WO2008079906A1 - 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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WO2008079906A1
WO2008079906A1 PCT/US2007/088237 US2007088237W WO2008079906A1 WO 2008079906 A1 WO2008079906 A1 WO 2008079906A1 US 2007088237 W US2007088237 W US 2007088237W WO 2008079906 A1 WO2008079906 A1 WO 2008079906A1
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Prior art keywords
lower alkyl
fluoro
heteroaryl
group
aryl
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PCT/US2007/088237
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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.
Priority to BRPI0722088A priority Critical patent/BRPI0722088A2/en
Priority to CA002673000A priority patent/CA2673000A1/en
Priority to MX2009006162A priority patent/MX2009006162A/en
Priority to JP2009543200A priority patent/JP2010514687A/en
Priority to AU2007336906A priority patent/AU2007336906A1/en
Priority to EP07855276A priority patent/EP2097414A1/en
Publication of WO2008079906A1 publication Critical patent/WO2008079906A1/en
Priority to NO20092251A priority patent/NO20092251L/en
Priority to MA32103A priority patent/MA31153B1/en

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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 in 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 during 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 actmty-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 without limitation, acrocephalosyndactyly type I, acute myeloid leukemia, AIDS-mduced
  • Compounds are contemplated that are active on protein kinases in general, including, but not limited to, AbI, Aktl , Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4.
  • the compounds are active on protein kinases including A-Raf, B-Raf and/or c-Raf-1, including any mutations thereof
  • compounds are of Fo ⁇ nula I, Formula II, or Formula III, as
  • 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 1:
  • R 1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -Nil;, -CN, -NO 2 , -C(O)OH.
  • R' is selected from the group consisting of halogen, lower alkyl, 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 , -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 , -NR 8 C(O)R 7 , -NR 8 C(S)R 7 , -NR 8 C(
  • R 3 is selected from the group consisting of hydrogen, fluoro and chloro
  • 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-a Iky 1 amino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 7 or as substituents 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 NH 2 , -C(O)NH 2 , -OR 9 , -SR 9 , -NR 8 R 9
  • R ⁇ at each occurrence is independently hydrogen or lower alkyl ;
  • R 9 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 wherein 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, provided, however, the compound is not
  • R 1 is selected from the group consisting of hydrogen, -CN, -OR 7 , -SR 7 , -NR S 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
  • -NR 8 R -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.
  • 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 R " 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 NII 2 , -C(O)NH 2 , -OR", -SR 9 , -NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 S(O) 2 R 9 ,
  • R 1 is hydrogen, -CN, -NR 8 R', -OR 7 , -S(O) 2 R', 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 .
  • R 1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C 2 .
  • 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" 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:
  • R 2a is as defined for R 2 for Formula I; and R 1 and R' are as defined for Formula I, provided, however, the compound is not
  • R 1 is selected from the group consisting of hydrogen, -CN, -OR 7 . -SR 7 , -NR V, -NR 8 C(O)R 7 , -NR 8 S(O) 2 R 7 , -C(O)NR S 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 substitucnts selected froin the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalky
  • R 1 is hydrogen, -CN, -NR S 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 2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 8 R 7 , -OR 7 or -S(O) 2 R 7 .
  • R 1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted aryl or heteroaryl.
  • 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
  • R 2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
  • lhe compound is selected from the group consisting of:
  • compounds have the structure according to the following Formula III:
  • R 6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, 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 3 R 7 , -C(S)NR 8 R ⁇ , -S(O) 2 NR 8 R 7 , -NR 8
  • R , R , R , R , and R are as defined for Formula I, provided, however, the compound is not
  • 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 ' , -S(O) 2 NR ⁇ R 7 , -S(O)R 7 , -S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroary], wherein lower alkyl is optionally substituted with one or more substiluents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalky
  • R 6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of -CN, -OR 7 , -SR 7 , -NR 8 R 7 , -NR 8 C(O)R " , -NR 8 S(O) 2 R 7 , -C(O)NR 8 R', -C(O)R " , -
  • 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 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 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.
  • 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', -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 7 or -S(O) 2 R 7 .
  • R 1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy. lower alkoxy substituted C 2 ⁇ 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 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-alkylamino, di-alkylamino, or cycloalkylamino
  • 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 ring atom), O.
  • methods are provided for treating a protem kinase mediated disease or condition in an animal subject, wherein the method invokes 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 compounds 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 c , 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 prolein kinase mediated disease or condition includes a disease or condition for which modulation
  • 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 compound of any one or more of Formula I, Formula II, or Formula III
  • the invention provides methods for treating a Raf protem 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 "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, ancLor m which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease or condition
  • the Raf protein kinase includes, but is not limited to, A-Raf, mutations of A-Raf, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1
  • the Raf protein kinase is B
  • DLMR 329323 5 14 Atty Dkt No 039363-3550 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 risk of the disease or condition
  • the method imolves administering to the subject an effectn e amount of one or more compounds of Formula I, Formula II, or Formula III m combination with one or more other therapies for the disease or condition
  • 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 ⁇ -Raf, B-Raf or c-Raf-1 kinase, respectively, including any mutations thereof, affects the development
  • a compound of Formula I, Formula II, or Formula III is an inhibitor of a Raf kinase and has 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 Raf kinase activity assay
  • 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 A-Raf, B-Raf, c-Raf-1 , B-Raf V600F mutant, or B-Raf V600E/T5291 mutant
  • a compound of Formula I, Formula II, or Formula III will selectively inhibit one 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 V600F mutant is present m a high percentage of some cancers such as melanoma, and compounds of Formula I, Formula II, or Formula III 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 other kinases, whether a kinase discussed herein, or other kinases
  • the compound may selectively inhibit the effects of a mutation of the kinase relatrvc to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf
  • the compound ma> selectively inhibit Fms relative to Kit Selective inhibition of one kinase relative to another is such that the IC 50 for the one kinase may be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold,
  • DLMR 329323 5 Atty. Dkt. No. : 039363-3550 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 compounds of Formula 1, 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 Formula I, Formula II, and/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 synergistically effective in treating the cancer
  • 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 compounds 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 administering to the subject an effective amount of a composition including one or more compounds 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 administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III in combination with one or more other suitable therapies for treating the disease
  • the invention provides methods for treating a cancer mediated by B-Raf V600E mutant or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including one or more of Formula I, Formula II, or Formula III in combination with one or more suitable anticancer therapies, such as one or more chemotherapeutic drugs
  • the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III, in combination with one or more other therapies or medical procedures
  • DLMR 329323 5 Atty Dkt No 039363-3550 effective in treating the cancer
  • Other therapies or medical procedures include suitable anticancer therapy (e g drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e g surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant)
  • the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapcutic agent (e g chemotherapeutic drug), radiation treatment (e g x-ray, ⁇ -ray. or electron, proton neutron, or ⁇ particle beam), hyperthermia heating (e g microwave, ultrasound, radio frequency ablation).
  • a chemotherapcutic agent e g chemotherapeutic drug
  • radiation treatment e g x-ray, ⁇ -ray. or electron, proton neutron, or ⁇ particle beam
  • hyperthermia heating e g microwave, ultrasound, radio frequency ablation
  • Vaccine therapy e g AFP gene hepatocellular carcinoma ⁇ accme, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendntic cell peptide vaccines
  • gene therapy e g Ad5CMV-p53 ⁇ ector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha
  • photodynamic therapy c g aminolevulinic acid, motexafin lutetium
  • the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III, m combination with one or more suitable chemotherapeutic agents
  • the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamme, bizelesin, busulfan, carboplatm, carboquone, carmustinc, chlorambucil, cisplatm, cyclophosphamide, dacarbazine, estramustme, fotemustme, hepsulfam, ifosfamide, lmprosulfan, irofulven, lomustine, mechlorethamme, melphalan, oxaliplatm, piposulfan, semustme, streptozocm, temozolomide,
  • an alkylating agent including, but not
  • DLMR 329323 5 Atty Dkt No 039363-3550 including, but not limited to, erlotinib, gcfitimb, flavopindol, imatmib mesylate, lapatinib, soralenib, sunitinib malate, AEE-788, 4G-013736, AMG 706, AMN 107, BMS-354825, BMS-599626.
  • the method of treating a cancer involves administering to the subject an effective amount of a composition including one or more of Formula I, Formula II, or Formula III in combination with a chemotherapeutic agent selected from 5-fluorouracil, carboplatin, dacarbazine
  • the invention provides a method of treating or prophylaxis of a disease or condition m a mammal, by administering to the mammal a therapeutically effective amount of one or more compounds 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 compounds 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 described herein
  • the composition is packaged, e g , in a vial, bottle, flask, which may be further packaged, e g , within a box, envelope, or bag, the composition is approved by the U S Pood and Drug 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 written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e g , a human, for a protein kinase-mediated disease or condition, and the composition is packaged m unit dose or single dose form, e g , single dose pills, capsules, or the like
  • the disease or condition is, for example without limitation, neurologic diseases, including, but not limited to, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, and Huntington's disease, neoplastic diseases and associated
  • neurologic diseases including, but not limited to, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, and Huntington's disease, neoplastic diseases and associated
  • DLMR 329323 5 18 Atty Dkt No 039363-3550 complications including, but not limited to, chemotherapy-induced hypoxia, gastrointestinal stromal tumors (GISTs) prostate tumors, mast cell tumors (including canme mast cell tumors), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas (e g sarcomas of neuroectodermal origin, leiomyosarcoma), carcinomas (e g lung, breast, pancreatic, colon, hepatocellular, renal, temale genital tract, squamous cell, carcinoma m situ), lymphoma (e g histiocytic lymphoma, non-Hodgkin s lymphoma
  • the invention provides methods for treating an A-Raf-mediated.
