WO2015106294A1 - Ligands de bcr-abl tyrosine kinase bivalents et leurs méthodes d'utilisation - Google Patents

Ligands de bcr-abl tyrosine kinase bivalents et leurs méthodes d'utilisation Download PDF

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WO2015106294A1
WO2015106294A1 PCT/US2015/011273 US2015011273W WO2015106294A1 WO 2015106294 A1 WO2015106294 A1 WO 2015106294A1 US 2015011273 W US2015011273 W US 2015011273W WO 2015106294 A1 WO2015106294 A1 WO 2015106294A1
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group
alkyl
carbon atoms
substituted
amino
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Kenneth W. Foreman
Meizhong Jin
Jutta Wanner
Douglas S. Werner
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Coferon,Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0838—Compounds with one or more Si-O-Si sequences

Definitions

  • Bcr gene at human chromosome 22
  • Abelson (Abl) tyrosine kinase gene at human chromosome 9 has been implicated as a cause of chronic myelogenous leukemia.
  • Several inhibitors of Bcr-Abl tyrosine kinase have been developed for the treatment of chronic myelogenous leukemia, for example imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.
  • the kinase domain of Bcr-Abl tyrosine kinase contains at least two binding pockets, i.e., a myristoyl binding pocket and an ATP binding pocket, and inhibitors of Bcr-Abl tyrosine kinase generally bind to the ATP binding pocket.
  • Bcr-Abl tyrosine kinase inhibitors in treating cancer (e.g., chronic myelogenous leukemia) has been limited by the emergence of resistant Bcr-Abl tyrosine kinase mutants.
  • a protein e.g., Bcr-Abl tyrosine kinase
  • Q 1 is a connecting moiety covalently bound to P 1 and P 2 , wherein Q 1 is selected from the group consisting of -Si(R 7 )(R 8 )-, -Si(R 7 )(R 8 )-0-, -0-Si(R 7 )(R 8 )-, -NR'-, -N(R' )C(0)-, ⁇ C(0)N(R' )-, -N( R " )SO >-. -SO N; R " ;-.
  • a method of treating a disease associated with Bcr-Abl tyrosine kinase in a patient in need thereof comprises administering to the patient the bivalent compound as described above.
  • FIG. 1 shows a screenshot of a protein X-ray crystal structure in which the structures of imatinib and dasatinib are overlaid, according to an embodiment.
  • FIG. 2 shows a non-limiting set of pharmacophores (i.e., ligands) with preferred attachment points for connecting the pharmacophores to connecting moieties indicated by arrows, according to an embodiment.
  • pharmacophores i.e., ligands
  • Described herein are compounds capable of modulating one or more biomolecules and, in some cases, modulating two or more binding sites on a protein (e.g., Bcr- Abl tyrosine kinase).
  • a protein e.g., Bcr- Abl tyrosine kinase
  • the bivalent compound may be capable of interacting with a relatively large target site as compared to the individual ligands that form the bivalent compound.
  • a target may comprise, in some embodiments, two protein binding sites separated by a distance such that a bivalent compound, but not an individual ligand moiety, may be capable of binding to both binding sites essentially simultaneously.
  • contemplated bivlalent compounds may bind to a target with greater affinity as compared to an individual ligand moiety binding affinity alone.
  • a bivalent compound that, e.g., may be capable of modulating proximal binding sites on the same target.
  • the proximal binding sites may be the myristoyl binding pocket and ATP binding pocket of Bcr-Abl tyrosine kinase.
  • bivalent compounds may bind to a first Bcr-Abl tyrosine kinase binding site and a second Bcr-Abl tyrosine kinase binding site.
  • the bivalent compound may be used for a variety of purposes.
  • the bivalent compound may be used to perturb a biological system.
  • the bivalent compound may bind to or modulate a target biomolecule, such as a protein (e.g., Bcr-Abl tyrosine kinase).
  • a contemplated bivalent compound may be used as a pharmaceutical.
  • a bivalent compound may bind to a target biomolecule with a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM, in some embodiments less than 1 pM, in some embodiments less than 1 fM, in some embodiments less than 1 aM, and in some embodiments less than 1 zM.
  • bivalent compounds of formula I are provided:
  • P 1 is a first ligand capable of modulating a first Bcr-Abl tyrosine kinase binding site
  • P 2 is a second ligand capable of modulating a second Bcr-Abl tyrosine kinase binding site
  • Q 1 is a connecting moiety covalently bound to P 1 and P 2 that comprises between 3 and 30 atoms, where the atoms are connected to form a cyclic or acyclic, substituted or
  • unsubstituted, branched or unbranched aliphatic moiety cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic moiety; substituted or unsubstituted phenyl or naphthyl moiety; substituted or unsubstituted heteroaryl moiety; or a combination thereof.
  • the ligand may be a pharmacophore.
  • a pharmacophore is typically an arrangement of the substituents of a moiety that confers biochemical or pharmacological effects (e.g., by targeting a Bcr-Abl tyrosine kinase).
  • identification of a pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule.
  • pharmacophores may be moieties derived from molecules previously known to bind to target biomolecules (e.g., proteins), fragments identified, for example, through NMR or crystallographic screening efforts, molecules that have been discovered to bind to target proteins after performing high- throughput screening of natural products libraries, previously synthesized commercial or non-commercial combinatorial compound libraries, or molecules that are discovered to bind to target proteins by screening of newly synthesized combinatorial libraries. Since most pre-existing combinatorial libraries are limited in the structural space and diversity that they encompass, newly synthesized combinatorial libraries may include molecules that are based on a variety of scaffolds.
  • a bivalent compound may include a first pharmacophore that may bind to the myristoyl binding pocket of Bcr-Abl tyrosine kinase and a second pharmacophore that may bind to the ATP binding pocket of Bcr-Abl tyrosine kinase.
  • a ligand e.g., a pharmacophore
  • an attachment point on a pharmacophore may be chosen so as to preserve at least some ability of the pharmacophore to bind to a binding site.
  • preferred attachment points may be identified using X-ray crystallography. The following description of a non-limiting exemplary method illustrates how a preferred attachment point may be identified. For example, as shown in FIG.
  • STI2 small molecule 1 10 (dark gray) labeled "STI2" in the PDB file [also known as Imatinib or Gleevec or STI-571] may be identified.
  • the Imatinib pyridyl ring (indicated by black circle 120) contains a nitrogen atom in the 3 position, which constitutes an adenine ring mimetic.
  • the corresponding adenine ring mimetic in the new pharmacophore 140 should be aligned to this element.
  • the final conformation and orientation of the newly aligned pharmacophore 140 in the site may be determined using a variety of approaches known to computational chemists, but can be done as simply as performing an energy minimization using a molecular mechanics forcefield.
