w PPI/ no PPI) Lower Upper mean for the three PK parameters for N - [ 5 - ( 3 , 5 - difluoroben Cmax (nm ) 22 1439 2609 55 49 62 zyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra AUCin 22 37498 62972 60 5 2 68 hydro - 2H -pyran - 4 - ylamino )- benzamide . Formulation 2A 30 (nM · hr ) was used as the reference for all relative bioavailability analysis . The food effect was also evaluated for the F2A formula tion , both with and without co -administration of a PPI. The results of the study are shown in the tables below . All Without PPI, minimal food effect was observed , with a values , except Tmar, are reported as the mean value ( CV ). 35 fed / fasted geometric mean ratio of 131 % . With co -admin The TmaxNOX values are reported as the median value and the istration of a PPI, a higher fed / fasted geometric mean ratio range . of 213 % was observed . However, the difference in food effect was significantly reduced compared to a similar study of the F1 formulation ( ~ 4x ) as summarized in the table Dose N Tmax Cmax AUC. 40 below . No PPI 22 Mean 4 . 0 2670 66000 % CV (2 -5 ) 24. 0 28 . 8 Geomean W PPI 22 Mean 4 .5 1500 39400 Ratio ( % ) GeoLSM ( Fed / C190 % % CV 1 (3 - 6 ) 30 .7 35 . 2 45 PPI Parameter 1 Fed Fasted Fasted ) Lower Upper Following a single dose of F2A at 800 mg (4x200 mg F2A No Cmax (nm ) 12 2468 2477 100 88 . 1 114 PPI AUCinf 12 79019 60113 131 108 160 capsules ) to healthy subjects under fasted conditions , F2A (nM · hr ) was readily absorbed , with detectable F2A in circulation at 50 W Cmax ( nm ) 9 2199 1480 149 122 180 0 . 5 hr post -dose and reaching median Tmax at 4 . 5 hr with PPI AUC in 9 91392 42457 215 169 269 lansoprazole , and 5 hr without lansoprazole . Mean terminal (nM hr ) half - life ( t12) was approximately 24 hours , supporting a once daily dosing regimen . FIG . 1 depicts a graphical In summary , formulation F2A greatly reduced the inter illustration comparing the effect of lansoprazole . As seen in 55 subject variability and food effect compared to formulation FIG . 1 , and as shown in the table above, a clear PPI effect F1. In addition , co -administration of a PPI with formulation is observed when using F2A with lansoprazole under fasted F2A results in a 40 % reduction of F2A exposure . The data also show that when F2A is administered with conditions , where the AUC . is approximately 67 % higher lansoprazole , the AUC . is approximately 80 % greater under without lansoprazole . 60 fed conditions compared to fasted conditions. The individual In addition to comparing the effects of lansoprazole , the difference of AUC . can be up to 3 times greater in fed above study was used to determine the effect of food with conditions compared to fasted conditions , as is shown in F2A treatment by comparing Period 2 with Period 3 for each FIG . 3 . treatment group . Group A received no lansoprazole under The full results of the study are shown in the tables below . fasting conditions in Period 2 , and no lansoprazole under fed 65 All values , except Tmor, are reported as the mean value % conditions in Period 3 . The table below shows the food effect CV ) . The Tor values are reported as the median value and without lansoprazole . See also FIG . 2 and FIG . 3 . the range . US 10 ,398 ,693 B2 137 138
Formulation F2A without PPI Formulation F2 A with PPI Tmax * Cmax AUCO- 24 AUC. t1/ 2 Tmax* Cmax AUCo- 24 AUC. 1/ 2 Period Food N ( hr ) (nM ) (nMhr ) (nM · hr) ( hr) N ( hr ) (nM ) (nM · hr ) (nM . hr ) (hr ) 1 Fasted Mean 10 3 . 5 2860 38300 7 1400 23. 7 12 3 . 0 1490 19000 35200 23 . 1 CV % ( 2 - 5 ) 28 . 8 27. 3 32 . 1 15 . 5 ( 3 - 5 ) 36 . 1 32 .5 36 . 4 20 .6 2 Fasted Mean 12 4 . 0 2510 34300 6 1600 23 . 2 10 5 .0 1520 22200 44300 24 . 5 CV % ( 3 - 5 ) 16 . 2 17 . 1 23. 8 12 . 1 ( 3 - 6 ) 24 . 8 26 . 2 31. 6 18 . 8 1 & 2 Fasted Mean 22 4 . 0 2670 36100 66000 23 . 4 22 4 .5 1500 20400 39400 23 . 8 CV % ( 2 - 5 ) 24 .0 23 . 0 28 . 8 13 . 5 ( 3 - 6 ) 30 . 7 29 .8 35 . 2 19 .5
Formulation F2A
MAX AUCO- 24 AUC t12 Period Food N ( NM ) (nM · hr ) ( nM · hr) ( hr) 2 Fasted Mean 10 5. 0 1520 22200 44300 24 . 5 CV % ( 3 - 6 ) 24 . 8 26 . 2 31. 6 18 . 8 w3 Fed Mean 1 12 2270 36600 95800 28 . 1 CV % ( 8 - 12 12 )) 26 .6 30 31 . 8 26 . 8 FIG . 4 summarizes the PK data for F2A under fed F2 and F2A improved inter -subject variability significantly conditions with a PPI. compared to F1 under fasted dosing in the presence of a PPI, 25 and exposure trends are higher for F2A than for F1, but not Example 15 to a statistically significant level. All three formulations provide similar inter - subject variability and absolute expo Formulation Comparison sure under fed conditions , when a high - fat meal was used . The pharmacokinetic data for administration of formula - z Example 16 tions F1 (pharmaceutical composition comprising N -[ 5 -( 3 , 30 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin Dose Comparisons 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide not comprising at least one acidulant) , F2 ( pharmaceutical com Pharmacokinetic parameters were evaluated for dosing position comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- as with food for formulation F1 following continuous dosing of 3 -yl ] -4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro - 2H -pyran - F1 at doses of 100 , 200 , 400 , and 800 mg/ m² / day . As shown 4 - ylamino ) - benzamide with fumaric acid as an acidulant ) in the table below , F1 exposure (Cmax and AUC ) increased and F2A (pharmaceutical composition comprising N - [ 5 - ( 3 , with the dose in a dose - proportional manner between 100 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin mg/ m² and 400 mg/ m² . Exposure trended approximately 1 -yl ) - 2 -( tetrahydro -2H -pyran -4 -ylamino )- benzamide with two times higher compared with Day 1 at each dose level . betaine hydrochloric acid as an acidulant) under fasted or 40 At 800 mg/m² , exposure of F1 is comparable to 400 mg/ m² fed conditions with a PPI are compared in the table below . dosing , and showed similar accumulation on Day 14 . Lower exposure was seen on Day 28 as compared to Day 14 , likely due to a combination of research variables . FASTED % CV Comparison Exposure Dose Day N Subject max(h ) C (nM ) AUC0(nMh - 24 ) Cmax AUC Cmax AUC, 100 mg/ m² 1 5 Mean 549 7500 CV % 4 - 8 37 . 5 28 . 6 F1 107 108 623 26700 50 Mean 1140 20400 F2 24 31 2110 59600 2 -8 35 1500 20 CV % 19 . 6 24 . 4 F2A 31 39400 200 mg/ m² 1 Mean 6 1450 21000 CV % 4 - 8 50 . 4 40 . 5 Mean 4 2120 33600 CV % 2 - 6 39 . 6 45 . 7 - 55 400 mg/m² 1 10 Mean 2730 413005 FED CV % 2 - 8 43 . 3 52 .5 Mean 4 4400 894000 % CV CV % 2 - 6 44 . 6 37 . 7 Comparison _ _ Exposure 800 mg/ m² Mean 3770 53200 CV % 4 - 8 51. 5 55 . 1 Cmax AUC . Cmax AUC . 5 Mean 6 5770 101000 Camera AUCA - 60 CV % 2 - 24 63 . 5 70 . 7 F1 36 30 2550 88600 28 3d Mean 4 3840 62400 F2 20 28 2560 102000 CV % 2 - 8 33 .5 44 . 1 F2A 32 2270 95800 Median and range of Tmax reported; In general , exposure is higher under fed conditions , and 65 N == 69 ; high - fat is better than medium -fat conditions . In addition , dall are at 600 mg dosing. exposure is higher without the administration of a PPI. Both US 10 , 398 ,693 B2 139 140 Example 17 -continued A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 - dif Amount Per Amount per luorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piperazin - 1 - yl) Component Capsule (mg ) Batch (g ) Silicified Microcrystalline Cellulose 124 . 15 74 . 49 2 -( tetrahydro -2H -pyran -4 -ylamino ) -benzamide and tartaric ( Prosolv SMCC 90 ) acid is prepared as follows . Hypromellose , USP (Methocel E5 ) 18 .00 10 . 80 Croscarmellose Sodium , NF/ EP (Ac - Di 11 . 25 6 .750 Sol) Amount Per Amount per ( L ) Tartaric Acid , USP /NF 80 . 85 48 .51 Component Capsule (mg ) Batch ( g ) 10 Magnesium Stearate , Non - Bovine Hyqual, 2 .250 1. 350 NF, EP Materials for step ( a ) Materials for step ( b ) N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol - 3 - 200. 0 132 . 0 Croscarmellose Sodium , NF/ EP ( AC - Di 11 . 25 6 . 750 yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 Sol) ( tetrahydro - 2H -pyran - 4 - ylamino ) 15 Magnesium Stearate, Non - Bovine Hyqual, 2 . 250 1 . 350 benzamide NF, EP Lactose Anhydrous, DT, NF 124 . 15 74 . 49 Hypromellose , USP (Methocel E5 ) 18 .00 10 . 80 Total 450 . 0 270 . 0 Croscarmellose Sodium , NF / EP ( AC -Di 11. 25 6 . 750 Sol) ( L ) Tartaric Acid , USP /NF 80 .85 53 . 36 20 Magnesium Stearate , Non - Bovine 2 .250 1 . 350 Example 19 Hyqual, NF, EP Materials for step (b ) A pharmaceutical composition comprising N - [ 5 -( 3, 5 -dif Croscarmellose Sodium , NF/ EP ( AC - Di 11 .25 6 .750 luorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) Sol) Magnesium Stearate , Non - Bovine 2 .250 1 . 350 25 2 - tetrahydro - 2H - pyran - 4 - ylamino )- benzamide and tartaric Hyqual, NF, EP acid is prepared utilizing the ingredients in the amounts listed below and according to a procedure similar to that Total 450 . 0 270 . 0 disclosed in Example 17 , except that except that the TFC ( a ) . Each of the components in the table above for step ( a ) is weighed out as set forth in Lab Micro Roller Compactor was used in step (a ) was set at the table for each batch of capsules. The N -15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - 30 (4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - 2H -pyran - 4 - ylamino) -benzamide is passed through a 30 mesh hand screen . Each of the lactose , hypromellose , and croscarmellose is the Frewitt Oscillator used in step ( a ) was equipped with a passed through a 20 mesh hand screen into a container. The tartaric acid is passed through a Frewitt Oscillator with a 0 . 4 mm opening screen and collected into a separate container. 0 .80 mm screen . The N -[ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - (4 -methyl - piperazin - 1 - yl) - 2 - (tetra hydro - 2H - pyran - 4 - ylamino ) - benzamide, lactose , hypromellose , and croscarmellose , and tartaric acid are placed into a V -blender and the mixture is blended for 10 minutes. The magnesium stearate is passed through a 20 mesh screen and added to the V - blender and the resulting mixture is blended for 5 minutes . The resulting blend is placed into a suitable Amount Per Amount per container lined with double - polyethylene bags. The mixture is granulated using TFC Lab Component Capsule (mg ) Batch ( g ) Micro Roller Compactor using a roller speed of 2 , 500 rpm and a roller hydraulic pressure of 500 psi until the fines are minimized . A 20 -mesh screen is used to screen out fines which are the added to the granulation mixture . The mixture is then passed through a Frewitt Materials for step ( a ) Oscillator equipped with a 0 . 80 mm screen . ( b ). The croscarmellose and magnesium stearate in the table above for step ( b ) are weighed N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol 200 . 0 132 . 0 and passed through a 20 -mesh screen . The mixture from step ( a ) above is added to a V -blender along with the extra - granular croscarmellose and blended for 10 minutes. The 40403 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 magnesium stearate is then added to the mixture and the resulting mixture is blended in ( tetrahydro - 2H -pyran - 4 -ylamino ) a V - blender for 5 minutes . benzamide c . Approximately 450 mg of the blend from step ( b ) is filled into gelatin capsule shells or Mannitol, USP 90 .00 54 .00 HPMC capsule shells and the resulting capsules are manually de - dusted as needed . ( Pearlitol 100SD ) Microcrystalline Cellulose 34 .15 20 . 49 ( Avicel PH 102) Example 18 45 Hypromellose , USP (Methocel E5 ) 18 . 00 10 .80 Croscarmellose Sodium , NF/ EP ( Ac 11 . 25 6 .750 Di- Sol ) A pharmaceutical composition comprising N - 15 - ( 3 , 5 - dif - ( L ) Tartaric Acid , USP/ NF 80 . 85 48 . 51 luorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piperazin - 1 - yl) Magnesium Stearate , Non - Bovine 2 . 250 1 . 350 2 -( tetrahydro -2H -pyran - 4 -ylamino )- benzamide and tartaric 50 Hyqual, NF, EP acid is prepared utilizing the ingredients in the amounts Materials for step (b ) listed below and according to a procedure similar to that Croscarmellose Sodium , NF / EP ( AC 11. 25 6 .750 disclosed in Example 17 , except that the TFC Lab Micro Di- Sol ) Roller Compactor was used in step ( a ) was set at a speed of Magnesium Stearate , Non - Bovine 2 . 250 1 . 350 2 ,500 rpm and a hydraulic pressure of 750 psi, and the 55 Hyqual, NF, EP Frewitt Oscillator used in step ( a ) was equipped with a 0 .80 Total 450 . 0 270 . 0 mm screen . Example 20 Amount Per Amount per 60 Component Capsule (mg ) Batch ( g ) A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 -dif Materials for step ( a ) luorobenzyl ) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) N - [ 5 - (3 ,5 - difluorobenzyl) - 1H - indazol - 3 - 200 . 0 132 .0 2 -( tetrahydro - 2H -pyran - 4 -ylamino )- benzamide and tartaric yl ]- 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 acid is prepared utilizing the ingredients in the amounts ( tetrahydro - 2H -pyran -4 - ylamino ) 65 listed below and according to a procedure similar to that benzamide disclosed in Example 17 , except that except that the TFC Lab Micro Roller Compactor was used in step ( a ) was set at US 10 , 398 ,693 B2 141 142 a speed of 2 , 500 rpm and a hydraulic pressure of 750 psi, and a 20 -mesh screen and charged into the blender, and blended the Frewitt Oscillator used in step ( a ) was equipped with a into the pre -mixture for 125 revolutions . The resulting 0 . 80 mm screen . pre - blend was then roller compacted and milled through a 0 .8 -mm screen . The microcrystalline cellulose, extragranu 5 lar crospovidone, and colloidal silicon dioxide was then Amount Amount Per per screened through a 20 -mesh screen . The blender was Component charged with the milled roller compacted pre - blend and the Capsule (mg ) Batch ( g ) screened microcrystalline cellulose , extragranular crospovi Materials for step ( a ) done , and colloidal silicon dioxide , and then blended for 250 N - [5 - (3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] 200 . 0 132 .0 10 revolutions. The extragranular magnesium stearate was 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro screened through a 20 -mesh screen and charged into the 2H -pyran - 4 - ylamino ) -benzamide blender . All components were final blended for 125 revolu Dicalcium Phosphate Anhydrous ( A - Tab ) 90 . 00 54 . 00 tions . Microcrystalline Cellulose 34 . 15 20 .49 ( Avicel PH 102 ) The resulting mixture was filled into HPMC capsule Hypromellose , USP (Methocel E5 ) 18 . 00 10 .80 15 shells , opaque white , size # 0 . The powder blend was filled Croscarmellose Sodium , NF /EP (AC - Di- Sol ) 11. 25 6 .750 into the capsules to achieve the target fill weight, using an ( L ) Tartaric Acid , USP /NF 80 . 85 48 .51 H & K 400 Encapsulator. The filled capsules were polished Magnesium Stearate , Non -Bovine Hyqual , 2 . 250 1 . 350 NF, EP using a capsule deduster , passed through a metal detector, Materials for step (b ) and passed through a weight sorter. 20 The fill weight range acceptance limits were set at 95 % to Croscarmellose Sodium , NF / EP (Ac -Di - Sol) 11 . 25 6 . 750 105 % . The weight sorting target range acceptable limits Magnesium Stearate , Non - Bovine Hyqual , 2 . 250 1 . 350 were set at 95 % to 105 % . Only those capsules meeting the NF, EP weight limits were used in the study described in Example Total 450 . 0 270 . 0 24 . - 25 Example 22 Example 21 Hereinafter Referred to as Pharmaceutical Composition “ F06 ” . Hereinafter Referred to as Pharmaceutical 30 Composition “ F05” A pharmaceutical composition comprising N - [5 - ( 3 , 5 -dif luorobenzyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 -dif 2 -( tetrahydro - 2H -pyran - 4 -ylamino )- benzamide and tartaric luorobenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - acid was prepared utilizing the ingredients in the amounts 2 -( tetrahydro - 2H -pyran - 4 -ylamino )- benzamide and tartaric 35 listed below and according to a procedure similar to that acid was prepared as follows. disclosed in Example 21 .