  • B-Raf-mediated or c-Raf-1 -mediated disease or condition in an animal subject e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats
  • 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
  • a disease or condition characterized by abnormal A-Raf, B-Raf, and/or c-Raf-1 activity e.g. kinase activity.
  • Invention methods involve administering to the subject suffering from or at risk of an A-Raf-mediated, B-Raf- mediated, and/or c-Raf-1 -mediated disease or condition an effective amount of one or more compounds of Formula I, Formula II or Formula III.
  • the A-Raf-meditated, B- Raf-mediated, and/or C-Raf mediated disease is selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g.
  • lymphoma e.g. histiocytic lymphoma
  • neurofibromatosis acute myeloid leukemia, myelodysplasia syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma
  • pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine
  • cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
  • inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, COPD) and chronic respiratory distress syndrome (ARDS); genetic developmental diseases, including
  • 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 graus, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hypothyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Ma ⁇ e-Tooth disease, Dejermc- Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease,
  • one or more compounds of Formula I, Formula II, or Formula 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, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytom
  • neurologic diseases including, but not limited
  • Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body 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-Marie-Tooth disease, Dejerine- Sotlas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, my
  • the compounds of Formula I, Formula II, or Formula III with kinase activity IC 50 less than 10 ⁇ M as determined in a standard assay described herein can be used to treat the following exemplary protein kinase mediated diseases and conditions related to protein kinases A-Raf, B-Raf and/or c-Raf-1, including any mutations thereof; for example without limitation: modulation of A-Raf, which is related to 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.
  • 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
  • diseases associated with muscle regeneration or degeneration including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive
  • 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 angiogencsis, neuroendocrine tumors such as medullary thyroid cancel , carcinoid, small cell lung cancer and pheochromocytoma, pam of neuropathic or inflammatory origin, including, but not limited to, acute pam, chronic pain, cancer-related pam, and migraine, cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (c g thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury, inflammation including, but not limited to, pso ⁇ asis, arthritis and autoimmune diseases and conditions, osteoarthritis, endo
  • Halogen refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I)
  • '"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
  • substituted lower alkyl denotes lower alkyl that is independently substituted, 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.
  • 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, -NHR, -C(O)NHR, and the like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any -O-.
  • “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 alkcnyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
  • a "substituted lower alkenyl” denotes lower alkenyl that is independently substituted, with one or more, preferably 1 , 2. 3, 4 or 5,
  • DLMR 329323 5 Atty. Dkt No,: 039363-3550 also 1 , 2, or 3 substituents, 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.
  • 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 -, -O-, -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 1 -C(O)R, and the like
  • substitution of the moiety is such that any -C(O)-, -C(S)-, -S(O)-, -S(O)a-, -O-, -S-, or N thereof (except where N is a heteroaryl rmg atom) are not bound to an alkene 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, -NIIR, -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.
  • An “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, 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.
  • 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 aikyne carbon of the alkynyl substituent or R group.
  • alkynyi 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 substituent (except where N is a heteroaryl ring atom) being bound to the alkynyl carbon bound to any O, S, or N of the moiety.
  • alkynyl carbon refers to any carbon withm an alkynyl group, whether saturated or part of the carbon to carbon t ⁇ ple bond
  • An “alkyne carbon” refers to a carbon within an alkynyl group that is part ot a carbon to carbon t ⁇ ple bond
  • Cycloalkyl refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ⁇ ng systems ot 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 otherw ise, 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
  • 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 nng 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 K, such as sulfmyl, sulfonyl and N-oxide of a tertiary ⁇ ng nitrogen
  • Heterocycloalkyl is also intended to include compounds in which a ⁇ ng carbon may be oxo substituted, i e the ⁇ ng 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,
  • Aryl alone or in combination refers to a monocyclic or bicyclic ⁇ ng 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
  • 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
  • Heteroaryl alone or in combination refers to a monocyclic aromatic ⁇ ng structure containing 5 or 6 nng 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 sulfmyl, sulfonyl and N-oxidc of a tertiary ring nitrogen A carbon or nitrogen atom is the point of attachment of the heteroaryl ⁇ ng structure such that a stable compound is produced Examples of heteroaryl groups include, but are not limited to, py ⁇ dinyl, py ⁇ dazinyl, pyrazinyl, quinaoxalyl, mdohzinyl, benzo[b]thienyl, quinazohnyl, pu ⁇ nyl,
  • Nonrogen containing hetcroaryl refers to heteroaryl wherein any heteroatoms are N, 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
  • “Lower alkoxy” denotes the group -OR Z , where R z is lower alkyl.
  • ⁇ "substituted lower alkoxy " ' denotes lower alkoxy in which R z is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound.
  • substitution of lower alkoxy is with 1 ,
  • 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 hetcroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy O.
  • alkoxy is described as a substitucnt 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.
  • Lower alkylthio denotes the group -SR aa , where R aa is lower alkyl.
  • a "substituted lower alkylthio” denotes lower alkylthio in which R aa is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, including descriptions of substituted cycloalkyl, heterocycloalkyl, 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 atoms, also 1 , 2, or 3 fluoro atoms. While it is understood that substitutions on alkylthio arc 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.
  • 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 ring atom), or to an alkene or alkyne carbon of the other moiety.
  • Amino or "amine” denotes the group -NH 2 .
  • Mono-alkylamino denotes the group -NHR bb where R bb is lower alkyl.
  • Di-alkylamino denotes the group NR bb R cc , where R bb and R cc are
  • Cycloalkylammo denotes the group -NR dd R ee , where R dd and R ee combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocyclodlkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with lower alkyl.
  • Examples of 5-7 membered heterocycloalkyl include, but are not limited to, pipendme, piperazme, 4-methylpiperazme, morpholmc, and thiomorphohne While it is understood that when mono-alkylammo, di-alkylarmno, 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-alkylamino, or cycloalkylammo as substituents is not bound to a carbon atom that is bound to an O, S, or N of the other moiety.
  • composition refers to a formulation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient
  • pharmaceutically acceptable indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e g , for 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 equrvalently 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 weight 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 m the relevant art for a particular biological system or therapeutic use
  • the terms “greater affinity " and “selcch ⁇ e” indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, i e , with a lower dissociation constant
  • the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-iold greater affinity
  • the term "synthesizing ' and like terms means chemical synthesis from one or more precursor materials
  • enzymes can be assayed based on their ability to act upon a detectable substrate
  • a compound or 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 tor an inhibitor or activator, respectively, with respect to, for example, an enzyme
  • 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 A-Raf, B-Raf, c-Raf-1 , and and any mutants thereof, and the use of such compounds in the treatment of diseases or conditions
  • Protem kinases play key roles m propagating biochemical signals in erse biological pathways More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions (i e , indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease neurological disease, and other diseases As such, kinases represent important control points for small molecule therapeutic mten ention Descnption of specific target protein kinases contemplated by the present invention follow
  • A-Raf Target kinase B-Raf (i e , v-rat murine sarcoma 3611 viral oncogene homolog 1 ) is a 67 6 kDa se ⁇ ne/threonme kinase encoded by chromosome XpI 1 4-pl 1 2 (symbol ARAF)
  • the mature protein comprises RBD (i e , Ras binding domain) and phorbol-esterOAG-type zinc finger domain and is involved in the transduction of mitogenic signals from the cell membrane to the nucleus
  • A-Raf inhibitors ma> be useful m treating neurologic diseases such 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, ovarian), lymph
  • 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 spmal 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 endocnne abnormalities including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy
  • diseases of penpheral nerve including, but not limited to, Char
  • B-Raf Target kinase B-Raf (i e , v-raf murine sarcoma oncogene homolog Bl) is a S4 4 kDa se ⁇ ne 'threonine kinase encoded by chromosome 7q34 (symbol BRAF)
  • the mature protein comprises RBD (i e , Ras binding domain), Cl (i e , protein kinase C conserved region 1 ) and STK (i e , se ⁇ ne/threonine kinase) domains
  • Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal neurons
  • genes of the RAF family encode kinases that are regulated by Ras and mediate cellular
  • B-Raf kinase is a key component of the RAS->Raf->MEK- >ERK/MAP kinase signaling pathway, which plays a fundamental role in the regulation of cell growth, division and proliferation, and, when constitutively activated, causes tumo ⁇ genesis Among several isoforms of Raf kinase, the B-type, or B-Raf, is the strongest activator of the dow nstream MAP kinase signaling
  • the BRAF gene is frequently mutated in a ⁇ ancty of human tumors, especially in malignant melanoma and colon carcinoma
  • the most common reported mutation was a missense thymine (T) to adenine (A) transversion at nucleotide 1796 (T1796A, 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 ot 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" (Balak, et al
  • Niiho ⁇ et al report that in 43 individuals with cardio-facio-cutaneous (CFC) syndrome they identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders (Niiho ⁇ et al , Nat Genet 2006, 38(3) 294-6)
  • c-Raf-1 Target kinase c-Raf-1 (i e , v-raf murine sarcoma viral oncogene homolog 1 ) is a 73 0 kDa STK encoded by chromosome 3p25 (symbol RAFl )
  • c-Raf-1 can be targeted to to the mitochond ⁇ a 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 apoptosu>, and c-Raf-1 phosphorylates BAD (i c , BCL2 -binding protein)
  • c-Raf-1 is implicated in carcinomas, including colorectal, ova ⁇ an, lung and renal cell carcinoma
  • C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood.
