US20030187026A1 - Kinase inhibitors - Google Patents
Kinase inhibitors Download PDFInfo
- Publication number
- US20030187026A1 US20030187026A1 US10/295,833 US29583302A US2003187026A1 US 20030187026 A1 US20030187026 A1 US 20030187026A1 US 29583302 A US29583302 A US 29583302A US 2003187026 A1 US2003187026 A1 US 2003187026A1
- Authority
- US
- United States
- Prior art keywords
- pyridin
- yloxy
- indol
- ethylamine
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- HFQQIKWONCXRBQ-XXIDSNJLSA-N C[C@H](COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1/C=C/C#N)CC1=CNC2=C1C=CC=C2 Chemical compound C[C@H](COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1/C=C/C#N)CC1=CNC2=C1C=CC=C2 HFQQIKWONCXRBQ-XXIDSNJLSA-N 0.000 description 1
- BQAFLSKWOHFYPB-UHFFFAOYSA-N ClC1=CC=C2C(=N1)N=CN=C2NC1=CC=CC=C1 Chemical compound ClC1=CC=C2C(=N1)N=CN=C2NC1=CC=CC=C1 BQAFLSKWOHFYPB-UHFFFAOYSA-N 0.000 description 1
- VRXZQRLAIVDILJ-UHFFFAOYSA-N ClC1=CC=C2C(Cl)=NC=NC2=N1 Chemical compound ClC1=CC=C2C(Cl)=NC=NC2=N1 VRXZQRLAIVDILJ-UHFFFAOYSA-N 0.000 description 1
- QCIRMZUADWAGRV-QHCPKHFHSA-N N#CC1=CC=CC=C1C[C@H](N)COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1 Chemical compound N#CC1=CC=CC=C1C[C@H](N)COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1 QCIRMZUADWAGRV-QHCPKHFHSA-N 0.000 description 1
- TWJUFZKEWNZWDF-UHFFFAOYSA-N NC(COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1)CC1=NNC2=C1C=CC=C2 Chemical compound NC(COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1)CC1=NNC2=C1C=CC=C2 TWJUFZKEWNZWDF-UHFFFAOYSA-N 0.000 description 1
- XUZVTSOARNRXJL-UHFFFAOYSA-N NC(COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1)COC1=CC2=C(C=CC=C2)C=C1 Chemical compound NC(COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1)COC1=CC2=C(C=CC=C2)C=C1 XUZVTSOARNRXJL-UHFFFAOYSA-N 0.000 description 1
- OACNMGJHMSINIK-IBGZPJMESA-N NC1=CC=C(C2=CN=CC(OC[C@@H](N)CC3=CNC4=C3C=CC=C4)=C2)C=C1 Chemical compound NC1=CC=C(C2=CN=CC(OC[C@@H](N)CC3=CNC4=C3C=CC=C4)=C2)C=C1 OACNMGJHMSINIK-IBGZPJMESA-N 0.000 description 1
- VQMJTIJDQMAPOX-JOCHJYFZSA-N N[C@@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=CC=C1 Chemical compound N[C@@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=CC=C1 VQMJTIJDQMAPOX-JOCHJYFZSA-N 0.000 description 1
- CAQXSLVFQJAZDV-QFIPXVFZSA-N N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=C(F)C=C1 Chemical compound N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=C(F)C=C1 CAQXSLVFQJAZDV-QFIPXVFZSA-N 0.000 description 1
- ITJZTJQKJMPXAO-SANMLTNESA-N N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=C2C=CC=CC2=C1 Chemical compound N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=C2C=CC=CC2=C1 ITJZTJQKJMPXAO-SANMLTNESA-N 0.000 description 1
- VQMJTIJDQMAPOX-QFIPXVFZSA-N N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=CC=C1 Chemical compound N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=CC=C1 VQMJTIJDQMAPOX-QFIPXVFZSA-N 0.000 description 1
- CSIODYUJBFAVFY-NRFANRHFSA-N N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=NC=C1 Chemical compound N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CC=NC=C1 CSIODYUJBFAVFY-NRFANRHFSA-N 0.000 description 1
- XUWKMEBHOZHGMG-DEOSSOPVSA-N N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CN=C2C=CC=CC2=C1 Chemical compound N[C@H](COC1=CC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CN=C2C=CC=CC2=C1 XUWKMEBHOZHGMG-DEOSSOPVSA-N 0.000 description 1
- NCPIWDKRXYPPHJ-ZWJWCZNUSA-N N[C@H](COC1=CC(C2=CC3=C(C=C2)NC(=O)/C3=C\C2CC2)=CN=C1)CC1=CNC2=C1C=CC=C2 Chemical compound N[C@H](COC1=CC(C2=CC3=C(C=C2)NC(=O)/C3=C\C2CC2)=CN=C1)CC1=CNC2=C1C=CC=C2 NCPIWDKRXYPPHJ-ZWJWCZNUSA-N 0.000 description 1
- VRKRFTNPHNNRGS-JOCHJYFZSA-N N[C@H](COC1=CC(C2=CC3=CC=NC=C3C=C2)=CN=C1)C1=CC=CC=C1 Chemical compound N[C@H](COC1=CC(C2=CC3=CC=NC=C3C=C2)=CN=C1)C1=CC=CC=C1 VRKRFTNPHNNRGS-JOCHJYFZSA-N 0.000 description 1
- VUHRELZASYVOIK-QFIPXVFZSA-N N[C@H](COC1=CC(C2=CC3=CC=NC=C3C=C2)=CN=C1)CC1CCCCC1 Chemical compound N[C@H](COC1=CC(C2=CC3=CC=NC=C3C=C2)=CN=C1)CC1CCCCC1 VUHRELZASYVOIK-QFIPXVFZSA-N 0.000 description 1
- KDQNHOKCWRLZDG-NRFANRHFSA-N N[C@H](COC1=CC(C2=NC3=C(C=C2)C(NC2=CC=CC=C2)=NC=N3)=CN=C1)CC1=CNC2=C1C=CC=C2 Chemical compound N[C@H](COC1=CC(C2=NC3=C(C=C2)C(NC2=CC=CC=C2)=NC=N3)=CN=C1)CC1=CNC2=C1C=CC=C2 KDQNHOKCWRLZDG-NRFANRHFSA-N 0.000 description 1
- SEYBNOPADGHXDO-QHCPKHFHSA-N N[C@H](COC1=CC(C2=NC3=C(C=C2)C(NCC2=CC=CC=C2)=NC=N3)=CN=C1)CC1=CNC2=C1C=CC=C2 Chemical compound N[C@H](COC1=CC(C2=NC3=C(C=C2)C(NCC2=CC=CC=C2)=NC=N3)=CN=C1)CC1=CNC2=C1C=CC=C2 SEYBNOPADGHXDO-QHCPKHFHSA-N 0.000 description 1
- XUZVTSOARNRXJL-VWLOTQADSA-N N[C@H](COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1)COC1=CC2=C(C=CC=C2)C=C1 Chemical compound N[C@H](COC1=CN=CC(C2=CC3=C(C=C2)C=NC=C3)=C1)COC1=CC2=C(C=CC=C2)C=C1 XUZVTSOARNRXJL-VWLOTQADSA-N 0.000 description 1
- BLABMYMEINJDBU-FQEVSTJZSA-N N[C@H](COC1=NC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CNC2=C1C=CC=C2 Chemical compound N[C@H](COC1=NC(C2=CC3=C(C=C2)C=NC=C3)=CN=C1)CC1=CNC2=C1C=CC=C2 BLABMYMEINJDBU-FQEVSTJZSA-N 0.000 description 1
- IGUXDXKIOOOGCJ-UHFFFAOYSA-N OC1=NC=NC2=NC(Cl)=CC=C12 Chemical compound OC1=NC=NC2=NC(Cl)=CC=C12 IGUXDXKIOOOGCJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
Definitions
- the present invention relates to compounds which are useful for inhibiting protein kinases, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
- Protein kinases have been clearly shown to be important in the progression of many disease states that are induced by the inappropriate proliferation of cells. These kinases are often found to be up-regulated in many hyperproliferative states such as cancer. These kinases may be important in cell signaling, where their inappropriate activation induces cells to proliferate (e.g. EGFR, ERBB2, VEGFR, FGFR, PDGFR, c-Met, IGF-1R, RET, TIE2). Alternatively, they may be involved in signal transduction within cells (e.g. c-Src, PKC, Akt, PKA, c-Abl, PDK-1). Often these signal transduction genes are recognized proto-oncogenes.
