WO2010096395A1 - Amides utilisés en tant qu'inhibiteurs des kinases - Google Patents

Amides utilisés en tant qu'inhibiteurs des kinases Download PDF

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Publication number
WO2010096395A1
WO2010096395A1 PCT/US2010/024343 US2010024343W WO2010096395A1 WO 2010096395 A1 WO2010096395 A1 WO 2010096395A1 US 2010024343 W US2010024343 W US 2010024343W WO 2010096395 A1 WO2010096395 A1 WO 2010096395A1
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alkyl
cycloalkyl
independently selected
haloalkyl
heterocycloalkyl
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PCT/US2010/024343
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English (en)
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Yongsheng Chen
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Syntech Solution Llc
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Priority to CN2010800081899A priority Critical patent/CN102316738A/zh
Publication of WO2010096395A1 publication Critical patent/WO2010096395A1/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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention is directed to amides, and pharmaceutical compositions thereof, which are inhibitors of kinases such as but not limited to BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.
  • kinases such as but not limited to BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.
  • Protein kinases are a group of enzymes that regulate diverse, important biological processes including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases exert their physiological functions through catalyzing the transfer of the ⁇ -phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides; and are intimately involved in the control of various important cell functions, perhaps most notably: signal transduction, differentiation, and proliferation. In addition to the functions in normal tissues/organs, many protein kinases also play more specialized roles in a host of human diseases including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases); when dysregulated, can cause tumor formation and growth, and further contribute to tumor maintenance and progression.
  • PKs Protein kinases
  • Protein kinases can be categorized as receptor type and non-receptor type.
  • Receptor tyrosine kinases have an extracellular portion, a transmembrane domain, and an intracellular portion, while non-receptor tyrosine kinases are entirely intracellular.
  • RTK mediated signal transduction is typically initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironment
  • VEGFR expression which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer.
  • BCR- AbI expression is an important predictor of response in chronic myelogenous leukemia and Src tyrosine kinase is an indicator of poor prognosis in all stages of colorectal cancer.
  • the present invention provides, inter alia, compounds that are inhibitors of kinases, including receptor tyrosine kinases such as but not limited to those of the BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily, having Formula I:
  • the present invention further provides compositions comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention further provides methods of inhibiting activity of a receptor or nonreceptor tyrosine kinase comprising contacting the kinase with a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of inhibiting the BCR AbI kinase signaling pathway in a cell comprising contacting the cell with a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of inhibiting the flt3 kinase signaling pathway in a cell comprising contacting the cell with a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of inhibiting the C-KIT kinase signaling pathway in a cell comprising contacting the cell with a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of inhibiting the proliferative activity of a cell comprising contacting the cell with a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of inhibiting tumor growth in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of inhibiting tumor metastasis in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of treating a disease in a patient, wherein said disease is associated with dysregulation of the BCR AbI signaling pathway, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides a compound of Formula I for use in therapy.
  • the present invention further provides a compoujd of Formula I for use in the preparation of a medicament for use in therapy.