Amount per Amount per Capsule 40 Capsule Component % w / w (mg ) Component % w /w (mg ) Intragranular Components Intragranular Components N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - 44 . 44 200 . 00 N - [5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 44 .44 200 . 00 methyl- piperazin - 1 - yl ) - 2 - ( tetrahydro - 2H -pyran - 4 methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 ylamino ) - benzamide ylamino ) -benzamide Lactose Anhydrous 32 . 44 146 . 00 Lactose Anhydrous 28 . 89 130 . 00 Hydroxypropyl Methylcellulose 4 . 00 18 . 00 Hydroxypropyl Methylcellulose 4 .00 18. 00 Crospovidone 2 . 78 12 . 50 Crospovidone 2 .78 12 . 50 Tartaric Acid 9 . 56 43 . 00 Tartaric Acid 13 . 11 59. 00 Magnesium Stearate 0 . 56 2 . 50 Magnesium Stearate 0 .56 2 .50 Extragranular Components 50 Extragranular Components Microcrystalline Cellulose 2 . 97 13 . 37 Microcrystalline Cellulose 2 . 97 13. 37 Crospovidone 2 . 50 11 . 25 Crospovidone 2 . 50 11. 25 Colloidal Silicon Dioxide 0 . 25 1 . 13 Colloidal Silicon Dioxide 0 . 25 1 . 13 Magnesium Stearate 0 . 50 2 . 25 Magnesium Stearate 0 .50 2 . 25 55 Total 100 . 0 450 .00 Total 100 . 0 450 .00 The tartaric acid was screened through a 30 -mesh screen . In some embodiments , composition of a capsule for F06 A blender was charged with the lactose , N - [ 5 - (3 ,5 - difluo - is as follows: robenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - 60 ( tetrahydro - 2H - pyran - 4 - ylamino ) -benzamide , hydroxypro pyl methylcellulose , intragranular crospovidone, and Amount screened tartaric acid and pre -blended for 250 revolutions. Component % w / w per Capsule (mg ) The resulting mixture was screened through a 30 -mesh Capsule , HPMC , Size 0 , Orange Opaque 1 each screen . The blender was charged with the screened pre - 65 Body and Orange Opaque Cap mixture , which was then blended for 250 revolutions . The Titanium Dioxide 1 . 5202 1 . 37 - 1 . 55 intragranular magnesium stearate was then screened through US 10 , 398 ,693 B2 143 144 - continued Pharmaceutical compositions F05, F06 , F07 , and milled F2A were administered orally with approximately 240 mL of Amount Component water, according to the randomization scheme. % w /w per Capsule (mg ) Subjects were randomized into four sequences, ABCDE , Hypromellose QSP 100 QSP 90 - 102 BDACF , CADBG , and DCBAH . Periods 1, 2, 3 , and 4 were FD & C Yellow # 6 0 .5774 0 .52 - 0 .59 conducted as a crossover design under fasting conditions QSP = Quantité Suffisante Pour ” (Quality Sufficient For) where all subjects received a single , oral dose of one of four Alternatively , a manufacturing process for pharmaceuti different formulations ( F05 , F06 , F07 , or F2A ) . In Period 5 . cal composition F06 and its encapsulation using the above - 10 subjects received a single , oral dose of only one formulation described capsule is disclosed in Example 26 . comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl) - 4 (4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro - 2H -pyran - 4 Example 23 ylamino )- benzamide as per the randomization schedule , 15 administered 30 minutes after the start of a high - fat, high Hereinafter Referred to as Pharmaceutical calorie meal ( described below as “ fed ” or “ fed conditions” ) . Composition “ F07 ” Following the administration of each respective dose of the formulation to each subject on day 1 of each period , phar A pharmaceutical composition comprising N - [5 -( 3 ,5 -dif macokinetic samples were taken for 120 hours post- admin luorobenzyl) -1H - indazol- 3 - yl ] -4 - (4 -methyl - piperazin - 1 -yl ) - “ istration in order to measure the amount of N - [5 - (3 , 5 2 -( tetrahydro -2H -pyran -4 -ylamino )- benzamide and tartaric difluorobenzyl) -1H - indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 acid was prepared utilizing the ingredients in the amounts yl) - 2 -( tetrahydro -2H -pyran - 4- ylamino ) -benzamide and its listed below and according to a procedure similar to that des -methyl metabolite . On day 1 of each dosing period , a disclosed in Example 21. 25 single dose of 16 mg ondansetron was administered without water approximately 30 to 45 minutes prior to administra tion of the respective formulation as a prophylactic , anti Amount per emetic agent. Additional doses of ondansetron were admin Capsule istered approximately 8 to 12 hours following dosing of the Component % w / w (mg ) 30 respective administration at the discretion of the investiga Intragranular Components tor. There was a washout period in each subject of at least 9 N - [ 5 - ( 3 ,5 - difluorobenzyl) - 1H - indazol - 3 -yl ) - 4 - (4 - 44 .44 200. 00 days between doses of the respective formulations. methyl- piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 A representative summary of Periods 1, 2 , 3 , 4 and 5 and ylamino ) -benzamide Lactose Anhydrous 25 . 33 114 . 00 35 the pharmaceutical compositions subjects in each sequence Hydroxypropyl Methylcellulose 4 . 00 18 .00 will receive in each Period is found below . Crospovidone 2 . 78 12 . 50 Tartaric Acid 16 . 67 75 .00 Magnesium Stearate 0 . 56 2 . 50 Extragranular Components NUVCCLSubiect Period 1 Period 2 Period 3 Period 4 Period 5 - 40 Group (fasted ) ( fasted ) ( fasted ) ( fasted ) ( fed ) Microcrystalline Cellulose 2 .97 13. 37 ABCDE TuF05 F06 F07 F2A F2A Crospovidone 2 . 50 11 . 25 BDACF F06 F05 F07 F07 Colloidal Silicon Dioxide 0 . 25 1 . 13 F2A 0 . 50 2 . 25 CADBG FO7 F05 F2A F06 F06 Magnesium Stearate DCBAH F2A F07 F06 F05 F05 Total 100 . 0 450. 00 45 Treatments A and H utilized three 200 mg strength F05 capsules . Example 24 Treatments B and G utilized three 200 mg strength F06 capsules . Comparative Pharmacokinetic Study of F05 , F06 , 50 Treatments C and F utilized three 200 mg strength F07 and F07 Formulations capsules. Treatments D and E utilized three 200 mg strength F2A A comparative pharmacokinetic study in healthy, human capsules . subjects was conducted comparing a 600 mg dosage strength 55 Treatments A , B , C , D , E , F , G , and H were as follows: of pharmaceutical composition F05 (as described in For all procedures scheduled post - N - [ 5 - ( 3 , 5 -difluoroben Example 20 ) , with a 600 mg dosage strength of pharmaceu zyl) - 1H - indazol- 3 - yl )- 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra tical composition F06 (as described in Example 21) , with a hydro - 2H -pyran -4 -ylamino ) benzamide dosing , time points 600 mg dosage strength of pharmaceutical composition F07 were relative to the time of N -[ 5 -( 3 , 5 -difluorobenzyl ) - 1H ( as described in Example 22 ) , and compared with a 600 mg 60 indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro dosage strength of pharmaceutical composition similar to 2H - pyran - 4 - ylamino )- benzamide dosing (i .e ., Hour () on F2A ( as described in Example 13 ) , except that the N - [ 5 - ( 3 , Day 1 ) . 5 -difluorobenzyl ) -1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - For all subjects , blood samples were collected at sched 1 - yl) - 2 -( tetrahydro - 2H - pyran -4 - ylamino ) - benzamide was 65 uled time points . Sampling time- points were relative to the milled prior to mixing with the excipients and encapsulating time of N - [5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) -4 - (4 the resulting pharmaceutical composition . methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) US 10 , 398 ,693 B2 145 146 benzamide dosing ( i. e . , Hour 0 on Day 1 ). Blood sampling azin - 1- yl) -2 -( tetrahydro - 2H -pyran -4 - ylamino )- benzamide for pharmacokinetic measurements were scheduled for the in plasma , as appropriate : AUC0- , AUCo- inf Cmax , Tmax following times ( in hours ) ( all time points were measured as The PK parameters AUCO- 13 AUCo- ing and Cmax for N - [ 5 ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piper relative to N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 5 azin - 1 - yl) - 2 - tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide methyl- piperazin -1 -yl ) - 2 - ( tetrahydro - 2H -pyran - 4 -ylamino ) were analyzed using analysis of variance (ANOVA ) model benzamide dosing , i . e . , hour 0 on day 4 of the study ) : 0 , 0 . 5 , to calculate the geometric least squares mean ( LSM ) ratio 1 , 2, 3 , 4, 5 , 6, 8 , 12 , 24 , 36 , 48 , 72 , 96 , and 120 . using natural log - transformed data . A 90 % confidence inter Subject plasma samples were analyzed for the presence of val (CI ) was constructed around the ratio of the geometric N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - 10 mean for the three PK parameters for N - 15 - ( 3 , 5 - difluoroben piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - vlamino ) -benz - zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra amide and the des -methyl metabolite of N - 15 - ( 3 , 5 - difluo hydro - 2H - pyran - 4 - ylamino ) -benzamide . robenzyl )- 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1 -yl ) - 22 . Formulation F2A was used as the reference for all relative (tetrahydro - 2H -pyran - 4 -ylamino ) -benzamide using bioavailability analysis . Fasted dosing was used as the analytical methods known to those of ordinary skill in the 15 reference for food effect analysis . The following assess art . ments were done: ( 1 ) the relative bioavailability of N - [ 5 - ( 3 , All subjects who received at least one dose of N - 15 - ( 3 , 5 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - (4 -methyl - piperazin - 1 1 -yl ) - 2 -( tetrahydro - 2H -pyran -4 -ylamino )- benzamide in four yl) - 2 - ( tetrahydro - 2H -pyran - 4 - ylamino ) - benzamide and had formulations under fasting conditions were evaluated by evaluable PK data made up the PK Population and was used 20 comparing Treatment A versus Treatment D , Treatment B for all PK analyses. Samples from all subjects were assayed versus Treatment D , and Treatment C versus Treatment D ; even if the subjects did not complete the study. All subjects (2 ) the effect of food on each of the four N -[ 5 - ( 3 ,5 -difluo who complied sufficiently with the protocol and displayed robenzyl ) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 an evaluable PK profile ( e. g ., exposure to treatment, avail (tetrahydro - 2H -pyran - 4 - ylamino ) -benzamide formulations ability of measurements and absence of major protocolotocol 2525 FSF05 , F06 , F07 , and F2A , were evaluated by comparing ( a ) violations ) was included in the statistical summary of PK for F05 , Treatment A versus Treatment H (within the same parameters . Inclusion in the statistical analysis of any sub treatment sequence ) , (b ) for F06 , Treatment B versus Treat ject who vomited within 8 hours after dosing of the respec ment G (within the same treatment sequence ) , ( c ) for F07 , tive formulation , i . e ., a period of time equal to two times the Treatment C versus Treatment F (within the same treatment mean tmax of entrectinib were evaluated at the time of 30 sequence ) , and (d ) for F2A , Treatment D versus Treatment analysis . Additionally , in the case of insufficient washout, E (within the same treatment sequence ); and ( 3 ) the relative subjects with a predose concentration that exceeded 5 % of bioavailability of N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 the Cmax for the treatment being tested were considered to yl] -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro - 2H - pyran - 4 have unevaluable PK and were excluded from PK summary ylamino )- benzamide in four formulations under fed condi statistics and bioequivalence assessment for that treatment. 35 tions were evaluated by comparing Treatment F versus Average bioequivalence comparison methodology was used Treatment E , Treatment G versus Treatment E , and Treat in comparing treatments received by the same subjects . In ment H versus Treatment E . order to prevent confounding of data , only subjects that had The results of the study are shown in the tables below . All evaluable PK in both comparison treatments were used for values are reported as the mean value ( % CV ) . For example , analysis . 40 for formulation F05 , the median Tmax for 48 subjects in the The following PK parameters were calculated for N - [5 fasted state was about 3 .58 hours, with a CV % of about ( 3 , 5 -difluorobenzyl )- 1H - indazol- 3 -yl ) -4 - ( 4 -methyl - piper 31 . 4 % .
Tmax Cmax AUCO- 120 AUC . Treatment Formulation Food N (hr ) (nM ) (nM * hr ) (nM * hr ) A F05 Fasted Mean 4 8 3 .58 2150 52900 53800 CV % 31. 4 30 . 2 34 . 8 35. 5 F06 Fasted Mean 48 3 .54 2260 56100 57200 CV % 31. 9 34 . 2 41 . 7 42 F07 Fasted Mean 48 3 .67 2300 57200 58300 CV % 299 . 27. 4 34 . 2 35 . 1 ? . F2A milled Fasted Mean 48 3 . 44 2340 57600 58800 CV % 28 . 1 28 . 1 39 40 . 3
T max AUC0- 12 0 AUC Treatment Formulation Food N ( hr ) (nM ) (nM * hr) (NM * hr ) H F05 Fed Mean 11 5 2440 58800 59400 CV % - 8 . 94 25 . 7 33 . 9 34 .2 G F06 Fed Mean 12 5 . 83 2600 71800 73300 CV % 229 . 15 917 . 19 F07 Fed Mean 12 5 . 42 2400 64400 65700 CV % 22. 9 17 20 . 4 21 . 3 E F2A milled Fed Mean 12 5 .25 2350 63200 64200 CV % 20 . 1 22 . 8 31 . 4 32 . 1 US 10 , 398 ,693 B2 147 148 Example 25 1 ) Manufacture of the Intragranular Blend : 1 . Charge N -[ 5 -( 3 ,5 -difluorobenzyl ) -1H - indazol- 3 -yl ] - 4 (4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 2H - pyran - 4 Hereinafter Referred to as Pharmaceutical ylamino ) -benzamide , Lactose Anhydrous , Hypromel Composition “ F06 - 100 ” lose , Tartaric acid , Crospovidone (Portion 1 ) into a tote blender and blend for approximately 125 revolutions. A pharmaceutical composition comprising N - [5 - ( 3 , 5 - dif Screen the pre -blend through a 30 -mesh screen . luorobenzyl) - 1H - indazol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 - yl) 2 . Charge the screened pre- blend into the blender and 2 - ( tetrahydro - 2H - pyran - 4 - ylamino )- benzamide and tartaric blend for approximately 250 revolutions . Screen the acid was prepared utilizing the ingredients in the amounts 10 pre -blend through a 30 -mesh screen . listed below and according to a procedure similar to that 3 . Charge the screened pre - blend into the blender and disclosed in Example 21. blend for approximately additional 250 revolutions. 4 . Screen Magnesium Stearate ( Portion 1 ) through a 20 -mesh screen and add to the blender and blend for Amount per 15 Capsule 125 revolutions. Component % w /w (mg ) 5 . Roller compact the blend to obtain the compacted material. Intragranular Components 6 . Pass the roller compacted material through a 0 . 80 mm N - [5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 - 44 . 44 100 . 00 screen . methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 20 2 ) Manufacture of the Extragranular Blend : ylamino ) -benzamide 1 . Using the yield of the milled material, adjust and Lactose Anhydrous 28 .89 65 .00 reweigh the required quantities of Microcrystalline Hydroxypropyl Methylcellulose 4 . 00 9 .00 Crospovidone 2 .78 6 . 25 Cellulose , Crospovidone (Portion 2 ) , Colloidal Silicon Tartaric Acid 13 . 11 29 . 50 Dioxide , and Magnesium Stearate (Portion 2 ) . Magnesium Stearate 0 . 56 1 . 25 25 2 . Screen the Microcrystalline Cellulose , Crospovidone Extragranular Components (Portion 2 ) , Colloidal Silicon Dioxide , and Magnesium Microcrystalline Cellulose 2 .97 6 . 685 Stearate (Portion 2 ) through a - 20 mesh screen , while Crospovidone 2 . 50 5 . 625 keeping the Magnesium Stearate separate . Colloidal Silicon Dioxide 0 . 25 0 . 565 3 . Charge the screened Microcrystalline Cellulose , Magnesium Stearate 0 . 50 1 . 125 _ 30 Crospovidone ( Portion 2 ) , Colloidal Silicon Dioxide , and milled material to the blender and blend for Total 100 . 0 225 .00 approximately 250 revolutions. 4 . Charge the screened Magnesium Stearate to the blender In some embodiments , composition of a capsule for and blend for approximately 125 revolutions to create F06 - 100 is as follows : 35 the final dry granulation blend . 3 ) Encapsulation : 1 . Fill the final dry granulation blend using the encapsu Amount lator, with continuous monitoring, into size 0 or size 2 Component % w /w per Capsule (mg ) HPMC capsule shell for 200 -mg and 100 -mg strengths, Capsule , HPMC , Size 2 , Yellow 1 each 40 respectively . Opaque Body and Yellow Opaque Cap 4 ) Packaging: Titanium Dioxide 1 . 4584 0 . 83 - 0 . 98 1 . 100 -mg Strength ( F06 - 100 ) : Fill thirty 100 -mg cap Hypromellose QSP 100 QSP 57 -65 sules into a 40 cc white HDPE bottle with one 0 . 5 - g FDA /E172 Yellow Iron Oxide 0 . 2307 0 . 13 - 0 . 15 desiccant canister, enclosed with a 33 mm white child QSP = Quantité Suffisante Pour” (Quality Sufficient For ) 45 resistant caps and induction heat sealed . 2 . 200 -mg Strength ( F06 ) : Fill ninety 200 -mg capsules Alternatively , a manufacturing process for pharmaceuti into a 150 cc white HDPE bottle with one 2 - g desiccant cal composition F06 - 100 and its encapsulation using the canister , enclosed with a 38 mm white child -resistant above -described capsule is disclosed in Example 26 . caps and induction heat sealed . 50 Para . A . A pharmaceutical composition , comprising N - [ 5 Example 26 ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl) - 4 - ( 4 -methyl - piper azin - 1- yl) - 2 -( tetrahydro -pyran -4 - ylamino )- benzamide and at least one acidulant. Manufacturing Process for Capsules Containing Para . B . The pharmaceutical composition of Para . A , F06 and F06 - 100 55 wherein said at least one acidulant is an organic acidulant . Para . C . The pharmaceutical composition of Para . A , The manufacturing process for capsules containing F06 wherein said at least one acidulant is selected from tartaric and F06 - 100 was divided into four parts : 1 ) manufacture of acid , maleic acid , fumaric acid , citric acid , and betaine the intragranular blend , 2 ) manufacture of the extragranular hydrochloride . blend , 3 ) encapsulation , and 4 ) capsule packaging . The first 60 Para . D . The pharmaceutical composition of Para . C , two parts (manufacture of the intragranular blend and manu - wherein said at least one acidulant is fumaric acid . facture of the extragranular blend ) form the dry granulation Para . E . The pharmaceutical composition of Para . C , blending process of F06 and F06 - 100 capsules. The dry wherein said fumaric acid is in a micronized form . granulation blending process consisted of the following Para . F . The pharmaceutical composition of Para . C , steps : Pre -blending , roller compaction , milling, blending , 65 wherein said at least one acidulant is tartaric acid . final blending ( lubrication ) , and encapsulation as detailed Para . G . The pharmaceutical composition of Para . C , below : wherein said at least one acidulant is maleic acid . US 10 , 398 ,693 B2 149 150 Para . H . The pharmaceutical composition of Para . C , zyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - (tetra wherein said at least one acidulant is citric acid . hydro -pyran - 4 - ylamino ) -benzamide . Para . I . The pharmaceutical composition of Para. C , Para . X . The pharmaceutical composition of Para . T , wherein said at least one acidulant is betaine hydrochloride. wherein said pharmaceutical composition comprises about Para . J . The pharmaceutical composition of any one of 5 50 mg of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) Paras. A - I, wherein the molar ratio between said N - 15 - ( 3 , 5 - 4 - ( 4 -methyl -piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 difluorobenzyl) - 1H - indazol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - ylamino ) -benzamide . Para . Y . The pharmaceutical composition of Para . T , yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide and said at wherein said pharmaceutical composition comprises about least one acidulant is from about 0 . 5 to about 2 . 10 100 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] Para . K . The pharmaceutical composition of Para . J , 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 wherein said molar ratio between said N - 15 - ( 3 , 5 - difluo ylamino )- benzamide . robenzyl )- 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 Para . Z . The pharmaceutical composition of Para . T , ( tetrahydro -pyran - 4 - ylamino ) -benzamide and said at least wherein said pharmaceutical composition comprises about one acidulant is from about 0 .75 to about 1 .75 . 