- kinases control cell cycle progression near the G1-S transition (e.g. Cdk2, Cdk4), at the G2-M transition (e.g. Wee1, Myt1, Chk1, Cdc2) or at the spindle checkpoint (Plk, Aurora1 or 2, Bub1 or 3).
- kinases are intimately linked to the DNA damage response (e.g. ATM, ATR, Chk1, Chk2). Disregulation of these cellular functions; cell signaling, signal transduction, cell cycle control, and DNA repair, are all hallmarks of hyperproliferative diseases, particularly cancer. It is therefore likely that pharmacological modulation of one or more kinases would be useful in slowing or stopping disease progression in these diseases.
- X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido;
- X′ is selected from the group consisting of C and N;
- Y is selected from the group consisting of C and N;
- Y′ is selected from the group consisting of C(R 9 ) and N; wherein R 9 is selected from the group consisting of hydrogen and -L 2 -L 3 (R 3 )(R 6 );
- Z is selected from the group consisting of C and N;
- L 1 is selected from the group consisting of a bond, —O—, —NR 5 —, alkenyl, alkynyl, —C(O)—, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(R 12 ) 2 —, —C(R 12 ) 2 N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—; wherein each group is drawn with its left end attached to R 1 and its right end attached to the aromatic ring;
- L 2 is selected from the group consisting of a bond, —O—, —C(R 12 ) 2 —, —S—, —N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—;
- L 3 is selected from the group consisting of a bond, alkylidene and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two substituents independently selected from the group consisting of alkoxy, amino, cyano, and hydroxy;
- R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle
- R 2 and R 4 are independently absent or selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocycle, hydroxyalkyl, and nitro; or
- R 2 and L 1 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle; or
- R 4 and L 2 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle; provided that when L 3 is alkylidene, R 4 and L 2 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle;
- R 3 is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
- R 6 is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
- R 5 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl;
- R 7 is absent or selected from the group consisting of hydrogen, alkyl, cyanoalkenyl, and -L 2 -L 3 (R 3 )(R 6 ); or
- R 7 and L 1 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle;
- each R 12 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.
- the present invention provides a compound of formula (II)
- L 1 is selected from the group consisting of a bond, —O—, —N(R 5 )—, alkenyl, alkynyl, —N(R 5 )C(O)—, and —C(O)N(R 5 )—;
- L 2 is selected from the group consisting of a bond, —O—, —N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—;
- L 3 is selected from the group consisting of a bond, alkylidene, and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two substituents independently selected from the group consisting of amino, cyano, and hydroxy;
- R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle
- R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl; wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; or
- R 2 and L 1 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, pyrazolyl, and phenyl; or
- R 4 and L 2 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl, and pyrrolyl; wherein the ring can be optionally substituted with oxo;
- R 4 and L 2 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl, and pyrrolyl; wherein the ring can be optionally substituted with oxo;
- R 3 is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
- R 6 are independently selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, and heteroarylalkoxy, heteroaryloxy, and heterocycle;
- R 5 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl;
- X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, amino, carboxy, cyano, and halo.
- the present invention provides a compound of formula (III)
- L 1 is selected from the group consisting of a bond, —O—, —N(R 5 )—, alkenyl, alkynyl, and —N(R 5 )C(O)—;
- L 2 is selected from the group consisting of a bond, —O—, —N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—;
- L 3 is alkylene, wherein the alkylene is substituted with one or two substituents independently selected from the group consisting of amino and hydroxy;
- R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle
- R 2 and R 4 are independently selected from the group consisting of hydrogen and halo;
- R 3 and R 6 are independently selected from the group consisting of hydrogen, aryl, arylalkoxy, and heteroaryl; provided that when L 1 and L 2 are bonds, at least one of R 3 and R 6 is other than hydrogen; and
- R 5 is selected from the group consisting of hydrogen and alkyl.
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is selected from the group consisting of a bond, —O—, —C(R 12 ) 2 —, —S—, —N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—; L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkylidene and the alky
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino,
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —O—; L 1 is alkenyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl;
- the present invention provides a compound of formula (I) wherein X is N; and X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; and X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —O—; L 3 is a bond; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —O—; L 3 is a bond; R 1 is heteroaryl; R 2 and R 4 are hydrogen; R 3 is absent; R 6 is heterocycle; and R 7 is hydrogen.
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —N(R 5 )C(O)—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, ary
- the present invention provides a compound of formula (I) wherein X is N; and X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —N(R 5 )C(O)—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is —N(R 5 )C(O)—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkynyl; L 2 is selected from the group consisting of a bond, —O—, —C(R 12 ) 2 —, —S—, —N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—; L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkylidene and the al
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkynyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is selected from the group consisting of a bond, —O—, —C(R 12 ) 2 —, —S—, —N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—; L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkylidene and the alkylene
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; and X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino,
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl; and
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl; and
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is hydrogen; X′ is N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is N; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl;
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is N; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl;
- the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X′ is C; Y is N; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R
- the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X′ is C; Y is N; Y′ is C(R 9 ), wherein R is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3
- the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X′ is C; Y is N; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is N; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R
- the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X′ is C; Y is N; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is N; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is N; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is N; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl;
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is N; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is N; L 1 is a bond; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl;
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is —C—; L 1 is a bond; L 2 is —N(R 5 )—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylal
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —N(R 5 )—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 5 is
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —N(R 5 )—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 5 is
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —N(R 5 )C(O)—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, aryl
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —N(R 5 )C(O)—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is —N(R 5 )C(O)—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is —N(R 5 )—; L 2 is selected from the group consisting of a bond, —O—, —C(R 12 ) 2 —, —S—, —N(R 5 )—, —N(R 5 )C(O)—, and —C(O)N(R 5 )—; L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkyliden
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is —N(R 5 )—; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkyn
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is —N(R 5 )—; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is L 1 -L 3 (R 3 )(R 6 ); Z is C; L 1 is —N(R 5 )—; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is a bond; L 3 is a bond; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thi
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is selected from the group consisting of a bond, —O—, —N(R 5 )—, alkenyl, alkynyl, —C(O)—, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(R 12 ) 2 —, —C(R 12 ) 2 —,
- the present invention provides a compound of formula (1) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is hydrogen; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 3 is alkylidene, wherein the alkylidene is substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl wherein the heteroaryl is isoquinolinyl; R 4 and L 2 , together with the carbon atoms to which they are attached, form a heterocycle wherein the heterocycle is pyrrolidinyl substituted with oxo; R 3 is hydrogen; R 6 is heteroaryl, wherein the heteroaryl is indolyl; and R 7 is hydrogen.
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; and X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is aryl wherein the aryl ring is phenyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is absent; R 6 is heteroaryl; and R 7 is
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is aryl wherein the aryl ring is phenyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is absent; R 6 is heteroaryl; and R 7 is hydrogen.
- the present invention provides a compound of formula (I) wherein X is N; X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is aryl wherein the aryl ring is phenyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is absent; R 6 is aryl; and R 7 is hydrogen.
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X′ is selected from the group consisting of C and N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is heteroaryl wherein the heteroaryl is pyrazolyl; L 2 is a bond; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 3 is hydrogen
- the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X′ is N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is heteroaryl wherein the heteroaryl is pyrazolyl; L 2 is a bond; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is hydrogen; R 6 is aryl; and R 7 is absent.
- the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X′ is N; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is heteroaryl wherein the heteroaryl is pyrazolyl; L 2 is a bond; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is aryl; R 3 is hydrogen; R 6 is aryl; and R 7 is absent.