  • the present invention provides, inter alia, compounds that are inhibitors of kinases, including receptor tyrosine kinases such as but not limited to those of the BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily, having Formula I:
  • X is N or CR 2 ;
  • R 1 is H, or aryl and heteroaryl each optionally substituted by 1, 2, 3, 4, or 5 -W-X-Y-Z;
  • R2, R3 and R7 is H, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, halo, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl, C 1-6 haloalkyl, ,CN, NO 2 , OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , S(O)R B , S(O)NR C R D , S(O) 2 R 8 , NR C S(O) 2 R B , and S(O) 2 NR C R D ; wherein said cycloalkyl, aryl, heterocycloalkyl, heteroary
  • B ring is heteroaryl
  • L is (CR 4 R 5 ) m , (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -( heterocycloalkylene)- (CR 4 R 5 ) q , wherein said cycloalkylene, heterocycloalkylene is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR
  • R 4 and R 5 are independently selected from H, halo, OH, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 1-6 alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C 1-6 haloalkyl, CN, and NO 2 ; or R 4 and R 5 together with the atom to which they are attached form a 3, 4, 5, 6, or 7- membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, Cue alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, Cue alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C 1-6 haloalkyl, CN, and NO 2 ;
  • R 8 H, Ci -6 alkyl, C 2 . 6 alkenyl, or C 2 . 6 alkyny, wherein said Ci -6 alkyl, C 2 . 6 alkenyl and C 2 . 6 alkyny is optionally substituted with 1, 2, or 3 substituents independently selected from halo, (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(arylene)-(CR 4 R 5 ) q , CN, OR a , SR a , C(O)R b , C(0)NR c R d , C(O)OR a , OC(O)R b , 0C(0)NR c R d , NR c R d , NR c C(0)R b , NR c C(0)NR c R d , NR c C(0)0R a ;
  • W and Ware independently absent or independently selected from alkylene, C 2 _ 6 alkenylene, C 2-6 alkynylene, O, S, NR h , CO, COO, C0NR h , SO, SO 2 , SONR h and NR 11 CONR 1 , wherein each of the C 1-6 alkylene, C 2 _6 alkenylene, and C 2 _6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, Ci_ 6 haloalkoxy, amino, C 1-6 alkylamino, and C 2 _ 8 dialkylamino;
  • X and X' are independently absent or independently selected from Cue alkylene, C 2 _6 alkenylene, C 2 _6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, where
  • Y and Y' are independently absent or independently selected from C 1-6 alkylene, C 2 -6 alkenylene, C 2 - 6 alkynylene, O, S, NR h , CO, COO, C0NR h , SO, SO 2 , SONR h , and NR 11 CONR 1 , wherein each of the C 1-6 alkylene, C 2 - 6 alkenylene, and C 2 - 6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, Cue alkyl, Cue haloalkyl, OH, Cue alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2 -8 dialkylamino;
  • R A is H, Ci_ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said Ci -4 alkyl, C 2 - 4 alkenyl, C 2 _ 4 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, and C M alkyl;
  • R B is H, Ci -4 alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said Ci -4 alkyl, C 2 . 4 alkenyl, or C 2 . 4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, and Ci -4 alkyl; R c and R D are independently selected from H, Ci -4 alkyl, C 2 .
  • R a , R al , R a2 and R" 3 are independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, and Ci_ 6 haloalkoxy;
  • R b , R bl , R b2 and R b3 are independently selected from H, Q -6 alkyl, Q -6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 .
  • Ci_ 6 haloalkyl C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C MO alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_ 6 alkyl, Ci_6 alkoxy, Ci_6 haloalkyl, and Ci_6 haloalkoxy; or R cl
  • R c2 and R d2 are independently selected from H, C MO alkyl, Ci_6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl, wherein said C M0 alkyl, Ci_ 6 haloalkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cyclo
  • R c3 and R d3 are independently selected from H, C M0 alkyl, Ci -6 haloalkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C MO alkyl, Ci_6 haloalkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CV 6 alkyl, alkoxy, Ci_6 haloalkyl, and or
  • R 8 is H, CN, and NO 2 ;
  • R h and R 1 are independently selected from H and Cue alkyl
  • R J is H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; m is O, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, or 4; q is O, 1, 2, 3, or 4;
  • Rl when X is CH, Rl is H;
  • the compound of the invention has Formula III; wherein Cy is cycloalkyl optionally substituted by 1, 2, 3, 4, or 5 -W-X-Y-Z.
  • the compound of the invention has Formula IV:
  • compounds of the invention have Formula III and Formula IV, wherein L is absent or C 1-6 alkyl; Cy is cycloalkyl optionally substituted by 1, 2, 3, 4, or 5 -W- X'-Y'-Z';
  • compounds of the invention have Formula III and Formula IV, wherein L is absent or Cue alkyl; Cy is heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5 -W -X'-Y'-Z' In some embodiments, compounds of the invention have Formula Formula IV, wherein L is absent or C 1-6 alkyl; and Cy is cycloalkyl optionally substituted by halo, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 .
