Classifications

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  • A61K31/415—1,2-Diazoles
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  • A61K31/42—Oxazoles
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  • A61K31/433—Thidiazoles
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  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions

• the present invention relates to kinases and compounds which modulate kinases, and uses therefor.
• Particular embodiments contemplate disease indications which are amenable to treatment by modulation of kinase activity by the compounds of the present invention.
• Compounds are contemplated that are active on protein kinases in general, including, but not limited to, Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk
• Also contemplated in accordance with the present invention are methods for the use of the above-described compounds in treating diseases and conditions associated with regulation of the activity of the above-described kinases.
• the use of compounds for therapeutic methods involving modulation of protein kinases are provided, as well as compounds that can be used for therapeutic methods involving modulation of protein kinases.
• compounds have the structure according to the following Formula I:
• the compound of Formula I has a structure according to the following sub-generic structure Formula Ia:
• L 1 is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, also —N(R 11 )—, —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —, also —N(R 11 )—C(O)—, wherein the left side (i.e.
• L 1 is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, also —N(R 11 )—, —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —, also —N(R 11 )—C(O)—, and each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group
• L 1 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 11 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, wherein the left side of L 1 is attached to Ar and the right side of L 1 is attached to the phenyl ring of Formula I or Ia.
• L 1 is —C(X)—N(R 1 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—
• each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably each R 11 and R 4 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and each R 11 and R 4 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• L 1 is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, also —N(R 11 )—N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2-5 also —N(R 11 )—C(O)—, wherein the left side (i.e.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and each R 11 and R 4 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• L 1 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, wherein the left side of L 1 is attached to Ar and the right side of L 1 is attached to the phenyl ring of Formula I or Ia.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• L 1 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—; and each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably each R 11 and R 4 are H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula Ib:
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and R 4 , R 11 , R 12 and R 13 are H.
• A is —C(O)—, and R 4 and R 11 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and R 11 are H.
• A is —C(O)—, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(O)—
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• R 4 and R 11 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and R 11 are H.
• A is —C(R 12 R 13 )—, and R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• A is —C(R 12 R 13 )—
• R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 12 and R 13 are H, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(R 12 R 13 )—;
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula Ic:
• R 4 is hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 is H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro and R 4 is hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and R 4 is H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula Id:
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and R 4 , R 11 , R 12 and R 13 are H.
• A is —C(O)—, and R 4 and R 11 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and are H.
• A is —C(O)—, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(O)—
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• R 4 and R 11 are hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and R 11 are H.
• A is —C(R 12 R 13 )—, and R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• A is —C(R 12 R 13 )—
• R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 12 and R 13 are H, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(R 12 R 13 )—;
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula Ie:
• R 4 is hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 is H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro and R 4 is hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and R 4 is H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula If:
• L 3 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—; and m, Ar, R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , R 13 , and X are as defined for Formula I.
• L 3 is —C(O)—N(R 11 )—, —C(R 12 R 13 )—O—, —O—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, wherein the left side of L 3 is attached to Ar and the right side of L 3 is attached to the phenyl ring of Formula If.
• L 3 is —C(O)—N(R 11 )—, —C(R 12 R 13 )—O—, —O—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula Ig:
• L 3 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—; and m, Ar, R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , R 13 , and X are as defined for Formula I.
• L 3 is —C(O)—N(R 11 )—, —C(R 12 R 13 )—O—, —O—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, wherein the left side of L 3 is attached to Ar and the right side of L 3 is attached to the phenyl ring of Formula Ig.
• L 3 is —C(O)—N(R 11 )—, —C(R 12 R 13 )—O—, —O—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula Ih:
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and R 4 , R 11 , R 12 and R 13 are H.
• A is —C(O)—, and R 4 and R 11 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and R 11 are H.
• A is —C(O)—, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(O)—
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• R 4 and R 11 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and R 11 are H.
• A is —C(R 12 R 13 )—, and R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• A is —C(R 12 R 13 )—
• R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 12 and R 13 are H, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(R 12 R 13 )—;
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula II:
• R a , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and R 4 , R 11 , R 12 and R 13 are H.
• A is —C(O)—, and R 4 and R 11 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and R 11 are H.
• A is —C(O)—, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(O)—
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• R 4 and R 11 are hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 and R 11 are H.
• A is —C(R 12 R 13 ), and R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• A is —C(R 12 R 13 )—
• R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 12 and R 13 are H, and R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• A is —C(R 12 R 13 )—;
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• R 4 , R 11 , R 12 and R 13 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 4 , R 11 , R 12 and R 13 are H.
• the compound of Formula I has a structure according to the following sub-generic structure Formula Ij:
• L 1 is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, also —N(R 11 )—, —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —, also —N(R 11 )—C(O)—, wherein the left side (i.e.
• L 1 is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(C)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, also —N(R 11 )—, —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —, also —N(R 11 )—C(O)—, and each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting
• L 1 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 12 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, wherein the left side of L 1 is attached to Ar and the right side of L 1 is attached to the phenyl ring of Formula Ij.
• L 1 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 11 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, and each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably each R 11 and R 4 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and each R 11 and R 4 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• L 1 is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, also —N(R 11 )—, —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —, also —N(R 11 )—C(O)—, wherein the left side (i.e.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• L 1 is a bond, —N(R 11 )—, —N(R 11 )—C(X)—, —N(R 11 )—S(O) 2 —, —N(R 11 )—C(NH)—, —N(R 11 )—C(X)—N(R 11 )—, or —N(R 11 )—S(O) 2 —N(R 11 )—, also —N(R 11 )—, —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —, also —N(R 11 )—C(X)—, or —N(R 11 )—S(O) 2 —, also —N(R 11 )—C(O)—; and each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro.
• R 2 is hydrogen, fluoro or chloro
• each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably R 2 is fluoro or chloro and each R 11 and R 4 are H.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro
• L 1 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—, wherein the left side of L 1 is attached to Ar and the right side of L 1 is attached to the phenyl ring of Formula Ij.
• R 2 is hydrogen, fluoro or chloro, preferably fluoro or chloro;
• L 1 is —C(X)—N(R 11 )—, —C(R 12 R 13 )—X—, —X—C(R 12 R 13 )—, —C(R 12 R 13 )—N(R 11 )—, or —N(R 11 )—C(R 12 R 13 )—; and each R 11 and R 4 are independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably each R 11 and R 4 are H.
• R 22 is mono-alkylamino, di-alkylamino, or optionally substituted heterocycloalkyl, preferably wherein heterocycloalkyl is a 5 or 6 membered nitrogen containing heterocycloalkyl, wherein a nitrogen of the heterocycloalkyl is bound to the S(O) 2 of Formula Ij.
• R 22 is mono-alkylamino, di-alkylamino or 5 or 6 membered nitrogen containing heterocycloalkyl, wherein the heterocycloalkyl is substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, wherein lower alkyl or the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalky
• Ar is monocyclic or bicyclic nitrogen containing heteroaryl. In some embodiments, Ar is selected from the group consisting of
• Ar is selected from the group consisting of
• Ar is selected from the group consisting of
• Ar is selected from the group consisting of
• Ar is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 16 at each occurrence is independently selected from the group consisting of halogen, —OH, —NH 2 , —CN, lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 20 R 21 , wherein lower alkyl and the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino or di-alkylamino are optionally substituted with one or more, preferably 1, 2, or 3 substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, or cycloalkylamino, wherein R 20 and R 21 are as defined in paragraph [0041].