  • the alphanumeric identifiers in FIG. 1 correspond to amino acid residues in the 3K5V structure, where the letter of the identifier is the one-letter amino acid symbol and the number of the identifier is the position of the amino acid residue in the primary sequence of the protein.
  • Attachment points such as the one labelled 150 on the aligned pharmacophore permit access to solvent exposed amino acid residues on the outer lip of the
  • ATP-binding pocket such as T338 and L389 in the 3K5V structure and are considered preferred attachment points for linkers. It should be apparent to those skilled in the art that overlays of the imatinib pharmacophore with other alternate pharmacophores can be used to identify potential attachment points.
  • FIG. 2 provides a non-limiting set of pharmacophores (i.e., ligands) showing preferred attachment points (indicated by arrows) for connecting the pharmacophore to a connecting moiety.
  • ligands i.e., ligands
  • preferred attachment points indicated by arrows
  • the ligands disclosed herein can be attached at any open site to a connector moiety as described herein. Such embodiments described below include specific references to each attachment site.
  • Exemplary binding site ligands include Bcr-Abl tyrosine kinase ATP binding site ligands represented by the formula: w herein:
  • R is:
  • R 6 is alkyl, alkenyl, aikynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryi, aralkyl, heterocyclo, or heterocyeioalkyl, each of which is unsubstituted or substituted with U 1 , L ' and one or more groups U J ;
  • R 2 is:
  • R 3 is:
  • (1) are each independently hydrogen or R 6 ;
  • R ' and R 8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubsiituted or substituted with U ⁇ U 2 and U 3 ; or
  • any two of R 9 , R 10 , and R n may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with U 1 , U z and U J ;
  • R i3 is:
  • R 14 is:
  • R i 5 is:
  • ⁇ ', U 2 and U 3 are each independently:
  • LI 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, eycloalkenylaikyl, aryl, aralkyi, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of U 1 , U 2 and U 3 ;
  • any two of U 1 , U z , and U 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
  • any two of U 1 , U", and U 3 may together be— O— (CH2 V----G— , where r is 1 to 5, completing a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
  • (1) are each independently hydrogen or U 6 ;
  • ⁇ ' and U 8 , or U°and U 10 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is un substituted or substituted with U 1 , U a d LP; or
  • U ? or U 8 together with U 9 , may be alkylene or alkenylene completing a. 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with U 1 , U 2 and U ;
  • U 11 and U 12 are each independently:
  • q 1 or 2;
  • a Bcr-Abl tyrosine kinase ligand may be represented by:
  • a Bcr-Abl tyrosine kinase ATP binding site ligand may be represented by imatinib, nilotinib, bosutinib, ponatinib, DCC-2036, GNF5, or bafetinib.
  • Exemplary Bcr-Abl tyrosine kinase myristoyl binding site ligands include those represented by the formula:
  • R ! is selected from the group consisting of -U ' R 6 R', -UOR' and -U 3 R' , wherein U 3 is a bond or Ci _ 4 alkylene, R 6 is hydrogen or C h alky 1 and R 7 is selected from the group consisting of Ce-ioaryl and Cs-eheteroaryl; wherein any aiyl or heteroaryl is optionally substituted with i to 3 radicals independently selected from the group consisting of halo, amin halo - substituted Cj_ 4 alkyl,
  • R is selected f rom the group consisting ofhydrogen, halo, amino, alo- substituted Ci.. 4 aikyl, Ci. 4 aikoxy and halo-substituted Cj . 4 alkoxy;
  • R 3 is selected from the group consisting of Cs-gheterocycloalkyl-Co ⁇ alkyl, CV ioheteroaryl-Co -4 alkyl and Ce-i oary l-Co ⁇ alkyl; wherein any alkyl group is optionally substituted with 1 to 3 radicals selected from the group consisting of hydroxy, halo and amino; and any aryi, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 3 radicals independently selected from the group consisting of halo, nitro, C h alky 1, halo-substituted hydroxy - Chalky], halo-substituted phenyl, Cs-sheterocycloalkyl, -
  • R 9 is hydroxy, C6-ioaryl--Co- 4 aikyi, C6-ioaryl-Co- 4 aikyloxy, CYioheteroaryl-Co- 4 aikyl, Cs-sheterocycloalkyl-Co ⁇ alkyl or Cs-scycloalkyl; wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl or alkyl of R 9 is further optionally substituted by up to 2 radicals selected from the group consisting of halo, hydroxy, cyano, amino, nitro, C i. 4 alkyl, hydroxy-Ct.
  • R i0 is Cs-eheteroaryl and R u is hydroxy-Ci -4 alkyl; wherein R 3 is substituted with Q 1 ; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds.
  • a Bcr-Abl tyrosine kinase ligand may be represented by:
  • Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
  • R 1 is pyrazolyl; wherein said pyrazolyl is unsubstituted or substituted with 1 to 2 R° groups;
  • R;2 is pyrroiidinyl: wherein said pyrrolidinyl is substituted with one R' group;
  • R J is selected from hydrogen and halo
  • R 4 is selected from » SF 5 and -Y 2 -CF 2 -Y 3 ;
  • R 6 at each occurrence is independently selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, cyano, trifiuoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;
  • R' is selected from hydroxy, methyl, halo, methoxy, hydroxy-methyl, amino, methyl- amino, amino-methyl, trifiuoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbiitanoyl)oxy, carboxy, methoxy-carbonyl, phosphonooxy, cyano, and amino-carbonyi;
  • Y is selected from CH and N;
  • Y 1 is selected from CH and N;
  • Y 2 is selected from CF 2 , O and S(0)o -2 ;
  • Y ' is selected from hydrogen, chioro, fiuoro, methyl, difluoromethyl, and
  • -Abl tyrosine kinase ligand may be represented by:
  • Exemplary Bcr-Abl tyrosine kinase myristoyl binding site ligands include those
  • Y at each occurrence is independently selected from N and CH;
  • Y 1 is selected from and CR 5 ; wherein R "1 is selected from hydrogen, methoxy and imidazolyl; wherein said imidazolyl is unsubstituted or substituted with methyl;
  • R 1 is selected from pyrazoiyl, thiazoiyl, pyrrolyl, imidazolyl, isoxazolyl, furanyl and thienyl; wherein said thiazoiyl, pyrrolyl, imidazolyl, isoxazolyl, furanyl, or thienyl of R 1 is unsubstituted or substituted with 1 to 3 R 6 groups;