  • C-Raf-1 inhibitors may also be useful for the treatment of acute myeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002, 8(25) 2243-8)
  • Raf-1 activators may be useful as treatment for neuroendoc ⁇ ne tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunmmalaiyaan et al , Anticancer Drugs 2006, 17(2) 139-42)
  • B-Raf and/or C-Raf-1 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, bi east, pancreatic, thyroid, renal, ovarian), lymphoma (e g histiocytic lymphoma)
  • 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, bi east, pancreatic, thyroid, renal, ovarian), lymphoma (e g histiocytic lymphoma)
  • Atty Dkt No 039363-3550 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 acute pain, chronic pam, cancer-related pain, and migraine, cardiovascular diseases including heart failuie, 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, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD), immunodeficienc> diseases, organ transplant rejection, graft versus host disease, renal or prostatic diseases including diabetic n
  • 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 ot other assays that can be utilized and can modify an assay ior a particular application
  • numerous papers concerning kinases describe assays that can be used
  • this sort ot assay can be formatted either in a fluorescence resonance energy transfer (PRIiI ) format, or using an AlphaScreen (amplified /uminescent proximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidm or the phosphor-specific antibody
  • PRIiI fluorescence resonance energy transfer
  • AlphaScreen amplified /uminescent proximity homogeneous assay
  • 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, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines.
  • a description of possible methods and routes of administration may be found, for example, in US Patent Application Serial number 11/473,347 (see also, PCT publication WO20G7002433), the disclosure of which is hereby incorporated by reference in its entirety.
  • solvents and reagents used or suggested are not limiting, and can be substituted appropriately with solvents and reagents known to those of skill in the art.
  • Reaction products may be isolated by means known in the art, such as extraction with a suitable solvent, precipitation from a suitable solvent, chromatography using a suitable solvent system, including silica gel column chromatography, HPLC, preparative TLC, and the like. Exemplary methods for synthesis of compounds of the present invention may be found in US Patent
  • an appropriate solvent e.g. methanol
  • 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.
  • a compound of Formula Xc in an appropriate solvent e.g. tetrahydrofuran
  • an oxidizing agent e.g.Dess-Martin periodane, TEMPO, DDQ
  • 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.
  • 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 -1 8 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 hexamethyltetramine 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 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
  • a protecting group e.g. triisopropylsilylchloride
  • a base e.g. sodium hydride
  • a solvent e.g. tetrahydrofuran
  • Compound of Formula Xh is synthesized by reacting a compound of Formula Xf m a solvent (e.g. tetrahydrofuran) with an organolithium reagent (e g. phenyl lithium) in a soh ent (e g tetrahydrofuran) under an inert atmosphere, cooled to -78 0 C.
  • a solvent e.g. tetrahydrofuran
  • organolithium reagent e g. phenyl lithium
  • soh ent e g tetrahydrofuran
  • 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. tetra-rx-buiyl ammonium fluoride) in an appropriate solvent (e.g. tetrahydrofuran).
  • P protecting group
  • solvent e.g. tetrahydrofuran
  • 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).
  • Step 1 Preparation of 5-(l -Methyl- 1 H-pyrazol-4-yi)-l H-pyrrolo[2 ,3-b] pyridine (46): [0095] 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).
  • Step 2 Preparation of pr ⁇ pane-2-sulfonic acid (2,4-diflnoro-3-formyl-phcnyl)-amide (49): [0098] To propanc-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).
  • Step 1 Preparation of(2,4-difluoro-phenyl)-carbamic acid benzyl ester (52): [0108] 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 KHSO 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 ⁇ f(2,4-difluoro-3-formyl- ⁇ henyl)-carbamic acid benzyl ester (53): [0109] Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52, 3.83 g, 14.5 mmol) in tetrahydrofuran (148 mL, 1.82 mol).
  • Step 3 Preparation of ⁇ 2,4-difluoro-3-[hydroxy-(lH-pyrrolo[2,3 ⁇ h]pyridin-3-yl)-methyl]-phenyl ⁇ - carbamic acid benzyl ester (54):
  • Step 4 Preparation of[2,4-difl ⁇ oro-3-(lH-pyrrolo[2,3-b]pyrid ⁇ ne-3-carbonyl)-phenyl]-carbam ⁇ c acid benzyl ester (55):
  • Step 5 Preparation of(3-Amino-2,6-difluoro-phenyl)-(5-chIoro-lH-pyrrolo[2,3-b]pyridin-3-yl) - methanone (56):
  • Example 8 Synthesis of 3- ⁇ 3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)- benzoyl]-lH-pyrrolo[2,3-b)pyridin-5-yl ⁇ -N-ethyl-propionamidc P-0035.
  • Step 2 Preparation of3- ⁇ 3-[2, 6-difluoro-3-(4 ⁇ trifluoromethyl-henzenesulfonylamino ⁇ -benzoyl]-lH- pyrrolo[2,3-b]pyridin-5-yl ⁇ -propionic acid (P-0034):
  • Step 3 Preparation of3- ⁇ 3-[2, 6-difluorn-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoylJ-lH- pyrr ⁇ lo[2,3-b]pyndin-5-yl ⁇ -N-ethyl ⁇ propionamide (P-0035):
  • 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 ICw ⁇ 10 ⁇ M under the test conditions employed.
  • Table I c Representative compounds with activity toward kinase B-Raf V600E/T529I with IC 50 1 10 ⁇ M under the test conditions employed.
  • Table 1 d Representative compounds with activity toward kinase c-Raf-1 with IC 50 ⁇ 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-OO 13 P-OOO 13
  • Example 10 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, temozolomide, or vinblastine, can be assessed for their effectiveness in killing human tumor cells.
  • a standard chemotherapeutic agent such as 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine
  • Human tumor cell lines such as A-375 (malignant melanoma), SK-MHL-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-MHL-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, Verviers, Belgium) containing 2 mM L-glutamine and supplemented with 10% fetal bovine serum (Ref DEl 4-801 E, Cambrex).
  • RPMI 1640 Ref BE12-702F, Cambrex, Verviers, Belgium
  • 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 are 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 supernatants 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 arc incubated in a 200 ⁇ l final ⁇ olume 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, dacarbazme, gefitinib, oxaliplatm, 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 TT, or Formula III, 5-fluorouracil, dacarbd
  • the mean of multiple measurements for each concentration is plotted vs the drug concentration 1 he dose-response curv es are plotted using XLFit 3 (IDBS, United Kingdom)
  • the ICso drug concentration to obtain 50% inhibition ot cell proliferation determination values are calculated using
  • DLMR 329323 5 Atty. Dkt. No.: 039363-3550 the XLFit 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 chetno therapeutic to be used in 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-fluorouracil, carboplatin. dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine, based on the IC 50 results.
  • the compounds and cells are treated per the IC50 determination described above and assayed by the MTT assay.
  • the combination index (CI) will 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 n , or IC 50 ) 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 x ) 1 and (DJ 2 i n the denominators are the doses (or concentrations) for compound 1 and compound 2 alone which demonstrate x% of inhibition, whereas (D)i and (D) 2 in the numerators are doses of both compounds (1 and 2) in combination that also inhibit x% (iso-effective).
  • the (D s )i and (D x ) 2 can be calculated from the median-effect equation of Chou et al, (J. Natl. Cancer Inst. 1994, 86: 1517-24):
  • D 1n is the median-effect dose that is obtained from the anti-log of x-intercept of the median-effect plot
  • any of the terms “comprising”, “'consisting essentially of and “consisting of may be replaced with either of the other two terms.
  • the invention also includes another embodiment wherein one of these terms is replaced with another of these terms.
  • the terms have their established meaning.
  • one embodiment may encompass a method “comprising” a series of steps, another embodiment would encompass a method “consisting essentially of the same steps, and a third embodiment would encompass a method "consisting of the same steps.