15 200 mg of said N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] Para . L . The pharmaceutical composition of Paraara .. deJ , 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 wherein said molar ratio between said N -[ 5 - ( 3 , 5 - difluo - Vlamino ) -benzamide . robenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - Para . AA . The pharmaceutical composition of Para . D , ( tetrahydro - pyran -4 - ylamino ) -benzamide and said at least wherein the particle size of said fumaric acid is such that it one acidulant is from about 1 to about 1 . 75 . 20 passes through a 60 -mesh screen . Para . M . The pharmaceutical composition of Para . J, Para . AB . The pharmaceutical composition of Para . A , wherein said molar ratio between said N -[ 5 -( 3 ,5 - difluo - wherein less than about 2 % of said N -[ 5 -( 3 ,5 -difluoroben robenzyl) - 1H - indazol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 zyl) - 1H - indazol- 3 - yl) - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetra ( tetrahydro - pyran - 4 - ylamino ) -benzamide and said at least hydro -pyran - 4 -ylamino ) -benzamide degrades in said phar one acidulant is from about 1 to about 1 . 5 . 25 maceutical composition after said pharmaceutical Para . N . The pharmaceutical composition of Para . J , composition is stored for 3 months in an open container at wherein said molar ratio between said N - 15 - ( 3 , 5 - difluo - 40° C . and 75 % relative humidity . robenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - Para . AC . The pharmaceutical composition of Para . A , ( tetrahydro -pyran - 4 - ylamino ) -benzamide and said at least wherein more than about 98 % of said N - 15 - ( 3 , 5 -difluo one acidulant is from about 1 .25 to about 1 .75 . 30 robenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 Para . O . The pharmaceutical composition of Para . J , ( tetrahydro -pyran - 4 -ylamino ) -benzamide is present in said wherein said molar ratio between said N - [ 5 - ( 3 , 5 - difluo - pharmaceutical composition after said pharmaceutical com robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 position is stored for 3 months in an open container at 40° ( tetrahydro -pyran - 4 -ylamino ) -benzamide and said at least C . and 75 % relative humidity . one acidulant is from about 1 to about 1 . 5 . 35 Para . AD . The pharmaceutical composition of Para . A , Para . P . The pharmaceutical composition of Para . J , wherein less than about 2 % of said N - [ 5 - ( 3 , 5 - difluoroben wherein said molar ratio between said N -[ 5 - (3 ,5 -difluo zyl) -1H - indazol - 3 -yl ) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetra robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - hydro -pyran - 4 -ylamino ) -benzamide degrades in said phar (tetrahydro -pyran - 4 -ylamino ) -benzamide and said at least maceutical composition after said pharmaceutical one acidulant is about 1 . 5 . 40 composition is stored for 3 months in an open container at Para . Q . The pharmaceutical composition of any one of 60° C . and 75 % relative humidity . Paras. A - P, wherein said pharmaceutical composition is in Para . AE . The pharmaceutical composition of Para . A , the form of a tablet or capsule . wherein more than about 98 % of said N - [5 - ( 3 , 5 - difluo Para . R . The pharmaceutical composition of Para . Q . robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 wherein said pharmaceutical composition is in the form of a 45 (tetrahydro - pyran - 4 - ylamino ) - benzamide is present in said tablet. pharmaceutical composition after said pharmaceutical com Para . S . The pharmaceutical composition of Para . Q , position is stored for 3 months in an open container at 60° wherein said pharmaceutical composition is in the form of a C . and 75 % relative humidity . capsule . Para . AF. A pharmaceutical composition comprising N - 15 Para . T . The pharmaceutical composition of any one of 50 ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl - piper Paras . A - S , wherein said pharmaceutical composition com - azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide and prises from about 25 mg to about 500 mg of said N - [ 5 - ( 3 , at least one pharmaceutically acceptable excipient, wherein 5 - difluorobenzyl ) -1H -indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin said pharmaceutical composition is in the form of a tablet or 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide . capsule, and wherein said tablet or capsule has a dissolution Para . U . The pharmaceutical composition of Para . T , 55 profile wherein at least about 30 % of said N - [ 5 - ( 3 , 5 -difluo wherein said pharmaceutical composition comprises from robenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 about 50 mg to about 450 mg of said N - 15 - ( 3 , 5 - difluoroben - (tetrahydro -pyran - 4 -ylamino ) -benzamide has been released zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra from said tablet or capsule at about 60 minutes when tested hydro -pyran -4 -ylamino )- benzamide . in USP Apparatus Type I Basket Method at 50 rpm in 500 Para . V . The pharmaceutical composition of Para . T , 60 mL of sodium acetate buffer at a pH of 4 .5 and at about 37° wherein said pharmaceutical composition comprises from C . about 50 mg to about 450 mg of said N - 15 - ( 3 , 5 - difluoroben - Para . AG . The pharmaceutical composition of Para . AF, zyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra - wherein said tablet or capsule has a dissolution profile hydro -pyran -4 -ylamino )- benzamide . wherein at least about 20 % of said N - 15 - ( 3 , 5 - difluoroben Para . W . The pharmaceutical composition of Para . T, 65 zyl) - 1H - indazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetra wherein said pharmaceutical composition comprises from hydro - pyran - 4 - ylamino ) - benzamide has been released from about 50 mg to about 200 mg of said N - [ 5 - ( 3 , 5 - difluoroben - said tablet or capsule at about 45 minutes when tested in US 10 , 398 ,693 B2 151 152 USP Apparatus Type I Basket Method at 50 rpm in 500 mL Para . AS . The pharmaceutical composition of Para . AN , of sodium acetate buffer at a pH of 4 .5 and at about 37° C . wherein said weight to weight ratio of said mannitol or Para . AH . The pharmaceutical composition of Para . AF , isomalt to said starch in said pharmaceutical composition is wherein said tablet or capsule has a dissolution profile about 2 to 1 . wherein at least about 15 % of said N - 15 - ( 3 , 5 - difluoroben - 5 Para . AT. The pharmaceutical composition of Para . AN , zyl) - 1H - indazol- 3 - v11- 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra - wherein said weight to weight ratio of said mannitol or isomalt to said starch in said pharmaceutical composition is hydro -pyran - 4 -ylamino )- benzamide has been released from about 1 . 8 . said tablet or capsule at about 30 minutes when tested in Para . AU . A pharmaceutical composition , comprising USP Apparatus Type I Basket Method at 50 rpm in 500 mL 10 N - [5 -( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 -yl ) -4 - (4 -methyl of sodium acetate buffer at a pH of 4 . 5 and at about 37° C . piperazin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 - ylamino )- benzamide Para . AI. A pharmaceutical composition comprising N - [ 5 and at least one acidulant, wherein said pharmaceutical ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) -4 - ( 4 -methyl - piper composition when administered to a subject in a fasted state azin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide and provides a pharmacokinetic profile in said subject wherein at least one pharmaceutically acceptable excipient , wherein 15 the Tmax of said N - [5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 said pharmaceutical composition is in the form of a tablet or yl] - 4 - ( 4 - methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 capsule , and wherein said tablet or capsule has a dissolution ylamino ) -benzamide in the plasma of said subject is between profile wherein at least about 50 % of said N - [ 5 - ( 3 , 5 - difluo10 about 2 hours and 6 hours following said administration of robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - said pharmaceutical composition to said subject. ( tetrahydro - pyran -4 -ylamino ) -benzamide has been released 20 Para . AV . A pharmaceutical composition , comprising from said tablet or capsule at about 60 minutes when tested N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl in USP Apparatus Type I Basket Method at 50 rpm in 500 piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 - ylamino )- benzamide mL of sodium acetate buffer at a pH of 4 . 5 and at about 37° and at least one acidulant, wherein said pharmaceutical composition when administered to a subject in a fed state Para . AJ. The pharmaceutical composition of Para . Al, 25 provides a pharmacokinetic profile in said subject wherein wherein said tablet or capsule has a dissolution profile the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 wherein at least about 40 % of said N - 15 - ( 3 , 5 - difluoroben - y1 ] - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 zyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetra - ylamino ) -benzamide in the plasma of said subject is between hydro - pyran - 4 - ylamino ) - benzamide has been released from about 5 hours and 12 hours following said administration of said tablet or capsule at about 45 minutes when tested in 30 said pharmaceutical composition to said subject. USP Apparatus Type I Basket Method at 50 rpm in 500 mL Para . AW . A pharmaceutical composition comprising of sodium acetate buffer at a pH of 4 . 5 and at about 37° C . N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl Para . AK . A solid pharmaceutical composition according piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide to Para . AI, wherein said tablet or capsule has a dissolution and at least one acidulant, wherein said pharmaceutical profile wherein at least about 20 % of said N - 15 - ( 3 ,5 - difluo - 35 composition when administered to a subject in a fasted state robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - at a total dose of about 800 mg of said N - [ 5 - ( 3 , 5 - difluo ( tetrahydro -pyran - 4 -ylamino )- benzamide has been released robenzyl) - 1H - indazol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 -yl ) -2 from said tablet or capsule at about 30 minutes when tested (tetrahydro -pyran - 4 -ylamino ) -benzamide provides a phar in USP Apparatus Type I Basket Method at 50 rpm in 500 macokinetic profile in said subject wherein the Cmax of said mL of sodium acetate buffer at a pH of 4 . 5 and at about 37° 40 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl C . piperazin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 - ylamino )- benzamide Para . AL . The pharmaceutical composition of any one of in the plasma of said subject is between about 2080 nM and Paras . A -AK , wherein said pharmaceutical composition fur about 2110 nM following said administration of said phar ther comprises mannitol or isomalt. maceutical composition to said subject. Para . AM . The pharmaceutical composition of Para . AL , 45 Para . AX . A pharmaceutical composition comprising wherein said pharmaceutical composition further comprises N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ] - 4 - ( 4 -methyl starch . piperazin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide Para . AN . The pharmaceutical composition of Para . AM , and at least one acidulant, wherein said pharmaceutical wherein the weight to weight ratio of said mannitol or composition when administered to a subject in a fasted state isomalt to said starch in said pharmaceutical composition is 50 at a total dose of about 800 mg of said N - [ 5 - ( 3 , 5 - difluo from about 1 to 1 to about 3 to 1 . robenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 Para . AO . The pharmaceutical composition of Para. AN , (tetrahydro -pyran - 4 -ylamino ) -benzamide provides a phar wherein said weight to weight ratio of said mannitol or macokinetic profile in said subject wherein the Cmax of said isomalt to said starch in said pharmaceutical composition is N - [ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - (4 -methyl from about 1 . 5 to 1 to about 3 to 1 . 55 piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran -4 -ylamino )- benzamide Para . AP. The pharmaceutical composition of Para . AN , in the plasma of said subject is between about 2080 nM and wherein said weight to weight ratio of said mannitol or about 2560 nM following said administration of said phar isomalt to said starch in said pharmaceutical composition is maceutical composition to said subject. from about 1 . 75 to 1 to about 3 to 1 . Para . AY. A pharmaceutical composition , comprising Para . AQ . The pharmaceutical composition of Para . AN , 60 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl wherein said weight to weight ratio of said mannitol or piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide isomalt to said starch in said pharmaceutical composition is and at least one acidulant, wherein said pharmaceutical from about 1 to 1 to about 2 . 5 to 1 . composition when administered to a subject in a fasted state Para . AR . The pharmaceutical composition of Para . AN , at a total dose of about 800 mg of said N - [ 5 - ( 3 , 5 - difluo wherein said weight to weight ratio of said mannitol or 65 robenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 isomalt to said starch in said pharmaceutical composition is (tetrahydro - pyran - 4 - ylamino ) - benzamide provides a phar from about 1 to 1 to about 2 to 1 . macokinetic profile in said subject wherein the Cmax of said US 10 , 398 ,693 B2 153 154 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) - benzamide piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide and at least one acidulant, wherein said pharmaceutical in the plasma of said subject is between 80 % to 125 % of composition when administered to a subject in a fed state at 2080 nM , based on a 90 percent confidence interval follow - a total dose of about 800 mg of said N -15 - ( 3 , 5 - difluoroben ing said administration of said pharmaceutical composition 5 zyl ) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetra to said subject. hydro - pyran - 4 - ylamino ) -benzamide provides a pharmacoki Para . AZ . A pharmaceutical composition , comprising netic profile in said subject wherein the AUC ( 0 to 24 ) of said N -[ 5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 -( 4 -methyl piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino )- benzamide piperazin - 1 - yl ) - 2 - (tetrahydro - pyran - 4 - ylamino ) -benzamide and at least one acidulant, wherein said pharmaceutical 10 in the plasma of said subject is within about 80 % to about composition when administered to a subject in a fed state at 125 % of 40 , 400 nM * hr at a 90 % confidence interval fol a total dose of about 800 mg of said N -[ 5 -( 3 ,5 - difluoroben - lowing said administration of said pharmaceutical compo zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra - sition to said subject . hydro - pyran - 4 - ylamino ) - benzamide provides a pharmacoki - Para . BE . The pharmaceutical composition of any one of netic profile in said subject wherein the Cmax of said N - [ 5 - 15 Paras . AA -BD , wherein said pharmaceutical composition is ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - in the form of a tablet or capsule . piperazin - 1- yl ) -2 -( tetrahydro -pyran -4 - ylamino ) -benzamide Para . BF . The pharmaceutical composition of Para . BE , in the plasma of said subject is between 80 % to 125 % of wherein said pharmaceutical composition is in the form of a 2560 nM , based on a 90 percent confidence interval follow - capsule . ing said administration of said pharmaceutical composition 20 Para . BG . A pharmaceutical composition , comprising : to said subject. N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4- methyl Para. BA . A pharmaceutical composition , comprising piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benz N - [ 5 - ( 3, 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl amide ; and piperazin - 1 - yl ) - 2 - tetrahydro -pyran - 4 - ylamino ) -benzamide means for delivering a Cmax of said N - [ 5 - ( 3 , 5 - difluo and at least one acidulant, wherein said pharmaceutical 25 robenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 composition when administered to a subject in a fasted state yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) - benzamide in the at a total dose of about 800 mg of said N - 55 - ( 3 , 5 - difluo plasma of a subject of between about 2080 nM and robenzyl) - 1H - indazol- 3 - yl] - 4 -( 4 -methyl - piperazin - 1 - yl) - 2 about 2100 nM following administration of said phar ( tetrahydro - pyran -4 - ylamino )- benzamide provides a phar maceutical composition to said subject in a fasted state , macokinetic profile in said subject wherein the AUC ( 0 to 24 ) 30 and wherein said composition comprises a total dose of of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 about 800 mg of said N -[ 5 -( 3 ,5 - difluorobenzyl) -1H methyl- piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 -ylamino ) indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra benzamide in the plasma of said subject is between about hydro - pyran - 4 - ylamino ) -benzamide . 28 , 900 nM * hr and about 30 ,800 nM * hr following said Para . BH . A pharmaceutical composition , comprising : administration of said pharmaceutical composition to said 35 N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl subject. piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz Para . BB . A pharmaceutical composition , comprising amide ; and N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl means for delivering a Cmax of said N - [ 5 - ( 3 , 5 -difluo piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 and at least one acidulant, wherein said pharmaceutical 40 yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide in the composition when administered to a subject in a fed rate at plasma of a subject of about 2560 nM following a total dose of about 800 mg of said N - [ 5 - ( 3 , 5 -difluoroben administration of said pharmaceutical composition to zyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra said subject in a fed state , and wherein said composi hydro -pyran - 4 - ylamino ) - benzamide provides a pharmacoki tion comprises a total dose of about 800 mg of said netic profile in said subject wherein the AUC (0 to 24 ) of said 45 N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl methyl- piperazin - 1- yl) -2 - ( tetrahydro -pyran - 4 piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide ylamino ) -benzamide . in the plasma of said subject is about 40 , 400 nM * hr fol Para . BI. A pharmaceutical composition , comprising : lowing said administration of said pharmaceutical compo - N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl sition to said subject. 