• R 3 is optionally substituted lower alkyl or optionally substituted C 3-6 cycloalkyl.
• R 3 is lower alkyl or C 3-6 cycloalkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, cycloalkylamino, and C 3-5 cycloalkyl, and wherein C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkyla
• R 3 is lower alkyl or C 3-6 cycloalkyl, wherein lower alkyl or C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio. In some embodiments, R 3 is optionally fluoro substituted lower alkyl or optionally fluoro substituted C 3-6 cycloalkyl.
• R 3 is lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, cycloalkylamino, also one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, and fluoro substituted di-alkylamino, also one or more substituents selected from the group consisting of fluoro
• R 3 is optionally substituted phenyl, also phenyl mono-substituted at the para position, also phenyl mono-substituted at the meta position.
• R 3 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, wherein lower alkyl or the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein the phenyl is mono-substituted at either the para or
• R 3 is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio, preferably wherein the phenyl is mono-substituted at either the para or meta position.
• the compound is selected from the group consisting of:
• a compound or group of compounds includes pharmaceutically acceptable salts of such compound(s), pharmaceutically acceptable formulations of such compound(s), prodrug(s), and all stereoisomers thereof.
• a compound of Formula I includes all sub-embodiments thereof (e.g. including Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, and Ij and all embodiments as described above).
• methods for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of one or more compound(s) of Formula I.
• treat refers to the administration of material, e.g., one or more compound(s) of Formula I, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated.
• methods for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of Formula I.
• the invention provides methods for treating a Raf protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of one or more compound(s) of Formula I.
• Raf protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a Raf kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease or condition.
• the Raf protein kinase includes, but is not limited to, A-Raf, mutations of A-Raf, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1.
• the Raf protein kinase is B-Raf mutation V600E.
• the Raf protein kinase is B-Raf mutation V600E/T529I.
• the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E mutant B-Raf.
• the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E/T5291 mutant B-Raf.
• the Raf protein kinase mediated disease or condition includes a disease or condition for which Raf modulation provides a therapeutic benefit, e.g. wherein treatment with Raf modulators, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
• the Raf modulator is a Raf inhibitor.
• the method involves administering to the subject an effective amount of a compound of Formula I in combination with one or more other therapies for the disease or condition.
• A-Raf, B-Raf or c-Raf-1 protein kinase mediated disease or condition refers to a disease or condition in which the biological function of an A-Raf, B-Raf or c-Raf-1 kinase, respectively, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the A-Raf, B-Raf or c-Raf-1 protein kinase, respectively, alters the development, course, and/or symptoms of the disease or condition.
• a compound of Formula I will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted kinase activity assay.
• a compound of Formula I will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to at least one kinase selected from the group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk,
• a compound of Formula I will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to at least one kinase selected from the group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP
• a compound of Formula I will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to at least one kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak, FGFR1, Flt1, Flt3, Flt4, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, PDGFRB, Pim1, PKC theta, Pyk2, Ret, Src, Stk6, TrkA, TrkB, Yes, and Zap70, including any mutations thereof.
• a compound of Formula I will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to at least one kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, Pim1, PKC theta, Pyk2, Src, Stk6, TrkA, TrkB, Yes, and Zap70, including any mutations thereof.
• a compound of Formula I will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to at least one kinase selected from the group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T529I mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, Kdr, Src and Ret, including any mutations thereof.
• a compound of Formula I will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant.
• a compound of Formula I will selectively inhibit one Raf kinase relative to one or more other Raf kinases.
• the compound of Formula I will selectively inhibit a mutation of the Raf kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf.
• a compound of Formula I will also inhibit the effects of a mutation of the kinase, including, but not limited to, a mutation that is related to a disease state, such as a cancer.
• a mutation that is related to a disease state such as a cancer.
• B-Raf V600E mutant is present in a high percentage of some cancers, such as melanoma, and compounds will inhibit the kinase activity of this mutant.
• a compound of Formula I may selectively inhibit one kinase relative to one or more other kinases, where preferably inhibition is selective with respect to any of the other kinases, whether a kinase discussed herein, or other kinases.
• the compound may selectively inhibit the effects of a mutation of the kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf.
• IC 50 for the one kinase may be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold, also 50-fold, or at least about 100-fold less than the IC 50 for any of the other kinases as determined in a generally accepted kinase activity assay.
• compositions that include a therapeutically effective amount of one or more compound(s) of Formula I and at least one pharmaceutically acceptable carrier, excipient, and/or diluent, including combinations of any two or more compounds of Formula I.
• the composition can further include a plurality of different pharmacologically active compounds, which can include a plurality of compounds of Formula I.
• the composition can include one or more compounds of Formula I along with one or more compounds that are therapeutically effective for the same disease indication.
• the composition includes one or more compounds of Formula I along with one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication.
• the composition includes one or more compounds of Formula I effective in treating a cancer and one or more other compounds that are effective in treating the cancer, further wherein the compounds are synergistically effective in treating the cancer.
• methods for modulating the activity of a protein kinase selected from the group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mn
• methods for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of a composition including one or more compound(s) of Formula I.
• methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2,
• the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta
• the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak, FGFR1, Flt1, Flt3, Flt4, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, PDGFRB, Pim1, PKC theta, Pyk2, Ret, Src, Stk6, TrkA, TrkB, Yes, and Zap70, including any mutations thereof, by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I.
• a protein kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EG
• the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAP4K4, MAPKAPK2, Met, p38, Pim1, PKC theta, Pyk2, Src, Stk6, TrkA, TrkB, Yes, and Zap70, including any mutations thereof, by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I.
• a protein kinase selected from the group consisting of Abl, A-Raf, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak, Fms, Irak4, Jnk1, Jn
• the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, Kdr, Src and Ret, including any mutations thereof, by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I.
• a protein kinase selected from the group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2,
• the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I.
• the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I in combination with one or more other suitable therapies for treating the disease.
• the invention provides methods for treating a cancer mediated by B-Raf V600E mutant or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I in combination with one or more suitable anticancer therapies, such as one or more chemotherapeutic drugs.
• the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I, in combination with one or more other therapies or medical procedures effective in treating the cancer.
• Other therapies or medical procedures include suitable anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant).
• the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g.
• x-ray, ⁇ -ray, or electron, proton, neutron, or a particle beam hyperthermia heating (e.g. microwave, ultrasound, radiofrequency ablation),
• Vaccine therapy e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines
• gene therapy e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha
• photodynamic therapy e.g. aminolevulinic acid, motexafin lutetium
• the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including one or more compound(s) of Formula I in combination with one or more suitable chemotherapeutic agents.
• the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; an antibiotic, including,
• the method of treating a cancer involves administering to the subject an effective amount of a composition including one or more compound(s) of Formula I in combination with a chemotherapeutic agent selected from 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, or erlotinib.