- the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 7 and L 1 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting aryl, heteroaryl and heterocycle; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 3 is hydrogen; and R 6 is selected from the group consisting of C(R 8
- the present invention provides a compound of formula (I) wherein X is N; and X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 7 and L 1 , together with the carbon atoms to which they are attached, form a ring that is a heteroaryl wherein the heteroaryl is pyridinyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is hydrogen; and R 6 is heteroaryl.
- the present invention provides a compound of formula (I) wherein X is N; and X′ is C; Y is C; Y′ is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 7 and L 1 , together with the carbon atoms to which they are attached, form a ring that is a heteroaryl wherein the heteroaryl is pyridinyl; L 2 is —O—; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is hydrogen; and R 6 is aryl.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
- the invention provides a method of inhibiting protein kinases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
- alkenyl refers to a group derived from a straight or branched chain hydrocarbon of up to six atoms containing at least one double bond.
- alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
- alkoxyalkyl refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.
- alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.
- alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon of one to six atoms.
- alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon of one to six atoms.
- alkylcarbonyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
- alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
- alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
- alkynyl refers to a group derived from a straight or branched chain hydrocarbon of two to six atoms containing at least one triple bond.
- amino refers to an amino group attached to the parent molecular moiety through a carbonyl group.
- amino refers to —NR a R b , wherein R a and R b are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, haloalkylcarbonyl, (NR c R d )alkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, (heterocycle)alkenyl, and (heterocycle)alkyl, wherein the aryl, the aryl part of the arylalkenyl, the arylalkyl, the heteroaryl, the heteroaryl part of the heteroarylalkenyl and the heteroarylalkyl, the heterocycle, and the heterocycle part of the (heterocycle)al
- aminoalkyl refers to an amino group attached to the parent molecular moiety through an alkyl group.
- aryl refers to a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group.
- Bicyclic fused ring systems are exemplified by a phenyl group fused to a cycloalkyl group, as defined herein, or another phenyl group.
- Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group, as defined herein, or another phenyl group.
- aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
- the aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylthio, amino, aminoalkyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heterocycle, (heterocycle)alkoxy, (heterocycle)alkyl, hydroxy, hydroxyalkyl, nitro, oxo, —C( ⁇ NOH)NH 2 , —C( ⁇ NH)NH 2 ; wherein the second aryl group, the aryl part of the arylalkoxy, the arylal
- arylalkenyl refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
- arylalkoxy refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
- arylalkyl refers to an aryl group attached to the parent molecular moiety through an alkyl group.
- arylalkylamino refers to an arylalkyl group attached to the parent molecular moiety through a nitrogen atom, wherein the nitrogen atom is substituted with hydrogen.
- arylalkylidene refers to an aryl group attached to the parent molecular moiety through an alkylidene group
- arylalkylthio refers to an arylalkyl group attached to the parent molecular moiety through a sulfur atom.
- arylalkynyl refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
- arylcarbonyl refers to an aryl group attached to the parent molecular moiety through a carbonyl group.
- aryloxy refers to an aryl group attached to the parent molecular moiety through an oxygen atom.
- arylsulfonyl refers to an aryl group attached to the parent molecular moiety through an sulfonyl group.
- arylthio refers to an aryl group attached to the parent molecular moiety through a sulfur atom.
- carbonyl refers to a —C(O)— group.
- cyano refers to —CN.
- cyanoalkenyl refers to a cyano group attached to the parent molecular moiety through an alkenyl group
- cycloalkyl refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
- Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, adamantyl, and the like.
- (cycloalkyl)alkylidene refers to a cycloalkyl group attached to the parent molecular moiety through an alkylidene group.
- halo refers to F, Cl, Br, or I.
- haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
- haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
- haloalkylcarbonyl refers to an haloalkyl group attached to the parent molecular moiety through a carbonyl group.
- heteroaryl refers to an aromatic five- or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon.
- the five-membered rings have two double bonds, and the six-membered rings have three double bonds.
- the heteroaryl groups are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
- heteroaryl also includes systems where a heteroaryl ring is fused to an aryl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
- Heteroaryls are exemplified by benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxadiazolyl, oxazolyl, purinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,
- heteroaryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkynyl, alkylcarbonyl, amino, aminoalkyl, aryl, arylalkoxy, arylalkyl, arylalkylthio, arylalkynyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heteroaryl group, heteroarylalkoxy, heteroarylalkyl, heterocycle, (heterocycle)alkoxy, (heterocycle)alkyl, hydroxy, hydroxyalkyl, nitro, and oxo, wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, the arylalky
- heteroarylalkenyl refers to a heteroaryl group attached to the parent molecular moiety through an alkenyl group.
- heteroarylalkoxy refers to a heteroaryl group attached to the parent molecular moiety through an alkoxy group.
- heteroarylalkyl refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.
- heteroarylalkylidene refers to a heteroaryl group attached to the parent molecular moiety through an alkylidene group.
- heteroaryloxy refers to a heteroaryl group attached to the parent molecular moiety through an oxygen atom.
- heteroarylsulfonyl refers to a heteroaryl group attached to the parent molecular moiety through a sulfonyl group.
- heterocycle refers to cyclic, non-aromatic, three-, four-, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
- the five-membered rings have zero or one double bonds and the six- and seven-membered rings have zero, one, or two double bonds.
- the heterocycle groups of the invention are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
- heterocycle also includes systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
- Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
- heterocycle groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylidene, amino, aminoalkyl, aryl, arylalkoxy, arylalkyl, arylalkylidene, cyano, (cycloalkyl)alkylidene, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroarylalkylidene, iminohydroxy, a second heterocycle, (heterocycle)alkoxy, (heterocycle)alkyl, (heterocycle)alkylidene, hydroxy, hydroxyalkyl, nitro, and oxo, wherein the aryl, the aryl part of the arylalkoxy and the
- (heterocycle)alkenyl refers to a heterocycle group attached to the parent molecular moiety through an alkenyl group.
- (heterocycle)alkoxy refers to a heterocycle group attached to the parent molecular group through an oxygen atom.
- (heterocycle)alkyl refers to a heterocycle group attached to the parent molecular moiety through an alkyl group.
- (heterocycle)alkylidene refers to a heterocycle group attached to the parent molecular moiety through an alkylidene group.
- hydroxy refers to —OH.
- hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
- aminohydroxy refers to ⁇ N(OH).
- —NR c R d refers to two groups, R c and R d , which are attached to the parent molecular moiety through a nitrogen atom.
- R c and R d are each independently selected from hydrogen and alkyl.
- (NR c R d )alkyl refers to a —NR c R d group attached to the parent molecular moiety through an alkyl group.
- (NR c R d )alkylcarbonyl refers to a (NR c R d )alkyl group attached to the parent molecular moiety through a carbonyl group.
- nitro refers to —NO 2 .
- sulfonyl refers to —S(O) 2 —.
- the compounds of the present invention can exist as therapeutically acceptable salts.
- terapéuticaally acceptable salt represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
- the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid.
- Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate,
- amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
- acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
- Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
- a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
- the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N′-dibenzylethylenediamine.
- Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
- the present compounds can also exist as therapeutically acceptable prodrugs.
- therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
- prodrug refers to compounds which are transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood.
- the invention contemplates various geometric isomers and mixtures thereof resulting from the arrangement of substituents around these carbon-carbon double bonds. It should be understood that the invention encompasses both isomeric forms, or mixtures thereof, which possess the ability to inhibit protein kinases. These substituents are designated as being in the E or Z configuration wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon double bond, and the term “Z” represents higher order substituents on the same side of the carbon-carbon double bond.
- the compounds can be administered alone or in combination with other anticancer agents.
- the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
- the compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
- parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
- Parenterally adminstered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
- the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
- acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
- the anticancer effect of parenterally administered compounds can be prolonged by slowing their absorption.
- One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
- the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
- Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
- injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
- biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
- the rate of drug release can be controlled.