  • R 1 is selected from pyrrolidinyl, piperidinyl, azetidinyl, morpholino, piperazinyl, 2-oxa- 6-azaspiro[3.4j-ocianyl, 3-azabicyc3o[3.1.0]hexan-3-yl, pyrrolo[3,4-c]pyrazo3-5(lH,4H,6H)-yL hexahydropyrrolo[3,4-c]pyrrolyl, 6-oxo-2,7-diazaspiro[4.4]-nonanyl, lH-pyrrolo[3,4- cjpyridinyl, 1 ,4-oxazepan-4-yl, 2-oxooxazolidinyl, j ,4-diazepanyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, 3,8-dioxa-10-azabicyclo[4.3.1]decan
  • R 3 is selected from hydrogen and halo;
  • R 4 is selected from -SF 5 and -Y 2 -CF 2 -Y 3 ;
  • R 33 is selected from hydrogen and C h alky 1;
  • R 3D is selected from and tetrahydro-2H-pyran-4-yI; wherein said aikyl of R 5 ° is unsubstituted or substituted with 1 to 3 groups independently selected from hydroxy and dimethyl-amino;
  • R° at each occurrence is independently selected from hydrogen, hydroxy, methyl, hydroxy, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl, cyclopropyl and dimethyl-amino-carbonyl;
  • R ' at each occurrence is independently selected from hydroxy, methyl, halo, methoxy, hydroxy-methyl, amino, methyl-amino, amino -methyl, trifluoromethyl, 2-hydroxypropan-2-yl, meihy l-carbonyl-amino, dimethyl-amino, 2-amino-3 -methylbutanoy l)oxy, carboxy, methoxy- carbonyl, phosphonooxy, cyano, and amino-carbonyl; or two R' groups combine with the atom to which they are attached to form a ring selected from cyclopropyl, azetidin-3-yl and 3- azabicycio[3.1.Ojhexan-3-yl;
  • Y 2 is selected from CF 2 , O and S(0)o- 2 ;
  • Y 3 is selected from hydrogen, halo, methyl, difluoromethyl and trifluoromethyl; or pharmaceutically acceptable salts thereof
  • Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
  • X is cycloaikyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more aikyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, aikyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, aikoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alky lth io of 1 -6 carbon atoms, hydroxy, trifluoromethyl, cyan
  • Y is -NH-, -0-, -S-, or - R-;
  • R is Ci-ealkyl
  • R ⁇ R , R ⁇ and R 4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethy], alomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynovloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1 -6 carbon atoms, alkylsulphonyl of
  • R 5 is alkyl of 1-6 carbon atoms, alkyl optionally substituted with one or more halogen atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethy], amino, nitro, cyano, or alkyl of 1 -6 carbon atoms groups;
  • R 6 is hydrogen, alkyl of 1-6 carbon atoms, or alkenyl of 2-6 carbon atoms
  • R ! is chloro or bromo
  • R* is hydrogen, alkyl of 1-6 carbon atoms, aminoaikyl of 1-6 carbon atoms, N- alky!ammoalkyl of 2-9 carbon atoms, ⁇ , ⁇ -dialkylaminoalkyl of 3-12 carbon atoms, - cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloaikyl-N-alkylaminoalkyl of 5- 18 carbon atoms, ⁇ , ⁇ -dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-aikyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperidino-N-alkyl wherein either alkyl group is 1 -6 carbon atoms, azacycloalkyl- -alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon
  • n is an integer from 1-4, q is an integer from 1 -3, and p is an integer from 0-3;
  • any two of the substituents R ! , R 2 , R:', or R 4 that are located on contiguous carbon atoms can together be the divalent radical -0-C(R 8 ) 2 -0-;
  • -Abl tyrosine kinase ligand may be represented by:
  • Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
  • Ring T is a 5-membered heteroaryl ring containing 1-2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R l groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1-4 R e groups;
  • Ring A is a 5- or 6-membered aryl or heteroaryl ring
  • Ring B is a 5- or 6-membered aryl or heteroaryl ring;
  • L 1 is selected from N ⁇ QO), C ⁇ NR 1 , ⁇ (0)0, NR 1 C(0)NR 1 , and OC(0)NR 1 ;
  • R 1 , R 2 , and R 3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
  • R 2 and R 3 taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0) r -;
  • each occurrence of R 4 is independently selected from alkyl, haloalkyl, trifluoromethyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
  • n 0, 1 , 2, 3 or 4;
  • n 2 or 3;
  • p 0, 1, 2, 3, 4 or 5;
  • r 0, 1 or 2;
  • a Bcr-Abl tyrosine kinase ligand may be represented by: or a pharmaceutically acceptable salt thereof.
  • Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
  • R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, or benzyl
  • R z represents phenyl substituted by one or two substituents selected from the group consisting of C h alky!, trifluoro-C t -salkyL hydroxy-Ci-ealkyl, amino-Ct-ealkyl, Ci-ealkyl- ammo-Ci-ealkyl, N-cyclo exyl-N-Ci-ealkylamino-Ct-galkyl, Ci- 6 alkoxy-C(0)-piperidino-Ci- 6 alkyl, N-Ci-ealkyl-piperazino-Ci-ealkyl,
  • Ci-ealkoxy hydroxy, Ci-ealkoxy, trifluoro-CVeaikoxy, IH-imidazolyi-Ci-ealkoxy, Ci- 6 alkyl-C(0)-, benzoyloxy, carboxy, carbamoyl, C h lky 1-carbamoyi, amino, Ci_ 6 alkyl-C(0)-amino, benzoylarnino, amino mono- or disubstituted by Ci-ealkyl, by hydroxy-Ci-ealkyl or by Q.
  • R 3 represents hydrogen, d-ealkyl, or halo
  • a Bcr-Abl tyrosine kinase ligand may be represented by: , or a pharmaceutically acceptable salt thereof.
  • Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
  • R 1 is 4-pyrazinyl, 1 -methyl- lH-pyrrolyl, amino- or amino-Cj.ealkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, lH-indolyl or 1H- imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or C...galkyl- substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen,
  • R 2 and R 3 are each independently of the other hydrogen or C h alk ], one or two of the radicals R 4 , R 5 , R 6 , R 7 and R 8 are each nitro, fluoro-substituted Cj -ealkoxy or a radical represented by:
  • X is oxo, thio, imino, N-Cj-6alkyl-imino, hydroximino or O-Cj-ealkyl-hydroximino
  • Y is oxygen or the group NH
  • n 0 or 1
  • R 10 is phenyl that is unsubstituted or substituted by halogen, cyano, Ci- 6 alkoxy, carboxy, Ci- 6 alkyl, or by 4-methyl-piperazinylmethyl; C5_7alkyl; thienyl; 2-naphthyl;
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, Cj- 6 alkyi that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or Q.ealkyl-QO)-, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy;
  • -Abl tyrosine kinase ligand may be represented by: , or a pharmaceutically acceptable salt thereof.
  • Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
  • E 1 is phenyl substituted with 1 , 2, or 3 groups independently selected from fluoro and methyl;
  • A is selected from the group consisting of imidazolyl and pyrazolvl, wherein A is substituted at any suitable position with a 10-membered bicyclic heteroaryl ring optionally substituted with 1 , 2, or 3 R 1 groups;
  • R 1 is independently selected from the group consisting of d-ealkyl, branched Cj. alkyf, Cs-scarbocyclyL halogen, fluoroCi-ealkyl wherein the alky! moiety can be partially or fully fluorinated, cyano, hydroxy 1, methoxy, oxo, (R 2 ) ? C(0)-, - (R 2 )C(0)R ⁇ i R ' bXSO *-. - (R 2 )S0 2 R 2 , -(CH 2 )qN(R 2 ) 2 , -0(CH 2 ) q N(R 2 ) 2 , -Oi CI l .
  • R 2 is H, Cj-ealkyl, branched Cs-yalkyl, Cj-gcarbocyclyl, or phenyl;
  • t is 1 , 2, or 3;
  • a Bcr-Abl tyrosine kinase ligand may be represented by:
  • Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the
  • Ring A is selected from the group consisting of phenylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, and triazinylene;
  • Ring B is selected from the group consisting of pyridyi, pyrimidinyl, pyrazinyl, pyridazinyl, and 1 ,2-dihy dropyridaziny 1, each optionally substituted with 1 , 2, or 3 groups independently selected from C h alky!, halo, and amino;
  • R ! is wherein R J is a saturated, nitrogen-containing heterocyclic group substituted by oxo, a saturated, nitrogen-containing heterocyclic group, aminoalkyl, monoalkylaminoalkyl, dialkylaminoaikyl, Ci-ealkoxy, d-ealkyl, alkyoxycarbonyl, halo, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl,
  • R is selected from Cuealkyl, halogen, haloalkyl, trifiuoromethyl, hydroxyalkyl, d_ ealkoxy, alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylamino, dialkylamino, nitro, carbamoyl, monoalkylcarbamoyl, dialkyicarbamoyl, and cyano;
  • R 3 is selected from hydrogen, C 3 - ⁇ alkoxy, and halo
  • R 4 is selected from hydrogen, Q-ealkyl, and halo
  • n 1, 2, 3, or 4;
  • a Bcr-Abl tyrosine kinase ligand may be represented by: , or a pharmaceutically acceptable salt thereof.
  • a contemplated bivalent compound may be selected from the group consisting of:
  • certain compounds contemplated herein comprise a first ligand and a second ligand covalently joined by a connector moiety.
  • such connector moieties do not have significant binding or other affinity towards an intended target.
  • a connector may contribute to the affinity of a ligand moiety to a target.
  • the connector moiety may be varied to control the spacing between two ligands. For example, in some cases, it may be desirable to adjust the spacing between two ligands so as, for instance, to achieve optimal binding of the bivalent compound to a target. In some cases, the connector moiety may be used to adjust the orientation of the ligands. In certain embodiments, the spacing and/or orientation the connector moiety relative to the ligand moiety can affect the binding affinity of the ligand moiety (e.g., a pharmacophore) to a target. In some cases, connector moieties with restricted degrees of freedom are preferred to reduce the entropic losses incurred upon the binding of a bivalent compound to its target biomolecule. In some embodiments, connector moieties with restricted degrees of freedom are preferred to promote cellular permeability of the bivalent compound.
  • the ligand moiety e.g., a pharmacophore
  • the connector moiety may be used for modular assembly of ligands.
  • a connector moiety may comprise a functional group formed from reaction of a first and second molecule.
  • a series of ligand moieties may be provided, where each ligand moiety comprises a common functional group that can participate in a reaction with a compatible functional group on a connector moiety.
  • the connector moiety may comprise a spacer having a first functional group that forms a bond with a first ligand moiety and a second functional group that forms a bond with a second ligand moiety.
  • Contemplated connector moieties may be any acceptable (e.g., pharmaceutically and/or chemically acceptable) bivalent linker.
  • such connecter moieties may comprise 3 to 30 atoms, 3 to 20 atoms, 3 to 15 atoms, 3 to 10 atoms, 5 to 15 atoms, 10 to 20 atoms, 15 to 25 atoms, 20 to 30 atoms, or 10 to 30 atoms.
  • the atoms may be connected in any suitable arrangement.
  • the atoms may be connected to form a cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic moiety; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic moiety; substituted or unsubstituted phenyl or naphthyl moiety; substituted or unsubstituted heteroaryl moiety; or a combination thereof.
  • a connector moiety may include a substituted or unsubstituted Ci-Cio alkylene, substituted or unsubstituted cycloalkylene, acyl, sulfone, phosphate, ester, carbamate, or amide.
  • contemplat oieties may include polymeric connectors, such a polyethylene glycol (e.g., , where n is 1, 2, 3, 4, 5, 6, 7, 8, 9,
  • X is O, S, NH, or -C(O)-) or other
  • the connector moiety may be substituted with -SiR 2 - and -SiR 2 -0-, where -SiR 2 - and -SiR 2 -0- are covalently bonded to form -SiR. 2 -0-SiR 2 -.
  • a connector may be from about 7 atoms to about 13 atoms in length, or about 8 atoms to about 12 atoms, or about 9 atoms to about 1 1 atoms in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other.
  • R 7 and R 8 are selected, independently for each occurrence, from the group consisting of -OH, Ci- 6 alkyl, -0-Ci_ 6 alkyl, C 2 _ 6 alkenyl, C3_ 6 cycloalkyl, -Ci_ 6 alkyl- NR a R b , phenyl and heteroaryl; wherein Ci_ 6 alkyl, C 2 _ 6 alkenyl, C3_ 6 cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, Ci- 6 alkyl, and phenyl; or
  • R 7 and R 8 together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; R' is, independently for each occurrence, selected from the group consisting of hydrogen and Ci- 4 alkyl; wherein may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and
  • s is an integer from 1-15.