• a chemotherapeutic agent selected from 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, or erlotinib.
• the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of one or more compound(s) of Formula I, a prodrug of such compound, a pharmaceutically acceptable salt of such compound or prodrug, or a pharmaceutically acceptable formulation of such compound or prodrug.
• the compound can be alone or can be part of a composition.
• the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of one or more compound(s) of Formula I, a prodrug of such compound, a pharmaceutically acceptable salt of such compound or prodrug, or a pharmaceutically acceptable formulation of such compound or prodrug in combination with one or more other suitable therapies for the disease or condition.
• kits that include a composition as described herein.
• the composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the composition is approved by the U.S.
• the composition is approved for administration to a mammal, e.g., a human, for a protein kinase mediated disease or condition;
• the invention kit includes written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a protein kinase-mediated disease or condition; and the composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.
• the disease or condition is, for example without limitation, neurologic diseases, including, but not limited to, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, and Huntington's disease; neoplastic diseases and associated complications, including, but not limited to, chemotherapy-induced hypoxia, gastrointestinal stromal tumors (GISTs), prostate tumors, mast cell tumors (including canine mast cell tumors), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g.
• neurologic diseases including, but not limited to, cerebrovascular ischemia, multi-infarct dementia
• sarcomas of neuroectodermal origin leiomyosarcoma
• carcinomas e.g. lung, breast, pancreatic, colon, hepatocellular, renal, female genital tract, squamous cell, carcinoma in situ
• lymphoma e.g. histiocytic lymphoma, non-Hodgkin's lymphoma
• MEN2 syndromes neurofibromatosis (including Schwann cell neoplasia), myelodysplastic syndrome, leukemia, tumor angiogenesis, cancers of the thyroid, liver, bone, skin, brain, central nervous system, pancreas, lung (e.g.
• small cell lung cancer non small cell lung cancer
• pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, bone pain, cancer-related pain and migraine
• cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, reperfusion injury and ischemia (e.g.
• inflammation including, but not limited to, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), systemic lupus erythematosis, Sjogren's Syndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, scarring (e.g.
• immunodeficiency diseases including, but not limited to, severe combined immunodeficiency (SCID), organ transplant rejection, and graft versus host disease
• SCID severe combined immunodeficiency
• renal or prostatic diseases including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complications, and hypertrophy
• metabolic diseases including, but not limited to, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysis and obesity
• infection including, but not limited to, Helicobacter pylori
• compounds of Formula I can be used in the preparation of a medicament for the treatment of a disease or condition is, for example without limitation, neurologic diseases, including, but not limited to, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, and Huntington's disease; neoplastic diseases and associated complications, including, but not limited to, chemotherapy-induced hypoxia, gastrointestinal stromal tumors (GISTs), prostate tumors, mast cell tumors (including canine mast cell tumors), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g.
• sarcomas of neuroectodermal origin leiomyosarcoma
• carcinomas e.g. lung, breast, pancreatic, colon, hepatocellular, renal, female genital tract, squamous cell, carcinoma in situ
• lymphoma e.g. histiocytic lymphoma, non-Hodgkin's lymphoma
• MEN2 syndromes neurofibromatosis (including Schwann cell neoplasia), myelodysplastic syndrome, leukemia, tumor angiogenesis, cancers of the thyroid, liver, bone, skin, brain, central nervous system, pancreas, lung (e.g.
• small cell lung cancer non small cell lung cancer
• pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, bone pain, cancer-related pain and migraine
• cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, reperfusion injury and ischemia (e.g.
• inflammation including, but not limited to, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), systemic lupus erythematosis, Sjogren's Syndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, scarring (e.g.
• immunodeficiency diseases including, but not limited to, severe combined immunodeficiency (SCID), organ transplant rejection, and graft versus host disease
• SCID severe combined immunodeficiency
• renal or prostatic diseases including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complications, and hypertrophy
• metabolic diseases including, but not limited to, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysis and obesity
• infection including, but not limited to, Helicobacter pylori
• the invention provides methods for treating an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, fami animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal A-Raf, B-Raf, and/or c-Raf-1 activity (e.g. kinase activity).
• an animal subject e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, fami animals such as horses, or pets such as dogs and cats
• a disease or condition characterized by abnormal A-Raf, B-Raf, and/or c-Raf-1 activity e.g. kinase activity.
• invention methods involve administering to the subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition an effective amount of compound of Formula I.
• the A-Raf-mediated, B-Raf-mediated, and/or c-Raf-1-mediated disease is selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g.
• lymphoma e.g. histiocytic lymphoma
• neurofibromatosis acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma
• pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine
• cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
• inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease; immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, No
• compounds of Formula I can be used in the preparation of a medicament for the treatment of an A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
• histiocytic lymphoma neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma
• pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine
• cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
• inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease; immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, COPD) and chronic respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not
• the compounds of Formula I with kinase activity IC 50 less than 10 ⁇ M as determined in a standard assay described herein can be used to treat protein kinase mediated diseases and conditions related to the following protein kinases, including any mutations thereof, for example without limitation:
• Halogen refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
• Haldroxyl or “hydroxy” refer to the group —OH.
• Thiol refers to the group —SH.
• “Lower alkyl” alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl.
• the straight chain or branched alkyl group is chemically feasible and attached at any available point to produce a stable compound.
• a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.
• an “optionally substituted lower alkyl” denotes lower alkyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of —F, —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH 2 , —C(S)—NH 2 , —S(O) 2 —NH 2 , —N(H)—C(O)—NH 2 , —N(H)—C(S)—NH 2 , —N(H)—S(O) 2 —NH 2 , —C(NH)—NH 2 , —O—R o , —S—R o , —O—C(O)—R o , —O—
• substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, attached at any available atom to produce a stable compound.
• fluoro substituted lower alkyl denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
• “Lower alkenyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion.
• the straight chain or branched lower alkenyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
• an “optionally substituted lower alkenyl” denotes lower alkenyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of —F, —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH 2 , —C(S)—NH 2 , —S(O) 2 —NH 2 , —N(H)—C(O)—NH 2 , —N(H)—C(S)—NH 2 , —N(H)—S(O) 2 —NH 2 , —C(NH)—NH 2 , —O—R o , —S—R o , —O—C(O)—R o , —
• substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, attached at any available atom to produce a stable compound.
• fluoro substituted lower alkenyl denotes a lower alkenyl group substituted with one or more fluoro atoms, where preferably the lower alkenyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms.
• C 3-6 alkenyl denotes lower alkenyl containing 3-6 carbon atoms.
• An “optionally substituted C 3-6 alkenyl” denotes optionally substituted lower alkenyl containing 3-6 carbon atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
• “Lower alkynyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, preferably one, carbon to carbon triple bond.
• the straight chain or branched lower alkynyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like.
• an “optionally substituted lower alkynyl” denotes lower alkynyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of —F, —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH 2 , —C(S)—NH 2 , —S(O) 2 —NH 2 , —N(H)—C(O)—NH 2 , —N(H)—C(S)—NH 2 , —N(H)—S(O) 2 —NH 2 , —C(NH)—NH 2 , —S—R o , —O—C(O)—R o , —O—C(S)—
• substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, attached at any available atom to produce a stable compound.