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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

Atty Dkt No 039363-3550
PYRROLO [2 , 3-B] PYRIDINE DERIVATIVES AS KINASE MODULATORS
RELATED PATENT APPLICATIONS
[0001] This application claims pnoπty to U S Prousional App No 60'876,95S, 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 U 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 understanding 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 herein by reference in its entirety
[0004] Receptor protein kinases regulate key signal transduction cascades that control or are involved in 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 during 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 actmty-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 without limitation, acrocephalosyndactyly type I, acute myeloid leukemia, AIDS-mduced
DLMR 329323 5 Atty. Dkt No 039363-3550 non-Hodgkin's lymphoma, Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, bacteπal infection, bladder cancer, cancer of the breast, cancer of the central nervous system, cancer of the colon, cancer oi 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, pam, Parkinson's disease, Pfeiffcr Syndrome, polycystic kidney disease, primary lymphoedema, prostate cancer, psoriasis, vascular restenosis, rheumatoid arthritis, dermal and tissue scarring, selective T-cell defect (S I D), severe combined immunodeficiency (SCID), small cell lung cancer, spinal cord injury, squamous cell carcinoma, systemic lupus erythematosa, testicular cancer, thrombotic microangiopathy syndromes, Wegener's granulomatosis, X-lmked agammaglobulinemia, viral infection, diabetic retinopathy, alopecia, erectile dysfunction, macular degeneration, chronic lymphocytic leukemia (CLL), myelodysplasia syndrome (MDS), neurofibromatosis, and tuberous sclerosis
[0006] I his 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, 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, HtI, rit3, Flt4, Fms Frk, Fyn, Gsk3α, Gsk3β, HCK, Hcr2/Erbb2 Her4/Erbb4, IGFlR, IKK beta, Irak4, Itk, Jakl , Jak2, Jak3, Jnkl, Jnk2, Jnk3, Kdr, Kit, Lck. Lyn, MΛP2K1 , MΛP2K2. MΛP4K4, MAPKAPK2, Met. Mnkl , MLKl , p38, PDGFRA, PDGFRB, PDPKl , Piml , Pim2, Pim3, PKC alpha, PKC beta, PKC theta, PIk 1 , Pyk2, Ret, ROCKl , ROCK2. Ron. Src. Stk6, Syk, TEC. Tie2, IrkA, TrkB, Yes, and'or Zap70, 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 Foπnula I, Formula II, or Formula III, as
2
DLMR 329323 5 Atty. Dkt. No.; 039363-3550 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 1:
Figure imgf000004_0001
Formula I all salts, prodrugs, tautomcrs and isomers thereof, wherein:
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -Nil;, -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 fluoro, -OH, -NH2, -C(O)OII, -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, -0Ry, -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 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,
DLMR 329323.5 Atty, Dkt. No.: 039363-3550
-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, -OR', -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, -NR15C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NRsRy, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R3 is selected from the group consisting of hydrogen, fluoro and chloro;
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-a Iky 1 amino, 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)2NR5R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
Rδ 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 wherein 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, provided, however, the compound is not
Figure imgf000005_0001
DLMR 329323 5 Atty. Dkt. No.: 039363-3550
Figure imgf000006_0001
[0010] In some embodiments of compounds of Formula I, R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NRSR7, -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
DLMR 329323.5 Atty. Dkt. No.: 039363-3550 heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selecled from the group consisting of -OIL -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, -SR'. -NR8R , -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, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R" 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)2NII2, -C(O)NH2, -OR", -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)XR9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
[0011] In some embodiments of compounds of Formula I, R1 is hydrogen, -CN, -NR8R', -OR7, -S(O)2R', 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.
[0012] 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 C2.6alkoxy, 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 cycloalkylamino, and R" is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
[0013] In one embodiment of compounds of Formula I, the compound is selected from the group consisting of:
4-Dutoxy-N-[3-(5-chloro-lH-pyrrolo[2,3-bJpyridine-3-carbonyl)-2,4-difluoro-phenyl]- benzenesulfonamide (P-0007),
N-p^S-Chloro-lH-pyrroloP.S-bJpyridine^-carbony^-Z^-difluoro-phcnylJ^-pyi'azol-l-yl- ben^enesulfonamide (P-0008), N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy-
DLMR 329323.5 Atty Dkt No 039363-3550 benzenesulfonamide (P-OOIl),
4-tert-But>l-N-[3-(5-chloro-lH-pyrrolo[2,3-b]pyridme-3-carbonyl)-2,4-dilluoro-phenyl]- benzenesulfonamide (P-0014),
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyπdme-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl- bcnzenesulfonamide (P-0015),
N- {2,4-Difluoro-3-[5-(2-metho\y-ethoxy)-lH-pyrrolo[2,3-b]pyridme-3-carbonyl]-phenyl} -4- lsopropyl-benzenesulfonamide (P-0018),
N- {2,4-Difluoro-3-f5-(4-methyl-lH-imidazol-2-yl)-] H-pynOlo[2,3-b]pyndme-3-carbonyl]-phen>l}-
4-isopropyl-ben7enesulfonamide (P-0019),
4-Difluoromethoxy-N- {2,4-difluoro-3-[5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyπdme-3- carbonylj-phenyl} -benzenesulfonamide (P-0020),
N-{2,4-Difluoro-3-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyπdme-3-carbonyl]-phcnyl}-4- propyl-bcnzenesulfonamide (P-0021),
M- {2,4-Difluoro-3-[5-(l-methyl-l H-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyτidme-3-carbonyl]-phenyl}-4- isopropyl-benzenesulfonamide (P-0022),
N-{2,4-Difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridme-3-carbon>l]-phenyl}-
4-propyl-benzenesulfonaniide (P-0023),
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 (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-Dimethyl-lH-imidazol-2->l)-lH-pyrrolo[2,3-b]pyridme-3-carbonyl]-2,4-difluoro- phenyl }-4-propyl-benzenesulfonamide (P-0027),
N-[2,4-Difluoro-3-(5-meth> l-lH-pyrrolo[2,3-b]ρyπdme-3-carbonyl)-phenyl]-4-tπfluoromethyl- benzenesulfonamide (P-0030),
N-[3-(5-Cyano-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-tnfluoromethyl- ben7enesulfondmide (P-0031),
(E)-3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzenesulfon>lammo)-ben7oyl]-lH-pyrrolo[2,3- b]pyπdin-5-yl} -acrylic acid methyl ester (P-0032),
3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzenesulfonyldmino)-benzo>'l]-lH-pyτrolo[2.3-b]pyridin-
5->l} -propionic aud methyl ester (P-0033),
3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-l H-pyrrolo[2,3-b]p3ridin-
5-yl}-propionic acid (P-0034),
3-{3-[2,6-Difluoro-3-(4-tπfluoromethyl-benzenesulfonylammo)-benzoyl]-lH-pyrrolo[2,3-b]pyπdm-
5-yl)--N-eth>l-propiondmide (P-0035) and all salts, prodrugs, tautomers, and isomers thereof
DLMR 329323 5 Atty. Dkt. No.: 039363-3550 [0014] In some embodiments, compounds have the structure according to the following Formula II:
Figure imgf000009_0001
Foπnula II all salts, prodrugs, tautomers and isomers thereof, wherein:
R2a is as defined for R2 for Formula I; and R1 and R' are as defined for Formula I, provided, however, the compound is not
Figure imgf000009_0002
DLMR 329323 S Atty. Dkt. No. : 039363-3550
[0015] In some embodiments of compounds of Formula II, R1 is selected from the group consisting of hydrogen, -CN, -OR7. -SR7, -NR V, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NRSR7, -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 substitucnts selected froin 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, -NRKC(0)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR5R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R2a 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 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 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)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.
[0016] In some embodiments of compounds of Formula II, R1 is hydrogen, -CN, -NRSR7, -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 R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7.
[0017] 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
Figure imgf000010_0001
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 R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
[0018] In one embodiment of compounds of Formula II, lhe compound is selected from the group consisting of:
3-[3-(5-Chloro-lH-p>τrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfaiτioyl]-benzoic acid (P-0004),
N-fS-fS-Chloro-lH-pyrroloP^-bJpvTidine-S-carbonylj^^-difluoro-phenylj^-difluoromethoxy- benzenesulfonamide (P-0016),
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-l H-imidazol-2-yl)- lH-pyrrolo[2,3-b]pyridine-3- carbonylj-phenyl} -benzenesulfonamide (P-0024) and all salts, prodrugs, tautomers, and isomers thereof.
[0019J In some embodiments, compounds have the structure according to the following Formula III:
Figure imgf000011_0001
Formula III all salts, prodrugs, tautomers and isomers thereof, wherein:
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)NR3R7, -C(S)NR8R^, -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)2R", wherein lower alky] is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OR7, -NR8R', 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, -NR^R", -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(0)2NRgRM, -C(O)R9, -C(O)NR8R9. halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
R , R , R , R , and R are as defined for Formula I, provided, however, the compound is not
Figure imgf000012_0001
10020] In some embodiments of compounds of Formula III, R1 is selected from the group consisting of hydrogen, -CN, -OR7. -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R', -S(O)2NR^R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroary], wherein lower alkyl is optionally substituted with one or more substiluents 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
11
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
-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)NRV, halogen, lower alky], 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)R", -NR8S(O)2R7, -C(O)NR8R', -C(O)R", -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 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)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
[0021] In some embodiments of compounds of Formula III, 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, -NR8R', -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.
[0022] In some embodiments of compounds of Formula III, R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy. lower alkoxy substituted C2^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 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 cycloalkylamino.