50 piperazin - 1 -yl ) -2 - ( tetrahydro -pyran - 4 - ylamino ) -benz Para . BC . A pharmaceutical composition , comprising amide ; and N -[ 5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl means for delivering an AUC ( 0 to 24 ) of said N - [ 5 - (3 , 5 piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - 4 -ylamino ) -benzamide difluorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piper and at least one acidulant, wherein said pharmaceutical azin - 1 -yl ) - 2 - (tetrahydro -pyran - 4 -ylamino )- benzamide composition when administered to a subject in a fasted state 55 in the plasma of a subject of between about 28 , 900 at a total dose of about 800 mg of said N - [ 5 - ( 3 , 5 - difluo nM * hr and about 30 , 800 nM * hr following administra robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 tion of said pharmaceutical composition to said subject ( tetrahydro -pyran - 4 -ylamino ) -benzamide provides a phar in a fasted state , and wherein said composition com macokinetic profile in said subject wherein the AUC ( 0 to 24 ) prises a total dose of about 800 mg of said N - 15 - ( 3 , 5 of said N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - (4 - 60 difluorobenzyl) - 1H -indazol - 3 -yl ] - 4 - (4 -methyl - piper methyl- piperazin -1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) azin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide . benzamide in the plasma of said subject is within about 80 % Para . BJ. A pharmaceutical composition , comprising: to about 125 % of 30 ,800 nM * hr at a 90 % confidence N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ] - 4 - ( 4 -methyl interval following said administration of said pharmaceuti piperazin - 1 - yl ) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benz cal composition to said subject. 65 amide ; and Para . BD . A pharmaceutical composition , comprising means for delivering an AUC ( 0 to 24 ) of said N - [ 5 -( 3 , 5 N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piper US 10 , 398 ,693 B2 155 156 azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide interval , following administration of said pharmaceu in the plasma of a subject of about 40 , 400 nM * hr tical composition to said subject in a fasted state , and following administration of said pharmaceutical com wherein said composition comprises a total dose of position to said subject in a fed state , and wherein said about 800 mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H composition comprises a total dose of about 800 mg of 5 indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetra said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 hydro - pyran - 4 - ylamino ) -benzamide . methyl -piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 Para . BP. A pharmaceutical composition , comprising : ylamino ) - benzamide . N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl Para . BK . A pharmaceutical composition , comprising : piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benz N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl- 10 amide; and piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz means for delivering an AUC ( 0 to 24 ) of said N - [ 5 - ( 3 , 5 amide; and difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piper means for delivering a Tmax of said N - [ 5 - ( 3 , 5 -difluo azin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 -ylamino )- benzamide robenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 in the plasma of a subject that is between 80 % to 125 % yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide in the 15 of 40 , 400 nM * hr , based on a 90 percent confidence plasma of a subject ofbetween about 2 hours and about interval, following administration of said pharmaceu 6 hours following administration of said pharmaceuti tical composition to said subject in a fed state , and cal composition to said subject in a fasted state . wherein said composition comprises a total dose of Para . BL . A pharmaceutical composition , comprising : about 800 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - 20 indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetra piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz hydro -pyran - 4 -ylamino ) -benzamide . amide; and Para . BQ . A pharmaceutical composition , comprising: means for delivering a TmaxMAX of said N -[ 5 - ( 3 , 5 - difluo - N - [ 5 -( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl robenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benz yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benzamide in the 25 amide ; and plasma of a subject ofbetween about 5 hours and about means for delivering said N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H 12 hours following administration of said pharmaceu indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetra tical composition to said subject in a fed state . hydro - pyran - 4 - ylamino ) -benzamide to a subject that Para . BM . A pharmaceutical composition , comprising : exhibits no food effect. N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ] - 4 - ( 4 -methyl - 30 Para . BR . A pharmaceutical composition comprising piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 -ylamino )- benz - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) -4 - ( 4 -methyl amide; and piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino )- benzamide , means for delivering a Cmax of said N - [ 5 - ( 3 , 5 -difluo wherein said pharmaceutical composition exhibits no food robenzyl )- 1H - indazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1 effect when administered to a subject. yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide in the 35 Para . BS . The pharmaceutical composition of Para . J , plasma of a subject that is between 80 % to 125 % of wherein said molar ratio between said N - [ 5 - ( 3 , 5 - difluo 2080 nM , based on a 90 percent confidence interval, robenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 following administration of said pharmaceutical com - ( tetrahydro -pyran - 4 -ylamino ) -benzamide and said at least position to said subject in a fasted state , and wherein one acidulant is from about 0 . 5 to about 1 . 5 . said composition comprises a total dose of about 800 40 Para . BT. The pharmaceutical composition of Para . J , mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 - wherein said molar ratio between said N - [ 5 - ( 3 , 5 - difluo yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - robenzyl ) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 ylamino ) -benzamide . (tetrahydro -pyran - 4 -ylamino ) -benzamide and said at least Para . BN . A pharmaceutical composition , comprising : one acidulant is from about 0 . 5 to about 1 . 25 . N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - 45 Para . BU . The pharmaceutical composition of Para . J , piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benz wherein said molar ratio between said N - [ 5 - ( 3 , 5 -difluo amide; and robenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 means for delivering a Cmax of said N -[ 5 -( 3 ,5 -difluo - (tetrahydro -pyran -4 - ylamino )- benzamide and said at least robenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piperazin - 1 one acidulant is from about 0 .5 to about 1 . yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide in the 50 Para . BV . The pharmaceutical composition of Para . J , plasma of a subject that is between 80 % to 125 % of wherein said molar ratio between said N -15 - ( 3 , 5 -difluo 2560 nM , based on a 90 percent confidence interval, robenzyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 following administration of said pharmaceutical com - ( tetrahydro -pyran - 4 -ylamino ) -benzamide and said at least position to said subject in a fed state, and wherein said one acidulant is about 1 . 2 . composition comprises a total dose of about 800 mg of 55 Para . BW . The pharmaceutical composition of Para . J , said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 wherein said molar ratio between said N - [ 5 - ( 3 , 5 - difluo methyl -piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 robenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 ylamino ) - benzamide. ( tetrahydro - pyran - 4 - ylamino ) -benzamide and said at least Para . BO . A pharmaceutical composition , comprising: one acidulant is about 0 . 9 . N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - 60 Para . BX . The pharmaceutical composition of Para . J , piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benz wherein said molar ratio between said N - [ 5 - ( 3 , 5 - difluo amide; and robenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 means for delivering an AUC (0 to 24 ) of said N - [ 5 - ( 3 , 5 - ( tetrahydro - pyran -4 - ylamino ) -benzamide and said at least difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piper - one acidulant is about 0 . 7 . azin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide 65 Para . BY. The pharmaceutical composition of Para . T , in the plasma of a subject that is between 80 % to 125 % wherein said pharmaceutical composition comprises from of 30 ,800 nM * hr, based on a 90 percent confidence about 50 mg to about 300 mg of said N - [5 -( 3 ,5 -difluoroben US 10 , 398 ,693 B2 157 158 zyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetra - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 hydro -pyran - 4 - ylamino ) -benzamide . ylamino ) - benzamide in the plasma of said subject is between Para . BZ . The pharmaceutical composition of Para . F , about 4 . 6 hours and 5 . 4 hours following said administration wherein the particle size of said tartaric acid is such that it of said pharmaceutical composition to said subject. passes through a 30 -mesh screen . 5 Para . CG . A pharmaceutical composition , comprising Para . CA . A pharmaceutical composition , comprising N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide and at least one acidulant, wherein said pharmaceutical and at least one acidulant, wherein said pharmaceutical composition when administered to a subject in a fed state composition when administered to a subject in a fasted state 10 provides a pharmacokinetic profile in said subject wherein provides a pharmacokinetic profile in said subject wherein the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 the Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] -4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 ylamino ) - benzamide in the plasma of said subject is between ylamino ) - benzamide in the plasma of said subject is between about 4 . 5 hours and 7 . 2 hours following said administration about 2 hours and 5 hours following said administration of 15 of said pharmaceutical composition to said subject. said pharmaceutical composition to said subject . Para . CH . A pharmaceutical composition , comprising Para . CB . A pharmaceutical composition , comprising N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - (4 -methyl piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide and at least one acidulant, wherein said pharmaceutical and at least one acidulant, wherein said pharmaceutical 20 composition when administered to a subject in a fed state composition when administered to a subject in a fasted state provides a pharmacokinetic profile in said subject wherein provides a pharmacokinetic profile in said subject wherein the Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 the Tmax of said N -[ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol -3 yl] -4 - (4 -methyl - piperazin - 1 - yl) -2 -( tetrahydro -pyran -4 yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 ylamino ) - benzamide in the plasma of said subject is between ylamino ) - benzamide in the plasma of said subject is between 25 about 4 . 2 hours and 6 . 7 hours following said administration about 2 . 5 hours and 4 . 7 hours following said administration of said pharmaceutical composition to said subject. of said pharmaceutical composition to said subject. Para . CI. A pharmaceutical composition comprising N - [5 Para. CC . A pharmaceutical composition , comprising (3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl )- 4 - (4 -methyl - piper N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - azin - 1- yl) -2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide and piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide 30 at least one acidulant, wherein said pharmaceutical compo and at least one acidulant, wherein said pharmaceutical sition when administered to a subject in a fasted state composition when administered to a subject in a fasted state provides a pharmacokinetic profile in said subject wherein provides a pharmacokinetic profile in said subject wherein the Cmax of said N - [5 - (3 , 5 -difluorobenzyl ) -1H - indazol- 3 the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 yl] -4 - (4 -methyl - piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - 35 ylamino ) -benzamide in the plasma of said subject is between ylamino )- benzamide in the plasma of said subject is between about 1200 nM and 3500 nM following said administration about 2 .4 hours and 4 . 7 hours following said administration of said pharmaceutical composition to said subject. of said pharmaceutical composition to said subject. Para . CJ. A pharmaceutical composition comprising N - [ 5 Para . CD . A pharmaceutical composition , comprising ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - (4 -methyl - piper N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 - ( 4 -methyl - 40 azin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide and piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide at least one acidulant, wherein said pharmaceutical compo and at least one acidulant, wherein said pharmaceutical sition when administered to a subject in a fasted state composition when administered to a subject in a fasted state provides a pharmacokinetic profile in said subject wherein provides a pharmacokinetic profile in said subject wherein the Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 the Tmax of said N - [ 5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 - 45 yl] -4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro -pyran -4 yl] - 4 -( 4 -methyl -piperazin -1 - yl) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide in the plasma of said subject is between ylamino ) - benzamide in the plasma of said subject is between about 1500 nM and about 2800 nM following said admin about 2 .6 hours and 4 . 8 hours following said administration istration of said pharmaceutical composition to said subject . of said pharmaceutical composition to said subject. Para . CK . A pharmaceutical composition comprising Para . CE . A pharmaceutical composition , comprising 50 N -[ 5 - (3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - y11 - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide and at least one acidulant, wherein said pharmaceutical and at least one acidulant, wherein said pharmaceutical composition when administered to a subject in a fasted state composition when administered to a subject in a fed state provides a pharmacokinetic profile in said subject wherein provides a pharmacokinetic profile in said subject wherein 55 the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 - methyl -piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 ylamino ) - benzamide in the plasma of said subject is between ylamino ) - benzamide in the plasma of said subject is between about 1490 nM and about 3030 nM following said admin about 4 hours and 8 hours following said administration of istration of said pharmaceutical composition to said subject . said pharmaceutical composition to said subject . 60 Para . CL . A pharmaceutical composition comprising Para . CF. A pharmaceutical composition , comprising N -[ 5 -( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl N - 15 -( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 -yl ) -2 - (tetrahydro -pyran - 4 -ylamino )- benzamide piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide and at least one acidulant, wherein said pharmaceutical and at least one acidulant, wherein said pharmaceutical composition when administered to a subject in a fasted state composition when administered to a subject in a fed state 65 provides a pharmacokinetic profile in said subject wherein provides a pharmacokinetic profile in said subject wherein the Cmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 yl] - 4 - ( 4 - methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 US 10 , 398 ,693 B2 159 160 ylamino ) - benzamide in the plasma of said subject is between pyran - 4 - ylamino ) - benzamide in the plasma of said subject is about 1670 nM and about 2930 nM following said admin between about 34 , 100 nM * hr and about 71 , 700 nM * hr istration of said pharmaceutical composition to said subject. following said administration of said pharmaceutical com Para . CM . A pharmaceutical composition comprising position to said subject. N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - 5 Para . CS . A pharmaceutical composition , comprising piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl and at least one acidulant , wherein said pharmaceutical piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide composition when administered to a subject in a fed state and at least one acidulant, wherein said pharmaceutical provides a pharmacokinetic profile in said subject wherein composition when administered to a subject in a fasted state the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - 10 provides a pharmacokinetic profile in said subject wherein yl ] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - tetrahydro -pyran - 4 the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H ylamino ) - benzamide in the plasma of said subject is between indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro about 1500 nM and about 3500 nM following said admin - pyran - 4 -ylamino ) -benzamide in the plasma of said subject is istration of said pharmaceutical composition to said subject between about 32 , 500 nM * hr and about 79, 700 nM * hr Para . CN . A pharmaceutical composition comprising 15 following said administration of said pharmaceutical com N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - position to said subject. piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide Para . CT . A pharmaceutical composition , comprising and at least one acidulant, wherein said pharmaceutical N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl composition when administered to a subject in a fed state piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide provides a pharmacokinetic profile in said subject wherein 20 and at least one acidulant, wherein said pharmaceutical the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - composition when administered to a subject in a fasted state yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 provides a pharmacokinetic profile in said subject wherein ylamino ) - benzamide in the plasma of said subject is between the AUC ( 0 to 120 ) of said N -[ 5 -( 3 , 5 - difluorobenzyl) - 1H about 1810 nM and about 3070 nM following said admin indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro istration of said pharmaceutical composition to said subject. 