  • a connector moiety may comprise:
  • R 8 R 7 , R 8 R 7 , R 8 R 7 , and R 8 R 7 wherein thee first group and the Si of the second group are connected by an oxygen atom;
  • R w is, independently for each occurrence, absent or selected from the group consisting of -Ci-4alkylene-, -0-Ci-4alkylene-, -N(R )-, -N(R )-Ci-4alkylene-, -0-, - C(0)Ci_ 4 alkylene-, -C(0)-0-Ci_ 4 alkylene-, -C 2 - 6 alkenylene-, -C 2 - 6 alkynylene-, -C3-
  • Ci- 4 alkylene, C 2 - 6 alkenylene, C 2 - 6 alkynylene, C3_ 6 cycloalkylene, phenylene, and heteroarylene may be optionally substituted by one, two, three, or more substituents independently selected from the group consisting of Ci- 4 alkoxy, -C(0)Ci_ 4 alkyl, -C(0)-0-Ci_ 4 alkyl, -C(O)- NR a R b , halogen, cyano, hydroxyl, and phenyl; or R w and R 7 , together with the silicon to which they are attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxyl, and Ci- 6 al
  • W 3 is, independently for each occurrence, (a) absent; or (b) selected from the group consisting of -Ci- 4 alkylene-, -0-Ci- 4 alkylene-, -C(0)-Ci_ 4 alkylene-, -N(R )-Ci_
  • R 7 and R 8 are selected, independently for each occurrence, from the group consisting of -OH, Ci- 6 alkyl, -0-Ci_ 6 alkyl, C 2 - 6 alkenyl, C3_ 6 cycloalkyl, -Ci_ 6 alkyl- NR a R b , phenyl and heteroaryl; wherein Ci- 6 alkyl, C 2 - 6 alkenyl, C3_ 6 cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, Ci- 6 alkyl, and phenyl; or
  • R 7 and R 8 together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl;
  • R', R a , and R b are selected, independently for each occurrence, from the group consisting of hydrogen and C 1-4 alkyl; wherein Ci-4alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; or
  • R a and R b together with the nitrogen to which they are attached, may form a 4-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, and N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;
  • BB independently for each occurrence, is a 4-7-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one, two, three, or more groups represented by R BB ; wherein R 7 , independently for each occurrence, may be optionally bonded to BB; and
  • each R BB is selected, independently for each occurrence, from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, - CONHR', substituted or unsubstituted aliphatic, and substituted or unsubstituted heteroaliphatic; or two R together with the atoms to which they are attached form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system.
  • a connector moiety may comprise:
  • a first group selected from the group consisting of:
  • R 7 and R 8 are as defined above.
  • R 7 and R 8 are Ci_ 6 alkyl.
  • the connector moiety is selected from the group consisting of:
  • a contemplated connector moiety may be an optionally substituted unsaturated heteroaliphatie moiety, wherein the optionaliy substituted unsaturated heteroaliphatie moiety comprises at least one functional group, e.g., one, two. three, or four groups, selected from -SiR 2 -, -SiR 2 -0-, -NR-, -N(R)C(0)-, -CfO)N(R)-, -N(R)S0 2 -, -S0 2 N(R)- , -0-, ⁇ -( ⁇ ; ( ⁇ ; ⁇ -.
  • the functional group may be positioned at any suitable position within the optionally substituted unsaturated heteroaliphatie moiety.
  • the optionally substituted unsaturated heteroaliphatie moiety may comprise 3 to 30 atoms, 3 to 20 atoms, 3 to 15 atoms, 3 to 10 atoms, 5 to 15 atoms, 10 to 20 atoms, 15 to 25 atoms, 20 to 30 atoms, or 10 to 30 atoms.
  • the optionally substituted " unsaturated heteroaliphatie moiety comprises at least one unsaturated group, e.g., an alkenylene group or an alkynylene group.
  • the optionally substituted unsaturated heteroaliphatie moiety may comprise I to 10, 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, 6 to 8, 7 to 9, or 8 to 10 unsaturated groups.
  • the optionally substituted unsaturated heteroaliphatie moiety may contain one, two, three, four, five, six, seven, eight, nine, or ten unsaturated groups.
  • the optionally substituted unsaturated heteroaliphatie moiety comprises a pl rality of unsaturated groups
  • the unsaturated groups may be alkenylene groups, alkynylene groups, or a mixture thereof.
  • An unsaturated group may be positioned at any suitable position within the optionally substituted unsaturated heteroaliphatie moiety.
  • an unsaturated group may be positioned adjacent to a ligand moiety (i.e., directly connected by a covalent bond) and/or a functional group.
  • an unsaturated group and a ligand moiety may be separated by one or more atoms.
  • the optionaliy substituted unsaturated heteroaliphatie moiety is directly connected to a first ligand moiety by a ftrst unsaturated group and directly connected to a second ligand moiety by a second unsaturated group.
  • a connector may have the following structure: , where:
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
  • R 1 and R 2 are, independently for each occurrence, selected from the group consisting of H, Ci- 6 alkyl, Ci- 6 heteroalkyl, phenyl, or heteroaryl, wherein alkyl, heteroalkyl, phenyl, and heteroaryl are optionally substituted with -OH, -NH 2 , -SH, -COOH, -C(0)NH 2 , halo, phenyl, and heteroaryl; or
  • a connector may comprise a phenyl, naphthyl, or mono or bicyclic heteroaryl ring, each optionally substituted.
  • a connector may comprise one or more of the following aryl structures:
  • a connector may comprise a triazole ring having the following structure:
  • a bivalent compound comprising a triazole-containing connector may have the following general structure:
  • Such triazole-joined compounds may be formed, e.g., as a result of a "click" type reaction (i.e., an azide-alkyne cycloaddition).
  • a first segment of a connector having a terminal alkyne and a second segment of a connector having a terminal azide may be joined by a "click" reaction to form a single connector joined by a triazole, as shown above.
  • the first connector and the second connector each are less than or equal to 20 atoms in length, or in some embodiments each are less than or equal to 12 atoms in length.
  • a triazole-containing connector may be represented by -
  • the triazole-containing connector may be represented by:
  • the optionally substituted unsaturated lieteroaliphati moiety may be: j Wherein .
  • R Li is, independently for each occurrence, selected from the groups consisting of hydrogen or any suitable substituent
  • W 2 is selected from the group consisting of -SiR 2 -, -SiR 2 -0-, -0-SiR 2 -, -NR-, ⁇
  • a connecter moiety may maximally span from about 5A to about 50A, in some embodiments about 5A to about 25 A, in some embodiments about 20A to about 50A, and in some embodiments about 6A to about 15A in length. In another embodiment, a connecter moiety may maximally span less than about 30A, in some embodiments less than about 20A, and in some embodiments less than about IOA.
  • a connecter moiety may maximally span from about 1 A to about 30A, in some embodiments about 1 A to about 20A, in some embodiments about 1 A to about IOA, in some embodiments about 1 A to about 5 A., in some embodiments about 20A to about 30A, in some embodiments about 15A to about 25A, in some embodiments about IOA to about 2()A, and in some embodiments about 5A to about 15.4, in length.
  • a connector moiety may maximally span about 1 A, about 3 A, about SA, about 7 A, about 9A, about 1 lA, about 13 A, about 15 , about 17A, about 19A, , about 21 A, about 23 A, about 25 A, about 27A, or about 29A.
  • a connector i.e., Q 1
  • Q 1 is selected from the group consisting of:
  • W 1 is, independently for each occurrence, NR.', O, or S;
  • R' is, independently for each occurrence, selected from the group consisting of hydrogen and C 1-4 alkyl; wherein C 1-4 alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and
  • s is an integer from 1-10.
