[go: up one dir, main page]

WO2012027239A1 - Nouveaux dérivés de pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine utilisés comme inhbiteurs de mtor - Google Patents

Nouveaux dérivés de pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine utilisés comme inhbiteurs de mtor Download PDF

Info

Publication number
WO2012027239A1
WO2012027239A1 PCT/US2011/048548 US2011048548W WO2012027239A1 WO 2012027239 A1 WO2012027239 A1 WO 2012027239A1 US 2011048548 W US2011048548 W US 2011048548W WO 2012027239 A1 WO2012027239 A1 WO 2012027239A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
membered
group
pyrazolo
pyrimidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/048548
Other languages
English (en)
Inventor
Lianyun Zhao
Duan Liu
M. Arshad Siddiqui
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Publication of WO2012027239A1 publication Critical patent/WO2012027239A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • This invention is directed to certain pyrazolo[l,5-a]pyrrolo[3,2-e]pyrimidine compounds of Formula (I) as inhibitors of mammalian Target Of Rapamycin (mTOR) kinase, which is also known as FRAP, RAFT, RAPT or SEP.
  • mTOR mammalian Target Of Rapamycin
  • the compounds may be useful in the treatment of cancer and other disorders where mTOR is deregulated.
  • the mammalian target of rapamycin is a central regulator of cell growth and proliferation and plays a gatekeeper role in the control of cell cycle progression.
  • the mTOR signaling pathway which integrates both extracellular and intracellular signals, is activated in certain cellular processes such as tumor formation, angiogenesis, insulin resistance, adipogenesis, and T-lymphocyte activation.
  • the mTOR signaling pathway is deregulated in diseases such as cancer and type 2 diabetes. See Laplante et al., J. Cell Science 122, pp 3589-3593 (2009).
  • mTOR mediates mitogenic signals from PI3K/AKT through to the downstream targets S6K1 (ribosomal S6 kinase 1), 4E-BP1 (eukaryotic translation initiation factor 4E- binding protein) and AKT.
  • S6K1 ribosomal S6 kinase 1
  • 4E-BP1 eukaryotic translation initiation factor 4E- binding protein
  • AKT eukaryotic translation initiation factor 4E- binding protein
  • mTORC2 Since mTORC2 is involved in the regulation of cell survival, metabolism, proliferation, and cytoskeletal organization in a rapamycin-independent manner, complete inhibition of mTOR function through inhibition of both mTORCl and mTORC2 may lead to a broader spectrum antitumor activity in the treatment of cancer or better efficacy. In addition, inhibition of both mTORCl and mTORC2 may lead to better efficacy in treating other diseases than through inhibition of mTORCl alone.
  • the present invention relates to certain pyrazolopyrrolopyrimidine compounds of Formula (I) as inhibitors of mammalian Target Of Rapamycin (mTOR) kinase, which is also known as FRAP, RAFT, RAPT or SEP.
  • mTOR mammalian Target Of Rapamycin
  • the compounds may be used in the treatment of cancer and other disorders where mTOR is deregulated.
  • the present invention further provides pharmaceutical compositions comprising the pyrazolopyrrolopyrimidine compounds.
  • the present invention thus relates to compounds of Formula I and pharmaceutically acceptable salts thereof, as detailed herein:
  • the present invention provides Pyrazolopyrrolopyrimidine Compounds, pharmaceutical compositions comprising a Pyrazolopyrrolopyrimidine Compound, and methods of using the Pyrazolopyrrolopyrimidine Compounds for treating cancer in a patient.
  • the present invention provides methods of using the Pyrazolopyrrolopyrimidine Compounds for treating a disease or disorder associated with deregulated mTOR activity in a patient.
  • M l and M 2 are independently selected from the group consisting of CN, -(CR ⁇ OR 1 , -(CR a R b ) 11 S(0) 2 R 5 , -(C ⁇ S ⁇ 1 , -(CR a R b ) n S(0) 2 NR ! R 2 , -(CR a R b ) felicitNR i S(0) 2 R 4 J -(CR a R b ) n C(0)NR 1 S(0) 2 R 2 , -(CR a R b ) n C(0)R ] J - (CR a R b ) n C(0)OR I , -(CR a R b ) n C(0)NR 1 R 2 ,
  • L and Z are bonded to any two carbons of the ring which M and M are not attached and are independently selected from the group consisting of CH 2 , C(H)(R 10 ) J C(R 10 )(R U ) J N(R 10 ), C(O), O, S, S(0) and S(0) 2;
  • T is not present such that L is bonded directly to Z, or T is selected from the group consisting of CH 2 , C(H)(R 10 ) f C(R 10 )(R n ) ; N(R 10 ), C(O), O, S, S(O) and S(0) 2 and C,-C alkylene, wherein said alkylene of T is unsubstituted or substituted with 1 to two substituents selected from the group consisting of C 1 -C 3 alkyl, halo, hydroxyl, C1-C3 alkoxy, amino, C1-C3 alkylaniino and Ci-C 3 dialkylamino;
  • R a , R b , R c and R d are independently selected from H, halogen and Ci-C 6 alkyl;
  • R 1 , R 2 and R 4 are independently selected from H, OH, halogen, NH 2 , -(CR a R b ) n O(CR c R d ) q R 8 , d-Cealkyl, C C 8 cycloalkyl, C 3 -C 8 cycloalkylC C 6 alkyl, Cg-Cjoaryld-Cealkyl, C 6 -C 10 aryl, 5- to 10-membered heteroarylCi-C 6 alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclylCi-Cealkyl, 5- to 10-membered heterocyclenylCj-C 6 alkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heterocyclenyl, wherein the alkyl, cycloalkyl,
  • cycloalkylalkyl arylalkyl, aryl, heteroarylalkyl, heteroaryl, heterocyclylalkyi
  • heterocyclenylalkyl heterocyclyl or heterocyclenyl is unsubstituted or substituted with one to three moieties which can be the same or different, each moiety being selected from the group consisting of halogen, C,-C 6 alkyl, C 3 -C 8 cycloalkyI, -CF 3; -CN, -C(0)OH, -(CR a R b ) n C(0)OH, - OCF 3 , -OR 9 , -C(0)R 9 , -NR 8 R 9 , -C(0)0-Ci-C 6 alkyl, -C(0)NR 8 R 9 ,
  • R 1 and R 2 form a 3- to 8- membered cycloalkyl, 5- to 6-membered heterocyclyl or 5- to 6- membered heterocyclenyl;
  • R 3 is selected from the group consisting of H, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo-CrCealkyl, -CF3, -C(0)R 9 , Ce-Cioaryl, C3-C 8 cycIoalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclenyl, Cg-Cioar lCi- C 6 alkyl, C3-CgcycloalkylCi-C 6 alkyl, 5- to 10-membered heteroarylQ-Csalkyl, 5- to 10- membered heterocyclylCi-Cgalkyl and 5- to 10-membered heterocyclenylQ-Cealkyl, wherein each of said aryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclenyl, arylalky
  • cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyi and heterocyclenylalkyl is unsubstituted or substituted with one to three moieties which can be the same or different, each moiety being selected from the group consisting of halogen, C Qalkyl, C -C 8 cycloalkyl, -CF 3 , -CN, - C(0)OH, -(CR a R b ) technicallyC(0)OH, -OCF 3 , -(CR a R b ) favorOR 9 , -(CR a R b ) cetC(0)R 9 , -(CR a R b ) n NR 8 R 9 , - (CR a R b ) » NR 8 ,
  • heterocyclenylalkyl is unsubstituted or substituted with one to five moieties, which can be the same or different, each moiety being selected from the group consisting of halogen, Ci-C ⁇ alkyl, C 3 -Cgcycloalkyl, -CF 3 , -CN, -C(0)OH, -(CR a R b ) n C(0)OH, -OCF 3 , -0-haloC r C 6 alkyl, -OR 9 , - C(0)R 9 , -NR 8 R 9 , -C(0)0-Ci-C 6 alkyl s -C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -S(0 2 )NR 8 R 9 , -NR 8 S(0 2 )R 9 , -SR 9 , and -S(0 2 )R 9 ;
  • R 6 and R 7 are independently selected from the group consisting of H, halogen, Ci-C 6 alkyl, C - Cgcycloalkyl. -CF 3 , -CN, -(CR a R b ) admirC(0)OH, -OCF 3 , -OR 9 , -C(0)R 9 , -NR 8 R 9 , -C(0)0-C r C 6 alkyl, -CR a R b , -0R a , -S(0)R a , -C(0)OR a , -S(0 2 )NR a R b , -NR a C(0)R , -NR a S(0 2 )R b ,- C(0)NR 8 R 9 , -SR 9 , and -S(0 2 )R 9 ;
  • R 8 and R 9 are independently selected from the group consisting of H, OH, Ci-C 6 alkyl, C 3 - Cgcycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclenyl, 5- to 10-membered heterocyclyl, C 3 -CscycloalkylCi-C 6 alkyl, Ce-CioarylCrCealkyl, 5- to 10- membered heteroarylCrCealkyl, 5- to 10-membered heterocyclylQ-Csalkyl, 5- to 10- membered heterocyclenylCi-C 6 alkyl, and said alkyl, cycloalkyl, aryl, heteroaryl,
  • heterocyclenyl, heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclenylalkyl or heterocyclylalkyl is optionally substituted with halogen, Ci-C 6 alkyl, C 3 -Cgcycloalkyl, -CF 3 , - CN, -(CR a R ) n C(0)OH, -OCF 3 , -OR a , -C(O), amino, -C(0)0-C r C 6 aikyl, -C(0)NR a R b , -SR a , and -S(0 2 )R a ; or R s and R 9 together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclyl ring;
  • R 10 and R 11 are independently selected from the group consisting of H, C 1 -C 3 alkyl, halo, hydroxyl, CrC 3 alkoxy, amino, Ci-C 3 alkylamino and Ci-C 3 dialkylamino;
  • n is independently 0, 1, 2, 3 or 4;
  • n is independently 0, 1, 2, 3 or 4;
  • q is independently 0, 1, 2, 3 or 4;
  • M 1 and M 2 are independently selected from the group consisting of CN, -(CR a R b ) n OR 1 , _ (CR a R b )nNR i R 2 ; _( CR a R b ) nR i > _(CR a R b ) n SR !
  • L and Z are bonded to any two carbons of the ring which are not attached to M 1 and M 2 and are both CH 2> and T is not present;
  • R a , R b , R c and R d are independently selected from H and Ci-C 6 alkyl;
  • R 1 , R 2 and R 4 are independently selected from H, OH, halogen, -(CR a R b ) n O(CR c R d ) q R 8 , C r C 6 alkyl, C 3 -Cgcycloalkyl, Cs-Cgcycloalkyld-Cealkyl, Cg-QoarylQ-Cealkyl, Q-Qoaryl, 5- to 10-membered heteroarylCi-C 6 alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclylC Cealkyl, 5- to 10-membered heterocyclyl, 5 ⁇ to 10-membered heterocyclenylC ⁇ Qalkyl and 5- to 10-membered heterocyclenyl, wherein the alkyl, cycloalkyl, cycloalkyl lkyl, arylalkyl, aryl, heteroarylalkyl, heteroaryl, heterocyclyiaikyl,
  • R is selected from the group consisting of Ce-Cioaryl, 5- to 10-membered heteroaryl, wherein each of said aryl or heteroaryl is unsubstituted or substituted with one to three moieties which can be the same or different, each moiety being selected from the group consisting of halogen, Ci-C 6 alkyl, C 6 -CioaryI, 5- to 10-membered heteroaryl, -CF 3 , -CN,
  • each of said heteroaryl or aryl is unsubstituted or substituted with one to three moieties, which can be the same or different, each moiety being selected from the group consisting of halogen, C C 6 alkyl, -CF 3i -CN, -C(0)OH, -(CR a R b ) n C(0)OH 5 -OCF 3; -O- haloCi-C 6 aIkyl, -0R a , -C(0)R a , -NR s R b , -C(0)0-Ci-C 6 alkyl, -C(0)NR a R b , -NR a
  • R 6 and R 7 are independently selected from the group consisting of H, -0R a , -NR a R , -SR a , - S(0)R a , -S(0 2 )R a , -C(0)C ] -C 6 alkyl, -C(0)NR a R b , -C(0)OR a , -S(0 2 )NR a R b , -NR a C(0)R b , - NR a S(0 2 )R b , Cj-C 6 alkyl, Cj-C 6 alkoxy, halogen, hydroxy], amino and -CN;
  • R 8 and R 9 are independently selected from the group consisting of H, OH, C f -Cealkyl, C 3 - Cgcycloalkyl, C6-Cjoaryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclenyl, 5- to 10-membered heterocyclyl, Cs-CgcycloalkylCt-Cealkyl, Ce-CioarylCrCealkyl, 5- to 10- membered heteroaryl C r C h alky 1, 5- to 10-membered heterocyclylCj-Cealkyl, 5- to 10- membered heterocyclenylCrCealkyl, and said alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclenylalkyi or heterocyclylalkyl is optionally substituted with halogen