- Transdermal patches can also provide controlled delivery of the compounds.
- the rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
- absorption enhancers can be used to increase absorption.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
- Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings.
- Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefore.
- Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
- Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches.
- the compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
- These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
- a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
- Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
- the total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight.
- Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
- the Akt1 assay uses His-Akt1-S36, a truncated Akt1 containing a His tag at the N-terminus, amino acid 139-460 of Akt1 and the following point mutations: S378A, S381A, T450D and S473D.
- the His-Akt1-S36 assay is run in 96 well plates by incubating 1 nM His-Akt1-S36, 5 ⁇ M Biotin-BAD-peptide (Biotin) and 5 ⁇ M 33 P-ATP in 50 ⁇ L of reaction buffer (20 mM HEPES, pH 7.5, 10 mM MgCl 2 , 0.009% Triton X-100) for 30 minutes at room temperature.
- Akt2, Akt3, PKA, PKC, Erk2, Chk1, Cdc2, Src, CK2, MAPK AP kinase 2, and SGK are carried out similarly using their specific biotinylated peptide substrates and buffer conditions.
- Compounds of the invention inhibited Akt by 0-100% at a concentration of 1 ⁇ M.
- Preferred compounds had percent inhibitions of between 77 and 100 at 1 ⁇ M and more preferred compounds had percent inhibitions of between 92 and 100 at 1 ⁇ M.
- the compounds of the invention are useful in treating disorders which are caused or exacerbated by increased protein kinase levels.
- This invention is intended to encompass compounds having formula (I) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
- compounds of formula (2) (Z is Cl, Br, I, or OTf) can be converted to compounds of formula (4) by treatment with compounds of formula (3) in the presence of triphenylphosphine and an activating agent such as DEAD.
- the reaction can be carried out neat or in the presence of a solvent such as THF, diethyl ether, and MTBE.
- the reaction temperature is typically about ⁇ 10° C. to about 35° C. and reaction times are typically about 8 to about 24 hours.
- Compounds of formula (4) can be converted to compounds of formula (Ia) by treatment with compounds of formula (5) (M is selected from B(OH) 2 ; Sn(R a ) 3 , where R a is an alkyl or aryl group; and hydrogen) in the presence of a palladium catalyst and an optional additive such as triethylamine.
- a palladium catalyst include Pd(PPh 3 ) 4 , and Pd(OAc) 2 and P(o-tol) 3 .
- Representative solvents include toluene, acetonitrile, and DME.
- the reaction is typically conducted at temperatures between about 60° C. and about 110° C. and reaction times are typically about 4 to about 12 hours.
- Scheme 2 shows that compounds of formula (6) (Z 1 and Z 2 are independently Cl, Br, I, or OTf) can be converted to compounds of formula (8) by treatment with compounds of formula (7) according to the procedure described in Scheme 1. These compounds can be converted to compounds of formula (9) by treatment with benzophenone imine, a palladium catalyst, and a base.
- palladium catalysts include Pd 2 dba 3 and a ligand such as BINAP, dppf, or dppe.
- Representative bases include sodium tert-butoxide and potassium tert-butoxide.
- the reaction is conducted in a solvent such as toluene, acetonitrile, or DME; at temperatures from about 60° C. to about 90° C.; and at times from about 8 to about 24 hours.
- Compounds of formula (9) can be treated with compounds of formula (10) in the presence of an acid such as acetic acid and then treated with sodium cyanoborohydride to provide compounds of formula (Ib).
- Representative solvents include methanol and ethanol. The reaction is typically conducted at about 20° C. to about 70° C. and reaction times are typically about 1 to about 4 hours.
- Scheme 3 shows the preparation of compounds of formula (Ic).
- Compounds of formula (11) (Z is Br) can be treated with a palladium catalyst under CO atmosphere to provide compounds of formula (12).
- palladium catalysts include PdCl 2 .dppf, PdCl 2 and BINAP, and PdCl 2 .dppe.
- Representative solvents include THF, water, DME, and mixtures thereof. The reaction is typically conducted at about 80° C. to about 100° C. and reaction times are typically between 12 and 24 hours.
- Compounds of formula (12) can be converted to compounds of formula (Ic) by treatment with a substituted amine in the presence of a coupling agent.
- Representative coupling agents include EDC, HOBt, DCC, DMAP, and mixtures thereof.
- solvents used include dichloromethane, DMF, and DME. The reaction is typically conducted at about 0° C. to about 35° C. and reaction times are typically about 12 to about 24 hours.
- Scheme 5 shows the synthesis of compounds of formula (Ie).
- Compounds of formula (15) can be converted to compounds of formula (16) by treatment with a reducing agent.
- reducing agents include Pd/C and ammonium formate, Pd/C and hydrogen, and PtO 2 and hydrogen.
- Representative solvents include methanol and ethanol. The reaction is typically conducted at about 50° C. to about 70° C. for about 15 minutes to about 2 hours.
- Compounds of formula (16) can be converted to compounds of formula (Ie) by treatment with an electrophile such as a halo-substituted heteroaryl group.
- electrophile such as a halo-substituted heteroaryl group.
- solvents used in these reactions include ethanol and methanol. The reaction is typically conducted at about 50° C. to about 70° C. for about 6 to about 18 hours.
- compounds of formula (8) can be converted to compounds of formula (If) (where L 2 is a bond) by treatment with compounds of formula (17) (M is B(OR z ) 2 , wherein R z is hydrogen or alkyl) in the presence of a palladium catalyst and a base such as cesium carbonate or sodium carbonate.
- a palladium catalyst and a base such as cesium carbonate or sodium carbonate.
- Representative palladium catalysts include PdCl 2 .dppf, Pd(PPh 3 ) 4 , and PdCl 2 (PPh 3 ) 2 .
- solvents used in these reactions include DMF, DME, and NMP.
- the reaction is typically conducted at about 30° C. to about 100° C. for about 4 to about 12 hours.
- Example 1A A mixture of Example 1A (0.8 g, 3.27 mmol), 4-vinylpyridine (0.69 g, 5.53 mmol), tri-o-tolylphosphine (0.6 g, 1.96 mmol), palladium acetate (0.16 g, 0.65 mmol) and triethylamine (0.66 g, 6.53 mmol) in acetonitrile (15 mL) was stirred for 8 hours at 80° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated under vacuum.
- Example 2A The desired product was prepared by substituting Example 2A for Example 1A in Example 1B. MS (DCI/NH 3 ) m/e 471 (M+H) + .
- Example 2B A solution of Example 2B (603 mg, 1.28 mmol) in dichloromethane (20 mL) at room temperature was treated with 4N HCl in dioxane (5 mL), stirred for 2 hours, and concentrated. The residue was dissolved in water (1.5 mL) and freeze-dried to provide the desired product as the hydrochloride salt (610 mg, 99%).
- Example 2B 500 mg, 1.06 mmol
- dichloromethane 5 mL
- trifluoroacetic acid 5 mL
- the residue was dissolved in water (1.5 mL) and freeze-dried to provide the desired product as the trifluoroacetate salt (643 mg, 85%).
- Example 2C A solution of Example 2C (150 mg, 0.400 mmol) in acetic acid (2.4 mL) at room temperature was treated portionwise with NaNO 2 (117 mg. 1.70 mmol), stirred for 18 hours, quenched with water (40 ⁇ L), stirred for an additional hour, poured into 2N NaOH, and extracted with isopropanol/dichloromethane. The combined extracts were concentrated. The residue was treated with LiOH.H 2 O (25 mg) in THF/water (1 mL/0.5 mL), heated to 55° C. overnight, diluted with dichloromethane, washed with water, dried (MgSO 4 ), filtered, and concentrated.
- the desired product was prepared as the trifluoroacetate salt by substituting 2-tert-butoxycarbonylamino-3-benzo[b]thiophen-3-yl-propan-1-ol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2D.
- the desired product was prepared as the hydrochloride salt by substituitng L-Boc-(4-(2,6-dichlorobenzyloxy)phenyl)alaninol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2C.
