WO2008109104A1 - Inhibiteurs bivalents de protéine kinase akt - Google Patents

Inhibiteurs bivalents de protéine kinase akt Download PDF

Info

Publication number
WO2008109104A1
WO2008109104A1 PCT/US2008/002925 US2008002925W WO2008109104A1 WO 2008109104 A1 WO2008109104 A1 WO 2008109104A1 US 2008002925 W US2008002925 W US 2008002925W WO 2008109104 A1 WO2008109104 A1 WO 2008109104A1
Authority
WO
WIPO (PCT)
Prior art keywords
nhch
formula
ring
chosen
nhc
Prior art date
Application number
PCT/US2008/002925
Other languages
English (en)
Inventor
Hartmuth C. Kolb
Si Wang
Govardhan R. Cherukupalli
Original Assignee
The Regents Of The University Of California
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 The Regents Of The University Of California filed Critical The Regents Of The University Of California
Publication of WO2008109104A1 publication Critical patent/WO2008109104A1/fr

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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • kinase enzymes are ubiquitous and have therefore been the subject of intensive study.
  • the subject of the present invention relates to a specific subgenus of kinase enzymes; Akt kinases and their inhibition as a means for abating cancer.
  • Protein kinases have generated considerable interest in the drug discovery community due to their involvement in key cellular processes, such as signal transduction and cell cycle control. 1"4 Being essential elements in pathways that mediate cell growth, cell division and programmed cell death, malfunctioning protein kinases are often responsible for the deregulation of signaling cascades and the oncogenic transformation of cells. The specific inhibition of such disease-related kinases promises to increase cure rates and to reduce toxic side-effects of chemotherapy.
  • a central issue that must be addressed in the development of protein kinase-based drugs is target-specificity, 5 ' 6 because of the presence of over 500 protein kinases in the human genome.
  • Serine/threonine (Ser/Thr) protein kinase Akt also known as Protein Kinase B (PKB) is involved in the regulation of multiple cellular processes such as glucose metabolism, transcription, apoptosis, cell proliferation, angiogenesis, and cell motility. 10"13 Available data strongly suggests Akt/PKB to be oncogenic, if over-expressed 14 ' 15 or constitutively activated. 16"18 The gain of function in AfVPKB affects two distinct areas of cellular regulation important to cancer, the regulation of apoptosis n ' 16>19"23 and the regulation of cell growth.
  • Akt/PKB inhibits apoptosis principally by down-regulating pro-apoptotic proteins like BAD (Bcl-2/Bcl-XL-antagonist, causing cell death), caspase-9 and forkhead transcription factor (FKHR).
  • BAD Bcl-2/Bcl-XL-antagonist, causing cell death
  • caspase-9 caspase-9
  • FKHR forkhead transcription factor
  • Cancer cells showing a gain in function of Akt are usually high sensitive to inhibitors of the Pl-3k/Akt signaling pathway, making Akt a promising target for drug development.
  • 24 ' 34 ' 56 ' 57 the oncogenic signal from the upstream kinase phosphatidylinositol 3-kinase (P1-3K) 25 ' 58 ' 69 travels through Akt, further increasing the importance of Akt as a cancer target.
  • P1-3K upstream kinase phosphatidylinositol 3-kinase
  • the present disclosure through the following embodiments, iterations, and examples relates to compounds which can provide for selective Akt kinase inhibition.
  • the compounds described herein can interact with the two binding domains of Akt kinases; the ATP binding domain and the substrate binding domain.
  • the Akt kinase inhibitors disclosed herein have the formula:
  • W and Y can be each independently chosen from: i) hydrogen; or ii) Ci-C 6 linear, branched, or cyclic alkyl; Z has the formula: the index b is 0 or 1 ; R can be chosen from: i) substituted or unsubstituted C 3 -C 7 carbocyclic rings; ii) substituted or unsubstituted C 1 -Cg heteroaryl rings; iii) substituted or unsubstituted C 1 -Cg heterocyclic rings; or v) substituted or unsubstituted phenyl; L can have the formula:
  • R 4 is hydrogen, methyl, ethyl, or propargyl; the indices x and y can each be independently from O to 6; the index z is O or 1 ; L 1 has the formula: -[C(R 5a R 5b )] m [R 8 ] q [C(R 6a R 6b )] n [R 9 ] r [C(R 7a R 7b )] p -
  • R 5a , R 5b , R 6a , R 6b , R 7a , and R 7b are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted C]-C 6 linear or branched alkyl; iii) substituted or unsubstituted C 6 aryl; iv) substituted or unsubstituted C 6 -Cg arylalkylene; v) -C(O)OR 10 ; or vi) -C(O)NR 113 R 1 lb ;
  • R 10 , R l la , and R l lb can each be independently chosen from hydrogen or Ci-C 4 linear or branched alkyl;
  • R 8 and R 9 are each independently chosen from: i) -NR 12 -; ii) - NR 12 NR 12 -; iii) -NR 12 C(O)-; iv) -C(O)NR 12 -; v) -C(O)-; vi) -OC(O)-; vii) -C(O)O-; or viii) -S-; and
  • R 12 is independently hydrogen or C1-C4 linear or branched alkyl;
  • the indices m, n, and p can each be independently from 0 to 6;
  • the indices q and r can be each independently 0 or 1.
  • compositions which comprise: a) an effective amount of one or more Akt kinase inhibitors or salts thereof as disclosed herein; and b) one or more excipients.
  • Disclosed herein are methods for treating cancer comprising administering to a patient in need of treatment an effective amount of one or more compounds as described herein.
  • Akt kinase inhibitors Disclosed herein are novel Akt kinase inhibitors, compositions comprising Akt kinase inhibitors, and methods for treating cancer.
  • Akt is a serine-threonine kinase and functions as the central component of the PDK activity thus serves to recruit important cellular signaling pathway that starts with PI 3- kinase (PDK) at the plasma membrane.
  • Akt has two major functional domains, an N- terminal pleckstrin homology domain that mediates lipid membrane interactions and a C- terminal kinase domain.
  • the molecular structure of Akt has been determined.
  • the human genome contains three Akt genes, coding for three closely related proteins, Aktl, Akt2, and Akt3.
  • the three Akt proteins have overlapping functions and activities but also appear to have specific tasks.
  • the pleckstrin homology domain of Akt binds to PIP3, the product of PBK. PBK activity thus serves to recruit Akt to the plasma membrane.
  • Akt enzymatic activity of Akt becomes activated by phosphorylation on threonine 308 in the activation loop and serine 47e in the hydrophobic tail.
  • the two kinases mediating this activation are PDK-I and DNA-dependent protein kinase. Phosphorylation of Akt induces a conformational change that distinguishes the active from the inactive kinase.
  • Akt Akt-activated Akt