  • n is independently 0, 1 or 2;
  • n 1;
  • q is independently 0, 1, or 2;
  • the compounds of the invention are under formula II or III
  • M ! and M 2 are independently selected from the group consisting of CN, -(CR a R )nOR ! ,
  • R a , R b , R c and R d are independently selected from H and Q-C3 alkyl;
  • R 1 , R 2 and R 4 are independently selected from H, OH, NH 2 , -(CR a R b ) n O(CR°R d ) q R 8 , Q- C 3 alkyl, 5- to 10-membered 5- to 10-membered heteroaryl, 5- to 10- membered heterocyclylCi-C 6 alkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclenylCj-Cealkyl and 5- to 10-membered heterocyclenyl, wherein the alkyl, heteroarylalkyl, heteroaryl, heterocyclylalkyl, heterocyclyl, heterocyclenylalkyi or
  • heterocyclenyl is unsubstituted or substituted with one to three moieties which can be the same or different, each moiety being selected from the group consisting of halogen, Ci-C 6 alkyl, - CF 3 , -CN, -C(0)OH 5 -(CR a R b ) n C(0)OH, -OCF 3?
  • M 1 is -(CR ⁇ Ol R ⁇ CrCs alkyl, -(CR a R b )nO(CR c R d ) q OH, COOH, or -(CR a R ) n C(0)OC 1 -C 3 alkyl;
  • M 2 is selected from the group consisting of CN, -(CR ⁇ OR 1 , -(CR ⁇ NR ⁇ 2 , -(CR a R b ) sanctionR s , -(CR ⁇ SR 1 , -(CR ⁇ SiO ⁇ 1 , -(CR a R b ) n S(0)R', -(CR a R b ) respectfulS(0) 2 NR 1 R 2 ,
  • M and M are independently selected from the group consisting of halo, -OCH 2 CH 2 OCH 3 , ⁇ OCH 2 CH 2 OH , -OCH 3 , -SCH 3 , -OH, ⁇ C(0)OH, - C(0)NHOCH 3i -C(0)NHOH, -C(0)NHCH 2 CH 2 OH, -CONH 2 and -CH 3; and all other substituents are as defined above.
  • M is ⁇ OCH 2 CH 2 OCH 3
  • M is -0CH 2 CH 2 0CH 3j and M is selected from the group consisting of -C(0)OH, -CONH 2 and -C(0)NH0H ; and all other substituents are as defined above.
  • M 1 is -OCBbCHbOCH , -TM0CH 2 CH 2 0H , -OH, -C3 ⁇ 4OH or - CH 2 CH 2 OH, and M 2 is selected from the group consisting of halo, CN, ⁇ 0CH 3?
  • M l is -OH, -CH 2 OH or -CH 2 CH 2 OH
  • M 2 is selected from the group consisting of halo, CN, -OCH 3 , -CH 2 OCH 3 , -SCH 3 , -OCH 2 CH 2 OCH 3 OH, -CH 2 OH, - CH 2 CH 2 OH, -C(0)OH, -C(0)CH 2 OH, -C(0)N(CH 3 ) 2 , -C0NH 2 , -CONHCH3, -C(0)NH0CH 3 , -C(0)N(CH 3 )0CH 3 , -C(0)NH0H, -C(0)NHCH 2 CH 2 OH, -CH 3, -CH 2 S0 2 CH 3 , CH 2 NHS0 2 CH 3> triazolyl, and oxadiazolyl, wherein said triazolyl, or oxadiazolyl are optionally substituted with methyl or halo ; and all other substitu
  • M 1 is -OH, -CH 2 OH or -CH 2 CH 2 0H
  • M 2 is selected from the group consisting of CN, -OCH 3 , -CH 2 OC3 ⁇ 4, -SCH 3 , -OCH 2 CH 2 OCH 3, -OH, -C3 ⁇ 4OH, - CH 2 CH 2 0H, -C(0)OH, -C(0)CH 2 OH, -CH 3 , -CH 2 S0 2 CH 3> CH 2 NHSO 2 CH 3 ; and all other substituents are as defined above.
  • M is ⁇ C(0)OH, and M is selected from the group consisting of halo, CN, NH 2 , -OCH 3 , -C3 ⁇ 4OCH 3; -SCH 3 , -OCH 2 CH 2 OC3 ⁇ 4, -OH, -CH 2 OH, -C3 ⁇ 4CH 2 0H, - C(0)OH, -C(0)C3 ⁇ 4OH, -C(0)N(CH 3 ) 2 , -CONH 2 , -CONHCH 3 , -C(0)NHOCH 3 , - C(0)N(CH 3 )OCH 3> -C(0)NHOH, -C(0)NHC3 ⁇ 4CH 2 OH, -CH 3 , -S0 2 CH 3 , -CH 2 S0 2 CH 3 , CH 2 NHS0 2 CH 3i -OCH 2 CH 2 -mor holinyl, triazolyl and oxadiazolyl, wherein said triazolyl or ox
  • M is-C(0)OH, and M is selected from the group consisting of halo, CN, NH 2 , -OCH 3i -SCH 3 , -CH 3 , -S0 2 CH 3 , -OCH 2 CH 2 -morpholinyl ; and all other substituents are as defined above.
  • R is a 5- to 6-membered heteroaryl or phenyl unsubstituted or substituted with one to three moieties, which can be the same or different, each moiety being selected from the group consisting of halogen, Ci-C 6 alkyl ?
  • alkyl, phenyl or heteroaryl is optionally substituted with one to three moieties, which can be the same or different, each moiety being selected from the group consisting of halogen, Ci-C 6 alkyl, -CF 3> -CN, -C(0)OH, -(CR a R b ) n C(0)OH, -OCF 3 , -O- haloCi-C 6 alkyl, -OR a , -C(0)R a , -NR a R , -C(0)0-Ci-C 6 alkyl, -C(0)NR a R b , -NR a C(0)R b , - S(0 2 )NR a R b , -NR a S(0 2 )R b f -SR a , and -S(0 2 )R a ; and all other substituents are as defined above.
  • R 3 is pyrazolyl, isoquinolinyl, pyrimidinyl, phenyl or pyridyl, unsubstituted or substituted with one to three moieties as defined above.
  • R 3 is unsubstituted or substituted pyrazolyl or pyridyl as defined above.
  • Ar is Ce-Cjoaryl or a 5- to 10-membered heteroaryl optionally substituted with one to three of R 12 , which can be the same or different, each R i2 being selected from the group consisting of halogen, C r C 6 alkyl, -CF 3 , -CN, -C(0)OH, -(CR a R b ) n C(0)OH, ⁇ OCF 3i -0-haloC r C 6 alkyI, - OR a , -C(0)R a , -NR a R b , -C(0)0-Ci-C 6 alkyl, -C(0)NR a R b , -NR a C(0)R b , -S(0 2 )NR a R b , - NR a S(0 2 )R b , -SR a , and -S(0 2 )R a .
  • Ar 1 is phenyl or a 5- to 6-
  • R 3 is
  • R 8 and R 9 are as defined above.
  • R 8 is H and R 9 is cyclopropyl.
  • Ar 1 is phenyl, pyrazolyl, pyrimidinyl, pyridyl, imidazolyl, pyrazinyl or thiazolyl optionally substituted with one to three of R .
  • Ar 1 is phenyl, pyridyl or imidazolyl optionally substituted with one to three of R 12 .
  • R is
  • Ar 1 is is phenyl , pyridyl, pyrazinyl or imidazolyl optionally substituted with one to three of R ! as defined above.
  • R is
  • Ar is is phenyl , pyridyl, pyrazinyl or imidazolyl optionally substituted with one to three of as defined above.
  • R is selected from the group consisting of
  • R is selected from the group consisting of halogen, Ci-C 6 alkyl f -CF 3 , and -OCF 3 . In another embodiment, R is selected from the group consisting of F and methyl.
  • R 6 and R 7 are independently selected from the group consisting of H, halo, -C(0)C]-C 6 alkyl, - S(0)2C C 6 alkyl and CN; and all other substituents are as defined above.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C ⁇ -C ⁇ o as in “Cj-Cio alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement.
  • Ci-Cio alkyl specifically includes methyl, ethyl, w-propyl, /-propyl, rc-butyl, t-butyl, /-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
  • alkyl refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety. In an embodiment, if the number of carbon atoms is not specified, the "alkyl” of “alkylaryl”, “alkylcycloalkyl” and “alkylheterocyclyl” refers to C1-C12 alkyl and in a further embodiment, refers to Cj-C6 alkyl.
  • cycloaikyl means a monocyclic saturated or unsaturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • the cycloaikyl is optionally bridged (i.e., forming a bicyclic moiety), for example with a methylene, ethylene or propylene bridge.
  • the cycloaikyl may be fused with an aryl group such as phenyl, and it is understood that the cycloaikyl substituent is attached via the cycloaikyl group.
  • cycloaikyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and so on.
  • alkyl refers to C1-C12 alkyl and in a further embodiment, “alkyl” refers to C1-C6 alkyl.
  • cycloaikyl refers to C3-C10 cycloaikyl and in a further embodiment, “cycloaikyl” refers to C3-C7 cycloaikyl.
  • alkyl include methyl, ethyl, ij-propyl, /-propyl, w-butyl, /-butyl and /-butyl.
  • alkylene means a hydrocarbon diradical group having the specified number of carbon atoms.
  • alkylene includes -CH2-, -CH2CH2- and the like.
  • alkylene refers to C1-C12 alkylene and in a further embodiment, “alkylene” refers to ⁇ - ⁇ alkylene.
  • alkenyl refers to a non- aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl.
  • alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on.
  • the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • substituents may be defined with a range of carbons that includes zero, such as (C()-C6)alkylene-aryl. If aryl is taken to be phenyl, this definition would include phenyl itself as well as -C3 ⁇ 4Ph, -CH2CH2PI1, CH(CH3)CH2CH(CH3)Ph, and so on.
  • Aryl is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • aryl is an aromatic ring of 6 to 14 carbons atoms, and includes a carbocyclic aromatic group fused with a 5 -or 6-membered cycloalkyl group such as indan.
  • carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, e.g. 1 -naphthyl and 2-naphthyl; anthracenyl, e.g. 1-anthracenyl, 2-anthracenyl;
  • phenanthrenyl e.g. 9-fiuorenonyl, indanyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains carbon and from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • Heteroaryl groups within the scope of this definition include but are not limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heteroaryl examples include, but are not limited to pyridyl, e.g., 2-pyridyl (also referred to as -pyridyl), 3-pyridyl (also referred to as ⁇ -pyridyl) and 4-pyridyl (also referred to as ( ⁇ - pyridyl); thienyl, e.g., 2-thienyl and 3-thienyl; furanyl, e.g., 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and 4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2-pyranyl and 3-pyranyl; pyrazolyl, e.g., 4-pyrazolyl and 5-pyrazolyl; thiazolyl, e.g., 2-thiazolyl, 4-thiazolyl and 5-thiazolyl;
  • heteroaryl may also include a “fused polycyclic aromatic", which is a heteroaryl fused with one or more other heteroaryl or nonaromatic heterocyclic ring.
  • examples include, quinolinyl and isoquinolinyl, e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 4- isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl;
  • benzofuranyl e.g. 2-benzofuranyl and 3 -benzofuranyl
  • dibenzofuranyl e.g. 2,3- dihydrobenzofuranyl
  • dibenzothiophenyl benzothienyl, e.g. 2-benzothienyI and 3- benzothienyl
  • indolyl e.g. 2-indolyl and 3-indolyl
  • benzothiazolyl e.g., 2-benzothiazolyl
  • benzooxazolyl e.g., 2-benzooxazolyl
  • benzimidazolyl e.g. 2-benzoimidazolyl
  • isoindolyl e.g. 1-isoindolyl and 3-isoindolyl
  • benzotriazolyl purinyl; thianaphthenyl, pyrazinyland the like.
  • Heterocyclyl m eans a non-aromatic saturated monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
  • the heterocyclyl contains 3 to 14, or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphor or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the heterocycle may be fused with an aromatic aryl group such as phenyl or heterocyclenyl.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
  • heterocyclenyl means a non-aromatic monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
  • the heterocyclenyl contains 3 to 14, or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen, phosphor or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S- dioxide.
  • suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,
  • An example oiety is pyrrolidinone:
  • heterocyclenyl is independently selected from the specified selection of heteroatoms.
  • alkylaryl group is an alkyl group substituted with an aryl group, for example, a phenyl group. Suitable aryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the aryl group.
  • An "alkylheteroaryl group” is an alkyl group substituted with a heteroaryl group. Suitable heteroaryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heteroaryl group.
  • alkylheterocyclyl group is an alkyl group substituted with a heterocyclyl group. Suitable heterocyclyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heterocyclyl group.