- the desired product was prepared as the hydrochloride salt by substituting L-Boc-3-benzyloxyalaminol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2C.
- Example 9A A mixture of Example 9A (9.37 g, 43.3 mmol), 4-vinylpyridine (14.0 mL, 130 mmol), tri-o-tolylphosphine (13.5 g, 44.4 mmol), palladium acetate (2.65 g, 11.8 mmol) and triethylamine (120 mL, 0.861 mol) in acetonitrile (40 mL) was heated to reflux overnight and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated under vacuum.
- Example 9B The desired product was prepared as the trifluoracetate salt by substituting Example 9B and (1S,2S)-2-(dimethylamino)-1-phenylpropan-1-ol for 3-bromo-5-hydroxypyridine and L-Boc-tryptophanol, respectively, in Example 2A then proceeding as described for Examples 2B and 2D.
- the desired product was prepared as the trifluoracetate salt by substituting L-Boc-(2-naphthyl)alaminol for L-Boc-tryptophanol in Example 92A then proceeding as described for Examples 2B and 2D.
- the concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product (2.18 g, 36%).
- Example 11A A mixture of Example 11A (1.88 g, 7.2 mmol), benzophenone imine (1.22 mL), Pd 2 (dba) 3 (66 mg), BINAP (125 mg), sodium tert-butoxide (0.97 g), and toluene (19 mL) was heated to 80° C. overnight and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate to provide a solid (2.44 g). This was stirred with 2N HCl (aq.) (5.0 mL) in THF (50 mL) at room temperature for 2 hours and concentrated.
- 2N HCl aq.
- Example 11B A mixture of Example 11B (52 mg, 0.264 mmol), L-Boc-tryptophanal (J. Med. Chem., 1985, 28(12), 1874.) (80 mg, 0.277 mmol) and acetic acid (80 ⁇ L) in methanol (4 mL) was stirred at room temperature for 3 hours, refluxed for 2 hours, cooled to room temperature, treated with sodium cyanoborohydride (35 mg) stirred for 1 hour, and filtered. The filtrate was concentrated and the residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the designed product (43 mg, 35%). MS (DCI/NH 3 ) m/e 470 (M+H) + .
- Example 11C A solution of Example 11C (40 mg, 0.085 mmol) in dichloromethane (3.0 mL) at room temperature was treated with 4N HCl in dioxane (0.5 mL), stirred for 1 hour, and concentrated to provide the desired product as the hydrochloride salt (30 mg, 74%).
- Example 12A A mixture of Example 12A in HBr/HOAc (30%, 50 mL) was stirred at 100° C. for 8 hours, cooled to room temperature and concentrated. The concentrate was partitioned between ethyl acetate and saturated Na 2 CO 3 (aq.). The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel with 30% ethyl acetate/hexane provided the desired product (0.51 g, 72%). MS (DCI/NH 3 ) m/e 209 (M+H) + .
- Example 12B The desired product was prepared by substituting Example 12B for 3-bromo-5-hydroxypyridine in Example 2A (0.78 g, 66%). MS (DCI/NH 3 ) m/e 481 (M+H) + .
- Example 13A (1.50 g, 3.125 mmol), Pd 2 (dba) 3 (71 mg, 0.078 mmol) and tri-o-tolylphosphine (71 mg, 0.23 mmol) in DMF (30 mL) was treated with 4-vinylpyridine (492 mg, 4.68 mmol) and triethylamine (1.30 mL, 9.4 mmol), purged with nitrogen, and heated to 100° C. for 4 hours. The mixture was cooled to room temperature, treated with ethyl acetate (200 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated.
- Example 2A 500 mg, 1.12 mmol
- Pd 2 Cl 2 (PPh 3 ) 2 77 mg, 0.112 mmol
- CuI 52 mg, 0.27 mmol
- DMF 7 mL
- trimethylsilylacetylene 475 ⁇ L, 3.36 mmol
- triethylamine 468 ⁇ L, 3.36 mmol
- the residual oil was purified by flash column chromatography on silica gel with 1:2 ethyl acetate/hexanes to provide the desired product (417 mg, 80%).
- MS (APCI) m/e 464 (M+H) + .
- Example 14A 400 mg, 0.86 mmol
- THF 6 mL
- tetrabutylammonium fluoride 1.0 M solution in THF, 1.12 mL, 1.12 mmol
- ethyl acetate 50 mL
- washed with brine dried (MgSO 4 )
- MS (APCI) m/e 392 (M+H) + .
- Example 14B A mixture of Example 14B (150 mg, 0.384 mmol), 4-bromopyridine hydrochloride (75 mg, 0.34 mmol), Pd 2 Cl 2 (PPh 3 ) 2 (27 mg, 0.0384 mmol), and CuI (18 mg, 0.093 mmol), was purged with nitrogen, treated with DMF (4 mL) and triethylamine (214 mL, 1.54 mmol), stirred at 50° C. for 20 hours, cooled to room temperature, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 2:1 ethyl acetate/hexanes to provide the desired product (122 mg, 68%). MS (APCI) m/e 469 (M+H) + .
- Example 14D 40 mg, 0.11 mmol
- 5% Pd/BaSO 4 8.1 mg
- quinoline 8.1 ⁇ L
- methanol 3 mL
- the filtrate was concentrated and the residual oil was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product (30 mg, 75%).
- Example 11B A mixture of Example 11B (200 mg, 1.0 mmol), HOBt (210 mg), EDC (290 mg), DMAP (25 mg) and Boc-homophenylalanine was stirred at room temperature overnight and concentrated. The residue was dissolved in ethyl acetate, washed sequentially with water, 5% NaHCO 3 , and water, dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (192 mg, 41%). MS (DCI/NH 3 ) m/e 459 (M+H) + .
- Example 2A A solution of Example 2A (1.30 g, 3.02 mmol) and PdCl 2 .dppf (123 mg) in THF/water (6.3 mL/6.3 mL) was heated to 100° C. under CO (800 psi) for 19 hours, cooled to room temperature, and diluted with water. The mixture was extracted with dichloromethane and the combined extracts were washed with water, dried (MgSO 4 ), filtered, and concentrated to provide the desired product (912 mg, 76%). MS (DCI/NH 3 ) m/e 396 (M+H) + .
- Example 17A A solution of Example 17A (410 mg, 1.0 mmol), 4-aminopyridine (100 mg, 1.0 mmol), EDC (960 mg), and HOBt (680 mg) in DMF (10 mL) was stirred at room temperature overnight, diluted with dichloromethane, washed with water, dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate/methanol (8:1) to provide the desired product (87 mg, 18%). MS (DCI/NH 3 ) m/e 488 (M+H) + .
- Example 18A A mixture of Example 18A (1.60 g, 6.3 mmol) and LiOH.H 2 O (2.64 g) in THF/water (50 mL/50 mL) was stirred at room temperature for 2 hours. The THF was removed under vacuum and the aqueous layer was acidified with 1N HCl (aq.). The solid was collected by filtration and dried to provide the desired product. MS (DCI/NH 3 ) m/e 227 (M+H) + .
- Example 19A A mixture of Example 19A (2.0 g, 9.387 mmol) and SOCl 2 (3.5 mL, 47.9 mmol) in benzene (10 mL) was stirred at room temperature for 24 hours and concentrated to provide the desired product (2.167 g, 99%).
- (DCI/NH 3 ) m/e 231, 233, 235 (M+H) + .
- the desired product was prepared as the hydrochloride salt by substituting Example 9B and N-tert-butoxylcarbonylaminoethanol (200 mg, 1.00 mmol) for 3-bromo-5-hydroxypyridine and L-Boc-tryptophanol, respectively, in Examples 2A and 2C.
- Example 19C 100 mg, 0.285 mmol
- Example 19B (66.0 mg, 0.285 mmol)
- triethylamine 250 ⁇ L, 1.79 mmol
- DMF 5 mL
- the aqueous layer was extracted three times with dichloromethane and the combined extracts were washed with water, dried (MgSO 4 ), filtered, and concentrated.