  • lung caner An important role of Akt in lung caner is suggested by the fact that about 50 percent of all non-small cell lung caners show enhanced expression of phosphorylated Akt and hence a gain in Akt functions. Included in these 50 percent Akt-positive tumors are those with a mutation in the EGF receptor. That mutation has been reported to be responsible for the constitutive activation of the Akt pathway in these tumors and accounts for the 10 percent of lung cancers that respond to treatment with the EGFR inhibitor Gefitinib.
  • kinase inhibitors function by blocking the ATP binding domain of the enzyme. Because the ATP binding domains of different kinases can be structurally similar, these inhibitors often suffer from a lack of specificity and have unacceptable side effects.
  • the present disclosure relates to the development of Akt inhibitors with high selectivity or high specificity.
  • the compounds disclosed herein can provide a solution to the problem of inhibitor specificity through the design and preparation of bivalent ligand inhibitors. One end of the compounds disclosed herein binds to the ATP binding domain while the other end extends into the substrate binding domain.
  • the substrate binding domain of each kinase is more specific to that particular kinase and the substrate binding domain of each different kinase is located at different distances away from the respective ATP binding domain.
  • the disclosed compounds comprise two separate units; one that can bind to the ATP binding domain and one that can bind to the substrate binding domain. These two units are connected to one another by a linking unit or tether. As discussed herein above, because the distance between these two domains varies from kinase to kinase, the length of the linking unit or tether which connects these two units can be optimized for a particular kinase.
  • This fact provides for compounds disclosed herein that can interact with a particular kinase with a high degree of selectivity, as well as specificity.
  • the methods disclosed herein provide a means for selecting a unit that can effectively interact with a kinase enzyme ATP binding domain, for selecting a unit that can effectively interact with a kinase enzyme substrate binding domain and for a means of forming a link or tether between the two units thereby forming a compound that can be an effective Akt kinase inhibitor.
  • hydrocarbyl stands for any carbon atom-based unit (organic molecule), said units optionally containing one or more organic functional group, including inorganic atom comprising salts, inter alia, carboxylate salts, quaternary ammonium salts.
  • organic hydrocarbyl Within the broad meaning of the term “hydrocarbyl” are the classes “acyclic hydrocarbyl” and “cyclic hydrocarbyl” which terms are used to divide hydrocarbyl units into cyclic and non-cyclic classes.
  • cyclic hydrocarbyl units may comprise only carbon atoms in the ring (carbocyclic and aryl rings) or may comprise one or more heteroatoms in the ring (heterocyclic and heteroaryl).
  • carbocyclic and aryl rings the lowest number of carbon atoms in a ring are 3 carbon atoms; cyclopropyl.
  • aryl the lowest number of carbon atoms in a ring are 6 carbon atoms; phenyl.
  • heterocyclic the lowest number of carbon atoms in a ring is 1 carbon atom; diazirinyl.
  • Ethylene oxide comprises 2 carbon atoms and is a C 2 heterocycle.
  • linear or branched alkyl non-limiting examples of which include, methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), wo-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), /so-butyl (C 4 ), tert- butyl (C 4 ), and the like; substituted linear or branched alkyl, non-limiting examples of which includes, hydroxymethyl (Ci), chloromethyl (Ci), trifluoromethyl (Ci), aminomethyl (C ⁇ ), 1-chloroethyl (C 2 ), 2-hydroxyethyl (C 2 ), 1 ,2-difluoroethyl (C 2 ), 3-carboxypropyl (C 3 ), and the like.
  • linear or branched alkenyl non-limiting examples of which include, ethenyl (C 2 ), 3- propenyl (C 3 ), 1-propenyl ⁇ also 2-methylethenyl) (C 3 ), isopropenyl ⁇ also 2- methylethen-2-yl) (C 3 ), buten-4-yl (C 4 ), and the like; substituted linear or branched alkenyl, non-limiting examples of which include, 2-chloroethenyl ⁇ also 2- chlorovinyl) (C 2 ), 4-hydroxybuten-l-yl (C 4 ), 7-hydroxy-7-methyloct-4-en-2-yl (C 9 ), 7-hydroxy-7-methyloct-3,5-dien-2-yl (C 9 ), and the like.
  • substituted and unsubstituted cyclic hydrocarbyl encompasses 5 categories of units:
  • carbocyclic is defined herein as "encompassing rings comprising from 3 to 20 carbon atoms, wherein the atoms which comprise said rings are limited to carbon atoms, and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms.”
  • substituted and unsubstituted carbocyclic rings which encompass the following categories of units: i) carbocyclic rings having a single substituted or unsubstituted hydrocarbon ring, non-limiting examples of which include, cyclopropyl (C 3 ), 2-methyl- cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), 2,3-dihydroxycyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclopentadienyl
  • C 5 cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cycloheptyl (C 7 ), cyclooctanyl (C 8 ), decalinyl (C 1 O), 2,5-dimethylcyclopentyl (C 5 ), S ⁇ -dichlorocyclohexyl (C 6 ), 4- hydroxycyclohexyl (C 6 ), and 3,3,5-trimethylcyclohex-l-yl (C 6 ).
  • carbocyclic rings having two or more substituted or unsubstituted fused hydrocarbon rings non-limiting examples of which include, octahydropentalenyl (C 8 ), octahydro-lH-indenyl (C 9 ), 3a,4,5,6,7,7a-hexahydro-3i/-inden-4-yl (C 9 ), decahydroazulenyl (C io).
  • carbocyclic rings which are substituted or unsubstituted bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • aryl is defined herein as "units encompassing at least one phenyl or naphthyl ring and wherein there are no heteroaryl or heterocyclic rings fused to the phenyl or naphthyl ring and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms.”
  • substituted and unsubstituted aryl rings which encompass the following categories of units: i) C 6 or C 1O substituted or unsubstituted aryl rings; phenyl and naphthyl rings whether substituted or unsubstituted, non- limiting examples of which include, phenyl (C 6 ), naphthylen-1-yl (Ci 0 ), naphthylen-2-yl (C io), 4-fluorophenyl (C 6 ), 2- hydroxyphenyl (C 6 ), 3-methylphenyl (C 6 ), 2-a
  • heterocyclic and/or “heterocycle” are defined herein as "units comprising one or more rings having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein further the ring which comprises the heteroatom is also not an aromatic ring.”
  • substituted and unsubstituted heterocyclic rings which encompass the following categories of units: i) heterocyclic units having a single ring containing one or more heteroatoms, non- limiting examples of which include, diazirinyl (Ci), aziridinyl (C 2 ), urazolyl (C 2 ), azetidinyl (C 3 ), pyrazolidinyl (C 3 ), imidazolidinyl (C 3 ), oxazolidinyl (C 3 ), isox