  • alkylheterocyclenyl group is an alkyl group substituted with a heterocyclenyl group. Suitable heterocyclenyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heterocyclenyl group.
  • alkylcycloalkyl group is an alkyl group substituted with a cycloalkyl group. Suitable cycloalkyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the cycloalkyl group.
  • arylalkyl group is an aryl group substituted with an alkyl group, for example, a phenyl group. Suitable aryl groups are described herein and suitable alkyl groups are described herein, The bond to the parent moiety is through the alkyl group.
  • heteroarylalkyl group is a heteroaryl group substituted with an alkyl group. Suitable heteroaryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • heterocyclylalkyl group is a heterocyclyl group substituted with an alkyl group. Suitable heterocyclyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • heterocyclenylalkyl group is a heterocyclenyl group substituted with an alkyl group. Suitable heterocyclenyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • cycloalkylalkyl group is a cycloalkyl group substituted with an alkyl group. Suitable cycloalkyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • aryloxy group is an aryl group that is attached to a compound via an oxygen (e.g., phenoxy).
  • alkoxy group is a straight chain or branched CrCn or cyclic C3-Ci 2 alkyl group that is connected to a compound via an oxygen atom.
  • alkoxy groups include but are not limited to methoxy, ethoxy and propoxy.
  • arylalkoxy group is an arylalkyl group that is attached to a compound via an oxygen on the alkyl portion of the arylalkyl (e.g., phenylmethoxy).
  • arylamino group as used herein, is an aryl group that is attached to a compound via a nitrogen.
  • alkylamino group as used herein, is an alkyl group that is attached to a compound via a nitrogen.
  • an "arylalkylamino group” is an arylalkyl group that is attached to a compound via a nitrogen on the alkyl portion of the arylalkyl.
  • alkylsulfonyl group is an alkyl group that is attached to a compound via the sulfur of a sulfonyl group.
  • substituents When a moiety is referred to as substituted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted.
  • the phrase "optionally substituted with one or more substituents" means, in one embodiment, one substituent, two substituents, three substituents, four substituents or five substituents.
  • the substitutable group can be a hydrogen atom that is replaced with a group other than hydrogen (i.e., a substituent group). Multiple substituent groups can be present. When multiple substituents are present, the substituents can be the same or different and substitution can be at any of the substitutable sites. Such means for substitution are well known in the art.
  • groups that are substituents are: alkyl, alkenyl or alkynyl groups (which can also be substituted, with one or more substituents), alkoxy groups (which can be substituted), a halogen or halo group (F, CI, Br, I), hydroxy, nitro, oxo, -CN, - COH, -COOH, amino, azido, N-alkylamino or ⁇ , ⁇ -dialkylamino (in which the alkyl groups can also be substituted), N-arylamino or ⁇ , ⁇ -diarylarnino (in which the aryl groups can also be substituted), esters (-C(O)-OR, where R can be a group such as alkyl, aryl, etc., which can be substituted), ureas (-NHC(O)-NHR, where R can be a group such as al
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., !4 C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes. For instance those compounds labeled with positron-emitting
  • isotopes like C or F can be useful for application m Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Additionally, isotopic substitution of a compound at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
  • PET Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • stereoisomers When structures of the same constitution differ in respect to the spatial arrangement of certain atoms or groups, they are stereoisomers, and the considerations that are significant in analyzing their interrelationships are topological. If the relationship between two stereoisomers is that of an object and its nonsuperimposable mirror image, the two structures are enantiomeric, and each structure is said to be chiral. Stereoisomers also include diastereomers, cis-trans isomers and conformational isomers. Diastereoisomers can be chiral or achiral, and are not mirror images of one another.
  • Cis-trans isomers differ only in the positions of atoms relative to a specified planes in cases where these atoms are, or are considered as if they were, parts of a rigid structure.
  • Conformational isomers are isomers that can be interconverted by rotations about formally single bonds. Examples of such
  • conformational isomers include cyclohexane conformations with chair and boat conformers, carbohydrates, linear alkane conformations with staggered, eclipsed and gauche confomers, etc. See J. Org. Chem. 35, 2849 (1970)
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms.
  • a chiral carbon can be designated with an asterisk (*).
  • bonds to the chiral carbon are depicted as straight lines in the Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Inglod- Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • the compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both
  • enantiomers and mixtures of enantiomers such as the specific 50:50 mixture referred to as a racemic mixtures.
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other . enantiomer.
  • the "R” forms of the compounds are substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the "S” forms.
  • “S” forms of the compounds are substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the "R'Hforms.
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%. In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of depicted compounds is at least about 90%.
  • a compound of the present invention When a compound of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in diastereoisomeric forms.
  • the compound when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
  • the pairs of enantiomers e.g., (S,S)/(R,R)
  • the stereoisomers that are not mirror-images e.g., (S,S) and (R,S) are diastereomers.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of such compounds and mixtures thereof.
  • an active agent or "a pharmacologically active agent” includes a single active agent as well a two or more different active agents in combination
  • reference to “a carrier” includes mixtures of two or more carriers as well as a single carrier, and the like.
  • This invention is also intended to encompass pro-drugs of the
  • pyrazolopyrrolopyrimidine compounds disclosed herein A prodrug of any of the compounds can be made using well-known pharmacological techniques.
  • pyrazolopyrrolopyrimidine compounds described herein noted above be prepared in the form of their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts organic and inorganic acids, for example, acid addition salts which may, for example, be hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, trifluoroacetic acid, formic acid and the like.
  • Pharmaceutically acceptable salts can also be prepared from by treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. Pharmaceutically acceptable salts can also be formed from elemental anions such as chlorine, bromine and iodine.
  • inorganic bases for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • Pharmaceutically acceptable salts can also be formed from elemental anions such as chlorine, bromine and iodine.
  • the active compounds disclosed can, as noted above, also be prepared in the form of their hydrates.
  • the term "hydrate” includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the
  • the active compounds disclosed noted above also be prepared in the form of a solvate with any organic or inorganic solvent, for example alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone, aromatic solvents and the like.
  • organic or inorganic solvent for example alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone, aromatic solvents and the like.
  • the active compounds disclosed can also be prepared in any solid or liquid physical form.
  • the compound can be in a crystalline form, in amorphous form, and have any particle size.
  • the compound particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.
  • the compounds of the present invention may also exhibit polymorphism.
  • This invention further includes different polymorphs of the compounds of the present invention.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
  • an active agent or "a pharmacologically active agent” includes a single active agent as well a two or more different active agents in combination
  • reference to "a carrier” includes mixtures of two or more carriers as well as a single carrier, and the like.
  • the Pyrazolopyrrolopyrimidine Compounds may be useful in human and veterinary medicine in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and
  • Pyrazolopyrrolopyrimidine Compounds may be useful in the treatment of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases,
  • neurological/neurodegenerative disorders arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease because of their mTOR inhibitory activity.
  • anti-proliferative e.g., ocular retinopathy
  • neuronal e.g., alopecia
  • cardiovascular disease because of their mTOR inhibitory activity.
  • the general value of the compounds of the invention in inhibiting mTOR can be determined, for example, using the assay described in Example 9.
  • the general value in inhibiting mTORCl or mTORC2 function can be evaluated using the assays described in Example 10.
  • Pyrazolopyrrolopyrimidine Compounds can be useful in the treatment of a variety of cancers, including (but not limited to) the following:
  • breast including BRCA-mutated breast cancer
  • colorectal colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
  • leukemia acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma;
  • CLL chronic lymphocytic leukemia
  • astrocytoma neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST”) and schwannomas;
  • melanoma multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoctanthoma, thyroid follicular cancer, endometrial cancer, gastrointestinal tract cancer and Kaposi's sarcoma.
  • inhibitors of kinases could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
  • any disease process e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
  • the Pyrazolopyrrolopyrimidine Compounds may induce or inhibit apoptosis.
  • the apoptotic response is aberrant in a variety of human diseases.
  • Pyrazolopyrrolopyrimidine Compounds, as modulators of apoptosis, can be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including, but not limited to, herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke
  • the Pyrazolopyrrolopyrimidine Compounds as inhibitors of kmases, can modulate the level of cellular RNA and DNA synthesis. These compounds would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