25 pyran - 4 - ylamino ) -benzamide in the plasma of said subject is Para . CO . A pharmaceutical composition comprising between about 37 , 100 nM * hr and about 77 , 300 nM * hr N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - y1 ] - 4 - ( 4 -methyl - following said administration of said pharmaceutical com piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide position to said subject. and at least one acidulant, wherein said pharmaceutical Para . CU . A pharmaceutical composition , comprising composition when administered to a subject in a fed state 30 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl provides a pharmacokinetic profile in said subject wherein piperazin - 1 -yl ) - 2 - tetrahydro -pyran - 4 - ylamino ) -benzamide the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - and at least one acidulant, wherein said pharmaceutical yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 composition when administered to a subject in a fed state ylamino ) - benzamide in the plasma of said subject is between provides a pharmacokinetic profile in said subject wherein about 2210 nM and about 2990 nM following said admin - 35 the AUC (0 to 120 ) of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H istration of said pharmaceutical composition to said subject . indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro Para . CP . A pharmaceutical composition comprising N - [ 5 - pyran - 4 - ylamino ) - benzamide in the plasma of said subject is ( 3 , 5 -difluorobenzyl )- 1H - indazol- 3 -yl ) -4 - ( 4 -methyl - piper between about 35, 000 nM * hr and about 90 ,000 nM * hr azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide and following said administration of said pharmaceutical com at least one acidulant, wherein said pharmaceutical compo - 40 position to said subject. sition when administered to a subject in a fed state provides Para . CV . A pharmaceutical composition , comprising a pharmacokinetic profile in said subject wherein the Cmax N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 - methyl of said N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 -( 4 - piperazin -1 - yl) - 2 - ( tetrahydro - pyran - 4 -ylamino ) -benzamide methyl- piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) and at least one acidulant, wherein said pharmaceutical benzamide in the plasma of said subject is between about 45 composition when administered to a subject in a fed state 1990 nM and about 2810 nM following said administration provides a pharmacokinetic profile in said subject wherein of said pharmaceutical composition to said subject . the AUC (0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H Para . CQ . A pharmaceutical composition , comprising indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl pyran - 4 - ylamino ) -benzamide in the plasma of said subject is piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide 50 between about 38 , 900 nM * hr and about 78 , 700 nM * hr and at least one acidulant, wherein said pharmaceutical following said administration of said pharmaceutical com composition when administered to a subject in a fasted state position to said subject. provides a pharmacokinetic profile in said subject wherein Para . CW . A pharmaceutical composition , comprising the AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 - difluorobenzyl ) - 1H - N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 55 piperazin - 1- yl) - 2 - ( tetrahydro - pyran -4 -ylamino ) -benzamide pyran - 4 - ylamino ) -benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical between about 30 ,000 nM * hr and about 85 ,000 nM * hr composition when administered to a subject in a fed state following said administration of said pharmaceutical com provides a pharmacokinetic profile in said subject wherein position to said subject. the AUC (0 to 120 ) of said N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H Para . CR . A pharmaceutical composition , comprising 60 indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl pyran -4 -ylamino ) -benzamide in the plasma of said subject is piperazin - 1 -yl ) -2 - (tetrahydro -pyran -4 -ylamino ) -benzamide between about 58, 900 nM * hr and about 84 ,700 nM * hr and at least one acidulant, wherein said pharmaceutical following said administration of said pharmaceutical com composition when administered to a subject in a fasted state position to said subject . provides a pharmacokinetic profile in said subject wherein 65 Para . CX . A pharmaceutical composition , comprising the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro piperazin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide US 10 , 398 ,693 B2 161 162 and at least one acidulant, wherein said pharmaceutical between about 35, 000 nM * hr and about 90 ,000 nM * hr composition when administered to a subject in a fed state following said administration of said pharmaceutical com provides a pharmacokinetic profile in said subject wherein position to said subject. the AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - Para. DD . A pharmaceutical composition , comprising indazol- 3 -y1 ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - 5 N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl pyran - 4 -ylamino ) - benzamide in the plasma of said subject is piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide arand at least one acidulant, wherein said pharmaceutical between about 51, 300 nM * hr and about 77 ,500 nM * hr composition when administered to a subject in a fed state following said administration of said pharmaceutical com provides a pharmacokinetic profile in said subject wherein position to said subject. 10 the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in Para . CY . A pharmaceutical composition , comprising dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro N - [5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl pyran - 4 - ylamino ) -benzamide in the plasma of said subject is piperazin - 1 - yl) - 2 - tetrahydro -pyran - 4 - ylamino ) -benzamide between about 39 ,100 nM * hr and about 79, 700 nM * hr and at least one acidulant, wherein said pharmaceutical following said administration of said pharmaceutical com composition when administered to a subject in a fastedi stalestate 15 positionpos to said subject. provides a pharmacokinetic profile in said subject wherein Para . DE . A pharmaceutical composition , comprising the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H -in - N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl dazol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide pyran - 4 - ylamino ) -benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical between about 30 , 000 nM * hr and about 85 ,000 nM * hr 20 composition when administered to a subject in a fed state following said administration of said pharmaceutical com provides a pharmacokinetic profile in said subject wherein position to said subject. the AUC ( infinity ) of said N -15 - ( 3 , 5 - difluorobenzyl ) - 1H - in Para . CZ . A pharmaceutical composition , comprising dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro N - [ 5 -( 3 , 5 - difluorobenzyl ) - 1H - indazol- 3 -yl ] -4 - (4 -methyl pyran - 4 - ylamino ) -benzamide in the plasma of said subject is piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide 25 between about 59, 400 nM * hr and about 87, 200 nM * hr and at least one acidulant, wherein said pharmaceutical following said administration of said pharmaceutical com composition when administered to a subject in a fasted state position to said subject. provides a pharmacokinetic profile in said subject wherein Para . DF . A pharmaceutical composition , comprising the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in N - [ 5 - ( 3 , 5 - difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - 30 piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide pyran - 4 - ylamino ) -benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical between about 34 ,700 nM * hr and about 72 , 900 nM * hr composition when administered to a subject in a fed state following said administration of said pharmaceutical com provides a pharmacokinetic profile in said subject wherein position to said subject. the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - in Para . DA . A pharmaceutical composition , comprising 35 dazol- 3 -yl ) - 4 - (4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl pyran - 4 -ylamino ) -benzamide in the plasma of said subject is piperazin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 -ylamino ) -benzamide between about 51 , 700 nM * hr and about 79, 700 nM * hr and at least one acidulant, wherein said pharmaceutical following said administration of said pharmaceutical com composition when administered to a subject in a fasted state position to said subject. provides a pharmacokinetic profile in said subject wherein 40 Para . DG . A pharmaceutical composition , comprising the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl dazol- 3 - yl ) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide pyran - 4 - ylamino ) -benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical between about 33 , 200 nM * hr and about 81 , 200 nM * hr composition when administered to a subject in a fasted state following said administration of said pharmaceutical com - 45 provides a pharmacokinetic profile in said subject wherein position to said subject . the Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 Para . DB . A pharmaceutical composition , comprising yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ] - 4 - ( 4 -methyl ylamino ) -benzamide in the plasma of said subject is within piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide about 80 % to about 125 % of 3 . 6 hours at a 90 % confidence and at least one acidulant, wherein said pharmaceutical 50 interval following said administration of said pharmaceuti composition when administered to a subject in a fasted state cal composition to said subject. provides a pharmacokinetic profile in said subject wherein Para . DH . A pharmaceutical composition , comprising the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl dazol- 3 - yl) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 -( tetrahydro piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benzamide pyran - 4 -ylamino ) - benzamide in the plasma of said subject is 55 and at least one acidulant, wherein said pharmaceutical between about 37 , 800 nM * hr and about 78 ,800 nM * hr composition when administered to a subject in a fasted state following said administration of said pharmaceutical com - provides a pharmacokinetic profile in said subject wherein position to said subject. the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 Para . DC . A pharmaceutical composition , comprising yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 N - 15 -( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ) - 4 -( 4 -methyl - 60 ylamino )- benzamide in the plasma of said subject is within piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 -ylamino )- benzamide about 80 % to about 125 % of 3 .5 hours at a 90 % confidence and at least one acidulant, wherein said pharmaceutical interval following said administration of said pharmaceuti composition when administered to a subject in a fed state cal composition to said subject. provides a pharmacokinetic profile in said subject wherein Para . DI. A pharmaceutical composition , comprising the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in - 65 N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro - piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide pyran -4 - ylamino )- benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical US 10 ,398 ,693 B2 163 164 composition when administered to a subject in a fasted state interval following said administration of said pharmaceuti provides a pharmacokinetic profile in said subject wherein cal composition to said subject . the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl ) -1H -indazol - 3 Para . DO . A pharmaceutical composition , comprising yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl ylamino ) - benzamide in the plasma of said subject is within 5 piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide about 80 % to about 125 % of 3 . 7 hours at a 90 % confidence and at least one acidulant, wherein said pharmaceutical interval following said administration of said pharmaceuti composition when administered to a subject in a fasted state cal composition to said subject . provides a pharmacokinetic profile in said subject wherein Para . DJ. A pharmaceutical composition , comprising the Cmax of said N - [5 - (3 ,5 -difluorobenzyl ) - 1H - indazol -3 N -[ 5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl 10 yl] -4 -( 4 -methyl - piperazin - 1 -yl ) -2 - ( tetrahydro -pyran - 4 piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide ylamino ) -benzamide in the plasma of said subject is within and at least one acidulant, wherein said pharmaceutical about 80 % to about 125 % of 2300 nM at a 90 % confidence composition when administered to a subject in a fed state interval following said administration of said pharmaceuti provides a pharmacokinetic profile in said subject wherein cal composition to said subject . the Tmax of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide ylamino ) -benzamide in the plasma of said subject is within and at least one acidulant, wherein said pharmaceutical about 80 % to about 125 % of 5 hours at a 90 % confidence composition when administered to a subject in a fed state interval following said administration of said pharmaceuti- 20 provides a pharmacokinetic profile in said subject wherein cal composition to said subject. the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 Para . DK . A pharmaceutical composition , comprising yl] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 N - [5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl - ylamino ) -benzamide in the plasma of said subject is within piperazin - 1 - yl) -2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide about 80 % to about 125 % of 2440 nM at a 90 % confidence and at least one acidulant, wherein said pharmaceutical 25 interval following said administration of said pharmaceuti composition when administered to a subject in a fed state cal composition to said subject . provides a pharmacokinetic profile in said subject wherein Para . DQ . A pharmaceutical composition , comprising the Tmax of said N - [ 5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 - N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ] - 4 -( 4 -methyl yl ] - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - tetrahydro -pyran - 4 piperazin - 1 - yl) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide ylamino ) - benzamide in the plasma of said subject is within 30 and at least one acidulant, wherein said pharmaceutical about 80 % to about 125 % of 5 . 8 hours at a 90 % confidence composition when administered to a subject in a fed state interval following said administration of said pharmaceuti - provides a pharmacokinetic profile in said subject wherein cal composition to said subject. the Cmax of said N - [5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 Para . DL . A pharmaceutical composition , comprising yl] -4 -( 4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro -pyran -4 N - [5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl - 35 ylamino ) -benzamide in the plasma of said subject is within piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino )- benzamide about 80 % to about 125 % of 2600 nM at a 90 % confidence and at least one acidulant, wherein said pharmaceutical interval following said administration of said pharmaceuti composition when administered to a subject in a fed state cal composition to said subject . provides a pharmacokinetic profile in said subject wherein Para . DR . A pharmaceutical composition , comprising the Tmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - 40 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl ] - 4 - ( 4 -methyl yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 piperazin - 1 - yl) - 2 - (tetrahydro - pyran - 4 - ylamino ) -benzamide ylamino ) - benzamide in the plasma of said subject is within and at least one acidulant, wherein said pharmaceutical about 80 % to about 125 % of 5 .4 hours at a 90 % confidence composition when administered to a subject in a fed state interval following said administration of said pharmaceuti provides a pharmacokinetic profile in said subject wherein cal composition to said subject. 