- the residue was chromatographed on silica gel with dichloromethane/methanol/NH 4 OH (100:5:0.5) to provide the free base.
- the material was treated with 2M HCl/Et 2 O to provide the hydrochloride salt (34.0 mg, 22%).
- Example 20A A solution of Example 20A (247 mg, 0.600 mmol), ammonium formate (400 mg, 6.34 mmol) and 10% Pd/C (25 mg) in methanol (10 mL) was heated to reflux for 30 minutes, cooled to room temperature, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate/hexanes (1:1) to provide the desired product (200 mg, 87%). MS (DCI/NH 3 ) m/e 382 (M+H) + .
- Example 20B A solution of Example 20B (41.2 mg, 0.108 mmol) and 2-amino-4-chloropyrimidine (14.0 mg, 0.108 mmol) in ethanol (0.5 mL) was heated to 80° C. for 13 hours and purified by flash column chromatography on silica gel with dichloromethane/methanol/NH 4 OH (100:5:0.5) to provide the desired product (50 mg, 98%). MS (DCI/NH 3 ) m/e 475(M+H) + .
- Example 21A A solution of Example 21A (1.0 g, 4.3 mmol) in 30% H 2 SO 4 (10 mL) at 0° C. was treated with NaNO 2 (386 mg, 5.6 mmol), stirred for 5 hours, treated with a solution of NaI (2.1 g, 14 mmol) in H 2 O (2 mL), stirred for 2 hours, treated with additional NaI (2.1 g, 14 mmol), stirred for 2 hours, poured into 30% NaOH (aq.) (200 mL) at 0° C. and extracted three times with 10% methanol/ethyl acetate. The combined organic phases were dried (MgSO 4 ), filtered, and concentrated.
- Example 21C 100 mg, 0.35 mmol
- THF 3 mL
- 9-BBN 0.5 M solution in THF, 0.70 mL, 0.35 mmol
- cannulated into a mixture of Example 21B 108 mg, 0.32 mmol
- PdCl 2 (dppf) 26 mg, 0.032 mmol
- Cs 2 CO 3 228 mg, 0.7 mmol
- the mixture was treated with ethyl acetate (50 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated.
- the residual oil was purified by flash column chromatography on silica gel with 80% ethyl acetate/hexanes to provide the desired product (69 mg, 40%).
- Example 2A A solution of Example 2A (250 mg, 0.56 mmol) in ethylene glycol dimethyl ether (20.0 mL) at room temperature was treated with tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol), stirred for 10 minutes, treated with a solution of (4-cyanophenyl)boronic acid (123 mg, 0.84 mmol) in ethanol (5.0 mL), stirred for 15 minutes, treated with 2M Na 2 CO 3 (aq.) (1.4 mL), heated to reflux for 4 hours, cooled to room temperature, and concentrated.
- tetrakis(triphenylphosphine)palladium(0) 32 mg, 0.03 mmol
- 4-cyanophenyl)boronic acid 123 mg, 0.84 mmol
- 2M Na 2 CO 3 aq.
- Example 22A A solution of Example 22A (20 mg, 0.043 mmol) in dichloromethane (2.0 mL) at 0° C. was treated dropwise with trifluoroacetic acid (0.5 mL) and stirred for 2 hours while warming to room temperature. The reaction mixture was concentrated to provide the desired product as the trifluoroacetate salt (27 mg, 88%).
- Example 23A 500 mg, 1.8 mmol
- Example 23B 600 mg, 3.5 mmol
- Pd 2 (dba) 3 42 mg; 0.045 mmol
- BINAP 56 mg; 0.09 mmol
- sodium tert-butoxide 350 mg; 3.6 mmol
- the combined extracts were washed successively with saturated NaHCO 3 , water, and brine, dried (Na 2 SO 4 ), and concentrated.
- the concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (97 mg, 18%).
- Example 23C A mixture-of Example 23C (175 mg, 0.58 mmol), benzophenone imine (150 mg, 0.83 mmol), Pd 2 (dba) 3 (54 mg, 0.06 mmol), BINAP (55 mg, 0.09 mmol), and sodium tert-butoxide (80 mg, 0.82 mmol) in 3 mL toluene was heated to 75-80° C. for 4 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (150 mg, 64%).
- Example 23D A mixture of Example 23D (145 mg; 0.36 mmol) in 3 mL THF at room temperature was treated with 10 drops of water and 3 drops of conc. HCl, stirred for 2 hours, and concentrated. The residue was partitioned between ethyl acetate and concentrated NaHCO 3 (aq). The aqueous layer was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% methanol/dichloromethane to provide the desired product (59 mg, 68%).
- Example 23E A mixture of Example 23E (55 mg, 0.23 mmol) and L-Boc-tryptophanal (84 mg, 0.29 mmol) in 2 mL dichloromethane at room temperature was treated with Ti(iPrO) 4 (1 mL), stirred for 2 hours, and concentrated. The residue was dissolved in 2 mL ethanol, treated with NaBH 3 CN (30 mg; 0.46 mmol), stirred for 2 hours, diluted with water, and filtered. The filter cake was washed with methanol and the filtrate was concentrated. The residue was suspended in methanol/dichloromethane and filtered. The filtrate was concentrated and the concentrate was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide the desired product (28 mg, 24%).
- Example 23F A solution of Example 23F (26 mg, 0.05 mmol) in 2 mL dichloromethane at room temperature was treated with 0.5 mL TFA, stirred for 3 hours, and concentrated. The concentrate was purifed by reverse phase HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA and the residue was dissolved in water and lyophilized to provide the desired product as the trifluoroacetate salt (27 mg, 70%).
- a sealed tube was charged with 5-hydroxyisoquinoline (0.15 g, 1.03 mmol), 3,5-dibromopyridine (0.24 g, 1.03 mmol), potassium carbonate (0.27 g, 2.0 mmol) and DMF (4 mL).
- the reaction was heated to 240° C. for 10 minutes in a personal chemistry microwave.
- the reaction was partitioned between water and ethyl acetate.
- the aqueous layer was extracted twice with ethyl acetate.
- the combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 2:1 ethyl acetate/hexanes to provide the desired product (0.071 g, 23%).
- Example 25A A mixture of Example 25A (11.4 g, 64 mmol) in 200 mL THF was cooled to ⁇ 78° C., treated with 1.6 M nBuLi in hexanes (100 mL, 160 mmol), warmed to 0 ° C., stirred for 1 hour, treated with a solution of DMF (22 g, 215 mmol) in 100 mL THF, warmed to room temperature, stirred for 1 hour, diluted with brine, and extracted three times with ethyl acetate. The combined extracts were washed with water, washed twice with brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (9.1 g, 69%).
- Example 25B A solution of Example 25B (870 mg, 4.2 mmol) in 3N HCl (aq.) (10 mL) was heated to reflux overnight, and extracted three times with diethyl ether. The aqueous layer was adjusted to pH>7 with solid K 2 CO 3 and extracted six times with 20% isopropanol/chloroform. The combined extracts were dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product (450 mg; 87%).
- Example 25C 450 mg, 3.68 mmol
- Example 25D 605 mg, 3.68 mmol
- 20 mL ethanol and 1.2 mL of 10% NaOH (aq) was heated to reflux for 3 hours and concentrated.
- the solid was collected and rinsed with ethyl acetate to provide the desired product (740 mg, 80%).
- Example 25F 100 mg, 0.45 mmol
- L-Boc-tryptophan 150 mg, 0.49 mmol
- Example 16A Boc-homophenylalanine
- Example 27A (0.25 g, 0.86 mmol) and Example 2A (0.444 g, 1.00 mmol) in 6 mL of DMF was treated with Pd 2 (dba) 3 (0.08 g, 0.086 mmol), tri-o-tolylphosphine (0.02 g, 0.04 mmol), and triethylamine (0.15 mL, 1.0 mmol), heated to 75° C. in a sealed tube for 8 hours, and concentrated. The residue was purified by flash column chromatography on silica gel with 2.5% methanol/dichloromethane to provide the desired product (0.125 g, 30%).