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkylyene refers to a linking alkyl group.
  • alkenyl refers to an alkyl group having one or more double carbon- carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • alkenylene refers to a linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon- carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • alkynylene refers to a linking alkynyl group.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCI 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.
  • arylene refers to a linking aryl group.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles. In some embodiments, cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulf ⁇ do substituent.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkylene refers to a linking cycloalkyl group.
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. As used herein, "heteroarylene” refers to a linking heteroaryl group.
  • heterocycloalkyl refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfido groups.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. As used herein, "heterocycloalkylene" refers to a linking heterocycloalkyl group.
  • arylcycloalkyl refers to cycloalkyl group substituted by an aryl group.
  • arylheterocycloalkyl refers to a heterocycloalkyl group substituted by an aryl group.
  • arylheteroaryl refers to a heteroaryl group substituted by an aryl group.
  • biasing refers to an aryl group substituted by another aryl group.
  • heteroarylcycloalkyl refers to a cycloalkyl group substituted by a heteroaryl group.
  • heteroarylheterocycloalkyl refers to a heterocycloalkyl group substituted by a heteroaryl group.
  • heteroarylaryl refers to an aryl group substituted by a heteroaryl group.
  • biheteroaryl refers to a heteroaryl group substituted by another heteroaryl group.
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • halosulfanyl refers to a sulfur group having one or more halogen substituents.
  • Example halosulfanyl groups include pentahalosulfanyl groups such as SF5.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • hydroxylalkyl refers to an alkyl group substituted by OH.
  • cyanoalkyl refers to an alkyl group substituted by CN.
  • alkoxyalkyl refers to an alkyl group substituted by an alkoxy group.
  • alkoxyalkoxy refers to an alkoxy group substituted by alkoxy.
  • haloalkoxy refers to an -O-(haloalkyl) group.
  • arylalkyl refers to alkyl substituted by aryl and "cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
  • amino refers to NH 2 .
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrugs refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. Synthesis
  • novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. The processes described herein can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV -visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV -visible), or mass spectrometry
  • chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective
  • the reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected. Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • An example method includes fractional recrystallization using a "chiral resolving acid" which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds of the invention can be prepared, for example, using the reaction pathways and techniques as described below.
  • a series of amide derivatives of formula 8 can be prepared by the method outlined in Scheme 1. Suzuki coupling of 2,4-dichloropyrimidine 2 with suitable boronic acid 1 produces the corresponding pyrimidine chloride 3 which can be converted to compound 5 by reaction with 3-aminobenzoate 4 under thermal conditions. Hydrolysis of compound 5 with base such as LiOH, NaOH, or KOH affords the acid 6 which can be conveniently transferred to the corresponding amide 8 by coupling with suitable amines 7 using acid-amine coupling reagents such as BOP, ByBOP, EDCI, HATU, HBTU or diethyl cyanophosphate and so on.
  • base such as LiOH, NaOH, or KOH
  • a series of pyrimidine esters of formula 5 can be prepared by the method outlined in Scheme 2.
  • Compound 5 can be very conveniently produced by thermal reaction of pyridinyl enaminone 10 with guanidine 9 which can be obtained by treatment of aniline 4 with cyanamide.
  • Compound 5 can be then transferred to the amide 8 as described above.
  • suitable ligand such as xantphos or BINAP
  • a series of imidazole derivatives of formula 7 can be prepared by the method outlined in Scheme 4. Copper-catalyzed N-arylation of imidazole 14 with aniline bromide 13 to yield compound 7 can be achieved under thermal conditions in the presence of CuI and amines such as N,N'-dimethylethylenediamine, ( ⁇ )-trans-cyclohexanediamine, 1,10-phenanthroline, or 8- hydroxyquinoline.
