WO2011017219A1 - Imidazoquinoxalinones et traitement anti-tumoral - Google Patents

Imidazoquinoxalinones et traitement anti-tumoral Download PDF

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WO2011017219A1
WO2011017219A1 PCT/US2010/043927 US2010043927W WO2011017219A1 WO 2011017219 A1 WO2011017219 A1 WO 2011017219A1 US 2010043927 W US2010043927 W US 2010043927W WO 2011017219 A1 WO2011017219 A1 WO 2011017219A1
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group
alkyl
compound
heteroaryl
aryl
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PCT/US2010/043927
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English (en)
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Wenchang Guo
Ching-Yi Hsieh
Wenzhe Huang
Ruiwu Liu
Kit S. Lam
Hsing-Jien Kung
Aimin Song
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The Regents Of The University Of California
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Publication of WO2011017219A1 publication Critical patent/WO2011017219A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Etk epidermal and endothelial tyrosine kinase
  • Btk Bruton's tyrosine kinase
  • Etk Overexpression of Etk is associated with the development of advanced prostate cancer and transgenic mice bearing this gene developed preneoplastic lesions of prostate cancer (Dai et al, 2006). Etk is also highly expressed in endothelial cells and involved in angiogenesis and metastasis (Zhang et al., 2003; Chang et al, 2007). There is also evidence that Etk plays a role in breast carcinogenesis, hepatocellular carcinoma, and nasopharyngeal cancer (Bagheri et al, 2001 ; Guo et al, 2006, 2007, 2008). Etk inhibitors thus would block growth of epithelial tumors and the processes of angiogenesis and metastasis.
  • Btk another family member, is expressed at high levels in B cells and B cell malignancies. Btk is critical for the maturation and activation of B cells. Btk is important for the survival of many leukemia cells and plays an important role in immune responses.
  • Btk tyrosine kinases in Tec family
  • Itk and Tec are also implicated in carcinogenesis (Chang et al. , 2007).
  • the present invention provides compounds of Formula I:
  • Radical R 1 of Formula I can be H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C] -6 haloalkyl, OR la , C ]-6 alkyl-OR la , -NR la R lb , -C 1 -6 alkyl -NR 13 R 1 b , -C(O)R la , -C(O)OR la , -OC(O)OR 13 , -C(O)NR 13 R 1 b , -NR 13 C(O)R 1 b , -OC(O)NR 13 R 1 b , -NR 13 C(O)OR 1 b ,
  • Radical L 1 of Formula I can be a bond, Ci -6 alkylene or Ci -6 heteroalkylene.
  • Radical R 2 of Formula I can be C 1-6 alkyl, -NR 2a R 2b , C 3-9 heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 R 5 substituents.
  • Radical L 2 of Formula I can be a bond, Ci -6 alkylene, Ci -6 heteroalkylene or Ci -6 alkylene-C(O)-.
  • Racial R 3 of Formula I can be -NR 6a R 6b , C 3-J0 cycloalkyl, C 3-9 heterocycloalkyl, aryl, aryl-oxy, heteroaryl or heteroaryl-oxy, each optionally substituted with 1 to 4 R 5 substituents.
  • Radical L 3 of Formula I can be a bond, C 2-6 alkenylene and C 2-6 alkynylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene.
  • Radical R 4 of Formula I can be H or C ]-6 alkyl.
  • Each of radical R 5 of Formula I can separately be Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, Ci -6 haloalkoxy, OR 53 , Ci -6 alkyl-OR 5a , aryl, heteroaryl, -NR 5a R 5b , Ci- ⁇ alkylaryl, -C 1-6 alkyl-heteroaryl, -C 1 -6 alkyl-NR 5a R 5b , -C(0)R 5a , -C(0)0R 5a , -OC(O)OR 53 , -C(O)NR 5a R 5b , -NR 5a C(O)R 5b , -OC(O)NR 5a R 5b , -NR 5a C(O)OR 5b ,
  • Each of radicals R 6a and R 6b of Formula I can separately be H or Cj -6 alkyl, wherein the Ci -6 alkyl group can optionally be substituted with C 2-6 alkenyl, C 2-6 alkynyl, halogen, Ci- 6 haloalkyl, OR 5a , -NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a , -OC(O)OR 53 , -C(O)NR 5a R 5b ,
  • Radical X of Formula I can be -O- or -N(R 7 )-.
  • Radical Y of Formula I can be C 1 -6 alkylene, Ci -6 heteroalkylene or heterocycloalkyl.
  • Subscript n of Formula I can be 0 or 1.
  • radicals R la , R I b , R 2a , R 2b , R 5a , R 5b and R 7 of Formula I can separately be H or Ci- 6 alkyl.
  • radicals R la and R lb , R 2a and R 2b , R 5a and R 5b , or R 7 and Y are optionally combined with the atom to which each is attached to form a C 3-8 heterocycloalkyl which can optionally be substituted with Ci -6 alkyl.
  • two R 5 groups are combined to form a C 3 - 8 heterocycloalkyl which can optionally be substituted with Ci -6 alkyl.
  • the present invention provides a pharmaceutical composition of a compound of Formula I and a pharmaceutically acceptable excipient.