- Example 27B A solution of Example 27B (0.125 g, 0.25 mmol) in dichloromethane (3 mL) at room temperature was treated with TFA (400 ⁇ L), stirred for 1 hour, and concentrated. The concentrate was azeotropically distilled with diethyl ether two times and the residue was purified by reverse phase HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the di-trifluoroacetate salt (0.110 g, 70%).
- the desired product was prepared by substituting D-Boc-tryptophanol for L-Boc tryptophanol in Example 2A.
- Example 2A A solution of Example 2A (1 g, 2.23 mmol) in DMA (15 mL) was treated with hexamethylditin (1.8 mL, 5.6 mmol) and Pd(PPh 3 ) 4 (0.4 g, 0.2 mmol), heated to 75° C. for 1.5 days, added to water, and extracted three times with ethyl acetate. The combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.4 g, 34%).
- Example 32A 0.2 g, 0.31 mmol
- 6-bromophthalimide 0.084 g, 0.4 mmol
- DMF dimethyl methyl
- Pd 2 dba 3 0.02 mmol
- tri-o-tolylphosphine 0.2 g, 0.01 mmol
- triethylamine 0.06 mL, 0.4 mmol
- the reaction was heated to 75° C. for 6 hours in a sealed tube and concentrated.
- the residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.116 g, 55%).
- Example 33A A solution of Example 33A (1.02 g, 4.47 mmol) in CCl 4 (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product (1.1 g, 79%).
- Example 33B A solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) at room temperature was treated with 1N NH 3 in methanol (7.14 mL, 7.14 mmol), stirred for 24 hours, and filtered. The filter cake was washed with diethyl ether (100 mL) to provide the desired product (0.4 g, 52%).
- Example 34A (6.5 g, 37 mmol) in acetic acid (100 mL) at room temperature was treated with Br 2 (4 mL, 84 mmol), stirred for 1 hour and 15 minutes, poured into water (200 mL), and filtered. The solid was washed with water (2 ⁇ 100 mL), and hexanes (2 ⁇ 100 mL), dissolved in diethyl ether, washed with brine (50 mL), and concentrated to provide the desired product (8.5 g, 89%).
- Example 34B A solution of Example 34B (6.28 g, 24.4 mmol) in THF (75 mL) was treated with concentrated HCl (aq.) (15 mL) and water (15 mL), heated to reflux for 1 hour, and concentrated to remove the THF.
- the aqueous solution was treated with additional water (5 mL) and concentrated HCl (5 mL), cooled to 0° C., treated with a solution of NaNO 2 (1.85 g, 26.84 mmol) in water (10 mL) in 5 portions, warmed to room temperature gradually over a 2-hour period, and stirred overnight at room temperature.
- the reaction was heated to reflux for 6 hours, and filtered.
- the solid was washed with water (50 mL) and diethyl ether (50 mL) and dried under vacuum to provide the desired product (3.0 g, 54%).
- Example 34C A solution of Example 34C (0.4 g, 1.8 mmol) in POCl 3 (2.5 mL) was heated to 100° C. for 2 hours, and poured slowly onto ice. The aqueous layer was cooled to 0° C. and adjusted to pH 5-7 with 50% NaOH. The aqueous layer was extracted with ethyl acetate (2 ⁇ 50 mL), and the combined organic layers were concentrated. The residue was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product (0.190 g, 43%).
- Example 34D A solution of Example 34D (2.6 g, 10.6 mmol) in ethanol (70 mL) was treated with hydrazine monohydrate (3 mL, 90% solution), stirred at room temperature for 3 days, and filtered. The solid washed with water (50 mL) and diethyl ether (50 mL) and dried under vacuum to provide the desired product (2.5 g, 100%).
- Example 34E A solution of Example 34E (3.5 g, 14 mmol) in water (50 mL) was heated to reflux, treated dropwise with a solution of CuSO 4 (2.8 g, 17.5 mmol) in water (20 mL), refluxed for 2 hours, cooled to room temperature, adjusted to pH 7 with saturated NaHCO 3 (aq), and extracted with ethyl acetate (2 ⁇ 25 mL). The combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.7 g, 24%).
- the desired product was prepared by as the trifluoroacetate salt substituting 5-bromo-3-(1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one for 6-bromophthalimide (L. Sun, et al., J. Med. Chem., 1998, 41, 2588.) in Example 32.
- Example 41A A solution of Example 41A (5.46 g, 21.3 mmol) and 3,5-dibromopyridine (5.03 g, 21.3 mmol) in DMF (25 mL) at room temperature was treated with NaH (60% in mineral oil, 1.08 g, 25.6 mmol) in several portions. The reaction was stirred at room temperature for 20 minutes, heated to 60° C. for 2 hours, and poured into water. The aqueous layer was extracted with diethyl ether and the combined extracts were washed with water, dried (MgSO 4 ), filtered, and concentrated.
- Example 41C A mixture of Example 41C (159 mg, 0.345 mmol), RaNi 2800 (525 mg), ammonia (2 mL), and triethylamine (2 mL) in methanol (20 mL) was stirred under hydrogen (60 psi) at room temperature for 73 hours and concentrated. The residue was triturated with ethyl acetate and methanol. The resulting solid was dissolved in trifluoroacetic acid (1 mL), stirred for 5 minutes at room temperature, and concentrated. The residue was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt (64 mg, 26%).
- Example 43A A solution of Example 43A (1.5 g, 5.6 mmol) in nitrobenzene (10 mL) was refluxed for 5 minutes, filtered, cooled to room temperature and filtered again. The solid was washed with hexanes and dried to provide the desired product (0.68 g, 55%). MS (DCI/NH 3 ) m/e 225 (M+H) + .
- Example 43B The desired product was prepared by substituting Example 43B for 3-bromo-5-hydroxypyridine in Example 2A. Purification by flash column chromatography on silica gel with 100% ethyl acetate provided the desired product (0.89 g, 72%). MS (DCI/NH 3 ) m/e 497 (M+H) + .
- Example 43C A mixture of Example 43C (0.33 g, 0.67 mmol), pyridine-4-boronic acid (0.13 g, 0.99 mmol), cesium floride (0.2 g, 1.34 mmol) and tetrakistriphenylphosphine palladium (0.038 g, 0.034 mmol) in DMF (10 mL) was stirred at 100° C. for 8 hours, treated with ethyl acetate (10 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% methanol/dichloromethane to provide the desired product (0.25 g, 76%). MS (DCI/NH 3 ) m/e 495 (M+H) + .
- Example 22 To a solution of Example 22 (200 mg, 0.43 mmol) in toluene (7.0 ml) and methanol (0.5 ml) were added hydroxylamine hydrochloride (33 mg, 0.48 mmol) and potassium tert-butoxide (54 mg, 0.48 mmol) and the mixture was stirred for 8 h at room temperature under a nitrogen atmosphere. Another portion of hydroxylamine hydrochloride (33 mg, 0.48 mmol) and potassium tert-butoxide (54 mg, 0.48 mmol) was added and the mixture was heated to 80° C. for 16 h. The mixture was concentrated and purified by column chromatography on silica gel using dichloromethane/methanol (15:1) as solvent system. Obtained were 130 mg (61%) of the product as a white powder.
- Example 75C 4-vinylpyridine in Example 2B.
- Purification on silica gel eluting with 100% ethyl acetate provided the title compound (0.15 g, 49%).
- Example 80A A suspension solution of Example 80A (1.5 g, 6.2 mmol) in POCl 3 (40 ml) was treated with PCl 5 (1.55 g, 7.4 mmol) and introduced HCl gas until solution was saturated. The reaction was stirred at 60° C. for 6 hours and concentrated under vacumm.
- Example 80B A mixture of Example 80B (1.8 g, 6.5 mmol), P (0.48 g, 15.5 mmol) and HI (3 ml, 48%) in acetic acid (20 ml) was refluxed for 8 hours, filtrated under hot condition and concentrated under vacumm. The residue was basified by adding sodium hydroxide solution, treated with ethyl acetate (200 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexane to provide the title compound (0.81 g, 50%). MS (DCI/NH 3 ) m/e 244 (M+H) + .