• fluoro substituted lower alkynyl denotes a lower alkynyl group substituted with one or more fluoro atoms, where preferably the lower alkynyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms.
• C 3-6 alkynyl denotes lower alkynyl containing 3-6 carbon atoms.
• An “optionally substituted C 3-6 alkynyl” denotes optionally substituted lower alkynyl containing 3-6 carbon atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
• Cycloalkyl refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
• An “optionally substituted cycloalkyl” is a cycloalkyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH 2 , —C(S)—NH 2 , —S(O) 2 —NH 2 , —N(H)—C(O)—NH 2 , —N(H)—C(S)—NH 2 , —N(H)—S(O) 2 —NH 2 , —C(NH)—NH 2 , —O—R o , —S—R o , —O—C(O)—R o ,
• C 3-6 cycloalkyl denotes cycloalkyl containing 3-6 carbon atoms.
• C 3-5 cycloalkyl denotes cycloalkyl containing 3-5 carbon atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
• Heterocycloalkyl refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e.
• the ring carbon is a carbonyl group, such as lactones and lactams.
• the point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained.
• heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl.
• “Nitrogen containing heterocycloalkyl” refers to heterocycloalkyl wherein at least one heteroatom is N.
• An “optionally substituted heterocycloalkyl” is a heterocycloalkyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH 2 , —C(S)—NH 2 , —S(O) 2 —NH 2 , —N(H)—C(O)—NH 2 , —N(H)—C(S)—NH 2 , —N(H)—S(O) 2 —NH 2 , —C(NH)—NH 2 , —O—R o , —S—R o , —O—C(O)—R o ,
• Aryl alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members.
• an “optionally substituted aryl” is an aryl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH 2 , —C(S)—NH 2 , —S(O) 2 —NH 2 , —N(H)—C(O)—NH 2 , —N(H)—C(S)—NH 2 , —N(H)—S(O) 2 —NH 2 , —C(NH)—NH 2 , —O—R o , —S—R o , —O—C(O)—R o , —O—C(S
• Heteroaryl alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced.
• heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl.
• Neitrogen containing heteroaryl refers to heteroaryl wherein at least one heteroatom is N. In some instances, for example when R groups of a nitrogen combine with the nitrogen to form a 5 or 7 membered nitrogen containing heteroaryl, any heteroatoms in such 5 or 7 membered heteroaryl are N.
• An “optionally substituted heteroaryl” is a heteroaryl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH 2 , —C(S)—NH 2 , —S(O) 2 —NH 2 , —N(H)—C(O)—NH 2 , —N(H)—C(S)—NH 2 , —N(H)—S(O) 2 —NH 2 , —C(NH)—NH 2 , —S—R o , —O—C(O)—R o , —O—C(S)—R o ,
• R o , R p , R c , R d , R e , R f and R g as used in the description of optional substituents for alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are defined as follows:
• all occurrences of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted C 3-6 alkenyl, optionally substituted lower alkynyl, or optionally substituted C 3-6 alkynyl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —NO 2 , —CN, —O—R 1a , —S—R 1a , —N(R 1a )—R 1a , —C(O)—R 1a , —C(S)—R 1a , —C(S)—O—R 1a , —C(O)—N(R 1a )—R 1a , —C(S)—N(R 1a )—R 1a , —S(O) 2 —N(R 1a )—R 1a , —C(NH)—N(R 1a )—R
• all occurrences of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted C 3-6 alkenyl, optionally substituted lower alkynyl, or optionally substituted C 3-6 alkynyl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —CN, —O—R 1a , —S—R 1a , —N(R 1a )—R 1a , —C(O)—R 1a , —C(S)—R 1a , —C(O)—O—R 1a , —C(O)—N(R 1a )—R 1a , —C(S)—N(R 1a )—R 1a , —S(O) 2 —N(R 1a )—R 1a , —N(R 1a )—C(O)—R 1a , —N(R 1
• “Lower alkoxy” denotes the group —OR z , where R z is lower alkyl. “Substituted lower alkoxy” denotes lower alkoxy in which R z is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to provide a stable compound. Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents.
• fluoro substituted lower alkoxy denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions on alkoxy are chemically feasible and attached at any available atom to provide a stable compound.
• Lower alkylthio denotes the group —SR aa , where R aa is lower alkyl.
• Substituted lower alkylthio denotes lower alkylthio in which R aa is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to provide a stable compound.
• substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents.
• fluoro substituted lower alkylthio denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions on alkylthio are chemically feasible and attached at any available atom to provide a stable compound.
• Amino or “amine” denotes the group —NH 2 .
• Mono-alkylamino denotes the group —NHR bb where R bb is lower alkyl.
• Di-alkylamino denotes the group NR bb R cc , where R bb and R cc are independently lower alkyl.
• “Cycloalkylamino” denotes the group —NR dd R ee , where R dd and R ee combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with lower alkyl.
• Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. It is understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on other moieties, these are chemically feasible and attached at any available atom to provide a stable compound.
• composition refers to a formulation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.
• pharmaceutically acceptable indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles.
• the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.
• the terms “synergistically effective” or “synergistic effect” indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself.
• ligand and “modulator” are used equivalently to refer to a compound that changes (i.e., increases or decreases) the activity of a target biomolecule, e.g., an enzyme such as a kinase.
• inhibitor refers to a modulator that decreases the activity of the target biomolecule.
• a ligand or modulator will be a small molecule, where “small molecule refers to a compound with a molecular weight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less.
• the terms “greater affinity” and “selective” indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, i.e., with a lower dissociation constant.
• the greater affinity i.e. selectivity
• the Willi “synthesizing” and like terms means chemical synthesis from one or more precursor materials.
• enzymes can be assayed based on their ability to act upon a detectable substrate.
• a compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules.
• the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase.
• a biological activity associated with a particular biomolecule such as a protein kinase.
• an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity of the biomolecule, such as an enzyme.
• Such activity is typically indicated in terms of an inhibitory concentration (IC 50 ) or excitation concentration (EC 50 ) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.
• IC 50 inhibitory concentration
• EC 50 excitation concentration
• the term “contacting” means that the compound(s) are caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction between the compound and other specified material can occur.
• isolated indicates that the sequence is separated from at least a portion of the amino acid and/or nucleic acid sequences with which it would normally be associated.
• the term “purified” indicates that the subject molecule constitutes a significantly greater proportion of the biomolecules in a composition than the proportion observed in a prior composition, e.g., in a cell culture.
• the greater proportion can be 2-fold, 5-fold, 10-fold, or more than 10-fold, with respect to the proportion found in the prior composition.
• the present invention concerns compounds of Formula I, and all sub-generic formulae, that are modulators of protein kinases, for example without limitation, the compounds are modulators of at least one of the kinases selected from the group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit,
• Protein kinases play key roles in propagating biochemical signals in diverse biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions (i.e., indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases. As such, kinases represent important control points for small molecule therapeutic intervention. Specific target protein kinases contemplated by the present invention are described in the art, including, without limitation, protein kinases as described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety, including all specifications, figures, and tables, and for all purposes, as well as the following:
• A-Raf Target kinase
• A-Raf i.e., v-raf murine sarcoma 3611 viral oncogene homolog 1
• ARAF ARAF
• the mature protein comprises RBD (i.e., Ras binding domain) and phorbol-ester/DAG-type zinc finger domain and is involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
• A-Raf inhibitors may be useful in treating neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
• neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease
• neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
• muscle regeneration or degeneration including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myos
• B-Raf Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogene homolog B1) is a 84.4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol: BRAF).