  • the present invention provides a method of treating B-cell leukemia or B-cell lymphoma, prostate cancer, or osteoporosis, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I.
  • the present invention provides a method for the inhibition of Btk, Etk, or Mertk by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I.
  • Figure 1 shows a scheme for the preparation of the compounds of the present invention.
  • Figure 2 shows the viability of LnCaP cells following treatment of compounds at 10 ⁇ M was measured using an MTT assay.
  • Figures 3A and 3B shows autophagy in CWR22Rvl-LC3 cells.
  • Figure 3A shows autophagosomes as visualized by GFP-LC3 "puncta.”
  • Figure 3B shows an immunoblot (CWR22Rvl) of endogenous LC3 isoforms.
  • Figure 4 shows inhibition of cell migration of PC3 human prostate cancer cells by compounds of the present invention.
  • Figure 5 shows inhibition of Btk kinase activity of compounds of the present invention.
  • Figure 6 shows inhibition of Etk kinase activity of a compound of the present invention.
  • Figure 7 shows percent growth of BCBLl, LnCap and RWPEl (immortalized human prostate cells) for compounds of the present invention at 20 ⁇ M. The data was obtained using the MTT assay described within.
  • Figure 8 shows percent growth of BCBL 1 , LnCap and RWPE 1 (immortalized human prostate cells) for compounds of the present invention at 5 ⁇ M. The data was obtained using the MTT assay described within.
  • Figure 9 shows percent growth of BCBLl, LnCap and RWPEl (immortalized human prostate cells) for compounds of the present invention at 1 ⁇ M. The data was obtained using the MTT assay described within.
  • Figure 10 shows inhibition of Mertk kinase activity of compounds of the present invention.
  • Figure 11 shows inhibition of Itk kinase activity of compounds of the present invention.
  • CTA06 is a positive control compound. The data was obtained using the TLC kinase inhibition assay described within.
  • Figure 12 shows growth inhibition of Jurkat, BCBLl, LnCap and RWPEl cells treated with compounds of the present invention. The data was obtained using the MTT assay described within. DETAILED DESCRIPTION OF THE INVENTION
  • alkyl refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated.
  • Ci-C 6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
  • Other alkyl groups include, but are not limited to heptyl, octyl, nonyl, decyl, etc.
  • Alkyl can include any number of carbons, such as 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 and 5-6.
  • alkylene refers to an alkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene.
  • a straight chain alkylene can be the bivalent radical of -(CH 2 ) n; where n is 1, 2, 3, 4, 5 or 6.
  • Alkylene groups include, but are not limited to, methylene, ethylene, propylene,
  • heteroalkyl refers to an alkyl group, as defined above, having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P.
  • the heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O) 2 -.
  • heteroalkyl can include ethers, thioethers and alkyl-amines.
  • the heteroalkyl group is typically monovalent, but can be divalent, such as when the heteroalkyl group links two moieties together, i.e., a
  • heteroalkylene The two moieties linked to the heteroalkylene can be linked to the same atom or different atoms of the heteroalkylene.
  • heteroalkylene refers to a heteroalkyl group, as defined above, linking at least two other groups.
  • the two moieties linked to the heteroalkylene can be linked to the same atom or different atoms of the heteroalkylene.
  • R', R 55 , R 5 ' 5 and R 5 ' 5 ' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include, but not be limited to, 1 -pyrrolidinyl and 4-morpholinyl.
  • alkenyl refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one double bond.
  • alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1 ,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1 ,4-hexadienyl, 1,5-hexadienyl, 2,4- hexadienyl, or 1,3,5-hexatrienyl.
  • Alkenyl groups can also have from 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbons.
  • the alkenyl groups is typically monovalent, but can be divalent, such as when the alkenyl group links two moieties together.
  • alkenylene refers to an alkenyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkenylene can be linked to the same atom or different atoms of the alkenylene.
  • Alkenylene groups include, but are not limited to, ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, sec-butenylene, pentenylene and hexenylene.
  • alkynyl refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one triple bond.
  • alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4- pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1 ,4-hexadiynyl, 1,5- hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatri
  • alkynylene refers to an alkynyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkynylene can be linked to the same atom or different atoms of the alkynylene.
  • Alkynylene groups include, but are not limited to, ethynylene, propynylene, isopropynylene, butynylene, sec-butynylene, pentynylene and hexynylene.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl refers to alkyl group, as defined above, where some or all of the hydrogen atoms are substituted with halogen atoms.
  • Halogen preferably represents chloro or fluoro, but may also be bromo or iodo.
  • haloalkyl includes trifluoromethyl, fluoromethyl, 1, 2,3,4, 5-pentafluoro-phenyl, etc.
  • perfluoro defines a compound or radical which has at least two available hydrogens substituted with fluorine.
  • perfluorophenyl refers to 1,2,3,4,5- pentafluorophenyl
  • perfluoromethane refers to 1,1,1 -trifluoromethyl
  • perfluoromethoxy refers to 1,1,1-trifluoromethoxy
  • alkoxy refers to alkyl group having an oxygen atom that either connects the alkoxy group to the point of attachment or is linked to two carbons of the alkoxy group.
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.
  • the alkoxy groups can be further substituted with a variety of substituents described within. For example, the alkoxy groups can be substituted with halogens to form a "halo-alkoxy" group.
