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WO2008079903A1 - Pyrrolo [2, 3-b] pyridine derivatives as kinase modulators - Google Patents

Pyrrolo [2, 3-b] pyridine derivatives as kinase modulators Download PDF

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Publication number
WO2008079903A1
WO2008079903A1 PCT/US2007/088231 US2007088231W WO2008079903A1 WO 2008079903 A1 WO2008079903 A1 WO 2008079903A1 US 2007088231 W US2007088231 W US 2007088231W WO 2008079903 A1 WO2008079903 A1 WO 2008079903A1
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Prior art keywords
lower alkyl
optionally substituted
fluoro
heteroaryl
group
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PCT/US2007/088231
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French (fr)
Inventor
Wayne Spevak
Hanna Cho
Prabha N. Ibrahim
Shenghua Shi
Shumeye Mamo
Sam Gillette
Hongyao Zhu
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Plexxikon, Inc.
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Application filed by Plexxikon, Inc. filed Critical Plexxikon, Inc.
Publication of WO2008079903A1 publication Critical patent/WO2008079903A1/en

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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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
  • Receptor protein kinases regulate key signal transduction cascades that control or are involved m the control of a plethora of physiological functions including cellular growth and proliferation, cell differentiation, cellular development, cell division, cell adhesion, stress response, short-range contact-mediated axonal guidance, transcription regulation, aberrant mitogenesis, angiogenesis, abnormal endothelial cell-cell or cell-matrix interactions dunng vascular development, inflammation, lymphohematopoietic stem cell activity, protective immunity against specific bacteria, allergic asthma, aberrant tissue-specific responses to the activation of the JNK signal transduction pathway, cell transformation, memory, apoptosis, competitive activity-dependent synapse modification at the neuromuscular synapse, immunological mediation of disease, and calcium regulation
  • Specific disease states associated with aberrant regulation of protein kinases include, for example w ithout limitation, acrocephalosyndactyly type I, acute myeloid leukemia, AIDS-mduced non-Hodgkin's lymphoma, Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, bacterial infection, bladder cancer, cancer of the breast, cancer of the central nervous system, cancer of the colon, cancer of the endometrium, cancer of the fallopian tube, cancer of the gastrointestinal tract, cancer of the ovary, heart failure, chronic myeloid leukemia, colon carcinoma, colorectal cancer, chronic obstructive pulmonary disease (COPD), Crouzon Syndrome, diabetes, diabetic nephropathy, emphysema, endometriosis, epidermoid cancer, fibrotic disorders, gastrointestinal stromal tumor (GIST), glomerulonephritis,
  • Compounds are contemplated that are active on protein kinases in general, including, but not limited to, ⁇ bl, ⁇ ktl , ⁇ kt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1, Csk, EGFR, EphAl , EphA2, EphB2, EphB4, Erk2, Fak, FGFRl, FGFR2, FGFR3, FGFR4, Fltl , Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2
  • the compounds are active on protein kinases including A-Raf, B-Raf and/or c-Raf-1 , including any mutations thereof.
  • compounds are of Formula I, Formula II, or Formula III, as described below.
  • 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:
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NlI 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 4 , -SR 4 , -NR 5 R 4 , -C(O)R 4 , -C(S)R 4 , -C(O)OR 4 , -C(O)NR 5 R 4 ,
  • R 2 is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NII 2 , -NHC(O)NH 7 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 4 , -SR 4 , -NR 5 R 4 , -C(O)R 4 , -C(S)R 4 , -C(O)OR 4 , -C(O)NR 5 R 4 , -C(S)NR 5 R 4 , -
  • R 3 is selected from the group consisting of hydrogen, fluoro and chloro
  • R 4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R "1 is optionally substituted lower alkenyl. no alkcne carbon thereof is bound to N, S, O.
  • R ! is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted hetcroaryl, -CN, -OR 4 , -SR 4 , -NR 5 R 4 , -C(O)R 4 , -C(O)NR 5 R 4 , -S(O) 2 NR 5 R 4 , -NR 5 C(O)R 4 , -NR ⁇ S(O) 2 R 4 , -S(O)R 4 , and -S(O) 2 R 4 , and R 2 is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN,
  • R 1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 7 , -SR 7 , -NR S R 7 , -C(O)R 7 , -C(S)R 7 , -C(O)OR 7 , -C(O)NR 8 R 7 , -C(S)NR 8 R 7 , -S(O) 2 NR 8 R 7 , -S(
  • R 1 is selected from the group consisting of hydrogen, -CN, -OR 7 , -SR 7 , -NR 8 R 7 , -NR 8 C(O)R 7 , -NR 8 S(O) 2 R 7 , -C(O)NR 8 R 7 , -C(O)R 7 , -S(O) 2 NR 8 R 7 , -S(O)R 7 , -S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl
  • R 1 is hydrogen, -CN, -NR 8 R 7 , -OR 7 , -S(O) 2 R 7 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR 8 R 7 , -OR 7 and -S(O) 2 R 7 , and R 2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 8 R 7 , -OR 7 or -S(O) 2 R 7 ; wherein R 7 and R 8 are as defined in paragraph [0011],
  • R 1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C 2 .
  • R 2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
  • the compound is selected from the group consisting of:
  • compounds have the structure according to the following Formula II:
  • R ia is as defined for R " for Formula I; and R 1 and R 3 are as defined for Formula I, provided, however, the compound is not
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR 4 , -SR 4 , -NR 5 R 4 , -C(O)R 4 , -C(O)NR 5 R 4 , -S(O) 2 NR 5 R 4 , -NR 5 C(O)R 4 , -NR 5 S(O) 2 R 4 , -S(O)R 4 , and -S(O) 2 R 4 , and R 2a is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR 4 , -SR 4 , -NR 5 R
  • R 1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NII 2 , -OR 7 , -SR 7 , -NR 8 R 7 , -C(O)R 7 , -C(S)R 7 , -C(O)OR 7 , -C(O)NR 8 R 7 , -C(S)NR 8 R 7 , -S(O) 2 NR 8 R 7 , -S
  • R 1 is selected from the group consisting of hydrogen, -CN, -OR 7 , -SR 7 , -NR 8 R 7 , -NR 8 C(O)R 7 , -NR 8 S(O) 2 R 7 , -C(O)NR 8 R 7 , -C(O)R 7 , -S(O) 2 NR 8 R 7 , -S(O)R 7 , -S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylammo, di-alkylamino, cycloalkyl, heterocycloalkyl
  • R 1 is hydrogen, -CN, -NR 8 R 7 , -OR 7 , -S(O) 2 R 7 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR 8 R 7 , -OR 7 and -S(O) 2 R 7 , and R 2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 8 R 7 , -OR 7 or -S(O) 2 R 7 ; wherein R 7 and R 8 are as defined in paragraph [0011],
  • R 1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted Ci.
  • R' a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
  • the compound is selected from the group consisting of:
  • compounds have the structure according to the following Formula III: formula III all salts, prodrugs, tautomers and isomers thereof, wherein
  • R 1 and R 1 arc as defined for Formula I, and R 6 is optionally substituted heteroaryl, provided, however, the compound is not
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR 4 , -SR 4 , -NR 5 R 4 , -C(O)R 4 , -C(O)NR 5 R 4 , -S(O) 2 NR 5 R 4 , -NR 5 C(O)R 4 , -NR 5 S(O) 2 R 4 , -S(O)R 4 , and -S(O) 2 R 4 , and R 6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted
  • R 1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 7 , -SR 7 , -NR 8 R 7 , -C(O)R 7 , -C(S)R 7 , -C(O)OR 7 , -C(O)NR 8 R 7 , -C(S)NR 8 R 7 , -S(O) 2 NR 8 R 7 , -S(
  • R 1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -OR 9 , -SR 9 , -NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 S(O) 2 R 9 , -S(O) 2 R 9 , -S(O) 2 NR 8 R 9 , -C(O)R 9 , -C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R 6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, and cycl
  • R 1 is selected from the group consisting of hydrogen, -CN, -OR 7 , -SR 7 , -NR 8 R 7 , -NR 8 C(O)R 7 , -NR 3 S(O) 2 R 7 , -C(O)NR 8 R 7 , -C(O)R 7 , -S(O) 2 NR 8 R 7 , -S(O)R 7 , -S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl
  • aryl, and hetcroaryl as a substituent of R 6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NlI 2 , -C(O)NH 2 , -OR ⁇ -SR 9 , -NR 8 R 9 .
  • R 1 is hydiogen, -CN, -NR 8 R 7 , -OR', -S(O) 2 R 7 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR 8 R 7 , -OR 7 and -S(O) 2 R 7 , and R 6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 8 R 7 , -OR' or -S(O) 2 R 7 ; wherein R 7 and R 8 are
  • R 1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, low r er alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C 2 6 alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylammo, di- alkylamino, and cycloalkylamino, and R 6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylammo, di-alkylamino, or cycloalky
  • the compound is selected from the group consisting of
  • compounds are excluded where N (except where N is a heteroaryl ring atom), O, or S is bound to a carbon that is also bound to N (except where N is a heteroaryl ⁇ ng atom), O, or S; or where N (except where N is a heteroaryl ring atom), O, C(S), C(O), or S(O) n (n is 0-2) is bound to an alkene carbon of an alkenyl group or bound to an alkyne carbon of an alkynyl group; accordingly, in some embodiments compounds which include linkages such as the following are excluded from the compounds provided: -NR-CH 2 -NR-, -0-CH 2 -NR-, -S-CII 2 -NR-, -NR-CH 2 -O-, -0-CH 2 -O-, -S-CH 2 -O-, -NR-CH 2 -S-, -0-CH 2 -S-, -S
  • 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 compounds of Formula I, Formula II, or Formula III
  • treat refers to the administration of material, e g , one or more compound of Formula I, Formula II, or Formula III, 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
  • protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a protein kinase affects the development, course, and or symptoms of the disease or condition, and/ or in which modulation of the protein kinase alters the development, course, and/or symptoms of the disease or condition
  • a protein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit
  • methods for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subj ect an effective amount of any one or more compound of Formula I, Formula II, or Formula III
  • the invention provides methods for treating a Raf protein kinase mediated disease or condition m an animal subject, wherein the method involves administering to the subject an effective amount of one or more compound of Formula I, Formula II, or Formula III
  • the terms "Raf protein kinase mediated disease or condition,” “Raf mediated disease or condition,” and the like refer 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 m which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease oi condition
  • the Raf protein kinase includes, but is not limited to, A-Raf, A-Raf mutations, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1
  • the Raf protein kinase is B
  • 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, Formula II, or Formula III w ill 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 any of Formula I, Formula II, or Formula III 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 AbI, Aktl , Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1
  • a compound of Formula I, Formula II, or Formula III 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 AbI, Akt 1 , Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl 5 c-Raf- 1, Csk, EGFR, EphAI, EphA2, EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Hcr2/Erbb2, Hcr4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jn
  • a compound of Formula I, Formula II, or Formula III will have an IC 5O 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 AbI, A-Raf, B-Raf, Btk, c-Raf-1 , EGFR, EphB2, Erk2, Fak, FGFRl , Fltl , Flt3, Flt4, Fms, Irak4, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAPKAP kinase 2, Met, p38, PDGFRB, Piml , PKC theta, Pyk2, Ret, Src, Stk ⁇ , Yes, and Zap70, including any mutations thereof.
  • a compound of Formula I, Formula II, or Formula III 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 AbI, A-Raf, B-Raf, Btk, c-Raf-1 , EGFR, EphB2, Erk2, Fak, Fins, Irak4, Jnkl , Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1 , MAPKAP kinase 2, Met, p38, Piml , PKC theta, Pyk2, Src, Stk6, Yes, and Zap70, including any mutations thereof
  • a compound of Formula I, Formula II, or Formula III 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 V600ET529I mutant, c-Raf-1 , Fak, FGFRl , FGFR2, FGFR3, FGFR4, Jnkl , Jnk2, Jnk3, Lck, Lyn, Met, Piml, Pim2, Pim3, Pyk2, Kdr, Src and Ret, including any mutations thereof.
  • a compound of Formula I, Formula II, or Formula III is an inhibitor of a Raf kinase and has an IC S0 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 Raf kinase activity assay
  • a compound of Formula I, Formula II, or Formula III will have an IC S o 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 B-Raf, c-Raf-1 , B-Raf V600E mutant, or B- Raf V600E/T529I mutant.
  • a compound of Formula I, Formula II, or Formula III will selectively inhibit one Raf kinase relative to one or more other Raf kinases. In some embodiments, the compound of Formula I, Formula II, or Formula III 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 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 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
  • the compound may selectively inhibit Fms relative to Kit.
  • 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 m a generally accepted kinase activity assay
  • compositions that include a therapeutically effective amount of one or more compound of Formula I, Formula II, or Formula III and at least one pharmaceutically acceptable carrier, excipient, and'or diluent, including combinations of any two or more compounds of Formula I, Formula II or Formula III
  • the composition can further include a plurality of different pharmacologically active compounds, which can include a plurality of compounds of F ormula I, Formula II, or Formula III
  • the composition can include one or more compounds of Formula I, Formula II, or Formula III 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, Formula II, or Formula III 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, Formula II, or Formula III effective in treating a cancer and one or more other compounds that are effective in treating the cancer, further wherein the compounds are syn
  • methods for modulating the activity of a protein kinase selected from the group consisting of AbI, Aktl, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1 , Csk, EGFR, EphAl , EphA2, EphB2, EphB4, Erk2, Fak, FGFRl , FGFR2, FGFR3, FGFR4, Fltl, Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 ,
  • 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 of Formula I, Formula II, or Formula III
  • methods are provided for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, Akt 1 , Akt2, Akt3 AI K Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1 , Csk, EGFR, fcphAl , EphA2, EphB2, EphB4, Erk2, Fak, FGFRl FGFR2, FGFR3, FGFR4, Fltl, Flt3, Flt4, Fms, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2 / Erbb2, Her4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl, Jak2, Jak3, Jnkl Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAP
  • the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, Akt 1 , Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl, c-Raf-1 , Csk, EGFR, EphAl , EphA2, FphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/ ⁇ rbb2, Her4 ⁇ rbb4, IGFl R, IKK beta, Irak4, Ilk, Jakl , Jak2, Jak3, Juki , Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1 , MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl , MLKl , p38, PD
  • the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, A-Raf, B-Raf, Btk, c-Raf-1 , EGFR, EphB2, Erk2, Fak, FGFRl, Fltl, Flt3, Flt4, Fms, Irak4, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAPKAPK2, Met, p38, PDGFRB, Piml, PKC thcta, Pyk2, Ret, Src, Stk ⁇ , Yes, and Zap70 by administenng to the subject an effective amount of a composition including one or more compound of Formula I, Formula II, or Formula III
  • the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, A-Raf, B-Raf, Btk, c-Raf 1 , EGFR, EphB2, Erk2, Fak, Fms, Irak4, Jnkl, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAPKAPK2, Met, p38, Piml , PKC theta, Pyk2, Src, Stk ⁇ , Yes, and Zap70 by administering to the subject an effective amount of a composition including one or more compound of Formula I, Formula II, or Formula III
  • 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/T529I mutant, c Raf-1, Fak, FGFRl, FGFR2, FGFR3, FGFR4, Jnkl , Jnk2, Jnk3, Lck, Lyn, Met, Piml, Pim2, Pim3, Pyk2, Kdr, Src and Ret by administering to the subject an effectrve amount of a composition including one or more compound of Formula I, Formula II, or Formula III
  • 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 administenng to the subject an effective amount of a composition including one or more compound of Formula I, Formula II or Formula III
  • the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600fc mutant, or B-Raf V600t ⁇ l 5291 mutant by administering to the subject an effective amount of a composition including one or more compound of Formula I, Formula II, or Formula III m 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
  • the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including onr or more compound of Formula I, Formula II, or Formula III, 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 (c 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 drag), radiation treatment (e g x-ray, ⁇ -ray, or electron, proton, neutron, or ⁇ particle beam), hyperthermia heating (e g microwave, ultrasound, radiofrequency ablation), Vaccine therapy (e g AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, ⁇ G-858, allogeneic GM-CSF-secret
  • 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 of Formula I, Formula II, or Formula III, 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, adozelesm, altretamme, bizelesm, busulfan, carboplatm, carboquone, carmustme, chlorambucil, cisplatm, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, lfosfamide, improsulfan, irofulven, lomustine, mechlorethamme, melphalan, oxaliplatin, prposulian, semustme, streptozocm, temozolomide, thiotcp
  • an alkylating agent including, but
  • anastrozole, androgens buserelin, diethylstilbestrol, exemestane, flutarmde, fulvestrant, goserelin, ldoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene, a taxanc, including, but not limited to, DJ-927, docetaxel, TPI 287, paclitaxel and DH ⁇ -pachtaxel, a retinoid, including, but not limited to, ahtretinom, bexarotene, fenretmide, isotretinoin, and tretinoin, an alkaloid, including, but not limited to, etoposide, homohar ⁇ ngtonme, teniposide vinblastine, vincristine, vindesine, and vmorelbine, an antiangiogemc agent, including, but not limited to, AE-941 (GW78
  • a topoisomerase inhibitor including, but not limited to amsac ⁇ ne, edotecarm, exatecan, irinotecan (also active metabolite SN-38 ( 7 -ethyl- 10-hydroxy-camptothecin)), rubitecan, topotecan, and 9-aminocamptothecm, a kinase inhibitor, including, but not limited to, erlotmib, gelitinib, tlavopindol, imatmib mesylate, lapatmib, sorafemb, sumtinib malate, AEE-788, ⁇ G-013736, AMG 706, AMN107, BMS-354825, BMS-599626.
  • a kinase inhibitor including, but not limited to, erlotmib, gelitinib, tlavopindol, imatmib mesylate, lapatmib, soraf
  • UCN-01 7 -hydroxystaurospo ⁇ ne
  • vatalamb a targeted signal transduction inhibitor including but not limited to bortezomib, geldanamycin, and rapamycin
  • a biological response modifier including, but not limited to, imiquimod, mterferon- ⁇ , and mterleukm-2, and other chemotherapeutics, including, but not limited to 3-AP (3-amino-2-carboxyaldchydc thioscmicarbazone), ammoglutethimide, asparaginase, bryostatin-1 , cilengitide, E7389, lxabepilone, procarbazine, sulmdac, temsirolimus tipifarnib
  • the method of treating a cancer involves administering to the subject an effectiv e amount of a composition including one or more compound of Formula I, Formula II, or Formula III in combination with a chcmothcrapcutic agent selected
  • 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 of Formula I, Formula II. or Formula III, a prodrug of such compound, or a pharmaceutically acceptable salt 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 of Formula I, Formula II, or Formula III, a prodrug of such compound, or a pharmaceutically acceptable salt 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 desc ⁇ bed 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 Food and Drag Administration or similar regulatory agency for administration to a mammal, e g , a human, 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 wntten 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 kmase-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, tor example without limitation, neurologic diseases, including, but not limited to, cerebrovascular ischemia, multi-mfarct 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 myelofibrosis, leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astromonia, pulmonary ischemia, or astromonia, pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary a
  • compounds of Formula I, Formula II, or tormula III 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, myelodysplasia syndrome, leukemia, tumor angiogenesis, neuroendocnne tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and p
  • neurologic diseases including, but not limited
  • muscular dystrophies including, but not limited to, Duchenne, Becker, Fmery-Dreifuss, I imb-Girdle. Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophics
  • motor neuron diseases including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spmal muscular atrophy, intermediate spmal muscular atrophy juvenile spmal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy
  • inflammatory myopathies including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis
  • diseases of the neuromuscular junction including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic svndrome
  • myopathies due to endoc ⁇ ne abnormalities including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy
  • the compounds of Formula I, Formula II, or Formula III with kinase activity IC,o 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
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • Aktl related to gast ⁇ c, prostate, colorectal, ova ⁇ an, pancreatic and breast cancer, glioblastoma and leukemia, as well as schizophrenia and bipolar disorders, and also use in combination with other chemotherapeutic drugs,
  • Akt2 related to hyperglycemia due to penpheral insulin resistance and nonsuppressible hepatic glucose production accompanied by inadequate compensatory hype ⁇ nsulmemia, also related to pancreatic, ovarian and breast cancer, Akt3, related to melanoma, prostate and breast cancer, ALK, related to non-Hodgkm lymphomas such as diffuse large B-cell lymphoma and anaplastic large cell lymphoma,
  • Alk5 related to pancreatic and biliary cancers, and cutaneous T-cell lymphoma, ⁇ -Raf, related to neurologic diseases such as multi-mfarct dementia, head injury, spmal 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, myelodysplastic syndrome, leukemia, tumor angiogenesis, pain of neuropathic or inflammatory origin, including acute pam chrome pain, cancer-related pain and migraine, and diseases associated w ith muscle regeneration or degeneration, including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to Duchenne, Becker, hmery-D
  • B-Raf or c-Raf-1 related to neurologic diseases, including, but not limited to, as multi-infarct dementia, head injury, spmal 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, ova ⁇ an), 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 pam, chronic pain, cancer-related pain, and migraine, cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac
  • glioblastoma e g glioblastoma multiforme
  • Cdk5 related to Alzheimer's disease, amyotrophic lateral sclerosis and Lewy body disease
  • Cdk ⁇ related to glioblastoma multiforme, non-Hodgkin's lymphoma, splenic marginal zone lymphoma, T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (1 -ALL),
  • CHKl related to DNA damage repair, sensitizes cells to chemotherapeutic agents, Csk, related to colon and pancreatic carcinomas and autoimmune pathology such as type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus, hGFR, related to breast, colorectal, bladder, prostate and non small cell lung cancer, squamous cell carcinomas of the head and neck cancer, oral cavity, and esophagus, and glioblastoma multiforme,
  • EphAl related to head and neck squamous cell carcinoma, hepatoma and lung cancer, bphA2, related to aberrant short-range contact-mediated axonal guidance, bladder, breast, prostate, colon, skm, cervical, ovarian, pancreatic and lung cancers, and metastatic melanoma, EphB2, related to angiogenesis disorder (e g ocular angiogenesis disease such as retinopathy), and cancer (e g glioblastoma, breast and liver cancer),
  • angiogenesis disorder e g ocular angiogenesis disease such as retinopathy
  • cancer e g glioblastoma, breast and liver cancer
  • EphB4 related to colorectal cancer (CRC), head and neck squamous cell carcinoma, and tumours of the prostate, breast, endometrium, and bladder, Erk2, related to aberrant proliferation, differentiation, transcription regulation and development, and may be useful in treating inflammation, for example inflammation associated with Lyme neuroborrehosis, and in treating cancers, such as gastric cancer,
  • Fak related to colon and breast tumors, and is also related to esophageal squamous cell carcinoma, melanoma, anaplastic astrocytoma, glioblastoma, ductal carcinoma m situ, prostate and hepatocellular carcinoma, and tumor metastases, and may also provide synergistic effects when used w ith other chemotherapeutic drugs, FGFRl, related to 8pl 1 myeloproliferative syndrome, FGFR2, related to Crouzon Syndrome, Jackson-Weiss Syndrome, Apert Syndrome, craniosynostosis, Pfeiffer Syndrome, acrocephalo syndactyly type V, and Beare-Stevenson Cutis Gyrata Syndrome,
  • FGFR3 related to angiogenesis, wound healing, achondroplasia, Muenke craniosynostosis, Crouzon syndrome, acanthosis nigricans, thanatophoric dysplasia, bladder carcinomas, and multiple myeloma,
  • FGFR4 related to cancer of the breast, lung, colon, medullary thyroid, pancreas, ovary, prostate, endometrium, and fallopian tube, head and neck squamous cell carcinomas and leiomyosarcoma,
  • Fltl related to non-small cell lung carcinoma, prostate carcinoma, and colorectal cancer
  • Flt3 related to acute myeloid leukemia, myel ⁇ dysplastic syndrome, acute lymphoblastic leukemia
  • Fms related to immune disorders, including, but not limited to, rheumatoid arthritis, systemic lupus erythematosa (SLE), and transplant rejection, inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, chrome obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis, metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and hpolysis, disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e g osteomyelitis), pen-prosthetic or wear-debris-mediated osteolysis, and
  • Frk related to acute myeloid leukemia and type 1 diabetes
  • Fyn related to Alzheimer's disease, schizophrenia and prevention of metastases, e g in melanoma and squamous cell carcinoma
  • GSK3 Gsk3 ⁇ and/or Gsk3 ⁇
  • CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes type II, bipolar disorders, stroke, cancer, chronic inflammatory disease, leucopenia, schizophrenia, chronic pain, neuropathic pain, and traumatic head injury,
  • HCK related to chronic myelogenous leukemia and acute lymphocytic leukemia
  • Her2/Erbb2 related to prostate and breast cancer
  • IIer4/Erbb4 related to childhood medulloblastoma
  • IGFlR related to prostate cancer, hepatocellular carcinoma
  • DCK beta related to leukemia of T-cells, necrosis, insulin resistance, and malignant neoplasms
  • Irak4 related to bacte ⁇ al infections, immunodeficiency syndrome, Crohn's disease, ulcerative colitis, asthma, chronic bronchitis, cardio hypertrophy, and kidney hypertension,
  • Jak2 related to mj eloproliferative disorders such as polycythaemia vera, myelofibrosis, essential thrombocythemia, myeloid metaplasia and leukemias, including acute lymphoblastic leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic leukemia, CMML, Philadelphia chromosome-negative CML, megakaryocyte leukemia, and acute erylhroid leukemia,
  • Jak3 related to X-linked severe combined immunodeficiency, myeloproliferative disorders, transplant rejection and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosa, ulcerative colitis, psonasis and multiple sclerosis,
  • Jnk Jnkl , Jnk2, Jnk3
  • metabolic diseases including type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, and hepatic steatosis
  • cardiovascular diseases such as atherosclerosis, ischemia (e g cerebrovascular ischemia, liver ischemia), reperfusion injury, cardiac hypertrophy
  • renal diseases such as chronic renal failure, neoplastic diseases and associated complications, including chemotherapy-mduced hypoxia, prostate tumors, myeloid leukemia and cancers of the liver, bone, skin, brain, pancreas, lung breast, colon, prostate and ovary, transplant rejection, pain of neuropathic or inflammatory origin including acute and chronic pain, inflammatory and autoimmune diseases including age-related macular degeneration, rheumatoid arthritis inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosa, Sjogren's Syndrome, psoriasis, scleroderma, chronic thyroiditis
  • Kdr related to anti-angiogenesis for treating solid lumor growth (e g ovarian, lung, breast prancreatic, prostate, colon, gastrointestinal stromal tumor, non small cell lung cancer, and epidermoid cancer), metastasis, psoriasis, rheumatoid arthritis, diabetic retinopathy and age related macular degeneration,
  • Kit related to malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma m situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosmophilia,
  • Lck related to acute lymphoblastic leukemia, T-cell lymphoma, lymphopenia, renal carcinoma, colon carcinoma severe combined immunodeficiency, multiple sclerosis, inflammatory bowel and type I diabetes
  • MAP2K1 related to acute myeloid leukemia, breast, ovarian and liver cancer
  • MAP2K2 related to cancer and inflammation
  • MAP4K4 related to metabolic indications, including re-sensitLdng fat and muscle cells to insulin, ameliorating the pathology in adipocytes, ameliorating the pathology m muscle cells, metabolic syndrome, and type II diabetes; a broad range of oncology indications, including blocking the migration, invasion and metastasis in many different tumor types, and T-cell mediated autoimmune diseases,
  • MAPKAPK2 cancer (e.g. prostate, breast), stroke, menengitis, and inflammatory disorders; Met, related to kidney, breast, bladder, non-small-cell lung, colorectal, and bladder cancers, and hepatocellular carcinoma; Mnkl, related to conditions associated with heat shock, nutrient deprivation, oxidative or osmotic stress, and infection of mammalian cells (e.g.
  • viruses such as adenovirus (Ad) or influenza virus
  • autoimmune diseases MLKl, related to neurodegenerative dibeases such as Alzheimer's disease and Parkinson's disease, and inflammatory disorders
  • p38 related to acute coronary syndrome, stroke, atherosclerosis, and inflammatory autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease
  • PDGFR PDGFRA, PDGFRB
  • idiopathic hypereosinophilic syndrome chronic eosinophilic leukemia, glioma, gastrointestinal stromal tumors (GISl s), juvenile myelomonocytic leukemia, metastatic medulloblastoma, atherogenesis, and restenosis.
  • PDGFRA related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, glioma, gastrointestinal stromal tumors (GISTs), juvenile myelomonocytic leukemia, metastatic medulloblastoma, atherogenesis, and restenosis
  • PDGFRB related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, and metastatic medulloblastoma, PDPKl, related to cancer and diabetes; Piml , related to cancers such as hematopoietic (e.g.
  • PKC alpha related to pituitary tumors and prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder, also may be used to sensitize chemotherapy in breast, colon, and non small cell lung cancers
  • PKC beta related to diabetic retinopathy
  • PKC-theta related to insulin resistance
  • Plkl related to cancers
  • lymphoma of the thyroid non-Hodgkin's lymphomas, colorectal cancers, leukemias and melanoma
  • Py k2 related to inflammation (e g osteoporosis, polycystic kidney disease rheumatoid arthintis and inflammatory bowel disease), CNS disease (e g Parkinson's disease and Alzheimer s disease), stroke and cancers (e g gliomas, breast cancer, and pancreatic cancer), Ret, related to cancer of the thyroid, neuroblastoma, familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasm type HA and HB (MEN2A, MEN2B), and neurodegenerative disorders (e g Hirschsprung's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis),
  • MTC familial medullary thyroid carcinoma
  • FMTC familial medullary thyroid carcinoma
  • MEN2A, MEN2B multiple endocrine ne
  • ROCK ROCK
  • cancers e g ova ⁇ an cancer, hepatocellular carcinoma, pancreatic cancer
  • ocular disease e g glaucoma
  • cardiac hypertrophy improved renal perfusion, transplant reiection, and acute respiratory distress syndrome
  • Ron related to cancer and inflammation
  • Src related to cancer and osteoporosis
  • Stk6 related to gast ⁇ c, bladder, breast, lung, CNS, ova ⁇ an, kidney, colon, prostate, pancreas, and cervical cancers
  • melanoma leukemia
  • neuroblastoma e g mantle cell lymphoma
  • TEC related to sepsis, septic shock, inflammation, rheumatoid arthritis, Crohn's disease, irritable bowel disease (IBD), and ulceratrve colitis
  • Tie2 related to cancer, arthritis (e g rheumatoid arthritis), and atherosclerosis, I rkA, related to pain (e g chronic pam, neuropathic pam), cancer (e g prostate cancer, lung cancer, pancreatic cancer), allergic disorders (e g asthma), arthritis, diabetic retinopathy, macular degeneration and psoriasis,
  • TrkB related to obesity, hyperphagia, developmental delays, cancer (e g prostate cancer, lung cancer, Wilms tumors, neuroblastoma, pancreatic cancer), vanous neuropathies (e g stioke, multiple sclerosis, transverse myelitis, and encephalitis), and diabetes Yes, related to ⁇ anous cancers including esophageal squamous cell carcinoma, and Zap70, related to AIDS, systemic lupus erythematosus, myasthenia gravis, atherosclerosis, rejection of transplanted organs or tissues, allograft rejection including acute and chronic allograft rejection, graft versus host disease, rheumatlioid arthritis, psoriasis, systemic sclerosis, atopic dermatitis eczematous dermatitis, alopecia, and inflammation of the nasal mucus membrane, including all forms of rhinitis
  • cancer e g prostate cancer, lung cancer, Wilm
  • Halogen refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
  • 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 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.
  • a “substituted lower alkyl” denotes lower alkyl that is 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 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR°, -OC(O)R 0 , -OC(S)R 0 , -C(O)R 0 , -C(S)R 0 ,
  • substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, 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.
  • substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -OR (e.g.
  • substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any O, S, orN of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkyl carbon bound to any O, S, or N of the moiety.
  • C 2 . 6 alkyl denotes lower alkyl containing 2-6 carbon atoms, A "substituted C 2 .
  • b alkyl denotes optionally substituted lower alkyl containing 2-6 carbon atoms.
  • a "substituted methyl” denotes methyl that is independently substituted, unless indicated otherwise, with 1, 2, or 3 substituents, wherein the substituents are selected as per optionally substituted lower alkyl.
  • C 1 . 3 alkylene refers to a divalent alkane-derived radical containing 1-3 carbon atoms, straight chain or branched, from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms.
  • CY 3 alkylene includes methylene -CH 2 -, ethylene -CH 2 CH 2 -, propylene -CH 2 CH 2 CH 2 -, and isopropylene -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-.
  • Ci -3 alkylene substituted with one or more substituents indicates C ⁇ 3 alkylene that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents as indicated, attached at any available atom to produce 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. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
  • a "substituted lower alkenyl” denotes lower alkenyl that is 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 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR U , -SR U , -OC(O)R 0 , -OC(S)R 0 , -C(O)R 0 ,
  • substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Fo ⁇ nula I, Formula II, or Formula III, 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. While it is understood that substitutions are attached at any available atom to produce a stable compound, substitution of alkenyl groups are such that -F, -C(O)-, -C(S)-, -C(NH)-, -S(O)-, -S(O) 2 -, -0-, -S-, or N (except where N is a heteroaryl ring atom), are not bound to an alkene carbon thereof.
  • alkenyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like
  • substitution of the moiety is such that any -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -O-, -S-, or N thereof (except where N is a heteroaryl ring atom) are not bound to an alkenc carbon of the alkenyl substituent or R group.
  • alkenyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)NHR, and the like
  • substitution of the alkenyl R group is such that substitution of the alkenyl carbon bound to any O, S, or N of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkenyl carbon bound to any O, S, or N of the moiety.
  • alkenyl carbon refers to any carbon within an alkenyl group, whether saturated or part of the carbon to carbon double bond.
  • An “alkene carbon” refers to a carbon within an alkenyl group that is part of a carbon to carbon double bond.
  • “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.
  • alkynyl groups include ethynyl, propynyl, butynyl, and the like.
  • a “substituted lower alkynyl” denotes lower alkynyl that is 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 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR", -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)
  • substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, 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.
  • substitutions are attached at any available atom to produce a stable compound
  • substitution of alkynyl groups are such that -F, -C(O)-, -C(S)-, -C(NH)-, -S(O)-, -S(O) 2 -, -O-, -S-, or N (except where N is a heteroaryl ring atom) are not bound to an alkyne carbon thereof.
  • alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like
  • substitution of the moiety is such that any -C(O)-, -C(S)-,-S(O)-, -S(O) 2 -, -O-, -S-, or N thereof (except where N is a heteroaryl ring atom) are not bound to an alkyne carbon of the alkynyl substituent or R group.
  • alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)NHR, and the like
  • substitution of the alkynyl R group is such that substitution of the alkynyl carbon bound to any O, S, or N of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substitucnt (except where N is a heteroaryl ring atom) being bound to the alkynyl carbon bound to any O, S, or N of the moiety
  • An “alkynyl carbon” refers to any carbon within an alkynyl group, whether saturated or part of the carbon to carbon triple bond.
  • An “alkyne carbon” refers to a carbon within an alkynyl group that is part of a carbon to carbon triple bond.
  • 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.
  • a "substituted cycloalkyl” is a cycloalkyl that is independently substituted, unless indicated othenvise, 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 , -NHC(O)NIl 2 , -NHC(S)NII 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR ⁇ , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)R
  • 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.
  • a “substituted heterocycloalkyl” is a heterocycloalkyl that is 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 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(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.
  • aromatic hydrocarbons such as phenyl or naphthyl
  • Arylene is a divalent aryl.
  • a "substituted aryl” is an aryl that is 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 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)R 0 ,
  • ⁇ eteroaryP' 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.
  • “Nitrogen containing heteroaryl” refers to heteroaryl wherein any heteroatoms are N.
  • Heteroarylene is a divalent heteroaryl.
  • a “substituted heteroaryl” is a heteroaryl that is 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 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) ⁇ NH 7 , -C(NH)NH 2 , -OR 0 , -SR 0 ,
  • R 0 , 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:
  • each R 0 , R p , and R L are independently selected from the group consisting of R d , R e , R f , and R 8 , or R p and R c combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -NO 2 , -CN, -OH, -NH 2 , -OR U , -SR", -NHR", -NR U R U , -R ⁇ and -R y ;
  • each R d is independently lower alkyl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH,, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -0C(0)R k , -OC(S)R k , -C(O)R k , -C(S)R k , -C(0)0R k , -C(S)OR k , -S(O)R k
  • each R e is independently lower alkenyl, wherein lower alkenyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -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 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -OC(0)R k , -OC(S)R k , -C(O)R k , -C(S)R k , -C(O)OR k , -C(S)OR k , -S(
  • each R f is independently lower alkynyl, wherein lower alkynyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -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 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -OC(O)R k , -OC(S)R k , -C(0)R k , -C(S)R k , -C(O)OR", -S(O)R k , -S(O
  • each R 8 is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents 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) 7 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -OC(O)R ⁇ -OC(S)R k , -C(0)R k
  • R k , RTM. and R" at each occurrence are independently selected from the group consisting of R h , R 1 , and R J , or RTM and R" combine with the nitrogen to which they are attached form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl arc optionally substituted with one or more, preferably 1 , 2.
  • each R h is independently lower alkyl optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of fluoro, -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 .
  • each R' is independently selected from the group consisting of lower alkenyl and lower alkynyl. wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -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 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR', -SR', -OC(O)R', -OC(S)R', -C(O)R r , -C(S)R', -
  • each R J is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2 or 3 substituents 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 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R r , -SR', -OC(O)R', -OC(S)R',
  • each R', R s , and R 1 at each occurrence are independently selected from the group consisting of lower alkyl, C ⁇ alkenyl, C 3 _ 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of-R y , fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the lower alkyl carbon bound to any O, S, or N, of -OR r , -SR r , -C(O)OR', -C(S)OR r , -C(
  • 6 alkynyl arc optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -R*, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the C 3 - 6 alkenyl or C 3 .
  • each R u is independently selected from the group consisting of lower alkyl, C 3 _ 6 alkenyl, C 34 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -R 3 , fluoro, -OH, -NH 2 , lower alkoxy.
  • 6 alkynyl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -R y , fluoro, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylammo, and cycloalkylamino, provided, however, that any substitution of the C 3 6 alkenyl or C 3 . ⁇ , alkynyl carbon bound to the O of -OR ⁇ S of -SR U , or N of -NHR U is fluoro, lower alkyl, fluoro substituted lower alkyl, or -R y , and wherein cycloalkyl, hctcrocycloalkyl, aryl, and heteroaryl are optionally substituted with
  • each R x is selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -R y , fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -R y , fluoro, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alk
  • each R y is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.
  • all occurrences of optionally substituted lower alkyl, optionally substituted C 2 6 alkyl, optionally substituted lower alkenyl, or optionally substituted lower 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, -0R l a , -SR Ia , -NR l a R la , -OC(O)R la , -OC(S)R la , -C(O)R Ia , -C(S)R la , -C(O)OR la , -C(S)OR 13 , -C(0)NR l a R lj .
  • all occurrences of optionally substituted lower alkyl, optionally substituted C 2 . 6 alkyl, optionally substituted lower alkcnyl, or optionally substituted lower alkynyl are optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -CN, -0R la , -SR la , -NR la R la , -C(O)R Ia , -C(S)R 13 , -C(O)OR la , -C(0)NR I a R la , -C(S)NR la R l a , -S(O) 2 NR l a R la , -NR l a C(0)R Ia , -NR l a C(S)R la , -NR la S(O) 2 R la , -S(O)R la , -S(O) 2 R 1 ",
  • 'Lower alkoxy denotes the group -OR', 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 desc ⁇ ption of compounds of Formula I, Formula II, or Formula III, including descriptions of substituted cycloalkyl, cyclohctcroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound
  • 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
  • “Lower alkylthio” denotes the group -SR aa , where R aa is lower alkyl
  • “Substituted lower alkylthio” denotes lower alkylthio m which R ao is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, Fo ⁇ nula IJ, or Formula III, including descriptions of substituted cycloalkyl, cycloheteroalkyl, aryl and heteroaryl, attached at any available atom to produce 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
  • “Ammo” or ' ⁇ amine” denotes the group -NH 2 .
  • “Mono-alkylammo” denotes the group -NHR bb where R bb is lower alkyl
  • Di-alkylammo denotes the group -NR bb R cc , where R bb and R cc are independently lower alkyl
  • Cycloalkylammo denotes the group -NR dd R ee , where R dd and R ee combine with the nitrogen to form a 5-7 membered hctcrocycloalkyl, where the heterocycloalkyl may Lontam an additional heteroatom withm 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, pipendme, piperazine, 4-methylpiperazine, morphohne, and thiomorpholme
  • 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 mjectibles
  • 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
  • a ligand or modulator will be a small molecule, where "small molecule refers to a compound with a molecular w eight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less
  • an "improved ligand” is one that possesses better pharmacological and/or pharmacokinetic properties than a reference compound, where “better” can be defined by one skilled in the relevant art for a particular biological system or therapeutic use
  • 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, / e , with a lower dissociation constant
  • the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold greater affinity
  • the term “synthesizing” and like terms means chemical synthesis from one or more precursor mate ⁇ als [0086]
  • assaying is meant the creation of expenmental conditions and the gathering of data regarding a particular result of the experimental conditions For example, enzymes can be assayed based on their ability to act upon a detectable substrate A compound or hgand 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
  • 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
  • the term "isolate” 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, compounds of Formula II and all sub-generic formulae, and compounds of Formula III 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 ⁇ bl, Aktl , Akt2, Akt3, ALK, Alk5, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl, c-Raf-1, Csk, EGFR, Eph ⁇ l , EphA2, EphB2, EphB4, Erk2, Fak, TGFRl , FGFR2, FGFR3, FGFR4, Fltl , Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2 / Erbb2, Hcr4/Erbb4, IGFlR
  • Protein kinases play key roles m propagating biochemical signals in diverse biological pathways More than 500 kinases have been described, and specific kinases have been implicated in a wide range ot diseases or conditions (i e indications), including for example without limitation, cancer, cardio ⁇ ascular disease, inflammatory disease, neurological disease, and other diseases As such, kinases represent important control points for small molecule therapeutic intervention
  • ot diseases or conditions including for example without limitation, cancer, cardio ⁇ ascular disease, inflammatory disease, neurological disease, and other diseases
  • kinases represent important control points for small molecule therapeutic intervention
  • Description of specific target protein kinases contemplated by the present invention may be found, for example, in US Patent Application Serial number 1 1 /473,347 (PCl publication WO2007002433) , the disclosure of which is hereby incorporated by reference in its entirety, in addition to the following
  • A-Raf T arget kinase A-Raf (i e , v-raf murine sarcoma 361 1 viral oncogene homolog 1) is a 67 6 kDa serine/threonine kinase encoded by chromosome XpI 1 4-pl 1 2 (symbol ARAF)
  • the mature protein compnscs RBD i e , Ras binding domain
  • phorbol-ester/DAG-type zinc finger domain and is involved in the transduction of mitogcmc 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
  • B-Raf Target kinase B-Raf (i e , v-raf murine sarcoma viral oncogene homolog B 1 ) is a 84 4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol BRAt)
  • the mature protein comprises RBD (i e , Ras binding domain), Cl (i e , protein kinase C conserved region 1) and STK (i e se ⁇ ne/threonine kinase) domains
  • Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane Io 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 grow th, division and proliferation, and, when constitutively activated, causes tumo ⁇ genesis
  • the B-type, or B-Raf is the strongest activator of the downstream MAP kinase signaling
  • the BRAF gene is frequently mutated m a variety of human tumors, especially in malignant melanoma and colon carcinoma
  • the most common reported mutation was a missense thymine ( 1) to adenine (A) transversion at nucleotide 1796 (T1796A, ammo acid change in the B-Raf protein is Val ⁇ 600> to Glu ⁇ 600> ) observed in 80% of malignant melanoma tumors
  • T1796A ammo acid change in the B-Raf protein is Val ⁇ 600> to Glu ⁇ 600>
  • 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
  • human tumors develop resistance to kinase inhibitors by mutating a specific ammo acid in the catalytic domain as the "gatekeeper' 1 (Balak, et al , CIm Cancer Res
  • 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 RAFl) 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
  • B-Rdf and/or C-Raf inhibitors may be useful in treating A-Raf-mediated, B-Raf-mediated or c-Raf-1 -mediated disease oi condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-intarct 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,
  • Exemplary Diseases Associated with c-Kit are useful for treating disorders related to c-kit e g , diseases related to unregulated kinase signal transduction, including cell proliferative disorders, fibrotic disorders and metabolic disorders, among others As described m more detail helow and in Lipson et al , U S 20040002534 (U S application 10/600, 868, filed June 23, 2003) which is incorporated herein by reference in its entirety, cell proliferate e disorders which can be treated by the present invention include cancers, and mast cell proliferative disorders
  • c-kit has also been associated with a number of different types of cancers
  • association between abnormalities in c-kit and disease are not restricted to cancer
  • c-kit has been associated with malignancies, including, but not limited to, mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma m situ, Schwann cell neoplasm associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canme mast cell tumors, and inflammatory diseases, including, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis,
  • c-fms has been associated with a number of different types of diseases as such c-fms has been associated with immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection, inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bow el syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hcmophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis, metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and hpolysis, disorders of bone structure, mineralization and bone formation and resorption, including but not limited to, osteoporosis, increased risk of fracture, Paget * s disease, hypercalcemia,
  • TrkA Target kinase TrkA (i e , neurotrophic tyrosine kinase, receptor, type 1 ) is a 140 kDa tyrosine kinase encoded by chromosome Iq21-q22 (symbol NTRKl) TrkA inhibitors may be useful m treating pain (e g chronic pam, neuropathic pam), cancer (e g prostate cancer lung cancer, myeloid leukemia, pancreatic cancer), allergic disorders (e g asthma), arthritis, diabetic retinopathy macular degeneration and psoriasis
  • pain e g chronic pam, neuropathic pam
  • cancer e g prostate cancer lung cancer, myeloid leukemia, pancreatic cancer
  • allergic disorders e g asthma
  • arthritis diabetic retinopathy macular degeneration
  • TrkA is a plasma member receptor composed of an extracellular domain (responsible for high affinity binding to nerve growth factor, NGF), a transmembrane segment and an intracellular protein tyrosine kinase domain (responsible to transmit the NGF signal to initiate and coordinate neuronal responses) NGF binding induces TrkA clustering on the membrane and activates the kinase The kinase initiates a cascade of protein phosphorylation events through multiple pathways including SHC/Ras/MAPK, PDK and PLCgI A TrkA kinase inhibitor would not prevent NGF/TrkA binding, but could prevent down-stream signal transduction
  • Nerve Growth Factor is produced by a number of tissues and inflammatory cells during tissue injury and host immune response It initiates and maintains hypersensitivity to incoming stimulus (hyperalgesia) and the perception of non-noxious stimuli (allodyma) Through its high- affinity receptor TrkA, NGF increases the excitation state of sensory neurons leading to the central nervous system (peripheral sensitization), and increases transmitter release from the dorsal spinal cord (central sensitization) In clinical trials, a single NGF subcutaneous injection generated local hyperalgesia persisting up to 7 weeks At doses above 0 1 microgram/kg, NGF caused muscle pam that varied from mild to moderate, primarily m the bulbar and truncal musculature Intravenous NGF produced earlier and more pronounced systemic effects (Petty et al, 1994, Ann Neurol 36 244-6) Conversely, 1 rkA kinase inhibitors could be used to treat diseases ot enhanced states of nociception
  • TrkA mRNA and protein levels in bronchial biopsies were increased significantly after allergen exposure in infiltrating mast cells before the onset of symptoms (Kassel et al, 2001, Clin Exp Allergy 31 :1432-40).
  • TrkB Target kinase TrkB (i.e., neurotrophic tyrosine kinase, receptor, type 2) is a 145 kDa tyrosine kinase encoded by chromosome 9q22.1 (symbol: NTRK2). TrkB inhibitors may be useful in treating various cancers and their metastases (e.g. prostate cancer, lung cancer, Wilms tumors, neuroblastoma, and pancreatic cancer), and various neuropathies (e.g. stroke, multiple sclerosis, transverse myelitis, and encephalitis).
  • various cancers and their metastases e.g. prostate cancer, lung cancer, Wilms tumors, neuroblastoma, and pancreatic cancer
  • various neuropathies e.g. stroke, multiple sclerosis, transverse myelitis, and encephalitis.
  • paresthesia was developed at the site of subcutaneous injection (Coulie et al, 2000, Gastroenterology 119:41-50). Intrathecal infusion of BDNF in humans also induced paresthesia and warmth as side effects (Ochs et al, 2000, Amyotroph Lateral Scler Other Motor Neuron Disord. 1 :201-6). Chronic paresthesia is often a symptom of an underlying neurological disease or traumatic nerve damage. Paresthesia can be caused by disorders affecting the central nervous system, such as stroke and transient ischemic attacks (mini-strokes), multiple sclerosis, transverse myelitis, and encephalitis.
  • Trkb kinase inhibitors could be used to treat certain patients with neuropathy.
  • BDNF is known to act at the synapses between primary sensory and spinal dorsal horn neurons to affect pam transmission during inflammation
  • the primary afferent is the only source of BDNF in the spinal cord, and it is up-regulated in the dorsal root ganglion (DRG) by peripheral NGF a few da ⁇ s after inflammation, and is transported and released into the superficial dorsal horn in an activity -dependent manner TrkB expression in the doisal horn also increases fo ⁇ a few days after inflammation
  • TRPC3 transient receptor potential canonicals
  • TrkB inhibitors could be used to treat a sub-population of cancer patients with an activated TrkB pathway
  • TrkB expression is correlated with perineural invasion, positive retroperitoneal margin, and shorter latency to development of liver metastasis (Sclabas et al, 2005, CIm Cancer Res VI l 440-449)
  • TrkB activates the PDK pathway to suppress anoikis (apoptosis resulting from loss of cell-matrix interactions) which is one of the physiological bamers to metastasis TrkB kinase inhibition could break down resistance to anoikis of metastasizing tumors (Douma ct al, 2004, Nature 430 1034-9) Therefore, TrkB inhibitors could have utility in a broad range of tumor types
  • MAP4K4 Target kinase MAP4K4
  • MAP4K4 Mitogen-activated protein kinase kinase 4, aka Hematopoietic progenitor kinase 'Germinal center kmase-like Kinase
  • HGK It is a member oi the human STE20/mitogen-activated protein kinase kinase kinase kinase kinase (MAP4K) family of serine ''threonine kinases and is the human ortholog of mouse NIK (Nck-mteracting kinase)
  • the N- terminus of the mature HGK protein has a catalytic kinase domain that shares 47% and 48% ammo acid
  • HGK-mduced JNK activation was inhibited by dominant-negative MAP2K4, MAP2K7, and TAK 1 mutants TNF -alpha also stimulated HGK kinase activity
  • HGK was identified as a putative effect of Rap2 to activate JNK (Mdchida et al J Biol Chem 279 15711-15714, 2004) This link establishes HGK as a potential target for a range of metabolic indications, since the JNK pathway clearly antagonizes insulin signaling An HGK inhibitor could rc-sensitize fat and muscle cells to insulin
  • HGK is found to be broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion (Wright et al MoI Cell Biol 23 2068-2082, 2003) Wright et al showed IIGK to be highly expressed m most tumor cell lines relative to normal tissue
  • An active role for this kinase m transformation was suggested by an inhibition of II-Ras(V12)-induced focus formation by expression of inactive, dominant-negative mutants of HGK in both fibroblast and epithelial cell lines
  • Expression of an inactive mutant of HGK also inhibited the anchorage- independent growth of cells yet had no effect on proliferation in monolayer culture
  • Expression of HGK mutants modulated mteg ⁇ n receptor expression and had a striking effect on hepatocyte growth factor-stimulated epithelial cell invasion
  • a small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as
  • HGK inhibitor could have utility in blocking the migration, invasion and metastasis in many ditferent tumor types
  • Insuhn-rcgulated glucose transporter GLU 14 is a key modulator of whole body glucose homeostasis, and its selective loss in adipose tissue or skeletal muscle causes insulin resistance and diabetes Using an KNA interference-based screen, Tang et al (Proc Natl Acad Sci U S A 103 2087- 2092, 2006) found 4 negative regulators of insulin-responsive glucose transport in mouse adipocytes Pctkl , Pftkl, Ikbka (CHUK), and HGK HGK suppressed expression of adipogenic transcription factors, C/EBPA, C/EBPB, and PPARG, and it suppressed surface expression of GLUT4 (SLC2A4), resulting in attenuated membrane hexose transport activity RNA interference-mediated depletion of HGK ea ⁇ ly m differentiation enhanced adipogenesis and triglyceride deposition, in fully differentiated adipocytes, loss of HGK upregulated
  • HGK inhibitors may be useful in treating metabolic indications, including re-sensitizing fat and muscle cells to insulin, ameliorating the pathology in adipocytes, ameliorating the pathology in muscle cells, metabolic syndrome and type II diabetes, a broad range of oncology indications, including blocking the migration, invasion and metastasis in many different tumor types, and T cell mediated autoimmune diseases
  • 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 assavs that can be utilized and can modify an assay for a particular application
  • numerous papers concerning kinases desc ⁇ be assays that can be used
  • this sort of assay can be formatted cither m a fluorescence resonance energy transfer (FRET) format or using an AlphaScreen (amplified /ummescent proximity ⁇ omogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidm or the phosphor-specific antibody
  • FRET fluorescence resonance energy transfer
  • AlphaScreen amplified /ummescent proximity ⁇ omogeneous assay
  • solvents include polar and non-polar solvents known to those of skill in the art, including polar aprotic and polar protic solvents
  • Polar solvents include, without limitation, protic solvents such as methanol, ethanol, isopropyl alcohol, t- butanol, n-butanol, acetic acid formic acid or water, or aprotic solvents such as tetrah>drofuran (THF), acetonit ⁇ le, dioxane, methylene chloride, dimethylsulfoxide (DMSO) acetone, N 1 N- dimethylformamide (DMF) N,N-dimethylacetamide (DMA), ethyl acetate, 1,2-dimethoxyethane, 1,2- dichloroethane, chloroform, 1,2-dichloroethane, or pyridine Polar solvents mdude a mixture of water with any of the above, or a mixture of any
  • reducing agent includes, without limitation, a reducing agent such as catalytic reducing agents using hydrogen and transition metal catalysts such as palladium, platinum, rhodium, etc (e g Pt/acetic acid/Hi), a mixture of t ⁇ fluoroacetic acid and tnethylsilane, borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, and a combination of sodium borohyd ⁇ de and boron t ⁇ fluo ⁇ de, metals such as reduced iron, zinc powder, magnesium etc , metal hydrogen complex compounds such as alkali metal borohyd ⁇ des (for example, potassium borohyd ⁇ de, sodium borohyd ⁇ de, lithium borohyd ⁇ de, zinc borohyd ⁇ de, sodium t ⁇ acetoxyborohyd ⁇ de, etc ), aluminum lithium hydride, etc , metal hydrides such as sodium hydride,
  • oxidizing agent includes, without limitation, an oxidizing agent such as Dess-Martm reagent, TFMPO (2,2,6,6-tetramethylpipe ⁇ dme-N- oxide), DDQ (2,3-Dichloro-5,6-dicyano-l ,4-benzoqumone), PDC (py ⁇ dimum dichromate), PCC (py ⁇ dinium chlorochromate), Pyridine SO3, Chromium t ⁇ oxide, p-mtroperbenzoic acid, magnesium monoperoxyphthalate, sodium pe ⁇ odate, potassium pe ⁇ odate, hydrogen peroxide, urea peroxide, alkali metal bromates, cumene hydroperoxide, tert-butyl peroxide, peracids such as perfomiic acid, peracctic acid, pert ⁇ fluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o- carboxy
  • a nitrogen protecting group is a chemical group covalently bound to a nitrogen atom of a compound that is used to protect the nitrogen from reaction during a synthetic step
  • the nitrogen protecting group may be added to a compound and removed m a subsequent step by methods known to those of skill in the art
  • invention compounds may exist m a number of different forms or derivatives, all within the scope of the present invention
  • Alternative forms or derivatives such as (a) Isomers, Prodrugs, and Active Metabolites (b) Tautomers, Stereoisomers, Regioisomers, and Sohated Forms (c) Prodrugs and Metabolites (d) Pharmaceutically acceptable salts and (e) Polymorphic forms, are descnbed, for example in US Patent Application Serial number 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference m its entirety
  • the methods, and compounds will typically be used in therapy for human subjects However, they may also be used to treat similar or identical indications in other animal subjects
  • the terms "subject,” "animal subject,” and the like refer to human and non-human vertebrates, e g mammals, such as non-human primates, sports and commercial animals, c g , equmes, bovines, porcines, ovmes, rodents, and pets, e g , canines and felines
  • a description of possible methods and routes of administration ma> be found, for example, m US Patent Application Serial number 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety
  • the mass spectrometry 1 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 of Formula X is synthesized by reacting a compound of Formula Xa (see Example 1) with a compound of Formula Xd (Y is as> defined in Example 1), e g benzoyl chloride, m the presence of a Lewis acid (e g aluminum trichloride) in an inert solvent (e.g. dichloromethane) under an inert atmosphere (e.g argon) at room temperature or with heating up to reflux for 1-18 hours.
  • a Lewis acid e g aluminum trichloride
  • an inert solvent e.g. dichloromethane
  • an inert atmosphere e.g argon
  • Compound of Formula Xe can be synthesized by reacting a compound of Formula Xa (see Example 1) with hexamcthyltetramine and acetic acid in water with heating to reflux for two hours After cooling, the desired compound precipitates and may be collected by filtration
  • Compound of Formula Xh is synthesized by reacting a compound of Formula Xf in a solvent (e.g. tetrahydrofuran) with an organolithium reagent (e.g. phenyl lithium) in a solvent (e.g. tetrahydrofuran) under an inert atmosphere, cooled to -78 0 C.
  • a solvent e.g. tetrahydrofuran
  • organolithium reagent e.g. phenyl lithium
  • An intermediate of compound of Formula X is synthesized by reacting a compound of Formula Xh with an appropriate reagent to remove the protecting group, P, (e.g. fc ⁇ r ⁇ -n-butyl ammonium fluoride) in an appropriate solvent (e.g. tetrahydrofuran).
  • P protecting group
  • tetrahydrofuran an appropriate solvent
  • the final product is isolated by standard procedures (e.g. extraction).
  • Compound of Formula X is synthesized by reacting the intermediate from Step 4 with an oxidizing agent (e.g. Dess-Martin periodane, TEMPO) in an aprotic solvent (e.g. tetrahydrofuran) typically at room temperature for 20 minutes.
  • an oxidizing agent e.g. Dess-Martin periodane, TEMPO
  • an aprotic solvent e.g. tetrahydrofuran
  • the desired compound is isolated by conventional means (e.g. extraction and silica gel chromatography).
  • Phenyl-(-lH-pyrrolo[2,3-bJpyridine-5-yl)-amine 1 was synthesized in three steps from 5- bromo-7-azaindole 1 as shown in Scheme 1.
  • Step 1 Preparation of 5 -hromo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b] pyridine (2): [0142] To 5-bromo-7-azaindole (1, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0 mmol) and trriisopropylsilyl chloride ( 2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate.
  • Step 2 Preparation of 5-phenyl-(l-triisopropylsilanyl-IH-pyrrolo[2,3-b]pyt ⁇ dine-5-yl)-amine (3): [0143] To 5-bromo-l-triisopropylsilanyl-lH-pyrrolo[2.3 ⁇ b]pyridine (2, 0, 10 g, 0.3 mmol) in toluene (5 mL) were added aniline (0.04 mL, 0.42 mmol), sodium ferf-butoxide (0.15 g, 1.56 mmol), tris(dibenzyllideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol) and (S) -(-)-2,2'- bis(diphenylphosphino)-!
  • Step 1 Preparation 5-chloro-l-triisopropylsilanyl-IH-pyrrolo[2,3-b]pyridine (S): [0146] To 5-bromo-l-triisopropylsilyl-7-azaindole (2, 1.60 g, 4.53 mmol, prepared as described in Example 4) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at -78 0 C, was added tert- butyllithium (1.70 M in hexane, 6.12 mL). The reaction was stirred for 1 hour, followed by addition of hexachlorocthane (1.29 g, 5.43 mmol).
  • Step 2 Preparation ofl-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (W).
  • W lH-Pyrrolo[2,3-b]pyridine-3-carbaldehyde
  • sodium hydride 50% in mineral oil, 1.5 g, 38 mmol
  • trriisopropylsilyl chloride 8.0 mL, 38 mmol
  • Step I ⁇ - Preparation of2-(l-tn ⁇ sopropyls ⁇ lcmyl-lH-pyrrolo[2,3-b]p ⁇ nd ⁇ n-5-yl)-propan-2-ol (11)
  • Step 1 Preparation of5-methyl-l-triisopropylsilanyl-lH-pyrrol ⁇ [2,3-h] ⁇ yrid ⁇ ne (14): [0157] To PdCl 2 (dppf) (0.04 g, 0.05 mmol) in toluene (10,0 mL) under an atmosphere of nitrogen were added 54>romo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (2, 0.3 g, 0.8 mmol, prepared as described in Example 1 , 1.0 mL in toluene) and methylmagnesium bromide (1.0 M in tetrahydrofuran, 3.0 mL, 3,0 mmol).
  • Example 9 Synthesis of 5-methoxy-lH-pyrrolo[2,3-b[pyridine 17 and related compounds. [0160] 5-Methoxy-lH-pyi ⁇ olo[2,3-b]pyiidine 17 was synthesized in one step from 5-bromo-lH pyrrolo[2,3-b]py ⁇ dme 1 as described in Scheme 6
  • Step I Preparation of3-Iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-h]pyndjne (37)
  • 3-Iodo-lH-pyr ⁇ olo[2,3-b]pyridine 36 (2 00 g, 8.20 mmol) was dissolved m N,N- dimethylformamidc (50 mL).
  • Sodium hyd ⁇ de (60% dispersion m mineral oil, 390 mg, 9.8 mmol) was added. After 20 minutes, t ⁇ isopropylsilyl chloride (1.74 mL, 8.20 mmol) was added dropwise.
  • Step 1 Preparation of l-(tert-Butyl-d ⁇ methyl-sUanyl)-3-iodo-lH-pyrrolo[2,3-b]pyridine (38)
  • 3-Iodo-lH-pyrrolo[2,3-b]pyridine 36 (1 1 1 g, 4 6 mmol) was dissolved in tetrahydrofuran (120 mL). Sodium hydride (60% dispersion in mineral oil, 0.13 g, 5.5 mmol) was added, followed by tert-butyldimethylsilyl chloride (0.85 g, 5.5 mmol). The reaction was stirred at room temperature overnight.
  • Step 1 Preparation of5-(l-MethyI ⁇ lH-pyrazol-4-yl)-lH-pyrroIo[2,3-b]pyridine (46): [0178] To 5-bromo-7-azaindole (1, 1.04 g, 5.28 mmol) in 1.00 M potassium carbonate in water (15.8 mL) and tetrahydrofuran (50.0 mL) were added l-methyl-4-(4,4,5,5-tetramethyl- [l ,3,2]dioxaborolan-2-yl)-lH-pyrazole (45, 1.65 g, 7.92 mmol), Tetrakis(triphenylphosphine)- palladium(O) (0.305 mg, 0.26 mmol) and tetra-n-butylammonium iodide (0.20 g, 0,53 mmol).