[0023] In one embodiment of compounds of Formula III, the compound is selected from the group consisting of;
Benzo[b]fhiophene-3-sulfonic acid P^S-chloro-lH-pyrroloPjS-bjpyridine-S-carbonyl^^-difluoro- phenyl]-amide (P-OOOl),
5-Methyl-2-trirluoromethyl-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),
DLMR 329323.5 12 Atty. Dkt. No.: 039363-3550
2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chIoro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0005),
S-Isoxazol-S-yl-thiophene^-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0006),
Benzothiazole-6-sulfonic acid [3-(5-chloro-lH-pyττolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phcnyl]-amide (P-0009),
1 -Methyl-3-tπfluoromethyl-I H-pyrazole-4-sulfonic acid [3-(5-chloro-l II-pyrrolo[2,3-b]pyridine-3- carbonyl)-2,4-difluoro-phenylJ-amide (P-OOlO),
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),
5-Methyl-benzo[b]thiophene -2 -sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyI)-2,4- difluoro-phenyl]-amide (P-OO 17),
5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-lH-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]pyridme-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0029),
Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-pbenyl]- amide (P-0036) and all salts, prodrugs, tautomers, and isomers thereof.
[0024] 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 ring atom), O. or S, except where the carbon forms a double bond with one of the heteroatoms, such as in an amide, carboxylic acid, and the like; 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-CH2-NR-. -NR-CH2-O-, -0-CH2-O-, -S-CH2-O-, -NR-CH2-S-, -0-CII2-S-, -S-CH2-S-. -NR-CH=CH-, -CH=CH-NR-, -NR-C ≡C-, -C =C-NR-, -0-CH=CH-, -CH=CH-O-, -OC sC-, -C -C-O-, -S(OV2-CH=CH-, -CH=CH-S(OV2-, -S(O)0 2-C =C-, -C -C-S(O)0-2-, -C(O)-CH=CH-, -CH=CH-C(O)-, -C ≡C-C(O)-, or -C(O)-C ≡C-, -C(S)-CH=CH-, -CH=CH-C(S)-, -C ≡C-C(S)-, or -C(S)-C ≡C-.
(0025] 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 I, Formula II, or Formula III described herein, it is understood that a
DLMR 329323.5 Atty Dkt No . 039363-3550 compound of Formula I includes all sub-embodiments thereof, a compound of Formula II includes all sub-embodiments thereof, and a compound of Pormula III includes all sub-embodiments thereof unless indicated otherwise
[0026] In one aspect, methods are provided for treating a protem kinase mediated disease or condition in an animal subject, wherein the method invokes 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 compounds 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 c , 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 prolein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit, e g wherein treatment with protem kinase inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition In one aspect, the method involves administering to the subject an effective amount of one or more compounds of Formula 1, formula II, or Foπnula III in combination with one or more other therapies for the disease or condition
[0027] 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 a compound of any one or more of Formula I, Formula II, or Formula III
[0028] In one aspect, the invention provides methods for treating a Raf protem 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 "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, ancLor m which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease or condition The Raf protein kinase includes, but is not limited to, A-Raf, mutations of A-Raf, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1 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
DLMR 329323 5 14 Atty Dkt No 039363-3550 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 risk of the disease or condition In one aspect, the method imolves administering to the subject an effectn e amount of one or more compounds of Formula I, Formula II, or Formula III m 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 Λ-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
[0029] In some embodiments, a compound of Formula I, Formula II, or Formula III is an inhibitor of a Raf kinase and has 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 Raf kinase activity assay 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 A-Raf, B-Raf, c-Raf-1 , B-Raf V600F mutant, or B-Raf V600E/T5291 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 the effects of a mutation or the Raf kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf
[0030] 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 V600F mutant is present m a high percentage of some cancers such as melanoma, and compounds of Formula I, Formula II, or Formula III will inhibit the kinase activity of this mutant
[0031] 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 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 relatrvc to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf In some embodiments, the compound ma> 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,
DLMR 329323 5 Atty. Dkt. No. : 039363-3550 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.
[0032] In another aspect, compositions are provided that include a therapeutically effective amount of one or more compounds of Formula 1, 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 Formula I, Formula II, and/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
[0033] 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 compounds of Formula I, Formula II, or Formula III
[0034] 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 administering to the subject an effective amount of a composition including one or more compounds 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 V600E mutant, or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III in 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 of Formula I, Formula II, or Formula III in combination with one or more suitable anticancer therapies, such as one or more chemotherapeutic drugs
[0035] In one aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III, in combination with one or more other therapies or medical procedures
DLMR 329323 5 Atty Dkt No 039363-3550 effective in treating the cancer Other therapies or medical procedures include suitable anticancer therapy (e g drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e g surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant) In one aspect, the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapcutic agent (e g chemotherapeutic drug), radiation treatment (e g x-ray, γ-ray. or electron, proton neutron, or α particle beam), hyperthermia heating (e g microwave, ultrasound, radio frequency ablation). Vaccine therapy (e g AFP gene hepatocellular carcinoma \accme, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendntic cell peptide vaccines), gene therapy (e g Ad5CMV-p53 \ector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (c g aminolevulinic acid, motexafin lutetium), surgery, and bone marrow and stem cell transplantation
[0036] 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 compounds of Formula I, Formula II, or Formula III, m 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, adozelesin, altretamme, bizelesin, busulfan, carboplatm, carboquone, carmustinc, chlorambucil, cisplatm, cyclophosphamide, dacarbazine, estramustme, fotemustme, hepsulfam, ifosfamide, lmprosulfan, irofulven, lomustine, mechlorethamme, melphalan, oxaliplatm, piposulfan, semustme, streptozocm, temozolomide, thiotepa, and treosulfan, an antibiotic, including, but not limited to, bleomycin, dactmomycm, daunorubicm, doxorubicin, epirubicin, idarubicin, menogaπl, mitomycin, mitoxantrone, neocarzmostatm, pentostatm, and phcamycm, an antimetabolite, including, but not limited to, azacitidme, capecitabme, cladπbme, clofarabine, cytarabine, decitabme, floxuπdme, fludarabine, 5-fluorouracil, ftorafur, gemcitabme, hydroxyurea, mercaptopuπne, methotrexate, nelarabme, pemetrexed, raltitrexed, thioguanme, and tπmetrexate, an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab, gahximab, gemtuzumab, panitumumab, pertuzumab, πtuximab, tositumomab, trastuzumab, and 90 Y ibntumomab tiuxetan a hormone or hormone antagonist, including, but not limited to, anastrozole, androgens, buserelm, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelm, idoxifene, letrozole, leuprohde, magestrol, raloxifene, tamoxifen, and toremifene, a taxane, including, but not limited to, DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; a retinoid, including, but not limited to, ahtrerinom bexarotene, fenretimde, isotretinoin, and tretinoin, an alkaloid, including, but not limited to, ctoposide, homoharπngtoninc, tcniposide, vinblastine, vincristine, vmdesme, and vmorelbme, an antiangiogemc agent including, but not limited to, AE-941 (GW 786034, Neovastat), ABT-510, 2-methoxyestradiol, lenahdomide, and thalidomide, a topoisomerase inhibitor, including, but not limited to, amsacπne, edotecann, exatecan, innotecan (also active metabolite SN-38 (7-ethyl- 10-hydroxy-camptothecm)), rubitecan, topotecan, and 9-ammocamptothecin, a kinase mhibitoi,
DLMR 329323 5 Atty Dkt No 039363-3550 including, but not limited to, erlotinib, gcfitimb, flavopindol, imatmib mesylate, lapatinib, soralenib, sunitinib malate, AEE-788, 4G-013736, AMG 706, AMN 107, BMS-354825, BMS-599626. UCN-Ol
Figure imgf000019_0001
and vatalanib, a targeted signal transduction inhibitor including, but not limited to bortezomib, geldanamycin, and rapam>cin, a biological response modifier, including, but not limited to, lmiquimod, mterfcron-α and interleukin-2, and other chemotherapeutics, including, but not limited to 3 -AP (3-armno-2-carboxyaldehyde thiosemicarbazone), ammoglutethimide, asparaginase, brvostatm-1, cilengitide, E7389, lxabepilone, procarbazine sulindac, temsirohmus, tipifarnib Preferably, the method of treating a cancer involves administering to the subject an effective amount of a composition including one or more of Formula I, Formula II, or Formula III in combination with a chemotherapeutic agent selected from 5-fluorouracil, carboplatin, dacarbazine, gefitimb, oxahplatm, paclitaxel, SIs -38, temozolomide, vinblastine, bevacizumab, cetuximab, or erlotinib
[0037] In another aspect, the invention provides a method of treating or prophylaxis of a disease or condition m a mammal, by administering to the mammal a therapeutically effective amount of one or more compounds 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 compounds 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
[0038] In a related aspect the invention provides kits that include a composition as described 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 Pood and Drug 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 written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e g , a human, for a protein kinase-mediated disease or condition, and the composition is packaged m unit dose or single dose form, e g , single dose pills, capsules, or the like
[0039] In aspects involving treatment or prophylaxis of a disease or condition with one or more compounds of Formula I, Formula II, or Formula III, the disease or condition is, for example without limitation, neurologic diseases, including, but not limited to, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, and Huntington's disease, neoplastic diseases and associated
DLMR 329323 5 18 Atty Dkt No 039363-3550 complications, including, but not limited to, chemotherapy-induced hypoxia, gastrointestinal stromal tumors (GISTs) prostate tumors, mast cell tumors (including canme mast cell tumors), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas (e g sarcomas of neuroectodermal origin, leiomyosarcoma), carcinomas (e g lung, breast, pancreatic, colon, hepatocellular, renal, temale genital tract, squamous cell, carcinoma m situ), lymphoma (e g histiocytic lymphoma, non-Hodgkin s lymphoma), MhN2 syndromes, neurofibromatosis (including Schwann cell neoplasia), myelodysplastic syndrome leukemia, tumor angiogenesis, cancers of the thyroid, liver, bone, skin, brain, central nenous 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, pam of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, bone 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, 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 erythematosis, Sjogren's Syndrome, Wegener's granulomatosis, 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 nephntis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complications, and hypertrophy, metabolic diseases, including, but not limited to, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, hpolvsis and 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), 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 I Pfeiffer's syndrome, Jackson- Weiss syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), I FOPARD 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 πsk of fracture, Paget's disease, hypercalcemia, and metastatis of cancer to
DLMR 329323 5 Atty. Dkt. No.: 039363-3550 bone; Grave's disease; Hirschsprung's disease; lymphedema; selective T-cell defect (STD); X-linked agammaglobulinemia; diabetic retinopathy: alopecia; erectile dysfunction; and tuberous sclerosis.