  • halo-alkoxy refers to an alkoxy group having at least one halogen.
  • Halo-alkoxy is as defined for alkoxy where some or all of the hydrogen atoms are substituted with halogen atoms.
  • the alkoxy groups can be substituted with 1, 2, 3, or more halogens.
  • Halo-alkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.
  • cycloalkyl refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated.
  • Monocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • Bicyclic and polycyclic rings include, for example, norbornane, decahydronaphthalene and adamantane.
  • C 3-8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane.
  • cycloalkylene refers to a cycloalkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene.
  • Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene.
  • the terms "heterocycle” or “heterocycloalkyl” refer to a ring system having from 3 ring members to about 20 ring members and from 1 to about 5 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O) 2 -.
  • heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and 1 ,4-dioxa-8- aza-spiro[4.5]dec-8-yl.
  • heterocycloalkylene refers to a heterocycloalkyl group, as defined above, linking at least two other groups. The two moieties linked to the
  • heterocycloalkylene can be linked to the same atom or different atoms of the
  • aryl refers to a monocyclic or fused bicyclic, tricyclic or greater, aromatic ring assembly containing 6 to 16 ring carbon atoms.
  • aryl may be phenyl, benzyl or naphthyl, preferably phenyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Aryl groups can be mono-, di- or tri-substituted by one, two or three radicals selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy and oxy-C 2 -C 3 -alkylene; all of which are optionally further substituted, for instance as hereinbefore defined; or 1- or 2-naphthyl; or 1- or 2- phenanthrenyl.
  • Alkylenedioxy is a divalent substitute attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy.
  • Oxy-C 2 -C 3 -alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or
  • oxypropylene An example for oxy- C 2 -C 3 -alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.
  • Preferred as aryl is naphthyl, phenyl or phenyl mono- or disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, especially phenyl or phenyl-mono- or disubstituted by alkoxy, halogen or trifluoromethyl, and in particular phenyl.
  • substituted phenyl groups as R are, e.g. 4-chlorophen-l-yl, 3,4- dichlorophen- 1 -yl, 4-methoxyphen- 1 -yl, 4-methylphen- 1 -yl, 4-aminomethylphen- 1 -yl, A- methoxyethylaminomethylphen- 1 -yl, 4-hydroxyethylaminomethylphen- 1 -yl, 4-hydroxyethyl- (methyl)-aminomethylphen-l-yl, 3-aminomethylphen-l-yl, 4-N-acetylaminomethylphen-l- yl, 4-aminophen-l-yl, 3-aminophen-l-yl, 2-aminophen-l-yl, 4-phenyl-phen-l-yl, A- (imidazol-l-yl)-phen-yl, 4-(imidazol-l-ylmethyl)-phen-l-yl
  • aryl-oxy refers to an aryl group, as defined above, where the aryl group is linked through an oxygen atom.
  • Aryl-oxy groups include, but are not limited to, phenyl-oxy.
  • arylene refers to an aryl group, as defined above, linking at least two other groups. The two moieties linked to the arylene are linked to different atoms of the arylene.
  • Arylene groups include, but are not limited to, phenyl ene.
  • arylene-oxy refers to an arylene group, as defined above, where one of the moieties linked to the arylene is linked through an oxygen atom.
  • Arylene- oxy groups include, but are not limited to, phenylene-oxy.
  • heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 4 of the ring atoms are a heteroatom each N, O or S.
  • heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any other radicals substituted, especially mono- or di-substituted, by e.g. alkyl, nitro or halogen.
  • Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3- pyridyl.
  • Thienyl represents 2- or 3-thienyl.
  • Quinolinyl represents preferably 2-, 3- or A- quinolinyl.
  • Isoquinolinyl represents preferably 1-, 3- or 4-isoquinolinyl.
  • Benzopyranyl, benzothiopyranyl represents preferably 3 -benzopyranyl or 3-benzothiopyranyl, respectively.
  • Thiazolyl represents preferably 2- or 4-thiazolyl, and most preferred, 4-thiazolyl.
  • Triazolyl is preferably 1-, 2- or 5-(l,2,4-triazolyl).
  • Tetrazolyl is preferably 5-tetrazolyl.
  • heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or any of the radicals substituted, especially mono- or di-substituted.
  • heteroaryl-oxy refers to a heteroaryl group, as defined above, where the heteroaryl group is linked through an oxygen atom.
  • Heteroaryl -oxy groups include, but are not limited to, pyridyl-oxy.
  • heteroarylene refers to an heteroaryl group, as defined above, linking at least two other groups. The two moieties linked to the heteroarylene are linked to different atoms of the heteroarylene.
  • alkyl-aryl refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent in order to link to the aryl component to the point of attachment. In some instances, the alkyl component can be absent.
  • the aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl.
  • alkyl-heteroaryl refers to a radical having an alkyl component and an heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent in order to link to the heteroaryl component to the point of attachment. In some instances, the alkyl component can be absent.
  • the heteroaryl component is as defined above.
  • salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
  • salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and
  • prodrug refers to covalently bonded carriers which are capable of releasing the active agent of the methods of the present invention, when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo.