  • Example 16 Preparation of propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH- pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide 51.
  • Propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine-3- carbonyl)-phenyl]-amide 51 was synthesized in four steps from 2,4-difluorophenylamine 47 as shown in Scheme 13,
  • Step I Preparation of propane-2-sulfonic acid (2, 4-difluoro-phenyl)-amide (48): [0180] To 2,4-difluoro-phenylamine (47, 4.0 mL, 40,0 mmol) in dichloromethane (50 mL) were added pyridine (3.37 mL, 42.3 mmol), propane-2-sulfonyl chloride (6.00 g, 42.3 mmol) and dimethylaminopyridine (0.20 g, 1 .64 mmol) under an atmosphere of nitrogen. The reaction was stirred at 45 °C overnight. The reaction was poured into water and extracted with ethyl acetate.
  • Step 2 Preparation of propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (49): [0181] To propane -2-sulfonic acid (2,4-difluoro-phenyl)-amide (48, 2.35 g, 9.95 mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooled with a dry ice/acetone bath was added 1.60 M of n-butyllithium (1.60 M in hexane, 6.53 mL, 10.45 mmol).
  • reaction was stirred for 40 minutes, and then another portion of n-butyllithium (1.60 M in hexane, 6.84 mL, 10.94 mmol). The reaction was stirred for 1 hour and N,N-dimethylformarnide (0.92 mL, 1 1.9 mmol) was added, The reaction was allowed to warm to room temperature overnight. The reaction was poured into water extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated.
  • Step 3 Preparation of propane ⁇ 2-sulfonic acid ⁇ 2,4-di ⁇ uoro-3-[hydroxy-(5-pyridin-3-yl-lH- pyrroln [2, 3-b]pyridin-3-yl) ⁇ methylj '-phenyl) '-amide (50): [0182] To propane-2-sulfonic acid (2,4-difluoro-3-formyl-phcnyl)-amide (49, 220.0 mg, 0.83 mmol) in methanol (15 mL) was added 5-pyndin-3-yl-lH-pyrrolo[2,3-b]pyridine (22, 150 0 mg, 0 77 mmol, prepared as described in Example 10) and potassium hydroxide (537.0 mg, 9,6 mmol) under an atmosphere of nitrogen.
  • Step 1 Preparation nf (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52): [0191] To 2,4-difluoroaniline (47, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and K.IISO 4 solution. The organic layer was dried (MgSO 4 ), concentrated and crystallized from hexanes to give compound 52 (15.6 g, 85%).
  • Step 2 Preparation of(2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (53): [0192] Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52, 3.83 g, 14.5 iTimol) in tetrahydrofuran (148 mL, 1.82 mol).
  • Step 3 Preparation of ⁇ 2,4-difluoro-3-[hydroxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl ⁇ - carbamic acid benzyl ester (54):
  • Step 5 Preparation of(3-Amino-2,6-difluoro-phenyl)-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl) - methanone (56):
  • Example 18 Synthesis of 3- ⁇ 3-[2,6-difluoro-3-(4-trifluoromethyl-benze ⁇ esulfo ⁇ ylamino)- benzoyl] -1 H-py rrolo [2,3-b] py ridin ⁇ 5-yl ⁇ -N-ethyl-propionamide P-0035.
  • Step 1 Preparation oj " 3- ⁇ 3 ⁇ [2, 6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lH- pyrrolo[2,3-b]pyridin-5-yl ⁇ -propionic acid methyl ester (P-0033):
  • Step 2 Preparation of 3- ⁇ 3-[2 ,6-difluoro-3-(4-trifluoromethyl ⁇ benzenesulfonylamino)-benzoyl] -1 H- pyrrolo[2,3-b]pyridin-5-yl ⁇ -pr ⁇ pionic acid (P-0034):
  • Step 3 Preparation of 3- ⁇ 3-[2,6-difluoro-3-(4-trifluoromcjthyl-benzenesulf ⁇ nylamino)-benzoyl] -1 H- pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-ethyl-propionamide (P-0035):
  • Assays for the activity of kinases including, but not limited to, B-Raf, B-Raf V600E, B-Raf V600E/T529I and c-Raf-1 are known in the art, for example as described in US Patent Application Serial number 1 1/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety.
  • Table Ia Representative compounds with activity toward kinase B-Raf with IC 50 ⁇ 10 ⁇ M under the test conditions employed.
  • Table Ib Representative compounds with activity toward kinase B-Raf V600E with IC 50 ⁇ 10 ⁇ M under the test conditions employed.
  • Table Ic Representative compounds with activity toward kinase B-Raf V600E/T529I with IC 50 ⁇ 10 ⁇ M under the test conditions employed.
  • Table 1 d Representative compounds with activity toward kinase Btk with IC 50 5 10 ⁇ M under the test conditions employed.
  • Table Ie Representative compounds with activity toward kinase c-Raf-1 with IC, P ⁇ 10 ⁇ M under the test conditions employed.
  • c-Raf-1 P-OOOl , P-0002, P-0003, P-0005, P-0006, P-0007, P-0008, P-0009, P-001 1 , P-0013,
  • Table 1 f Representative compounds with activity toward kinase Fit 1 with IC 50 ⁇ 10 ⁇ M under the test conditions employed.
  • Table Ig Representative compounds with activity toward kinase Fms with iC ⁇ o ⁇ 10 ⁇ M under the test conditions employed.
  • Table Ih Representative compounds with activity toward kinase Jnkl with ICso l 10 ⁇ M under the test conditions employed.
  • Table 1 i Representative compounds with activity toward kinase Kdr with 1C SO 5 10 ⁇ M under the test conditions employed.
  • Kdr P-0001, P-0002, P-0003, P-0004, P-0005, P-0008, P-0010, P-001 1 , P-0013, P-OO 14,
  • Table Ij Representative compounds with activity toward kinase Kit with IC 50 ⁇ 10 ⁇ M under the test conditions employed.
  • Kit P-0001, P-0002, P-0003, P-0005, P-0006, P-0007, P-0008, P-0009, P-0010, P-0011, P-0013, P-OO 14, P-0015, P-0016, P-OO 17, P-0018, P-0019, P-0020, P-0021 , P-0022, P-0023, P-0024, P-0025, P-0026, P-0027, P-0028, P-0029, P-0032, P-0035
  • Table Ik Representative compounds with activity toward kinase Src with IC 50 ⁇ 10 ⁇ M under the test conditions employed.
  • TEC P-0016 Table Im. Representative compounds with activity toward kinase p38 with ICso ⁇ 10 ⁇ M under the test conditions employed.
  • Example 19 Efficacy of Compounds in Combination with Standard-of-Care Chemotherapeutic agents in four human cancer cell lines.
  • Compounds of the invention such as compounds of Formula I, Formula II, or Formula III, in combination with a standard chemotherapeutic agent, such as 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, lemozolomide, 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, lemozolomide, or vinblastine
  • Human tumor cell lines such as A-375 (malignant melanoma), SK-MEL-2 (malignant melanoma, skin metastasis), COLO 205 (colorectal adenocarcinoma, ascites metastasis) or SW-620 (colorectal adenocarcinoma, lymph node metastasis) can be treated with a compound of Formula I, Formula II, or Formula III alone, or in combination with one of the above-mentioned chemotherapeutic agents.
  • A-375 malignant melanoma
  • SK-MEL-2 malignant melanoma, skin metastasis
  • COLO 205 colonrectal adenocarcinoma, ascites metastasis
  • SW-620 colonrectal adenocarcinoma, lymph node metastasis
  • Tumor cells are grown as a monolayer at 37 0 C in a humidified atmosphere (5% CO 2 , 95% air).
  • Cells are grown in a suitable culture medium, e.g. RPMI 1640 (Ref BE12-702F, Cambrex, Venders, Belgium) containing 2 mM L-glutamine and supplemented with 10% fetal bovine serum (Ref DEl 4-80 IE, Cambrex).
  • RPMI 1640 Ref BE12-702F, Cambrex, Venders, Belgium
  • fetal bovine serum Ref DEl 4-80 IE, Cambrex
  • the tumor cells are detached from the culture flask by a 5-minute treatment with trypsin-versene (Ref 02-007E, Cambrex), diluted in Hanks' medium without calcium or magnesium (Ref BE10-543F, Cambrex). Trypsin treatment is neutralized by culture medium addition. The cells are counted in a hemocytometer and their viability assessed by 0.25%
  • the cell lines arc checked for mycoplasma contamination with the Mycotect assay kit (Ref 15672-017, Invitrogen, Cergy-Pontoise, France) in accordance with the manufacturer's instructions.
  • the mycoplasma test is assayed from the culture supematants of the cell lines and compared to negative and positive controls.
  • the tumor cells (10,000 per well) are plated in 96-well flat-bottom microtitration plates (Ref 055260, Nunc, Dutscher, Brumath, France) and incubated at 37 0 C for 24 hours before treatment in 100 ⁇ l of drug-free culture medium supplemented with 10% FBS.
  • the tumor cells are incubated in a 200 ⁇ l final volume of RPMI 1640 supplemented with 10% FBS and containing either a compound of Formula I, Formula II, or Formula III, or one of 5-fluorouracil, carboplatm, dacarbazine, gefitimb, oxahplatin, paclitaxel, SN-38, temozolomide, or vinblastine
  • a suitable concentration range such as 10 8 to 10 ⁇ M for a compound of Formula I.
  • Formula II is a suitable concentration range, such as 10 8 to 10 ⁇ M for a compound of Formula I.
  • 5- fluorouracil 50 mg/ml, Dakota Pha ⁇ n, LePlessis Robmson, Irance
  • carboplatm (10 mg ml, Aguettant, Lyon, France)
  • paclitaxel (6 mg'ml, Bristol-Myers Squibb SpA, Rueil Malmaison, France)
  • dacarbazine Sigma, Samt Quentm Fallavier, France
  • vinblastine Lilly France S A , Saint Cloud, France
  • MTT MTT assay
  • 20 ⁇ l of a 5 mg/ml solution 0 22 ⁇ m filtered tctrazohum reagent (MTT, Ref M2128, Sigma) m Phosphate Buffered Saline (PBS, Ref BE17-517Q, Cambrex) is added in each well
  • Culture plates are incubated for 2 h at 37 0 C
  • the resulting supernatant is removed and formazan crystals dissolved with 200 ⁇ l of DMSO per well
  • Absorbency (OD) is measured at 570 nm in each well using VICTOR 1 ' *1 1420 multilabeled counter (Wallac, PcrkinElmer, Courtaboeuf, France)
  • the IC 50 for each compound on each cell line is determined from the OD measurements of each sample The dose response inhibition ot cell proliferation is expressed as
  • IC (OD of drug exposed cells / OD of drug free wells) x 100
  • the mean of multiple measurements for each concentration is plotted vs the drug concentration
  • the dose-response curves arc plotted using XLFit 3 (IDBS, United Kingdom)
  • the IC 50 (drag concentration to obtain 50% inhibition of cell proliferation) determination values are calculated using the XLF it 3 from semi-log curves
  • the IC 50 value determined for each compound in each cell line is used to determine the concentration of a compound of Formula I, Formula II, or Formula III, and of the standard chemotherapeutic to be used m combination
  • the cells are treated with a combination of five concentrations of a compound of Formula I, Formula II, or Formula III and five concentrations of one of 5-fiuorouracil, carboplatm dacarbazme, gefitimb, oxahplatin, paclitaxel, SN-38, temozolomide, or vinblastine based on the IC 5O results
  • the compounds and cells are treated per the 1C50 determination described above and assayed by the MTT assay
  • the combination index (CI) w ill be calculated by the Chou et al equation (Adv Enzyme Regul 1984, 22 27-55 , Encyclopaedia of human biology, Academic Press, 1991, 2 371 -9, Synergism and Antagonism in Chemotherapy, Academic Press, 1991 , 61-102) which takes into account both the potency (D m or ICj 0 ) and the shape of the dose-effect curve (the m value)
  • the general equation for the CI of the two compounds is given by
  • the (D x ) i and (D x ) 7 can be calculated from the median-effect equation of Chou et al (J Natl Cancer Inst 1994, 86 1517-24) where
  • the invention illustrate ely desc ⁇ bed herein suitably may be practiced in the absence of any clement or elements, limitation or limitations which is not specifically disclosed herein
  • any of the terms “comprising”, “consisting essentially of” and “consisting of may be replaced with either of the other two te ⁇ ns
  • the invention also includes another embodiment wherein one of these terms is replaced with another of these terms, In each embodiment, 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.
  • the terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

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Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

Description

PYRROLO [2 , 3-B] PYRIDINE DERIVATIVES AS KINASE MODULATORS
RELATED PATENT APPLICATIONS
[0001] This application claims priority to U S Provisional App No 60/876,953, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed December 21, 2006, and is related to U S Patent App No 1 1 /473,347, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed June 21, 2006, which claims the benefit of L S Provisional App No 60/731 ,528, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed October 28, 2005, and U S Provisional App No 60/692,960, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed June 22, 2005, all of which are incorporated herein by reference in their entireties and for all purposes
FIELD OF THE INVENTION
[0002] 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
BACKGROUND OF THE INVENTION
[0003] The information provided herein is intended solely to assist the undei standing of the reader None of the information provided nor references cited is admitted to be prior art to the present invention Each of the references cited herein is incorporated in its entirety
[0004] Receptor protein kinases regulate key signal transduction cascades that control or are involved m the control of a plethora of physiological functions including cellular growth and proliferation, cell differentiation, cellular development, cell division, cell adhesion, stress response, short-range contact-mediated axonal guidance, transcription regulation, aberrant mitogenesis, angiogenesis, abnormal endothelial cell-cell or cell-matrix interactions dunng vascular development, inflammation, lymphohematopoietic stem cell activity, protective immunity against specific bacteria, allergic asthma, aberrant tissue-specific responses to the activation of the JNK signal transduction pathway, cell transformation, memory, apoptosis, competitive activity-dependent synapse modification at the neuromuscular synapse, immunological mediation of disease, and calcium regulation
[0005] Specific disease states associated with aberrant regulation of protein kinases include, for example w ithout limitation, acrocephalosyndactyly type I, acute myeloid leukemia, AIDS-mduced non-Hodgkin's lymphoma, Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, bacterial infection, bladder cancer, cancer of the breast, cancer of the central nervous system, cancer of the colon, cancer of the endometrium, cancer of the fallopian tube, cancer of the gastrointestinal tract, cancer of the ovary, heart failure, chronic myeloid leukemia, colon carcinoma, colorectal cancer, chronic obstructive pulmonary disease (COPD), Crouzon Syndrome, diabetes, diabetic nephropathy, emphysema, endometriosis, epidermoid cancer, fibrotic disorders, gastrointestinal stromal tumor (GIST), glomerulonephritis, Graves' disease, head injury, hepatocellular carcinoma, Hirschsprung's disease, human gliomas, immunodeficiency diseases, inflammatory disorders, ischemic stroke, Jackson- Weiss syndrome, leiomyosarcoma, leukemias, lupus nephritis, malignant melanoma, malignant nephrosclerosis, mastocytosis, mast cell tumors, melanoma of the colon, MEN2 syndromes, metabolic disorders, migraine, multiple sclerosis, myeloproliferative disorders, nephritis, neurodegenerative diseases, neurotraumatic diseases, non small cell lung cancer, organ transplant rejection, osteoporosis, pain, Parkinson's disease, Pfeiffer Syndrome, polycystic kidney disease, primary lymphoedema, prostate cancer, psoriasis, vascular restenosis, rheumatoid arthritis, dermal and tissue scarring, selective T-cell defect (STD), severe combined immunodeficiency (SCID), small cell lung cancer, spinal cord injury, squamous cell carcinoma, systemic lupus erythematosis, testicular cancer, thrombotic microangiopathy syndromes, Wegener's granulomatosis, X-linked agammaglobulinemia, viral infection, diabetic retinopathy, alopecia, erectile dysfunction, macular degeneration, chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), neurofibromatosis, and tuberous sclerosis.
[0006J This application is related to the following published patent applications: WO 2004024895, US 20040142864, WO 2004078923, US 20050170431 , WO 2005028624, US 20050164300, and WO 2005062795, each of which are hereby incorporated by reference herein in their entireties including all specifications, figures, and tables, and for all purposes.
SUMMARY OF THE INVENTION
[0007] Compounds are contemplated that are active on protein kinases in general, including, but not limited to, Λbl, Λktl , Λkt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1, Csk, EGFR, EphAl , EphA2, EphB2, EphB4, Erk2, Fak, FGFRl, FGFR2, FGFR3, FGFR4, Fltl , Flt3, Flt4, Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl , MLKl , p38, PDGFRA, PDGFRB, PDPKl , Piml , Pim2, Pim3, PKC alpha, PKC beta, PKC theta, PIkI 1 Pyk2, Ret, ROCKl, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkΛ, TrkB, Yes, and/or Zap 70, including any mutations of these kinases. In some aspects, the compounds are active on protein kinases including A-Raf, B-Raf and/or c-Raf-1 , including any mutations thereof. In some aspects, compounds are of Formula I, Formula II, or Formula III, as described below.
[0008] 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. Thus, 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.
[0009] In some embodiments, compounds have the structure according to the following Formula I:
Figure imgf000004_0001
Formula I all salts, prodrugs, tautomers and isomers thereof, wherein:
R1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NlI2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, and -S(O)2R4;
R2 is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NII2, -NHC(O)NH7, -NHC(S)NH2, -NHS(O)2NH2, -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2. -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, and -S(O)2R4;
R3 is selected from the group consisting of hydrogen, fluoro and chloro;
R4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R"1 is optionally substituted lower alkenyl. no alkcne carbon thereof is bound to N, S, O. S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR^C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, or -S(O)2R4, optionally substituted lower alkynyl, provided, however, that when R4 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR3C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, or -S(O)2R4, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R5 is selected from the group consisting of hydrogen and optionally substituted lower alkyl,
provided, however, the compound is not
Figure imgf000005_0001
H
Figure imgf000005_0002
Figure imgf000006_0001
[0010] In some embodiments of compounds of Formula I, R! is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted hetcroaryl, -CN, -OR4, -SR4, -NR5R4, -C(O)R4, -C(O)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR^S(O)2R4, -S(O)R4, and -S(O)2R4, and R2 is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR4, -SR4, -NR5R4, -C(O)R4, -C(O)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5S(O)2R4, -S(O)R4, and -S(O)2R4.
[0011] In some embodiments of compounds of Formula I, R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NRSR7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR11S(O)2R7, -NR8C(O)NH2. -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR6S(O)2NH2, -NR^S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl arc optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, C(O)OH, -C(O)NH2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkeπyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR', -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR3R", -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R2 is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R', -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R", -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NRV, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OR7, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; wherein R is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R' or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
[0012] In some embodiments of compounds of Formula I, R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R2 is selected from the group consisting of -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R', -NR8S(O),R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; wherein R7, R8 and R9 are as defined in paragraph [0011].
[0013] In some embodiments of compounds of Foπnula I, R1 is hydrogen, -CN, -NR8R7, -OR7, -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7; wherein R7 and R8 are as defined in paragraph [0011],
[0014] In some embodiments of compounds of Formula I, R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2.6 alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di- alkylamino, and cycloalkylamino, and R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino .
[0015] In one embodiment of compounds of Foπnula I, the compound is selected from the group consisting of:
4-Butoxy-N-[3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- benzenesulfonamide (P-0007), N-[3-(5-Chloro-l H-pyrτolo[2,3-b]pyridme-3-carbonyl)-2,4-difluoro-plienyl]-4-p>razol-l -yl- benzenesulfoπdmide (P-0008),
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyndme-3-carbonyl)-2,4-difluoro-phenyl]-4 lsopropoxy- benzenesulfonamide (P-OOIl),
4-tert-Butyl-N-[3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- ben/enesulfonamide (P-0014),
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyndme-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl- benzenesulfonamide (P-0015),
N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-lH-pyrrolo[2,3-b]pyπdine-3-carbonyl]-phenyl}-4- isopropyl-benzenesulfonamide (P-0018)
N-{2,4-Difluoro-3-[5-(4-methyl-lH-imidazol-2-yl)-l H-pyrrolo[2,3-blpyπdine-3-carbonyl]-phenyl} -
4-isopropyl-benzenesulfonamide (P-0019),
4-Difluoromethox>-N-{2,4-difluoro-3-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-3- carbonyl] -phenyl }-benzenesulfonamidc (P-0020),
N-{2,4-Difluoro-3-[5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolof2,3-b]pyridine-3-carbonyl]-phenyl}-4- propyl-benzenesulfonamide (P-0021),
N-{2,4-Difluoro-3-[5-(l -methyl-l H-pyra7ol-4-yl)-lH-pyrrolo[2,3-b]pyndme-3-carbonyl]-phcnyl}-4- isopropyl-benzenesulfonamide (P-0022),
N-{2,4-Difluoro-3-[5-(5-methyl-lH-imidazol-2-y])-lH-pyrrolof2,3-b]pyridme-3-carbonyl]-phenyl} -
4-propyl-benzenesulfonamide (P-0023),
N- {2,4-Difluoro-3-[5 -(5 -methy 1- 1 H-imidazol-2-yl)- 1 H-pyrrolo [2,3 -b]pyndme-3 -carbonyl] -phenyl } -
4-tπfluoromethyl-benzenesulfonamide (P-0025),
N-{2,4~Difluoro-3-[5-(l -methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyndine-3-carbonyl]-phenyl} -
4-propyl-benzenesulfonamide (P-0026),
N-{3-[5-(l 5-Dimetliyl-lH-imida7θl-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- phen> 1 } -4-propyl-bcnzcncsulfonamide (P-0027),
N-[2,4-Difluoro-3-(5 methyl-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-tnfluoromethyl- benzenesulfonamide (P-0030),
N-[3-(5-Cyano-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phcnyl]-4-trifluoromethyl- benzenesulfonamidc (P-0031),
(E)-3-{3 [2,6-Difluoro-3-(4-tπfluoromethyl-benzenesulfonylamino)-benzoyl]-lH-pyrrolo[2,3- b]pyridin-5-yl} -acrylic acid methyl ester (P-0032),
3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzenesulfonylamino)-bcnzoyl]-l H-pyrrolo[2,3-b]pyπdm-
5 -yl} -propionic acid methyl ester (P-0033),
3-{3-[2,6-Diiluoro-3-(4-tnfluoromethyl-benzenesulfonylamino)-benzoyl]-l H-pyrrolo[2,3-b]pyπdin-
5 -yl} -propionic acid (P-0034),
3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzencsulfonylamino)-benzoyl]-lH-pyrrolo[2,3-b]pyπdm- 5-yl}-N-ethyl-propionamide (P-0035) and all salts, prodrugs, tautomers, and isomers thereof.
[0016] In some embodiments, compounds have the structure according to the following Formula II:
Figure imgf000010_0001
Formula II all salts, prodrugs, tautomers and isomers thereof, wherein:
Ria is as defined for R" for Formula I; and R1 and R3 are as defined for Formula I, provided, however, the compound is not
Figure imgf000010_0002
Figure imgf000011_0001
[0017] In some embodiments of compounds of Formula II, R1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR4, -SR4, -NR5R4, -C(O)R4, -C(O)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5S(O)2R4, -S(O)R4, and -S(O)2R4, and R2a is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR4, -SR4, -NR5R4, -C(O)R4, -C(O)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5S(O)2R4, -S(O)R4, and -S(O)2R4.
[0018] In some embodiments of compounds of Formula II, R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NII2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, -C(O)OH, -C(O)NH2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R~a is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NlIC(O)NH2, -NHC(S)NH2, -NHS(O)2NH,,, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR15C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OR1, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl aryl, and heteroaryl as R2a or as subslituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH3, -OR9, -SR9, -NRSR9, NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NRV, halogen, lower alkyl, fluoro substituted low er alkyl, and cycloalkylammo, wherein R7 is selected from the group consisting of lower alkyl, cycloalkyl heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylammo, R8 at each occurrence is independently hydrogen or lower alkyl, and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino di-alkylammo, and cycloalkylammo, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy
[0019] In some embodiments of compounds of Formula II, R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylammo, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 01 as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R0, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylammo, and R2a is selected from the group consisting of -CN, -OR1, -SR7, -NR8R7, -NR8C(O)R", -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R", -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylammo, di- alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R~a or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH1, -OR9, -SR9, -NRSR9, -NRsC(0)Ry, -NR8S(O)2R*, -S(0):RQ, -S(O)2NR8R9, -C(O)R", -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; wherein R7, R8 and R9 are as defined for paragraph [0011],
[0020] In some embodiments of compounds of Formula II, R1 is hydrogen, -CN, -NR8R7, -OR7, -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7; wherein R7 and R8 are as defined in paragraph [0011],
[0021] In some embodiments of compounds of Formula II, R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted Ci.6 alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di- alkylamino, and cycloalkylamino, and R'a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
[0022] In one embodiment of compounds of Formula 11, the compound is selected from the group consisting of:
3-[3-(5-Chloro-lH-pyrτolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid (P-0004),
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy- benzenesulfonamide (P-OOl 6),
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-l H-imida7ol-2-yl)-lH-p>τrolo[2,3-b]pyridine-3- carbonyl]-phenyl} -benzenesulfonamide (P-0024) and all salts, prodrugs, tautomers, and isomers thereof,
[0023| In some embodiments, compounds have the structure according to the following Formula III:
Figure imgf000014_0001
formula III all salts, prodrugs, tautomers and isomers thereof, wherein
R1 and R1 arc as defined for Formula I, and R6 is optionally substituted heteroaryl, provided, however, the compound is not
Figure imgf000014_0002
Figure imgf000015_0001
[0024] In some embodiments of compounds of Formula III, R1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR4, -SR4, -NR5R4, -C(O)R4, -C(O)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5S(O)2R4, -S(O)R4, and -S(O)2R4, and R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR4, -SR4, -NR5R4, -C(O)R4, -C(O)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NRSS(O)2R4, -S(O)R4, and -S(O)2R4, where R4 and R5 are as defined for Formula I.
[0025] In some embodiments of compounds of Formula III, R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, C(O)OH, -C(O)NH2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl. and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NII2, -C(S)NH2, -NHC(O)NH7, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OR7, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NII2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; wherein R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R' or as substituenls of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
[0026] In some embodiments of compounds of Formula III, R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR3S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylammo, cycloalkyl, heterocycloalkyl, aryl, and hcteroaryl, and wherein cycloalkyl, heterocycloalkyl. aryl, and hetcroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NlI2, -C(O)NH2, -ORΛ -SR9, -NR8R9. -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NRV, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylammo; wherein R7, R8 and R9 are as defined for paragraph [0011].
[0027] In some embodiments of compounds of Formula III, R1 is hydiogen, -CN, -NR8R7, -OR', -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and R6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR' or -S(O)2R7; wherein R7 and R8 are as defined m paragraph [0011].
[0028] In some embodiments of compounds of Formula III, R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lowrer alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2 6 alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylammo, di- alkylamino, and cycloalkylamino, and R6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylammo, di-alkylamino, or cycloalkylamino.
[0029] In one embodiment of compounds of Formula III, the compound is selected from the group consisting of
Ben7o[b]thiophene-3-sulfonic acid ^-(S-chloro-lH-pyrroloP^-bJpyπdme-S-carbony^-Z^-difluoro- phenyl]-amide (P-OOOl),
5-Methyl-2-tπfluoromethyl-furan-3-sulfomc acid [3-(5-chloro-lH-pyiτolo[2,3-b]pyridme-3- carbonyl)-2,4-difluoro-phenyl]-amide (P-0002),
5-Oxa7ol-5-yl-thiophene-2-sulfomc acid [3-{5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0003),
2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-lH-pyrτolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0005),
5-Isoxazol-5-yl-thiophene-2-sulfomc acid [3-(5-chloro-l H-pyrrolo[2,3-b]pyπdme-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0006), Benzothiazole-6-sulfonic acid [3-(5-chloro-lH-pyrτolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl] -amide (P-0009), l -Methyl-3-trifluoromethyl-lH-pyrazole-4-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyπdme-3- carbonyl)-2,4-difluoro-phenyl]-amide (P-OOlO),
Benzo[l, 2, 5]thiadiazoe-5 -sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridme-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0013),
5-Methyl-benzo[b]thiophene-2-sulfomc acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyndine-3-carbonyl)-2,4- difluoro-phenyl] -amide (P-OO 17),
5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyndine-3-carbonyl)-2,4-difluoro- phenyl] -amide (P-0028), l-Methyl-lH-pyrazole-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyπdme-3-carbonyl)-2,4- difluoro-phenyl] -amide (P-0029),
Pyridine-2-sulfoπic acid [2,4-difluoro-3-(5-methoxy-lH-pyrrolo[2,3-b]pyπdme-3-carbonyl)-phenyl]- amide (P-0036) and all salts, prodrags, tautomers, and isomers thereof.
[0030] In some embodiments of the above compounds, compounds are excluded where N (except where N is a heteroaryl ring atom), O, or S is bound to a carbon that is also bound to N (except where N is a heteroaryl πng atom), O, or S; or where N (except where N is a heteroaryl ring atom), O, C(S), C(O), or S(O)n (n is 0-2) is bound to an alkene carbon of an alkenyl group or bound to an alkyne carbon of an alkynyl group; accordingly, in some embodiments compounds which include linkages such as the following are excluded from the compounds provided: -NR-CH2-NR-, -0-CH2-NR-, -S-CII2-NR-, -NR-CH2-O-, -0-CH2-O-, -S-CH2-O-, -NR-CH2-S-, -0-CH2-S-, -S-CH2-S-, -NR-CH=CH-, -CH=CH-NR-, -NR-C ≡€-, -C ≡€-NR-, -0-CH=CH-, -CH=CH-O-, -O-C ≡C-, -C ≡€-O-, -S(OV2-CH=CH-, -CH=CH-S(OV2-, -S(O)0 2-C =€-, -C =e-S(O)0 2-, -C(O)-CH=CII-, -CH=CH-C(O)-, -C ≡€-C(O)-, or -C(O)-C ≡€-, -C(S)-CH=CH-, -CH=CH-C(S)-, -C ≡€-C(S)-, or
-c(S)-c ≡e-.
[0031] In reference to compounds herein, unless clearly indicated to the contrary, specification of a compound or group of compounds includes pharmaceutically acceptable salts of such compound(s), prodrug(s), and all stereoisomers thereof. In reference to compositions, kits, methods of use, etc. of compounds of Formula 1, Formula II, or Formula III described herein, it is understood (unless indicated otherwise) that a compound of Formula I includes all sub-embodiments thereof, a compound of Formula II includes all sub-embodiments thereof, and a compound of Formula III includes all sub-embodiments thereof.