  • Reaction of imidazole 14 with compound 17 can yield the cyano-imidazole 18.
  • Hydrolysis of the cyano group in 18 under base conditions can give the corresponding acid 19 which can be converted to the N-Boc aniline 20 by treatment with diphenylphosphorylazide and followed reflux in tert-butanol. Removals of the protecting N-Boc group in 20 with acid such HCl and TFA can afford the compound 7.
  • a series of imidazole derivatives of formula 14 can be prepared by the method outlined in Scheme 7.
  • Compound 14 can be conveniently obtained by reaction of alpha-bromo-ketone 22 with formimidamide acetate.
  • compound 14 can be obtained by reaction of formimidamide acetate with alpha-chloro -ketone 25 which can be prepared from the corresponding acid 23 by the method outline in Scheme 8.
  • the imidazole derivatives 14 can be prepared from the suitable aldehyde 26 with tosylmethlisonitrile followed treatment with ammonia as the method outlined in Schem 9.
  • a series of imidazole derivatives of formula 33 can be prepared by the method outlined in Scheme 10.
  • Amide 28 which can be obtained from the acid 27 can be transferred to the corresponding ketone 31 by treatment with the reagent 30 which can be in situ generated from the iodide 29 by reaction with EtMgBr, or i-PrMgBr. Reduction of the ketonr 31 with hydrazine can produce the imidazole 33.
  • a series of aniline derivatives of formula 35 and final compound 36 can be prepared by the method outlined in Scheme 11. Suzuki coupling of aniline bromide 13 with suitable heteroaryl boronic acid 34 can yield the corresponding aniline 35, which was converted to the final compound 36 using condition described previousely.
  • a series of aniline derivatives of formula 37 and final compound 38 can be prepared by the method outlined in Scheme 12. Cu catalyzed coupling of aniline bromide 13 with suitable heteroaryl compound 39 can yield the corresponding aniline 37, which was converted to the final compound 38 using condition described previousely.
  • Example protein kinases modulated by the compounds of the invention include RTKs of of the PDGF subfamily (e.g., the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II), of the FLK subfamily (e.g., Kinase insert Domain-Receptor fetal liver kinase- 1 (KDR/FLK-1), the fetal liver kinase 4 (FLK- 4) and the fms-like tyrosine kinases 1 and 3 (fit- 1 and flt-3)), of the FGF receptor family (e.g., FGFRl, FGFR2, FGFR3 and FGFR4), and of the Src, AbI subfamilies.
  • RTKs of of the PDGF subfamily e.g., the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II
  • the FLK subfamily e.g., Kinase
  • modulate is meant to refer to an ability to increase or decrease activity of an enzyme or receptor. Modulation can occur in vitro or in vivo. Modulation can further occur in a cell. Accordingly, compounds of the invention can be used in methods of modulating a protein kinase, such as an RTK, by contacting the enzyme (or cell or sample containing the enzyme) with any one or more of the compounds or compositions described herein. In some embodiments, the compounds of the invention are useful in treating diseases such as cancer, atherosclerosis, lung fibrosis, renal fibrosis and regeneration, liver disease, allergic disorder, inflammatory disease, autoimmune disorder, cerebrovascular disease, cardiovascular disease, or condition associated with organ transplantation. In further embodiments, the compounds of the invention can be useful in methods of inhibiting tumor growth or metastasis of a tumor in a patient.