  • Prodrugs of the active agents of the present invention include active agents wherein a hydroxy, amidino, guanidino, amino, carboxylic or a similar group is modified.
  • the term "pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject.
  • Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
  • binders include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
  • the terms “treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom or condition.
  • the treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.
  • Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
  • the compounds of the present invention are those of
  • Radical R of Formula I can be H, d -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, Ci -6 haloalkyl, OR la , C -6 alkyl-OR la , -NR la R lb , -C,_ 6 alkyl-NR la R Ib , -C(O)R la , -C(O)OR la , -OC(O)OR 13 , -C(O)NR la R lb , -NR la C(O)R lb , -OC(O)NR la R lb , -NR la C(O)OR lb , -NR la C(O)OR lb ,
  • Radical L 1 of Formula I can be a bond, Ci -6 alkylene or Ci -6 heteroalkylene.
  • Radical R 2 of Formula I can be C 1 -6 alkyl, -NR 2a R 2b , C 3-9 heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 R 5 substituents.
  • Radical L 2 of Formula I can be a bond, Ci -6 alkylene, Cj -6 heteroalkylene or Ci -6 alkylene-C(O)-.
  • Racial R 3 of Formula I can be -NR 6a R 6b , C 3-I0 cycloalkyl, C 3-9 heterocycloalkyl, aryl, aryl-oxy, heteroaryl or heteroaryl-oxy, each optionally substituted with 1 to 4 R 5 substituents.
  • Radical L 3 of Formula I can be a bond, C 2-6 alkenylene and C 2-6 alkynylene, cycloalkylene, heterocycloalkylene, arylene or heteroaryl ene.
  • Radical R 4 of Formula I can be H or C 1-6 alkyl.
  • Each of radical R 5 of Formula I can separately be Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, Q -6 haloalkyl, C 1-6 haloalkoxy, OR 5a , C 1-6 alkyl-OR 5a , aryl, heteroaryl, -NR 5a R 5b , C 1-6 alkylaryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alkyl-NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a ,
  • -NR 5a C(O)NR 5a R 5b , -CN, -NO 2 , -N 3 , ( 0), -SR 5a , -S(O)R 5a , -S(O) 2 R 5a , -NR 5a S(O) 2 R 5b , -NR 5a S(O) 2 aryl, -S(O) 2 NR 5a R 5b , -NR 5a S(O) 2 NR 5a R 5b or heteroaryl-oxy.
  • Radical X of Formula I can be -O- or -N(R 7 )-.
  • Radical Y of Formula I can be C 1-6 alkylene, C 1-6 heteroalkylene or heterocycloalkyl.
  • Subscript n of Formula I can be 0 or 1.
  • Each of radicals R la , R lb , R 2a , R 2b , R 5a , R 5b and R 7 of Formula I can separately be H or C 1-6 alkyl.
  • radicals R la and R lb , R 2a and R 2b , R 5a and R 5b , or R 7 and Y are optionally combined with the atom to which each is attached to form a C 3-8 heterocycloalkyl which can optionally be substituted with C 1-6 alkyl.
  • two R 5 groups are combined to form a C 3 - 8 heterocycloalkyl which can optionally be substituted with C 1-6 alkyl.
  • Radical R 1 of Formula I can be C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, OR la , C 1-6 alkyl-OR la , -NR l a R lb , -C 1-6 alkyl-NR l a R Ib , -C(O)R I a , -C(O)OR 13 , -OC(O)OR' 3 , -C(O)NR l3 R lb , -NR l3 C(0)R lb , -OC(O)NR l a R lb , -NR la C(O)OR i b , -NR !a C(0)NR la R lb , -CN, -NO 2 , -N 3 , -SR la , -S(O)R 13 , -S(O) 2 R 13
  • Radical L 1 of Formula I can be a bond, C 1 -6 alkylene or C 1-6 heteroalkylene.
  • Radical R of Formula I can be C 1-6 alkyl, -NR 2a R 2b , C 3-9 heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1 to 4 R 5 substituents.
  • Radical L of Formula I can be a bond, C 1-6 alkylene, Ci -6 heteroalkylene or Q -6 alkylene-C(O)-.
  • Racial R 3 of Formula I can be -NR 6a R 6b , C 3-I0 cycloalkyl, C 3-9 heterocycloalkyl, aryl, aryl-oxy, heteroaryl or heteroaryl-oxy, each optionally substituted with 1 to 4 R 5 substituents.
  • Radical L 3 of Formula I can be a bond, C 2-6 alkenylene and C 2-6 alkynylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene.
  • Radical R 4 of Formula I can be H or Ci -6 alkyl.
  • Radical Y of Formula I can be Cj -6 alkylene, Ci -6 heteroalkylene or heterocycloalkyl.
  • Subscript n of Formula I can be O or 1.
  • Each of radicals R l a , R lb , R 2a , R 2b , R 5a , R 5b and R 7 of Formula I can separately be H or Ci -6 alkyl.
  • radicals R l a and R Ib , R 2a and R 2b , R 5a and R 5b , or R 7 and Y are optionally combined with the atom to which each is attached to form a C 3-8 heterocycloalkyl.
  • radical R 1 of Formula I can be Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, Ci -6 haloalkyl, OR l a , C 1-6 alkyl-OR la , -NR la R lb , -C 1-6 alkyl-NR l a R lb , -C(O)R la , -C(O)OR !