[0032] In one aspect, methods are provided 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 compounds of Formula I, Formula II, or Formula III The terms "treat," "therapy," and like terms refer to the administration of material, e g , one or more compound of Formula I, Formula II, or Formula III, 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 The term "protein kinase mediated disease or condition" refers to a disease or condition in which the biological function of a protein kinase affects the development, course, and or symptoms of the disease or condition, and/ or in which modulation of the protein kinase alters the development, course, and/or symptoms of the disease or condition A protein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit, e g wherein treatment w ith protein kinase inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at πsk of the disease or condition In one aspect, the method involves administering to the subject an effective amount of a compound of Formula I, Formula II, or Formula III in combination with one or more other therapies for the disease or condition
[0033] In one aspect, methods are provided for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subj ect an effective amount of any one or more compound of Formula I, Formula II, or Formula III
10034] In one aspect, the invention provides methods for treating a Raf protein kinase mediated disease or condition m an animal subject, wherein the method involves administering to the subject an effective amount of one or more compound of Formula I, Formula II, or Formula III The terms "Raf protein kinase mediated disease or condition," "Raf mediated disease or condition," and the like refer 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 m which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease oi condition The Raf protein kinase includes, but is not limited to, A-Raf, A-Raf mutations, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1 In some embodiments, the Raf protein kinase is B-Raf mutation V600E In some embodiments, the Raf protein kinase is B-Raf mutation V600E/T529I In some embodiments, the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E mutant B-Raf In some embodiments, the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E/T529I mutant B-Raf The Raf protein kinase mediated disease or condition includes a disease or condition for which Raf inhibition provides a therapeutic benefit, e g wherein treatment with Raf inhibitors, including compounds described herein provides a therapeutic benefit to the subject suffering from or at πsk of the disease or condition In one aspect, the method involves administering to the subject an effective amount of a compound of Formula I, Formula II, or Formula III in combination with one or more other therapies for the disease or condition. Similarly, the terms "A-Raf, B-Raf or c-Raf-1 protein kinase mediated disease or condition," "A-Raf, B-Raf or c-Raf-1 mediated disease or condition," and the like refer 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,
[0035] In some embodiments, a compound of Formula I, Formula II, or Formula III w ill have an IC50 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, In some embodiments, a compound of any of Formula I, Formula II, or Formula III will have an IC50 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 AbI, Aktl , Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1 , Csk, EGFR, EphAI , EphA2, EphB2, EphB4, Erk2, Fak, FGFRl, FGFR2, FGFR3, FGFR4, Fltl, Flt3, FH4, Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGFI R, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl , MLKl , p38, PDGFRA, PDGFRB, PDPKl, Piml , Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plkl , Pyk2, Ret, ROCKl , ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including any mutations thereof.
[0036] In some embodiments, a compound of Formula I, Formula II, or Formula III will have an IC50 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 AbI, Akt 1 , Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl5 c-Raf- 1, Csk, EGFR, EphAI, EphA2, EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3α, Gsk3β, HCK, Hcr2/Erbb2, Hcr4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl , Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1 , MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl , MLKl , p38, PDPKl , Piml, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plkl , Pyk2, Ron, Src, Stkό, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including any mutations thereof.
[0037] In some embodiments, a compound of Formula I, Formula II, or Formula III will have an IC5O 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 AbI, A-Raf, B-Raf, Btk, c-Raf-1 , EGFR, EphB2, Erk2, Fak, FGFRl , Fltl , Flt3, Flt4, Fms, Irak4, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAPKAP kinase 2, Met, p38, PDGFRB, Piml , PKC theta, Pyk2, Ret, Src, Stkό, Yes, and Zap70, including any mutations thereof. [0038] In some embodiments, a compound of Formula I, Formula II, or Formula III will have an IC50 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 AbI, A-Raf, B-Raf, Btk, c-Raf-1 , EGFR, EphB2, Erk2, Fak, Fins, Irak4, Jnkl , Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1 , MAPKAP kinase 2, Met, p38, Piml , PKC theta, Pyk2, Src, Stk6, Yes, and Zap70, including any mutations thereof
[0039] In some embodiments, a compound of Formula I, Formula II, or Formula III will have an IC50 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 V600ET529I mutant, c-Raf-1 , Fak, FGFRl , FGFR2, FGFR3, FGFR4, Jnkl , Jnk2, Jnk3, Lck, Lyn, Met, Piml, Pim2, Pim3, Pyk2, Kdr, Src and Ret, including any mutations thereof.
[0040] In some embodiments, a compound of Formula I, Formula II, or Formula III is an inhibitor of a Raf kinase and has an ICS0 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 Raf kinase activity assay In some embodiments, a compound of Formula I, Formula II, or Formula III will have an ICSo 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 B-Raf, c-Raf-1 , B-Raf V600E mutant, or B- Raf V600E/T529I mutant. In some embodiments, a compound of Formula I, Formula II, or Formula III will selectively inhibit one Raf kinase relative to one or more other Raf kinases. In some embodiments, the compound of Formula I, Formula II, or Formula III 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.
[0041] Further to any of the above mentioned embodiments, a compound 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. For example, 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
[0042] Further to any of the above embodiments, a compound 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. In some embodiments, 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 In some embodiments, the compound may selectively inhibit Fms relative to Kit. Selective inhibition of one kinase relative to another is such that the IC50 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 IC50 for any of the other kinases as determined m a generally accepted kinase activity assay
[0043] In another aspect, compositions are provided that include a therapeutically effective amount of one or more compound of Formula I, Formula II, or Formula III and at least one pharmaceutically acceptable carrier, excipient, and'or diluent, including combinations of any two or more compounds of Formula I, Formula II or Formula III The composition can further include a plurality of different pharmacologically active compounds, which can include a plurality of compounds of F ormula I, Formula II, or Formula III In another aspect, the composition can include one or more compounds of Formula I, Formula II, or Formula III along with one or more compounds that are therapeutically effective for the same disease indication In one aspect, the composition includes one or more compounds of Formula I, Formula II, or Formula III 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 In one aspect, the composition includes one or more compounds of Formula I, Formula II, or Formula III 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
[0044] In another aspect, methods are provided for modulating the activity of a protein kinase selected from the group consisting of AbI, Aktl, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1 , Csk, EGFR, EphAl , EphA2, EphB2, EphB4, Erk2, Fak, FGFRl , FGFR2, FGFR3, FGFR4, Fltl, Flt3, Flt4, Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl , MI Kl , p38, PDGFRA, PDGFRB, PDPKl , Piml, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plkl, Pyk2, Ret, ROCKl , ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70 by contacting the protein kinase with an effective amount of one or more compound of Formula I, Formula II, or Formula III
[0045] In another aspect, methods are provided 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 of Formula I, Formula II, or Formula III
[0046] In one aspect, methods are provided for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, Akt 1 , Akt2, Akt3 AI K Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl , c-Raf-1 , Csk, EGFR, fcphAl , EphA2, EphB2, EphB4, Erk2, Fak, FGFRl FGFR2, FGFR3, FGFR4, Fltl, Flt3, Flt4, Fms, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl, Jak2, Jak3, Jnkl Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl , MLKl , p38, PDGFRA, PDGFRB, PDPKl , Piml , Pim2, Pim3, PKC alpha, PKC beta, PKC thcta, PIk 1 , Pyk2, Ret, ROCKl , ROCK2, Ron, Src, Stk6, Syk, TEC, 1 ie2, TrkΛ, TrkB, Yes. and Zap70 by administenng to the subject an effective amount of a composition including one or more compound of Formula I, Formula II, or Formula III
[0047] In one aspect the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, Akt 1 , Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl, c-Raf-1 , Csk, EGFR, EphAl , EphA2, FphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3α, Gsk3β, HCK, Her2/Εrbb2, Her4Εrbb4, IGFl R, IKK beta, Irak4, Ilk, Jakl , Jak2, Jak3, Juki , Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1 , MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl , MLKl , p38, PDPKl, Piml , Pim2, Pim3, PKC alpha, PKC beta, PKC theta, PIk 1 , Pyk2, Ron, Src, Stk6, Syk, TEC Tie2, TrkA, TrkB, Yes, and Zap70 by administenng to the subject an effective amount of a composition including one or more compound of Formula I, Formula TT, or Formula III
[0048] In one aspect, the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, A-Raf, B-Raf, Btk, c-Raf-1 , EGFR, EphB2, Erk2, Fak, FGFRl, Fltl, Flt3, Flt4, Fms, Irak4, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAPKAPK2, Met, p38, PDGFRB, Piml, PKC thcta, Pyk2, Ret, Src, Stkό, Yes, and Zap70 by administenng to the subject an effective amount of a composition including one or more compound of Formula I, Formula II, or Formula III
[0049] In one aspect, the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of AbI, A-Raf, B-Raf, Btk, c-Raf 1 , EGFR, EphB2, Erk2, Fak, Fms, Irak4, Jnkl, Jnk2, Jnk3, Kit, Lck, Lyn, MAP2K1, MAPKAPK2, Met, p38, Piml , PKC theta, Pyk2, Src, Stkό, Yes, and Zap70 by administering to the subject an effective amount of a composition including one or more compound of Formula I, Formula II, or Formula III
[0050] In one aspect, 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/T529I mutant, c Raf-1, Fak, FGFRl, FGFR2, FGFR3, FGFR4, Jnkl , Jnk2, Jnk3, Lck, Lyn, Met, Piml, Pim2, Pim3, Pyk2, Kdr, Src and Ret by administering to the subject an effectrve amount of a composition including one or more compound of Formula I, Formula II, or Formula III
[0051] In one aspect, 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 administenng to the subject an effective amount of a composition including one or more compound of Formula I, Formula II or Formula III In one aspect, the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600fc mutant, or B-Raf V600tΛl 5291 mutant by administering to the subject an effective amount of a composition including one or more compound of Formula I, Formula II, or Formula III m combination with one or more other suitable therapies for treating the disease In one aspect, 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 of Formula I, Formula II, or Formula III in combination with one or more suitable anticancer therapies, such as one or more chemotherapeutic drags
[0052] In one aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including onr or more compound of Formula I, Formula II, or Formula III, 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 (c 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) In one aspect, the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e g chemotherapeutic drag), radiation treatment (e g x-ray, γ-ray, or electron, proton, neutron, or α particle beam), hyperthermia heating (e g microwave, ultrasound, radiofrequency ablation), Vaccine therapy (e g AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, ΛG-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), surgery, or bone marrow and stem cell transplantation
[0053] In a preferred embodiment, 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 of Formula I, Formula II, or Formula III, in combination with one or more suitable chemotherapeutic agents In one aspect, the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesm, altretamme, bizelesm, busulfan, carboplatm, carboquone, carmustme, chlorambucil, cisplatm, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, lfosfamide, improsulfan, irofulven, lomustine, mechlorethamme, melphalan, oxaliplatin, prposulian, semustme, streptozocm, temozolomide, thiotcpa, and trcosulfan, an antibiotic, including, but not limited to, bleomycin, dactmomycm, daunorubicin, doxorubicin, epirubicm, ldarabicm, menogaπl, mitomycin, mitoxantrone, neocarzinostatm, pentostatm, and phcamycin, an antimetabolite, including, but not limited to, azacitidme, capecitabme, cladnbme, clofarabme, cytarabme, decitabme, floxuπdine, fludarabme, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopuπne, methotrexate, nelarabme, pemetrexed, raltitrexed, thioguanine, and tπmetrexate, an immunotherapy, including, but not limited to, alemtu7umab, bevacizumab, cetuximab, galiximab, gcmtuzumab, panitumumab, pertuzumab, ntuximab, tositumomab, trastuzumab, and 90 Y ibntumomab tiuxetan a hormone or hormone antagonist, including, but not limited to. anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutarmde, fulvestrant, goserelin, ldoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene, a taxanc, including, but not limited to, DJ-927, docetaxel, TPI 287, paclitaxel and DHΛ-pachtaxel, a retinoid, including, but not limited to, ahtretinom, bexarotene, fenretmide, isotretinoin, and tretinoin, an alkaloid, including, but not limited to, etoposide, homoharπngtonme, teniposide vinblastine, vincristine, vindesine, and vmorelbine, an antiangiogemc agent, including, but not limited to, AE-941 (GW786034, Ncovastat), ABT-510, 2-methoxyestradiol, lenahdomide. and thalidomide, a topoisomerase inhibitor, including, but not limited to amsacπne, edotecarm, exatecan, irinotecan (also active metabolite SN-38 (7-ethyl- 10-hydroxy-camptothecin)), rubitecan, topotecan, and 9-aminocamptothecm, a kinase inhibitor, including, but not limited to, erlotmib, gelitinib, tlavopindol, imatmib mesylate, lapatmib, sorafemb, sumtinib malate, AEE-788, ΛG-013736, AMG 706, AMN107, BMS-354825, BMS-599626. UCN-01 (7-hydroxystaurospoπne), and vatalamb. a targeted signal transduction inhibitor including but not limited to bortezomib, geldanamycin, and rapamycin, a biological response modifier, including, but not limited to, imiquimod, mterferon-α, and mterleukm-2, and other chemotherapeutics, including, but not limited to 3-AP (3-amino-2-carboxyaldchydc thioscmicarbazone), ammoglutethimide, asparaginase, bryostatin-1 , cilengitide, E7389, lxabepilone, procarbazine, sulmdac, temsirolimus tipifarnib Preferably, the method of treating a cancer involves administering to the subject an effectiv e amount of a composition including one or more compound of Formula I, Formula II, or Formula III in combination with a chcmothcrapcutic agent selected from 5-fluorouracil, carboplatin, dacarbazme, gefitmib, oxahplatm, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, or erlotmib
[0054] In another aspect, 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 of Formula I, Formula II. or Formula III, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug The compound can be alone or can be part of a composition In another aspect, 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 of Formula I, Formula II, or Formula III, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug in combination with one or more other suitable therapies for the disease or condition
[0055] In a related aspect, the invention provides kits that include a composition as descπbed herein In some embodiments, 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 Food and Drag Administration or similar regulatory agency for administration to a mammal, e g , a human, 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 wntten 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 kmase-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
[0056] In aspects involving treatment or prophylaxis of a disease or condition with the compounds of Formula I, Foπnula II, or Formula III, the disease or condition is, tor example without limitation, neurologic diseases, including, but not limited to, cerebrovascular ischemia, multi-mfarct 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 myelofibrosis, 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 (c g lung, breast, pancreatic, colon, hepatocellular, renal, female genital tract, squamous cell, carcinoma m situ), lymphoma (e g histiocytic lymphoma, non-Hodgkin's lymphoma), MEN2 syndromes, neurofibromatosis (including Schwann cell neoplasm), 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), breast, colon, bladder, prostate, gastrointestinal tract, endometrium, fallopian tube, testes and ovary, and metastasis of tumors to other tissues, pain of neuropathic or inflammatory origin, including, but not limited to, acute pam, chronic pam, bone pain, cancer-related pam 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 cerebrovascular ischemia, liver ischemia), inflammation including, but not limited to, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, systemic lupus erythematosa, Sjogren's Syndrome, Wegener's granulomatosis, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, psoriasis, scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, scarring (e g dermal, tissue), vascular restenosis, fibrotic disorders, hypereosmophiha, CNS inflammation pancreatitis nephritis, atopic dermatitis, and hepatitis, immunodeficiency diseases , including, but not limited to, severe combined immunodeficiency (SCID), organ transplant rejection, and graft versus host disease, renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis interstitial nephritis, Lupus nephπtis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complications, and renal hypertrophy, metabolic diseases, including, but not limited to, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, hpolysis and 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), acute respiratory distress syndrome (ARDS), asthma, allergy, bronchitis, emphysema, and pulmonary fibrosis, genetic developmental diseases, including, but not limited to, Noonan's syndrome, Crouzon syndrome, acrocephalosyndactyly type 1, Pfeiffer's syndrome, Jackson-Weiss syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPAEX) syndrome, cardio- faciocutaneous syndrome (CFC) and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, disorders of bone structure, mineralization and bone reformation and resorption, including, but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, osteomyelitis, pen-prosthetic or wear-debris-mediated osteolysis, and metastatis of cancer to bone, Grave's disease, Hirschsprung's disease, lymphoedema, selective T-cell defect (STD), X-hnked agammaglobulinemia, diabetic retinopathy, alopecia, erectile dysfunction, tuberous sclerosis, and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopema, 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 spmal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spmal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Maπe-Tooth disease, Dejeπne- Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofruttokmase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglyecrate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency) [0057] In aspects involving treatment or proph>laxis of a disease or condition with the compounds of Formula I, Formula II, or Formula III, the invention provides methods for treating an Λ-Raf- mediated, B-Raf-mediated and/or c-Raf-1 -mediated disease or condition m an animal subject (e g a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm 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) Invention methods involve administering to the subject suffering from or at πsk of an Λ-Raf-mediated, B-Raf- mediated and/or c-Raf-1 -mediated disease or condition an effective amount of compound of Formula I, Formula II or Formula III In one embodiment, the A-Raf-mediated, B-Raf-mcdiatcd, and^or c-Raf- 1 -mediated disease is selected from the group consisting of neurologic diseases, including, but not limited to, multi-mfarct dementia, head injury, spmal 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, ovanan), lymphoma (e g histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocnne 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 thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury, 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, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome) LEOPARD syndrome, cardio- faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopema, muscular dystrophics (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 spmal muscular atrophy spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Maπe- Tooth disease, Dejenne- Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemalme myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokmase deficiency, dcbrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency)
[0058] In a related aspect, compounds of Formula I, Formula II, or tormula III, 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, myelodysplasia syndrome, leukemia, tumor angiogenesis, neuroendocnne tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and phcochromocytoma, 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 thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury, 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 \ersus 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 pylon, 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, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio- faciocutaneous syndrome (CFC), and neural crest syndrome abnoimahties causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopenia. muscular dystrophies (including, but not limited to, Duchenne, Becker, Fmery-Dreifuss, I imb-Girdle. Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophics), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spmal muscular atrophy, intermediate spmal muscular atrophy juvenile spmal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic svndrome), myopathies due to endocπne abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peπpheral nerve (including, but not limited to, Charcot-Mane-Tooth disease, Dejerme- Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases ot muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency)
[0059] The compounds of Formula I, Formula II, or Formula III with kinase activity IC,o less than 10 μM 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
AbI, related to chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML),
Aktl , related to gastπc, prostate, colorectal, ovaπan, pancreatic and breast cancer, glioblastoma and leukemia, as well as schizophrenia and bipolar disorders, and also use in combination with other chemotherapeutic drugs,
Akt2, related to hyperglycemia due to penpheral insulin resistance and nonsuppressible hepatic glucose production accompanied by inadequate compensatory hypeπnsulmemia, also related to pancreatic, ovarian and breast cancer, Akt3, related to melanoma, prostate and breast cancer, ALK, related to non-Hodgkm lymphomas such as diffuse large B-cell lymphoma and anaplastic large cell lymphoma,
Alk5, related to pancreatic and biliary cancers, and cutaneous T-cell lymphoma, Λ-Raf, related to neurologic diseases such as multi-mfarct dementia, head injury, spmal 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, myelodysplastic syndrome, leukemia, tumor angiogenesis, pain of neuropathic or inflammatory origin, including acute pam chrome pain, cancer-related pain and migraine, and diseases associated w ith muscle regeneration or degeneration, including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to Duchenne, Becker, hmery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotome, 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, spmal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambcrt-Laton syndrome, and congenital myasthenic syndrome), myopathies due to endocπne abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peπpheral nerve (including, but not limited to, Charcot- Maπe-Tooth disease, Dejeπne-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokmase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency)
B-Raf or c-Raf-1 , related to neurologic diseases, including, but not limited to, as multi-infarct dementia, head injury, spmal 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, ovaπan), 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 pam, chronic 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, inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometπosis, 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 01 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 pylon, Hepatitis and Influenza \iruses, 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, Noonan's syndrome, Costello syndrome (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), and neural ciest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases ,
Brk. related to breast and colon cancer, and head and neck squamous cell carunoma, Btk, related to X-linked agammaglobulinemia, acute lymphocytic leukemia, autoimmune diseases such as multiple sclerosis, systemic lupus erythematosa, rheumatoid arthritis, and Graves' disease, immune suppression in organ transplant, and drug sensitivity of B-lineage cells, Cdk2, related to prostate, breast, colorectal and ovanan cancer, Cdk4, related to glioblastoma (e g glioblastoma multiforme), anaplastic astrocytoma, and breast cancer,
Cdk5, related to Alzheimer's disease, amyotrophic lateral sclerosis and Lewy body disease, Cdkό, related to glioblastoma multiforme, non-Hodgkin's lymphoma, splenic marginal zone lymphoma, T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (1 -ALL),
CHKl, related to DNA damage repair, sensitizes cells to chemotherapeutic agents, Csk, related to colon and pancreatic carcinomas and autoimmune pathology such as type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus, hGFR, related to breast, colorectal, bladder, prostate and non small cell lung cancer, squamous cell carcinomas of the head and neck cancer, oral cavity, and esophagus, and glioblastoma multiforme,
EphAl , related to head and neck squamous cell carcinoma, hepatoma and lung cancer, bphA2, related to aberrant short-range contact-mediated axonal guidance, bladder, breast, prostate, colon, skm, cervical, ovarian, pancreatic and lung cancers, and metastatic melanoma, EphB2, related to angiogenesis disorder (e g ocular angiogenesis disease such as retinopathy), and cancer (e g glioblastoma, breast and liver cancer),
EphB4, related to colorectal cancer (CRC), head and neck squamous cell carcinoma, and tumours of the prostate, breast, endometrium, and bladder, Erk2, related to aberrant proliferation, differentiation, transcription regulation and development, and may be useful in treating inflammation, for example inflammation associated with Lyme neuroborrehosis, and in treating cancers, such as gastric cancer,
Fak, related to colon and breast tumors, and is also related to esophageal squamous cell carcinoma, melanoma, anaplastic astrocytoma, glioblastoma, ductal carcinoma m situ, prostate and hepatocellular carcinoma, and tumor metastases, and may also provide synergistic effects when used w ith other chemotherapeutic drugs, FGFRl, related to 8pl 1 myeloproliferative syndrome, FGFR2, related to Crouzon Syndrome, Jackson-Weiss Syndrome, Apert Syndrome, craniosynostosis, Pfeiffer Syndrome, acrocephalo syndactyly type V, and Beare-Stevenson Cutis Gyrata Syndrome,
FGFR3, related to angiogenesis, wound healing, achondroplasia, Muenke craniosynostosis, Crouzon syndrome, acanthosis nigricans, thanatophoric dysplasia, bladder carcinomas, and multiple myeloma,
FGFR4, related to cancer of the breast, lung, colon, medullary thyroid, pancreas, ovary, prostate, endometrium, and fallopian tube, head and neck squamous cell carcinomas and leiomyosarcoma,
Fltl, related to non-small cell lung carcinoma, prostate carcinoma, and colorectal cancer, Flt3, related to acute myeloid leukemia, myelυdysplastic syndrome, acute lymphoblastic leukemia,
Flt4, related to primary lymphoedema,
Fms, related to immune disorders, including, but not limited to, rheumatoid arthritis, systemic lupus erythematosa (SLE), and transplant rejection, inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, chrome obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis, metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and hpolysis, disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e g osteomyelitis), pen-prosthetic or wear-debris-mediated osteolysis, and metastasis of cancer to bone, kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e g glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e g diabetic nephropathy), and renal hypertrophy, disorders of the central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory and chronic pam, including, but not limited to, bone pain, and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia (AMI ), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis,
Frk, related to acute myeloid leukemia and type 1 diabetes,
Fyn, related to Alzheimer's disease, schizophrenia and prevention of metastases, e g in melanoma and squamous cell carcinoma,
GSK3 (Gsk3α and/or Gsk3β), related to CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes type II, bipolar disorders, stroke, cancer, chronic inflammatory disease, leucopenia, schizophrenia, chronic pain, neuropathic pain, and traumatic head injury,
HCK, related to chronic myelogenous leukemia and acute lymphocytic leukemia,
Her2/Erbb2, related to prostate and breast cancer
IIer4/Erbb4, related to childhood medulloblastoma,
IGFlR, related to prostate cancer, hepatocellular carcinoma,
DCK beta, related to leukemia of T-cells, necrosis, insulin resistance, and malignant neoplasms,
Irak4, related to bacteπal infections, immunodeficiency syndrome, Crohn's disease, ulcerative colitis, asthma, chronic bronchitis, cardio hypertrophy, and kidney hypertension,
Itk, related to allergic asthma,
Jakl , related to Hepatitis C virus infection,
Jak2, related to mj eloproliferative disorders such as polycythaemia vera, myelofibrosis, essential thrombocythemia, myeloid metaplasia and leukemias, including acute lymphoblastic leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic leukemia, CMML, Philadelphia chromosome-negative CML, megakaryocyte leukemia, and acute erylhroid leukemia,
Jak3, related to X-linked severe combined immunodeficiency, myeloproliferative disorders, transplant rejection and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosa, ulcerative colitis, psonasis and multiple sclerosis,
Jnk (Jnkl , Jnk2, Jnk3), related to metabolic diseases including type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, and hepatic steatosis, cardiovascular diseases such as atherosclerosis, ischemia (e g cerebrovascular ischemia, liver ischemia), reperfusion injury, cardiac hypertrophy, renal diseases such as chronic renal failure, neoplastic diseases and associated complications, including chemotherapy-mduced hypoxia, prostate tumors, myeloid leukemia and cancers of the liver, bone, skin, brain, pancreas, lung breast, colon, prostate and ovary, transplant rejection, pain of neuropathic or inflammatory origin including acute and chronic pain, inflammatory and autoimmune diseases including age-related macular degeneration, rheumatoid arthritis inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosa, Sjogren's Syndrome, psoriasis, scleroderma, chronic thyroiditis Gra\e's disease, myasthenia gravis, and multiple sclerosis, and inflammation in other organs including CNS inflammation, pancreatitis, nephritis, atopic dermatitis, and hepatitis airway inflammatory diseases such as asthma, allergy, bronchitis, pulmonary fibrosis, chrome obstructive pulmonary disease, neurologic diseases such as stroke, cerebrovascular ischemia, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, dementia, senile chorea head and spinal cord trauma, and Huntmgton's disease More particularly, Juki is related to type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity and hepatic steatosis, Jnk2 is related to atherosclerosis, and Jnk3 is related to inflammatory diseases including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosa, Sjogren's Syndrome, psoriasis and multiple sclerosis, airway inflammatory diseases such as asthma, allergy, pulmonary fibrosis, and chronic obstructive pulmonary disease, and inflammation in other organs, such as CNS inflammation, pancreatitis, nephritis, and hepatitis, neurologic diseases such as stroke, cerebrovascular ischemia, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntmgton's disease, and neoplastic diseases such as prostate tumors and myeloid leukemia,
Kdr, related to anti-angiogenesis for treating solid lumor growth (e g ovarian, lung, breast prancreatic, prostate, colon, gastrointestinal stromal tumor, non small cell lung cancer, and epidermoid cancer), metastasis, psoriasis, rheumatoid arthritis, diabetic retinopathy and age related macular degeneration,
Kit, related to malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma m situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosmophilia,
Lck, related to acute lymphoblastic leukemia, T-cell lymphoma, lymphopenia, renal carcinoma, colon carcinoma severe combined immunodeficiency, multiple sclerosis, inflammatory bowel and type I diabetes,
Lvn, related to
MAP2K1, related to acute myeloid leukemia, breast, ovarian and liver cancer,
MAP2K2, related to cancer and inflammation, MAP4K4, related to metabolic indications, including re-sensitLdng fat and muscle cells to insulin, ameliorating the pathology in adipocytes, ameliorating the pathology m muscle cells, metabolic syndrome, and type II diabetes; a broad range of oncology indications, including blocking the migration, invasion and metastasis in many different tumor types, and T-cell mediated autoimmune diseases,
MAPKAPK2, cancer (e.g. prostate, breast), stroke, menengitis, and inflammatory disorders; Met, related to kidney, breast, bladder, non-small-cell lung, colorectal, and bladder cancers, and hepatocellular carcinoma; Mnkl, related to conditions associated with heat shock, nutrient deprivation, oxidative or osmotic stress, and infection of mammalian cells (e.g. with viruses such as adenovirus (Ad) or influenza virus), and autoimmune diseases; MLKl, related to neurodegenerative dibeases such as Alzheimer's disease and Parkinson's disease, and inflammatory disorders; p38, related to acute coronary syndrome, stroke, atherosclerosis, and inflammatory autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease; PDGFR (PDGFRA, PDGFRB), related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, glioma, gastrointestinal stromal tumors (GISl s), juvenile myelomonocytic leukemia, metastatic medulloblastoma, atherogenesis, and restenosis. More particularly, PDGFRA related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, glioma, gastrointestinal stromal tumors (GISTs), juvenile myelomonocytic leukemia, metastatic medulloblastoma, atherogenesis, and restenosis, and PDGFRB related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, and metastatic medulloblastoma, PDPKl, related to cancer and diabetes; Piml , related to cancers such as hematopoietic (e.g. acute myeloid and acute lymphoid leukemias) and prostate cancers, and non-Hodgkin's lymphomas; Pim2, related to lymphomas; Pim3, related to hepatocellular carcinoma; PKC alpha, related to pituitary tumors and prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder, also may be used to sensitize chemotherapy in breast, colon, and non small cell lung cancers, PKC beta, related to diabetic retinopathy, PKC-theta, related to insulin resistance, T-cell lymphoma, Plkl, related to cancers (e.g. lymphoma of the thyroid, non-Hodgkin's lymphomas, colorectal cancers, leukemias and melanoma), also useful as sensitizer in chemotherapy; Py k2, related to inflammation (e g osteoporosis, polycystic kidney disease rheumatoid arthintis and inflammatory bowel disease), CNS disease (e g Parkinson's disease and Alzheimer s disease), stroke and cancers (e g gliomas, breast cancer, and pancreatic cancer), Ret, related to cancer of the thyroid, neuroblastoma, familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasm type HA and HB (MEN2A, MEN2B), and neurodegenerative disorders (e g Hirschsprung's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis),
ROCK (ROCK-I, ROCK-2), related to cancers (e g ovaπan cancer, hepatocellular carcinoma, pancreatic cancer), ocular disease (e g glaucoma), cardiac hypertrophy, improved renal perfusion, transplant reiection, and acute respiratory distress syndrome,
Ron, related to cancer and inflammation, Src, related to cancer and osteoporosis, Stk6, related to gastπc, bladder, breast, lung, CNS, ovaπan, kidney, colon, prostate, pancreas, and cervical cancers, melanoma, leukemia, and neuroblastoma, Syk, related to lymphomas (e g mantle cell lymphoma), TEC, related to sepsis, septic shock, inflammation, rheumatoid arthritis, Crohn's disease, irritable bowel disease (IBD), and ulceratrve colitis,
Tie2 (TEK), related to cancer, arthritis (e g rheumatoid arthritis), and atherosclerosis, I rkA, related to pain (e g chronic pam, neuropathic pam), cancer (e g prostate cancer, lung cancer, pancreatic cancer), allergic disorders (e g asthma), arthritis, diabetic retinopathy, macular degeneration and psoriasis,
TrkB, related to obesity, hyperphagia, developmental delays, cancer (e g prostate cancer, lung cancer, Wilms tumors, neuroblastoma, pancreatic cancer), vanous neuropathies (e g stioke, multiple sclerosis, transverse myelitis, and encephalitis), and diabetes Yes, related to \anous cancers including esophageal squamous cell carcinoma, and Zap70, related to AIDS, systemic lupus erythematosus, myasthenia gravis, atherosclerosis, rejection of transplanted organs or tissues, allograft rejection including acute and chronic allograft rejection, graft versus host disease, rheumatlioid arthritis, psoriasis, systemic sclerosis, atopic dermatitis eczematous dermatitis, alopecia, and inflammation of the nasal mucus membrane, including all forms of rhinitis
[0060] Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0061] As used herein the following definitions apply unless clearly indicated otherwise:
[0062] "Halogen" refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
[0063] "Hydroxyl" or "hydroxy" refer to the group -OH.
[0064] "Thiol" refers to the group -SH.