  • diseases such as cancer, atherosclerosis, lung fibrosis, renal fibrosis and regeneration, liver disease, allergic disorder, inflammatory disease, autoimmune disorder, cerebrovascular disease, cardiovascular disease, or
  • Example cancers treatable by the methods herein include bladder cancer; breast cancer; cervical cancer; cholangiocarcinoma cancer; colorectal cancer; esophageal cancer; gastric cancer; head and neck cancer; cancer of the kidney; liver cancer; lung cancer; nasopharygeal cancer; ovarian cancer; pancreatic cancer; prostate cancer; thyroid cancer; osteosarcoma; synovial sarcoma; rhabdomyosarcoma; MFH/fibrosarcoma; leiomyosarcoma; Kaposi's sarcoma; multiple myeloma; lymphoma; adult T cell leukemia; acute myelogenous leukemia; chronic myeloid leukemia; glioblastoma; astrocytoma; melanoma; mesothelioma; or Wilm's tumor, and the like.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a compound of the invention with a protein kinase includes the administration of a compound of the present invention to an individual or patient, such as a human, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation of the protein kinase.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder;
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • One or more additional pharmaceutical agents or treatment methods such as, for example, chemotherapeutics, anti-cancer agents, cytotoxic agents, or anti-cancer therapies (e.g., radiation, hormone, etc.), can be used in combination with the compounds of the present invention for treatment of the diseases, disorders or conditions described herein.
  • the agents or therapies can be administered together with the compounds of the invention (e.g., combined into a single dosage form), or the agents or therapies can be administered simultaneously or sequentially by separate routes of administration.
  • Suitable anti-cancer agents include kinase inhibiting agents including trastuzumab (Herceptin), imatinib (Gleevec), gefitinib (Iressa), erlotinib hydrochloride (Tarceva), cetuximab
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene- melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitros
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitor
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel
  • cytotoxic agents include navelbene, CPT-I l, anastrazole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafme.
  • cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4- IBB and PD-I, or antibodies to cytokines (IL-IO, TGF-D, etc.). Further antibody therapeutics include antibodies to tyrosine kinases and/or their ligands such as anti-HGF antibodies and/or anti-c-Met antibodies.
  • antibody is meant to include whole antibodies (e.g., monoclonal, polyclonal, chimeric, humanized, human, etc.) as well as antigen-binding fragments thereof.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • anti-cancer agents include anti-cancer vaccines such as dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • Methods for the safe and effective administration of most of the above agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference” (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.
  • the compounds of the invention can be administered in the form of pharmaceutical compositions which is a combination of a compound of the invention and a pharmaceutically acceptable carrier.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral adminstration. Some typical dose ranges are from about C g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.
  • Another aspect of the present invention relates to fluorescent dye, spin lable, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the protein kinase target in tissue samples, including human, and for identifying kinase ligands by inhibition binding of a labeled compound.
  • the present invention includes kinase enzyme assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to H (also written as D for deuterium), H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro IDO enzyme labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 I , 131 1, 35 S or will generally be most useful. For radio-imaging applications 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art.
  • a radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • the ability of a test compound to compete with the radio-labeled compound for binding to the enzyme directly correlates to its binding affinity.
  • kits useful for example, in the treatment or prevention of diseases, such as cancer and other diseases referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt thereof.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the invention will be described in greater detail by way of specific examples.
  • Compounds of the invention are assayed to measure their capacity to inhibit protein kinases such as c-kit, PDGFR ⁇ , AbI, BCR-AbI, FGFR3, FLT3, Lck, KDR, and Epha2 kinase, or mutant forms thereof, using assays generally described below, or using assays known in the art.
  • protein kinases such as c-kit, PDGFR ⁇ , AbI, BCR-AbI, FGFR3, FLT3, Lck, KDR, and Epha2 kinase, or mutant forms thereof.
  • the murine cell line used is the 32D hemopoietic progenitor cell line transformed with BCR-AbI cDNA (32D-p210). These cells are maintained in RPMI/10% fetal calf serum
  • Ba/F3 transfectants (expressing full length wild type Bcr-Abl or BCR-AbI with kinase domain point mutations) were generated, selected and maintained as described in ref (La Rosse P. Corbin AS, Stoffregen EP, Deininger MW, Druker BJ, Cancer Res 2002, 62, 7149-53).
  • BCR- AbI autophosphorylation is quantified with capture Elisa using a c-abl specific capture antibody and an antiphosphotyrosine antibody.