J0040] In aspects involving treatment or prophylaxis of a disease or condition with one or more compounds of Formula I, Formula II, or Formula III, the invention provides methods for treating an A-Raf-mediated. B-Raf-mediated or c-Raf-1 -mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, 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 risk of an A-Raf-mediated, B-Raf- mediated, and/or c-Raf-1 -mediated disease or condition an effective amount of one or more compounds of Formula I, Formula II or Formula III. In one embodiment, the A-Raf-meditated, B- Raf-mediated, and/or C-Raf mediated disease is selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplasia syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. 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, Nooaan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, eardiø-facϊocutaneøus 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, sarcopenia, muscular dystrophies (including, but not limited to, Duclienne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular
DLMR 329323.5 20 Atty Dkt. No 039363-3550
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 graus, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hypothyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Maπe-Tooth disease, Dejermc- Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemahne myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of 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, phosphoglyceratc mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency)
[0041] In a related aspect, one or more compounds of Formula I, Formula II, or Formula 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, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma, pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine, cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e g 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 obesitj, infection, including, but not limited to, Helicobacter pvlon 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,
21
DLMR 329323 5 Atty. Dkt. No.; 039363-3550 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, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne., Becker, Emery-Dreifuss, Limb-Girdle. Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body 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-Marie-Tooth disease, Dejerine- Sotlas 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, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palrαatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and tnyoadenylate deaminase deficiency).
[0042 J The compounds of Formula I, Formula II, or Formula III with kinase activity IC50 less than 10 μM as determined in a standard assay described herein can be used to treat the following exemplary protein kinase mediated diseases and conditions related to protein kinases A-Raf, B-Raf and/or c-Raf-1, including any mutations thereof; for example without limitation: modulation of A-Raf, which is related to 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, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive
22
DLMR 329323.5 Atty Dkt. No 039363-3550 spinal muscular atrophy, intermediate spmal muscular atrophy, juvenile spinal muscular atrophj, spinal bulbar muscular atrophy, and adult spmal muscular atrophy), inflammatory myopathies (including, but not hrmted 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, nemalme myopathy, myotubular myopathy, and peπodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial m>opathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency), modulation of B-Raf and/or c-Raf- 1 , which is related to neurologic diseases, including, but not limited to, multi-mfarct 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 angiogencsis, neuroendocrine tumors such as medullary thyroid cancel , carcinoid, small cell lung cancer and pheochromocytoma, pam of neuropathic or inflammatory origin, including, but not limited to, acute pam, chronic pain, cancer-related pam, and migraine, cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (c g thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury, inflammation including, but not limited to, psoπasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scaπmg, 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, Helicobac ter 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
DLMR 3293235 Atty. Dkt. No : 039363-3550 syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases,
[0043] Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0044] As used herein the following definitions apply unless cleaily indicated otherwise:
[0045] "Halogen" refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I)
J0046] "Hydroxyl" or "hydroxy" refer to the group -OH
[0047] "Thiol" refers to the group -SII.
[0048] '"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 Λ "substituted lower alkyl" denotes lower alkyl that is independently substituted, 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. 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, -NHR, -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-, or -N- of the moiety (except where -N- is a heteroaryl nng atom) excludes substituents that would result in any -O-, -S-, or -N- of the substituent (except where -N- is a heteroaryl nng atom) being bound to the alkyl carbon bound to any -O-, -S-, or -N- of the moiety .
[0049] "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 alkcnyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like. A "substituted lower alkenyl" denotes lower alkenyl that is independently substituted, with one or more, preferably 1 , 2. 3, 4 or 5,
DLMR 329323 5 Atty. Dkt No,: 039363-3550 also 1 , 2, or 3 substituents, 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-, -O-, -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, -NHR1 -C(O)R, and the like, substitution of the moiety is such that any -C(O)-, -C(S)-, -S(O)-, -S(O)a-, -O-, -S-, or N thereof (except where N is a heteroaryl rmg atom) are not bound to an alkene 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, -NIIR, -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. An "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.
[0050] "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, 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. 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 aikyne carbon of the alkynyl substituent or R group. Further, where alkynyi 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 substituent (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
DLMR 329323.3 Atty Dkt No 039363-3550
"alkynyl carbon" refers to any carbon withm an alkynyl group, whether saturated or part of the carbon to carbon tπple bond An "alkyne carbon" refers to a carbon within an alkynyl group that is part ot a carbon to carbon tπple bond
[0051} "Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon πng systems ot 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 otherw ise, 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
[0052) "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 nng 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 K, such as sulfmyl, sulfonyl and N-oxide of a tertiary πng nitrogen Heterocycloalkyl is also intended to include compounds in which a πng carbon may be oxo substituted, i e the πng 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, morpholmo, tetrahydrofuranyl, dihydropyπdmyl, pipeπdmyl, pyrrolidmyl, pyrrolidonyl, piperazmyl, dihydrobenzofliryl, 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
[0053] "Aryl" alone or in combination refers to a monocyclic or bicyclic πng 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 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
[0054] "Heteroaryl" alone or in combination refers to a monocyclic aromatic πng structure containing 5 or 6 nng 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 sulfmyl, sulfonyl and N-oxidc of a tertiary ring nitrogen A carbon or nitrogen atom is the point of attachment of the heteroaryl πng structure such that a stable compound is produced Examples of heteroaryl groups include, but are not limited to, pyπdinyl, pyπdazinyl, pyrazinyl, quinaoxalyl, mdohzinyl, benzo[b]thienyl, quinazohnyl, puπnyl, indolyl, quinohnyl, pyπmidinyl,
DLMR 329323 5 Atty. Dkt. No.: 039363-3550 pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl. tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. "Nitrogen containing hetcroaryl" refers to heteroaryl wherein any heteroatoms are N, 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.
[0055] "Lower alkoxy" denotes the group -ORZ, where Rz is lower alkyl. Λ "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 description of compounds of Formula I, Formula II, or Formula III, including descriptions of substituted cycloalkyl, heterocycloalkyl, 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 hetcroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy O. Further, where alkoxy is described as a substitucnt 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.
10056] "Lower alkylthio" denotes the group -SRaa, where Raa is lower alkyl. A "substituted lower alkylthio" denotes lower alkylthio in which Raa is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, including descriptions of substituted cycloalkyl, heterocycloalkyl, 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 arc 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 ring atom), or to an alkene or alkyne carbon of the other moiety.
[00571 "Amino" or "amine" denotes the group -NH2. "Mono-alkylamino" denotes the group -NHRbb where Rbb is lower alkyl. "Di-alkylamino" denotes the group NRbbRcc, where Rbb and Rcc are
27
DLMR 329323.5 Atty Dkt. No.: 039363-3550 independently lower alkyl "Cycloalkylammo" denotes the group -NRddRee, where Rdd and Ree combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocyclodlkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with lower alkyl. Examples of 5-7 membered heterocycloalkyl include, but are not limited to, pipendme, piperazme, 4-methylpiperazme, morpholmc, and thiomorphohne While it is understood that when mono-alkylammo, di-alkylarmno, 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-alkylamino, or cycloalkylammo as substituents is not bound to a carbon atom that is bound to an O, S, or N of the other moiety.
[0058] Λs 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 excipient
[0059] I he 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
[0060] 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.