[0065] "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 attached at any available point to produce a stable compound. In many embodiments, 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. A "substituted lower alkyl" denotes lower alkyl that is 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, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR0, -SR°, -OC(O)R0, -OC(S)R0, -C(O)R0, -C(S)R0, -C(O)OR0, -C(S)OR0, -S(O)R0, -S(O)2R0, -C(O)NHR0, -C(S)NHR0, -C(O)NR0R0, -C(S)NR0R0, -S(O)2NHR0, -S(O)2NR0R0, -C(NII)NHR0, -C(NH)NRPRC, -NHC(O)R0, -NHC(S)R0, -NR0C(O)R0, -NR0C(S)R0, -NHS(O)2R0, -NR0S(O)2R0, -NHC(O)NHR0, -NHC(S)NHR0, -NR0C(O)NH2, -NR0C(S)NH2, -NR0C(O)NHR0, -NR0C(S)NHR0, -NHC(O)NR0R0, -NHC(S)NR0R0, -NR0C(O)NR0R0, -NR0C(S)NR0R0, -NHS(O)2NHR0, -NR0S(O)2NH2, -NR0S(O)2NHR0, -NIIS(O)2NR0R0, -NR0S(O)2NR0R0, -NHR0, -NR0R0, -Rc, -Rf, and -Rg. Furthermore, possible substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, attached at any available atom to produce a stable compound. For example "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. While it is understood that substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -OR (e.g. alkoxy), -SR (e.g. thioalkyl), -NHR (e.g. alkylamino), -C(O)NHR, and the like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any O, S, orN of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkyl carbon bound to any O, S, or N of the moiety. "C2.6 alkyl" denotes lower alkyl containing 2-6 carbon atoms, A "substituted C2.b alkyl" denotes optionally substituted lower alkyl containing 2-6 carbon atoms. A "substituted methyl" denotes methyl that is independently substituted, unless indicated otherwise, with 1, 2, or 3 substituents, wherein the substituents are selected as per optionally substituted lower alkyl.
[0066] "C 1.3 alkylene" refers to a divalent alkane-derived radical containing 1-3 carbon atoms, straight chain or branched, from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms. CY3 alkylene includes methylene -CH2-, ethylene -CH2CH2-, propylene -CH2CH2CH2-, and isopropylene -CH(CH3)CH2- or -CH2CH(CH3)-. Ci-3 alkylene substituted with one or more substituents indicates C^3 alkylene that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents as indicated, attached at any available atom to produce a stable compound.
[0067] "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. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like. A "substituted lower alkenyl" denotes lower alkenyl that is 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, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -ORU, -SRU, -OC(O)R0, -OC(S)R0, -C(O)R0, -C(S)R0, -C(O)OR0, -C(S)OR0, -S(O)R0, -S(O)2R0, -C(O)NHR0, -C(S)NHR0, -C(O)NR0R0, -C(S)NR0R0, -S(O)3NHR0, -S(O)2NR0R0, -C(NH)NHR0, -C(NH)NRPRC, -NHC(O)R0, -NHC(S)R0, -NR0C(O)R0, -NR0C(S)R0, -NHS(O)2R0, -NR0S(O)2R0, -NHC(O)NHR0, -NHC(S)NHR0, -NR0C(O)NH2, -NR0C(S)NH2, -NR0C(O)NHR0, -NR0C(S)NHR", -NHC(0)NRuRϋ, -NHC(S)NR0R0, -NR0C(O)NR0R0, -NR0C(S)NR0R0, -NHS(O)2NHR0, -NR0S(O)2NH2, -NR0S(O)2NHR0. -NHS(O)2NR0R0, -NR0S(O)2NR0R0, -NHR0, -NR0R0, -Rd, -Rf, and -RB. Further, possible substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Foπnula I, Formula II, or Formula III, attached at any available atom to produce a stable compound. For example "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. While it is understood that substitutions are attached at any available atom to produce a stable compound, substitution of alkenyl groups are such that -F, -C(O)-, -C(S)-, -C(NH)-, -S(O)-, -S(O)2-, -0-, -S-, or N (except where N is a heteroaryl ring atom), are not bound to an alkene carbon thereof. Further, where alkenyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like, substitution of the moiety is such that any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -O-, -S-, or N thereof (except where N is a heteroaryl ring atom) are not bound to an alkenc carbon of the alkenyl substituent or R group. Further, where alkenyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)NHR, and the like, substitution of the alkenyl R group is such that substitution of the alkenyl carbon bound to any O, S, or N of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkenyl carbon bound to any O, S, or N of the moiety. Λn "alkenyl carbon" refers to any carbon within an alkenyl group, whether saturated or part of the carbon to carbon double bond. An "alkene carbon" refers to a carbon within an alkenyl group that is part of a carbon to carbon double bond.
[0068] "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. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. A "substituted lower alkynyl" denotes lower alkynyl that is 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, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR", -SR0, -OC(O)R0, -OC(S)R0, -C(O)R", -C(S)R0, -C(O)OR0, -C(S)OR0, -S(O)R0, -S(O)2R0, -C(O)NHR0, -C(S)NHR0, -C(O)NR0R0, -C(S)NR0R0, -S(O)2NHR0, -S(O)2NR0R0, -C(NH)NHR0, -C(NH)NRPRC, -NHC(O)R0, -NHC(S)R0, -NR0C(O)R0, -NR0C(S)R0, -NHS(O)2R0, -NR0S(O)2R0, -NHC(O)NHR0, -NHC(S)NHR0, -NR0C(O)NH2, -NR0C(S)NH2, -NR0C(O)NHR0, -NR0C(S)NHR0, -NHC(O)NR0R0, -NHC(S)NR0R0, -NR0C(O)NR0R0, -NR0C(S)NR0R0, -NHS(O)2NHR0, -NR0S(O)2NH2, -NR0S(O)2NHR0, -NHS(O)2NR0R0, -NR0S(O)2NR0R0, -NHR0, -NR0R0, -Rd, -Re, and -Rg. Further, possible substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, attached at any available atom to produce a stable compound. For example "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. While it is understood that substitutions are attached at any available atom to produce a stable compound, substitution of alkynyl groups are such that -F, -C(O)-, -C(S)-, -C(NH)-, -S(O)-, -S(O)2-, -O-, -S-, or N (except where N is a heteroaryl ring atom) are not bound to an alkyne carbon thereof. Further, where alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like, substitution of the moiety is such that any -C(O)-, -C(S)-,-S(O)-, -S(O)2-, -O-, -S-, or N thereof (except where N is a heteroaryl ring atom) are not bound to an alkyne carbon of the alkynyl substituent or R group. Further, where alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)NHR, and the like, substitution of the alkynyl R group is such that substitution of the alkynyl carbon bound to any O, S, or N of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substitucnt (except where N is a heteroaryl ring atom) being bound to the alkynyl carbon bound to any O, S, or N of the moiety, An "alkynyl carbon" refers to any carbon within an alkynyl group, whether saturated or part of the carbon to carbon triple bond. An "alkyne carbon" refers to a carbon within an alkynyl group that is part of a carbon to carbon triple bond.
|0069] "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. A "substituted cycloalkyl" is a cycloalkyl that is independently substituted, unless indicated othenvise, 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, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NIl2, -NHC(S)NII2, -NHS(O)2NH2, -C(NH)NH2, -ORα, -SR0, -OC(O)R0, -OC(S)R0, -C(O)R0, -C(S)R0, -C(O)OR0, -C(S)OR0, -S(O)R0, -S(O)2R0, -C(O)NHR0, -C(S)NHR0, -C(O)NR0R0, -C(S)NR0R0, -S(O)2NHR0, -S(O)2NR0R0, -C(NH)NHR0, -C(NH)NRPRC, -NHC(O)R0, -NHC(S)R0, -NR0C(O)R0, -NR0C(S)R0, -NIIS(O)2R0, -NR0S(O)2R0, -NHC(O)NIIR0, -NHC(S)NHR0, -NR0C(O)NH2, -NR0C(S)NH2, -NR0C(O)NHR0, -NR0C(S)NHR0, -NHC(O)NR0R0, -NHC(S)NR0R0, -NR0C(O)NR0R0, -NR0C(S)NR0R0, -NHS(O)2NHR0, -NH0S(O)2NH2, -NR0S(O)2NHR0, -NHS(O)2NR0R0, -NR0S(O)2NR0R0, -NHR0, -NR0R0, -Rd, -Re, -Rf, and -R6
[0070] "Hctcrocycloalkyl" 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. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. A "substituted heterocycloalkyl" is a heterocycloalkyl that is 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, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR0, -SR0, -OC(O)R0, -OC(S)R0, -C(O)R0, -C(S)R0, -C(O)OR0, -C(S)OR0, -S(O)R0, -S(O)3R0, -C(O)NHR", -C(S)NHR0, -C(O)NR0R0, -C(S)NR0R0, -S(O)2NHR0, -S(O)2NR0R0, -C(NH)NHR0, -C(NH)NRPRC, -NHC(O)R0, -NHC(S)R0, -NR0C(O)R0, -NR0C(S)R0, -NHS(O)2R0, -NR0S(O)2R0, -NHC(O)NHR0, -NHC(S)NHR0, -NR0C(O)NH2, -NR0C(S)NH2, -NR0C(O)NHR0, -NR0C(S)NHR0, -NHC(O)NR0R0, -NHC(S)NR0R0, -NR0C(O)NR0R0, -NR0C(S)NR0R0, -NHS(O)2NHR0, -NR0S(O)2NII2, -NR0S(O)2NHR0, -NHS(O)2NR0R0, -NR0S(O)2NR3R0, -NHR0, -NR0R0, -Rd, -Re, -Rf, and -Rg.
[0071] "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. "Arylene" is a divalent aryl. A "substituted aryl" is an aryl that is 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, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR0, -SR0, -OC(O)R0, -OC(S)R0, -C(O)R0, -C(S)R0, -C(O)OR0, -C(S)OR0, -S(O)R0, -S(O)2R0, -C(O)NHR0, -C(S)NHR0, -C(O)NR0R0, -C(S)NR0R0, -S(O)2NIIR0, -S(O)2NR0R0, -C(NH)NHR0, -C(NH)NRPRC, -NHC(O)R0, -NHC(S)R0, -NR0C(O)R0, -NR0C(S)R0, -NHS(O)2R0, -NR0S(O)2R0, -NHC(O)NHR0, -NHC(S)NHR0, -NR0C(O)NH2, -NR0C(S)NH2, -NR0C(O)NHR0, -NR0C(S)NHR0, -NHC(O)NR0R0, -NHC(S)NR0R0, -NR0C(O)NR0R0, -NR0C(S)NR0R0, -NHS(O)2NHR0, -NR0S(O)2NH2, -NR0S(O)2NHR0, -NHS(O)2NR0R0, -NR0S(O)2NR0R0, -NHR0, -NR0R0, -Rd, -Re, -Rf, and -Rg. A "substituted arylene" is a divalent substituted aryl,
[0072] "ΗeteroaryP' 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. Examples of 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. "Nitrogen containing heteroaryl" refers to heteroaryl wherein any heteroatoms are N. "Heteroarylene" is a divalent heteroaryl. A "substituted heteroaryl" is a heteroaryl that is 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, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)^NH7, -C(NH)NH2, -OR0, -SR0, -OC(O)R0, -OC(S)R0, -C(O)R0, -C(S)R0, -C(O)OR0, -C(S)OR0, -S(O)R0, -S(O)2R0, -C(O)NHR0, -C(S)NHR0, -C(O)NR0R0. -C(S)NR0R0, -S(O)2NHR0, -S(O)2NIl0R0, -C(NH)NHR0, -C(NH)NRURC, -NHC(O)R0, -NIIC(S)R0, -NR0C(O)R0, -NR0C(S)R0. -NHS(O)2R0, -NR0S(O)2R0, -NHC(O)NHR0, -NHC(S)NHR0, -NR0C(O)NH2, -NR0C(S)NH,, -NR0C(O)NHR0, -NR0C(S)NHR0, -NHC(O)NR0R0, -NHC(S)NR0R0, -NR0C(O)NR0R0, -NR0C(S)NR0R0, -NHS(O)2NHR0, -NR0S(O)2NH2, -NR0S(O)2NHR0, -NHS(O)2NR0R0, -NR0S(O)2NR0R0, -NHR0, -NR0R0, -Rd, -Re, -Rf, and -R6. "Substituted heteroarylene-' is a divalent substituted hetcroaryl.
[0073] The variables R0, Rp, Rc, Rd, Re, Rf and Rg as used in the description of optional substituents for alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are defined as follows:
each R0, Rp, and RL are independently selected from the group consisting of Rd, Re, Rf, and R8, or Rp and Rc combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -NO2, -CN, -OH, -NH2, -ORU, -SR", -NHR", -NRURU, -R\ and -Ry;
each Rd is independently lower alkyl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH,, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rk, -SRk, -0C(0)Rk, -OC(S)Rk, -C(O)Rk, -C(S)Rk, -C(0)0Rk, -C(S)ORk, -S(O)Rk, -S(O)2R\
Figure imgf000043_0001
-C(S)NHRk, -C(0)NRkRk, -C(S)NRkRk, -S(O)2NHR", -S(0)2NRkR\ -C(NH)NHRk, -C(NH)NR111R", -NHC(0)Rk, -NHC(S)Rk, -NRkC(O)Rk, -NRkC(S)Rk, -NHS(0)2Rk, -NRkS(O)2Rk, -NHC(O)NHRk, -NHC(S)NHRk, -NRkC(0)NH2, -NRkC(S)NH2, -NRkC(0)NHRk, -NRkC(S)NHRk, -NHC(0)NRkRk, -NHC(S)NRkRk, -NRkC(O)NRkRk, -NRkC(S)NRkRk, -NHS(0)2NHRk, -NRkS(O)2NH2, -NRkS(0)2NHRk, -NHS(0)2NRkRk, -NRkS(0)2NRkRk,
Figure imgf000043_0002
-NRkRk, -R1, and -RJ;
each Re is independently lower alkenyl, wherein lower alkenyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rk, -SRk, -OC(0)Rk, -OC(S)Rk, -C(O)Rk, -C(S)Rk, -C(O)ORk, -C(S)ORk, -S(O)Rk, -S(O)2Rk, -C(0)NHRk, -C(S)NHRk, -C(O)NRkRk, -C(S)NRkRk, -S(0)2NHRk, -S(0)2NRkR\ -C(NH)NHRk, -C(NH)NR111R", -NHC(0)Rk, -NHC(S)Rk, -NRkC(0)Rk, -NRkC(S)Rk, -NHS(0)2Rk, -NRkS(0)2Rk, -NHC(0)NHRk, -NHC(S)NHRk, -NRkC(0)NH2, -NR11C(S)NH2, -NR"C(O)NHR\ -NRkC(S)NHRk, -NHC(O)NRV, -NHC(S)NRV, -NRkC(O)NRkRk,
-NRkC(S)NRk RRkk,, --NNHHSS((OO))22NNHHRRkk,, -NRkS(O)2NH2, -NRkS(O)2NHRk, -NHS(O),NRV, -NRkS(O)2NRkRk, -NHRk, -NRkRk, -R1', and -R>;
each Rf is independently lower alkynyl, wherein lower alkynyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rk, -SRk, -OC(O)Rk, -OC(S)Rk, -C(0)Rk, -C(S)Rk, -C(O)OR",
Figure imgf000044_0001
-S(O)Rk, -S(O)2R", -C(0)NHRk, -C(S)NHRk, -C(0)NRkRk, -C(S)NRkRk, -S(0)2NIIRk, -S(O)2NRV, -C(NH)NHRk, -C(NH)NR111R", -NHC(0)Rk, -NHC(S)Rk, -NRkC(0)Rk, -NRkC(S)Rk, -NHS(0)2Rk, -NRkS(O)2Rk, -NHC(0)NHRk, -NHC(S)NHRk, -NRkC(0)NH2, -NRkC(S)NH2. -NRkC(0)NHRk, -NRkC(S)NHRk, -NHC(0)NRkRk, -NHC(S)NRkRk, -NRkC(0)NRkRk, -NRkC(S)NRkRk, -NHS(0)2NHRk, -NRkS(O)2NH2, -NRkS(0)2NHRk, -NHS(O)2NRkRk, -NRkS(0)2NRkRk, -NHRk, -NRkRk, -Rh, and -RJ;
each R8 is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)7NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rk, -SRk, -OC(O)R\ -OC(S)Rk, -C(0)Rk, -C(S)Rk, -C(0)0R\ -C(S)ORk, -S(O)Rk, -S(O)2Rk, -C(0)NHRk, -C(S)NHRk, -C(0)NRkRk, -C(S)NRkRk, -S(0)2NHRk, -S(O)2NRV, -C(NH)NHRk, -C(NH)NRmRn, -NHC(0)Rk, -NHC(S)Rk, -NRkC(0)Rk, -NRkC(S)Rk, -NHS(0)2Rk, -NRkS(0)2Rk, -NHC(0)NHRk, -NHC(S)NHRk, -NRkC(0)NH2, -NRkC(S)NH2, -NRkC(0)NHRk, -NRkC(S)NHRk, -NHC(0)NRkRk, -NHC(S)NRV, -NRkC(0)NRV, -NRkC(S)NRV, -NHS(0)2NHRk, -NRkS(O)2NH2, -NRkS(0)2NHRk, -NHS(O)2NRV, -NRkS(0)2NRkRk, -NHRk, -NRV, -Rh, -R1, and -RJ;
wherein Rk, R™. and R" at each occurrence are independently selected from the group consisting of Rh, R1, and RJ, or R™ and R" combine with the nitrogen to which they are attached form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl arc optionally substituted with one or more, preferably 1 , 2. 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -NO2, -CN, -OH, -NH2, OR", -SR", -NHR", -NR11R", -Rx, and -Ry;
wherein each Rh is independently lower alkyl optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2. -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rr, -SRr, -0C(0)Rr, -OC(S)Rr, -C(0)Rr, -C(S)Rr, -C(0)0Rr, -C(S)ORr, -S(O)Rr, -S(O)2R', -C(O)NHR', -C(S)NHRr, -C(O)NRrRr, -C(S)NR1H1, -S(O)2NHRr, -S(O)2NR1H', -C(NH)NHRr, -C(NH)NRIl', -NHC(O)Rr, -NIIC(S)R', -NR'C(O)Rr, -NR'C(S)R', -NHS(O)2R', -NR'S(O)2R', -NHC(O)NHRr, -NHC(S)NHR', -NR'C(O)NH2, -NR1C(S)NH2, -NRrC(O)NHRr, -NRt(S)NHR', -NHC(O)NR'R', -NHC(S)NRTt', -NR'C(O)NRrRr, -NRt(S)NRIl1, -NHS(O)2NHR', -NR'S(O)2NH2, -NR'S(O)2NHRf, -NHS(O)2NRrRr, -NRrS(O)2NRrRr, -NHR', -NRH', -R1, and -R1;
wherein each R' is independently selected from the group consisting of lower alkenyl and lower alkynyl. wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR', -SR', -OC(O)R', -OC(S)R', -C(O)Rr, -C(S)R', -C(O)OR', -C(S)OR', -S(O)R', -S(O)2R', -C(0)NHRr, -C(S)NHR', -C(O)NR1U', -C(S)NRrRr, -S(O)2NHR', -S(O)2NR'R', -C(NH)NHR', -C(NH)NR5R', -NHC(O)R', -NHC(S)R', -NR'C(0)Rr, -NRt(S)R', -NHS(O)2R', -NR'S(O)2Rr, -NHC(O)NHR', -NHC(S)NHR', -NRt(O)NH2, -NRt(S)NH2, -NRt(O)NHR', -NRt(S)NHR', -NHC(0)NR'Rr, -NHC(S)NR'Rr, -NRt(O)NR1R', -NRt(S)NRH', -NHS(O)2NHR', -NR'S(O)2NH2, -NRrS(0)2NHRr, -NHS(0)2NR'Rr, -NR1S(O)2NR1R', -NHR', -NR'R', and -R1;
wherein each RJ is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rr, -SR', -OC(O)R', -OC(S)R', -C(O)R', -C(S)R', -C(O)OR', -C(S)ORr, -S(O)Rr, -S(O)2R', -C(O)NHR', -C(S)NIIR', -C(0)NR'Rr, -C(S)NR1R', -S(O)2NHR', -S(O)2NR'R', -C(NH)NHR', -C(NH)NR5R', -NHC(O)R', -NHC(S)R', -NRt(O)R', -NRt(S)R', -NHS(O)2R', -NR1S(O)2R', -NHC(O)NHR', -NHC(S)NHR', -NRt(O)NH2, -NRt(S)NH2, -NRt(O)NHR', -NRt(S)NHR', -NHC(0)NR'R', -NHC(S)NR1R', -NRt(O)NR1R', -NRt(S)NR1U', -NHS(O)2NHR', -NR'S(O)2NH2, -NR'S(0)2NHR', -NIIS(O)2NR1R', -NR'S(0)2NR'Rr, -NHR', -NR'R', cycloalkylamino, and -R*;
wherein each R', Rs, and R1 at each occurrence are independently selected from the group consisting of lower alkyl, C^ alkenyl, C3_6 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of-Ry, fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the lower alkyl carbon bound to any O, S, or N, of -ORr, -SRr, -C(O)OR', -C(S)ORr, -C(0)NHRr, -C(S)NHR', -C(O)NR1R1, -C(S)NRrRr, -S(0)2NHRr, -S(O)2NR1R', -C(NH)NHR', -NRrC(0)Rr, -NRrC(S)Rr, -NRrS(0)2Rr, -NHC(0)NHRr, -NHC(S)NHRr, -NR1C(O)NH2, -NRrC(S)NH2, -NR'C(0)NHRr, -NRrC(S)NHRr, -NHC(0)NRrRr, -NHC(S)NRrRr, -NR^(O)NR1R1, -NRrC(S)NRrRr, -NHS(0)2NHRr, -NR1S(O)2NH2, -NRrS(0)2NHRr, -NHS(0)2NR'Rr, -NRrS(0)2NRrRr, -NHRr, or -NRrRr is selected from the group consisting of fluoro and -Ry, and wherein C3.e alkenyl or C3.6 alkynyl arc optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -R*, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the C3-6 alkenyl or C3.6 alkynyl carbon bound to any O, S, or N, of -0Rr, -SRr, -C(O)OR', -C(S)OR', -C(O)NHR', -C(S)NTIR', -C(O)NRTl', -C(S)NR'Rr, -S(O)2NHR', -S(0)2NRrR', -C(NH)NHR', -NR'C(0)Rr, -NR1C(S)R', -NR'S(0)2Rr, -NHC(O)NIIR1, -NHC(S)NHR', -NR'C(0)NH2, -NR1C(S)NH2, -NR1C(O)NHR', -NR'C(S)NHR', -NHC(0)NR'R', -NHC(S)NR'R', -NR'C(0)NRrR', -NR'C(S)NR'R', -NHS(O)2NHR', -NR'S(O)2NH2, -NR'S(0)2NHR', -NHS(0)2NRrR', -NR1S(O)2NR1R', -NHR', or -NR'R' is selected from the group consisting of fluoro, lower alkyl, fluoro substituted lower alkyl, and -Ry, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, or Rs and R* combine with the nitrogen to which they are attached form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -NO2, -CN, -OH, -NII2, OR", -SRU, -NHR11, -NRURU, -R\ and -Ry;
wherein each Ru is independently selected from the group consisting of lower alkyl, C3_6 alkenyl, C34 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -R3, fluoro, -OH, -NH2, lower alkoxy. fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the lower alkyl carbon bound to the O of -ORU, S of -SR11, or N of -NHR" is fluoro or -Ry, and wherein C^1, alkenyl or C3.6 alkynyl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -Ry, fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylammo, and cycloalkylamino, provided, however, that any substitution of the C3 6 alkenyl or C3.<, alkynyl carbon bound to the O of -OR\ S of -SRU, or N of -NHRU is fluoro, lower alkyl, fluoro substituted lower alkyl, or -Ry, and wherein cycloalkyl, hctcrocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino ;
wherein each Rx is selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -Ry, fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -Ry, fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
wherein each Ry is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.
[0074] In some embodiments, all occurrences of optionally substituted lower alkyl, optionally substituted C2 6 alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, -NO2, -CN, -0Rl a, -SRIa, -NRl aRla, -OC(O)Rla, -OC(S)Rla, -C(O)RIa, -C(S)Rla, -C(O)ORla, -C(S)OR13, -C(0)NRl aRlj. -C(S)NRlaRla, -S(O)2NRlaRIa, -C(NH)NR)aRl a, -NRlaC(O)Rls, -NRlaC(S)Rla, -NRl aS(O)2RIa, -NRlaC(0)NRlaRla, -NRidC(S)NRlaRl a, -NRldS(O)2NRlaRla, -S(O)RId, -S(O)2R13, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of halogen, -NO2, -CN, -0Rl a, -SRla, -NRlaRl a, -OC(O)Rla, -OC(S)RIa, -C(O)Rla, -C(S)RIa, -C(O)OR13, -C(S)ORla, -C(O)NRl aRl a, -C(S)NRlaRl s, -S(O)2NRlaRla, -C(NH)NRlaRla, -NRlaC(O)RIa, -NRlaC(S)Rla, -NRlaS(O)2Rla, -NRlaC(O)NRlaRIa, -NRIaC(S)NRlaRIa, -NRlaS(O)2NRlaRla, -S(O)Rla, -S(O)2Rl a, -Rlb, and lower alkyl optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and -Rlb, and all occurrences of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5-7 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylene, optionally substituted hcteroaryl, optionally substituted heteroarylene, or optionally substituted 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, also 1 , 2, or 3 groups or substituents selected from the group consisting of halogen, -NO2, -CN, -0Rla, -SRIa, -NRlaRla, -OC(O)R12, -OC(S)Rla, -C(O)Rla, -C(S)Rla, -C(O)ORla, -C(S)ORla, -C(O)NRlaRla, -C(S)NRIaRl a, -S(0)2NRlaRla, -C(NH)NRlaRla, -NRlaC(0)Rla, -NRlaC(S)Rla, -NRlaS(O)2Rla, -NRlaC(0)NRlaRla, -NRlaC(S)NRlaRla, -NRl3S(O)2NRlaRla, -S(O)Rla, -S(O)2Rla, -Rl b, and lower alkyl optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and -Rlb, wherein Rla is selected from the group consisting of hydrogen, provided, however, that hydrogen is not bound to any of C(S), C(O), S(O), or S(O)2 of -OC(O)R13, -OC(S)Rla, -C(0)Rla, -C(S)Rla, -NRl aC(O)Rla, -NRlaC(S)Rla, -NRlaS(0)2Rla, -S(O)Rla, or -S(O)2Rla, -Rlb, and lower alkyl optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and -Rlb, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -ORla, -SRIa, -NRlaRl a, -C(0)0Rla, -C(S)ORla, -C(O)NRl aRla, -C(S)NRlaRl a, -S(O)2NRlaRla, -C(NH)NRlaRla, -NRlaC(O)Rla, -NRl aC(S)Rla, -NRlaS(O)2RIa, -NRlaC(0)NRlaRla, -NRl3C(S)NRlaRla, or -NRlaS(0)2NRlaRla, is fluoro or -Rlb, and wherein -Rlb is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of halogen, -CN, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.