45 the Cmax of said N - [ 5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 Para . DM . A pharmaceutical composition , comprising yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - y1 ] - 4 - ( 4 -methyl - ylamino ) -benzamide in the plasma of said subject is within piperazin -1 -yl ) - 2 -( tetrahydro - pyran - 4 -ylamino ) -benzamide about 80 % to about 125 % of 2400 nM at a 90 % confidence and at least one acidulant, wherein said pharmaceutical interval following said administration of said pharmaceuti composition when administered to a subject in a fasted state 50 cal composition to said subject . provides a pharmacokinetic profile in said subject wherein Para . DS . A pharmaceutical composition , comprising the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl yl] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide ylamino ) - benzamide in the plasma of said subject is within and at least one acidulant, wherein said pharmaceutical about 80 % to about 125 % of 2150 nM at a 90 % confidence 55 composition when administered to a subject in a fasted state interval following said administration of said pharmaceuti provides a pharmacokinetic profile in said subject wherein cal composition to said subject. the AUC (0 to 120 ) of said N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H Para . DN . A pharmaceutical composition , comprising indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro N - [5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - y11- 4 - ( 4 -methyl - pyran - 4 - ylamino ) -benzamide in the plasma of said subject is piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide 60 within about 80 % to about 125 % of 52 ,900 nM * hr at a 90 % and at least one acidulant, wherein said pharmaceutical confidence interval following said administration of said composition when administered to a subject in a fasted state pharmaceutical composition to said subject. provides a pharmacokinetic profile in said subject wherein Para . DT . A pharmaceutical composition , comprising the Cmax of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 - methyl yl] - 4 - (4 -methyl -piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 - 65 piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - ylamino ) -benzamide ylamino ) -benzamide in the plasma of said subject is within and at least one acidulant, wherein said pharmaceutical about 80 % to about 125 % of 2260 nM at a 90 % confidence composition when administered to a subject in a fasted state US 10 , 398 ,693 B2 165 166 provides a pharmacokinetic profile in said subject wherein Para . DZ . A pharmaceutical composition , comprising the AUC (0 to 120 ) of said N - [5 -( 3, 5 - difluorobenzyl) - 1H - N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide pyran - 4 - ylamino ) -benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical within about 80 % to about 125 % of 56 , 100 nM * hr at a 90 % 5 composition when administered to a subject in a fasted state confidence interval following said administration of said provides a pharmacokinetic profile in said subject wherein pharmaceutical composition to said subject . the AUC ( infinity ) of said N -15 - ( 3 , 5 - difluorobenzyl ) - 1H - in Para . DU . A pharmaceutical composition , comprising dazol- 3 -yl ] - 4 -( 4 -methyl - piperazin - 1- yl) -2 - ( tetrahydro N -[ 5 - (3 , 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 -( 4 -methyl pyran - 4 -ylamino )- benzamide in the plasma of said subject is piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide 10 within about 80 % to about 125 % of 57 , 200 nM * hr at a 90 % and at least one acidulant, wherein said pharmaceutical confidence interval following said administration of said composition when administered to a subject in a fasted state pharmaceutical composition to said subject. provides a pharmacokinetic profile in said subject wherein Para . EA . A pharmaceutical composition , comprising the AUC ( 0 to 120 ) of said N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - y11- 4 - ( 4 -methyl indazol- 3 - yl) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - (tetrahydro - 15 piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide pyran - 4 - ylamino ) -benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical within about 80 % to about 125 % of 57 ,200 nM * hr at a 90 % composition when administered to a subject in a fasted state confidence interval following said administration of said provides a pharmacokinetic profile in said subject wherein pharmaceutical composition to said subject. the AUC (infinity ) of said N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H -in Para . DV . A pharmaceutical composition , comprising 20 dazol- 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - ( tetrahydro N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- pyran - 4 -ylamino ) -benzamide in the plasma of said subject is piperazin - 1 - yl) - 2 -( tetrahydro -pyran - 4 - ylamino ) - benzamide within about 80 % to about 125 % of 58 , 300 nM * hr at a 90 % and at least one acidulant, wherein said pharmaceutical confidence interval following said administration of said composition when administered to a subject in a fed state pharmaceutical composition to said subject. provides a pharmacokinetic profile in said subject wherein 25 Para . EB . A pharmaceutical composition , comprising the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 - yl) - 2 - ( tetrahydro piperazin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide pyran - 4 - ylamino ) -benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical within about 80 % to about 125 % of 58 , 800 nM * hr at a 90 % composition when administered to a subject in a fed state confidence interval following said administration of said 30 provides a pharmacokinetic profile in said subject wherein pharmaceutical composition to said subject. the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in Para . DW . A pharmaceutical composition , comprising dazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 -yl ] - 4 - ( 4 -methyl - pyran - 4 - ylamino ) -benzamide in the plasma of said subject is piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide within about 80 % to about 125 % of 59, 400 nM * hr at a 90 % and at least one acidulant, wherein said pharmaceutical 35 confidence interval following said administration of said composition when administered to a subject in a fed state pharmaceutical composition to said subject . provides a pharmacokinetic profile in said subject wherein Para . EC . A pharmaceutical composition , comprising the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl ) - 2 - (tetrahydro piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide pyran - 4 - ylamino ) - benzamide in the plasma of said subject is 40 and at least one acidulant, wherein said pharmaceutical within about 80 % to about 125 % of 71, 800 nM * hr at a 90 % composition when administered to a subject in a fed state confidence interval following said administration of said provides a pharmacokinetic profile in said subject wherein pharmaceutical composition to said subject . the AUC ( infinity ) of said N -[ 5 - ( 3 ,5 -difluorobenzyl ) - 1H - in Para . DX . A pharmaceutical composition , comprising dazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro N - 15 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl ) -4 - ( 4 -methyl - 45 pyran - 4 -ylamino ) -benzamide in the plasma of said subject is piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide within about 80 % to about 125 % of 73 ,300 nM * hr at a 90 % and at least one acidulant, wherein said pharmaceutical confidence interval following said administration of said composition when administered to a subject in a fed state pharmaceutical composition to said subject . provides a pharmacokinetic profile in said subject wherein Para . ED . A pharmaceutical composition , comprising the AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - 50 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl indazol - 3 - yl) -4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) - benzamide pyran - 4 - ylamino )- benzamide in the plasma of said subject is and at least one acidulant, wherein said pharmaceutical within about 80 % to about 125 % of 64 , 400 nM * hr at a 90 % composition when administered to a subject in a fed state confidence interval following said administration of said provides a pharmacokinetic profile in said subject wherein pharmaceutical composition to said subject. 55 the AUC ( infinity ) of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - in Para . DY. A pharmaceutical composition , comprising dazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - pyran - 4 - ylamino ) -benzamide in the plasma of said subject is piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benzamide within about 80 % to about 125 % of 65 ,700 nM * hr at a 90 % and at least one acidulant, wherein said pharmaceutical confidence interval following said administration of said composition when administered to a subject in a fasted state 60 pharmaceutical composition to said subject. provides a pharmacokinetic profile in said subject wherein Para . EE . A pharmaceutical composition , comprising : the AUC ( infinity ) of said N - 15 - ( 3 , 5 -difluorobenzyl ) - 1H - in - N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl dazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 -yl ) - 2 - ( tetrahydro piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benz pyran - 4 -ylamino ) -benzamide in the plasma of said subject is amide ; and within about 80 % to about 125 % of 53 ,800 nM * hr at a 90 % 65 means for delivering a Tmax of said N - [ 5 - ( 3 , 5 - difluo confidence interval following said administration of said robenzyl ) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 pharmaceutical composition to said subject . yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide in the US 10 , 398 ,693 B2 167 168 plasma of a subject of between about 2 hours and about means for delivering a Cmax of said N - [ 5 - ( 3 , 5 - difluo 5 hours following administration of said pharmaceuti robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 cal composition to said subject in a fasted state . yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benzamide in the Para . EF. A pharmaceutical composition , comprising : plasma of a subject of between about 1810 nM and N -[ 5 - (3 , 5 -difluorobenzyl ) -1H - indazol- 3 -yl ] -4 -( 4 -methyl about 3070 nM following administration of said phar piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz maceutical composition to said subject in a fed state . amide; and Para . EM . A pharmaceutical composition , comprising: means for delivering a Tmax of said N -[ 5 -( 3 ,5 - difluo - N -[ 5 -( 3 ,5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benz yl) - 2 - ( tetrahydro - pyran -4 - ylamino ) -benzamide in the 10 plasma of a subject of between about 4 hours and about means for delivering a Cmax of said N - 15 - ( 3 , 5 -difluo 6 hours following administration of said pharmaceuti robenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 -methyl - piperazin - 1 cal composition to said subject in a fed state . yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide in the Para . EG . A pharmaceutical composition , comprising : plasma of a subject of between about 2210 nM and N - [5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - 15 about 2990 nM following administration of said phar piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benz maceutical composition to said subject in a fed state . amide ; and Para . EN . A pharmaceutical composition , comprising : means for delivering a Tmax of said N - [ 5 - ( 3 , 5 - difluo - N - [ 5 -( 3 , 5 - difluorobenzyl) -1H - indazol - 3 - yl) - 4 - ( 4 -methyl robenzyl) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1 piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benz yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide in the 20 amide ; and plasma of a subject of between about 4 hours and about means for delivering a Cmax of said N - [ 5 - ( 3 , 5 -difluo 8 hours following administration of said pharmaceuti robenzyl) - 1H - indazol - 3 - yl ] - 4 -( 4 -methyl - piperazin - 1 cal composition to said subject in a fed state . yl) - 2 - ( tetrahydro - pyran -4 - ylamino ) -benzamide in the Para . EH . A pharmaceutical composition , comprising : plasma of a subject of between about 1990 nM and N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] -4 - ( 4 -methyl - 25 about 2810 nM following administration of said phar piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benz maceutical composition to said subject in a fed state . amide; and Para . EO . A pharmaceutical composition , comprising : means for delivering a Tmax of said N - [ 5 - ( 3 , 5 - difluo - N - [ 5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl robenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl -piperazin - 1 piperazin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benz yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide in the 30 amide ; and plasma of a subject of between about 4 hours and about means for delivering an AUC (0 to 120 ) of said N - [5 - (3 , 7 hours following administration of said pharmaceuti 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piper cal composition to said subject in a fed state . azin - 1 - yl) - 2 - (tetrahydro -pyran - 4 -ylamino ) -benzamide Para . El. A pharmaceutical composition , comprising : in the plasma of a subject of between about 34 , 100 N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 - ( 4 -methyl - 35 nM * hr and about 71 , 700 nM * hr following administra piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz tion of said pharmaceutical composition to said subject amide; and in a fasted state . means for delivering a Cmax of said N - [ 5 - ( 3 , 5 - difluo Para . EP . A pharmaceutical composition , comprising : robenzyl) - 1H - indazol- 3 -yl ) -4 - (4 -methyl - piperazin - 1 - N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - (4 -methyl yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benzamide in the 40 piperazin - 1- yl) -2 -( tetrahydro -pyran - 4 -ylamino ) -benz plasma of a subject of between about 1500 nM and amide; and about 2800 nM following administration of said phar means for delivering an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , maceutical composition to said subject in a fasted state . 5 - difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piper Para . EJ. A pharmaceutical composition , comprising : azin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide N -[ 5 - (3 , 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) - 4 -( 4 -methyl - 45 in the plasma of a subject of between about 32 ,500 piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz nM * hr and about 79 ,700 nM * hr following administra amide; and tion of said pharmaceutical composition to said subject means for delivering a Cmax of said N -[ 5 -( 3 ,5 - difluo in a fasted state . robenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 Para . EQ . A pharmaceutical composition , comprising : yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benzamide in the 50 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl plasma of a subject of between about 1490 nM and piperazin - 1 - yl) -2 -( tetrahydro -pyran -4 - ylamino )- benz about 3030 nM following administration of said phar PIamide ; and maceutical composition to said subject in a fasted state . means for delivering an AUC (0 to 120 ) of said N - [ 5 - ( 3 , Para . EK . A pharmaceutical composition , comprising : 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl- piper N - [5 -( 3 , 5 -difluorobenzyl ) - 1H - indazol - 3 -yl ) - 4 - ( 4 -methyl - 55 azin - 1 - yl) - 2 -( tetrahydro -pyran -4 -ylamino )- benzamide piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benz in the plasma of a subject of between about 37 , 100 amide ; and nM * hr and about 77 , 300 nM * hr following administra means for delivering a Cmax of said N - [ 5 - ( 3 , 5 - difluo tion of said pharmaceutical composition to said subject robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 in a fasted state . yl) - 2 -( tetrahydro - pyran - 4 - ylamino ) -benzamide in the 60 Para . ER . A pharmaceutical composition , comprising: plasma of a subject of between about 1670 nM and N -[ 5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl about 2930 nM following administration of said phar piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benz maceutical composition to said subject in a fasted state . amide; and Para . EL . A pharmaceutical composition , comprising : means for delivering an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , N -[ 5 - (3 , 5 -difluorobenzyl ) -1H - indazol- 3 -yl ] -4 -( 4 -methyl - 65 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl -piper piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - ylamino ) -benz azin - 1 -yl ) -2 -( tetrahydro - pyran -4 -ylamino ) -benzamide amide ; and in the plasma of a subject of between about 38 , 900 US 10 , 398 ,693 B2 169 170 nM * hr and about 78 , 700 nM * hr following administra nM hr and about 79, 700 nM * hr following administra tion of said pharmaceutical composition to said subject tion of said pharmaceutical composition to said subject in a fed state . in a fed state . Para . ES . A pharmaceutical composition , comprising : Para . EY. A pharmaceutical composition , comprising : N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -v11 - 4 - ( 4 -methyl - 5 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 -ylamino ) -benz piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz amide ; and amide ; and means for delivering an AUC ( infinity ) of said N - [5 -( 3 , 5 means for delivering an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , difluorobenzyl) - 1H - indazol- 3 - yl) -4 - ( 4 -methyl - piper 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piper azin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide in the plasma of a subject of between about 59 , 400 in the plasma of a subject of between about 58 , 900 nM " hr and about 87 , 200 nM * hr following administra nM * hr and about 84 , 700 nM * hr following administra tion of said pharmaceutical composition to said subject tion of said pharmaceutical composition to said subject in a fed state . in a fed state . 