  • viral infections including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.
  • the Pyrazolopyrrolopyrimidine Compounds may also be useful in the chemoprevention of cancer.
  • Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the
  • the Pyrazolopyrrolopyrimidine Compounds may also be useful in inhibiting tumor angiogenesis and metastasis.
  • Another aspect of this invention is a method of treating a patient (e.g., human) having a disease or condition associated with mTOR kmases by administering a therapeutically effective amount of a Pyrazolopyrrolopyrimidine Compound, or a pharmaceutically acceptable salt of said compound to the patient.
  • the present invention also provides the Use of the Pyrazolopyrrolopyrimidine Compounds for the preparation of a medicament for the treatment of cancer.
  • the invention also provides the Pyrazolopyrrolopyrimidine Compounds for use in the treatment of cancer.
  • an example dosage for administration to a patient is about 0.001 to 1000 mg/kg of body weight/day of the Pyrazolopyrrolopyrimidine Compound.
  • Another example dosage is about 0.01 to 25 mg kg of body weight/day of the Pyrazolopyrrolopyrimidine Compound, or a pharmaceutically acceptable salt of said compound.
  • the dosage regimen utilizing the compounds of the present invention can be selected in accordance with a variety of factors including type, species, age, weight, sex and the type of cancer being treated; the severity (i.e., stage) of the disease to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.
  • the term "therapeutically effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutic effect is dependent upon the disease or disorder being treated or the biological effect desired. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disease or disorder and/or inhibition (partial or complete) of progression of the disease.
  • the amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject's response to treatment.
  • a therapeutically effective amount can be an amount that selectively induces terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, or an amount that induces terminal differentiation of tumor cells.
  • the method of the present invention is intended for the treatment or
  • Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • the compounds of the present invention can be administered alone or in combination with other therapies suitable for the disease or disorder being treated. Where separate dosage formulations are used, the compound and the other therapeutic agent can be administered at essentially the same time (concurrently) or at separately staggered times (sequentially).
  • the pharmaceutical combination is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial therapeutic effect of the compound and the other therapeutic agent are realized by the patient at substantially the same time. In an embodiment, such beneficial effect is achieved when the target blood level concentrations of each active drug are maintained at substantially the same time.
  • the instant compounds are also useful in combination with known therapeutic agents and anti-cancer agents.
  • instant compounds are useful in combination with known anti-cancer agents.
  • Combinations of the presently disclosed compounds with other anticancer or chemotherapeutic agents are within the scope of the invention. Therefore, the present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier and optionally other threrapeutic ingredients, such as an anti-cancer agent. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cyto static agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, agents that interfere with cell cycle checkpoints, agents that interfere with receptor tyrosine kinases (RT s) and cancer vaccines.
  • the instant compounds are particularly useful when co-administered with radiation therapy.
  • the instant compounds are also useful in combination with known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, diethylstibestral, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fluoxymestero, lfulvestrant, 4-[7-(2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4- [2-( 1 -piperidinyl)ethoxy]phenyl]-2H- 1 -benzopyran-3-yl]-phenyl- 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • hormonal agents include: aromatase inhibitors (e.g., aminoglutethimide, anastrozole and tetrazole), luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone.
  • aromatase inhibitors e.g., aminoglutethimide, anastrozole and tetrazole
  • LHRH luteinizing hormone release hormone
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a- difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4- carboxyphenyl retinamide.
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of histone deacetylase, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • cytotoxic agents include, but are not limited to, sertenef, cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, tasonermin, lonidamine, carboplatin, altretamine, dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofu!ven, dexifo
  • hypoxia activatable compound is tirapazamine.
  • proteasome inhibitors include but are not limited to lactacystin and bortezomib.
  • microtubule inhibitors/microtubule-stabilising agents include vincristine, vinblastine, vindesine, vinzolidine, vinorelbme, vindesine sulfate, 3',4'-didehydro- 4'-deoxy-8'-norvincaleukoblastine s podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)), paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vmflunme, cryptophycin, 2,3,4,5,6 ⁇ pentafiuoro-N-(3- fluoro-4-methoxyphenyl) benzene sulfonamide, anhydro vinblastine, N,N-dimethyl-L-valyl-L- valyl-N-
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3' s 4'-0-exo-benzylidene-chartreusin, 9-methoxy- N,N-dimethyl-5-nitropyrazolo[3 J 4,5-kl]acridine-2-(6H) propanamine, 1 -amino-9-ethyl-5- fluoro-2,3-dihydro-9-hydroxy-4-methyl- 1 H, 12H-benzo[de]pyrano [3 ' , 4 ' :b,7] - indolizino[l ,2b]quinoline-10,l 3(9H, 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]- (20S)camptothecin, BNP1350, BNPI1100, BN80915, BN
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1 , inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kifl4, inhibitors of Mphosphl and inhibitors of Rab6-KIFL,
  • histone deacetylase inhibitors include, but are not limited to, SAHA, TSA, oxamflatin, PXD101 , G98, valproic acid and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A, et al. J. Med. Chem. 46(24): 5097-5116 (2003).
  • “Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-Rl .
  • PLK Polo-like kinases
  • An example of an "aurora kinase inhibitor” is VX-680.
  • Antiproliferative agents includes anti sense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'- methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro- benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938,
  • simvastatin ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239)
  • pravastatin PRA V ACHOL® ; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589)
  • fluvastatin LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,1 18,853, 5,290,946 and 5,356,896) and atorvastatin
  • HMG-Co A reductase inhibitors see U.S. Pat Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952.
  • the structural formulas of these and additional HMG-Co A reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and
  • HMG-CoA reductase inhibitor as used herein includes all
  • lactone and open-acid forms i.e., where the lactone ring is opened to form the free acid
  • salt and ester forms of compounds which have HMG- Co A reductase inhibitory activity and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and
  • GGPTase-II geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt- 1 (VEGFR1) and Flk-l/ DR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors., MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-a, interleukin-12, erythropoietin (epoietin-a), granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF (sargramostim), pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cycl
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • carboxyamidotriazole combretastatin A-4, squalamine, 6-0- chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin- 1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med.
  • agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679- 692 (2000)).
  • agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80: 10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001)).
  • TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed January 18, 2002).
  • Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • agents include inhibitors of ATR, ATM, the Chkl and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7- hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • agents that interfere with receptor tyrosine kinases refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression.
  • agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met.
  • Further agents include inhibitors of RTKs shown as described by Bume- Jensen and Hunter, Nature, 411 :355-365, 2001.
  • inhibitors of cell proliferation and survival signaling pathway refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of CD20 (rituximab), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K family kinase (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO
  • inhibitors of Raf kinase for example BAY-43-9006
  • inhibitors of ME for example CI-1040 and PD-098059
  • inhibitors of mTOR for example Wyeth CCI-779 and Ariad AP23573.
  • Such agents include small molecule inhibitor compounds and antibody antagonists.
  • Ridaforolimus also known as AP 23573, MK-8669 and deforolimus, is a unique, non-prodrug analog of rapmycin that has antiproliferative activity in a broad range of human tumor cell lines in vitro and in murine tumor xenograft models utilizing human tumor cell lines. Ridaforolimus has been administered to patients with advanced cancer and is currently in clinical development for various advanced malignancies, including studies in patients with advanced soft tissue or bone sarcomas.
  • ridaforolimus is generally well-tolerated with a predictable and manageable adverse even profile, and possess anti-tumor activity in a broad range of cancers.
  • a description and preparation of ridaforolimus is described in U.S. Patent No. 7,091,213 to Ariad Gene
  • Temsirolimus also known as Torisel®, is currently marketed for the treatment of renal cell carcinoma.
  • a description and preparation of temsirolimus is described in U.S. Patent No. 5,362,718 to American Home Products Corporation.
  • Everolimus also known as Certican® or RADOOl, marketed by Novartis, has greater stability and enhanced solubility in organic solvents, as well as more favorable pharmokinetics with fewer side effects than rapamycin (sirolimus).
  • Everolimus has been used in conjunction with microemulsion cyclosporin
  • Apoptosis inducing agents include activators of TNF receptor family members (including the TRAIL receptors).