[0061] 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
[0062] As used herein, the terms "ligand" and "modulator" are used equrvalently 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 weight 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 m the relevant art for a particular biological system or therapeutic use
28
DLMR 329323 5 Atty Dkt No 039363-3550
[0063] In the context of compounds binding to a target, the terms "greater affinity" and "selcch\e" indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, i e , with a lower dissociation constant In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-iold greater affinity
[0064] As used herein in connection with compounds of the lm ention, the term "synthesizing ' and like terms means chemical synthesis from one or more precursor materials
[0065] By "assaying" is meant the creation of experimental 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
[0066] 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 tor an inhibitor or activator, respectively, with respect to, for example, an enzyme
[0067] 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 A-Raf, B-Raf, c-Raf-1 , and and any mutants thereof, and the use of such compounds in the treatment of diseases or conditions
Kinase targets and indications of the invention
[0068] Protem kinases play key roles m propagating biochemical signals in
Figure imgf000030_0001
erse biological pathways More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions (i e , indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease neurological disease, and other diseases As such, kinases represent important control points for small molecule therapeutic mten ention Descnption of specific target protein kinases contemplated by the present invention follow
DLMR 329323 5 29 Atty Dkt No 039363-3550
10069) A-Raf: Target kinase B-Raf (i e , v-rat murine sarcoma 3611 viral oncogene homolog 1 ) is a 67 6 kDa seπne/threonme kinase encoded by chromosome XpI 1 4-pl 1 2 (symbol ARAF) The mature protein comprises RBD (i e , Ras binding domain) and phorbol-esterOAG-type zinc finger domain and is involved in the transduction of mitogenic signals from the cell membrane to the nucleus A-Raf inhibitors ma> be useful m treating neurologic diseases such 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, ovarian), lymphoma (e g histiocytic lymphoma), neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angio genesis, pain ot neuropathic or inflammatory origin, including acute pam, chronic pain, cancer-related pain and migraine, and diseases associated with muscle regeneration or degeneration, including but not limited to, vascular restenosis, sarcopema, muscular dystrophics (including, but not limited to, Duchcnnc. Becker, bmery-Drcifuss, Limb-Girdle, Facioscapulohumeral, Myotome, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), 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 spmal 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 endocnne abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of penpheral nerve (including, but not limited to, Charcot-Maπe-Tooth disease, Dejerme- Sottas disease, and Fnedreich'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, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl tiansferase deficiency, phosphoglyccratc kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency)
[0070] B-Raf: Target kinase B-Raf (i e , v-raf murine sarcoma
Figure imgf000031_0001
oncogene homolog Bl) is a S4 4 kDa seπne 'threonine kinase encoded by chromosome 7q34 (symbol BRAF) The mature protein comprises RBD (i e , Ras binding domain), Cl (i e , protein kinase C conserved region 1 ) and STK (i e , seπne/threonine kinase) domains
[0071] Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal neurons As such, genes of the RAF family encode kinases that are regulated by Ras and mediate cellular
DLMR 329323 5 Atty Dkt No 039363-3550 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 growth, 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 dow nstream MAP kinase signaling
10072) The BRAF gene is frequently mutated in a \ancty of human tumors, especially in malignant melanoma and colon carcinoma The most common reported mutation was a missense thymine (T) to adenine (A) transversion at nucleotide 1796 (T1796A, 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 ot 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" (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
[0073] Niihoπ et al , report that in 43 individuals with cardio-facio-cutaneous (CFC) syndrome they identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders (Niihoπ et al , Nat Genet 2006, 38(3) 294-6)
10074) 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 mitochondπa 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 apoptosu>, and c-Raf-1 phosphorylates BAD (i c , BCL2 -binding protein) c-Raf-1 is implicated in carcinomas, including colorectal, ovaπan, lung and renal cell carcinoma C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood. J D et al , 2002, Science 296, 2404) C-Raf-1 inhibitors may also be useful for the treatment of acute myeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002, 8(25) 2243-8) Raf-1 activators may be useful as treatment for neuroendocπne tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunmmalaiyaan et al , Anticancer Drugs 2006, 17(2) 139-42)
[00751 B-Raf and/or C-Raf-1 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, bi east, pancreatic, thyroid, renal, ovarian), lymphoma (e g histiocytic lymphoma)
DLMR 329323 5 US2007/088237
Atty Dkt No 039363-3550 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 acute pain, chronic pam, cancer-related pain, and migraine, cardiovascular diseases including heart failuie, 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, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD), immunodeficienc> diseases, organ transplant rejection, graft versus host disease, renal or prostatic diseases including diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, metabolic disorders, obesity, infection, including, but not limited to Helicobacter pylon Hepatitis and Influenza viruses, fever, sepsis, pulmonary diseases including chronic obstructne pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS), genetic developmental diseases such as 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 endocnne diseases
Kinase Activity Assays
[0076] 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 in the Examples below, one of ordinary skill in the art will know ot other assays that can be utilized and can modify an assay ior a particular application For example, numerous papers concerning kinases describe assays that can be used
[0077] Additional alternative assays can employ binding determinations For example, this sort ot assay can be formatted either in a fluorescence resonance energy transfer (PRIiI ) format, or using an AlphaScreen (amplified /uminescent proximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidm or the phosphor-specific antibody
Organic Synthetic Techniques
[0078] A wide array of organic synthetic techniques exist in the art to facilitate constructing potential modulators Many of these organic synthetic methods are described in detail in standard reference sources utilized by those skilled m the art One example of such a reference is Maich, 1994, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, New York, McG raw 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
DLMR 329323 5 Atty. Dkt. No.; 039363-3550 Alternative Compound Forms or Derivatives
[0079] Compounds contemplated herein arc described with reference to both generic formulae and specific compounds, In addition, invention compounds may exist in 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 Solvated Forms (c) Prodrugs and Metabolites (d) Pharmaceutically acceptable salts and (e) Polymorphic forms, are described, for example, in US Patent Application Serial number 11/473,347 (see also, PCT publication WO2O07OG2433), the disclosure of which is hereby incorporated by reference in its entirety.
Administration
[0080] 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, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines. A description of possible methods and routes of administration may be found, for example, in US Patent Application Serial number 11/473,347 (see also, PCT publication WO20G7002433), the disclosure of which is hereby incorporated by reference in its entirety.
EXAMPLES
[0081] A number of examples illustrative of the present invention are described below. In most cases, alternative techniques could also be used. The examples are intended to be illustrative and are not limiting or restrictive to the scope of the invention. Unless specifically noted to the contrary, in cases where a compound number is not preceeded by a "P-" (e.g., "P-0001 ") in the Examples section, compound naming and/or enumeration is not related to naming and/or enumeration employed in other sections of this application. Similarly, structure and substituent naming and enumeration within the Examples are independent of structure and substituent naming and enumeration in above sections of this application unless clearly indicated otherwise.
[0082J In the following Examples, it is understood that the solvents and reagents used or suggested are not limiting, and can be substituted appropriately with solvents and reagents known to those of skill in the art. Reaction products may be isolated by means known in the art, such as extraction with a suitable solvent, precipitation from a suitable solvent, chromatography using a suitable solvent system, including silica gel column chromatography, HPLC, preparative TLC, and the like. Exemplary methods for synthesis of compounds of the present invention may be found in US Patent
DLMR 329323.6 Atty. Dkt. No.: 039363-3550
Application Serial number 1 1/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference. The lH-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 imgf000035_0001
Step 1 - Preparation of compounds of Formula Xc and Xd
[0083] 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 1, Formula II, or Formula III, e.g. Y is:
Figure imgf000035_0002
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
[0084] 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 imgf000035_0003
34
DLMR 329323.5 Atty Dkt No, 039363-3550
Step -I- Synthesis of compound of Formula X
[0085] 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 -1 8 hours The desired compound X is isolated by extraction and silica gel column chromatography
Example 3. Synthesis of Compounds of Formula X
Figure imgf000036_0001
Step - 1 - Synthesis of c ompound Xe
|U086] Compound of Formula Xe can be synthesized by reacting a compound of Formula Xa (see Example 1 ) with hexamethyltetramine 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
[0087] 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 Xh
[0088| Compound of Formula Xh is synthesized by reacting a compound of Formula Xf m a solvent (e.g. tetrahydrofuran) with an organolithium reagent (e g. phenyl lithium) in a soh ent (e g tetrahydrofuran) under an inert atmosphere, cooled to -78 0C. An appropπate organolithium reagent
can also be prepared by reacting compounds of Formula Xg, where Y1 is -X- "
Figure imgf000036_0002
R2
DLMR 329323 5 35 Atty. Dkt No.: 039363-3550
or -R6 ( * indicates attachment point to the sulfone), where R2, 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
[0089] 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. tetra-rx-buiyl 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
[0090} 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 5-pyridin-3-yl-lB-pyrrolo[2,3-bJpyridine 22.
[0091] 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 imgf000037_0001
Step 1 - Preparation of5-pyridm-3-yl-lH-pyrrolo[2,3-b]pyridme (22):
[0092] 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 mot) 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+f = 196.1.
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
[0093] 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-pyττolo[2,3-b]pyridine and reacting with a suitable aryl or heteroaryl halide (i.e. coupling with the boronic acid ester on the azamdole, 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-(5-Methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine (34),
5-(l -Methyl-lH-iinidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine (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-Tetramethyl-[l ,3,2] dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine starting material (column 1) and the appropriate reagent to 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 imgf000038_0001
Example 5: Synthesis of 5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrroloI2,3-b]pyridine 46.
[0094[ 5-(l-Methyl-lH-pyrazol-4-yl)-lII-pyrrolo[2,3-b]pyridine 46 was synthesized in one step from 5-bromo-lH-pyrrolo[2,3-b]pyridine 1 as shown in Scheme 12.
37
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
Scheme 12
Figure imgf000039_0001
Step 1 - Preparation of 5-(l -Methyl- 1 H-pyrazol-4-yi)-l H-pyrrolo[2 ,3-b] pyridine (46): [0095] 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 6: Preparation of propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH- pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyll-amide 51.