- Example 80D for Example 27A in Example 27B.
- Example 89A A suspension of Example 89A (439 mg, 1.58 mmol), (BOC) 2 O (1.040 g, 4.77 mmol), DMAP (50 mg, 0.41 mmol), and triethylamine (670 ⁇ L, 4.81 mmol) in THF (10 mL) was stirred at rt overnight. Reaction was concentrated and chromatographed on silica gel eluting with AcOEt:hexane (1:1) to give the title compound (511 mg, 68%). MS (DCI/NH 3 ) m/z 477, 479(M+1).
- Example 89B was converted to the title compound according to the procedures described for Example 51, Steps 4 and 5. MS (DCI/NH 3 ) m/z 314(M+1) + .
- Example 90B A solution of Example 90B (616 mg, 2.76 mmol), BOC 2 O (1.81 g), DMAP (67 mg), and triethylamine (1.15 mL) in acetonitrile (15 mL) was stirred at rt for 2 h. The reaction was concentrated and the residue was chromatographed on silica gel eluting with AcOEt:hexane (3:7) to give the title compound (1.18 g, 71%). MS (DCI/NH 3 ) m/z 423 (M+1) + .
- the desired product was prepared by substituting 5-bromo-2-fluorobenzonitrile for 6-bromoisoquinoline in Example 27A.
- Example 97A for in Example 27A in Example 27B.
- Example 97B 120 mg, 0.25 mmol
- 98% hydrazine 5 mL
- poured over ice diluted with brine
- extracted with ethyl acetate dried over MgSO 4 , and concentrated.
- Purification by flash chromatography (7% MeOH/CH 2 Cl 2 ) provided the desired product (103 mg, 84%).
- Example 27C A solution of Example 27C (175 mg, 0.35 mmol), N-Boc-glycine (91 mg, 0.52 mmol), EDC (100 mg), iPr 2 EtN (0.30 mL) and DMAP (10 mg) in CH 2 Cl 2 (7 mL) was stirred at room temperature overnight, diluted with EtOAc, washed with water and brine, dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol/CH 2 Cl 2 to provide the desired product (112 mg, 58%).
- Example 102A A solution of Example 102A (26.6 g; 121 mmol) and manganese(IV) oxide (53 g; 610 mmol) in p-dioxane (500 mL) was heated at reflux for 4 hrs., cooled, filtered through Celite®, evaporated, and purified by flash chromatography (5-10% Et 2 O/hexane) to yield the desired product as a nearly colorless oil that solidified upon standing (20.5 g; 78%).
- Example 102C A mixture of Example 102C (10.08 g, 47.8 mmol), hexamethyl-di-tin 2 (18 g, 55 mmol) and tetrakis(triphenylphosphine)palladium (5.5 g, 4.8 mmol) in toluene (100 ml) was stirred at 95° C. for 6 h. The mixture was then evaporated and the residue was taken into ethyl acetate (300 ml), washed with saturated sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml).
- Example Example 102D was prepared by substituting Example 27A in Example 27B.
- Example 103A (665 mg; 3.0 mmol) in thionyl chloride (7 mL) was heated at reflux for 2 hrs., concentrated, and azeotroped with toluene to give a colorless oil that was carried on with no further purification.
- Example 103C for Example 102B in Example 102C.
- the desired product was prepared as the trifluoroacetate salt by substituting N-[2-trimethylsilanyl)ethoxy ⁇ methyl)-2-imidazolyl lithium chloride for methyl magnesium bromide in Example 102 without doing the last step.
- Example 109A 40 mg; 0.06 mmol
- MeOH 4 mL
- conc. HCl 1 mL
- heated at reflux for 6 hrs. concentrated and purified by reverse phase HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product as the trifluoroacetate salt.
- Example 35A The reaction between Example 35A and morpholine was carried out according to the procedure described by U. Wrstonono, K. Majewska, J. Dudzinska-Usarewicz, M. Bemas, Pharmzie, 1986, 41, 472-474.
- Example 102C (500 mg; 2.37 mmol) was added to a mixture of 60% NaH (115 mg; 2.84 mmol) in DMF (10 mL). After 15 min. at r.t. iodomethane (456 mg; 3.21 mmol) was added, the reaction was stirred for 2 hrs then diluted with water and extracted with EtOAc. The extracts were rinsed with water and brine, dried (MgSO 4 ), evaporated, and isolated by flash chromatography (1:1 Et 2 O:hexane) to give the desired product (360 mg; 67%).
- Example 35A The reaction between Example 35A and N-methyl piperazine was carried out according to the procedure described by U. Wrstonono, K. Majewska, J. Dudzinska-Usarewicz, M. Bemas, Pharmzie, 1986, 41, 472-474.
- Example 35A The reaction between Example 35A and dimethylamine was carried out according to the procedure described by U. Wrstonono, K. Majewska, J. Dudzinska-Usarewicz, M. Bemas, Pharmzie, 1986, 41, 472-474.
- Example 116A (0.03 g, 0.06 mmol) in 2 mL of MeOH was cooled to 0° C. then treated with aniline (0.018 g 0.2 mmol), NaBH 3 CN (0.004 g, 0.06 mmol) and AcOH (1 ml). The mixture was allowed to warm to room temperature overnight. The mixture was diluted with ethyl acetate (20 ml), washed with water (10 ml) and brine (10 ml). The ethyl acetate was evaporated off and the residue was used without further purification.
- Example 116A (0.03 g, 0.06 mmol) was dissolved in 2 mL of MeOH and cooled to 0° C., then treated with NaBH 4 (0.003 g, 0.08 mmol). The mixture was allowed to warm to room temperature over 2 h. The mixture was diluted with ethyl acetate (20 ml), washed with water (10 ml) and brine (10 ml). The ethyl acetate was evaporated off and the residue was used without further purification.
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US10/317,914 US6831175B2 (en) | 2001-12-13 | 2002-12-12 | Kinase inhibitors |
AU2002353147A AU2002353147A1 (en) | 2001-12-13 | 2002-12-12 | 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer |
JP2003552299A JP2005516927A (ja) | 2001-12-13 | 2002-12-12 | 癌治療用のキナーゼ阻害剤としての3−(フェニル−アルコキシ)−5−(フェニル)−ピリジン誘導体および関連化合物 |
PCT/US2002/039915 WO2003051366A2 (fr) | 2001-12-13 | 2002-12-12 | Inhibiteurs de kinase |
CA002470214A CA2470214A1 (fr) | 2001-12-13 | 2002-12-12 | Inhibiteurs de kinase |
EP02790126A EP1463505A2 (fr) | 2001-12-13 | 2002-12-12 | Derives de la 3-(phenyl-alkoxy)-5-(phenyl)-pyridine et composes similaires avec activite inhibiteur de kinase pour le traitement du cancer. |
TW91136090A TW200301122A (en) | 2001-12-13 | 2002-12-13 | Kinase inhibitors |
ARP020104851 AR037832A1 (es) | 2001-12-13 | 2002-12-13 | Compuesto derivado de piridina, composicion farmaceutica que lo comprende y su uso en la fabricacion de un medicamento |
MXPA04005810 MXPA04005810A (es) | 2001-12-13 | 2004-06-14 | Derivados de 3 (fenilalcoxi) -5- (fenil)piridina y compuestos relacionados como inhibidores de quinasa para el tratamiento de cancer. |
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US10/317,914 US6831175B2 (en) | 2001-12-13 | 2002-12-12 | Kinase inhibitors |
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- 2002-11-18 US US10/295,833 patent/US20030187026A1/en not_active Abandoned
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US20030199511A1 (en) | 2003-10-23 |
US6831175B2 (en) | 2004-12-14 |
WO2003051366A3 (fr) | 2004-03-25 |
WO2003051366A2 (fr) | 2003-06-26 |
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