  • heterocyclic units having 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-l//-pyrrolizinyl (C 7 ), 3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazolyl (C 7 ), 3a,4,5,6,7,7a-hexahydro-lH- indolyl (C 8 ), 1,2,3,4-tetrahydroquinolinyl (C 9 ), and decahydro-lH- cycloocta[b]pyrrolyl (Cio).
  • heteroaryl is defined herein as "encompassing one or more rings comprising from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein further at least one of the rings which comprises a heteroatom is an aromatic ring.”
  • substituted and unsubstituted heterocyclic rings which encompass the following categories of units: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl (C 1 ), [l,2,3]triazolyl (C 2 ), [l,2,4]triazolyl (C 2 ), triazinyl (C 3 ), thiazolyl (C 3 ), lH-imidazolyl (C 3 ), oxazolyl (C 3 ), furanyl (C 4 ), thioph
  • Ci-C 6 tethered cyclic hydrocarbyl units (whether carbocyclic units, C 6 or C 10 aryl units, heterocyclic units, or heteroaryl units) which connected to another moiety, unit, or core of the molecule by way of a Cj-C 6 alkylene unit.
  • Non- limiting examples of tethered cyclic hydrocarbyl units include benzyl Ci-(C 6 ) having the formula:
  • R a is optionally one or more independently chosen substitutions for hydrogen.
  • Further examples include other aryl units, inter alia, (2- hydroxyphenyl)hexyl C 6 -(C 6 ); naphthalen-2-ylmethyl Ci-(Cio), 4-fiuorobenzyl Ci- (C 6 ), 2-(3-hydroxy-phenyl)ethyl C 2 -(C 6 ), as well as substituted and unsubstituted C 3 -
  • Cio alkylenecarbocyclic units for example, cyclopropylmethyl Cj-(C 3 ), cyclopentylethyl C 2 -(C 5 ), cyclohexyhnethyl C]-(C 6 );. Included within this category are substituted and unsubstituted C 1 -Ci 0 alkylene-heteroaryl units, for example a 2- picolyl Ci-(C 6 ) unit having the formula:
  • Ci-C) 2 tethered cyclic hydrocarbyl units include Ci-C 1O alkyleneheterocyclic units and alkylene-heteroaryl units, non-limiting examples of which include, aziridinylmethyl Cr(C 2 ) and oxazol-
  • Ci-(C 3 ) 2-ylmethyl Ci-(C 3 ).
  • carbocyclic rings are from C 3 to C 2 o; aryl rings are C 6 or do; heterocyclic rings are from Ci to C 9 ; and heteroaryl rings are from Ci to C 9 .
  • fused ring units as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be characterized and referred to herein as being encompassed by the cyclic family corresponding to the heteroatom containing ring, although the artisan may have alternative characterizations.
  • 1,2,3,4- tetrahydroquinoline having the formula: is, for the purposes of the present invention, considered a heterocyclic unit.
  • 6,7-Dihydro- 5i/-cyclopentapyrimidine having the formula: is, for the purposes of the present invent considered a heteroaryl unit.
  • aryl ring When a fused ring unit contains heteroatoms in both a saturated ring (heterocyclic ring) and an aryl ring (heteroaryl ring), the aryl ring will predominate and determine the type of category to which the ring is assigned herein for the purposes of describing the invention.
  • l,2,3,4-tetrahydro-[l,8]naphthyridine having the formula:
  • substituted is used throughout the specification.
  • substituted unit or moiety is a hydrocarbyl unit or moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below.”
  • the units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit.
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • Three hydrogen replacement includes cyano, and the like.
  • substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced.
  • 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring (aryl ring)", (N,N-dimethyl-5-amino)octanyl is a " substituted C 8 linear alkyl unit, 3-guanidinopropyl is a "substituted C 3 linear alkyl unit,” and
  • 2-carboxypyridinyl is a "substituted heteroaryl unit.”
  • units which can substitute for hydrogen atoms on a carbocyclic, aryl, heterocyclic, or heteroaryl unit i) Ci-C 4 linear or branched alkyl; for example, methyl (C 1 ), ethyl (C 2 ), n-propyl
  • each R 30 is independently hydrogen, substituted or unsubstituted C 1 -C 4 linear, branched, or cyclic alkyl; or two R 30 units can be taken together to form a ring comprising 3-7 atoms.
  • Substituents suitable for replacement of a hydrogen atom are further defined herein below.
  • the compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids.
  • anions that can form salts with basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like.
  • cations that can form salts of acidic groups: sodium, lithium, potassium, calcium, magnesium, bismuth, and the like.
  • Akt Kinase Inhibitors The Akt kinase inhibitors disclosed herein have the formula: wherein the following depicts one non-limiting example of the various units of the Akt kinase inhibitors as described herein.
  • the tether/linking unit depicted in the example herein above comprises a triazolyl unit that can be formed by reaction of an azide and an acetylene unit, and a linking unit L, which length can be adjusted by the formulator so that the distance between the ATP binding domain unit and the substrate binding domain unit is optimized for a particular Akt kinase.
  • the Z unit comprises a second linking unit L 1 which length can also be adjusted by the formulator to optimize the distance between binding domains of a particular Akt kinase.
  • the ATP Binding Domain Unit of the compounds disclosed herein can be any analog of Adenosine Triphosphate (ATP)which can effectively bind to the domain of Akt kinase that normally binds ATP.
  • ATP Adenosine Triphosphate
  • the ATP Binding Domain Unit can typically employ a 7,8-disubstituted-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazine derivative as shown above, bonded to the tether/linking unit at the 6 position, and having optional W and Y substituents at the 7 and 8 positions.
  • One to three additional substituents may also optionally be bonded to the phenyl ring, at any position thereon, such as for example independently selected substituents such as hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, OC(O)CH 3 , SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , S(O) 2 NHCH 3 , SC 2 H 5 , methyl, ethyl, propyl, isopropyl, vinyl, allyl, CN, CH 2 OH, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , C(O)H, C(O)CH 3 , methoxy, ethoxy, or isopropoxy groups.
  • substituents such as hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, OC(O)CH 3 , SCH 3 ,
  • W can be chosen from: i) hydrogen; or ii) C 1 -C 6 linear, branched, or cyclic alkyl.
  • W can be hydrogen, W can be methyl,
  • W can be independently chosen from ethyl (C 2 ), n-propyl (C 3 ), /so-propyl (C 3 ), n- butyl (C 4 ), iso-buty ⁇ (C 4 ), sec-butyl (C 4 ), and tert-butyl (C 4 ), W can be independently chosen from cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ), or can be