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat. 5,861,419, U.S. Pat. 6,001,843, U.S. Pat. 6,020,343, U.S. Pat. 5,409,944, U.S. Pat. 5,436,265, U.S. Pat.
  • Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5i3 ⁇ 4-furanone; and 5-chloro-3-(4- methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, ⁇ 862, 5-methoxy-4-[2-methyl-3-(3-methyl-2- butenyl)oxiranyl]-l -oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate J acetyldinanaline, 5-amino- 1 ⁇ [[3,5-dichloro-4-(4-chIorobenzoyl)phenyl]methyl]-l H- 1 ,2,3-triazoIe-4-carboxamide,CM 101 , squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7- (carbonyl-bis[imino-N-methyl-4 J 2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]- carbonylimino]-bis
  • integrated circuit blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological Hgand to the ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological Hgand to both the ⁇ ⁇ 3 integrin and the ⁇ ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ ⁇ 6; ⁇ ⁇ 8 ? ⁇ ⁇ ?
  • the term also refers to antagonists of any combination of ⁇ ⁇ ⁇ 3, ⁇ 5, ⁇ ⁇ 6, ⁇ ⁇ ⁇ 8 > ⁇ ⁇ ⁇ , ⁇ 3 ⁇ 4 ⁇ ⁇ , 5 ⁇ , ⁇ 6 ⁇ and ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N- (trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5- yl)methylidenyl)indolin-2-one, 17-(allylamino)- 17-demethoxygeldanamycin, 4-(3-chloro-4- fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, ⁇ 1382, 2,3,9,10,11,12- hexahydro- 10-(hydroxymethyl)- 10-hydroxy-9-methy 1-9, 12-epoxy- 1 H-diindolo [1,2,3- fg:3',2', -kl]pyrrolo[3,4
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the instantly claimed compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J. Biol. Chem. 1999; 274:91 16-9121 ; Invest.
  • PPAR- ⁇ agonists and PPAR- ⁇ / agonists include, but are not limited to, thiazolidinediones (such as DRP2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT- 501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l 5 2-benzisoxazol-6- yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chloro-4- (4-fluorophenoxy) pheny
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No.
  • Duc-4 Duc-4, NF-1 , NF-2, RB, WT1, BRCA1, BRCA2, a uPA/uPAR antagonist
  • a uPA/uPAR antagonist adenovirus-Mediated Delivery of a uPA uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice
  • interferon gamma J. Immunol. 2000;
  • the compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • a compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • anti-emetic agents especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron,
  • GABAB receptor agonists such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos.
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol
  • an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid.
  • Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147;
  • the neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-( )-(l-(R)-(3,5- bis(trifluoromethy l)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo ⁇ lH,4H- 1,2,4- triazolo)methyl)rnorpholme, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, bacillus Calmette-Guerin, octreotide, isoprinosine and Zadaxin.
  • an immunologic-enhancing drug such as levamisole, bacillus Calmette-Guerin, octreotide, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, mmodronate, neridronate, piridionate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • a compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • aromatase inhibitors include but are not limited to anastrozole, letrozole and exemestane.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination withcompounds which induce terminal differentiation of the neoplastic cells.
  • Suitable differentiation agents include the compounds disclosed in any one or more of the following references.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with ⁇ -secretase inhibitors.
  • a method of treating cancer comprises administering a therapeutically effective amount of a compound of Formula I in combination with radiation therapy and/or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxiccytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR- ⁇ agonists, PPAR- ⁇ agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine
  • the compounds of the instant invention are useful in combination with the following therapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bendamustine hydrochloride (Treanda®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous
  • Busulfex® busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (GHadel®);
  • cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); dalteparm sodium injection (Fragmin®); Darbepoetin alfa (Aranesp®);
  • dasatinib (Spry eel®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); degarelix (Firmagon®);
  • Denileukin diftitox Ontak®
  • dexrazoxane Zinecard®
  • doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone ®); dromostanolone propionate (Masterone Injection®); eculizumab injection (Soliris®); Elliott's B Solution (Elliott's B Solution®); eltrombopag (Promacta®); epirubicin (Ellence®); Epoetin alfa (epogen®);
  • erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP- 16 (Vepesid®); everolimus tablets (Afinitor®); exemestane (Aromasin®); ferumoxytol (Feraheme Injection®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®);
  • fludarabine Fludarabine
  • fiuorouracil 5-FU
  • fulvestrant Fluoride
  • Gefitinib Iressa®
  • gemcitabine Gamzar®
  • gemtuzumab ozogamicin Mylotarg®
  • goserelin acetate Zoladex Implant®
  • goserelin acetate Zoladex®
  • histrelin acetate Histrelin implant®
  • Hydrea® hydroxyurea
  • Zevalin® idarubicin
  • Idamycin® idarubicin
  • IFEX® ifosfamide
  • Gleevec® imatinib mesylate
  • Roferon A® interferon alfa 2a
  • Interferon alfa-2b (Intron A®); iobenguane 1 123 injection (AdreView®); irinotecan
  • mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin- 50®); nelarabine (Arranon®); nilotinib (Tasigna®); Nofetumomab (Verluma®); ofatumumab (Arzerra®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); panitumumab (Vectibix®); pazopanib tablets (Votrienttm®);
  • pegademase Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman
  • romidepsin Istodax®
  • romiplostim plate®
  • sargramostim Leukine®
  • Sargramostim Prokine®
  • sorafenib Nexavar®
  • streptozocin Zanosar®
  • sunitinib maleate Sutent®
  • talc Sclerosol®
  • tamoxifen Nolvadex®
  • temozolomide Temodar®
  • temsirolimus Torisel®
  • te iposide VM-26
  • testolactone Teslac®
  • thioguanine 6-TG
  • Thioguanine® thiotepa
  • topotecan Hycamtin®
  • toremifene Fareston®
  • Tositumomab Bexxar®
  • Tositumomab/I-131 tositumomab Bexxar®
  • Non-Hmiting examples of other suitable anti-cancer agents for combination with the instant compounds are selected from the group consisting of a Cytostatic agent, Cisplatin, Deforolimus (described in PCT publication No. 2003/064383), Doxorubicin, liposomal doxorubicin (e.g., Caelyx®, Myocet®, Doxil®), Taxotere, Taxol, Etoposide, Irinotecan, Camptostar, Topotecan, Paclitaxel, Docetaxel, Epothilones, Tamoxifen, 5-Fluorouracil, Methoxtrexate, Temozolomide, cyclophosphamide, SCH 66336, Rl 15777®, L778,123®, BMS 214662®, Iressa®, Tarceva®, Antibodies to EGFR, antibodies to IGFR (including, for example, those published in US 2005/0136063 published June 23, 2005), ESK inhibitors,
  • Triethylenemelamine Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, Floxuridine, Cytarabine, 6 Mercaptopurine, 6 Thioguanine, Fludarabine phosphate, Oxaliplatin, Leucovirin, ELOXATINTM, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarabicin, Mithramycin, Deoxycoformycin, Mitomycin C, L Asparaginase, Teniposide 17a- Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,
  • the invention provides a method of treating cancer, the method comprising administering an amount of a Pyrazolopyrrolopyrimidine Compound or a pharmaceutically acceptable salt thereof, and an amount of one additional anticancer agent selected from the group consisting of Adriamycin, Altretamine, Amidox, Aminoglutethimide, Amsacrine, Anastrazole, Antibodies to EGFR, 3-AP, Aphidicolon, Ara-C, Arsenic trioxide, L Asparaginase, Bevacizumab, Bleomycin, BMS 214662, Bortezomib, Busulfan, Campath, Camptostar, Capecitabine, Carboplatin, Carmustine, Centrosome associated protein E ("CENP- E”) inhibitors, Cetuximab, Cladribine, Chlorambucil, Chlormethine, Chlorotrianisene,
  • Epothilones Epothilones, ERK inhibitors, Erlotinib, Etoposide, 17 -Ethinylestradiol, Estramustine, Exemestane, Floxuridine, Fludarabine, Fludarabine phosphate, 5-Fluorouracil,
  • Nilotinib Oxaliplatin, Paclitaxel, Panitubimab, Pentostatin, Pipobroman, Porfimer,
  • Triethylenemelamine Triethylenethiophosphoramine, Trimidox, Uracil mustard, Vinblastine, Vincristine, Vindesine, and Vinorelbine.
  • the invention provides a method of treating cancer, the method comprising administering an amount of a Pyrazolopyrrolopyrimidine Compound or a pharmaceutically acceptable salt thereof, and an amount of one or more of a MAP Kinase pathway inhibitor such as bRaf, MEK, or ERK inhibitors to a patient in need thereof.
  • a MAP Kinase pathway inhibitor such as bRaf, MEK, or ERK inhibitors
  • the invention provides a method of treating cancer, the method comprising administering an amount of a Pyrazolopyrrolopyrimidine Compound or a pharmaceutically acceptable salt thereof, and an amount of one or more of ERK inhibitors (for example, compounds described in WO2008/156739, WO2007/070398, WO 2008/156739 and US publication 2007/0232610) to a patient in need thereof.
  • ERK inhibitors for example, compounds described in WO2008/156739, WO2007/070398, WO 2008/156739 and US publication 2007/0232610
  • the invention provides a method of treating cancer, the method comprising administering an amount of a Pyrazolopyrrolopyrimidine Compound or a pharmaceutically acceptable salt thereof, and an amount of one or more of an anti-IGF-lR antibody.
  • Specific anti-IGF-lR antibodies include, but are not limited to, dalotuzumab, figitumumab, cixutumumab, SHC 717454, Roche R1507, EMI 64 or Amgen AMG479.
  • the instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a compound of Formula I and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyi-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and an agent that interferes with a cell cycle checkpoint.
  • a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a compound of Formula I and
  • compositions which comprise at least one Pyrazolopyrrolopyrimidine Compound, or a pharmaceutically acceptable salt of said compound and at least one pharmaceutically acceptable carrier.
  • the Pyrazolopyrrolopyrimidine Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • the present invention provides pharmaceutical compositions comprising an effective amount of at least one Pyrazolopyrrolopyrimidine Compound and a pharmaceutically acceptable carrier.
  • the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.) ; Remington 's