• the mature protein comprises RBD (i.e., Ras binding domain), Cl (i.e., protein kinase C conserved region 1) and STK (i.e., serine/threonine kinase) domains.
• Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal neurons.
• genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals.
• B-Raf kinase is a key component of the RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays a fundamental role in the regulation of cell growth, division and proliferation, and, when constitutively activated, causes tumorigenesis.
• the B-type, or B-Raf is the strongest activator of the downstream MAP kinase signaling.
• the BRAF gene is frequently mutated in a variety of human tumors, especially in malignant melanoma and colon carcinoma.
• the most common reported mutation was a missense thymine (T) to adenine (A) transversion at nucleotide 1796 (T1796A; amino acid change in the B-Raf protein is Val ⁇ 600> to Glu ⁇ 600>) observed in 80% of malignant melanoma tumors.
• T1796A missense thymine
• A adenine transversion at nucleotide 1796
• Functional analysis reveals that this transversion is the only detected mutation that causes constitutive activation of B-Raf kinase activity, independent of RAS activation, by converting B-Raf into a dominant transforming protein.
• Niihori et al. report that in 43 individuals with cardio-facio-cutaneous (CFC) syndrome, they identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders (Niihori et al., Nat. Genet. 2006, 38(3):294-6).
• c-Raf-1 Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viral oncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAF1).
• c-Raf-1 can be targeted to to the mitochondria by BCL2 (i.e., oncogene B-cell leukemia 2) which is a regulator of apoptotic cell death. Active c-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1 phosphorylates BAD (i.e., BCL2-binding protein).
• BAD i.e., BCL2-binding protein
• c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lung and renal cell carcinoma. C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). C-Raf-1 inhibitors may also be useful for the treatment of acute myeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002, 8(25):2243-8).
• Raf-1 activators may be useful as treatment for neuroendocrine tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17(2):139-42).
• Raf inhibitors may be useful in treating A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
• histiocytic lymphoma neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma
• pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine
• cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
• inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, COPD) and chronic respiratory distress syndrome (ARDS); genetic developmental diseases, including
• a number of different assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group or kinases.
• assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group or kinases.
• one of ordinary skill in the art will know of other assays that can be utilized and can modify an assay for a particular application. For example, numerous papers concerning kinases describe assays that can be used.
• Additional alternative assays can employ binding determinations.
• this sort of assay can be formatted either in a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen (amplified luminescentproximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phosphor-specific antibody.
• FRET fluorescence resonance energy transfer
• AlphaScreen amplified luminescentproximity homogeneous assay
• invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention.
• Alternative foul's or derivatives include, for example, (a) prodrugs, and active metabolites (b) tautomers, isomers (including stereoisomers and regioisomers), and racemic mixtures (c) pharmaceutically acceptable salts and formulations and (d) solid forms, including different crystal foul's, polymorphic or amorphous solids, including hydrates and solvates thereof, and other forms.
• the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts.
• Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
• Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
• the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
• some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
• Esters include, for example, esters of a carboxylic acid group, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenol groups.
• prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
• Prodrugs may proceed from prodrug form to active foul' in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.
• bioprecursor prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs.
• bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
• the formation of active drug compound involves a metabolic process or reaction that is one of the follow types:
• Oxidative reactions are exemplified without limitation to reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, as well as other oxidative reactions.
• Reductive reactions are exemplified without limitation to reactions such as reduction of carbonyl functionalitites, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.
• Reactions without change in the state of oxidation are exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.
• Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improves uptake and/or localized delivery to a site(s) of action.
• a transport moiety e.g., that improves uptake and/or localized delivery to a site(s) of action.
• the linkage between the drug moiety and the transport moiety is a covalent bond
• the prodrug is inactive or less active than the drug compound
• the prodrug and any release transport moiety are acceptably non-toxic.
• the transport moiety is intended to enhance uptake
• the release of the transport moiety should be rapid.
• it is desirable to utilize a moiety that provides slow release e.g., certain polymers or other moieties, such as cyclodextrins.
• carrier prodrugs are often advantageous for orally administered drugs.
• the transport moiety provides targeted delivery of the drug, for example the drug maybe conjugated to an antibody or antibody fragment.
• Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
• lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.
• Metabolites e.g., active metabolites
• prodrugs as described above, e.g., bioprecursor prodrugs.
• metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic processes in the body of a subject.
• active metabolites are such pharmacologically active derivative compounds.
• the prodrug compound is generally inactive or of lower activity than the metabolic product.
• the parent compound may be either an active compound or may be an inactive prodrug.
• one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic activity and/or carboxyl groups can be esterified, e.g., glucuronidation.
• carboxyl groups can be esterified, e.g., glucuronidation.
• there can be more than one metabolite where an intermediate metabolite(s) is further metabolized to provide an active metabolite.
• a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and can be further metabolized to provide an active metabolite.
• Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein. See, e.g., Bertolini et al., 1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997 , J Pharm Sci 86(7):756-757; Bagshawe, 1995 , Drug Dev. Res., 34:220-230; Wermuth, supra.
• some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms.
• compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. enantiomers or diastereomers).
• stereoisomers i.e., essentially free of other stereoisomers
• racemates i.e., essentially free of other stereoisomers
• stereoisomers include geometric isomers, such as cis- or trans-orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms are included within the formulae provided herein.
• a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e.).
• 60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”) or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e
• an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
• the compound is present in optically pure form, such optically pure form being prepared and/or isolated by methods known in the art (e.g. by recrystallization techniques, chiral synthetic techniques (including synthesis from optically pure starting materials), and chromatographic separation using a chiral column.
• compounds of Formula I can be in the form of pharmaceutically acceptable salts, or can be formulated as pharmaceutically acceptable salts.
• Contemplated pharmaceutically acceptable salt forms include, without limitation, mono, bis, tris, tetrakis, and so on.
• Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
• a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, hydroxymaleate, methyl
• pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri-alkylamines, or salts derived from amino acids such as L-histidine, L-glycine, L-lysine, and L-arginine.
• bases addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,
• salts can be prepared by standard techniques.
• the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
• a salt can be prepared by reacting the free base and acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an appropriate inorganic or organic base.
• the pharmaceutically acceptable salt of the different compounds may be present as a complex.
• complexes include 8-chlorotheophylline complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes.
• the compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co-crystals, or may be in an amorphous form, or may be any combination thereof (e.g. partially crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the scope of the present invention and specified formulae.
• salts are formed by acid/base addition, i.e.
• co-crystals are a new chemical species that is formed between neutral compounds, resulting in the compound and an additional molecular species in the same crystal structure.
• the formulae are intended to cover hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures.
• the indicated structures include both hydrated and non-hydrated forms.
• Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, or ethanolamine
• Compounds of Formula I can be administered by different routes, including injection (i.e. parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant. Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (hereby incorporated by reference herein).
• compositions will comprise carriers or excipients, which may be chosen to facilitate administration of the compound by a particular route.
• carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like.
• Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like.
• WFI water for injection
• oral administration may be used.
• Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
• Compounds of Formula I may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or oily solutions) and the like.
• Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or codliver oil.
• fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol
• cellulose preparations for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povid
• the oral dosage formulations may also contain disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations. Also provided are dragee cores with suitable coatings.
• concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• compositions that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• injection parenteral administration
• Compounds of Formula I for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
• Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
• the compounds may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.
• transmucosal, topical or transdermal administration may be used.
• penetrants appropriate to the barrier to be permeated are used.
• penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
• detergents may be used to facilitate permeation.
• Transmucosal administration for example, may be through nasal sprays or suppositories (rectal or vaginal).
• Compositions of compounds of Formula I for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art.
• Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12 ). In some embodiments, carriers are selected such that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of solvent (e.g., an oil), is admixed.
• solvent e.g., an oil
• administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
• a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
• the dosage administration will be continuous rather than intermittent throughout the dosage regimen.
• compounds are administered as inhalants.
• Compounds of Formula I may be formulated as dry powder or a suitable solution, suspension, or aerosol.
• Powders and solutions may be formulated with suitable additives known in the art.
• powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts.
• Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like.
• the compounds of Formula I may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratroprium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single or double stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.
• corticosteroids such as
• the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitro, e.g. the compound IC 50 vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g. biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject being treated. Multiple doses may be used.
• the compounds of Formula I may also be used in combination with other therapies for treating the same disease.
• Such combination use includes administration of the compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies.
• dosage may be modified for one or more of the compounds of the invention or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.
• use in combination includes use with other therapies, drugs, medical procedures etc., where the other therapy or procedure may be administered at different times (e.g. within a short time, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than a compound of Formula I, or at the same time as a compound of Formula I.
• Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound of Formula I administered within a short time or longer time before or after the other therapy or procedure.
• the present invention provides for delivery of a compound of Formula I and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration.
• the use in combination for any route of administration includes delivery of a compound of Formula I and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered.
• the other drug therapy may be co-administered with a compound of Formula I.
• Use in combination by co-administration includes administration of co-formulations or formulations of chemically joined compounds, or administration of two or more compounds in separate formulations within a short time of each other (e.g.
• Co-administration of separate formulations includes co-administration by delivery via one device, for example the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other.
• Co-formulations of a compound of Formula I and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they are chemically joined, yet still maintain their biological activity.
• Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two active components.
• the mass spectrometry result indicated for a compound may have more than one value due to the isotope distribution of an atom in the molecule, such as a compound having a bromo or chloro substituent.
• Compound 1 (R 2 and R 4 as defined in paragraph [0004]) is dissolved in an anhydrous solvent (e.g. tetrahydrofuran) under nitrogen atmosphere.
• anhydrous solvent e.g. tetrahydrofuran
• the solution is cooled down with the aid of a dry ice and acetone bath.
• a base e.g. n-butyllithium
• 1,2-bis(chlorodimethylsilyl)ethane at low temperature (typically below ⁇ 70° C.).
• the resulting mixture is stirred at low temperature for 1-2 hours.
• a base e.g. n-butyllithium
• ethyl chloroformate e.g. n-butyllithium
• the resulting mixture is allowed to warm to room temperature and then stirred at room temperature for 1-3 days.
• the reaction mixture is quenched by an acid solution, stirred at room temperature for a couple of hours, and then basified.
• the mixture is extracted with an organic solvent (e.g. dichloromethane or ethyl acetate).
• the desired compound 2 is purified by chromatography.
• a base e.g. lithium hydroxide or sodium hydroxide
• the resulting suspension is stirred in a heated oil bath for over 10 hours.
• the reaction mixture is cooled down to room temperature and then acidified with an acid solution such as concentrated hydrochloric acid.
• the aqueous layer is separated and extracted with an appropriate organic solvent (e.g. ethyl acetate).
• the desired compound 4 is purified by chromatography.
• Compound 7 (R 2 as defined in paragraph [0004]) is dissolved in an appropriate solvent (e.g. methanol). To this solution is added catalyst (e.g. palladium on carbon). The suspension is then placed under a hydrogen atmosphere and shaken at room temperature for over 12 hours. The catalyst is removed by filtration on a pad of celite and washed with an appropriate solvent (e.g. methanol). The filtrate is concentrated under reduced pressure to give compound 8, which is used in the next step without further purification.
• an appropriate solvent e.g. methanol
• a base e.g. sodium hydride
• an appropriate alkylating agent e.g. halide
• the reaction mixture is stirred at room temperature or heated in an oil bath as necessary, for a few hours.
• the reaction mixture is then poured into water.
• the organic layer is collected and the aqueous layer is extracted with an appropriate organic solvent (e.g. ethyl acetate or dichloromethane).
• the organic solvents are then combined.
• the desired compound 10 (R 4 as defined in paragraph [0004]) is purified by chromatography.
• a mixture of compound 10, an appropriate boronic acid 11 (Ar, m and R 1 as defined in paragraph [0004]), and a catalyst (e.g. tetrakis(triphenylphosphine)palladium) in a mixture of base (e.g. aqueous solution of potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile) is heated in an oil bath or is irradiated in a microwave system at over 100° C. for an appropriate time depending on starting materials.
• the reaction mixture is poured into water and then extracted with an appropriate organic solvent (e.g. dichloromethane or ethyl acetate). The organic solvents are then combined.
• the desired compound of Formula Ic (L 2 is S(O) 2 ) or Id is purified by chromatography.
• Compound 13 (LG is a suitable leaving group) is prepared by converting compound 12 into a mesylate or triflate by reacting with the corresponding sulfonyl chloride in an appropriate organic solvent. It can also be converted into the corresponding bromide by reacting with an appropriate agent (e.g. phosphorous tribromide) in the presence of an appropriate base (e.g. pyridine).
• an appropriate agent e.g. phosphorous tribromide
• an appropriate base e.g. pyridine
• Step 3 Synthesis of Compound of Formula I where L 1 is —CH 2 NR 11 —:
• amine 6 is added to a mixture of compound 13 and a base (e.g. cesium carbonate) in an appropriate organic solvent (e.g. acetonitrile).
• an appropriate organic solvent e.g. acetonitrile
• the reaction mixture is stirred at room temperature, or heated in an oil bath if necessary, for 2-24 hours.
• the reaction mixture is poured into water and then extracted with an appropriate organic solvent (e.g. dichloromethane or ethyl acetate). The organic solvents are then combined.
• the desired compound of Formula I is purified by chromatography.
• Step 3 Synthesis of Compound of Formula I where L 1 is —CH 2 NR 11 —:
• amine 6 Ar, m, R 1 and R 11 as defined in paragraph [0004]
• reducing agent e.g. triethylsilane and trifluoroacetic acid
• the reaction mixture is heated in an oil bath for 2-24 hours.