[0075] In some embodiments, all occurrences of optionally substituted lower alkyl, optionally substituted C2.6 alkyl, optionally substituted lower alkcnyl, or optionally substituted lower alkynyl are optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -CN, -0Rla, -SRla, -NRlaRla, -C(O)RIa, -C(S)R13, -C(O)ORla, -C(0)NRI aRla, -C(S)NRlaRl a, -S(O)2NRl aRla, -NRl aC(0)RIa, -NRl aC(S)Rla, -NRlaS(O)2Rla, -S(O)Rla, -S(O)2R1", cycloalkyl heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, ar\l and heteroaryl arc optionally substituted w ith one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of halogen, -CN, -ORla, -SRla, -NRlaRla, -C(O)Rla, -C(S)RI a, -C(O)OR!a, -C(0)NRl!lRla, -C(S)NRlaRla, -S(O)2NRuRIa, -NRlaC(O)RIa, -NR!aC(S)Rla, -NRIaS(O)2Rla, -S(O)R", -S(O)2R a, -R1 , and lower alkyl optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylammo, di-alkylammo, and -Rl b, and all occurrences of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5-7 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylcne, optionally substituted heteroaryl, optionally substituted heteroarylene, or optionally substituted 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, also 1 , 2, or 3 groups or substituents selected from the group consisting of halogen, -CN, -ORla, -SR1", -NR'"RU, -C(O)Rla, -C(S)Rla, -C(O)OR18, -C(0)NRlaRla, -C(S)NRlaRl a, -S(O)2NR13R13, -NR!aC(0)Rla, -NRlaC(S)Rl a, -NRlaS(0)2Rla, -S(O)Rld, -S(O)2R13, -Rlb, and lower alkyl optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and -Rl b, wherein Rl a is selected from the group consisting of hydrogen, provided, however, that hydrogen is not bound to any of C(S), C(O), S(O), or S(O)2 of -C(O)Rla, -C(S)Rla, -NRlaC(0)Rla, -NRlaC(S)Rla, -NRlaS(O)2Ru, -S(O)Rla, or -S(O)2R13, -Rlb, and lower alkyl optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylammo, and -Rl b, provided, however, that any substitution of the alkyl carbon bound to O, S, or N ol -0Rla, -SRld, -NRlaRl a, -C(0)0Rla, -C(O)NRlaR'\ -C(S)NRlaRla, -S(0)2NRlaRla, -NRl aC(0)R!a, -NR!aC(S)Rla, or -NRlaS(0)2Rla, is fluoio or -Rl b, and wherein -Rlb is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more, also 1 , 2 or 3 groups or substituents selected from the group consisting of halogen, -CN, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylammo, di-alkylamino, and cycloalkylammo
[0076] 'Lower alkoxy" denotes the group -OR', where Rz is lower alkyl "Substituted lower alkoxy" denotes lower alkoxy in which Rz is lower alkyl substituted with one or more substituents as indicated herein, for example, in the descπption of compounds of Formula I, Formula II, or Formula III, including descriptions of substituted cycloalkyl, cyclohctcroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound Preferably, substitution of lower alkoxy is with 1 , 2, 3, 4, or 5 substituents, also 1 , 2, or 3 substituents For example "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 While it is understood that substitutions on alkoxy are attached at any available atom to produce a stable compound, substitution of alkoxy is such that O, S, or N (except where N is a heteroaryl nng atom), are not bound to the alkyl carbon bound to the alkoxy O Further, where alkoxy is described as a substituent of another moiety the alkoxy oxygen is not bound to a carbon atom that is bound to an O, S, or N of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety
[0077] "Lower alkylthio" denotes the group -SRaa, where Raa is lower alkyl "Substituted lower alkylthio" denotes lower alkylthio m which Rao is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, Foπnula IJ, or Formula III, including descriptions of substituted cycloalkyl, cycloheteroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound Preferably, substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1 , 2, or 3 substituents For example "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 While it is understood that substitutions on alkylthio are attached at any available atom to produce a stable compound, substitution of alkylthio is such that O, S, or N (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkylthio S Further, where alkylthio is described as a substituent of another moiety, the alkylthio sulfur is not bound to a carbon atom that is bound to an O, S, or N of the other moiety (except where N is a heteroaryl nng atom), or to an alkene or alkyne carbon of the other moiety
[0078] "Ammo" or '■amine" denotes the group -NH2. "Mono-alkylammo" denotes the group -NHRbb where Rbb is lower alkyl "Di-alkylammo" denotes the group -NRbbRcc, where Rbb and Rcc are independently lower alkyl "Cycloalkylammo" denotes the group -NRddRee, where Rdd and Ree combine with the nitrogen to form a 5-7 membered hctcrocycloalkyl, where the heterocycloalkyl may Lontam an additional heteroatom withm 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, pipendme, piperazine, 4-methylpiperazine, morphohne, and thiomorpholme While it is understood that when mono-alkylamino, di-alkylammo, or cycloalkylammo are substituents on other moieties that are attached at any available atom to produce a stable compound, the nitrogen of mono-alkylammo, di-alkylammo, or cycloalkylammo as substituents is not bound to a carbon atom that is bound to an O, S, or N of the other moiety [0079] As used herein, the term "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 excφient
[0080] The term "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 mjectibles
[0081] In the present context, 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
[0082] In the present context, 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
[0083] As used herein, the terms "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 Generally a ligand or modulator will be a small molecule, where "small molecule refers to a compound with a molecular w eight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less Thus, an "improved ligand" is one that possesses better pharmacological and/or pharmacokinetic properties than a reference compound, where "better" can be defined by one skilled in the relevant art for a particular biological system or therapeutic use
[0084] In the context of compounds binding to a target, 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, / e , with a lower dissociation constant In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold greater affinity
[0085] As used herein in connection with compounds of the invention, the term "synthesizing" and like terms means chemical synthesis from one or more precursor mateπals [0086] By "assaying" is meant the creation of expenmental conditions and the gathering of data regarding a particular result of the experimental conditions For example, enzymes can be assayed based on their ability to act upon a detectable substrate A compound or hgand can be assayed based on its ability to bind to a particular target molecule or molecules
[0087] As used herein, 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 For example, 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 (IC50) or excitation concentration (EC50) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme
[0088] In the context of the use, testing, or screening of compounds that are or may be modulators, 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
[0089] As used herein m connection with ammo acid or nucleic acid sequence, the term "isolate" 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
[0090] In connection with ammo acid or nucleic sequences, 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
[0091] The present invention concerns compounds of Formula I, and all sub-generic formulae, compounds of Formula II and all sub-generic formulae, and compounds of Formula III 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 Λbl, Aktl , Akt2, Akt3, ALK, Alk5, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHKl, c-Raf-1, Csk, EGFR, EphΛl , EphA2, EphB2, EphB4, Erk2, Fak, TGFRl , FGFR2, FGFR3, FGFR4, Fltl , Flt3, Flt4, Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Hcr4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl , Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1 , MAP2K2, MΛP4K4, MAPKAPK2, Met, Mnkl , MLKl, p38, PDGFRA, PDGFRB, PDPKl , Piml , Pim2, Pim3, PKC alpha, PKC beta, PKC theta, PIk 1 , P>k2, Ret, ROCKl ROCK2, Ron, Src, Stk6, Syk, I EC, Tie2, TrkA, IrLB, Yes, and Zap70, and the use of such compounds m the treatment of diseases or conditions
Kinase targets and indications of the invention
[0092] Protein kinases play key roles m propagating biochemical signals in diverse biological pathways More than 500 kinases have been described, and specific kinases have been implicated in a wide range ot diseases or conditions (i e indications), including for example without limitation, cancer, cardio\ ascular disease, inflammatory disease, neurological disease, and other diseases As such, kinases represent important control points for small molecule therapeutic intervention Description of specific target protein kinases contemplated by the present invention may be found, for example, in US Patent Application Serial number 1 1 /473,347 (PCl publication WO2007002433) , the disclosure of which is hereby incorporated by reference in its entirety, in addition to the following
Exemplary diseases associated with Raf kinases
[0093] A-Raf: T arget kinase A-Raf (i e , v-raf murine sarcoma 361 1 viral oncogene homolog 1) is a 67 6 kDa serine/threonine kinase encoded by chromosome XpI 1 4-pl 1 2 (symbol ARAF) The mature protein compnscs RBD (i e , Ras binding domain) and phorbol-ester/DAG-type zinc finger domain and is involved in the transduction of mitogcmc 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 histiocytic lymphoma), neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, pain of neuropathic or inflammatory origin, including acute pain, chronic pain, cancer-related pain and migraine, and diseases associated with muscle regeneration or degeneration, including, but not limited to, vascular restenosis, sarcopema, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotome, 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 myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocπne abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Mane-I ooth disease, Dejeπne- Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease nemalme myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to phosphorylase deficiency, acid maltase deficiency, phosphofructokmase deficiency, debranther enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency)
[0094] B-Raf: Target kinase B-Raf (i e , v-raf murine sarcoma viral oncogene homolog B 1 ) is a 84 4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol BRAt) The mature protein comprises RBD (i e , Ras binding domain), Cl (i e , protein kinase C conserved region 1) and STK (i e seπne/threonine kinase) domains
[0095] Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane Io the nucleus and may play a role in the postsynaptic responses of hippocampal neurons As such, genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals Indeed, 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 grow th, division and proliferation, and, when constitutively activated, causes tumoπgenesis Among several isoforms of Raf kinase, the B-type, or B-Raf, is the strongest activator of the downstream MAP kinase signaling
[0096] The BRAF gene is frequently mutated m a variety of human tumors, especially in malignant melanoma and colon carcinoma The most common reported mutation was a missense thymine ( 1) to adenine (A) transversion at nucleotide 1796 (T1796A, ammo acid change in the B-Raf protein is Val<600> to Glu<600> ) observed in 80% of malignant melanoma tumors 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 Based on precedents, human tumors develop resistance to kinase inhibitors by mutating a specific ammo acid in the catalytic domain as the "gatekeeper'1 (Balak, et al , CIm Cancer Res 2006, 12 6494-501) Mutation of Thr-529 in BRAF to He is thus anticipated as a mechanism of resistance to BRAF inhibitors, and this can be envisioned as a transition in codon 529 from ACC to ATC
[0097] Niihoπ et al , report that in 43 individuals with cardio-facio-cutaneous (CFC) syndrome, they identified two heterozygous KRAS mutations m 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 (Nnhon et al , Nat Genet 2006, 38(3) 294-6) [0098] 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 RAFl) 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-bmdmg protein) c-Raf-1 is implicated in carcinomas, including colorectal, o\ aπan, 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-RaI-I 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 (Kunmmalaiyaan et al , Anticancer Drugs 2006, 17(2) 139-42)
[0099] B-Rdf and/or C-Raf inhibitors may be useful in treating A-Raf-mediated, B-Raf-mediated or c-Raf-1 -mediated disease oi condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-intarct 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 pam, 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, and reperfusion injury, 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 pylon 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, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LtOP ARD syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases
Exemplary Diseases Associated with c-Kit. [0100] The compounds described herein are useful for treating disorders related to c-kit e g , diseases related to unregulated kinase signal transduction, including cell proliferative disorders, fibrotic disorders and metabolic disorders, among others As described m more detail helow and in Lipson et al , U S 20040002534 (U S application 10/600, 868, filed June 23, 2003) which is incorporated herein by reference in its entirety, cell proliferate e disorders which can be treated by the present invention include cancers, and mast cell proliferative disorders
[0101] The presence of c-kit has also been associated with a number of different types of cancers In addition, the association between abnormalities in c-kit and disease are not restricted to cancer As such, c-kit has been associated with malignancies, including, but not limited to, mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma m situ, Schwann cell neoplasm associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canme mast cell tumors, and inflammatory diseases, including, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia
Exemplary diseases associated with c-fms
[0102] The presence of c-fms has been associated with a number of different types of diseases As such c-fms has been associated with immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection, inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bow el syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hcmophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis, metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and hpolysis, disorders of bone structure, mineralization and bone formation and resorption, including but not limited to, osteoporosis, increased risk of fracture, Paget *s disease, hypercalcemia, infection-mediated osteolysis (e g osteomyelitis), pen-prosthetic or wear-debns- mediated osteolysis, and metastasis of cancer to bone, kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e g glomerulonephritis, interstitial nephritis Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e g diabetic nephropathy), and renal hypertrophy, disorders of the central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory and chronic pain, including, but not limited to, bone pain, and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer ovarian cancer, melanoma, glioblastoma multiforme metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis
Exemplary diseases associated with TrkA and TrkB
[0103] TrkA: Target kinase TrkA (i e , neurotrophic tyrosine kinase, receptor, type 1 ) is a 140 kDa tyrosine kinase encoded by chromosome Iq21-q22 (symbol NTRKl) TrkA inhibitors may be useful m treating pain (e g chronic pam, neuropathic pam), cancer (e g prostate cancer lung cancer, myeloid leukemia, pancreatic cancer), allergic disorders (e g asthma), arthritis, diabetic retinopathy macular degeneration and psoriasis
[0104] TrkA is a plasma member receptor composed of an extracellular domain (responsible for high affinity binding to nerve growth factor, NGF), a transmembrane segment and an intracellular protein tyrosine kinase domain (responsible to transmit the NGF signal to initiate and coordinate neuronal responses) NGF binding induces TrkA clustering on the membrane and activates the kinase The kinase initiates a cascade of protein phosphorylation events through multiple pathways including SHC/Ras/MAPK, PDK and PLCgI A TrkA kinase inhibitor would not prevent NGF/TrkA binding, but could prevent down-stream signal transduction
|0105] Nerve Growth Factor (NGF) is produced by a number of tissues and inflammatory cells during tissue injury and host immune response It initiates and maintains hypersensitivity to incoming stimulus (hyperalgesia) and the perception of non-noxious stimuli (allodyma) Through its high- affinity receptor TrkA, NGF increases the excitation state of sensory neurons leading to the central nervous system (peripheral sensitization), and increases transmitter release from the dorsal spinal cord (central sensitization) In clinical trials, a single NGF subcutaneous injection generated local hyperalgesia persisting up to 7 weeks At doses above 0 1 microgram/kg, NGF caused muscle pam that varied from mild to moderate, primarily m the bulbar and truncal musculature Intravenous NGF produced earlier and more pronounced systemic effects (Petty et al, 1994, Ann Neurol 36 244-6) Conversely, 1 rkA kinase inhibitors could be used to treat diseases ot enhanced states of nociception
[0106] In Complete Freund's Adjuvant (CFA)-induced hmd-paw inflammation, spmal nerve ligation and streptozoticin-induced neuropathic pam models, a single intraperitoneal injection of anti- NGF reversed established tactile allodyma from day 3 to day 7 following treatment Tn the mouse CCI model, anti-NGF reversed tactile allodyma when administered 2 weeks alter surgery Repeated administration of this antibody to CCI mice for 3 weeks produced a sustained reversal of tactile dllodynia (Wild et al, 2007, J Pharmacol Exp Ther 322 282-287)
[0107] Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. Anti-NGF produced a significant reduction in both early and late stage bone cancer pain-related behaviors. This therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. All nerve fibers that innervate the bone express TrkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors (Halvorson et al, 2005, Cancer Res. 65:9426-35).
[0108] In patients with mild asthma due to exposure to cat allergen, NGF expression was strongly induced in epithelial cells, fibroblasts, blood vessels, and a few infiltrating cells. TrkA mRNA and protein levels in bronchial biopsies were increased significantly after allergen exposure in infiltrating mast cells before the onset of symptoms (Kassel et al, 2001, Clin Exp Allergy 31 :1432-40).
[0109] The late phase reaction in asthma following allergen provocation is dominated by an influx of activated eosinophils into the bronchial lumen, which correlates with the release of eosinophilic products into the airways to increase disease severity. The viability and activation of eosinophils from patients with mild asthma were significantly enhanced after NGF stimulation. Addition of neutralizing anti-NGF antibodies ex vivo abrogated the effects (Nassentein et al, 2003, J Exp Med 198:455-467). TrkA kinase inhibitors could decrease this paracrine loop between the respiratory tract and infiltrating mast cells as well as endobronchial eosinophils, and thus be useful for the treatment of asthma and other allergic disorders.
[0110] TrkB: Target kinase TrkB (i.e., neurotrophic tyrosine kinase, receptor, type 2) is a 145 kDa tyrosine kinase encoded by chromosome 9q22.1 (symbol: NTRK2). TrkB inhibitors may be useful in treating various cancers and their metastases (e.g. prostate cancer, lung cancer, Wilms tumors, neuroblastoma, and pancreatic cancer), and various neuropathies (e.g. stroke, multiple sclerosis, transverse myelitis, and encephalitis).
[0111] In clinical trials with recombinant BDNF, paresthesia was developed at the site of subcutaneous injection (Coulie et al, 2000, Gastroenterology 119:41-50). Intrathecal infusion of BDNF in humans also induced paresthesia and warmth as side effects (Ochs et al, 2000, Amyotroph Lateral Scler Other Motor Neuron Disord. 1 :201-6). Chronic paresthesia is often a symptom of an underlying neurological disease or traumatic nerve damage. Paresthesia can be caused by disorders affecting the central nervous system, such as stroke and transient ischemic attacks (mini-strokes), multiple sclerosis, transverse myelitis, and encephalitis. Since BDNF binds to TrkB specifically with high affinity these neuropath effects are mediated through TrkB signaling. Thus Trkb kinase inhibitors could be used to treat certain patients with neuropathy. [0112] BDNF is known to act at the synapses between primary sensory and spinal dorsal horn neurons to affect pam transmission during inflammation The primary afferent is the only source of BDNF in the spinal cord, and it is up-regulated in the dorsal root ganglion (DRG) by peripheral NGF a few da\s after inflammation, and is transported and released into the superficial dorsal horn in an activity -dependent manner TrkB expression in the doisal horn also increases foτ a few days after inflammation These findings suggest that BDNF may act duπng the restricted pcπod in the early phase of inflammation Through TrkB, BDNF activates two distinct channels (1) transient receptor potential canonicals (TRPC3), which produces a slow response by opening of a non-selective cation channel, and (2) Na+ channel, which mediates a rapid depolarization in the hippocampus These channels have been strongly associated with inflammatory pam Anti-BDNF significantly increased the withdrawal threshold in CFA-treated rats, a model of inflammatory pam Since the swelling at the site oi CFA injection was not affected by antiserum, the residual component might be due to peripheral sensitization (Matayoshi et al, 2005, J Physiol 569 685-95)
[0113] In patients with neuroblastomas, co-expression of TrkB and BDNF, co-expression of TrkB with N-Myc amplification, and expression of truncated TrkB are found to be associated with poorer clinical outcome (Nakagawara et al, 1994, MoI Cell Biol 14 759-767) Co-expression of TrkB with its ligand BDNF could generate a positive feedback loop through autocrine and paracrine loops Also TrkB truncations found m these tumors generate activated forms of the intracellular protein tyrosine kinase The constitutively active TrkB signals through multiple pathways to promote cancer initiation, progression and metastasis These truncated TrkB kinases were also found m hepatocellular carcinoma (Yang et al, 2005, Cancer Res 65 219-225) Thus TrkB inhibitors could be used to treat a sub-population of cancer patients with an activated TrkB pathway
[0114] In patients with pancreatic cancer, TrkB expression is correlated with perineural invasion, positive retroperitoneal margin, and shorter latency to development of liver metastasis (Sclabas et al, 2005, CIm Cancer Res VI l 440-449) Mechanistically, TrkB activates the PDK pathway to suppress anoikis (apoptosis resulting from loss of cell-matrix interactions) which is one of the physiological bamers to metastasis TrkB kinase inhibition could break down resistance to anoikis of metastasizing tumors (Douma ct al, 2004, Nature 430 1034-9) Therefore, TrkB inhibitors could have utility in a broad range of tumor types
Exemplary diseases associated with MAPK4K
[0115] MAP4K4; Target kinase MAP4K4 (i e , Mitogen-activated protein kinase kinase 4, aka Hematopoietic progenitor kinase 'Germinal center kmase-like Kinase) is a 130 kDa senne/threonme kinase encoded by chromosome 2ql 1 2-ql2 (symbol MΛP4K4) and is also known as HGK It is a member oi the human STE20/mitogen-activated protein kinase kinase kinase kinase (MAP4K) family of serine ''threonine kinases and is the human ortholog of mouse NIK (Nck-mteracting kinase) The N- terminus of the mature HGK protein has a catalytic kinase domain that shares 47% and 48% ammo acid sequence identity to the catalytic domain of Hematopoietic progenitor kinase 1 (HPKl) and Germinal center kinase (GCK), respectively Yao et al (J Biol Chem 274 21 18-2125, 1999) identified 2 IIGK lsoforms, one of which has no prolme-πeh domains, and another, longer variant that contains such domains and appears to be expressed in bram only Northern blot analysis revealed expression of 3 HGK transcripts of approximately 4 6, 6 5, and 8 5 kb in heart, bram, skeletal muscle pancreas, placenta liver, lung, and kidney By Western blot analysis with a polyclonal antibody, Yao et al (J Biol Chem 274 21 18-2125, 1999) found that the 130-kD protein is expressed in multiple cell lines
[0116] Expression of HGK in transfected cell lines resulted in strong INK activation and, in turn, c- jun transcriptional activity (Yao et al J Biol Chem 274 2118-2125, 1999) HGK-mduced JNK activation was inhibited by dominant-negative MAP2K4, MAP2K7, and TAK 1 mutants TNF -alpha also stimulated HGK kinase activity HGK was identified as a putative effect of Rap2 to activate JNK (Mdchida et al J Biol Chem 279 15711-15714, 2004) This link establishes HGK as a potential target for a range of metabolic indications, since the JNK pathway clearly antagonizes insulin signaling An HGK inhibitor could rc-sensitize fat and muscle cells to insulin
[0117] HGK is found to be broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion (Wright et al MoI Cell Biol 23 2068-2082, 2003) Wright et al showed IIGK to be highly expressed m most tumor cell lines relative to normal tissue An active role for this kinase m transformation was suggested by an inhibition of II-Ras(V12)-induced focus formation by expression of inactive, dominant-negative mutants of HGK in both fibroblast and epithelial cell lines Expression of an inactive mutant of HGK also inhibited the anchorage- independent growth of cells yet had no effect on proliferation in monolayer culture Expression of HGK mutants modulated mtegπn receptor expression and had a striking effect on hepatocyte growth factor-stimulated epithelial cell invasion Together, these results suggest an important role for HGK in cell transformation and invasiveness More recently, a small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase (Collins et al Proc Natl Acad Sci USA, 103 3775-3780, 2006) Collins et al showed that the knockdown of the IIGK transcπpt inhibited the migration of multiple carcinoma cell lines, indicating a broad role in cell motility, and potently suppressed the invasion of SKOV-3 cells in vitro The effect of HGK on cellular migration was found to be mediated through JNK kinase, independent of API activation and downstream transcription Accordingly, small molecule inhibition of c-Jun N-tcrmmal kinase suppressed SKOV-3 cell migration, underscoring the potential therapeutic utility of mitogen-activated protein kinase pathway inhibition in cancer progression (Collins et a! Proc Natl Acad Sci USA, 103 3775-3780, 2006) These studies strongly support HGK as a target in a broad range of oncology indications In particular, an HGK inhibitor could have utility in blocking the migration, invasion and metastasis in many ditferent tumor types
[0118] Activation of T-cells by antigens initiates a complex series of signal-transduction events that are critical for immune responses Mack et al (Immunol Lett 96, 129-145, 2005) developed a genetic screen to survey the functional roles of kinases in antigen mediated T cell activation and identified 19 protein kinases that were previously implicated in T-cell signaling processes and 12 kinases that were not previously linked to T-cell activation, including HGK siRNA studies showed a role for HGK in antigen mediated T-cell responses in Jurkat and primary T-cells In addition, by analyzing multiple promoter elements using reporter assays, Mack et al ha\e shown that MΛP4K4 is implicated in the activation of the TNF-alpha promoter Therefore, inhibition of HGK could have broad therapeutic utility for T-cell-mediated autoimmune diseases
[0119] Insuhn-rcgulated glucose transporter GLU 14 is a key modulator of whole body glucose homeostasis, and its selective loss in adipose tissue or skeletal muscle causes insulin resistance and diabetes Using an KNA interference-based screen, Tang et al (Proc Natl Acad Sci U S A 103 2087- 2092, 2006) found 4 negative regulators of insulin-responsive glucose transport in mouse adipocytes Pctkl , Pftkl, Ikbka (CHUK), and HGK HGK suppressed expression of adipogenic transcription factors, C/EBPA, C/EBPB, and PPARG, and it suppressed surface expression of GLUT4 (SLC2A4), resulting in attenuated membrane hexose transport activity RNA interference-mediated depletion of HGK eaτly m differentiation enhanced adipogenesis and triglyceride deposition, in fully differentiated adipocytes, loss of HGK upregulated GLUT4 expression Conversely, conditions that inhibited adipogenesis, such as TNF-alpha treatment or PPARG depletion, markedly upregulated HGK Tang et al (Proc Natl Acad Su U S A 103 2087-2092, 2006) concluded that MAP4K4-dependent signaling inhibited PPARG -responsive gene expression, adipogenesis, and insulin-stimulated glucose transport turthcπnorc, TNF-alpha signaling to down-regulate GLUT4 is impaired in the absence of HGK, indicating that HGK expression is required for optimal TNF-alpha action This study further supports HGK as a target m metabolic disease, and suggests a role for HGK inhibition in ameliorating the pathology in adipocytes
[0120] In a separate study (Bouzakπ and Zierath J Biol Chem 282 7783 7789, 2007), using small interfeπng RNA (siRNA) to suppress the expression of HGK protein 85% in primary human skeletal muscle cells, TNF-alpha-mduced insulin resistance on glucose uptake was completely prevented HGK silencing inhibited TNF-alpha-induccd negative signaling inputs by presenting excessive JNK and FRK 1/2 phosphorylation, as well as IRS 1 serine phosphorylation These results highlight the HGICJNKyERK IRS module in the negative regulation of insulin signaling to glucose transport m response to TNF-alpha Depletion of HGK also presented TNF-alpha-mduced insulin resistance on AKT and the AKT substrate 160 (AS 160), providing evidence that appropriate insulin signaling inputs for glucose metabolism were rescued The authors suggested that strategies to inhibit HGK may be efficacious in the prevention of TNP -alpha-induced inhibitor)' signals that cause skeletal muscle insulin resistance on glucose metabolism in humans Moreover, in myotubes from lnsulin- resistant type II diabetic patients, siRNΛ against HGK restored insulin action on glucose uptake to levels observed in healthy subjects This study further supports HGK as a target in metabolic diseases such as type II diabetes, and suggests a role for HGK inhibition in ameliorating the pathology in muscle cells
[0121] HGK inhibitors may be useful in treating metabolic indications, including re-sensitizing fat and muscle cells to insulin, ameliorating the pathology in adipocytes, ameliorating the pathology in muscle cells, metabolic syndrome and type II diabetes, a broad range of oncology indications, including blocking the migration, invasion and metastasis in many different tumor types, and T cell mediated autoimmune diseases
Kinase Activity Assays
[0122] 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 In addition to the assay mentioned m the Examples below, one of ordinary skill in the art will know of other assavs that can be utilized and can modify an assay for a particular application For example, numerous papers concerning kinases descπbe assays that can be used
[0123] Additional alternative assays can employ binding determinations For example, this sort of assay can be formatted cither m a fluorescence resonance energy transfer (FRET) format or using an AlphaScreen (amplified /ummescent proximity Λomogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidm or the phosphor-specific antibody
Organic Synthetic Techniques
[0124] A wide array of organic synthetic techniques exist in the art to facilitate the construction of potential modulators Many of these organic synthetic methods are described in detail in standard reference sources utilized by those skilled in the art One example of such a reference is March 1994, Advanced Organic Chemistry,. Reactions, Mechanisms and Structure, New York, McGraw Hill Thus, the techniques useful to synthesize a potential modulator of kinase function are readily available to those skilled in the art of organic chemical synthesis
[0125] Regarding the synthetic examples described herein, solvents include polar and non-polar solvents known to those of skill in the art, including polar aprotic and polar protic solvents Polar solvents include, without limitation, protic solvents such as methanol, ethanol, isopropyl alcohol, t- butanol, n-butanol, acetic acid formic acid or water, or aprotic solvents such as tetrah>drofuran (THF), acetonitπle, dioxane, methylene chloride, dimethylsulfoxide (DMSO) acetone, N1N- dimethylformamide (DMF) N,N-dimethylacetamide (DMA), ethyl acetate, 1,2-dimethoxyethane, 1,2- dichloroethane, chloroform, 1,2-dichloroethane, or pyridine Polar solvents mdude a mixture of water with any of the above, or a mixture of any two or more of the above Apolar solvents include, without limitation, toluene, benzene, chlorobenzene, xylenes and hexanes
[0126] Regarding the synthetic examples described herein, reducing agent includes, without limitation, a reducing agent such as catalytic reducing agents using hydrogen and transition metal catalysts such as palladium, platinum, rhodium, etc (e g Pt/acetic acid/Hi), a mixture of tπfluoroacetic acid and tnethylsilane, borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, and a combination of sodium borohydπde and boron tπfluoπde, metals such as reduced iron, zinc powder, magnesium etc , metal hydrogen complex compounds such as alkali metal borohydπdes (for example, potassium borohydπde, sodium borohydπde, lithium borohydπde, zinc borohydπde, sodium tπacetoxyborohydπde, etc ), aluminum lithium hydride, etc , metal hydrides such as sodium hydride, etc , organic tin compounds (tnphenyltm hydride, etc ), and metal salts such as nickel compounds, zinc compounds, tin compounds (for example tin(II) chloride), and samarium lodide/pivalic acid/hexamethylphorphoric tπamide
[0127] Regarding the synthetic examples descπbed herein, oxidizing agent includes, without limitation, an oxidizing agent such as Dess-Martm reagent, TFMPO (2,2,6,6-tetramethylpipeπdme-N- oxide), DDQ (2,3-Dichloro-5,6-dicyano-l ,4-benzoqumone), PDC (pyπdimum dichromate), PCC (pyπdinium chlorochromate), Pyridine SO3, Chromium tπoxide, p-mtroperbenzoic acid, magnesium monoperoxyphthalate, sodium peπodate, potassium peπodate, hydrogen peroxide, urea peroxide, alkali metal bromates, cumene hydroperoxide, tert-butyl peroxide, peracids such as perfomiic acid, peracctic acid, pertπfluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o- carboxyperbenzoic acid and the like, sodium metaperiodate, bichromic acid, bichromates such as sodium bichromate, potassium bichromate, permanganic acid, permanganates such as potassium permanganate, sodium permanganate, and lead salts such as lead tetraacetate
[0128] Regarding the synthetic examples described herein, a nitrogen protecting group is a chemical group covalently bound to a nitrogen atom of a compound that is used to protect the nitrogen from reaction during a synthetic step The nitrogen protecting group may be added to a compound and removed m a subsequent step by methods known to those of skill in the art Nitrogen protecting groups include, without limitation, carbamates, amides, N-sulfon>l derivatives, groups of formula -C(O)OR, wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CHCH2-, and the like, groups of the formula -C(O)R', wherein R' is, for example, methyl, phen>l, tπfluoromethyl, and the like, groups of the formula -SO2R", wherein R" is, for example, tolyl, phenyl, tπfluoromethyl, 2,2,5,7,8-pentamethyIchroman-6-yl, 2,3,6-tπmethyl-4-methoκyphenyl, and the like, and silanyl containing groups, such as 2-tπmethylsilylethoxymethyl, t-butyldimethylsilyl, trnsopropylsilyl, and the like Other suitable nitrogen protecting groups may be found m texts such as T W Greene & P G M Wutb, Protective Groups in Organic Synthesis, John Wiley & Sons 1991
Alternative Compound Forms or Derivatives
[0129] Compounds contemplated herein are described with reference to both generic foπnulae and specific compounds In addition, invention compounds may exist m a number of different forms or derivatives, all within the scope of the present invention Alternative forms or derivatives, such as (a) Isomers, Prodrugs, and Active Metabolites (b) Tautomers, Stereoisomers, Regioisomers, and Sohated Forms (c) Prodrugs and Metabolites (d) Pharmaceutically acceptable salts and (e) Polymorphic forms, are descnbed, for example in US Patent Application Serial number 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference m its entirety
Administration
[0130] The methods, and compounds will typically be used in therapy for human subjects However, they may also be used to treat similar or identical indications in other animal subjects In this context, the terms "subject," "animal subject," and the like refer to human and non-human vertebrates, e g mammals, such as non-human primates, sports and commercial animals, c g , equmes, bovines, porcines, ovmes, rodents, and pets, e g , canines and felines A description of possible methods and routes of administration ma> be found, for example, m US Patent Application Serial number 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety
EXAMPLES
[0131] Examples related to the present invention are described below In most cases, alternative techniques can be used The examples are intended to be illustrative and are not limiting or restrictive to the scope of the invention In some examples, the mass spectrometry1 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
[0132] Unless specifically indicated otherwise, the Formula enumeration and R group enumeration used m the following examples is not related to such enumeration m other sections of this application The reagents and solvents used in these examples can be readily substituted with appropriate alternatives as are known in the art and isolation of products is readily achieved by methods known in the art, including, but not limited to, extraction, crystallization, and chromatographic methods. In addition to the following Examples, exemplary methods for synthesis of compounds of the present invention may be found in US Patent Application Serial number 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety. The llϊ-pyrrolo[2,3-b]pyridine core of compounds described in the examples may also be referred to as 7-azaindole in the examples.
Example 1. Synthesis of compounds of Formula X
Figure imgf000065_0001
Step 1 - Preparation of compounds of Formula Xc and Xd
(0133) To a compound of Formula Xa (R1 is as defined in paragraph [0009]) and a compound of Formula Xb (Y is consistent with compounds of Formula I, Foπnula II, or Formula III, e.g. Y is:
Figure imgf000065_0002
, or ) where R2 and R3 are as defined in paragraph [0009], and R6 is as defined in paragraph [0023], where * indicates the attachment point to the carbonyl carbon) is added an appropriate solvent (e.g. methanol) followed by an appropriate base (e.g. potassium hydroxide, sodium methoxide). The reaction is typically allowed to stir at room temperature overnight. Isolation by conventional means (e.g. extraction, washing and filtering) affords a mixture containing compound of Formula Xc, which may be isolated by silica gel chromatography if desired.
Step 2 - Preparation of compounds of Formula X
[0134] To a compound of Formula Xc in an appropriate solvent (e.g. tetrahydrofuran) is added an oxidizing agent (e.g.Dess-Martin periodane, TEMPO, DDQ). Typically, the reaction is allowed to stir at room temperature for 20 minutes. Isolation by conventional means (e.g. extraction and silica gel column chromatography) affords compounds of Formula X, Example 2. Synthesis of Compounds of Formula X
Figure imgf000066_0001
Step -1- Synthesis of compound oj Formula X
[0135] Compound of Formula X is synthesized by reacting a compound of Formula Xa (see Example 1) with a compound of Formula Xd (Y is as> defined in Example 1), e g benzoyl chloride, m the presence of a Lewis acid (e g aluminum trichloride) in an inert solvent (e.g. dichloromethane) under an inert atmosphere (e.g argon) at room temperature or with heating up to reflux for 1-18 hours. The desired compound X is isolated by extraction and silica gel column chromatography.
Example 3. Synthesis of Compounds of Formula X
Figure imgf000066_0002
Step - 1 — Synthesis of compound Xe
[0136] Compound of Formula Xe can be synthesized by reacting a compound of Formula Xa (see Example 1) with hexamcthyltetramine and acetic acid in water with heating to reflux for two hours After cooling, the desired compound precipitates and may be collected by filtration
Step - 2 - Synthesis of compound of Formula Xf
[0137] Compound of Formula Xf, where P is a nitrogen protecting group, is synthesized by reacting a compound Xe with an appropriate reagent to introduce a protecting group (e.g. triisopropylsilylchloride) and a base (e g sodium hydride) in a solvent (e g. tetrahydrofuran) typically at room temperature for 8-12 hours The desired compound is isolated by conventional means (e.g. extraction) Step - 3 — Synthesis of compound of Formula XJi
[0138] Compound of Formula Xh is synthesized by reacting a compound of Formula Xf in a solvent (e.g. tetrahydrofuran) with an organolithium reagent (e.g. phenyl lithium) in a solvent (e.g. tetrahydrofuran) under an inert atmosphere, cooled to -78 0C. An appropriate organolithium reagent
can also be prepared by reacting compounds of Formula Xg, where Y is
Figure imgf000067_0001
^- ^-^ , * , or -R ( * indicates attachment point to the sulfone), where R", R3 and R6 are as defined in Example 1, with an organolithium reagent (e.g. butyllithium) in a solvent (e.g. tetrahydrofuran) under an inert atmosphere, cooled to -78 0C. The reaction is typically allowed to warm to room temperature and stirred for 30 minutes. The desired compound is isolated by conventional means (e.g. extraction).