  • a connector is selected from the group consisting of: -S-(C 2 -6alkylene-0) s -C 2 -6alkylene-S-; -0-(CH 2 -CH 2 -0) s -; and -O-Ci-isalkylene- 0-; wherein s is an integer from 1-10.
  • the connector is -0-(CH 2 -CH 2 -0) s -.
  • the connector is selected from the group consisting of: -S-(CH 2 -CH 2 -CH 2 -0) s - CH 2 -CH 2 -CH 2 -S-; -S-(CH 2 -CH 2 -0) s -CH 2 -CH 2 -S-; and -0-(CH 2 ) u -0-; wherein u is an integer from 1-15.
  • u is 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, or 15.
  • s is 2, 3, 4, 5, 6, 7, or 8.
  • a connector i.e., Q 1
  • Q 1 is selected from the group consisting of:
  • W 1 is, independently for each occurrence, N, O, or S; s is an integer from 1-10; and t is an integer from 3-10.
  • a connector is selected from the group consisting of: -S-(C3_ 6 alkylene-0) s -Ci_ 6 alkylene-S-; -S-(CH 2 -CH 2 -0) t -Ci_ 6 alkylene-S-; -0-(CH 2 -CH 2 -0) s -; and -0-Ci_i 5 alkylene-0-; wherein s is an integer from 1-10, and t is an integer from 3-10.
  • the connector is -0-(CH 2 -CH 2 -0) s -.
  • the connector is selected from the group consisting of: -S-(CH 2 -CH 2 -CH 2 -0) s -CH 2 -CH 2 -CH 2 -S-; -S-(CH 2 -CH 2 -0) t -CH 2 -CH 2 - S-; and -0-(CH 2 ) u -0-; wherein u is an integer from 1-15.
  • u is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
  • s is 2, 3, 4, 5, 6, 7, or 8.
  • the synthetic route in Scheme Xa illustrates a general method for preparing ligand-connector derivatives. The method involves attaching the desired substituents to the carbonyl substituent.
  • the desired connector can be installed by reacting the ligand 1 with the appropriate nucleophile 2 to provide 3 (ligand-connector derivative).
  • Scheme Xa provides for a connector (Q 1 ).
  • the desired connector attached at the carbonyl substituent can be installed by reacting carboxylic acid 1 with common coupling reagents such as l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and hydroxybenzotriazole (HOBt) and then further reacting the resultant activated ester with the appropriate nucleophile, for example, amine 2, to provide 3 (ligand-connector derivative).
  • EDC l-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • HOBt hydroxybenzotriazole
  • the connector may be selected from the group consisting of:
  • n may be 0, 1, 2, 3,4 or i
  • Q 1 may generally be represented for example, by: where n may be 0, 1, 2, 3, 4, 5, or 6.
  • Any free amino group seen in the connector examples of Table A above may be functionalized further to include additional functional groups.
  • the attachment point on the ligand may be further elaborated to incorporate not only a connector moiety, but also a second ligand, as e.g., represented by:
  • the Q x -P 2 moiety may be formed from direct attachment of Q x -P 2 to the carbonyl, or the Q x -P 2 moiety may be formed from the further functionalization of any free amino group seen in the -NH-R examples (i.e., Q 1 examples) of Table A above to include the second ligand moiety (P 2 ).
  • Q x -P 2 may be represented by the structure:
  • n 0, 1, 2, 3, 4, or 5, e.g. n is 1 to 5.
  • Q x -P 2 may be represented by the structure:
  • n 0, 1, 2, 3, 4 or 5, e.g. n is 1 to 5.
  • the synthetic route in Scheme Xb illustrates another general method for preparing ligand-connector derivatives (i.e., P ⁇ Q 1 derivatives). The method involves attaching the desired substituents to an -OH group (e.g., a phenol group) of the ligand.
  • an -OH group e.g., a phenol group
  • X Br, CI, I, O s or OTs
  • the connector (Q 1 ) may be selected from the group consisting of:
  • n 1, 2, 3, 4 or 5.
  • Any free amino group seen in the Q 1 examples of Table B above may be functionalized further to include additional functional groups, e.g., a benzoyl moiety.
  • the P 1 may be further elaborated to incorporate not only the connector moiety (Q 1 ), but also a second ligand (P 2 ), as represented by:
  • X Br, CI, I, OMs or OTs
  • the Q x -P 2 moiety may be formed from direct attachment of Q x -P 2 to the phenyl ether, or the Q x -P 2 moiety may be formed from the further functionalization of any free amino group seen in the Q 1 examples of Table B above to include the second ligand (P 2 ).
  • the synthetic route in Scheme Xc illustrates a general method for preparing ligand-connector derivatives. The method involves attaching the desired carbonyl substituents to the free amine to form an amide, urea, or carbamate. For example, the carbonyl group can be installed by reacting amine 12 (see Scheme Xd) with carboxylic acid 13 to provide 14
  • -C(0)R i.e., Q 1
  • Q 1 Q 1
  • contemplated bivalent compounds may be administered to a patient in need thereof.
  • a method of administering a patient may be administered to a patient in need thereof.
  • the target biomolecule may be a protein. In other embodiments, the target biomolecule may be nucleic acid.
  • a method of modulating two or more target biomolecule binding sites is provided, e.g., of Bcr-Abl tyrosine kinase.
  • a compound may be used to inhibit or facilitate protein-protein interactions.
  • a compound may be capable of activating or inactivating a signaling pathway.
  • a compound may bind to a target protein and affect the conformation of the target protein such that the target protein is more biologically active as compared to when the compound does not bind the target protein.
  • the compound may bind to one region (e.g., domain) of a target molecule.
  • the compound may bind to two regions of a target molecule.
  • the compound may bind to a first region of a first target molecule and a second region of a second target molecule.
  • P 1 and P 2 of Formula I may each be capable of binding to a Bcr-Abl tyrosine kinase binding site.
  • one of P 1 may be capable of binding to the myristoyl binding pocket of Bcr-Abl tyrosine kinase and and P 2 may be capable of binding to the ATP binding pocket of Bcr-Abl tyrosine kinase.
  • a contemplated bivalent compound may be capable of binding to a first binding site and a second binding site, wherein the protein domain is within, e.g., about 40 A, or about 50 A, of the binding site.
  • the compounds contemplated herein may be used in a method for treating diseases or conditions for which a Bcr-Abl tyrosine kinase inhibitor is indicated, for example, a compound may be used for treating treating cancer, such as chronic myelogenous leukemia.
  • a method of treating a disease associated with a Bcr-Abl tyrosine kinase in a patient in need thereof is provided herein.