  • -OC(O)OR 13 -C(0)NR la R lb , -NR la C(O)R lb , -OC(O)NR 13 R 1 b , -NR la C(0)0R lb , -NR la C(O)NR la R lb , -CN, -NO 2 , -N 3 , -SR la , -S(O)R la , -S(O) 2 R la ,
  • the compounds of the present are those of Formula Ia:
  • radical R 1 of Formula Ia can be Ci -6 alkyl, OR la , -NR !a R ib , -C(O)R la , -C(O)OR l a , -OC(O)OR 13 , -C(0)NR la R lb , -NR la C(O)R lb , -0C(0)NR la R lb , -NR la C(O)OR Ib , -NR la C(0)NR la R lb , -SR la , -S(O)R 1 a , -S(O) 2 R 13 , -NR la S(0) 2 R !b ,
  • Radical L 1 of Formula Ia can be Cj -6 alkylene.
  • Radical R 2 of Formula Ia can be C 3-9 heterocycloalkyl.
  • Radical L 2 of Formula Ia can be Ci -6 alkylene.
  • Radical R 3 of Formula Ia can be aryl or heteroaryl.
  • Radical L 3 of Formula Ia can be a bond or C 2-6 alkenylene.
  • L 1 is a bond or Ci -6 alkylene.
  • R 1 is aryl. In some other embodiments, R 1 is phenyl. In still other embodiments, R 5 can be H, halogen, or Ci -6 haloalkyl. In yet other embodiments, R 5 is F or Cl. In another embodiment, L 1 is a bond or Ci -6 alkylene, and R 1 is aryl.
  • L 2 can be Ci -6 alkylene.
  • R 2 can be heterocycloalkyl.
  • R 2 can be a nitrogen containing heterocycloalkyl.
  • radical R 2 can be aziridine, azetidane, 1,3-diazazitidine, pyrolidine, pyrolidin-2-one, piperidine, 1,2-piperazine, 1,3-piperazine, 1 ,4-piperazine, or azocane.
  • R 2 can be a C 5-6 heterocycloalkyl containing one nitrogen heteroatom.
  • L 2 is Ci -6 alkylene and R 2 is a heterocycloalkyl.
  • L 3 is a bond, arylene or heteroarylene.
  • L 3 is a bond. In some other embodiments, L 3 is arylene, such as phenylene. In yet other embodiments, L 3 is heteroarylene, such as thiophene.
  • R 3 is heteroaryl.
  • radical R 3 can be phenyl, pyrrole, pyrazole, imidzaole, pyridine, pyrimidine, pyrazine, pyridazine, 1 ,2,4- triazine, 1,3,5-triazine, pyrrolizine, indole, quinoline, isoquinoline, benzimidazole, indazole, quinolizine, cinnoline, quinazoline, phthalazine, naphthyridine, carboline, or carbazole.
  • L 3 is aryl or heteroaryl
  • R 3 is heteroaryl.
  • R 1 , L 3 and R 3 is aryl, arylene, heteroaryl or heteroarylene. In some embodiments, at least one of R 1 and R 3 is aryl or heteroaryl. In other embodiments, at least one of L 3 and R 3 is heteroaryl or heteroarylene.
  • R 1 is phenyl, optionally substituted with halogen, L 1 is a bond or Ci -6 alkylene, R 2 is piperidine, L 2 is Ci -6 alkylene, R 3 is a heteroaryl, L 3 is selected from the group consisting of a bond, phenylene or thiophene, and R 4 is hydrogen.
  • radical R 1 of Formula Ia can be C ]-6 alkyl, -C(O)OR l a or phenyl.
  • Radical L 1 of Formula Ia can be Ci -6 alkylene.
  • Radical R 2 of Formula Ia can be pyrolidine or pyrolidin-2-one.
  • Radical L 2 of Formula Ia can be Ci -6 alkylene.
  • Radical R 5a of Formula Ia can be Cj -6 alkyl.
  • Radical R 3 of Formula Ia can be phenyl or carbazole. Radical L 3 of Formula Ia can be a bond or C 2-6 alkenylene.
  • R is Ci -6 alkyl
  • the compounds of Formula I can be any organic compound having the same or similarity. [0094] in some embodiments, the compounds of Formula I can be any organic compound having the same or identical to the compounds of Formula I.
  • the compound can have the formula:
  • L 1 is a bond or Ci -6 alkylene, and R 5 is H or halogen. In yet other embodiments, L ! is a bond. In still yet other embodiments, L 1 is Ci -6 alkylene. In some other embodiments, R 5 is H. In still other embodiments, R 5 is halogen. In yet other embodiments, R 5 is F or Cl. In some other embodiments, L 2 is Ci -6 alkylene and R 2 is a C 5-6 heterocycloalkyl containing 1 N heteroatom. In still other embodiments, L is a bond, arylene or heteroarylene, and R 3 is heteroarylene. In other embodiments, L 3 is a bond. In some other embodiments, L 3 is phenylene. In still other embodiments, L is thiophene. In another embodiment, R 3 is pyridyl. In some embodiments, R 3 is 4-pyridyl. In some embodiments, the compounds can have the formula:
  • the compound can have the formula:
  • the compounds of Formula I can be any organic compound having the same or similarity. [0096] in some other embodiments, the compounds of Formula I can be any organic compound having the same or similarity.