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • the Pyrazolopyrrolopyrimidine Compounds of the present invention may also be delivered transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., anti-cancer activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • the Pyrazolopyrrolopyrimidine Compound is administered orally.
  • the Pyrazolopyrrolopyrimidine Compound is administered intravenously.
  • the Pyrazolopyrrolopyrimidine Compound is administered topically.
  • the Pyrazolopyrrolopyrimidine Compounds is administered sublingually.
  • a pharmaceutical preparation comprising at least one Pyrazolopyrrolopyrimidine Compound is in unit dosage form.
  • the preparation is subdivided into unit doses containing effective amounts of the active components.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Pyrazolopyrrolopyrimidine Compound(s) by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1% to about 70% or from about 5% to about 60% of the Pyrazolopyrrolopyrimidine Compound(s) by weight or volume.
  • the quantity of Pyrazolopyrrolopyrimidine Compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to about 5000 mg. In various embodiments, the quantity is from about 10 mg to about 5000 mg, about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 50 mg.
  • the total daily dosage may be divided and administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24 hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24 hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24 hour period.
  • a total daily dosage of the Pyrazolopyrrolopyrimidine Compounds range from about 0.1 to about 5000 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration. In one embodiment, the dosage is from about 1 to about 200 mg day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 10 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 100 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses.
  • compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one
  • Pyrazolopyrrolopyrimidine Compound or a pharmaceutically acceptable salt thereof (ii) one or more additional therapeutic agents that are not a Pyrazolopyrrolopyrimidine Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat disease or disorder associated with dysregulated mTOR activity, such as a cancer.
  • the present invention also provides methods of using the
  • pyrazolopyrrolopyrimidine compounds of the present invention for inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells thereby inhibiting the proliferation of such cells.
  • the methods can be practiced in vivo or in vitro.
  • the present invention provides in vitro methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells, by contacting the cells with an effective amount of any one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the present invention relates to an in vitro method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells.
  • the method comprises contacting the cells under suitable conditions with an effective amount of one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the invention in another embodiment, relates to an in vitro method of selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting proliferation of such cells.
  • the method comprises contacting the cells under suitable conditions with an effective amount of one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the invention in another embodiment, relates to an in vitro method of selectively inducing apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells.
  • the method comprises contacting the cells under suitable conditions with an effective amount of one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the invention in another embodiment, relates to an in vitro method of inducing terminal differentiation of tumor cells in a tumor comprising contacting the cells with an effective amount of any one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the methods of the present invention can be practiced in vitro, it is contemplated that the preferred embodiment for the methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and of inhibiting mTor will comprise contacting the cells in vivo, i.e., by administering the compounds to a subject harboring neoplastic cells or tumor cells in need of treatment.
  • the present invention provides in vivo methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells in a subject, thereby inhibiting proliferation of such cells in the subject, by administering to the subject an effective amount of any one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the present invention relates to a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells in a subject.
  • the method comprises administering to the subject an effective amount of one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the invention in another embodiment, relates to a method of selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting proliferation of such cells in a subject.
  • the method comprises administering to the subject an effective amount of one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the invention in another embodiment, relates to a method of selectively inducing apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells in a subject.
  • the method comprises administering to the subject an effective amount of one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the invention in another embodiment, relates to a method of treating a patient having a tumor characterized by proliferation of neoplastic cells.
  • the method comprises administering to the patient one or more of the pyrazolopyrrolopyrimidine compounds described herein.
  • the amount of compound is effective to selectively induce terminal differentiation, induce cell growth arrest and/or induce apoptosis of such neoplastic cells and thereby inhibit their proliferation.
  • kits comprising a therapeutically effective amount of at least one Pyrazolopyrrolopyrimidine Compound, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle or diluent.
  • kits comprising an amount of at least one Pyrazolopyrrolopyrimidine Compound, or a pharmaceutically acceptable salt of said compound and an amount of at least one additional anti-cancer agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect.
  • the at least one Pyrazolopyrrolopyrimidine Compound and the at least one additional anticancer agent are provided in the same container.
  • the at least one Pyrazolopyrrolopyrimidine Compound and the at least one additional anti-cancer agent are provided in separate containers.
  • pH concentration of hydronium ions in a solution
  • LiHMDS Lithium bis(trimethylsilyl)amide
  • HMDS hexamethyldisilazane
  • Bu3SnCN tributyltin cyanide Pd[P(t-Bu) 3 ] 2 : bis(tributyl)Phosphme) palladium
  • Pd(PPh 3 )4 tetrakis(triphenylphosphine) palladium
  • UV ultraviolet
  • Step 1 Preparation of ethyl l,4-dioxaspiro[4,5]decane-8-carboxylate
  • the ketone (25 g, 146.9 mmol) was mixed together with p-TsOH (2.85 g, 15 mmol) and ethylene glycol (25 mL) in benzene (300 mL). The mixture was refluxed with D-M trap and stirred overnight. After the concentration to remove the solvent, the residue was taken up with EtOAc (250 mL) and washed with NaHC0 3 (aq.) and brine. The organic was dried over Na 2 S0 4 and concentrated. The crude product was purified with column (silica gel, 0-50% EtOAc/Hexane) to give the product (27.0 g).
  • Step 2 Preparation of ethyl 8-methyl-L4-dioxaspiro[4.5]decane-8-carboxylate
  • Step 3 Preparation of ethyl l-methyl-4-oxocyclohexanecarhoxylate
  • the ketal compound (2.09 g, 9.17 mmol) was dissolved in CAN (100 mL) and water (50 mL).
  • H 4 ) 2 Ce(N03)6 (503 mg, 0.92 mmol) was added in water (50 mL) was added and the mixture was heated up to 70 °C and stirred for 1 hour. After cooling down to room temperature, water (100 mL) was added and extracted with Et 2 0 (100 mL x 3) and the organics was dried over Na 2 S0 4 . After concentration, the crude was purified with column (0-30% EtOAc/Hexane) to give the product (1.72 g).
  • Step 4 Preparation of ethyl l-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3- enecarboxylate
  • Step 5 Preparation of ethyl l-methyl-4-(4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2- yl)cyclqhex-3-enecarboxylate
  • Step 6 Preparation of ethyl 4-(7-(bis((2-(trimethylsiiyl)ethoxy)methyl)amino pyrazolo[l,5-
  • Step 7 Preparation of ethyl 4-(7-(bis((2-(trimethylsilyI)ethoxy)methv amino)pyrazolo l,5- a]pyrimidin-5-yl)- 1 -methylcyclohexanecarboxylate
  • Step 8 Preparation of ethyl 4-f7-(bis((2 (trimethylsilyl)ethoxy)methyl)amino)-3- iodopyrazolo[l,5-a1pyrimidin-5-yl)-l-methylcyclohexanecarboxylate
  • Step 9 Preparation of ethyl 4-r7-(bisff2-(trimethylsilyl)ethoxy)mcthyl amino)-3-(6- fluoroquinolin-3- vDpyrazolo 1 , 5-a]pvrimidin- 5 -y 1)- 1 -methvicyclohexanecarbox l ate
  • Step 10 Preparation of ethyl 4-i7-(bis(f2-(trimethylsilyl)ethoxy)methyl amino -6-bromo-3-(6- fluoroquinolin-3 -vDpyrazolo [ 1 , - ] pyrimidin-5 -y IV 1 -methylcyclohexanecarboxylate
  • Step 11 Preparation of (ZVethyj 4-f7-(bis((2-(trimethylsiIyl)ethoxy)methyl amino -6-(2- ethoxyvinyl)-3 -(6-fluoroquinolm-3 -yl pyrazolo[ 1 , 5 -ajpyrimidin- 5-> ⁇ )-1 - methylcyclohexanecarboxylate
  • Step 12 Preparation of ethyl 4-(3-(6-fluoroquinolin-3-yl -8H-pyrazolo[l,5-alpyrrolo 3,2- e]pyrimidin-5-yl)- 1 -methylcyclohexanecarboxylate
  • Step 13 Preparation of (lj3 ⁇ 4,4J?)-4-(3-(6-fluoroquinolin-3-vl)-8H-pyrazolo[L5-g]pyrrolo 3,2- glpyrimidm-5-yl -l-methylcyclohexanecarboxylic acid (Compound 1) and l 1 g,4i$ r )-4-(3-(6- fluoroquinolin-3-yl)-8H-pyrazolo[1 -a]pyrrolop,2-g]pyrimidin-5-yl)-l- methylcvclohexanecarboxylic acid (Compound 2)
  • Step 1 Preparation of ethyl 4-cyano ⁇ 4 ⁇ hydroxycyclohexanecarboxylate
  • the hydroxyl compound (28.9 g, 146.7 mmol), trimethyloxonium tetrafluoroborate (26.62 g, 180 mmol) and l,8-bis(dimethylamino)naphthalene (38.58 g, 180 mmol) were mixed in dry DCM (500 mL). The resulting mixture was stirred at room temperature overnight and then filtered through celite. The organics was washed with water, brine and dried over Na 2 S0 4 . After concentration, the crude was purified with column (silica gel, 0-30%) to give the product (19 g).
  • Step 5 Preparation of ( 1 R.4RV4-(7-(bis((2- (trimethylsilyl)ethoxy)methyl)amino pvrazolo [ 1 ,5 -alpyrimidin-5-yl)- 1 - methoxycyclohexanecarbonitrile and (lS,4S -4-(7-(bis((2- (trimethylsilyl)ethoxy)methyl)amino)pyrazoIo[L5-a1pyrimidin-5-yl)- 1 - methoxycyclohexanecarbonitrile
  • Step 6 Preparation of (1 S,4S)-4-(7-(bis((2-ftrimethylsilyl)ethoxy methyl)amino)pyrazolof 1 ,5- a] pyrimidin-5 -y I)- 1 -methoxycyclohexanecarboxylic acid
  • the cyano compound isomer 1 (13 g, 24.4 mmol) was dissolved in EtOH (50 mL) and KOH (20%, 30 mL) was added followed by H 2 0 2 (30%, 3.0 mL). The resulting mixture was heated up to 100°C and stirred overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The aqueous pH value was adjusted to ⁇ 6 with 6N HC1 and extracted with EtOAc (300 mL x 3). The combined organics was dried over Na 2 S0 4 and concentrated to give the crude product (9.7 g) and be used in the next step without further purification.