15 Para . EZ. A pharmaceutical composition , comprising : Para . ET. A pharmaceutical composition , comprising : N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl N - [5 -( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) - benz piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 -ylamino ) -benz amide ; and amide; and means for delivering an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 means for delivering an AUC ( 0 to 120 ) of said N -[ 5 -( 3 , 20 difluorobenzyl) - 1H - indazol- 3 - yl) -4 - ( 4 -methyl - piper 5 - difluorobenzyl) - 1H -indazol - 3 -yl ) - 4 - ( 4 -methyl -piper azin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide in the plasma of a subject of between about 51, 700 in the plasma of a subject of between about 51, 300 nM * hr and about 79 ,700 nM * hr following administra nM * hr and about 77 ,500 nM * hr following administra tion of said pharmaceutical composition to said subject tion of said pharmaceutical composition to said subject 25 in a fed state . in a fed state . Para . FA . A pharmaceutical composition , comprising : Para . EU . A pharmaceutical composition , comprising : N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benz piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benz amide ; and amide ; and 30 means for delivering an Tmax of said N -[ 5 -( 3 ,5 -difluo means for delivering an AUC ( infinity ) of said N -[ 5 - (3 , 5 robenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 difluorobenzyl) - 1H -indazol - 3 -yl ) -4 - (4 -methyl - piper yl) - 2 - (tetrahydro -pyran -4 -ylamino )- benzamide in the azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide plasma of a subject that is between 80 % to 125 % of 3 .6 in the plasma of a subject of between about 34 , 700 hours , based on a 90 percent confidence interval , fol nM * hr and about 72 ,900 nM * hr following administra - 35 lowing administration of said pharmaceutical compo tion of said pharmaceutical composition to said subject sition to said subject in a fasted state . in a fasted state . Para . FB . A pharmaceutical composition , comprising : Para . EV. A pharmaceutical composition , comprising : N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benz piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) -benz - 40 amide ; and amide ; and means for delivering an Tmax of said N - [ 5 - ( 3 , 5 -difluo means for delivering an AUC ( infinity ) of said N - [5 - (3 , 5 robenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 difluorobenzyl) - 1H - indazol- 3 -yl ) -4 - ( 4 -methyl - piper yl) - 2 -( tetrahydro -pyran - 4 -ylamino )- benzamide in the azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide plasma of a subject that is between 80 % to 125 % of 3 .5 in the plasma of a subject of between about 33 ,200 45 hours , based on a 90 percent confidence interval , fol nM * hr and about 81 , 200 nM * hr following administra lowing administration of said pharmaceutical compo tion of said pharmaceutical composition to said subject sition to said subject in a fasted state . in a fasted state . Para . FC . A pharmaceutical composition , comprising : Para . EW . A pharmaceutical composition , comprising : N -[ 5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl- 50 piperazin - 1 - yl ) - 2 - (tetrahydro -pyran - 4 - ylamino )- benz piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz na amide ; and amide; and means for delivering an Tmax of said N - [ 5 - ( 3 , 5 - difluo means for delivering an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 robenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 difluorobenzyl) - 1H -indazol - 3 -yl ) -4 - (4 -methyl - piper yl) - 2 - ( tetrahydro -pyran -4 - ylamino )- benzamide in the azin - 1 - yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino )- benzamide 55 plasma of a subject that is between 80 % to 125 % of 3 . 7 in the plasma of a subject of between about 37, 800 hours , based on a 90 percent confidence interval , fol nM * hr and about 78 ,800 nM * hr following administra lowing administration of said pharmaceutical compo tion of said pharmaceutical composition to said subject sition to said subject in a fasted state. in a fasted state . Para . FD . A pharmaceutical composition , comprising : Para . EX . A pharmaceutical composition , comprising : 60 N - 15 - ( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 - yl ) -4 - ( 4 -methyl N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - ylamino ) -benz piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benz amide ; and amide ; and means for delivering an Tmax of said N - [ 5 - ( 3 , 5 - difluo means for delivering an AUC ( infinity ) of said N -[ 5 - (3 , 5 robenzyl) - 1H - indazol- 3 - yl] -4 - (4 -methyl - piperazin - 1 difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl - piper- 65 yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide in the azin - 1 - yl) - 2 - (tetrahydro - pyran - 4 - ylamino ) -benzamide plasma of a subject that is between 80 % to 125 % of 5 in the plasma of a subject of between about 39 , 100 hours , based on a 90 percent confidence interval, fol US 10 , 398 ,693 B2 171 172 lowing administration of said pharmaceutical compo following administration of said pharmaceutical com sition to said subject in a fed state . position to said subject in a fed state . Para . FE . A pharmaceutical composition , comprising : Para . FK . A pharmaceutical composition , comprising : N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl piperazin - 1 - yl) - 2 - tetrahydro -pyran - 4 -ylamino )- benz - 5 piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino )- benz amide; and amide ; and means for delivering an Tmax of said N - [ 5 - ( 3 , 5 - difluo means for delivering an Cmax of said N - [ 5 - ( 3 , 5 - difluo robenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 robenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 yl) - 2 - ( tetrahydro - pyran -4 - ylamino ) -benzamide in the yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide in the plasma of a subject that is between 80 % to 125 % of 5 . 8 10 plasma of a subject that is between 80 % to 125 % of hours , based on a 90 percent confidence interval , fol 2600 nM , based on a 90 percent confidence interval, lowing administration of said pharmaceutical compo following administration of said pharmaceutical com sition to said subject in a fed state . position to said subject in a fed state . Para . FF . A pharmaceutical composition , comprising : 16 Para . FL . A pharmaceutical composition , comprising : N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benz piperazin - 1 -yl ) - 2- ( tetrahydro -pyran - 4 -ylamino )- benz amide ; and amide; and means for delivering an Tmax of said N - [ 5 - ( 3 , 5 -difluo means for delivering an Cmax of said N - [ 5 - ( 3 , 5 - difluo robenzyl )- 1H - indazol- 3 -yl ) - 4 -( 4 -methyl - piperazin - 1- 20 robenzyl ) -1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 yl) - 2 - ( tetrahydro - pyran -4 - ylamino ) -benzamide in the yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide in the plasma of a subject that is between 80 % to 125 % of 5 . 4 plasma of a subject that is between 80 % to 125 % of hours , based on a 90 percent confidence interval, fol 2400 nM , based on a 90 percent confidence interval, lowing administration of said pharmaceutical compo following administration of said pharmaceutical com sition to said subject in a fed state . 25 position to said subject in a fed state . Para . FG . A pharmaceutical composition , comprising : Para . FM . A pharmaceutical composition , comprising : N - 15 - ( 3 ,5 - difluorobenzyl) - 1H -indazol - 3 - y1 ] -4 - ( 4 -methyl N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - ylamino ) -benz amide ; and amide ; and means for delivering an Cmax of said N - [ 5 - ( 3 , 5 - difluo - 30 means for delivering an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , robenzyl) - 1H - indazol - 3 - yl) - 4 - ( 4 -methyl - piperazin - 1 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piper yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide in the azin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 -ylamino )- benzamide plasma of a subject that is between 80 % to 125 % of in the plasma of a subject that is between 80 % to 125 % 2150 nM , based on a 90 percent confidence interval, of 52 , 900 nM * hr, based on a 90 percent confidence following administration of said pharmaceutical com - 35 interval , following administration of said pharmaceu position to said subject in a fasted state . tical composition to said subject in a fasted state . Para . FH . A pharmaceutical composition , comprising : Para . FN . A pharmaceutical composition , comprising : N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benz piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benz amide ; and 40 amide; and means for delivering an Cmax of said N -[ 5 -( 3 ,5 - difluo means for delivering an AUC ( 0 to 120 ) of said N -[ 5 - ( 3 , robenzyl) - 1H - indazol- 3 - yl] -4 - ( 4 -methyl -piperazin - 1 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl- piper yl) - 2 - ( tetrahydro -pyran -4 -ylamino ) -benzamide in the azin - 1 - yl) - 2 - (tetrahydro -pyran - 4 -ylamino )- benzamide plasma of a subject that is between 80 % to 125 % of in the plasma of a subject that is between 80 % to 125 % 2260 nM , based on a 90 percent confidence interval, 45 of 56 , 100 nM * hr, based on a 90 percent confidence following administration of said pharmaceutical com interval, following administration of said pharmaceu position to said subject in a fasted state . tical composition to said subject in a fasted state . Para . FI. A pharmaceutical composition , comprising: Para . FO . A pharmaceutical composition , comprising : N -[ 5 - (3 , 5 -difluorobenzyl ) - 1H -indazol - 3 -yl ) -4 -( 4 -methyl N -[ 5 - (3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl) - 4 -( 4 -methyl piperazin - 1 -yl )- 2 -( tetrahydro -pyran - 4 - ylamino ) -benz - 50 piperazin - 1 -yl ) -2 - ( tetrahydro - pyran - 4 - ylamino )- benz amide ; and amide; and means for delivering an Cmax of said N - [ 5 - ( 3 , 5 - difluo means for delivering an AUC ( 0 to 120 ) of said N -[ 5 - ( 3 , robenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piper yl) - 2 - ( tetrahydro -pyran -4 - ylamino )- benzamide in the azin - 1 - yl) - 2 -( tetrahydro -pyran -4 -ylamino )- benzamide plasma of a subject that is between 80 % to 125 % of 55 in the plasma of a subject that is between 80 % to 125 % 2300 nM , based on a 90 percent confidence interval, of 57 ,200 nM * hr, based on a 90 percent confidence following administration of said pharmaceutical com interval, following administration of said pharmaceu position to said subject in a fasted state . tical composition to said subject in a fasted state . Para . FJ. A pharmaceutical composition , comprising: Para . FP . A pharmaceutical composition , comprising : N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl) -4 - ( 4 -methyl - 60 N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H -indazol - 3 - yl] - 4 - ( 4 -methyl piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz piperazin - 1 -yl ) -2 -( tetrahydro -pyran - 4 - ylamino ) -benz amide; and amide ; and means for delivering an Cmax of said N - [ 5 - ( 3 , 5 -difluo means for delivering an AUC ( 0 to 120 ) of said N - [5 - (3 , robenzyl) - 1H - indazol- 3 - yl] - 4 - ( 4 - methyl- piperazin - 1 5 - difluorobenzyl) - 1H -indazol - 3 -yl ] - 4 - ( 4 -methyl - piper yl) - 2 - ( tetrahydro -pyran -4 - ylamino )- benzamide in the 65 azin - 1 -yl ) - 2 - (tetrahydro -pyran - 4 -ylamino )- benzamide plasma of a subject that is between 80 % to 125 % of in the plasma of a subject that is between 80 % to 125 % 2440 nM , based on a 90 percent confidence interval, of 58 , 800 nM * hr, based on a 90 percent confidence US 10 , 398 ,693 B2 173 174 interval , following administration of said pharmaceu interval , following administration of said pharmaceu tical composition to said subject in a fed state. tical composition to said subject in a fed state . Para . FQ . A pharmaceutical composition , comprising : Para . FW . A pharmaceutical composition , comprising : N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl N -[ 5 - ( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino )- benz - 5 piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benz amide ; and amide; and means for delivering an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 means for delivering an AUC ( 0 to 120 ) of said N -[ 5 -( 3 , difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl - piper 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) -4 - ( 4 -methyl - piper azin - 1 - yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benzamide in the plasma of a subject that is between 80 % to 125 % in the plasma of a subject that is between 80 % to 125 % of 73 , 300 nM * hr, based on a 90 percent confidence of 71 , 800 nM * hr, based on a 90 percent confidence interval, following administration of said pharmaceu interval , following administration of said pharmaceu tical composition to said subject in a fed state. tical composition to said subject in a fed state . Para . FX . A pharmaceutical composition , comprising: Para . FR . A pharmaceutical composition , comprising : 15 N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - v1] - 4 - ( 4 -methyl N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 - ( 4 - methyl piperazin - 1 - yl) - 2 - (tetrahydro -pyran - 4 - ylamino ) - benz piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benz amide ; and amide ; and means for delivering an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 means for delivering an AUC ( 0 to 120 ) of said N - [ 5 - ( 3 , difluorobenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piper 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl - piper - 20 azin - 1 -yl ) - 2 - (tetrahydro -pyran - 4 -ylamino )- benzamide azin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benzamide in the plasma of a subject that is between 80 % to 125 % in the plasma of a subject that is between 80 % to 125 % of 65, 700 nM * hr, based on a 90 percent confidence of 64 ,400 nM * hr, based on a 90 percent confidence interval, following administration of said pharmaceu interval, following administration of said pharmaceu tical composition to said subject in a fed state . tical composition to said subject in a fed state . 25 Para . FY. The pharmaceutical composition of any one of Para . FS. A pharmaceutical composition , comprising : Paras . CA - ED , wherein said at least one acidulant is tartaric N -[ 5 -( 3, 5 -difluorobenzyl ) - 1H - indazol- 3 -yl ) - 4 -( 4 -methyl acid . piperazin - 1 -yl ) - 2 -( tetrahydro -pyran - 4 -ylamino ) -benz Para . FZ . The pharmaceutical composition of any one of amide ; and Paras . CA - FY , wherein said composition comprises a total means for delivering an AUC ( infinity ) of said N - [ 5 - ( 3 , 5 - 30 dose of about 600 mg of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H difluorobenzyl) - 1H - indazol- 3 - yl) - 4 - ( 4 -methyl -piper - indazol- 3 - yl ) - 4 - ( 4 - methyl- piperazin - 1 - yl) - 2 - ( tetrahydro azin - 1 - yl) - 2 -( tetrahydro - pyran -4 -ylamino )- benzamide pyran - 4 -ylamino )- benzamide . in the plasma of a subject that is between 80 % to 125 % Para . GA . The pharmaceutical composition of any one of of 53 ,800 nM * hr, based on a 90 percent confidence Paras . CA -FZ , wherein said pharmaceutical composition is interval, following administration of said pharmaceu - 35 in the form of a tablet or capsule . tical composition to said subject in a fasted state . Para . GB . The pharmaceutical composition of any one of Para . FT. A pharmaceutical composition , comprising : Paras. CA -GA , wherein said pharmaceutical composition is N - [5 -( 3 ,5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - (4 -methyl in the form of a capsule . piperazin - 1 -yl ) - 2 - ( tetrahydro - pyran - 4 - ylamino ) - benz Para . GC . The pharmaceutical composition of any one of amide ; and 40 Paras . A -GB further comprising lactose , hypromellose , means for delivering an AUC ( infinity ) of said N -[ 5 - (3 , 5 crospovidone , microcrystalline cellulose , colloidal silicon difluorobenzyl) - 1H -indazol - 3 - yl) - 4 - ( 4 -methyl -piper - dioxide , or magnesium stearate , or any combination of two azin - 1 - yl) - 2 -( tetrahydro -pyran -4 - ylamino ) -benzamide or more thereof. in the plasma of a subject that is between 80 % to 125 % Para . GD . The pharmaceutical composition of Para . GC of 57 , 200 nM * hr, based on a 90 percent confidence 45 comprising about 20 % w / w to about 60 % w / w N - 15 - ( 3 , 5 interval, following administration of said pharmaceu - difluorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl -piperazin - 1 tical composition to said subject in a fasted state . yl ) -2 - ( tetrahydro - pyran - 4 - ylamino )- benzamide , about 5 % Para . FU . A pharmaceutical composition , comprising : w / w / to about 20 % w / w tartaric acid , about 15 % w / w to N - 15 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 - yl ) - 4 - ( 4 -methyl - about 35 % w /w lactose , about 1 % w /w to about 10 % w / w piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 - ylamino ) -benz - 50 hypromellose , about 1 % w / w to about 5 % w / w microcrys amide ; and talline cellulose , about 1 % w / w to about 10 % w / w crospovi means for delivering an AUC infinity ) of said N - [ 5 - ( 3 , 5 done , about 0 .05 % w / w to about 5 % w / w colloidal silicon difluorobenzyl) -1H - indazol- 3 - yl ) -4 -( 4 -methyl - piper dioxide , and about 0 .1 % w / w to about 5 % w / w magnesium azin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 -ylamino )- benzamide stearate . in the plasma of a subject that is between 80 % to 125 % 55 Para . GE . The pharmaceutical composition of Para . GC of 58 ,300 nM * hr, based on a 90 percent confidence comprising about 40 % w / w to about 50 % w / w N - [ 5 - ( 3 , 5 interval, following administration of said pharmaceu difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl -piperazin - 1 tical composition to said subject in a fasted state . yl) - 2 - ( tetrahydro -pyran -4 - ylamino )- benzamide , about 10 % Para . FV . A pharmaceutical composition , comprising : w /w / to about 15 % w / w tartaric acid , about 25 % w / w to N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - 60 about 30 % w / w lactose , about 3 % w / w to about 5 w / w piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 - ylamino ) - benz hypromellose (hydroxypropyl methylcellulose ) , about 2 % amide; and w / w to about 4 % w / w microcrystalline cellulose , about 4 % means for delivering an AUC ( infinity ) of said N -15 - (3 , 5 - w / w to about 7 % w / w crospovidone , about 0 . 