  • the compounds of Formula I can be [0099] In still other embodiments, the compound can be:
  • the compound of the present invention can be CTAOOl, CTA020, CTA033, CTA036, CTA041, CTA042, CTA045, CTA047, CTA048, CTA051, CTA056, CTA065, CTA067, CTA 109, or CTAl 21.
  • the compound of the present invention can be CTA004, CTA008, CTAOl 3, CTA014, CTAOl 7, CTA038, CTA040, or CTA062.
  • the compound of the present invention can be CTAOOl, CTA004, CTA008, CTA013, CTA014, CTA017, CTA020, CTA033, CTA036, CTA038, CTA040, CTA041, CTA042, CTA045, CTA047, CTA048, CTA051, CTA056, CTA065, CTA067, CTA109, or CTA121.
  • the compound can be CTAOOl, CTA020, CTA033, CTA036, CTA041, CTA042, CTA045, CTA047, CTA048, CTA051, CTA056, CTA062, CTA065, CTA067, CTA109, or CTA121.
  • the compound is CTA056. In still yet other embodiments, the compound can be CTA056, CTA092, CTA093, CTA095, CTA097 or CTA099. In another embodiment, the compound can be CTA129, CTA151, CTA163 or CTA164. In some embodiments, the compound can be CTAl 51. In another embodiment, the compound can be CTA056 or CTA151.
  • salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and
  • acid addition salts such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid
  • a basic group such as pyridyl
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
  • Prodrug and metabolite forms of the compounds of the present invention are also included in the present invention.
  • the compounds of the present invention can be formulated in a variety of different manners known to one of skill in the art.
  • Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there are a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington 's Pharmaceutical Sciences, 20 th ed., 2003, supra).
  • the compounds of the present invention can be prepared and administered in a wide variety of oral, injectible and topical dosage forms.
  • the compounds of the present invention can also be prepared and administered in parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally or topically, e.g., in a liquid or gel form or as a patch.
  • Formulations suitable for administration can consist of (a) liquid solutions, such as an effective amount of a compound of the present invention suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets, depots or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; (d) suitable emulsions; and (e) patches.
  • liquid solutions such as an effective amount of a compound of the present invention suspended in diluents, such as water, saline or PEG 400
  • capsules, sachets, depots or tablets each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin
  • suspensions in an appropriate liquid such as suitable emulsions; and (e) patches.
  • pharmaceutical forms can include a pharmaceutically acceptable excipient, such as one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers.
  • a pharmaceutically acceptable excipient such as one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives,
  • Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.
  • a flavor e.g., sucrose
  • an inert base such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • Preferred pharmaceutical preparations can deliver the compounds of the invention in a sustained release formulation.
  • the pharmaceutical preparations are typically delivered to a mammal, including humans and non-human mammals.
  • Non-human mammals treated using the present methods include domesticated animals ⁇ i.e., canine, feline, murine, rodentia, and lagomorpha) and agricultural animals (bovine, equine, ovine, porcine).
  • the compounds of the present invention can be administered as frequently as necessary, including hourly, daily, weekly or monthly.
  • the compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.0001 mg/kg to about 1000 mg/kg daily.
  • a daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. For example, dosages can be empirically determined considering the type and stage of disease diagnosed in a particular patient.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. Doses can be given daily, or on alternate days, as determined by the treating physician.
  • Doses can also be given on a regular or continuous basis over longer periods of time (weeks, months or years), such as through the use of a subdermal capsule, sachet or depot, or via a patch.
  • the pharmaceutical compositions can be administered to the patient in a variety of ways, including topically, parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally.
  • the pharmaceutical compositions are administered parenterally, topically, intravenously, intramuscularly or orally.
  • the pharmaceutically effective amount of a composition required as a dose will depend on the route of administration, the type of disease being treated, and the physical characteristics of the patient.
  • the dose can be tailored to achieve a desired effect, but will depend on such factors as body surface area, weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the present invention provides a pharmaceutical composition of a compound of Formula I and a pharmaceutically acceptable excipient.
  • the compounds of the present invention can be used to treat a variety of conditions.
  • the compounds can be used to treat B-cell and T-cell malignancies, such as leukemia and lymphoma, cancer, such as prostate cancer, as well as osteoporosis.
  • B-cell/T-cell malignancies such as leukemia and lymphoma
  • cancer such as prostate cancer
  • osteoporosis such as osteoporosis
  • the compounds of the present invention are useful for the treatment of a variety of B-cell and T-cell malignancies.
  • B-cells (Bone-cells in mammals) and T-cells are
  • B-cells primarily make antibodies (known as plasma B-cells) in response to an antigen, thereby tagging the antigen for destruction.
  • Plasma B-cells are activated in response to an antigen and are formed from memory B-cells.
  • Memory B-cells are long lived B-cells that have been exposed to the antigen previously (exposure of a na ⁇ ve B-cell to the antigen), and thus "remember" the antigen and are able to mount a quicker response via the plasma B-cells than would otherwise be possible.