Step - 4 - Synthesis of an intermediate of compound of Formula X
|0139] An intermediate of compound of Formula X is synthesized by reacting a compound of Formula Xh with an appropriate reagent to remove the protecting group, P, (e.g. fcϊrα-n-butyl ammonium fluoride) in an appropriate solvent (e.g. tetrahydrofuran). The final product is isolated by standard procedures (e.g. extraction).
Step - 5 Synthesis of compound of Formula X
|0140] Compound of Formula X is synthesized by reacting the intermediate from Step 4 with an oxidizing agent (e.g. Dess-Martin periodane, TEMPO) in an aprotic solvent (e.g. tetrahydrofuran) typically at room temperature for 20 minutes. The desired compound is isolated by conventional means (e.g. extraction and silica gel chromatography).
Example 4: Synthesis of phenyl-(-lH-pyrrolo]2,3-b]pyridine-5-yl)-amine 4
[0141] Phenyl-(-lH-pyrrolo[2,3-bJpyridine-5-yl)-amine 1 was synthesized in three steps from 5- bromo-7-azaindole 1 as shown in Scheme 1.
Scheme 1
Figure imgf000067_0002
Step 1 - Preparation of 5 -hromo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b] pyridine (2): [0142] To 5-bromo-7-azaindole (1, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0 mmol) and trriisopropylsilyl chloride ( 2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10 % ethyl acetate in hexane to give the compound (2, 1.6 g, 59%). MS(ESI)[MTH+J+ = 352.3.
Step 2 - Preparation of 5-phenyl-(l-triisopropylsilanyl-IH-pyrrolo[2,3-b]pytϊdine-5-yl)-amine (3): [0143] To 5-bromo-l-triisopropylsilanyl-lH-pyrrolo[2.3~b]pyridine (2, 0, 10 g, 0.3 mmol) in toluene (5 mL) were added aniline (0.04 mL, 0.42 mmol), sodium ferf-butoxide (0.15 g, 1.56 mmol), tris(dibenzyllideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol) and (S) -(-)-2,2'- bis(diphenylphosphino)-! , 1 ' -binaphthyl (6.3 mg, 0.01 mmol). The reaction was heated to 160 0C for 10 minutes in a CEM Discover microwave instrument. The reaction was concentrated and purified by silica gel column chromatography eluting with 3 % ethyl acetate in hexane to give the compound (3, 40 mg, 40%). MS(ESI)[M+H+]+ - 366.6.
Step 3 - Preparation ofphenyl-(-lH-pyrrolo[2,3-b]pyridine-5-yl)-amine (4):
[0144] To 5-phenyl-(l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-5-yl)-amint; (3, 0.14 g, mmol) in tetrahydrofuran (3.0 mL) was added tetra-n-butylammonium fluoride (0.197 g, 0.76 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was concentrated and purified by silica gel column chromatography eluting with 3 % ethyl acetate in hexane to give the compound (4, 60 mg, 76 %). MS(ESI)[M+HT = 210.3.
Example 5: Synthesis of 5-chIoro-lH-pyrroIo[2,3-b]pyridine 6.
[0145] 5-Chloro-lH-pyrrolo[2,3-b]pyridine 6 was synthesized in two steps from 5-bromo-l- triisoproρylsilyl-7-azaindole 2 as shown in Scheme 2.
Scheme 2
Figure imgf000068_0001
Step 1 - Preparation 5-chloro-l-triisopropylsilanyl-IH-pyrrolo[2,3-b]pyridine (S): [0146] To 5-bromo-l-triisopropylsilyl-7-azaindole (2, 1.60 g, 4.53 mmol, prepared as described in Example 4) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at -78 0C, was added tert- butyllithium (1.70 M in hexane, 6.12 mL). The reaction was stirred for 1 hour, followed by addition of hexachlorocthane (1.29 g, 5.43 mmol). The reaction was stirred for 3 hours, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude compound (5, 1.60 g). MS(ESI) [M+tT] ' = 309.3. Step 2 - Preparation 5-chlυro-lH-pyrroln[2,3-h]pyridine (6):
[0147] To 5-chloro-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]ρyridine (5, 1.40 g, 4.53 mmol) in tctrahydrofuran (15 mL) was added tøfr-α-n-butylammonium fluoride (1.42 g, 5.43 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated and isolated by silica gel column chromatography cluting with 30% ethyl acetate in hexane to give the compound (6, 0.40 g. 58% over 2 steps). MS(ESI)[M-H+]^ = 153.1.
[01481 5-Fluoro-lH-pyrrolo[2,3-b]pyridine 7
Figure imgf000069_0001
was prepared using the protocol of Scheme 2, substituting hexachloroethane with N-fluoro-N- (phenylsulfonyl)-benzenesulfonamide in Step 1. MS(ESI) [M + H+]" = 137.1.
Example 6: Synthesis of l-triisopropylsilanyl-lH-pyrrolo|2,3-b]pyridine-3-carbaldehyde 10.
10149] l -Triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde 10 was synthesized in two steps from 7-azaindole 8 as described in Scheme 3.
Scheme 3
Figure imgf000069_0002
Step 1 - Preparation of lH-pyrrυlo[2,3-h]pyridine-3-carbaldehyde (9):
|0150] To lH-Pyrrolo[2,3-b]pyridine (8, 16.0 g, 135 mmol) in water (110 mL), were added hexamefhylenetetramine (26.0 g, 185 mmol), and acetic acid (55.0 mL, 967 mmol). The reaction was refluxed for 12 hours. Water (329 mL) was added and the reaction was cooled to room temperature.
The reaction was filtrated and washed with water to give the compound (9, 15.0 g, 76%).
MS(ESI)[M+H+]+ = 147.
Step 2 - Preparation ofl-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (W). [0151] To lH-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (9, 4.05 g, 27.71 mmol) in tetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil, 1.5 g, 38 mmol) and trriisopropylsilyl chloride (8.0 mL, 38 mmol) under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10 % ethyl acetate in hexanc to give the compound (10, 3 O g. 36%) MS(LSI)[M+H ]+ = 303
Example 7: Synthesis of 5-isopropyl-lH-pyrroIo[2,3-b]pyridine 13.
[0152] 5-Isopropvl-lH-pyrrolo[2,3-b]pyndine 13 was synthesized in three steps from 5-bromo-l- tπisoproρylsilanyl-l H-pyrrolo[2,3-b]pyπdine 2 as described in Scheme 4
Scheme 4
Figure imgf000070_0001
Step I ~- Preparation of2-(l-tnιsopropylsιlcmyl-lH-pyrrolo[2,3-b]p\ndιn-5-yl)-propan-2-ol (11) [0153] Io 5-bromo-l-tnisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (2, 2 0 g, 5 66 mmol, prepared as described in Example 1) in tetrahydrofuran (20 0 ml_), cooled in a -78 °C acetone/dry ice bath, under an atmosphere of nitrogen, was added tert-butyllithium (1 7 M m tetrahydrofuran, 7 3 mL, 12 mmol) dropwise After 20 minutes, acetone (0 830 mL, 1 1 mmol) was added dropwise to the reaction The reaction was stirred for 30 minutes at -78 0C and then allowed to reach room temperature The reaction was poured into water and extracted with eth>l acetate The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered The filtrate was concentrated and purified b> silica gel column chromatography eluting with 10 % ethyl acetate in hexane to give the compound (11, 1 30 g, 69%) MS(ESI)[M+H+]+ = 333
Step 2 ~ Preparation of 5-ιsopropenyl-lH-pyrrolo[2,3~b] pyridine (12)
[0154] To 2-(l-tπisopropylsilanyl-l H-pyrrolo[2,3-b]pyridin-5-yl)-propan-2-ol (11, 0 500 g, 1 5 mmol) in acetomtrile (10 0 mL) were added tπethylsilane (1 00 mL, 6 3 mmol) and trifluoroacetic acid (0 50 mL, 6 5 mmol) under an atmosphere of nitrogen The reaction was reiluxed for 3 hours, then cooled down to room temperature The reaction was poured into water and extracted with ethyl acetate The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered The filtrate was concentrated and purified by silica gel column chromatography eluting with 50 % ethyl acetate in hexane to give the compound (12, 0 200 g, 84%) MS(ESI)[M+H*]+ = 159
Step 3- Preparation of 5-ιsopropyl-l H-pyrrυlo[2,3-b]pyi idwe (13)
|0155] To 5-isopropenyl-lH-pyrrolo[2,3-b]pyπdine (12, 0 080 g, 0 501 mmol) in tetrahydrofuran (5 0 mL) was added 20 % palladium hydroxide on carbon (5 0 mg) The reaction was stirred under hydrogen at 40 psi for 30 minutes The reaction mixture was filtered and concentrated to give the compound (13, 0 078 g, 96%) MS(ESI)[MH-H+]4 = 161 Example 8: Synthesis of 5-methyl-lH~pyrroloI2,3-b]pyridine 15.
[0156) 5-Methyl-l II-pyrrolo[2,3-bJpyridine 15 was synthesized in two steps from 5-bromo-l- tπisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine 2 as described in Scheme 5.
Scheme 5
Figure imgf000071_0001
Step 1 - Preparation of5-methyl-l-triisopropylsilanyl-lH-pyrrolυ[2,3-h]μyridϊne (14): [0157] To PdCl2(dppf) (0.04 g, 0.05 mmol) in toluene (10,0 mL) under an atmosphere of nitrogen were added 54>romo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (2, 0.3 g, 0.8 mmol, prepared as described in Example 1 , 1.0 mL in toluene) and methylmagnesium bromide (1.0 M in tetrahydrofuran, 3.0 mL, 3,0 mmol). The reaction was stirred 90 0C for 2 hours and then allowed to reach to room temperature. The reaction was poured into citric acid (0.1 M in water) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50 % ethyl acetate in hexane to give the compound (14, 0.16 g, 60.0 %). MS(ESI)[M+HY = 289.4.
Step 2 - Preparation of S -methyl- IH-pyrrolo [2.3-b] pyridine (15):
[0158] To 5-Methyl-l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (14, 0.160 g, 0.55 mmol) in tetrahydrofuran (3.0 mL) was added telra-n-butylammonium fluoride (0.145 g, 0.55 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to provide light yellow solid (15, 0.07 g, 95%). MS(ESI) [M+H+]+ - 133.2.
[01591 5-Methyl-lH-pyrrolo[2,3-b]pyridine 16
Figure imgf000071_0002
was prepared following the protocol of Scheme 5, substituting methylmagnesium bromide with ethylmagnesium bromide in Step 1.
Example 9: Synthesis of 5-methoxy-lH-pyrrolo[2,3-b[pyridine 17 and related compounds. [0160] 5-Methoxy-lH-pyiτolo[2,3-b]pyiidine 17 was synthesized in one step from 5-bromo-lH pyrrolo[2,3-b]pyπdme 1 as described in Scheme 6
Scheme 6
Figure imgf000072_0001
Step 1 — Preparation of 5-methoxy-lH-pyrrυh[2 3-h] pyridine (17)
[0161] To 5-bromo-7-a7amdole (1, 500 0 mg, 2 53 mmol) in N.N-dimethylformamide (8 mL) were added coppcr(I) iodide (966 mg, 5 08 mmol) and sodium methoxide in methanol (3 M, 5 mL) The reaction was stirred overnight at 120 0C under an atmosphere of Argon The reaction was poured into water, and extracted with ethyl acetate The oi ganic layer was dπed over anhydrous sodium sulfate filtered The filtiate was concentrated and purified with silica gel column chromatograph eluting with 20% cth>l acetate in hexane to give white solid (17, 140 mg, 28%) MS(ESI)[M+H+]+ = 149 1 In an alternative method, 2 3 g (1 1 7 mmol) 5-bromo-7-azamdole (1, 2 3 g, 1 1 7 mmol) was dissolved in 75 mL N,N-dimethylformamide and 50 ml methanol (50 mL), adding sodium methoxide (32 g, 0 6 mol) and copper-(I) bromide (3 2 g, 22 4 mmol) at room temperature The reaction was stirred for three hours at 100 °C under an atmosphere of argon The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride ammonium hydroxide (4 1) The organic layer was extracted with ammonium chloride ammonium hydroxide (4 1), washed with brine, dπed o\er anhydrous sodium sulfate, filtered and concentrated The desired compound was isolated by silica gel column chromatography eluting with 30% to 70% ethyl acetate in hexanes to give a yellow solid (17, 0 27 g, 15 6%) MS(ESI) [M + H+]+= 149 2
[0162] 5-Ethoxy-lH-pyrrolo[2 3-b]pyπdme 18
Figure imgf000072_0002
was prepared using the protocol of Scheme 6, substituting methanol with ethanol and sodium methoxide with sodium ethoxide
[0163] 5-(2-Methoxy-ethoxy)-lH-pyrrolo[2,3-b]pyridinc 19
Figure imgf000072_0003
was prepared using the protocol of Scheme 6, substituting methanol with 2-methoxy-ethanol and sodium methoxide with sodium 2-mcthoxy-ethoxide (prepared from 2 methoxy-ethanol and sodium hydride) MS(ESI) [M + HT]+ = 193 3 [0164] Diethyl- [2-( 1 H-pyrrolo [2,3 -b]pyridin-5-yloxy)-elhy 1] -amine 20
Figure imgf000073_0001
was prepared using the protocol of Scheme 6, substituting methanol with 2-diethylamino-ethanol and sodium methoxide with sodium 2-diethylamino-ethoxide (prepared from 2 2-diethylamino-ethanol and sodium hydride). MS(ESI) [M + H+J+ = 234.5.
Example 10: Synthesis of 5-pyridin-3-yl-lII-pyrrolo[2,3-blpyridine 22.
[0165] 5-Pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 was synthesized in one step from 5-bromo-lH- pyrrolo[2,3-b]pyridine 1 as described in Scheme 7.
Scheme 7
Figure imgf000073_0002
Step 1 - Preparation υf 5-pyridin-3-yl-lH-pyrrolo[2,3-b] pyridine (22):
[0166] To 5-bromo-7-azaindole (1, 1 ,00 g, 5.08 mmol) in water (13.0 mL) and acetonitrile (36 mL) were added pyridine-3 -boronic acid (21, 1.0 g, 8.1 mmol), potassium carbonate (1.79 g, 0.0130 mol) and Tetrakis(triphenylphosphine)palladium(0) (50.0 mg, 0.043 mmol) under an atmosphere of nitrogen. The reaction mixture was heated to 170 0C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide a light yellow solid (22, 820 mg, 82%). MS(ESI)[M+H+]+ - 196.1.
[0167] Additional compounds were prepared following the protocol of Scheme 7, either by substituting pyridine-3-boronic acid with an appropriate boronic acid or by substituting the 5-bromo- 7-azaindole with 5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine and reacting with a suitable aryl or heteroaryl halide (i.e. coupling with the boronic acid ester on the azaindole, and the halide on the group to be coupled to the 5-position of the azaindole). The following compounds were prepared by this procedure:
5-(4-Chloro-phenyl)-lH-pyrrolo[2,3-b]pyridine (23),
5-(4-Fluoro-phenyl)-l H-pyrrolo[2,3-b]pyridine (24),
5-Phcnyl-lH-pyrrolo[2,3-b]pyridine (25),
5-(6-Methoxy-pyridin-3-yl)-l H-pyrrolo [2,3 -b]pyridine (26), 5-(2-Methoxy-pyrimidin-5-yl)-lH-pyrrolo[2,3-b]pyridine (27),
5-Pyridin-4-yl-lH-pyrrolo[2,3-b]pyridinc (28).
4-(l H-Pyrrolo[2,3-b)pyridin-5-yl)-benzenesulfonamide (29),
3-(lH-Pyrrolo[2,3-b]pyridin-5-yl)-benzenesulfonamide (30),
5-P\τimidin-5-yl-lH-pyrrolo[2,3-b]ρyridine (31),
5-(3-Methanesulfonyl-phenyl)-lH-pyrrolo[2,3-b]pyridine (32),
3-(lH-Pyrrolo[2,3-b]pyridin-5-yl)-benzarnide (33),
5-(5-Methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine (34),
5-(l -Melhyl-l H-imida7ol-2-yl)-lH-pyrrolo[2,3-b]pyridinc (35), and
5-(l ,5-Dimethyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine (59). The following table indicates either 5-bromo-7-azaindole or 5-(4,4,5,5-Telramethyl-[l ,3,2] dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine starting material (column 1) and the appropriate reagent Io be coupled to the 5 position of the azaindole (column 2) to afford the resulting compound (column 3), with the observed mass given in column 4.
Figure imgf000074_0001
Figure imgf000075_0001
Example 11: Synthesis of 3-lodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-blpyridine 37
[0168] 3-Iodo-l-tπisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine 37 was synthesized in one step from 3~Iodo-lH-pyrrolo[2,3-b]pyridine 36 as shown in Scheme 8. Scheme 8
Figure imgf000076_0001
Step I - Preparation of3-Iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-h]pyndjne (37) [0169] 3-Iodo-lH-pyrτolo[2,3-b]pyridine 36 (2 00 g, 8.20 mmol) was dissolved m N,N- dimethylformamidc (50 mL). Sodium hydπde (60% dispersion m mineral oil, 390 mg, 9.8 mmol) was added. After 20 minutes, tπisopropylsilyl chloride (1.74 mL, 8.20 mmol) was added dropwise. After 1.5 hours, the reaction was poured into water and extracted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The organic portions were dried over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography, 0-25% gradient ethyl acetate/ hexane gave compound 37 as a white solid (3.224 g, 98.2%). 1H-NMR was consistent with the desired compound.
Example 12: Synthesis of l-(tert-Butyl-dimethyl-silanyl)-3-iodo-lH-pyrroIo[2,3-b] pyridine 38
[0170] l-(tert-Butyl-dimethyl-silanyl)-3-iodo-lH-pyrrolo[2,3-b]pyridine 38 was synthesized in one step from 3-Iodo-lH-pyrrolo[2,3-b]pyridine 36 as shown in Scheme 9.
Scheme 9
Figure imgf000076_0002
Step 1 - Preparation of l-(tert-Butyl-dιmethyl-sUanyl)-3-iodo-lH-pyrrolo[2,3-b]pyridine (38) [0171] 3-Iodo-lH-pyrrolo[2,3-b]pyridine 36 (1 1 1 g, 4 6 mmol) was dissolved in tetrahydrofuran (120 mL). Sodium hydride (60% dispersion in mineral oil, 0.13 g, 5.5 mmol) was added, followed by tert-butyldimethylsilyl chloride (0.85 g, 5.5 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate The organic portion was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate m hexane to give the compound as a white solid (38, 100 mg, 15%).
Example 13: Synthesis of 5-chloro-3-iodo-l-triisopropyIsiIanyI-lH-pyrruIo[2,3-b]pyridine 40 [0172] 5-Ch]oro-3-iodo-l-tnisopropylsilanyl-lH-pyrrolo[2,3-b]pyndinc 40 was synthesized in one step from 5-Ch]oro-3-iodo-lH-pyrrolo[2,3-b]pyridme 39 as shown in Scheme 10
Scheme 10
Figure imgf000077_0001
Step 1 Preparation of5-Chloro-3-wdo~-l-trusopropylsιlanyl-lH-pyrrolo[2,3-b]pyndιnε (40) [0173] 5-Chloro-3-iodo-lH-pyrrolo[2,3-b]pyridine (39, 31 2 g, 0 112 mol) was dissolved in N- methylpyrrolidmone (800 mL) and NaH (60% dispersion, 4 93 g, 0 123 mol) was added at room temperature The resulting mixture was stirred for 30 minutes To this mixture was then added tπisopropylsilylchloπde (24 0 mL, 0 1 12 mol) and the resulting mixture was stirred for 2 hours The reaction was quenched with water and extracted with ethyl acetate three times, washed by brine, dried, filtered, and concentrated in vacuo The residue was subjected to silica gel flash chromatography (eluted by heptane to 5% ethyl acetate/heptane) to afford the desired compound (43 g, 88 %) as a pale-yellow solid
Example 14: Synthesis of 5-[4-(2-methoxyethoxy)-phenyl]-lH-pyrrolo[2,3-b]pyridine 44
[0174] 5-[4-(2-Methoxyethoxy)-phenyl]-lH-pyrrolo[2,3-b]pyπdme 44 was synthesized m two steps from 4-bromophenol 41 as shown in Scheme 1 1
Scheme 11
Figure imgf000077_0002
Step 1 Preparation l-Bromo-4-(2-methoxy-cthoxy)-benzene (42)
[0175] To a solution of 4-bromophenol (41, 5 0 g, 28 9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4 40 g, 31 8 mmol) and l-bromo-2-methoxyethane (5 00 g, 36 0 mmol) under an atmosphere oi nitrogen The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure The residue was slurried m ethyl acetate (50 mL) and filtered The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered Silica gel column chromatography (0-10% ethyl acetate m hexanes) gave the desired compound as a colorless oil (42, 3 2 g, 48%) Step 2 - Preparation of 5-[4-(2-Metlιoxy-ethoxy)-phenyl] - 1 H-pyrrolo[2,3-b]pyridine (44): [0176] To a solution of 5-(4,4,5,5,-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-lH-pyrrolol[2,3- b]pyridine (43, 1.1 g, 4.3 mmol) in tetrahydrofuran (40 mL) was added l -brαmo-4-(2-methoxy- ethoxy)-benzene (42, 1 ,50 g, 6.49 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.25 g, 0.21 mmol). The reaction mixture was stirred with potassium carbonate solution (10 mL, 1.0 M) and warmed to reflux overnight. The biphasic reaction mixture was diluted with ethyl acetate (50 mL) and saturated sodium carbonate solution (20 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and purified by silica gel column chromatography (50-100% ethyl acetate in hexanes) to give the desired compound as a colorless solid (44, 782 mg, 67%). MS (ESI) [M+HT= 267.4.
Example 15: Synthesis of 5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-bJpyridine 46.
[0177] 5-(l-Methyl-l H-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine 46 was synthesized in one step from 5-bromo-lH-ρyrrolo[2,3-b]pyridine 1 as shown in Scheme 12.
Scheme 12
Step 1 — Preparation of5-(l-MethyI~lH-pyrazol-4-yl)-lH-pyrroIo[2,3-b]pyridine (46): [0178] To 5-bromo-7-azaindole (1, 1.04 g, 5.28 mmol) in 1.00 M potassium carbonate in water (15.8 mL) and tetrahydrofuran (50.0 mL) were added l-methyl-4-(4,4,5,5-tetramethyl- [l ,3,2]dioxaborolan-2-yl)-lH-pyrazole (45, 1.65 g, 7.92 mmol), Tetrakis(triphenylphosphine)- palladium(O) (0.305 mg, 0.26 mmol) and tetra-n-butylammonium iodide (0.20 g, 0,53 mmol). The reaction mixture was stirred at 70 0C overnight. The reaction mixture was poured into water and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide a light yellow solid (46, 670 mg, 64.0%). MS(ESI)[M+H+]+ = 199.4.
Example 16: Preparation of propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH- pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide 51. [0179] Propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine-3- carbonyl)-phenyl]-amide 51 was synthesized in four steps from 2,4-difluorophenylamine 47 as shown in Scheme 13,
Scheme 13
Figure imgf000079_0001
Step I - Preparation of propane-2-sulfonic acid (2, 4-difluoro-phenyl)-amide (48): [0180] To 2,4-difluoro-phenylamine (47, 4.0 mL, 40,0 mmol) in dichloromethane (50 mL) were added pyridine (3.37 mL, 42.3 mmol), propane-2-sulfonyl chloride (6.00 g, 42.3 mmol) and dimethylaminopyridine (0.20 g, 1 .64 mmol) under an atmosphere of nitrogen. The reaction was stirred at 45 °C overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography 3% methanol in methylene chloride to give a white solid (48, 8.0 g, 85%). MS(ESI) [M-H+]" = 234.0.
Step 2 - Preparation of propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (49): [0181] To propane -2-sulfonic acid (2,4-difluoro-phenyl)-amide (48, 2.35 g, 9.95 mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooled with a dry ice/acetone bath was added 1.60 M of n-butyllithium (1.60 M in hexane, 6.53 mL, 10.45 mmol). The reaction was stirred for 40 minutes, and then another portion of n-butyllithium (1.60 M in hexane, 6.84 mL, 10.94 mmol). The reaction was stirred for 1 hour and N,N-dimethylformarnide (0.92 mL, 1 1.9 mmol) was added, The reaction was allowed to warm to room temperature overnight. The reaction was poured into water extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography (dichloromcthanc/methanol 5%) to give the compound (49, 1.4 g, 53.4%), MS(ESI) [M H4]" = 263.4.
Step 3 - Preparation of propane~2-sulfonic acid {2,4-diβuoro-3-[hydroxy-(5-pyridin-3-yl-lH- pyrroln [2, 3-b]pyridin-3-yl)~methylj '-phenyl) '-amide (50): [0182] To propane-2-sulfonic acid (2,4-difluoro-3-formyl-phcnyl)-amide (49, 220.0 mg, 0.83 mmol) in methanol (15 mL) was added 5-pyndin-3-yl-lH-pyrrolo[2,3-b]pyridine (22, 150 0 mg, 0 77 mmol, prepared as described in Example 10) and potassium hydroxide (537.0 mg, 9,6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in dichloromethane to give the compound (50. 160 mg, 45 3%) In this step, minor compound propane-2-sulfonic acid {2,4-difluoro-3-[methoxy-(5-pyπdm- 3-yl-lH-pyrrolo[2,3-b]pyπdin-3-yl)-methyl]-phenyl} -amide was also formed and isolated. MS(ESI) [M + HT = 460.1.
Step 4 - Preparation of propane- 2 -sulfonic acid [2,4-difluorυ-3-(5-pyridιn-3-yl-lH-pyrrola[2,3- h]pyndιne-3-carbonyl)-phenyl] -amide (51):
[0183] To propane-2-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-lH-pyrrolo[2,3- b]pyridin-3-yl)-methyl]-phenyl} -amide (50, 40.0 mg, 0.087 mmol) in tetrahydrofuran (10 mL) was added Dess-Martin periodane (48 0 mg, 0.1 1 mmol). The reaction was stirred at room temperature for 5 minutes. The reaction was poured into sodium thiosulfatc and potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to give the compound (51, 13 4 mg, 33 5%) MS(ESI) [M + H+] ' = 458.1.
[0184] N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl} - 4-isoproρyl-benzenesulfonamide P-0018
Figure imgf000080_0001
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with 4- lsopropyl-phenyl sulfonyl chloπde in step 1 and 5-pyndin-3-yl-lH-pyrrolo[2,3-b]pyπdine 22 with 5- (2-methoxy-ethoxy)-l H-pyrrolo[2,3-b]pyridine 19 (see Example 9) in step 3 MS(ESI) [M - H'] ~ 530
[0185] N-{2,4-Difluoro-3-[5-(4-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl}-4-isopropyl-benzenesulfonamide P-0019
Figure imgf000081_0001
was prepared following the protocol of Scheme 13, substituting ρropane-2-sulfonyl chloride with 4-isopropyl-phenyl sulfonyl chloride in Step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(5-methyl-lII-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine 34 (see Example 10) in step 3. MS(ESI) [M - H+] = 536,
[0186] N-{2,4-Difluoro-3-[5-(l-methyl-lH-pyrazol-4-yl)-l H-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl} -4-isopropyl-benzenesulfonamide P-0022
Figure imgf000081_0002
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with 4-isopropyl-phenyl sulfonyl chloride in Step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine 46 (see Example 15) in step 3. MS(ESI) [M - HT = 536.
[0187] N-{2,4-Difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl} -4-trifluoromethyl-benzenesulfonamide P-0025
Figure imgf000081_0003
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with 4-trifluoromethyl-phenyl sulfonyl chloride in Step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(5-methyl-lII-imidazol-2-yl)-lII-pyrrolo[2,3-b]pyridine 34 (see Example 10). MS(ESI) [M - H+]- - 562.
[0188] N-{2,4-Diiluoro-3-[5-(l-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl}-4-propyl-benzenesulfonamide P-0026
Figure imgf000081_0004
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with propane sulfonyl chloride in Step 1 and 5-pyridm-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(5- methyl-lH-imidazol-2-yl)-lH-pyrrolof2,3-b]pyridine 35 (see Example 10). MS(ESI) [M - H+]" = 536,2.
[0189] N-{3-[5-(l,5-Dimethyl-lII-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridme-3-carbonyl]-2,4- difluoro-phenyl} -4-propyl-benzenesulfonamide P-0027
Figure imgf000082_0001
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with propane sulfonyl chloride in Step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(l ,5- dimethyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine (59) (see Example 10). MS(ESI) [M - H+P 550.1.
Example 17: Synthesis of N-[3-(5-chloro-lH-pyrrolo[2,3-bJpyridine-3-carbonyl)-2,4-difluoro- pheπylI-3,5-difluorobenzenesulfoπamide 58
[0190] Compound P-1841 was synthesized in six steps from 2,4-difluoroaniline 47 as shown in Scheme 14.
Scheme 14
Figure imgf000082_0002
Step 1 - Preparation nf (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52): [0191] To 2,4-difluoroaniline (47, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and K.IISO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 52 (15.6 g, 85%).
Step 2 - Preparation of(2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (53): [0192] Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52, 3.83 g, 14.5 iTimol) in tetrahydrofuran (148 mL, 1.82 mol). The solution was chilled to — 78 0C and n-butyllithium (1.60 M in hexane, 19.1 mL, 30.0 mmol) was added over 30 minutes followed by the addition of, N,N-dimethylformamide (1.12 mL, 14.5 mol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ether to give compound 53 (3.0 g, 71 %).
Step 3 - Preparation of{2,4-difluoro-3-[hydroxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}- carbamic acid benzyl ester (54):
[0193] Into a round bottom flask was added 5-chloro-lH-pyrrolo[2,3-b]pyridine (6, 0.524 g, 3.43 mmol, prepared as described in Example 5) in methanol (5.00 mL, 0.123 mol). Potassium hydroxide (0.800 g, 14.2 mmol) and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (53, 1.02 g, 3.5 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was poured into IN HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ethyl acetate to give compound 54 (710 ing, 46%).
Figure imgf000083_0001
Step 4 - Preparation of[2,4-difluoro-3-(lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phcnyl]-carbamic acid benzyl ester (55):
[0194] Into a round bottom flask was added {2,4-difluoro-3-[hydroxy-(lH-pyrrolo[2,3-b]pyridin-3- yl)-methyl]-phenyl}-carbamic acid benzyl ester (54, 1.01 g, 2.28 mmol) in tetrahydrofuran (5.00 mL, 0.0616 mol). Dess-Martin periodinane (1.20 g, 2.89 mmol) was added in portions. The reaction mixture was stirred at ambient temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography to give compound 55 (914 ing, 91 %). MS(ESI)[M-HI'] '' = 442.
Step 5 - Preparation of(3-Amino-2,6-difluoro-phenyl)-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl) - methanone (56):
[0195] [2,4-difluoro-3-(lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-carbamic acid benzyl ester (55, 800 mg, 1.81 mmol) was added to 10 M NaOH (15.00 mL) and warmed to reflux overnight. The reaction mixture was diluted with 30 mL of water and was extracted with ethyl acetate to give compound 56 (450 mg, 81% ). Step 6 -Preparation of N-[3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- 3, 5-diflnorobenzeπ esulfonamide (58) :
[0196] Into a microwave reaction vessel were combined (3-amino-2,6-difluoro-phenyl)-(5-chloro- lH-pyrrolo[2,3-b]pyridin-3-yl) -methanone (56, 50 mg, 0.16 mmol), 3,5-difluorobenzenesulfonyl chloride (57, 103 mg, 0.49 mmol), pyridine (0.5 mL, 6.1820 mol) and tetrahydrofuran (3.0 mL,). The reaction was warmed in the CEM microwave at 300 watts, 130 CC for 10 minutes. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was collected, dried over Na2SO1J, filtered and concentrated. The compound (58) was isolated using column chromatography (silica, hexane:ethyl acetate 70:30) to obtain 36 mg (46%) compound. MS = 482.0.