  • W can be independently chosen from n-pentyl (Cs), 1-methylbutyl (C 5 ), 2-methylbutyl (C 5 ), 3-methylbutyl (C 5 ), 1 ,2-dimethyl-propyl (C 6 ), 1-methylpentyl (C 6 ), 2-methylpentyl (C 6 ), 3- methylpentyl (C 6 ), 4-methyl-pentyl (C 6 ), 1 ,2-dimethylbutyl (C 6 ),l-ethylbutyl (C 6 ), and 1- isopropylpropyl (C 6 ).
  • Y can be chosen from: i) hydrogen; or ii) Cj-C 6 linear, branched, or cyclic alkyl.
  • Y can be cyclobutyl (C 4 ), Y can be hydrogen, Y can be independently chosen from hydrogen, wo-propyl (C 3 ), and cyclobutyl (C 4 ),
  • Y can be methyl (C 1 ),
  • Y can be independently chosen from ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n- butyl (C 4 ), /sobutyl (C 4 ), sec-butyl (C 4 ), and tert-butyl (C 4 ), or
  • Y can be independently chosen from cyclopropyl (C 3 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ), n-pentyl (C 5 ), 1-methylbutyl (C 5 ), 2-methylbutyl (C 5 ), 3-methylbutyl (C 5 ), 1,2-dimethyl-propyl (C 6 ), 1-methylpentyl (C 6 ), 2-methylpentyl (C 6 ), 3-methylpentyl (C 6 ), 4- methyl-pentyl (C 6 ), 1,2-dimethylbutyl (C 6 ),l-ethylbutyl (C 6 ), and l-wo-propylpropyl (C 6 ).
  • L is a linking group which is part of the tether/linking unit that connects the substrate binding domain unit to the 3-phenyl-6-amino-[ 1 ,2,4]triazolo[4,3-&]pyridazinyl ATP binding domain unit.
  • R la , R lb , R 2a , and R 2b can be each independently chosen from: i) hydrogen; or ii) Ci -C4 linear or branched alkyl;
  • R 4 can be hydrogen, methyl, ethyl, or propargyl (-CH 2 CCH);
  • the indices x and y are each independently from O to 6; the index z is O or 1
  • R Ia and R lb can be each independently chosen from hydrogen, methyl, or ethyl, and the index y is from 1 to 3.
  • Non-limiting examples of such L units include units chosen from: i) -CH 2 C(CH 3 ) 2 CH 2 NHCH 2 -; ii) -CH 2 C(CH 3 ) 2 CH 2 NHCH 2 CH 2 -; iii) -CH 2 C(CHa) 2 CH 2 NHCH 2 CH 2 CH 2 -; iv) -CH 2 CH(CH 3 )CH 2 NHCH 2 -; v) -CH 2 CH(CH 3 )CH 2 NHCH 2 CH 2 -; vi) -CH 2 CH(CH 3 )CH 2 NHCH 2 CH 2 CH 2 -; vii) -CH 2 CH 2 CH 2 NHCH 2 -; ii) -CH 2 CH 2 CH 2 NHCH 2 CH 2 -; and iii) -CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 -.
  • L units relates to linking units having the formula: -(CH 2 )C(R 1 V)(CH 2 )NHC(O)[CH 2 J y - wherein R Ia and R lb can be each independently chosen from hydrogen, methyl, or ethyl, and the index y is from 1 to 3.
  • Non-limiting examples of this embodiment of L units include units chosen from: i) -CH 2 C(CH 3 ) 2 CH 2 NHC(O)CH 2 -; ii) -CH 2 C(CH 3 )ZCH 2 NHC(O)CH 2 CH 2 -; iii) -CH 2 C(CHa) 2 CH 2 NHC(O)CH 2 CH 2 CH 2 -; iv) -CH 2 CH(CH 3 )CH 2 NHC(O)CH 2 -; v) -CH 2 CH(CH 3 )CH 2 NHC(O)CH 2 CH 2 -; vi) -CH 2 CH(CH 3 )CH 2 NHC(O)CH 2 CH 2 CH 2 -; vii) -CH 2 CH 2 CH 2 NHC(O)CH 2 -; ii) -CH 2 CH 2 CH 2 NHC(O)CH 2 CH 2 -; and iii) -CH 2 CH 2 CH 2 NHC(O)CH 2 CH 2 -.
  • the Substrate Binding Domain Unit which can be termed the "2" unit, is moiety whose structure is optimized to provide highly specific binding to the Substrate Binding Domain of Akt.
  • R can be chosen from: i) substituted or unsubstituted C 3 -C 7 carbocyclic rings; ii) substituted or unsubstituted C 1 -C 9 heteroaryl rings; iii) substituted or unsubstituted C 1 -C 9 heterocyclic rings; or v) substituted or unsubstituted phenyl.
  • R can be a substituted or unsubstituted Ci, C 2 , C 3 , or C 4 heteroaryl or heterocyclic 5-member ring/
  • R units which can be independently chosen from: i) a pyrrolidinyl ring having the formula; ⁇ ) a pyrrolyl ring having the formula: iii) a 4,5-dihydroimidazolyl ring having the formula: iv) a pyrazolyl ring having the formula: v) an imidazolyl ring having the formula: vi) a [l,2,3]triazolyl ring having the formula: vii) a [1,2,4] triazolyl ring having the formula: viii) tetrazolyl ring having the formula: ix) a [1,3,4] or [l,2,4]oxadiazolyl ring having the formula: x) a pyrrolidinonyl ring having the formula: x) a pyrrol
  • Non-limiting examples of substituted Ci, C 2 , C 3 , or C 4 heteroaryl or heterocyclic 5- member rings can include: i) 3-methylisoxazol-5-yl and 5-methylisoxazol-3-yl having the formulae:
  • R units relates to substituted or unsubstituted C 3 , C 4 or C 5 heterocyclic or heteroaryl 6-member rings, non-limiting examples of which can be independently chosen from: i) a morpholinyl ring having the formula:
  • Non-limiting examples of units which can substituted for one or more hydrogen ring atoms of the C 2 , C 3 , or C 4 heteroaryl or heterocyclic 6-member ring are independently chosen from: a) C 1 -C 4 linear or branched alkyl; b) C 1 -C 4 linear or branched alkoxy; c) -C(O)OR 13 ; or d) -SO 2 NR 14a R 14b ; wherein R 13 ,R 14a , and R 14b are each independently hydrogen, methyl or ethyl.
  • Non-limiting examples of substituted C 3 , C 4 , or C 5 heteroaryl or heterocyclic 6- member rings include: i) 4,6-dimethylpyrimidin-2-yl and 4-hydroxy-6-methylpyrimidin-2-yl having the formulae;
  • R units relates to substituted or unsubstituted C 7 , C 8 or C 9 heterocyclic or heteroaryl fused rings, non-limiting examples of which can be independently chosen from: i) benzoimidazolyl rings having the formula:
  • Non-limiting examples of units which can substitute for one or more hydrogen ring atoms of the C 7 , C 8 , or C 9 heteroaryl or heterocyclic fused rings can be independently chosen from: a) Ci -C 4 linear or branched alkyl; b) Ci -C 4 linear or branched alkoxy; c) -C(O)OR 13 ; or d) -SO 2 NR 14a R 14b ; wherein R 13 ,R 14a , and R 14b can be each independently hydrogen, methyl or ethyl.
  • Non-limiting examples of substituted C 7 , C 8 , or C 9 heteroaryl or heterocyclic fused rings include: i) 2-methylquinazolin-4-yl and 2-methylquinazolinon-3-yl having the formulae:
  • R units relates to substituted or unsubstituted C 3 -C 7 carbocyclic rings independently chosen from cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclobutyl (C 4 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (C 6 ), and cycloheptyl (C 7 ).
  • R units relates to substituted or unsubstituted phenyl
  • units which can substitute for hydrogen include one or more units independently chosen from: a) Ci-C 4 linear or branched alkyl; for example, methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), wo-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), wo-butyl (C 4 ), and tert- butyl (C 4 ); b) Ci-C 4 linear or branched alkoxy; for example, methoxy (Ci), ethoxy (C 2 ), n- propoxy (C 3 ), /sopropoxy (C 3 ), n-butoxy (C 4 ), sec-butoxy (C 4 ), /so-butoxy
  • Non-limiting examples of substituted phenyl units that can be used in preparing the compounds disclosed herein include:
  • R 5a , R 5b , R 6a , R 6b , R 7a , and RTM are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, /so-butyl, 5ec-butyl, benzyl, -C(O)OR 10 ;
  • R 10 is chosen from hydrogen or Ci-C 4 linear or branched alkyl;
  • R 9 is chosen from: i) -NHC(O)-; ii) -C(O)NH-; or i ⁇ ) -S-; the indices m, n, and p each independently have the value from 0 to 4.