1 % w / w to difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piper about 1 % w / w colloidal silicon dioxide , and about 0 . 5 % w / w azin - 1 -yl ) - 2 -( tetrahydro - pyran - 4 -ylamino )- benzamide 65 to about 2 % w / w magnesium stearate . in the plasma of a subject that is between 80 % to 125 % Para . GF. The pharmaceutical composition of any one of of 59, 400 nM * hr, based on a 90 percent confidence Paras. GC -GE , wherein lactose is anhydrous lactose . US 10 , 398 ,693 B2 175 176 Para . GG . The pharmaceutical composition of any one of Para . GP. A method of treating a subject having TrkB Paras. A -GF , wherein N - [ 5 - ( 3 , 5 -difluorobenzyl )- 1H - inda - positive cancer , the method comprising administering to the zol -3 -yl ) -4 - (4 -methyl - piperazin - 1 -yl ) - 2 - (tetrahydro -pyran - subject the pharmaceutical composition of any one of Paras . 4 -ylamino ) -benzamide and the at least one acidulant are A -GH . present in the composition as an admixture . In other words, 5 Para . GQ . A method of treating a subject having TrkC N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol - 3 - yl] - 4 - ( 4 -methyl positive cancer , the method comprising administering to the piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide subject the pharmaceutical composition of any one of Paras . is not present in the composition as the salt form of the at A -GH . least one acidulant. Para . GH . A pharmaceutical composition comprising 10 p . Para . GR . A pharmaceutical composition of any one of N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - ( 4 -methyl 18 Paras . A -GH for use in a method of treating a subject having piperazin - 1 - yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) - benzamide, cancer. tartaric acid , anhydrous lactose , hypromellose , microcrys Para . GS . A pharmaceutical composition of any one of talline cellulose, crospovidone , colloidal silicon dioxide, and Paras . A -GH for use in a method of treating a subject having magnesium stearate , wherein the composition is prepared in 15 ALALK , ROS1 , TrkA , TrkB , or TrkC positive cancer , or a a method comprising: combination thereof. adding N - 15 - (3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl) - 4 -( 4 - Para . GT. A pharmaceutical composition of any one of methyl- piperazin - 1 -yl ) - 2 - ( tetrahydro -pyran - 4 Paras . A -GH for use in a method of treating a subject having ylamino ) - benzamide ; anhydrous lactose ; hypromel- ALK positive cancer. lose ; a first portion of crospovidone ; and tartaric acid 20 Para . GU . A pharmaceutical composition of any one of together and blending to form a first admixture ; Paras. A -GH for use in a method of treating a subject having sieving the first admixture to form a sieved first admix - ROS1, TrkA , TrkB , or TrkC positive cancer , or a combina ture ; tion thereof. blending the sieved first admixture to form a second Para . GV. A pharmaceutical composition of any one of admixture ; 25 Paras . A -GH for use in a method of treating a subject having sieving the second admixture to form a sieved second ROS1 positive cancer. admixture ; Para . GW . A pharmaceutical composition of any one of blending the sieved second admixture to form a third Paras. A -GH for use in a method of treating a subject having admixture ; adding a first portion of magnesium stearate to the third 30 +TrkA1 , TrkB , or TrkC positive cancer , or a combination admixture and blending to form a fourth admixture ; compacting and milling the fourth admixture to form a Para . GX . A pharmaceutical composition of any one of fifth admixture ; Paras . A -GH for use in a method of treating a subject having adding microcrystalline cellulose , a second portion of TrkA positive cancer. crospovidone, and colloidal silicon dioxide to the fifth 35 Para . GY. A pharmaceutical composition of any one of admixture and blending to form a sixth admixture ; and Paras. A -GH for use in a method of treating a subject having adding a second portion of magnesium stearate to the TrkB positive cancer. sixth admixture and blending to form the pharmaceu Para . GZ. A pharmaceutical composition of any one of tical composition . Paras . A -GH for use in a method of treating a subject having Para .GI . A method of treating a subject having cancer , the 40 TrkC positive cancer . method comprising administering to the subject the phar - Para . HA . Use of the pharmaceutical composition of any maceutical composition of any one of Paras. A -GH . one of Paras . A -GH for the preparation of a medicament for Para . GJ. A method of treating a subject having ALK , the treatment of cancer. ROS1 , TrkA , TrkB , or TrkC positive cancer , or a combina - Para . HB . Use of the pharmaceutical composition of any tion thereof, the method comprising administering to the 45 one of Paras . A -GH for the preparation of a medicament for subject the pharmaceutical composition of any one of Paras. the treatment of ALK , ROS1, TrkA , TrkB , or TrkC positive A -GH . cancer , or a combination thereof. Para . GK . A method of treating a subject having ALK Para . HC . Use of the pharmaceutical composition of any positive cancer, the method comprising administering to the one of Paras . A -GH for the preparation of a medicament for subject the pharmaceutical composition of any one of Paras . 50 the treatment of ALK positive cancer. A -GH . Para . HD . Use of the pharmaceutical composition of any Para . GL . A method of treating a subject having ROS1 , one of Paras. A -GH for the preparation of a medicament for TrkA , TrkB , or TrkC positive cancer , or a combination the treatment of ROS1, TrkA , TrkB , or TrkC positive cancer , thereof, the method comprising administering to the subject or a combination thereof. the pharmaceutical composition of any one of Paras . A -GH . 55 Para . HE . Use of the pharmaceutical composition of any Para . GM . A method of treating a subject having ROS1 one of Paras . A -GH for the preparation of a medicament for positive cancer, the method comprising administering to the the treatment of ROS1 positive cancer. subject the pharmaceutical composition of any one of Paras . Para . HF . Use of the pharmaceutical composition of any A -GH . one of Paras. A -GH for the preparation of a medicament for Para . GN . A method of treating a subject having TrkA , 60 the treatment of TrkA , TrkB , or TrkC positive cancer , or a TrkB , or TrkC positive cancer, or a combination thereof , the combination thereof . method comprising administering to the subject the phar - Para . HG . Use of the pharmaceutical composition of any maceutical composition of any one of Paras . A -GH . one of Paras. A -GH for the preparation of a medicament for Para . GO . A method of treating a subject having Trk? the treatment of TrkA positive cancer. positive cancer, the method comprising administering to the 65 Para . HH . Use of the pharmaceutical composition of any subject the pharmaceutical composition of any one of Paras one of Paras . A -GH for the preparation of a medicament for A -GH . the treatment of TrkB positive cancer. US 10 , 398 ,693 B2 177 178 Para . HI. Use of the pharmaceutical composition of any 7 . The pharmaceutical composition of claim 3 , wherein one of Paras . A -GH for the preparation of a medicament for said at least one acidulant is maleic acid . the treatment of TrkC positive cancer . 8 . The pharmaceutical composition of claim 3 , wherein As will be understood by one skilled in the art , for any and said at least one acidulant is citric acid . all purposes, such as in terms of providing a written descrip - 5 9 . The pharmaceutical composition of claim 3 , wherein tion , all ranges provided herein also encompass any and all said at least one acidulant is betaine hydrochloride . possible sub - ranges and combinations of sub - ranges thereof. 10 . The pharmaceutical composition of claim 1 , wherein Any listed range can be easily recognized as sufficiently the molar ratio between said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H describing and enabling the same range being broken down indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - ( tetrahydro into at least equal halves, thirds, quarters, fifths , tenths, etc . 10 pyran - 4 - ylamino ) -benzamide and said at least one acidulant As a non - limiting example , each range discussed herein can is from about 0 .5 to about 2 . be readily broken down into a lower third , middle third and 11 . The pharmaceutical composition of claim 1 , wherein upper third , etc . As will also be understood by one skilled in said pharmaceutical composition is in the form of a tablet or the art all language such as " up to , " " at least ," " greater than , ” capsule . “ less than ,” and the like include the number recited and refer 15 12 . The pharmaceutical composition of claim 1 , wherein to ranges which can be subsequently broken down into said pharmaceutical composition comprises from about 25 sub - ranges as discussed above . Finally , as will be under - mg to about 800 mg of said N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H stood by one skilled in the art , a range includes each subject indazol- 3 - yl ) - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 - (tetrahydro member . Thus , for example , a group having 1 - 3 articles pyran - 4 - ylamino ) - benzamide. refers to groups having 1 , 2 , or 3 articles . Similarly , a group 20 13. The pharmaceutical composition of claim 4 , wherein having 1 - 5 articles refers to groups having 1 , 2 , 3 , 4 , or 5 the particle size of said fumaric acid is such that it passes articles , and so forth . through a 60 -mesh screen . Headings , e . g ., ( a ), (b ), ( i ) etc , are presented merely for 14 . The pharmaceutical composition of claim 1 , wherein ease of reading the specification and claims. The use of less than about 2 % of said N - [ 5 - ( 3 , 5 - difluorobenzyl) - 1H headings in the specification or claims does not require the 25 indazol- 3 -yl ) - 4 -( 4 -methyl -piperazin - 1- yl) - 2 -( tetrahydro steps or elements be performed in alphabetical or numerical pyran - 4 -ylamino ) -benzamide degrades in said pharmaceuti order or the order in which they are presented . cal composition after said pharmaceutical composition is The above description discloses several methods and stored for 3 months in an open container at 40° C . and 75 % materials of the present disclosure . The embodiments dis relative humidity . closed herein are susceptible to modifications in themethods 30 15 . A pharmaceutical composition comprising N - [ 5 - ( 3 , 5 and materials , as well as alterations in the fabrication difluorobenzyl) - 1H - indazol- 3 -yl ) - 4 - ( 4 -methyl - piperazin - 1 methods and equipment. Such modifications will become yl) - 2 - ( tetrahydro - pyran - 4 - ylamino ) -benzamide and at least apparent to those skilled in the art from a consideration of one pharmaceutically acceptable excipient , wherein said this disclosure or practice of the embodiments provided pharmaceutical composition is in the form of a tablet or herein . Consequently , it is not intended that the embodi- 35 capsule , and wherein said tablet or capsule has a dissolution ments disclosed herein be limited to the specific embodi- profile wherein at least about 30 % of said N - [ 5 - ( 3 , 5 -difluo ments provided herein , but that it cover all modifications and robenzyl) - 1H - indazol- 3 - yl ] - 4 - ( 4 -methyl - piperazin - 1 - yl) - 2 alternatives coming within the true scope and spirit of the ( tetrahydro - pyran - 4 - ylamino )- benzamide has been released disclosure . from said tablet or capsule at about 60 minutes when tested All references cited herein , including but not limited to 40 in USP Apparatus Type I Basket Method at 50 rpm in 500 published and unpublished applications, patents, and litera - mL of sodium acetate buffer at a pH of 4 . 5 and at about 37° ture references , are incorporated herein by reference in their C . entirety and are hereby made a part of this specification . To 16 . The pharmaceutical composition of claim 1 , wherein the extent publications and patents or patent applications said pharmaceutical composition further comprises mannitol incorporated by reference contradict the disclosure con - 45 or isomalt . tained in the specification , the specification is intended to 17 . The pharmaceutical composition of claim 16 , wherein supersede and /or take precedence over any such contradic - said pharmaceutical composition further comprises starch . tory material. 18 . The pharmaceutical composition of claim 17 , wherein the weight to weight ratio of said mannitol or isomalt to said What is claimed is : 50 starch in said pharmaceutical composition is from about 1 to 1 . A pharmaceutical composition , comprising N - [5 - (3 , 5 - 1 to about 3 to 1 . difluorobenzyl) - 1H -indazol - 3 -yl ] -4 - (4 -methyl - piperazin - 1 - 19 . The pharmaceutical composition of claim 1 , wherein yl) - 2 - ( tetrahydro - pyran - 4 -ylamino )- benzamide and at least said pharmaceutical composition when administered to a one acidulant present in the pharmaceutical composition as subject in a fasted state provides a pharmacokinetic profile a solid admixture . 55 in said subject wherein the Tmax of said N - [ 5 - ( 3 , 5 - difluo 2 . The pharmaceutical composition of claim 1 , wherein robenzyl) - 1H -indazol - 3 -yl ) - 4 -( 4 -methyl -piperazin - 1 - yl) - 2 said at least one acidulant is an organic acidulant . (tetrahydro -pyran -4 -ylamino ) -benzamide in the plasma of 3 . The pharmaceutical composition of claim 1, wherein said subject is between about 2 hours and 6 hours following said at least one acidulant is selected from tartaric acid , said administration of said pharmaceutical composition to maleic acid , fumaric acid , citric acid , and betaine hydro - 60 said subject. chloride . 20 . The pharmaceutical composition of claim 1 , wherein 4 . The pharmaceutical composition of claim 3 , wherein said pharmaceutical composition exhibits no food effect said at least one acidulant is tartaric acid . when administered to a subject . 5 . The pharmaceutical composition of claim 3 , wherein 21 . The pharmaceutical composition of claim 1 further said at least one acidulant is fumaric acid . 65 comprising lactose, hypromellose , crospovidone, microcrys 6 . The pharmaceutical composition of claim 3 , wherein talline cellulose , colloidal silicon dioxide , or magnesium said fumaric acid is in a micronized form . stearate , or any combination of two or more thereof. US 10 , 398 ,693 B2 179 180 22 . The pharmaceutical composition of claim 21 com lulose , crospovidone , colloidal silicon dioxide, and magne prising about 20 % w / w to about 60 % w / w N - [5 - ( 3 , 5 sium stearate , wherein the composition is prepared in a difluorobenzyl) - 1H - indazol- 3 -yl ] - 4 - (4 -methyl - piperazin - 1 method comprising : adding N - [ 5 - ( 3 , 5 -difluorobenzyl ) - 1H - indazol- 3 - yl] - 4 - ( 4 yl) - 2 - ( tetrahydro -pyran -4 -ylamino )- benzamide , about 5 % methyl - piperazin - 1 - yl) - 2 - ( tetrahydro - pyran - 4 w / w / to about 20 % w / w tartaric acid , about 15 % w / w to 5 ylamino ) -benzamide ; anhydrous lactose ; hypromel about 35 % w /w lactose , about 1 % w / w to about 10 % w / w lose ; a first portion of crospovidone ; and tartaric acid hypromellose , about 1 % w / w to about 5 % w / w microcrys together and blending to form a first solid admixture ; talline cellulose , about 1 % w / w to about 10 % w / w crospovi sieving the first solid admixture to form a sieved first solid done , about 0 . 05 % w / w to about 5 % w / w colloidal silicon admixture ; dioxide, and about 0 . 1 % w / w to about 5 % w / w magnesium 10 blending the sieved first solid admixture to form a second stearate . solid admixture ; 23 . The pharmaceutical composition of claim 21 com sieving the second solid admixture to form a sieved prising about 40 % w /w to about 50 % w /w N - [5 - (3 , 5 second solid admixture ; difluorobenzyl) - 1H -indazol - 3 -yl ) -4 - (4 -methyl - piperazin - 1 blending the sieved second solid admixture to form a third yl) - 2 -( tetrahydro -pyran -4 - ylamino )- benzamide , about 10 % solid admixture ; w /w / to about 15 % w /w tartaric acid , about 25 % w / w to adding a first portion of magnesium stearate to the third about 30 % w / w lactose , about 3 % w / w to about 5 w / w solid admixture and blending to form a fourth solid hypromellose (hydroxypropyl methylcellulose ), about 2 % admixture ; w / w to about 4 % w / w microcrystalline cellulose , about 4 % 20 compacting and milling the fourth solid admixture to form w / w to about 7 % w / w crospovidone, about 0 . 1 % w / w to a fifth solid admixture ; about 1 % w / w colloidal silicon dioxide , and about 0 . 5 % w / w adding microcrystalline cellulose , a second portion of to about 2 % w / w magnesium stearate . crospovidone , and colloidal silicon dioxide to the fifth 24 . The pharmaceutical composition of claim 21 , wherein solid admixture and blending to form a sixth solid lactose is anhydrous lactose . 25 admixture ; and 25 . A pharmaceutical composition comprising N - 15 - ( 3 , 5 adding a second portion of magnesium stearate to the difluorobenzyl) - 1H -indazol - 3 -yl ) -4 - (4 -methyl - piperazin - 1 sixth solid admixture and blending to form the phar yl) - 2 - ( tetrahydro -pyran - 4 -ylamino ) -benzamide , tartaric maceutical composition . acid , anhydrous lactose , hypromellose , microcrystalline cel