  • 32D-p210 cells are plated in 96 well TC plates at 2xlO 5 cells per well in 50 ⁇ L of medium. 50 ⁇ L two-fold serial dilutions of the test compounds (C max is 10 ⁇ M) are added to each well.
  • the cells are incubated for 90 minutes at 37 0 C, 5% CO 2 .
  • the cells are then treated for 1 hour on ice with 150 ⁇ L of lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA and 1% NP-40) containing protease and phosphatase inhibitors.
  • 50 ⁇ L of cell lysate is added to 96-well optiplates previously coated with anti-abl specific antibody and blocked. The plates are incubated for 4 hours at 4 0 C.
  • test compounds of the invention that inhibit the proliferation of the BCR-AbI expressing cells, inhibit the cellular BCR-AbI autophosphorylation in a dose-dependent manner.
  • the murine cell line used is the Ba/F3 murine pro-B cell line that overexpresses full length FLT3 construct. These cells are maintained in RPMI 1640/10% fetal bovine serum
  • Compounds of the invention are tested for their ability to inhibit transformed Ba/F3-TEL- FGFR3 cells proliferation, which is depended on FGFR3 cellular kinase activity.
  • Ba/F3-TEL- FGFR3 are cultured up to 800,000 cells/mL in suspension, with RPMI 1640 supplemented with 10% fetal bovine serum as the culture medium. Cells are dispensed into 384-well format plate at 5000 cell/well in 50 ⁇ L culture medium.
  • Compounds of the invention are dissolved and diluted in dimethylsufoxide (DMSO). Twelve points 1 :3 serial dilutions are made into DMSO to create concentrations gradient ranging typically from 10 mM to 0.05 JUM.
  • DMSO dimethylsufoxide
  • AlamarBlue® (TREK Diagnostic Systems), which can be used to monitor the reducing environment created by proliferating cells, are added to cells at final concentration of 10%. After additional four hours of incubation in a 37 0 C cell culture incubator, fluorescence signals from reduced AlamarBlue® (Excitation at 530 nm, Emission at 580 nm) are quantified on Analyst GT (Molecular Devices Corp.). IC 50 values are calculated by linear regression analysis of the percentage inhibition of each compound at 12 concentrations.
  • HGF hematopoietic growth factors
  • the FMA3 and P815 cell lines are mastocytoma cells expressing endogenous mutated forms of Kit, i.e., frame deletion in the murine juxtamembrane coding region of the receptor-codons 573 to 579.
  • Kit endogenous mutated forms of Kit
  • the human leukaemic MC line HMC-I expresses a double point mutation (i.e. mutations JM-V560G and the kinase domain mutation kitD816V), whereas the HMCl subclone ⁇ l55 expresses only the mutation JM- V560G.
  • the membrane was then incubated either with HRP-conjugated goat anti mouse IgG antibody or with HRP- conjugated goat anti rabbit IgG antibody (Immunotech), Proteins of interest were then visualized by incubation with ECL reagent (Amersham).
  • the biologicl activity of the examples is list in the following:
  • Example 2 BCR Able: ⁇ 12 nM, cKit: ⁇ 12 nM, EPHA2: ⁇ 12 nM LCK: 1882 nM PDGFR beta: 25 nM

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Abstract

La présente invention concerne des amides, et des compositions pharmaceutiques en contenant, qui sont des inhibiteurs des kinases telles que BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 et la sous-famille des PDGFR, amides pouvant être utilisés dans le cadre du traitement du cancer et d'autres maladies associées à la dérégulation des voies des kinases.
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WO2014176259A1 (fr) 2013-04-22 2014-10-30 Icahn School Of Medicine At Mount Sinai Mutations du gène pdgfrb et du gène notch3 responsables de la myofibromatose infantile autosomique dominante
US8975235B2 (en) 2011-03-20 2015-03-10 Intermune, Inc. Lysophosphatidic acid receptor antagonists
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