  • a first embodiment of L 1 units relates to units having the formula:
  • each R 5a and R 5b is independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, js ⁇ -propyl, iso-butyl, and sec-butyl; and m is from 1 to 4.
  • L 1 Another related embodiment of L 1 relates to compounds which can be connected to the core scaffold by a methylene unit: -CH 2 -.
  • methylene unit -CH 2 -.
  • Z units include units having the formulae:
  • L 1 relates to compounds that can be connected to the core scaffold by alkylene units that are longer than a methylene unit, wherein R 5a and R 5b are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, zso-propyl, iso- butyl, and sec-butyl; for example, unit chosen from: i) -CH 2 CH 2 -; ii) -CH 2 CH 2 CH 2 -; iii) -CH 2 CH 2 CH 2 CH 2 -; iv) -CH 2 CH(CH 3 )CH 2 -; v) -CH 2 CH(CH 3 )CH 2 CH 2 -; vi) -CH 2 CH 2 CH(CH 3 )CH 2 -; and vii) -CH 2 CH[CH 2 CH(CH 3 ) 2 ]CH 2 -.
  • R 5a and R 5b are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, zso-propy
  • L 1 units relates to units having the formula:
  • L 1 relates to compounds wherein the indices m and n can each be equal to 1 thereby providing L 1 units having the formula:
  • -CHR 5a C(O)NHCHR 6a non-limiting examples of which can be chosen from: i) -CH 2 C(O)NHCH 2 -; ii) -CH(CH 3 )C(O)NHCH 2 -; iii) -CH 2 C(O)NHCH(CH 3 )-; iv) -CH(CH 3 )C(O)NHCH(CH 3 )-; v) -CH[CH(CH 3 ) 2 ]C(O)NHCH 2 -; vi) -CH 2 C(O)NHCH[CH(CH 3 ) 2 ]-; vii) -CH[CH(CH 3 ) 2 ]C(O)NHCH[CH(CH 3 ) 2 ]-; v) -CH[CH(CH 3 ) 2 C(O)NHCH(CH 3 )-; vi) -CH(CH 3 )C(O)NHCH[CH(CH 3 ) 2 ]-; vii)
  • the L 1 units of this aspect can have any stereochemical formula which the formulator chooses, for example, the L 1 unit having the formula:
  • L 1 relates to compounds wherein R 5b and R 6b can both be hydrogen and at least one of the indices m or n is equal to 2 thereby providing L 1 units having the formula: i) -(CHR 5a )C(O)NH(CHR 6a ) 2 -; ii) -(CHR 5a ) 2 C(O)NH(CHR 6a )-; or iii) -(CHR 5a ) 2 C(O)NH(CHR 6a ) 2 -.
  • Non-limiting examples of this aspect of this embodiment of L 1 include: i) -CH 2 C(O)NHCH 2 CH 2 -; ii) -CH(CH 3 )C(O)NHCH[CH(CH 3 )CH(CH 3 ) 2 ]CH 2 -; iii) -CH(CH 2 C6H 5 )C(O)NHCH[CH(CH 3 )CH(CH3) 2 ]CH2-; iv) -CH(CH 2 C 6 H 5 )C(O)NHCH[CH(CH 3 ) 2 ]CH 2 -; v) -CH(CH 2 OH)C(O)NHCH[CH 2 CH(CH 3 ) 2 ]CH 2 -; vi) -CH(CH 3 )C(O)NHCH[CH 2 CH(CH 3 ) 2 ]CH 2 -; vii) -CH[CH(CH 3 ) 2 ]C(O)NHCH[CH 2 CH(CH 3 ) 2 ]CH 2
  • L 1 units taken together with R units provides for the following non-limiting examples of Z units having the formulae:
  • L 1 units relates to units having the formula: -[C(R 5a R 5b )] m C(O)NH[C(R 6a R 6b )] n - wherein each R 5a , R 511 , R 6a , and R 6b can be independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, /so-propyl, w ⁇ -butyl, sec-butyl, and benzyl; and at least one R 5a or R 6a can be a unit having the formula: -C(O)OR 10 ; R 10 can be chosen from hydrogen, methyl, or ethyl; and the indices m and n are each independently from 1 to 4.
  • Non-limiting examples of this embodiment of L 1 include: i) -CH 2 C(O)NHCH(CO 2 CH 3 )-; ii) -CH(CO 2 CH 3 )C(O)NHCH 2 -; iii) -CH(CH 3 )C(O)NHCH(CO 2 CH 3 )-; iv) -CH(CO 2 CH 3 )C(O)NHCH(CH 3 )-; v) -CH(CH 3 )C(O)NHCH(CO 2 CH 3 )CH 2 -; and vi) -CH(CO 2 CH 3 )CH 2 C(O)NHCH 2 CH 2 -.
  • Another related embodiment of L 1 units relate to units having the formula:
  • R 5a , R 513 , R 6a , R 6b , R 7a , and R 715 can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, zso-propyl, w ⁇ -butyl, sec-butyl, benzyl, -C(O)OR 10 ;
  • R 10 can be chosen from hydrogen or Ci-C 4 linear or branched alkyl;
  • R 9 can be chosen from: i) -NHC(O)-; ii) -C(O)NH-; or iii) -S-; the indices m, n, and p independently have the value from O to 4.
  • L 1 units Another related embodiment of L 1 units relates to compounds having the formula:
  • R 5a , R 6a , R 6b , and R 7a can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, iso-butyl, sec-butyl, benzyl, and -C(O)OR 10 ; the indices m and p are equal to 1 and the index n is equal to 1 or 2.
  • Non-limiting examples of this embodiment of L 1 units include: i) -CH 2 C(O)NHCH(CO 2 CH 3 )CH 2 SCH 2 -; ii) -CH 2 C(O)NHCH 2 CH(CO 2 CH 3 )SCH 2 -; iii) -CH 2 C(O)NHCH(CO 2 CH 3 )CH 2 SCH(CH 3 )-; iv) -CH 2 C(O)NHCH 2 CH(CO 2 CH 3 )SCH(CH 3 )-; v) -CH(CH 3 )C(O)NHCH(CO 2 CH 3 )CH 2 SCH 2 -; and vi) -CH(CH 3 )C(O)NHCH 2 CH(CO 2 CH 3 )SCH 2 -.
  • L 1 units relates to compounds having the formula: -C(R 5a H)C(O)NH[C(R 6a R 6b )] , -2 NHC(R 7a H)- wherein R 5a , R 6a , R 6b , and R 7a can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, /so-propyl, iso-butyl, sec-butyl, benzyl, and -C(O)OR 10 ; the indices m and p are equal to 1 and the index n is equal to 1 or 2.
  • Non-limiting examples of this aspect of this embodiment of L ⁇ units include: i) -CH 2 C(O)NHCH(CO 2 CH 3 )CH 2 NHCH 2 -; ii) -CH 2 C(O)NHCH 2 CH(CO 2 CH 3 )NHCH 2 -; iii) -CH 2 C(O)NHCH(CO 2 CH 3 )CH 2 NHCH(CH 3 )-; iv) -CH 2 C(O)NHCH 2 CH(CO 2 CH 3 )NHCH(CH 3 )-; v) -CH(CH 3 )C(O)NHCH(CO 2 CH 3 )CH 2 NHCH 2 -; and vi) -CH(CH 3 )C(O)NHCH 2 CH(CO 2 CH 3 )NHCH 2 -.
  • a further aspect of this embodiment of L 1 units relates to compounds having the formula:
  • R 5a , R 6a , R 6b , and R 7a can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, /s ⁇ -propyl, iso-butyl, sec-butyl, benzyl, and -C(O)OR 10 ; the indices m and p are equal to 1 and the index n is equal to 1 or 2.
  • Non-limiting examples of this embodiment of L 1 units include: i) -CH 2 C(O)NHCH(CO 2 CH 3 )CH 2 C(O)CH 2 -; ii) -CH 2 C(O)NHCH 2 CH(CO 2 CH 3 )C(O)CH 2 -; iii) -CH 2 C(O)NHCH(CO 2 CH 3 )CH 2 C(O)CH(CH 3 )-; iv) -CH 2 C(O)NHCH 2 CH(CO 2 CH 3 )C(O)CH(CH 3 )-; v) -CH(CH 3 )C(O)NHCH(CO 2 CH 3 )CH 2 C(O)CH 2 -; and vi) -CH(CH 3 )C(O)NHCH 2 CH(CO 2 CH 3 )C(O)CH 2 -.
  • R 6a , R 6b , and R 7a are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, wo-butyl, .fee-butyl, benzyl; the index n is equal to 1 or 2 and the index p is equal to O or 1.
  • Non-limiting examples of this aspect of this embodiment of L 1 units include: i) -CH 2 SCH 2 -; ii) -CH 2 CH 2 SCH 2 -; iii) - CH 2 CH 2 SCH(CH 3 )-; iv) - CH 2 CH[CH(CH 3 )ISCH 2 CH 2 -; v) -CH 2 S-; and vi) -CH 2 CH 2 S-. All L units disclosed herein can be present either in their racemic form, for example, a unit having the formula:
  • L 1 units having the formula:
  • the compounds disclosed herein can be assembled using a process wherein the unit that comprises the ATP binding domain unit and the unit that comprises the substrate binding domain unit are linked together through the tether/linking unit.
  • One manner in which this connecting of binding domain units can be affected is by a process known as "click" chemistry.
  • This chemical reaction is between a compound comprising an acetylene unit and a compound comprising an azide unit.