  • the carboxylic acid compound (9.7 g, 17.6 mmol) was dissolved in DCM (150 mL) and TMSCHN 2 (2.0 M in hexane, 24.4 mL) was added. The mixture was stirred at room temperature
  • Step 8 Preparation of lS,4S)-methyl 4-C7-fbis(f2-(tfimethylsilyl)ethoxy methyl)amino)-3- iodopyrazolo[ 1 ,5-a]pyrimidin-5-yD- 1 -methoxycyclohexanecarboxylate
  • Step 9 Preparation of (T S,4S)-methyl 4-(7-fbisf(2-(trimethvlsilvf)ethoxv methyl)amino -3-C6- phenylpyridin-3 - yOpyrazolo [ L 5 -a] pyrimidin-5-yl)- 1 -methoxycyclohexanecarboxylate
  • Step 10 Preparation of (lS,4S)-methyl 4-(7-(bis((2-ftrimethyisilyl)ethoxy methyl amino)-6- bromo-3 -(6-phenyrpyridin-3 -yl)pyrazolo [ 1 , 5 -a] pyrimidin-5-vD- 1 - methoxycyclohexanecarboxylate
  • Step 1 1 Preparation of ilS,4SVmethyl 4-(7-(bisCf2-ftrimethylsilyl)ethoxy)methyl)amino)-6- ((Z)-2-ethoxyvinyl)-3-f6-phenylpyridin-3-yl)pyrazolo[ 5-a]pyrimidin-5-yl)-l- methoxycyclohexanecarboxylate
  • Step 12 Preparation of f lS.4SVmetfayl l-methoxy-4-f3-f6-phenylpyridin-3-vlV8H- pyrazolo[l,5-a]pyrrolo[3,2-e " )pyrimidin-5-yncyclohexanecarboxvlate
  • Step 12 Preparation of flS n 4S)-l-methoxy-4-(3-(6-phenylpyridin-3-yl)-8H-pyrazolo[L5- a]pyrrolo[3,2-e]pyrimidin-5-yl cyclohexanecarboxylic acid (Compound 14)
  • the carboxylic acid was made in example 3 Step 6.
  • the carboxylic acid (3.35 g 5 6.1 mmol) was dissolved in dry THF (50 mL) and cooled to 0°C.
  • the N-methylmorpholine (657 mg, 6.5 mmol) was added followed by the addition of iso-butyl chloroformate (888 mg, 6.5 mmol).
  • the mixture was stirred at 0°C for 2 hours and NaB3 ⁇ 4 (495 mg, 13 mmol) in water (5 mL) was added carefully.
  • the resulting mixture was stirred at 0 °C for 30 min followed by room temperature for another 30 min.
  • the solvent was removed under reduced pressure and extracted with EtOAc.
  • Step, 2 Preparation of (4-(7-(bis((2-(trimethylsilyl ' )ethoxy)methyl)amino -3-iodopyrazolo[l ,5- a]pyrimidin-5-yl)- 1 -methoxycycIohexyDmethanol
  • Step 4 Preparation of f4-(7-(bisf(2-(trimethylsilyl)ethoxy methyl)aminoV6-bromo-3-f6- phenylpyridin-3 - vDpyrazolo [ 1 ,5-a]pyrimidin : 5 ⁇ yl)- 1 -methoxycvclohexyl)methanol
  • Step 5 Preparation of inR,4R -4-f7-rbis(q-(trimethylsilvnethoxy methvnamino)-6-iiZ -2- ethoxyvinyl -3-(6-phenylpyridin.-3-yl)pyrazolo L5-a]pyrimidin-5-yl)-l- methoxycvclohexyDmethanol
  • Step 6 Preparation of (( lR,4R)-l-methoxy-4-r3-(6-phenylpyridin-3-yl)-8H-pyrazolo[l,5- a1pyrrolo[3,2-e1pyrimidin-5-yl)cyclohexyl)methanol (Compound 20)
  • Step 1 Preparation of ethyl 4-methylenecyclohexanecarboxylate
  • Step 3 Preparation of 5-(4-methylenecyclohexyl)-N,N-bis((2- (trimethylsilyl ethoxv)methvl)pyrazolo [ 1 ,5-a]pyrimidin-7-amine
  • Step 4 Preparation of 4-(7-fbis((2-( ' trimethylsiiyl)ethoxy methyl)amino ' )pyrazolo[K5- flf]pyrimidin-5-yl)- 1 -f hydroxymethvDcyclohexanol
  • Step 5 Preparation of 4-(7-(bis((2-(trimethylsilyl ethoxy methvnamino -3-iodopyrazolo L5- ajpyrimidin-5-yl)- 1 -(hydroxymethyl)cyclohexanol
  • Step 7 Preparation of 4-(7-(bisf(2-(trimethylsilynethoxy methyl)amino)-6-bromo-3-f6- phenylpyridin-3-yl pyrazolo[ 1 ,,5-a]pyrimidin-5-yl)- 1 -f hydroxymethyDcyclohexanol
  • the bromo compound was prepared with the same condition described in example 1 Step 10. HPLC-MS T R - 3.06 min (UV 254 nm); mass calculated for formula C 3 6H5 2 BrNs0 4 Si 2 753.3, observed LCMS m/z 754.2 (M+H).
  • Step 8 Preparation of fZV4-(7-fbis(f2-rtrimethylsilyl)ethoxv)methyl amino)-6-(2- ethoxwinyl)-3-(6-phenylpyridin-3-yl pyrazolo[L5-a1pyrimidin-5-yl)- 1 - (hvdroxymethyl)cyclohexanol
  • Step 9 Preparation of l-ihydroxymethvi)-4-(3- 6-phenylpyridin-3-yl -8H-pyrazolo[l,5- i3 ⁇ 4]pyrrolo[3,2-e]pyrimidin-5-yl)cvclohexanol f Compound 22)
  • the mTOR assay buffer contained 10 mM Hepes (pH 7.4), 50 mM NaCl, 100 ⁇ / ⁇ BSA, 50 mM ⁇ -glycerophosphate, 10 mM MnCl 2 and 0.5 mM DTT.
  • An active truncated mTOR enzyme was prepared similarly to that reported by Toral-Barza et al., Biochemical and Biophysical Research Communications 332, pp 304-310 (2005).
  • the reaction was incubated for one hour at 30°C, Anti phospho p70-S6K(Thr389) (-1.7 ng/well, anti-phospho-p70S6K-cryptate (Pho-p70S6- Kin-K cat# 64CUSKAY, from Cisbio)) and anti GST-XL665 (1 :1 Ratio with the substrate GST-S6K, anti GST-XL665, cat# 61GSTXLB) Cisbio) were added after the reaction was stopped.
  • the plates were read (PHERAstar, BMG) at least 2 hours after adding the anti phospho p70-S6K and the anti GST-XL665.
  • PC3 cells prostate tumor cell-line that contains a mutation in the tumor suppressor PTEN, that promotes the phosphorylation and activation of AKT and 4E-BP1 were used in the immunofluorescence assay.
  • PC3 cells were seeded on 384 well plates (black clear bottom, Matrix #4332) overnight.
  • PC3 cells were then treated with 40 ⁇ of the serially diluted test compounds (in 5% fetal bovine serum, F12 medium containing 0.25% DMSO) for ninety minutes at 37°C. The test compound solution was removed, and the plates were washed gently two times with 25 ⁇ phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the cells were fixed by adding 25 ⁇ of Prefer reagent (from Anatech LTD, Cat#414, a glyoxal fixative for fixing proteins within a cell) for sixty minutes followed by three washes with PBS. 5% Goat serum in PBS/0.3% Triton was used to block non-specific binding (60 minutes).
  • Prefer reagent from Anatech LTD, Cat#414, a glyoxal fixative for fixing proteins within a cell
  • the primary antibodies targeting pAKT S473 and p4E-BPl Thr37/46 were diluted into PBS/0.3% Triton and incubated with the cells overnight at 4°C.
  • the antibodies targeting pAKTS473 (Cat# 4085, Cell signaling) and p4E-BPl Thr37/46 (Cat#2855, Cell signaling) were used at a 1 TOO dilution. Plates were washed three times with PBS/0.1% Tween 20 before adding the secondary antibody at a 1 :200 dilution, (goat anti-rabbit containing a fluorescent label, Alexa Fluor 488, Cat# ⁇ 008, Invitrogen) in PBS/0.3% Triton for 60 minutes.
  • Top is the maximum signal without Compound (+ DMSO only) and Bottom represents maximum inhibition.
  • Y is the fluorescence at some compound concentration.
  • the control used to determine the fluorescent intensities for 100% pAKT S473 or 100% phosphorylated p4E-BPl Thr37/46 were measured from untreated wells that contained only DMSO, instead of test compound.
  • Table 5 lists representative compounds of the invention with activity data whereby the IC50 values are rated “A”, “B,” “C,” or “D.”
  • the IC50 values are rated “A” for IC50 values in the range of 1 nM to 100 nM, "B” for IC50 values in the range from 100 nM to 1000 nM, "C” for IC S0 values in the range from 1000 nM to 2000 nM, "D” for IC 50 values in the range from 2000 nM to 5000 nM and "E” for IC 50 values of 5000 nM to 15 ⁇ .
  • This in vitro assay utilizes recombinant His-CHKl expressed in the baculovirus expression system as an enzyme source and a biotinyiated peptide based on CDC25C as substrate (biotin- RSGLYRSPSMPENLNRPR).
  • Staurosporine 100 ⁇ g: CALBIOCHEM, Cat. # 569397
  • concentrations will be 1 ⁇ ATP (cold) and 0.2 ⁇ Ci/reaction.
  • ICsn DETERMINATIONS Dose-response curves were plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC 50 values, the dose-response curves were then fitted to a standard sigmoidai curve and IC50 values were derived by nonlinear regression analysis.
  • BACULOVIRUS CONSTRUCTIONS Cyclin E was cloned into pVL1393 (Pharmingen, La Jolla, California) by PCR, with the addition of 5 histidine residues at the amino-terminal end to allow purification on nickel resin. The expressed protein was approximately 45kDa. CDK2 was cloned into pVL1393 by PCR, with the addition of a haemaglutinin epitope tag at the carboxy-terminal end (YDVPDYAS). The expressed protein was approximately 34kDa in size.
  • ENZYME PRODUCTION Recombinant baculovirases expressing cyclin E and CDK2 were co-infected into SF9 cells at an equal multiplicity of infection (MOI ⁇ S), for 48 hrs. Cells were harvested by centrifugation at 1000 RPM for 10 minutes, then pellets lysed on ice for 30 minutes in five times the pellet volume of lysis buffer containing 50mM Tris pH 8.0, 150mM NaCl, 1% NP40, ImM DTT and protease inhibitors (Roche Diagnostics GmbH, Mannheim, Germany). Lysates were spun down at 15000 RPM for 10 minutes and the supernatant retained.
  • MOI ⁇ S multiplicity of infection
  • Cyclin E/CDK2 kinase assays can be performed as described below in low protein binding 96-well plates (Corning Inc, Coming, New York).
  • Enzyme is diluted to a final concentration of 50 ⁇ in kinase buffer containing 50mM Tris pH 8.0, 10 mM MgCl 2j l mM DTT, and 0.1 mM sodium orthovanadate.
  • the substrate used in these reactions is a biotinylated peptide derived from Histone HI (from Amersham, UK).
  • the substrate is thawed on ice and diluted to 2 ⁇ in kinase buffer.
  • Test compounds are diluted in 10% DMSO to desirable concentrations.
  • 20 ⁇ , of the 50 ⁇ / ⁇ , enzyme solution (1 g of enzyme) and 20 ⁇ of the 2 ⁇ substrate solution are mixed, then combined with 10 ⁇ , of diluted compound in each well for testing.
  • the kinase reaction is initiated by addition of 50 ixL of 2 ⁇ ATP and 0,1 ⁇ of 33 P-ATP (from Amersham, UK).
  • the reaction iss allowed to run for 1 hour at room temperature, then is stopped by adding 200 h of stop buffer containing 0.1% Triton X-100, 1 mM ATP, 5mM EDTA, and 5 mg/mL streptavidine coated SPA beads (from Amersham, UK) for 15 minutes.
  • the SPA beads are then captured onto a 96-well GF/B filter plate (Packard/Perkin Elmer Life Sciences) using a Filtermate universal harvester (Packard/Perkin Elmer Life Sciences.).
  • Nonspecific signals are eliminated by washing the beads twice with 2M NaCl then twice with 2 M NaCl with 1% phosphoric acid.
  • the radioactive signal can then be measured using, for example, a TopCount 96 well liquid scintillation counter (from Packard/Perkin Elmer Life Sciences).
  • ICg DETERMFNATIONS: Dose-response curves are plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound is plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC50 values, the dose-response curves are then fitted to a standard sigmoidal curve and IC50 values can be derived using nonlinear regression analysis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne certains composés de pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine représentés par la formule (I) utilisés comme inhibiteurs de la kinase de la cible de la rapamycine chez les mammifères (mTOR), qui est également connue en tant que FRAP, RAFT, RAPT ou SEP. Les composés peuvent être utilisés pour traiter le cancer et d'autres troubles dans lesquels mTOR est dérégulé. L'invention concerne également des compositions pharmaceutiques comprenant les composés de pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine compounds.
PCT/US2011/048548 2010-08-23 2011-08-22 Nouveaux dérivés de pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine utilisés comme inhbiteurs de mtor Ceased WO2012027239A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37594110P 2010-08-23 2010-08-23
US61/375,941 2010-08-23