  • B-cell and T-cell malignancies include, but are not limited to, autoimmune disorders, leukemias such as B-cell acute lymphocytic leukemia and B-cell chronic lymphocytic leukemia, lymphomas such as non-Hodgkin's lymphomas and B-cell lymphoma, or multiple myeloma. Other B-cell and T-cell malignancies can be treated by the compounds of the present invention. [0119] Given the important role of Btk in B-cell malignancies, the activities of these agents to inhibit Btk was used to identify compounds for the treatment of B-cell malignancies. In addition, the effect of these agents on treatment of B-cell malignancies was also identified using BCBLl cells (human lymphoma cells) and MTT growth inhibition assay.
  • BCBLl cells human lymphoma cells
  • the present invention provides a method of treating leukemia or lymphoma, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of the present invention, thereby treating the leukemia or lymphoma.
  • the leukemia or lymphoma can be treated by inhibiting Itk. In other embodiments, the leukemia or lymphoma can be treated by inhibiting Btk.
  • the present invention provides a method of treating B-cell leukemia or B-cell lymphoma, by administering to a subject in need thereof, a
  • the compounds of the present invention are useful for the treatment of cancer, such as breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, non- small cell lung cancer, brain cancer, cancer of the larynx, gall bladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, and kidney cancer, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfa
  • cancer
  • the cancer is prostate cancer.
  • Compounds useful for the treatment of cancer can be identified by any number of methods known to one of skill in the art. For example, LnCaP cells can be seeded at 5,000 cells/well in 96-well plate overnight and treated with the compounds of the present invention. The cell viability can then be measured using any means known in the art, such as using an MTT assay. Using the assay described herein, compounds of Formula I were identified as active for the treatment of prostate cancer, see Table 3. Any prostate cancer cell line can be used to test for the efficacy of a compound of the present invention for the treatment of prostate cancer, for example, LnCaP, PC3, DU145 and CWR22Rvl . [0125] In some embodiments, the present invention provides a method of treating prostate cancer, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I, thereby treating the prostate cancer.
  • Tyrosine Kinases of the Tec Family are useful for the inhibition of tyrosine kinases.
  • Tyrosine kinases that can be inhibited by the compounds of the present invention include, but are not limited to, the Tec family and the Axl-Sky-Mer family of tyrosine kinases.
  • Tyrosine kinases of the Tec family are involved in the regulation of immune functions, including T-cell signaling and activation.
  • Tyrosine kinases of the Tec family include epithelial and endothelial tyrosine kinases (Etk), Bruton's tyrosine kinase (Btk), IL2- inducible T-cell kinase (Itk), among others.
  • Tyrosine kinases of the Axl-Sky-Mer family are involved in leukemia, gastric cancer, prostate cancer, as well as immune diseases.
  • Tyrosine kinases of the Axl-Sky-Mer family include the c-mer protooncogene tyrosine kinase, or Mer tyrosine kinase (Mertk).
  • Compounds useful for the inhibition of tyrosine kinase activity can be identified by any number of methods known to one of skill in the art. For example, compounds can be incubated with Btk and a substrate, such as YIYGSFK, in a kinase reaction using 33 P-ATP. The products of the reaction can be analyzed by any means known to one of skill in the art. For example, the product can be analyzed on a TLC (Thin Layer Chromatography) plate to determine if the compound inhibits Btk. The same assay is useful for the identification of compounds that inhibit other tyrosine kinases, such as Etk, Itk and Mertk. When Mertk is the target, the substrate can be TSFYGRH.
  • the present invention provides a method for the inhibition of Bruton's tyrosine kinase (Btk) by administering to a subject in need thereof, a
  • the present invention provides a method for the inhibition of epithelial and endothelial tyrosine kinases (Etk) by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I 5 thereby inhibiting Etk.
  • Etk epithelial and endothelial tyrosine kinases
  • the present invention provides a method for the inhibition of Mer tyrosine kinase (Mertk) by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I, thereby inhibiting Mertk.
  • the present invention provides a method for the inhibition of IL2-inducible T-cell kinase (Itk) by administering to a subject in need thereof, a
  • the present invention provides a method of inhibiting a tyrosine kinase including epithelial and endothelial tyrosine kinases (Etk), Bruton's tyrosine kinase (Btk), Mer tyrosine kinase (Mertk) or IL2-inducible T-cell kinase (Itk), the method comprising administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of the present invention, thereby inhibiting the tyrosine kinase.
  • Etk epithelial and endothelial tyrosine kinases
  • Btk Bruton's tyrosine kinase
  • Mertyrosine kinase Mer tyrosine kinase
  • Itk IL2-inducible T-cell kinase
  • the compounds of the present invention are useful for the treatment of osteoporosis.
  • Bruton's tyrosine kinase (Btk) and tyrosine kinase (Tec), tyrosine kinases essential for B cell development, have been shown to regulate osteoclast differentiation by linking two essential pathways for osteoclast differentiation: RANKL and ITAM.
  • RANK and ITAM signaling both signal through formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLC- mediated activation of calcium signal (J Immunol 2009, 182(l):329-339).
  • Mice with tyrosine kinases Btk and Tec knockdown developed severe osteoporosis that was associated with a defect in bone resorption.
  • Compounds of the present invention useful as small molecule inhibitors of Btk can be used to decrease osteoclast activation and prevent bone loss.