  • the click chemistry forms a [l,2,3]triazolyl unit which can have two different substitution patterns depending upon which compound comprises the azide unit and which comprises the acetylene unit. This method serves as a convenient and facile means for joining the two separate units.
  • 3-phenyl-6-amino-[l,2,4]triazole[4,3-6]pyridazinyl is an example of an Akt enzyme ATP binding domain unit and this unit comprises an azide unit.
  • the Akt enzyme substrate binding domain unit comprises an acetylene unit.
  • This non-limiting example depicts the manner in which the two binding domain units are combined to form the final Akt kinase inhibitor.
  • the reaction is typically conducted in the presence of sodium ascorbate and CuSO 4 at room temperature for approximately 12 hours. However, the conditions can be modified by the formulator to fit the specific molecules undergoing reaction.
  • ATP binding domains are found in most of the known kinases. Although ATP is a specific molecule, the structure of the ATP binding domain is not conserved among kinase species, therefore, one aspect of the present invention which provides increased specificity and selectivity to the final bivalent ligand compounds relates to identifying a unit which binds more tightly and selectively to the ATP binding domain of ATP binding domain-containing kinases. Precursors of these ATP binding domain units prior to connection to the substrate binding domain units, can have the formulae:
  • an azide moiety or an acetylene moiety provides one half of the two units which are reacted together to form a [l,2,3]triazole thereby linking the two portions of the final molecule together.
  • Non-limiting examples of ATP binding domain units that can be suitable for combining with a variety of substrate binding domain units include:
  • Table A below provides examples of Akt-1 inhibition for various units within the first embodiment of ATP binding domain units disclosed herein.
  • acetylenyl (terminal acetylene unit) comprising compounds having the formula:
  • Non-limiting examples of ATP binding domain units of this embodiment that are suitable for testing as ATP binding domain units in bivalent kinase inhibitors include:
  • Table B below provides examples of Akt-1 inhibition for various units within this further embodiment of ATP binding domain units disclosed herein.
  • the ATP binding domain units disclosed herein either comprise an azide unit or an acetylene unit for use in forming the [l,2,3]triazole linkage.
  • the core scaffold of the ATP binding domain units can be prepared by the following general procedure outlined herein below in Scheme I.
  • Reagents and conditions (a) H 2 SO 4 , (NHj) 2 S 2 O 8 , AgNO 3 , H 2 O.
  • Reagents and conditions (b) TEA HCl, p-xylene, 130 0 C.
  • Starting materials of type A can be made by the same procedure utilizing 3,6- dichloro-pyridazine and the acid WCO 2 H, or the starting materials can be purchased.
  • the formulator can then attach a selected linker comprising either an acetylene or an azide moiety.
  • Scheme II herein below depicts one of many general schemes useful for preparing and attaching a linking unit comprising an acetylene moiety to the core 3-phenyl- [l,2,4]triazolo[4,3-b]pyridazinyl ATP binding domain unit.
  • Scheme III herein below is a further non-limiting example of forming and attaching a linking unit which comprises an acetylene moiety to the core 3-phenyl-[l,2,4]triazolo[4,3- bjpyridazinyl ATP binding domain unit.
  • Reagents and conditions (b): dioxane; 80 0 C, 12 hr.
  • Scheme IV herein below depicts one of many general schemes useful for preparing and attaching a linking unit comprising an azide moiety to the core 3-phenyl- [l,2,4]triazolo[4,3-b]pyridazinyl ATP binding domain unit.
  • the substrate binding domain units disclosed herein either comprise an azide unit or an acetylene unit for use in forming the [l,2,3]triazole linkage.
  • a non-limiting example of the preparation of a substrate binding domain unit is depicted herein below in Scheme V.
  • Reagents and conditions (a) CuSO 4 , sodium ascorbate, MeOH; rt.
  • Reagents and conditions (c) NaN 3 , DMF; rt. This procedure depicts a substituted (R 30 unit containing) [l,2,3]triazole R unit, wherein the L 1 unit is methylene (-CH 2 -).
  • L 1 is a unit having the formula: wherein R 5a , R 5b , R 6a , and R 6b are defined herein above.
  • Units of this type can be prepared according to the general procedure outlined herein below in Scheme VI.
  • R 30 is hydrogen or a substitution for hydrogen as described herein above.
  • Reagents and conditions (e) EDCI, HOBt, NaHCO 3 , THF; rt
  • the compounds (compounds) of the present invention are arranged into several Categories to assist the formulator in applying a rational synthetic strategy for the preparation of compounds which are not expressly exampled herein.
  • the arrangement into Categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.
  • Category I of the compounds disclosed herein relates to Akt kinase inhibitors having the formula:
  • R units which are C 2 , C 3 , or C 4 substituted or unsubstituted 5-member heterocyclic or heteroaryl units and Y units are further described herein below in Table I.
  • Reagents and conditions (a) H 2 SO 4 , (NH 4 ⁇ S 2 O 8 , AgNO 3 , H 2 O; 70 0 C.
  • Reagents and conditions (d) DBU; 25 0 C, 18 hr.
  • Reagents and conditions (f) Na ascorbate, CuSO 4 , MeOH/H 2 O; 25 0 C, 18 hr.
  • the aqueous layer was basified by the addition of solid K 2 CO 3 . Some dark insoluble solid was removed by filtration at this stage and the aqueous layer was then extracted with dichloromethane (300 mL). The combined extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient of hexane/ethyl acetate 5% - 40%) to yield the desired compound (12.46 g, 36%) as a white solid.
  • cyclobutane carboxylic acid can be substituted by acetic acid (C 2 ), propanoic acid (C 3 ), isobutyric acid (C 4 ), and the like.
  • step (c) 5-bromopent-l-yne can be substituted by 4-bromobut-l-yne, 3- bromoprop-1-yne (propargyl bromide), and the like, hi step (f) the heteroaryl or heterocyclic azides describe herein above in the section describing substrate and further exampled herein can be substituted for 4-(azidomethy)-3-methyl-5-phenylisoxazole.
  • Category II relates to compounds having the formula:
  • L 1 can be a unit having the formula: -[C(R 5a R 5b )] m C(O)NH[C(R 6a R 6b )] n - wherein R 5a , R 5b , R 6a , R 6b , and the indices m and n are further described herein below in Table II and R units are C 2 , C 3 , or C 4 substituted or unsubstituted 5-member heterocyclic or heteroaryl units.
  • Reagents and conditions (f): EDCI, HOBt, DMF, NaHCO 3 , rt.
  • reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours before being poured into ice.
  • aqueous phase was extracted with dichloromethane (2 x 200 mL).