• the reaction mixture is concentrated, poured into water and then extracted with an appropriate organic solvent (e.g. dichloromethane or ethyl acetate).
• an appropriate organic solvent e.g. dichloromethane or ethyl acetate.
• the organic layers are then combined.
• the desired compound of Formula I is purified by chromatography.
• compounds of Formula I where L 1 is —CH 2 NR 11 — may be prepared by reduction of compounds of Formula Ib or Id wherein A is —C(O)— (e.g. prepared as described in Example 1) with an appropriate reducing agent (e.g. borane or diisobutylaluminum hydride).
• an appropriate reducing agent e.g. borane or diisobutylaluminum hydride.
• 1,2-Bis(chlorodimethylsilyl)ethane (24.80 g) was dissolved in 80 mL of anhydrous tetrahydrofuran and slowly added dropwise to the reaction mixture while maintaining the temperature below ⁇ 70° C.
• the resulting mixture was stirred at ⁇ 78° C. for 1 hour, then n-butyllithium (2.5 M, 45 mL) was slowly added dropwise maintaining the temperature below ⁇ 70° C.
• the mixture was then stirred for 30 minutes at ⁇ 78° C., then warmed up to 15° C. over 1 hour.
• the reaction mixture was cooled down to ⁇ 78° C.
• n-butyllithium 2.5 M, 50 mL was slowly added dropwise maintaining the temperature below ⁇ 70° C.
• the mixture was stirred at ⁇ 70° C. for 90 minutes, then 13.40 mL of ethylchloroformate was slowly added dropwise maintaining the temperature below ⁇ 70° C.
• the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 64 hours.
• the reaction was quenched by careful addition of a solution of 50 mL of concentrated hydrochloric acid in 160 mL of water while cooling with an ice/water bath.
• the mixture was stirred at room temperature for 2 hours, then made basic by addition of potassium carbonate.
• the mixture was extracted with 3 ⁇ 100 mL of ethyl acetate and the combined organic extracts were washed with 50 mL of brine and dried with magnesium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the desired compound (15, 17 g, 72%).
• 3-Amino-6-chloro-2-fluorobenzoic acid ethyl ester (15, 17 g) was dissolved in 785 mL of dichloromethane, to which 13.2 mL of pyridine was added, followed by propane-1-sulfonylchloride (16, 12.8 g). The reaction mixture was stirred at room temperature for 18 hours, then poured into 400 mL of water. The organic layer was separated and the aqueous layer was extracted with 200 mL of dicholormethane. The combined organic extracts were dried over magnesium sulfate to give an orange oil (41 g). Trituration in 150 mL of diethylether removed the pyridine salt as a white solid.
• 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid 18 was suspended in anhydrous dichloromethane (30 mL/g). Dimethylformamide (2 drops) was added and the suspension cooled in an ice/water bath. Oxalyl chloride (5 eq) was slowly added dropwise. The bath was then removed and the reaction mixture stirred at room temperature for 2 to 3 hours and the solids slowly disappeared. Dichloromethane and excess oxalyl chloride were removed under reduced pressure and the residue was used without further purification in the next step.
• 6-Bromo-pyridin-3-ylamine (20, 3.16 g, 18.26 mmol) was dissolved in 55 mL of anhydrous tetrahydrofuran. Triethylamine (1.85 g, 2.55 mL, 18.26 mmol) was added and the mixture cooled in an ice/salt bath. A solution of 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 3.8 g, 12.17 mmol) in 55 mL of anhydrous tetrahydrofuran was slowly added dropwise to the reaction mixture.
• Step 6 Preparation 6-chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamide (P-0011)
• N-(6-bromo-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (21, 250 mg, 0.555 mmol) was placed in a microwave vial along with palladium acetate (12.5 mg, 0.055 mmol), BINAP (69 mg, 0.111 mmol), potassium tert-butoxide (124 mg, 1.11 mmol) and 2-amino-5-methyl-thiazole (22, 190 mg, 1.66 mmol). Dimethylformamide (2.5 mL) was added and the vial sealed. The mixture was then heated at 150° C. in a microwave for 3 hours.
• the black mixture was diluted with 50 mL of ethyl acetate and washed with 15 mL of water, then 15 mL of 0.67 M hydrochloric acid solution, 15 mL of water and finally 15 mL of brine.
• the organic phase was dried over magnesium sulfate. After removal of the solvent, the residue was purified by preparative TLC and then HPLC to provide the desired compound as a white solid (P-0011, 10 mg).
• 2-Bromo-5-nitro-pyridine (23, 400 mg) was placed in a microwave vial. Isopropylamine (24, 3 mL) was added and the vial sealed. The mixture was then heated at 120° C. for 30 minutes using a Biotage Initiator EXP microwave. The crude mixture was then absorbed on a column and purified by silica gel chromatography. The fractions containing the desired compound were combined and concentrated to provide the desired compound as a yellow solid.
• the 6-isopropylamino-3-nitro pyridine 25 was dissolved in methanol (35 mL/g). Palladium on carbon catalyst (10%, wet, ⁇ 100 mg) was added and the suspension was placed under a hydrogen atmosphere at room temperature overnight ( ⁇ 18 hours). The catalyst was removed by filtration on a pad of celite and washed with 2 ⁇ 10 mL of methanol. The filtrate was concentrated under reduced pressure to provide the desired compound, which was used without further purification in the next step.
• Step 3 Preparation of 6-chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide (P-0005)
• N*2*-isopropyl-pyridine-2,5-diamine (26, 155 mg, 1.01 mmol) was dissolved in 4 mL of anhydrous tetrahydrofuran. Triethylamine (103 mg, 142 ⁇ L, 1.01 mmol) was added and the mixture cooled in an ice/salt bath. 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 200 mg, 0.68 mmol) in 4 mL of anhydrous tetrahydrofuran was then slowly added dropwise.
• N-(2-Acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide P-0004 was synthesized in three steps from 2-amino-5-nitropyrimidine 27 as shown in Scheme 6.
• 2-Amino-5-nitropyrimidine (27, 500 mg) was suspended in 5 mL of acetic anhydride. The mixture was heated at 160° C. for two hours, then cooled to room temperature. The solids were filtered and washed with 5 mL of water, then suspended in 10 mL of water and the pH was brought to 8-9 by addition of 25% ammonium hydroxide solution. The solids were filtered, washed with 2 ⁇ 10 mL cold water and recrystallized from ethyl acetate to provide the desired compound as beige needles (28, 382 mg, 58%).
• N-(5-Nitro-pyrimidin-2-yl)-acetamide (28, 620 mg) was suspended in 31 mL of methanol. Palladium on carbon catalyst (10%, wet, 60 mg) was added and the suspension was placed under hydrogen atmosphere for 17 hours. The catalyst was filtered off on a pad of celite and washed with 2 ⁇ 30 mL of methanol. The filtrate was concentrated under reduced pressure to provide the desired compound as pale yellow needles (29, 520 mg, 100%).
• N-(5-amino-pyrimidin-2-yl)-acetamide (29, 154 mg, 1.01 mmol) was dissolved in 3 mL of anhydrous tetrahydrofuran. Triethylamine (103 mg, 142 ⁇ L, 1.01 mmol) was added and the mixture cooled in an ice/salt bath. 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 200 mg, 0.68 mmol) in 3 mL of anhydrous tetrahydrofuran was then slowly added dropwise.