  • Such compounds can be identified using bone marrow cells (BMMs) from 2-month-old C57BL mice.
  • the BMMs can be cultured with the compound (at 0, 10 "10 , 10 "8 , 10 "6 M) supplemented with 20ng/ml mCSF and 100ng/ml RANKL for 7-10 days.
  • TRAP+ cell formation, representing mature osteoclasts, can be monitored. Dentine resorption pit area can also be monitored.
  • the present invention provides a method of treating osteoporosis, by administering to a subject in need thereof, a pharmaceutically acceptable amount of a compound of Formula I, thereby treating osteoporosis.
  • CWR22Rvl and LNCaP cells stably transfected with GFP-LC3 were examined under fluorescence microscopy, 24 hours after treatment with either CTA003 or 6RF3 at 10 ⁇ M concentration.
  • the autophagic process started as early as 4 hours post-treatment and lasts for at least 36 hours.
  • Cells treated with different level of CTA003 were further examined for the conversion of endogenous LC3-I to LC3-II forms.
  • Figure 3 A shows autophagosomes as visualized by GFP-LC3 "puncta.”
  • Figure 3B shows an immunoblot (CWR22Rvl) of endogenous LC3 isoforms.
  • PC3 cells were grown to the indicated confluence (0 h) and treated with the corresponding agents (5 ⁇ M). Cell migration was visualized using "wound-healing" assay (0 h and 24 h). (See Figure 4.)
  • Inhibition of Btk kinase activity was determined by incubating purified Btk (50 nM) and the corresponding compounds with the substrate (YIYGSFK) in a kinase reaction.
  • LFM-A 13 is a known Btk inhibitor and was used as a control in these experiments (Uckun, 2008).
  • Figure 5 shows the inhibition of Btk using the compounds of the present invention, as well as the concentration-dependent inhibition of Btk by CTA041, CTA008, and CTA013 compared with LFM-A13.
  • BMMs bone marrow cells
  • CTA013 at 0, 10 ⁇ 10 , 10 "8 , 10 "6 M
  • 20ng/ml mCSF and lOOng/ml RANKL for 7-10 days.
  • TRAP+ cells formation representing mature osteoclasts, were found to decrease by 12% , 30-40% and more than 90%, respectively, in 10 "10 , 10 "8 , 10 "6 M.
  • Dentine resorption pit area was about 40% lower in the 10 "10 M concentration and was not detectable in 10 ⁇ 8 and 10 "6 M concentrations.
  • CTAO 13 was found to exhibit similar effects on gene expression that associate with osteoclastogenesis.
  • OSCAR receptor for Fc ⁇
  • Trem2 receptor for Dap 12
  • TRAF6 a key signaling adaptor for RANK
  • Trap5b osteoclast maturation

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Abstract

La présente invention porte sur des composés de Formule I ainsi que sur des compositions pharmaceutiques comprenant des composés de Formule I. La présente invention porte également sur des procédés de traitement d'une leucémie et d'un lymphome à cellules B, d'un cancer de la prostate et de l'ostéoporose. La présente invention porte également sur des procédés d'inhibition de Btk, Etk, Itk et Mer.
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EP2726077A2 (fr) * 2011-06-28 2014-05-07 Pharmacyclics, Inc. Procédés et compositions visant à inhiber la résorption osseuse
EP2726077A4 (fr) * 2011-06-28 2014-12-10 Pharmacyclics Inc Procédés et compositions visant à inhiber la résorption osseuse
WO2013153539A1 (fr) * 2012-04-13 2013-10-17 Glenmark Pharmaceuticals S.A. Composés tricycliques à titre d'inhibiteurs de kinases tec
WO2014065440A1 (fr) * 2012-10-26 2014-05-01 Canon Kabushiki Kaisha Médicament inhibiteur de cellules cancéreuses et sonde de détection de cellules souches cancéreuses
US10220024B2 (en) 2012-10-26 2019-03-05 Canon Kabushiki Kaisha Method of inhibiting cancer cell, method for detecting cancer cell, and system for detecting cancer cell
CN103804307A (zh) * 2012-11-06 2014-05-21 韩冰 一类治疗缺血性脑损伤的化合物及其用途
EP4115886A1 (fr) 2013-10-25 2023-01-11 Pharmacyclics LLC Procédés de traitement et de prévention de la maladie du greffon contre l'hôte
WO2017040617A1 (fr) 2015-08-31 2017-03-09 Pharmacyclics Llc Combinaisons d'inhibiteurs de btk pour le traitement du myélome multiple
WO2018085731A2 (fr) 2016-11-03 2018-05-11 Juno Therapeutics, Inc. Polythérapie de type thérapie cellulaire t et inhibiteur de btk
WO2019213184A1 (fr) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Polythérapie d'une thérapie par lymphocytes t à récepteur antigénique chimérique (car) et d'un inhibiteur de btk
WO2023220655A1 (fr) 2022-05-11 2023-11-16 Celgene Corporation Méthodes pour surmonter la résistance aux médicaments par ré-sensibilisation de cellules cancéreuses à un traitement avec une thérapie antérieure par l'intermédiaire d'un traitement avec une thérapie par lymphocytes t

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