  • the combined organic extracts were washed with brine (200 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the residue was purified by flash chromatography on silica gel (ethyl acetate/hexane 10%- 30%) to afford 9.72 g of the desired compound (71%) as an oil.
  • Akt kinase inhibitors The following are non-limiting examples of other Akt kinase inhibitors:
  • N 1 (7-Cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-6]pyridazin-6-yl)-2,2-dimethyl-N 3 -(3- ⁇ l-[(3,5-dimethyl-lH-pyrazol-l-yl)methyl]-lH-l,2,3-triazol-4-yl ⁇ propyl)propane-l,3- diamine: ESI-MS: m/z 568 [M+ ⁇ ].
  • Activated Akt has numerous and diverse functions that affect a broad spectrum of cellular activities related to growth, survival and differentiation. Because it was first isolated as the oncoprotein transduced by a leukemogenic murine retrovirus, its inhibition can be seen to inhibition can be seen as a potential for halting oncogenic transformation in cells.
  • the compounds of the present invention are effective in the following disease states or conditions: i) as binary targeted Akt kinase inhibitors providing kinase specific inhibition of EGF receptor (EGFR) tyrosine kinase and thereby induces regression in lung cancers that carry a specific EGFR mutation; ii) Akt has been found to inhibit cell apoptosis by the following mechanisms: a) down-regulating pro-apoptotic proteins; b) stimulating translation through Target of Rapamycin (TOR); c) by promoting transcription via nuclear factor KB (NFKB); d) interfering with cyclin-dependent kinase inhibitor p27; and e) interfering with the tumor suppressor FoxOl . 60"73
  • Akt activity in cancer cells can result in resistance to drug-induce apoptosis and enhances cell replication.
  • Inhibition of Akt activity can provide a means of treating cancers, inter alia, breast, lung, colorectal, and prostate.
  • Each of the disease states or conditions which the formulator desires to treat can require differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the testing procedures known to the artisan.
  • the present disclosure further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, can release the compounds described herein.
  • One iteration of this aspect includes the pharmaceutically acceptable salts of the compoundcompounds described herein.
  • the formulator for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present compoundcompounds over another since the compounds themselves are the active species which mitigate the disease processes described herein.
  • compositions or formulations which comprise the Akt kinase inhibitors according to the present invention.
  • the compositions of the present invention comprise: a) an effective amount of one or more Akt kinase inhibitors or salts thereof as described herein; and b) one or more excipients.
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • compositions according to this disclosure include: a) from about 0.001 mg to about 1000 mg of one or more Akt kinase inhibitors according to the present invention; and b) one or more excipients.
  • compositions a) from about 0.01 mg to about 100 mg of one or more Akt kinase inhibitors according to the present invention; and b) one or more excipients.
  • a further embodiment according to this disclosure relates to the following compositions: a) from about 0.1 mg to about 10 mg of one or more Akt kinase inhibitors according to the present invention; and b) one or more excipients.
  • an effective amount means "an amount of one or more 1-N- amino-2-imidazolidinones, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result.”
  • An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated.
  • dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the compositions of this disclosure can be administered as frequently as necessary to achieve a therapeutic amount.
  • This disclosure also relates to a method for controlling cancer, inter alia, breast cancer, lung cancer, colorectal cancer, prostate cancer, and the like.
  • the disclosed method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the Akt kinase inhibitors according to this disclosure.
  • This disclosure relates to:
  • a method for treating cancer comprising administering to a patient in need of treatment an effective amount of one or more compounds as described herein.
  • the present invention also relates to the use of the Akt kinases according to this disclosure in the manufacture of a medicament for the treatment of cancer and related disorders.
  • the present invention relates to a method for treating cancer in a mammal, said method comprising administering to said mammal an effective amount of one or more Akt kinases according to this disclosure.
  • the present invention relates to a method for treating cancer in a human, said method comprising administering to said human an effective amount of one or more Akt kinases according to this disclosure.
  • the present invention relates to a method for inhibiting Akt kinase activity in humans comprising administering to said human an effective amount of one or more Akt kinases according to this disclosure.
  • the compounds of the present invention can be used in the manufacture of one or more medicaments, non-limiting examples of these medicaments are:
  • a compound for use in the manufacture of a medicament for the treatment of breast cancer A compound for use in the manufacture of a medicament for the treatment of lung cancer.
  • a compound for use in the manufacture of a medicament for the treatment of colorectal cancer is provided.
  • PROCEDURES A compound for use in the manufacture of a medicament for the treatment of prostate cancer.
  • the assay for Akt inhibitors was performed using the K-LISA Akt activity kit from Calbiochem (Cat. No. CBAOl 9), which is a rapid, sensitive, ELISA-based (Enzyme- Linked-Immunosorbent- Assay) activity assay. It utilizes a biotinylated peptide substrate (Crosstide, i.e., GRPRTSSFAEG) that is phosphorylated on the second serine by Aktl, Akt2, Akt3.
  • a biotinylated peptide substrate Rosstide, i.e., GRPRTSSFAEG
  • biotinylated Akt substrate and sample containing Akt are incubated in the presence of ATP in wells of a streptavidin-coated 96-well plate, which allows for phosphorylation and substrate capture, through biotine-streptavidine binding, in a single step.
  • the extent of phosphorylation is detected colorimetrically with an anti-phosphoserine antibody.
  • Akt IC 50 values for compounds disclosed herein.
  • Non-small cell lung cancers frequently express phosphorylated Akt; an immunohistochemical study. APMIS 110, 587-592 (2002).
  • AKT proto-oncongene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 23, 201-205 (2002).
  • AKT2 a putative oncongene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl. Acad. Sci. USA 89, 9267-9271 (1992).
  • Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of DcappaB-alpha that can be inhibited by the tumor suppressor PTEN.