• N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamide P-0008 was synthesized in three steps from 2,6-difluoro-3-nitro-benzoic acid 30 and N-(5-amino-pyridin-2-yl)-acetamide 31 as shown in Scheme 7.
• 2,6-difluoro-3-nitro-benzoic acid (30, 500 mg) was dissolved in 15 mL of anhydrous dichloromethane. N,N-Dimethylformamide (1 drop) was then added and the mixture cooled to 5° C. in an ice/water bath. Oxalyl chloride (1.1 mL, 5 eq) was slowly added dropwise.
• reaction mixture was stirred at room temperature for two hours, then concentrated under reduced pressure to give a yellow solid residue, which was dissolved in 5 mL of anhydrous tetrahydrofuran and slowly added dropwise to a solution of N-(5-amino-pyridin-2-yl)-acetamide (31, 558 mg, 1.5 eq) and triethylamine (0.52 mL) in 10 mL of anhydrous tetrahydrofuran. The resulting suspension was stirred at room temperature overnight.
• the mixture was diluted with 50 mL of ethyl acetate, washed with 2 ⁇ 25 mL of water, then 25 mL brine, dried over magnesium sulfate and concentrated to provide the crude desired compound as a brown solid (32, 980 mg, 84%), which was used in the next step without further purification.
• N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (32, 950 mg) was suspended in 15 mL of methanol. Palladium on carbon catalyst (10%, wet, 100 mg) was added and the suspension was placed under hydrogen atmosphere for 17 hours. The catalyst was filtered off on a pad of celite and washed with 2 ⁇ 20 mL of methanol. The filtrate was concentrated under reduced pressure to provide the desired compound as a black solid (33, 750 mg, 86%).
• Step 3 Preparation of N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamide (P-0008)
• 2-Amino-5-nitro-pyridine 34, 500 mg was dissolved in 5 mL of anhydrous tetrahydrofuran.
• N-Methyl morpholine (436 mg, 1.2 eq) was added and the mixture cooled to ⁇ 10° C. in an ice/salt acetone bath.
• a solution of isopropenyl chloroformate (520 mg) in 5 mL of tetrahydrofuran was then slowly added dropwise while maintaining the temperature below ⁇ 10° C. The reaction mixture was stirred at room temperature overnight, then diluted with 25 mL of ethyl acetate and 20 mL of water.
• the aqueous layer was separated and extracted with 2 ⁇ 25 mL of ethyl acetate.
• the combined organic extracts were washed with 25 mL of half saturated brine and dried over magnesium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the desired compound as a white solid (35, 0.52 g, 65%).
• Step 4 Preparation of pyrrolidine-1-carboxylic acid ⁇ 5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]pyridin-2-yl ⁇ -amide (P-0006)
• Pyrrolidine-1-carboxylic acid (5-amino-pyridin-2-yl)-amide (38, 100 mg, 0.48 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran.
• Triethylamine 49 mg, 67 ⁇ L, 0.48 mmol
• 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 100 mg, 0.34 mmol) in 1 mL of anhydrous tetrahydrofuran was then slowly added dropwise.
• 3-Aminoquinoline (39, 172 mg, 1.19 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran. Triethylamine (120 mg, 170 ⁇ L, 1.19 mmol) was added and the mixture cooled in an ice/salt bath. 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (19, 250 mg, 0.80 mmol) in 5 mL of anhydrous tetrahydrofuran was slowly added dropwise.
• Step 3 Preparation of propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl ⁇ -amide (P-0019)
• Step 3a Preparation of quinoline-3-carboxylic acid [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-0024)
• Step 3b Preparation of propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl ⁇ -amide (P-0025)
• Additional compounds may be prepared following the protocol of Scheme 13, optionally replacing propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 43 with N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (prepared following the protocol of Scheme 11, Example 11, steps 1 and 2 using 4-trifluoromethyl-benzenesulfonyl chloride in Step 1 in place of propane-1-sulfonyl chloride 16) in Step 1 and 3-hydroxyquinoline 51 with a suitable alcohol in Step 3.
• the following compounds may be prepared by this method:
• Additional compounds may be synthesized in six steps according to the following Scheme 15 or in four steps according the following Scheme 16.
• the purified Boc-protected amine is dissolved in dichloromethane, trifluoroacetic acid is added and the reaction stirred at room temperature, monitoring by TLC for the disappearance of starting material.
• the completed reaction is neutralised by pouring into a cooled saturated solution of sodium hydrogen carbonate and then extracted 3 ⁇ into dichloromethane. The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide the desired compound.
• carboxylic acid 55 (R a is optionally substituted heteroaryl), anhydrous tetrahydrofuran, 1 drop anhydrous dimethylformamide, and oxalyl chloride are added under nitrogen.
• the reaction mixture is allowed to stir at room temperature for 1.5 hours, then concentrated to dryness.
• the resulting residue is diluted with anhydrous tetrahydrofuran, then triethylamine and (3-amino-2,4-difluoro-phenyl)-carbamic acid methyl ester 54 are added and allowed to stir at room temperature overnight.
• the reaction is diluted with water extracted 3 ⁇ into ethyl acetate.
• the organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo to provide the desired compound as a crude solid, which is purified by silica gel column chromatography (hexane:ethyl acetate gradient).
• reaction is allowed to stir at 60° C. and monitored by TLC. When complete, reaction is extracted with 1N aqueous HCl and ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and volatile solvents removed to provide the desired compound as a crude solid.
• 2,6-Difluoro-3-nitrobenzoic acid 60 is converted to 2,6-difluoro-3-nitro-phenylamine 61 following the methods described in Scheme 15, Step 3.
• 2,6-Difluoro-3-nitro-phenylamine 61 is reacted with compound 55 following the methods described in Scheme 15, Step 4 to provide the desired compound 62.
• Representative compounds screened by at least one of the methods described above, or by similar methods, having IC 50 of less than 10 ⁇ M under the test conditions employed are shown in tables 2a (A-Raf), 2b (B-Raf), 2c (B-Raf V600E), 2d (c-Raf-1), 2e (Brk), 2f (Btk), 2g (Csk), 2h (Fak), 21 (Fms), 2j (Kdr), 2k (Kit), 2l (Lck), 2m (Lyn), 2n (Src), 2o (TrkA), and 2p (Yes).
• c-Raf-1 P-0001, P-0002, P-0004, P-0008, P-0009, P-0011, P-0013, P-0015, P-0016, P-0017, P-0020, P-0021, P-0027
• TrkA P-0002, P-0011
• Compounds of the invention in combination with a standard chemotherapeutic agent, such as 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine, can be assessed for their effectiveness in killing human tumor cells.
• a standard chemotherapeutic agent such as 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine.
• any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms.
• the invention also includes another embodiment wherein one of these terms is replaced with another of these terms.
• the terms have their established meaning.
• one embodiment may encompass a method “comprising” a series of steps, another embodiment would encompass a method “consisting essentially of” the same steps, and a third embodiment would encompass a method “consisting of” the same steps.

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