  • a compound in the manufacture of a medicament for the treatment of diseases or conditions for which a Bcr-Abl tyrosine kinase inhibitor inhibitor is indicated is indicated.
  • a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer such as chronic myelogenous leukemia.
  • cancers e.g., cancers such as including hematological, epithelial including lung, breast and colon carcinomas, mesenchymal, hepatic, renal and neurological tumors
  • contemplated herein is a method of treating squamous cell carcinoma, midline carcinoma or leukemia such as acute myeloid leukemia in a patient in need thereof comprising administering a contemplated bivalent compound.
  • a ligand moiety (e.g., a pharmacophore) may have a molecular weight between 50 Da and 2000 Da, in some embodiments between 50 Da and 1500 Da, in some embodiments, between 50 Da and 1000 Da, and in some embodiments, between 50 Da and 500 Da. In certain embodiments, a ligand moiety may have a molecular weight of less than 2000 Da, in some embodiments, less than 1000 Da, and in some embodiments less than 500 Da.
  • the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.
  • compositions may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.
  • Treatment can be continued for as long or as short a period as desired.
  • the compositions may be administered on a regimen of, for example, one to four or more times per day.
  • a suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely.
  • a treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.
  • compositions comprising bivalent compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier provided.
  • the present disclosure provides pharmaceutical compositions bivalent compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • solid dosage forms for oral administration capsules, tablets, pills, dragees, powders, granules and the like
  • the subject composition is mixed with one or more
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4)
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.
  • solution retarding agents such as paraffin
  • absorption accelerators such as quaternary ammonium compounds
  • wetting agents such as, for example, acetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such a talc,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds may alternatively be administered by aerosol.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants
  • enteral pharmaceutical formulations including a disclosed pharmaceutical composition comprising bivalent compounds, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are provided.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleat, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such
  • kits are provided containing one or more compositions.
  • Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to treat a disease or condition.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . " etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • compositions that include a second active agent, or administering a second active agent.
  • the compounds, as described herein may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • the substituent when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the term "substituted" is contemplated to include all permissible substituents of organic and inorganic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • substituents include acyl; aliphatic; heteroaliphatic; phenyl; naphthyl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy;
  • the compounds described herein are not intended to be limited in any manner by the permissible substituents of organic compounds. In some embodiments, combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • acyl refers to a moiety that includes a carbonyl group.
  • an acyl group may have a general formula selected from - C(0)R x ; -C0 2 (Rx); -C(0)N(R x ) 2 ; -OC(0)R x ; -OC0 2 R x ; and -OC(0)N(R x ) 2 ; wherein each occurrence of R x independently includes, but is not limited to, hydrogen, aliphatic,
  • heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • heteroaliphatic refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
  • Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
  • aryl refers to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl or aromatic refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • Heteroaryl moieties may be selected from: pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl, aromatic, heteroaryl, and heteroaromatic groups described herein can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with a group selected from: Ci_ 6 alkyl; phenyl; heteroaryl; benzyl; heteroarylalkyl; Ci_ 6 alkoxy; Ci_ 6 cycloalkoxy; Ci_ 6 heterocyclylalkoxy; heterocyclyloxyalkyl; C2- 6 alkenyloxy; C 2 _
  • heterocyclic refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.
  • heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C2- 6 alkenyl, and C 3- 4 alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkenyloxy refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O).
  • alkenoxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C3_ 6 alkenyloxy.
  • alkenyloxy groups include, but are not limited to allyloxy, butenyloxy, etc.
  • alkoxy refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-).
  • exemplary alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as Ci- 6 alkoxy, and C 2 - C6alkoxy, respectively.
  • exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
  • alkoxycarbonyl refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-).
  • exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as Ci_ 6 alkoxycarbonyl.
  • exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
  • alkynyloxy refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)).
  • exemplary alkynyloxy groups include, but are not limited to, propynyloxy.
  • alkyl refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci- 6 alkyl, Ci_ 4 alkyl, and Ci_ 3 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, 2- methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 3-methyl-2-butyl, 2,2-dimethyl-l -propyl, 2-methyl- 1-pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkylene refers to a bivalent saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as -Ci_ 6 alkylene-, -Ci_ 4 alkylene-, and -Ci_ 3 alkylene-, respectively, where the alkylene has two open valences.
  • Exemplary alkyl groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, 2-methyl-l -propylene, 2- methyl-2-propylene, 2-methyl-l -butylene, 3 -methyl- 1-butylene, 3-methyl-2-butylene, 2,2- dimethyl-1 -propylene, 2-methyl-l -pentylene, 3 -methyl- 1-pentylene, 4-methyl-l-pentylene, 2- methyl-2-pentylene, 3-methyl-2-pentylene, 4-methyl-2-pentylene, 2,2-dimethyl- 1-butylene, 3, 3 -dimethyl- 1-butylene, 2-ethyl- 1-butylene, butylene, isobutylene, t-butylene, pentylene, isopentylene, neopentylene, hexylene, etc.
  • alkylcarbonyl refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-).
  • exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as Ci_
  • alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C 2 - 6 alkynyl, and C3_ 6 alkynyl, respectively.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
  • carbonyl refers to the radical -C(O)-.
  • carboxylic acid refers to a group of formula -CO 2 H.
  • cyano refers to the radical -CN.
  • cycloalkoxy refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-).
  • cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C3_ 6 cycloalkyl or C4_ 6 cycloalkyl and derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.
  • halo or halogen as used herein refer to F, CI, Br, or I.
  • heterocyclylalkoxy refers to a heterocyclyl- alkyl-O- group.
  • heterocyclyloxyalkyl refers to a heterocyclyl-O-alkyl- group.
  • heterocyclyloxy refers to a heterocyclyl-O- group.
  • heteroaryloxy refers to a heteroaryl-O- group.
  • hydroxy and “hydroxyl” as used herein refers to the radical -OH.
  • connection refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed connecting moiety (i.e., linker) and a pharmacophore.
  • Contemplated connectors are generally hydrolytically stable.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated is desirably a mammal in which treatment of obesity, or weight loss is desired.
  • “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.
  • the compounds are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.
  • salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, >-toluenesulfonate and pamoate (i.e., l, l'-methylene-
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein comprises all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R” or "5,” depending on the configuration of substituents around the stereogenic carbon atom.
  • Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. [00152]
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers.
  • the enantiomers and diastereomers may be designated by the symbols "(+),” "(-).” “R” or “5,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the "Z” or "is” configuration wherein the terms "Z" and "is” are used in accordance with
  • trans represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans.”
  • stereoisomers when used herein comprises all geometric isomers, enantiomers or diastereomers. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure.
  • Individual enantiomers and diastereomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.
  • Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compound is amorphous.
  • the compound is a polymorph.
  • the compound is in a crystalline form.
  • isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 10 B, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • a compound may have one or more H atom replaced with deuterium.
  • isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci_8)alkyl, (C2-i2)alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
  • di-N,N-(Ci-C2)alkylamino(C2-C 3 )alkyl such as ⁇ -dimethylaminoethyl
  • carbamoyl-(Ci-C2)alkyl N,N-di(Ci-C2)alkylcarbamoyl-(Ci-C2)alkyl
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci_ 6)alkanoyloxymethyl, l-((Ci-6)alkanoyloxy)ethyl, 1 -methyl- l-((Ci-6)alkanoyloxy)ethyl (Ci- 6 )alkoxycarbonyloxymethyl, N-(Ci_6)alkoxycarbonylaminomethyl, succinoyl, (Ci_6)alkanoyl, a- amino(Ci_4)alkanoyl, arylacyl and a-aminoacyl, or ⁇ -aminoacyl-a-aminoacyl, where each a- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -P(0)(0(Ci-C6)alkyl) 2 or glycosyl (
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyalkyl derivative, an
  • oxodioxolenyl (oxodioxolenyl)methyl derivative, an N-Mannich base, imine, or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine.
  • a starting material or intermediate used in the synthesis of a contemplated compound may have an enantiomeric excess greater than 0, e.g., greater than about 95%, greater than about 98%, greater than about 99%, or essentially 100%.
  • a starting material or intermediate may be essentially stereoisomerically pure.
  • partial or complete loss of chiral integrity may occur during the synthesis of the contemplated compound thereby reducing or eliminating the enantiomeric excess.
  • a stereoisomerically pure starting material or intermediate is used in a synthesis of a contemplated compound
  • partial or complete loss of chiral integrity results in a stereoisomeric mixture.
  • a stereoisomeric mixture may be partially or essentially completely resolved by subjecting the stereoisomeric mixture to a chiral purification technique (e.g., chiral HPLC purification).
  • reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo resulting in a crude compound which was purified by chromatography on silica gel eluting with 3% methanol in DCM to obtain 1.20 g, 73% yield of the title compound as light yellow sticky solid.
  • reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo resulting in a crude compound which was purified by chromatography on silica gel eluting with 1-3% methanol in DCM to give 320 mg, 75% yield of the title compound as colorless thick oil.
  • reaction mixture was partitioned between ethyl acetate (10 mL) and water (5 mL) and separated.
  • the aqueous layer was extracted with ethyl acetate (3 X 10 mL) and the combined organic layers were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to give 20 mg, 12% yield of the title compound as an off white solid.
  • reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo resulting in a crude compound which was purified by chromatography on silica gel eluting with 1-3% methanol in DCM to obtain 1.0 g, 70% yield of the title compound as light yellow sticky solid.
  • reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo resulting in the crude compound which was purified by chromatography on silica gel eluting with 5-10 % methanolic ammonia in DCM and repurified by preparative TLC (10% MeOH in DCM) to give 25 mg, 7% yield, of the title compound as light brown solid.
  • K562 purchased from ATCC: CCL-243 or BaF3 cells expressing either wild type BCR-Abl or mutant BCR-Abl (T3151) (obtained from Dr James Griffin Lab, Dana-Faber cancer Institute, Boston MA) were plated into 96 well plates (10,000 cells/well). Serial dilutions of compound starting at 10 ⁇ were added to the cells and the plates incubated at 37 °C for 72 hours at which point CellTitreGlo Reagent (Promega) was added to each plate and luminescence measured. Cell viability was determined relative to DMSO treated cells and GI50 values obtained after plotting dose-dependent effects using PRISM.
  • Group A GI50 range of 0.1-30 nM
  • Group B GI50 range of 30-100 nM
  • Group C GI50 range of 100 nM - 30 ⁇ .
  • Example 9 ABL1 (v/t) Omnia kinase assay
  • kinase domain from wild type human Abll kinases, Ala46-Val515, were purchased from Cayman Chemical (Ann Arbor, MI), and were purified in the absence of detergent to allow GNF5 and analogues to bind in the myristoyl binding site.
  • Abl kinase activity was measured in a semi-continuous fluorescence-based kinase assay (Omnia) utilizing a synthetic peptide Y6 which was purchased from Life Technologies (Carlsbad, CA).
  • Assay was run in the presence of 20 mM HEPES pH 8.0, 50 mM NaCl, 10 mM MgC12, .05% BSA, 10 ⁇ sodium vanadate, 200 ⁇ DTT, 2% DMSO, and 10 ⁇ Y6 peptide at protein concentrations of 25 nM for wild type Abll and 6 nM for the T3151 mutant Abll .
  • the assay was performed at the ATP Km, which was determined to be 40 ⁇ for the wild type Abll and 10 ⁇ for the T3151 mutant Abl 1.
  • Abl 1 inhibitors were titrated in 100% DMSO and then diluted ten-fold into reaction buffer, which was followed by a subsequent ten-fold dilution into the assay plate.

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Abstract

L'invention concerne des composés pouvant moduler une ou plusieurs biomolécules sensiblement simultanément, par ex., de moduler au moins deux sites de liaison sur une protéine, par ex., la Bcr-Abl tyrosine kinase, ainsi que des méthodes pour le traitement de maladies liées à ladite modulation d'une protéine comprenant différents cancers, et comprenant en outre des cancers chimio-résistants.
PCT/US2015/011273 2014-01-13 2015-01-13 Ligands de bcr-abl tyrosine kinase bivalents et leurs méthodes d'utilisation WO2015106294A1 (fr)

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WO2023196991A1 (fr) * 2022-04-08 2023-10-12 The Brigham And Women's Hospital, Inc. Molécules chimériques bifonctionnelles pour le marquage de kinases avec des fractions de liaison cibles et leurs méthodes d'utilisation
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US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
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US11801237B2 (en) 2019-12-30 2023-10-31 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11612591B2 (en) 2019-12-30 2023-03-28 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11844788B1 (en) 2019-12-30 2023-12-19 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11850240B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11576903B2 (en) 2019-12-30 2023-02-14 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11903933B2 (en) 2019-12-30 2024-02-20 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11911370B1 (en) 2019-12-30 2024-02-27 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11918564B1 (en) 2019-12-30 2024-03-05 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
WO2023114759A3 (fr) * 2021-12-13 2023-07-27 The Regents Of The University Of California Inhibiteurs d'abl et leurs utilisations
WO2023196991A1 (fr) * 2022-04-08 2023-10-12 The Brigham And Women's Hospital, Inc. Molécules chimériques bifonctionnelles pour le marquage de kinases avec des fractions de liaison cibles et leurs méthodes d'utilisation
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

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