Publications (1)

Publication Number Publication Date
WO2012027239A1 true WO2012027239A1 (fr) 2012-03-01

Family

ID=45723756

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/048548 Ceased WO2012027239A1 (fr) 2010-08-23 2011-08-22 Nouveaux dérivés de pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine utilisés comme inhbiteurs de mtor

Country Status (1)

Country Link
WO (1) WO2012027239A1 (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2608669A4 (fr) * 2010-08-23 2014-01-22 Merck Sharp & Dohme Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
WO2023169336A1 (fr) * 2022-03-09 2023-09-14 成都科岭源医药技术有限公司 Composé pyridazine, son procédé de préparation et son utilisation
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12534463B2 (en) 2023-10-20 2026-01-27 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055479A (en) * 1988-06-16 1991-10-08 Sankyo Company, Limited Method of treating cachexia
US6057330A (en) * 1997-02-03 2000-05-02 Pola Chemical Industries, Inc. Pyrrolopyrazolopyrimidine compound and medicine comprising the same as active ingredient
US20050004159A1 (en) * 1999-12-13 2005-01-06 Eisai Co., Ltd. Tricyclic fused heterocyclic compound, process for preparing it and medicament comprising it

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055479A (en) * 1988-06-16 1991-10-08 Sankyo Company, Limited Method of treating cachexia
US6057330A (en) * 1997-02-03 2000-05-02 Pola Chemical Industries, Inc. Pyrrolopyrazolopyrimidine compound and medicine comprising the same as active ingredient
US20050004159A1 (en) * 1999-12-13 2005-01-06 Eisai Co., Ltd. Tricyclic fused heterocyclic compound, process for preparing it and medicament comprising it

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8883801B2 (en) 2010-08-23 2014-11-11 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors
EP2608669A4 (fr) * 2010-08-23 2014-01-22 Merck Sharp & Dohme Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10131667B2 (en) 2012-06-13 2018-11-20 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9745311B2 (en) 2012-08-10 2017-08-29 Incyte Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10040790B2 (en) 2013-04-19 2018-08-07 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US10450313B2 (en) 2013-04-19 2019-10-22 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11014923B2 (en) 2015-02-20 2021-05-25 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10738048B2 (en) 2015-02-20 2020-08-11 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10251892B2 (en) 2015-02-20 2019-04-09 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10214528B2 (en) 2015-02-20 2019-02-26 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10016438B2 (en) 2015-02-20 2018-07-10 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9801889B2 (en) 2015-02-20 2017-10-31 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11173162B2 (en) 2015-02-20 2021-11-16 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US12024517B2 (en) 2018-05-04 2024-07-02 Incyte Corporation Salts of an FGFR inhibitor
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US12473286B2 (en) 2018-05-04 2025-11-18 Incyte Corporation Salts of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12083124B2 (en) 2019-10-14 2024-09-10 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US12168660B2 (en) 2019-12-04 2024-12-17 Incyte Corporation Derivatives of an FGFR inhibitor
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
WO2023169336A1 (fr) * 2022-03-09 2023-09-14 成都科岭源医药技术有限公司 Composé pyridazine, son procédé de préparation et son utilisation
US12534463B2 (en) 2023-10-20 2026-01-27 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors

Similar Documents

Publication Publication Date Title
EP2608669B1 (fr) Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
WO2012027239A1 (fr) Nouveaux dérivés de pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine utilisés comme inhbiteurs de mtor
EP2934535B1 (fr) Pyrrolopyrimidines substituées en tant qu'inhibiteurs de hdm2
EP2770987B1 (fr) Nouveaux composés qui sont des inhibiteurs d'erk
EP2584903B1 (fr) Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk
US9227971B2 (en) Pyrazolo[1,5-a]pyrimidine compounds as mTOR inhibitors
US9351965B2 (en) Indazole derivatives useful as ERK inhibitors
KR20150060724A (ko) Erk 억제제인 신규 화합물
EP2953470B1 (fr) Purines 2,6,7 substituées utilisées en tant qu'inhibiteurs de hdm2
EP2632462A1 (fr) Nouveaux dérivés de hétéroaryl-carboxamide utilisés comme inhibiteurs de la pdk1
EP4161522A1 (fr) Dérivés de pyrazolo [4,3-d]pyrimidine et leurs procédés d'utilisation pour le traitement de troubles prolifératifs cellulaires
EP2736338B1 (fr) Composés tricycliques fusionnés comme inhibiteurs de mtor
US20250059220A1 (en) Substituted benzothiophene derivatives and methods of use thereof
WO2012027240A1 (fr) Inhibiteurs tricycliques fusionnés de la cible de la rapamycine chez les mammifères
EP2608668B1 (fr) Inhibiteurs tricycliques condensés de mtor (mammalian target of rapamycin)
WO2012058174A1 (fr) Nouveaux dérivés thiazole-carboxamide en tant qu'inhibiteurs de pdk1
WO2012047569A1 (fr) Composés tricycliques accolés inhibiteurs de la cible mammifère de la rapamycine
EP2616451A1 (fr) Nouveaux dérivés de thiazol-carboximide en tant qu'inhibiteurs de pdk-1
WO2013016160A1 (fr) Dérivés inédits d'imidazo[1,2-a]pyrazine utilisables en tant qu'inhibiteurs de mtor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11820440

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11820440

Country of ref document: EP

Kind code of ref document: A1