[0197] Additional compounds were prepared following the protocol of Scheme 14, optionally substituting 5-chloro-lH-pyrrolo[2,3-b]pyridine 6 with an appropriate azaindole (see Examples 5, 10 or 15) in Step 3 and/or 3,5-difluorobenzenesulfonyl chloride 57 with an appropriate sulfonyl chloride in Step 6. The following compounds were prepared by this procedure:
Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-OOOl),
5 -Methyl-2-trifluoromethyl-furan -3 -sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3- carbonyl)-2,4-difluoro-phenyl]-amide (P-0002),
5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl] -amide (P-0003),
3-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid (P-0004),
2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0005),
5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chIoro-lII-pyrrolo[2,3-b]pyridine-3-carbonyl)-
2,4-difluoro-phenyl]-amide (P-0006),
4-Butoxy-N-[3-(5-chloro-l H-pyrrolo[2s3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- benzenesulfonamide (P-0007),
N-[3-(5-Chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-l -yl- benzenesulfonamide (P-0008),
Benzothiazole-6-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]-amide (P-0009), l-Methyl-3-trifluoromethyl-lII-pyrazole-4-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-bJpyridme-
3-carbonyl)-2,4-difluoro-phenyl]-amide (P-OOlO),
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy- benzenesulfonamide (P-OOI l),
Benzo[l ,2,5]thiadiazoe-5-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl] -amide (P-0013),
4-tcrt-Butyl-N-[3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- benzenesulfonamide (P-0014),
N-fS-CS-Chloro-lH-pyrroloP^-bjpyridine-S-carbony^^^-difluoro-phenylJ^-propyl- benzenesulfonamide (P-0015),
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy- benzenesulfonamide (P-OOl 6),
5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3~carbonyl)-
2,4-difluoro-phenyl]-amide (P-0017),
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(l -methyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-
3-carbonyl]-phenyl}-benzenesulfonamide (P-0020),
N-{2,4-Difluoro-3-[5-(l -methyl-l H-pyτazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonylJ- phenyl}-4-propyl-bcnzcncsulfonamide (P-0021),
N-{2,4-Difluoro-3-[5-(5-methyl-l H-iinidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl }-4-propyl-benzenesulfonamide (P-0023), and
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-lII-imidazol-2-yl)-lH-pyrrolo[2,3- b]pyridine-3-carbonyl]-phenyl} -benzenesulfonamide (P-0024),
5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl] -amide (P-0028),
1 -Methyl- lH-pyrazole-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0029),
N-[2,4-Difluoro-3-(5-methyl-lH-pyπ"olo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl- benzenesulfonamide (P-0030),
N-[3-(5-Cyano-lH-pyπOlo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl- benzenesulfonamide (P-0031),
(E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lII-pyrτolo[2,3- b]pyridin-5-yl} -acrylic acid methyl ester (P-0032), and
Pyridine -2 -sulfonic acid [2)4-difluoro-3-(5-methoxy-lH-pyrrolo[2,3-b]pyridinc-3-carbonyl)- phenylj-amide (P-0036).
The following table indicates the azaindole used in step 3 (column 2) and the sulfonyl chloride used in step 6 (column 3) to afford the target compound (column 4). The compound number is provided in column 1, with the observed mass given in column 5.
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Example 18: Synthesis of 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzeπesulfoπylamino)- benzoyl] -1 H-py rrolo [2,3-b] py ridin~5-yl}-N-ethyl-propionamide P-0035.
[0198] 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylammo)-benzoyl]-lH-pyrrolo[2,3- b]pyridm-5-yl}-N-ethyl-propionamide P-0035 was synthesized in three steps from (E)-3-{3-[2,6- Difluoro-3 -(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]- 1 H-pyrrolo [2,3-b]pyridin-5 -yl } - acrylic acid methyl ester P-0032 as shown in Scheme 15. Scheme 15
Figure imgf000089_0001
Step 1 -Preparation oj"3-{3~[2, 6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lH- pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester (P-0033):
[0199] To (E)-3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]4H- pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester (P-0032, 229 mg , 0.41 mmol, prepared as described in Example 17) was added methanol (15 mL) and tetrahydrofuran (5 mL), The solution was degassed with nitrogen for 5 minutes, followed by the addition of Pd/C (10% weight, 30 mg). The reaction mixture was allowed to stir under an atmosphere of hydrogen at room temperature for 18 hrs. After removing Pd/C and volatiles, the residue was purified through a quick silica plug clutcd with ethyl acetate. Solvent was removed to provide an off-white solid (P-0033, 222 mg, 96%). MS (ESI) [M+Hf] '=568.3.
Step 2 — Preparation of 3-{3-[2 ,6-difluoro-3-(4-trifluoromethyl~benzenesulfonylamino)-benzoyl] -1 H- pyrrolo[2,3-b]pyridin-5-yl}-prυpionic acid (P-0034):
[0003] To 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lH-pyrrolo[2,3- b]pyridin-5-yl} -propionic acid methyl ester (P-0033, 215 mg, 0.38 mmol) dissolved in tetrahydrofuran (30 mL) was added 1 N lithium hydroxide solution (15 mL). The mixture was heated at 50 0C for 2 hrs, then acidified to pH~l-2 with 6 N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to provide an off-white solid (P-0034, 202 mg, 96%). MS (ESI) [M+H4]+=554.0.
Step 3 - Preparation of 3-{3-[2,6-difluoro-3-(4-trifluoromcjthyl-benzenesulfυnylamino)-benzoyl] -1 H- pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide (P-0035):
[0200] To 3-{3-[2,6-difluoro-3-(4-tπfluoromethyl-benzenesulfonylamino)-benzoyl]-lH- pyrrolo[2,3-b]pyridm-5-yl} -propionic acid (P-0034, 42 mg, 0.076 mmol) dissolved in tetrahydrofuran (3 mL) was added a 2.0 M solution of ethylamine in tetrahydrofuran (1 10 μL, 0.23 mmol) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol), The reaction mixture was stirred at room temperature for 16 hrs, then extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (methanol/dichloromethane), with the cluting solvents removed via lyophilizing to provide a white fluffy solid (P-0035, 13 mg, 30%). MS (ESI) [KMTf= 581.0,
Example 19: Kinase Activity Assays
[0201] Assays for the activity of kinases, including, but not limited to, B-Raf, B-Raf V600E, B-Raf V600E/T529I and c-Raf-1 are known in the art, for example as described in US Patent Application Serial number 1 1/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety.
[0202] Representative compounds screened by at least one of the methods described in US Patent Application Serial number 1 1/473,347, or by similar methods, having IC50 of less than 10 μM under the test conditions employed are shown in tables Ia (B-Raf), Ib (B-Raf V600E), Ic (B-Raf V600E/T529I), I d (Btk), I e (c-Raf-1 ), If (FItI), Ig (Fms), Ih (Jnkl), Ii (Kdr), Ij (Kit), Ik (Src). 11 (TEC), Im (p38), and I n (HGK).
Table Ia. Representative compounds with activity toward kinase B-Raf with IC50 ≤ 10 μM under the test conditions employed.
B-Raf P-0001 , P-0002, P-0003, P-0005 P-0006, P-0007, P-0009, P-001 1, P-OO 13, P-OO 14,
P-0015, P-0016, P-OO 17, P-0018 P-OO 19, P-0020, P-0021 , P-0022, P-0023, P-0024,
P-0025, P-0026, P-0027, P-0028, P-0030, P-0031, P-0032, P-0033, P-0034, P-0035,
P-0036
Table Ib. Representative compounds with activity toward kinase B-Raf V600E with IC50 < 10 μM under the test conditions employed.
B-Raf P-0001 , P-0002, P-0003, P-0005, P-0006, P-0007, P-0009, P-OO 13, P-OO 14, P-OO 15,
V600E P-0016, P-OO 17, P-OO 19, P-0020, P-0021 , P-0022, P-0023, P-0024, P-0025, P-0028,
P-0029, P-0030, P-0031, P-0032, P-0033, P-0034, P-0035
Table Ic. Representative compounds with activity toward kinase B-Raf V600E/T529I with IC50 < 10 μM under the test conditions employed.
Figure imgf000090_0001
Table 1 d. Representative compounds with activity toward kinase Btk with IC505 10 μM under the test conditions employed.
Figure imgf000090_0002
Table Ie. Representative compounds with activity toward kinase c-Raf-1 with IC,P < 10 μM under the test conditions employed. c-Raf-1 : P-OOOl , P-0002, P-0003, P-0005, P-0006, P-0007, P-0008, P-0009, P-001 1 , P-0013,
P-OO 14, P-0015. P-0016, P-OO 17, P-0018, P-0019, P-0020, P-0021 , P-0022, P-0023,
P-0025, P-0030, P-0031
Table 1 f . Representative compounds with activity toward kinase Fit 1 with IC50 < 10 μM under the test conditions employed.
FhT : P-OO 16, P-0020, P-0025, P-0026, P-0031
Table Ig. Representative compounds with activity toward kinase Fms with iC\o ≤ 10 μM under the test conditions employed.
Fms: P-0001, P-0002, P-0003, P-0005, P-0006, P-0009, P-0010, P-001 1, P-0013, P-OO 14, P-0015, P-0016, P-0020, P-0021 , P-0022, P-0023, P-0024, P-0027, P-0028, P-0035
Table Ih Representative compounds with activity toward kinase Jnkl with ICso l 10 μM under the test conditions employed.
[ Jnkl : P-OO 19, P-0020, P-0025
Table 1 i. Representative compounds with activity toward kinase Kdr with 1CSO 5 10 μM under the test conditions employed.
Kdr: P-0001, P-0002, P-0003, P-0004, P-0005, P-0008, P-0010, P-001 1 , P-0013, P-OO 14,
P-OO 16, P-OO 18, P-0019, P-0020, P-0021 , P-0022 P-0023, P-0024, P-0025, P-0026,
P-0027, P-0028, P-0029, P-0032, P-0034
Table Ij. Representative compounds with activity toward kinase Kit with IC50 < 10 μM under the test conditions employed.
Kit: P-0001, P-0002, P-0003, P-0005, P-0006, P-0007, P-0008, P-0009, P-0010, P-0011, P-0013, P-OO 14, P-0015, P-0016, P-OO 17, P-0018, P-0019, P-0020, P-0021 , P-0022, P-0023, P-0024, P-0025, P-0026, P-0027, P-0028, P-0029, P-0032, P-0035
Table Ik. Representative compounds with activity toward kinase Src with IC50 < 10 μM under the test conditions employed.
Src: P-0002, P-0003, P-0004, P-0005, P-0006, P-0008, P-0009, P-0010, P-0011, P-0013,
P-0015, P-OO 16, P-OO 17, P-0018, P-0019, P-0020, P-0021 , P-0022, P-0023, P-0024,
P-0025, P-0026, P-0028, P-0029, P-0031, P-0036
Table 11. Representative compounds with activity toward kinase TEC with IC50 £ 10 μM under the test conditions employed.
TEC: P-0016 Table Im. Representative compounds with activity toward kinase p38 with ICso < 10 μM under the test conditions employed.
P38: P-0020, P-0028, P-0029
Table In. Representative compounds with activity toward kinase HGK with IC50 < 10 μM under the test conditions employed.
HGK: P-0020
Example 19: Efficacy of Compounds in Combination with Standard-of-Care Chemotherapeutic agents in four human cancer cell lines.
[0203] Compounds of the invention, such as compounds of Formula I, Formula II, or Formula III, in combination with a standard chemotherapeutic agent, such as 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, lemozolomide, or vinblastine, can be assessed for their effectiveness in killing human tumor cells. Human tumor cell lines, such as A-375 (malignant melanoma), SK-MEL-2 (malignant melanoma, skin metastasis), COLO 205 (colorectal adenocarcinoma, ascites metastasis) or SW-620 (colorectal adenocarcinoma, lymph node metastasis) can be treated with a compound of Formula I, Formula II, or Formula III alone, or in combination with one of the above-mentioned chemotherapeutic agents.
[0204] Tumor cells are grown as a monolayer at 37 0C in a humidified atmosphere (5% CO2, 95% air). Cells are grown in a suitable culture medium, e.g. RPMI 1640 (Ref BE12-702F, Cambrex, Venders, Belgium) containing 2 mM L-glutamine and supplemented with 10% fetal bovine serum (Ref DEl 4-80 IE, Cambrex). For experimental use, the tumor cells are detached from the culture flask by a 5-minute treatment with trypsin-versene (Ref 02-007E, Cambrex), diluted in Hanks' medium without calcium or magnesium (Ref BE10-543F, Cambrex). Trypsin treatment is neutralized by culture medium addition. The cells are counted in a hemocytometer and their viability assessed by 0.25% trypan blue exclusion.
The cell lines arc checked for mycoplasma contamination with the Mycotect assay kit (Ref 15672-017, Invitrogen, Cergy-Pontoise, France) in accordance with the manufacturer's instructions. The mycoplasma test is assayed from the culture supematants of the cell lines and compared to negative and positive controls.
[0205] The tumor cells (10,000 per well) are plated in 96-well flat-bottom microtitration plates (Ref 055260, Nunc, Dutscher, Brumath, France) and incubated at 37 0C for 24 hours before treatment in 100 μl of drug-free culture medium supplemented with 10% FBS. In order to assess the IC50 of each compound to be used for each cell line, the tumor cells are incubated in a 200 μl final volume of RPMI 1640 supplemented with 10% FBS and containing either a compound of Formula I, Formula II, or Formula III, or one of 5-fluorouracil, carboplatm, dacarbazine, gefitimb, oxahplatin, paclitaxel, SN-38, temozolomide, or vinblastine The compounds are tested in a suitable concentration range, such as 10 8 to 10 ^ M for a compound of Formula I. Formula II. or Formula III, 5-fluorouracil dacarbazine or gefitimb, 109 to 104 M for carboplatm oxahplatin, or temozolomide, 10 " to 10 6 M for paclitaxel or SN-38, and 10 15 to 10 10 M for vinblastine Compounds of Formula I, Formula IT, or Formula III are dissolved in DMSO and diluted with culture medium to the desired concentrations 5- fluorouracil (50 mg/ml, Dakota Phaπn, LePlessis Robmson, Irance), carboplatm (10 mg ml, Aguettant, Lyon, France), and paclitaxel (6 mg'ml, Bristol-Myers Squibb SpA, Rueil Malmaison, France), are diluted with culture medium to the desired concentrations Dacarbazine (Sigma, Samt Quentm Fallavier, France) and vinblastine (Lilly France S A , Saint Cloud, France) are dissolved m NaCl 0 9% and diluted with culture medium to the desired concentrations Gefitimb is dissolved in a mixed solution of RPMI 1640 and DMSO and diluted with culture medium to the desired concentrations (maximum final DMSO of 0 1% v/v) SN-38 (LKT Laboratories, Inc , St Paul, Minnesota) is dissolved in DMSO and diluted with culture medium to the desired concentrations (maximum final DMSO of 0 1% v/v) l emozolomide (LKT Laboratories, Inc , St Paul, Minnesota) is dissolved in water for injection and diluted with culture medium to the desired concentrations Cells are incubated for 96 hours in the presence of test substances at 37 0C under 5% CO2 At the end of treatments, the cytotoxic activity is evaluated by an M IT assay
[0206] For the MTT assay, at the end of the cells treatment, 20 μl of a 5 mg/ml solution 0 22 μm filtered tctrazohum reagent (MTT, Ref M2128, Sigma) m Phosphate Buffered Saline (PBS, Ref BE17-517Q, Cambrex), is added in each well Culture plates are incubated for 2 h at 37 0C The resulting supernatant is removed and formazan crystals dissolved with 200 μl of DMSO per well Absorbency (OD) is measured at 570 nm in each well using VICTOR1'*1 1420 multilabeled counter (Wallac, PcrkinElmer, Courtaboeuf, France)
[0207] The IC50 for each compound on each cell line is determined from the OD measurements of each sample The dose response inhibition ot cell proliferation is expressed as
IC = (OD of drug exposed cells / OD of drug free wells) x 100
The mean of multiple measurements for each concentration is plotted vs the drug concentration The dose-response curves arc plotted using XLFit 3 (IDBS, United Kingdom) The IC50 (drag concentration to obtain 50% inhibition of cell proliferation) determination values are calculated using the XLF it 3 from semi-log curves The IC50 value determined for each compound in each cell line is used to determine the concentration of a compound of Formula I, Formula II, or Formula III, and of the standard chemotherapeutic to be used m combination
[0208] The cells are treated with a combination of five concentrations of a compound of Formula I, Formula II, or Formula III and five concentrations of one of 5-fiuorouracil, carboplatm dacarbazme, gefitimb, oxahplatin, paclitaxel, SN-38, temozolomide, or vinblastine based on the IC5O results The compounds and cells are treated per the 1C50 determination described above and assayed by the MTT assay
[0209] The results are assessed to determine whether the combination is synergistic or antagonistic The compound interactions are calculated by multiple drug effect analysis and arc performed by the median equation principle according to the methodology described by Chou and Talalay (Adv Enzyme Regul 1984, 22 27-55)
[0210] The combination index (CI) w ill be calculated by the Chou et al equation (Adv Enzyme Regul 1984, 22 27-55 , Encyclopaedia of human biology, Academic Press, 1991, 2 371 -9, Synergism and Antagonism in Chemotherapy, Academic Press, 1991 , 61-102) which takes into account both the potency (Dm or ICj0) and the shape of the dose-effect curve (the m value) The general equation for the CI of the two compounds is given by
(D)1 _ (D)2 _ (D)1 (D)2
CI = - + + ■
(DJ1 (DJ1 (DMDJ2 where
(Dx)1 and (Dx)2 in the denominators are the doses (or concentrations) for compound 1 and compound 2 alone which demonstrate x% of inhibition, whereas (D)1 and (D)? m the numerators are doses of both compounds (1 and 2) in combination that also inhibit x% (i so-effective) CI<1, =1 , and >1 indicate synergism, additive effect and antagonism, respcctrv ely
[0211] The (Dx) i and (Dx)7 can be calculated from the median-effect equation of Chou et al (J Natl Cancer Inst 1994, 86 1517-24)
Figure imgf000095_0001
where
D1n is the median-effect dose that is obtained from the anti-log of x-intercept of the median-effect plot, x = log(D) versus y = log lΛ'O/J} , or Dn, = 10 b ιntei"pt) m, and m is the slope of the median-effect plot and /a is the fraction of cells affected by the treatment
Each CI w ill be calculated with CalcuSyn software (Biosoft, UK) from the mean affected fraction at each drug ratio concentration
[0212] Additional examples of certain methods contemplated by the present invention may be found m the following applications U S Patent Publ No 2006/058339, App Ser No 11 '154,287, U S Patent Publ No 2006/058340, App Ser No 1 1/154,988, U S Prov App No 60/682,076, filed May 17, 2005, U S Prov App No 60/682,058, filed May 17, 2005, U S Prov App No 60/682,063, filed May 17, 2005, U S Prov App No 60/682,051, filed May 17, 2005, U S Prov App No 60/682,042, filed May 17, 2005, U S Prov App No 60/692,750, filed June 22, 2005, and U S Prov App No 60/692,960, filed June 22, 2005, U S Prov App No 60/731,528, filed October 28, 2005, U S Patent App No 1 1 /435,381, filed May 16, 2006, and U S Patent App No 1 1/473,347, filed June 21, 2006, each of which are hereby incorporated by reference herein m their entireties including all specifications, figures, and tables, and for all purposes
[0213] AU patents and other references cited m the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference m its entirety individually
[0214] One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein The methods, variances, and compositions descπbed herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention Changes therein and other uses w ill occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims
[0215] It will be readily apparent to one skilled m the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention Por example, variations can be made to crystallization or co-crystallization conditions for Ret and Ret surrogate proteins and/or various kinase domain sequences can be used Thus, such additional embodiments are within the scope of the present invention and the following claims.
[0216] The invention illustrate ely descπbed herein suitably may be practiced in the absence of any clement or elements, limitation or limitations which is not specifically disclosed herein Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of may be replaced with either of the other two teπns Thus, for an embodiment of the invention using one of the terms, the invention also includes another embodiment wherein one of these terms is replaced with another of these terms, In each embodiment, the terms have their established meaning. Thus, for example, 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. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and vaπation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
(0217] In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group
|0218] Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention.
[0219] Thus, additional embodiments are within the scope of the invention and within the following claims

Claims

CLAIMSWhat is claimed is:
1. A compound having the chemical structure of Formula I,
Figure imgf000097_0001
all salts, prodrugs, tautomers and isomers thereof, wherein:
R1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2. -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)1NH2, -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR^C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, and -S(O)2R4:
R2 is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR3R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, and -S(O)2R4;
R is selected from the group consisting of hydrogen, fluoro and chloro;
R4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R4 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4. -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, or -S(O)1R4, optionally substituted lower alkynyl, provided, however, that when R4 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NRSS(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, or -S(O)2R4, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted hctcroaryl; and R5 is selected from the group consisting of hydrogen and optionally substituted lower alkyl,
provided, however, the compound is not
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000099_0001
2. The compound of Claim 1, wherein:
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)KR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, -OH, -NH2, C(O)OH, -C(O)NH2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R2 is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR3C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, -OR7, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R or as substituents of lower alkyi are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R' is selected from the group consisting oflower alkyl. cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R8 at each occurrence is independently hydrogen or lower alkyl; and R at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, 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, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
3. The compound of Claim 2, wherein:
R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
R2 is selected from the group consisting of -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted w ith one or more substituents selected from the group consisting of fluoro, lower alkox>, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO,, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino
4. The compound of Claim 3, wherein
R1 is hydrogen, -CN, -NR8R7, -OR7, -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclodlkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and
R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R", -OR7 or -S(O)2R7
5. The compound of Claim 4, wherein
R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2 6alkoxy, dryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected irom the group consisting of fluoro, chloro lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and
R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted low er alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylammo, di-alkylammo, or cycloalkylamino
6. The compound of Claim 1, wherein the compound is selected from the group consisting of
4-Butoxy-N-[3-(5-chloro-lH-pyrrolo[2,3-b]pyπdme-3-cdrbonyl)-2,4-difluoro-phenyl]- bcnzenesulfonamide,
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyπdine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-l -yl- benzenesulfonamide,
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyπdine-3-carbonyl)-2,4-difluoro-phcnyl]-4-isopropoxy- benzenesulfonamide,
4-tert-Butyl-N-[3-(5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- ben/enesulfonamide, N-[3-(5-Chloro-l H-pyrrolo[2,3-b]pyπdine-3-carboπyl)-2,4-difluoro-phenyl]-4-propyl- benzenesulfonamide,
N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-lH-pyrrolo[2,3-b]pyπdme-3-carbonyl]-phenyl}-4- lsopropyl-benzenesulfonamide,
N-{2,4-Difluoro-3-[5-(4-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl } -4-isopropyl-benzenesulfonamide,
4-Difluoromethoxy-N- {2,4-difluoro-3-[5-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-pyrrolo[2,3-b]pyπdmc-
3-carbonyl]-phenyl} -benzenesulfonamide,
N-{2,4-Difluoro-3-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]p>Tidine-3-carbonyl]- pheiry 1 j -4-propyl-benzenesulfonamide,
N-{2,4-Difluoro-3-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyrid3ne-3-carbonyl]- phenyl}-4-isopropyl-benzenesulfonamide,
N-{214-Difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbony]]- phenyl } -4-propyl-benzenesulfonamide,
N-{2,4-Difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-l H-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl) -4-tπfluoromethyl-benzenesulfonamide,
N-{2>4-Difluoro-3-[5-(l -methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyπdme-3-carbonyl]- phenyl ) -4 -propyl-benzenesu lfonamide,
N-{3-[5-(l,5-DimethyHH-imidazol-2-yl)-lH-ρyrrolo[2,3-b]pyπdme-3-carbonyl]-2,4-difluoro- phenyl} -4-propyl-benzenesulfonamide,
N-[2,4-Difluoro-3-(5-methyl-lH-pyrrolo[2,3-b]pyπdine-3-carboπy])-phenyl]-4-tπfluoromethyl- benzenesulfonamide,
N-[3-(5-Cyano-lH-pyrrolo[2,3-b]pyπdine-3-carbonyl)-2,4-difluoro-phenyl]-4-tπfluoromethyl- benzenesulfonamide,
(E)-3-{3-[2,6-Difluoro-3-(4-tnfluoromethyl-benzenesulfonylani]no)-ben7oyl]-l H-pyrrolo[2,3- b]pyπdm-5-yl} -acrylic acid methyl ester,
3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzeπesulfonylamino)-benzoyl]-lH-pyrrolo[2,3- b]pyπdm-5-yl} -propionic acid methyl ester,
3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzeπesulfonylamino)-benzoyl]-l H-pyrrolo[2,3- b]pyπdin-5-yl} -propionic acid,
3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzenesulfonylamino)-benzoyl]-lH-pyrrolo[2,3- b]pyridm-5-yl} -N-eth>l-propionamide; and all salts, piodrugs, tautomers, and isomers thereof
7. A compound having the chemical structure of Formula II,
Figure imgf000103_0001
all salts, prodrugs, tautomers and isomers thereof, wherein;
R1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH3, -NHS(O)2NH2, -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR3C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, and -S(O)2R4;
R2a is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, and -S(O)2R4;
R3 is selected from the group consisting of hydrogen, fluoro and chloro;
R4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R4 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R+, or -S(O)2R4, optionally substituted lower alkynyl, provided, however, that when R4 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH1, -NR5S(O)2NR5R4, -S(O)R4, or -S(O)2R4, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted hetcroaryl; and R5 is selected from the group consisting of hydrogen and optionally substituted lower alkyl,
Figure imgf000104_0001
8. The compound of Claim 7, wherein;
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH3, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR^S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR5C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR3S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, -OH, -NH2, C(O)OII, -C(O)NlI2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -Nil;, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R*, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R2a is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, -OR7, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2a or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH7, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, 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, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted low er alkoxy
9. The compound of Claim 8, wherein
R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR\ -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, hctcrocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono- dlkylammo, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylammo, and
R2a is selected from the group consisting of -CN, -OR7,
Figure imgf000106_0001
-NR8R7, -NR8C(O)R7, -NR8S(O)2R , -C(O)NR8R7, -C(O)R7, -S(O),NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono- alkylammo, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2a or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O),R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylammo
10, I he compound of Claim 9, wherein
R1 is hydrogen. -CN, -NR8R7, -OR7, -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and
R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR" or -S(O)2R7
11. The compound of Claim 10, wherein;
R is hydrogen, -CN, iluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2^aIkOXy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-aikylamino, di-alkylamino, and cycloalkylamino, and
R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
12. The compound of Claim 7, wherein the compound is selected from the group consisting of:
3-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-ρhenylsulfamoyl]-benzoic acid,
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy- benzenesulfonamide,
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-lH-pyrroIo[2,3- b]pyridine-3-carbonyl]~phenyl} -benzenesulfonamide; and all salts, prodrugs, tautomers, and isomers thereof.
13. Λ compound having the chemical structure of Formula III,
Figure imgf000107_0001
all salts, prodrugs, tautomers and isomers thereof, wherein:
R1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NII2, -NHS(O)2NH2, -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, and -S(O)2R4;
R} is selected from the group consisting of hydrogen, fluoro and chloro; R4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R4 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR3C(S)R4, -NR5S(O)1R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, or -S(O)2R4, optionally substituted lower alkynyl, provided, however, that when R4 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of -OR4, -SR4, -NR5R4, -C(O)R4, -C(S)R4, -C(O)OR4, -C(O)NR5R4, -C(S)NR5R4, -S(O)2NR5R4, -NR5C(O)R4, -NR5C(S)R4, -NR5S(O)2R4, -NR5C(O)NH2, -NR5C(O)NR5R4, -NR5C(S)NH2, -NR5C(S)NR5R4, -NR5S(O)2NH2, -NR5S(O)2NR5R4, -S(O)R4, or -S(O)2R4, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R5 is selected from the group consisting of hydrogen and optionally substituted lower alkyl; and R6 is optionally substituted heteroaryl, provided, however, the compound is not
Figure imgf000108_0001
Figure imgf000109_0001
14. The compound of Claim 13, wherein:
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH1, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, -OH, -NH2, C(O)OH, -C(O)NH2, -OR7, -NR8R1, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R", -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, -OR7, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R", -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; R' is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R8 at each occurrence is independently hydrogen or lower alkyl; and R at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, 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, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
15. The compound of Claim 14, wherein:
R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)1R9, -S(O)1R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 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, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylammo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH7, -CN, -NO2, -S(O)2NII1, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR^C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)7NR8R9, -C(O)R9, -C(O)NRV, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylammo
16. The compound of Claim 15, wherein
R1 is hydrogen, -CN, -NR8R7, -OR7, -S(O)7R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and
R6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7
17. The compound of Claim 16, whcrcm
R' IS hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2 6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy. mono-alkylamino, di-alkylamino, and cycloalkylammo, and
R6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl. fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di- alkylamino, or cycloalkylammo
18. The compound of Claim 13, wherein the compound is selected from the group consisting of
Benzo[b]thiophene-3-sulfomc acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyϊ] -amide,
5-Methyl-2-tπfluoromethyl-furan-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyπdine-3- carbonyl)-2,4-difluoro-phenyl]-amide,
S-Oxazol-S-yl-thiophene^-sulromc acid [3-(5-chloro-l H-pyrrolo[2,3-b]pyridme-3-carbonyl)-2,4- difluoro-phenyl]-amide,
2-Oxo-2H-chromene-6-sulfomc acid [3-(5-chloio-l H-pyrrolo[2,3-bJpyπdme-3-carbonyl)-2,4- difluoro-phenyl]-amide,
no S-Isoxazol-S-yl-thiophene^-sulfonic acid [3-(5-chloro-l H-pyrrolo[2,3-b]pyndine-3-carbonyl)- 2,4-difluoro-phenyl]-amide,
Bcnzothiazole-6-sulfoinc acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyπdine-3-carbonyl)-2,4-difluoro- phenyl] -amide, l-Methyl-34πfluoromethyl-lH-pyrazole-4-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyπdme-
3-carbonyl)-2,4-difluoro-phenyl]-amidc,
Benzo[l ,2,5]thiadiazoe-5-sulfomc acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyndine-3-carbonyl)-2,4- difluoro-phenyl] -amide,
5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-ch]oro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-
2 ,4-difluoro-phenyl] -amide ,
5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-lH-pyrτolo[2 3-b]pyridme-3-carbonyl)-2,4- difluoro-phenyl]-amide, l -Methyl-lH-pyrazole-3-sulfonic acid [3-(5-chJoro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl] -amide,
Pyndine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-lH-pyrrolo[2,3-b]pyπdme-3-carbonyl)- phenyl]-amide, and all salts, prodrugs, tautomers, and isomers thereof
19. A composition comprising a pharmaceutically acceptable carrier, and a compound according to any of Claims 1-18
20. A method for treating a subject suffering trom or at risk of an A-Raf-mediated, B-Raf- mediated and/or c-Raf-1 -mediated disease or condition, comprising administering to the subject an effective amount of a compound of any of Claims 1-18 or a composition of Claim 19
21. The method of Claim 20, wherein the compound or composition is approved for administration to a human
22. The method of Claim 21, wherein the disease or condition is selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Abheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, rcperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, \ascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity, Helicobacter pylori infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio- faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle
23. A kit comprising a compound according to any of Claims 1-18 or a composition according to Claim 19.
24. The kit of Claim 23, wherein the compound or composition is approved for a medical indication selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pam, inflammatory pain, acute pain, chronic pain, cancer- related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity, Helicobacter pylori infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle.
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