Landscapes

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

Abstract

L'invention concerne des composés qui sont des inhibiteurs de kinase Akt efficaces dans le traitement du cancer. Les composés décrits ici sont des ligands bivalents pouvant se lier avec le domaine de liaison ATP d'enzyme kinase et le domaine de liaison de substrat d'enzyme kinase.
PCT/US2008/002925 2007-03-07 2008-03-05 Inhibiteurs bivalents de protéine kinase akt WO2008109104A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90577207P 2007-03-07 2007-03-07
US60/905,772 2007-03-07

Publications (1)

Publication Number Publication Date
WO2008109104A1 true WO2008109104A1 (fr) 2008-09-12

Family

ID=39738620

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/002925 WO2008109104A1 (fr) 2007-03-07 2008-03-05 Inhibiteurs bivalents de protéine kinase akt

Country Status (1)

Country Link
WO (1) WO2008109104A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009081197A1 (fr) * 2007-12-21 2009-07-02 Astrazeneca Ab Dérivés bicycliques destinés à être utilisés dans le traitement d'affections associées au récepteur des androgènes
WO2011080510A1 (fr) 2009-12-31 2011-07-07 Centro Nacional De Investigaciones Oncológicas (Cnio) Composés tricycliques pour une utilisation comme inhibiteurs de la kinase
CN102482280A (zh) * 2009-05-11 2012-05-30 阿斯利康(瑞典)有限公司 作为雄激素受体的配体的[1，2，4]三唑并[4，3-b]哒嗪
WO2012098387A1 (fr) 2011-01-18 2012-07-26 Centro Nacional De Investigaciones Oncológicas (Cnio) Dérivés de triazolo[4,3-b]pyridazines au cycle 6,7 fusionné utilisés en tant qu'inhibiteurs de pim
JP2012517462A (ja) * 2009-02-10 2012-08-02 アストラゼネカ アクチボラグ トリアゾロ［４，３−ｂ］ピリダジン誘導体および前立腺癌のためのそれらの使用
WO2013004984A1 (fr) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncologicas (Cnio) Composés tricycliques pour l'utilisation en tant qu'inhibiteurs de kinase
WO2013005041A1 (fr) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) Composés hétérocycliques tricycliques en tant qu'inhibiteurs de kinases
WO2013005057A1 (fr) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) Nouveaux composés
WO2014076146A1 (fr) * 2012-11-13 2014-05-22 Boehringer Ingelheim International Gmbh Dérivés triazolopyridazines
WO2016154029A1 (fr) * 2015-03-20 2016-09-29 Massachusetts Institute Of Technology Formation de macromolécules par croissance itérative et composés associés
US10328074B2 (en) 2012-11-16 2019-06-25 Boehringer Ingelheim International Gmbh Substituted [1,2,4]triazolo[4,3-a]pyrazines as BRD4 inhibitors
CN110204548A (zh) * 2019-06-04 2019-09-06 河南科技大学第一附属医院 一种具有杀菌消毒作用的哒嗪并三氮唑类药物分子及其制备方法和应用
WO2019173516A1 (fr) 2018-03-06 2019-09-12 Icahn School Of Medicine At Mount Sinai Composés de dégradation/interruption de sérine thréonine kinase (akt) et procédés d'utilisation
US11510920B2 (en) 2016-10-28 2022-11-29 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating EZH2-mediated cancer
US11541051B2 (en) 2016-12-08 2023-01-03 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating CDK4/6-mediated cancer
US12103924B2 (en) 2020-06-01 2024-10-01 Icahn School Of Medicine At Mount Sinai Mitogen-activated protein kinase kinase (MEK) degradation compounds and methods of use
US12110295B2 (en) 2018-06-21 2024-10-08 Icahn School Of Medicine At Mount Sinai WD40 repeat domain protein 5 (WDR5) degradation/disruption compounds and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040116433A1 (en) * 2002-04-08 2004-06-17 Owens Andrew Pate Inhibitors of akt activity
US20050130954A1 (en) * 2003-11-21 2005-06-16 Mitchell Ian S. AKT protein kinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040116433A1 (en) * 2002-04-08 2004-06-17 Owens Andrew Pate Inhibitors of akt activity
US20050130954A1 (en) * 2003-11-21 2005-06-16 Mitchell Ian S. AKT protein kinase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUMAR ET AL.: "AKT Crystal Structure and AKT Specific Inhibitors", ONCOGENE, vol. 24, no. 7493-7501, 2005, pages 7495 - 7498 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009081197A1 (fr) * 2007-12-21 2009-07-02 Astrazeneca Ab Dérivés bicycliques destinés à être utilisés dans le traitement d'affections associées au récepteur des androgènes
US8003649B2 (en) 2007-12-21 2011-08-23 Astrazeneca Ab Bicyclic derivatives for use in the treatment of androgen receptor associated conditions-155
EA017144B1 (ru) * 2007-12-21 2012-10-30 Астразенека Аб N-содержащие бициклические производные для применения при лечении состояний, связанных с андрогенным рецептором
JP2012517462A (ja) * 2009-02-10 2012-08-02 アストラゼネカ アクチボラグ トリアゾロ［４，３−ｂ］ピリダジン誘導体および前立腺癌のためのそれらの使用
US8258140B2 (en) 2009-02-10 2012-09-04 Astrazeneca Ab Chemical compounds—643
CN102482280A (zh) * 2009-05-11 2012-05-30 阿斯利康(瑞典)有限公司 作为雄激素受体的配体的[1，2，4]三唑并[4，3-b]哒嗪
WO2011080510A1 (fr) 2009-12-31 2011-07-07 Centro Nacional De Investigaciones Oncológicas (Cnio) Composés tricycliques pour une utilisation comme inhibiteurs de la kinase
US9682991B2 (en) 2009-12-31 2017-06-20 Fundación Centro Nacional De Investigaciones Oncologicas Carlos Iii Tricyclic compounds for use as kinase inhibitors
WO2012098387A1 (fr) 2011-01-18 2012-07-26 Centro Nacional De Investigaciones Oncológicas (Cnio) Dérivés de triazolo[4,3-b]pyridazines au cycle 6,7 fusionné utilisés en tant qu'inhibiteurs de pim
WO2013004984A1 (fr) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncologicas (Cnio) Composés tricycliques pour l'utilisation en tant qu'inhibiteurs de kinase
WO2013005041A1 (fr) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) Composés hétérocycliques tricycliques en tant qu'inhibiteurs de kinases
WO2013005057A1 (fr) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) Nouveaux composés
US9422290B2 (en) 2012-11-13 2016-08-23 Boehringer Ingelheim International Gmbh Triazolopyridazine
WO2014076146A1 (fr) * 2012-11-13 2014-05-22 Boehringer Ingelheim International Gmbh Dérivés triazolopyridazines
US11077107B2 (en) 2012-11-16 2021-08-03 Boehringer Ingelheim International Gmbh Triazolopyrazine
US10328074B2 (en) 2012-11-16 2019-06-25 Boehringer Ingelheim International Gmbh Substituted [1,2,4]triazolo[4,3-a]pyrazines as BRD4 inhibitors
US10125124B2 (en) 2015-03-20 2018-11-13 Massachusetts Institute Of Technology Formation of macromolecules using iterative growth and related compounds
WO2016154029A1 (fr) * 2015-03-20 2016-09-29 Massachusetts Institute Of Technology Formation de macromolécules par croissance itérative et composés associés
US11510920B2 (en) 2016-10-28 2022-11-29 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating EZH2-mediated cancer
US11541051B2 (en) 2016-12-08 2023-01-03 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating CDK4/6-mediated cancer
JP2021515013A (ja) * 2018-03-06 2021-06-17 アイカーン スクール オブ メディスン アット マウント シナイ セリンスレオニンキナーゼ（ａｋｔ）分解／破壊化合物および使用方法
EP3762381A4 (fr) * 2018-03-06 2022-01-05 Icahn School of Medicine at Mount Sinai Composés de dégradation/interruption de sérine thréonine kinase (akt) et procédés d'utilisation
US11472799B2 (en) 2018-03-06 2022-10-18 Icahn School Of Medicine At Mount Sinai Serine threonine kinase (AKT) degradation / disruption compounds and methods of use
WO2019173516A1 (fr) 2018-03-06 2019-09-12 Icahn School Of Medicine At Mount Sinai Composés de dégradation/interruption de sérine thréonine kinase (akt) et procédés d'utilisation
US12110295B2 (en) 2018-06-21 2024-10-08 Icahn School Of Medicine At Mount Sinai WD40 repeat domain protein 5 (WDR5) degradation/disruption compounds and methods of use
CN110204548A (zh) * 2019-06-04 2019-09-06 河南科技大学第一附属医院 一种具有杀菌消毒作用的哒嗪并三氮唑类药物分子及其制备方法和应用
US12103924B2 (en) 2020-06-01 2024-10-01 Icahn School Of Medicine At Mount Sinai Mitogen-activated protein kinase kinase (MEK) degradation compounds and methods of use

Similar Documents

Publication Publication Date Title
WO2008109104A1 (fr) Inhibiteurs bivalents de protéine kinase akt
JP7201586B2 (ja) 神経保護作用、自己免疫性ならびに癌の疾患および病状において有用な１，２－ジチオラン化合物
KR101779272B1 (ko) 키나제 억제제로서의 신규 벤즈이미다졸 유도체
ES2431368T3 (es) Derivado de isoquinolina substituido en posición 8 y su utilización
ES2316546T3 (es) 2-arilamino-pirimidinas para el tratamiento de trastornos asociados a gsk3.
EP2493862B1 (fr) Dérivés imidazole comme inhibiteurs de l'ido
ES2436623T3 (es) Nuevos derivados de 1,2,4-triazol y procedimientos para su fabricación
JP5734532B2 (ja) アゾールベンゼン誘導体
JP6896701B2 (ja) イミダゾリルアミド誘導体
PH12014501504B1 (en) THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASES
JP2023027203A (ja) ピリミジン化合物及びその医薬用途
MX2011006171A (es) Compuestos de carbazol carboxamida utiles como inhibidores de cinasa.
HUE030519T2 (en) Pyridazinone derivatives
US20200069648A1 (en) Haloallylamine pyrazole derivative inhibitors of lysyl oxidases and uses thereof
US20190071416A1 (en) Compounds for treatment of cancer and epigenetics
US20220144854A1 (en) Macrocyclic compounds
TW202128706A (zh) 新型雜環化合物
KR20240035830A (ko) 피리디논 mk2 저해제 및 이의 용도
JP2023036991A (ja) Ｅｈｍｔ２阻害剤としてのアミン置換複素環化合物、その塩、及びそれらの合成方法
CN110573503A (zh) 作为plk1抑制剂的吡咯衍生物
CA2983040C (fr) Composes d'imidazole heterocycliques, compositions pharmaceutiques les contenant, leur procede de preparation et utilisation
JP2019001715A (ja) 三環性化合物
WO2020095912A1 (fr) Dérivé de benzimidazole
US20230312556A1 (en) Arylamide compound, pharmaceutical composition comprising same, and preparation method therefor and use thereof
AU2016341259A1 (en) Pyridone derivatives and their use as kinase inhibitors

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: 08726459

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: 08726459

Country of ref document: EP

Kind code of ref document: A1