[0096] 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 imgf000039_0002
Step 1 - Preparation of propane-2-sulfonic add (2,4-difluoro-pheny!)-amide (48):
[0097] 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
38
DLMR 329323.5 Λtty. Dkt. No. : 039363-3550 dimethylaminopyridine (0.20 g, 1.64 mmol) under an atmosphere of nitrogen. The reaction was stirred at 45 0C 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 prυpane-2-sulfonic acid (2,4-diflnoro-3-formyl-phcnyl)-amide (49): [0098] To propanc-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-dimethylformamide (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 (dichloromethane/mcthanol 5%) to give the compound (49, 1.4 g, 53.4%). MS(ESI) [M - H+]-= 263.4.
Step 3 - Preparation of 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):
[0099] To proρane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (49, 220.0 mg, 0.83 mmol) in methanol (15 mL) was added 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine (22, 150.0 mg, 0.77 mmol, prepared as described in Example 4) 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 dichlυromethane to give the compound (50, 160 mg, 45.3%). In this step, minor compound propane-2-sulfonic acid {2,4-difluoro-3-[methoxy-(5-pyridin- 3-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide was also formed and isolated. MS(ESl) [M + Wγ = 460.1.
Step 4 - Preparation of propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH-pyrrolo/2,3- b] pyridιne-3-carbonyl)-phenyl] -amide (51):
[0100] To propane-2-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-l H-pyrrolo[2,3- b]pyridin-3-yl)-methyl]-pheny]} -amide (50, 40.0 mg, 0.087 mmol) in tetrahydrofuran (10 mL) was added Dess-Martm periodane (48.0 mg, 0.11 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
DLMR 329323.5 Atty. Dkt. No.; 039363-3550 sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography cluting with 5% methanol in methylene chloride to give the compound (51, 13.4 mg, 33.5%). MS(ESI) [M + HT = 458.1.
[0101] N-{2.4-Difluoro-3-[5-(2-methoxy-ethoxy)-lH-pyπOlo[2,3-b]pyridinc-3-carbonyl]-phenyl}- 4 -isopropy 1 -benzenesu 1 fonamide P-OO 18
Figure imgf000041_0001
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- (2-methoxy-ethoxy)- lH-pyrrolo[2,3-b]pyridine 19 in step 3. MS(ESI) [M - H+] = 530.
[0102] 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 imgf000041_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-(5-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine 34 (see Example 4) in step 3. MS(ESI) [M - H+]" = 536.
[0103] N-{2,4-Difluoro-3-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl) -4-isopropyl-benzenesulfonamide P-0022
Figure imgf000041_0003
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-pyrroIo[2,3-b]pyridine 22 with 5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine 46 (see Example 5) in step 3. MS(ESI) [M ■ H+]" = 536.
[0104] 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
40
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
Figure imgf000042_0001
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-yHH-pyrrolo[2,3-b]pyridine 22 with 5-(5-methyl-lH-imidazol-2-yl)-lH-pyiτolo[2,3-b]pyridine 34 (see Example 4). MS(ESI) [M - H*]' = 562.
[0105] N-{2,4-Difluoro-3-[5-(l-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonylJ- phenyl }-4-propyl-benzenesulfonamide P-0026
Figure imgf000042_0002
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-l H-pyrrolo[2,3-b]pyridine 22 with 5-(5- methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine 35 (see Example 4). MS(ESI) [M - H+]" - 536.2.
[01061 N-IS-tS-tUS-Dimcthyl-l H-imidazol^-yO-l H-pyrroloP^-bJpyridine-S-carbonyl]^^- difluoro-phenyl} -4-propyl-benzenesulfonamide P-0027
Figure imgf000042_0003
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 4). MS(ESI) [M - W] ■ 550.1.
Example 7; Synthesis of N-[3-(5-cMoro-lH-pyrrolo[2,3-b]pyridine-3-carbonyJ)-2,4-difluoro- phenyl]-3,5-difluorobenzenesuIfonamidc 58
[0107] Compound P-1841 was synthesized in six steps from 2,4-difluoroaniline 47 as shown in Scheme 14.
41
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
Scheme 14
Figure imgf000043_0001
Step 1 - Preparation of(2,4-difluoro-phenyl)-carbamic acid benzyl ester (52): [0108] 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 KHSO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 52 (15.6 g, 85%).
Step 2 - Preparation υf(2,4-difluoro-3-formyl-ρhenyl)-carbamic acid benzyl ester (53): [0109] Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52, 3.83 g, 14.5 mmol) 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~h]pyridin-3-yl)-methyl]-phenyl}- carbamic acid benzyl ester (54):
[0110] Into a round bottom flask was added 5-chloro-lH-pyrrolo[2,3-b]pyridine (6, 0.524 g, 3.43 mmol) 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 vvashed with brine, dried over sodium sulfate, concentrated and crystallized from ethyl acetate to give compound 54 (710 mg, 46%). MS(ESI)[M+!!']' = 444.
DLMR 329323.5 42 Atty, Dkt. No.: 039363-3550
Step 4 - Preparation of[2,4-diflιιoro-3-(lH-pyrrolo[2,3-b]pyridιne-3-carbonyl)-phenyl]-carbamιc acid benzyl ester (55):
[0111] Into a round bottom flask was added {2,4-difluoro-3-[hydroxy-(l H-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 mg, 91%). MS(ESI)[M+tT]* = 442.
Step 5 - Preparation of(3-Amino-2,6-difluoro-phenyl)-(5-chIoro-lH-pyrrolo[2,3-b]pyridin-3-yl) - methanone (56):
[01121 [2,4-difluoro-3-(lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phcnyl]-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 ofN-[3-(5-chloro-lH-pyrrolol2,3-bjpyridine-3-carbony!)-2,4~difluoro-phenyl]- 3, 5-difluoroben∑enesulfonamide (58):
[0113] 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 °C for 10 minutes. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was collected, dried over Na2SO4, 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.
[0114] Additional compounds were prepared following the protocol of Scheme 14, optionally substituting 5-chloro-l H-pyrrolo[2,3-b]pyridine 6 with an appropriate azaindole 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-l H-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[2,34jJpyridine-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-phenylj-amide (P-0003),
3-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid (P-0004),
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
2-Oxo-2H-chromene-6-sulfonic acid [3-(5-ehloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- diΩuorophenyl]-amide (P-0005),
S-Isoxazol-S-yl-thiophene^-sulfonic acid [3-(5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-
2,4-difluoro-phenyl]-amide (P-0006),
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-] 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-lH-pyrazole-4-sulfonic acid [3-(5-chloro-lH-pyrτolo[2,3-b]pyridine-
3-carbonyl)-2,4-difluoro-phenyl]-amide (P-OOlO),
N-[3-(5-Chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy- benzenesulfonamide (P-OOIl),
Benzofl ,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-tert-Butyl-N-f3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- bcnzcnesulfonamide (P-0014),
N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl- benzenesulfonamide (P-0015),N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridinc-3-carbonyl)-2,4- difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide (P-0016),
5-Methyl-benzo[b]thiophene-2 -sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-
2,4-difluoro-phenyl]-amide (P-0017),
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(l -methyl- l H-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-
3 -carbonyl] -phenyl } -benzenesulfonamide (P-0020),
N-{2,4-Difluoro-3-[5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl}-4-propyl -benzenesulfonamide (P-0021),
N-{2,4-Difluoro-3-[5-(5-methyl-lII-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- phenyl} -4-propyl -benzenesulfonamide (P-0023),
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-lH-pyπolo[2.3- b]pyridine-3-carbonyl]-ρhenyl} -benzenesulfonamide (P-0024),
5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide (P-0028), l -Methyl-lH-pyrazole-3-sulfonic acid [3-(5-chloro-lH- pyrτolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phcπyl]-amide (P-0029),N-[2,4-Difluoro-3-(5- methyl-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamidc
(P-0030),N-[3-(5-Cyano-lII-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-
44
DLMR 329323.5 Atty. Dkt. No.: 039363-3550 trifluoromethyl-benzenesulfonamide (P-0031),
(E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-ben7oyl]-l H-pyrTolo[2.3- b]pyridin-5-yl} -acrylic acid methyl ester (P-0032), and
Pyridine-2 -sulfonic acid [2,4-ditluoro-3-(5-methoxy-lH-pyiτolo[2,3-b]pyridine-3-carbonyl)- pheπylj-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 imgf000046_0001
DLMR 329323 5 45 88237 Atty. Dkt. No : 039363-3550
Figure imgf000047_0001
DLMR 329323 5 46 Atty. Dkt. No.: 039363-3550
Figure imgf000048_0001
DLMR_329323 5 47 Atty. Dkt. No. : 039363-3550
Example 8: Synthesis of 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)- benzoyl]-lH-pyrrolo[2,3-b)pyridin-5-yl}-N-ethyl-propionamidc P-0035.
[0115] 3-{3-[2.6-Difluoro-3-(4-trifluoromethyl-ben2enesulfonylamino)-benzoyl]-lH-pyrrolo[2.3- b]pyridin-5-yl} -N-ethyl-propionamide P-0035 was synthesized in three steps from (E)-3- {3-[2,6- Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lH-pyπOlo[2,3-bJpyridin-5-yl}- acrylic acid methyl ester P-0032 as shown in Scheme 15.
Scheme 15
Figure imgf000049_0001
Step 1 Preparation of3-{3-[2, 6-difluoro-3-(4-triβuoromethyl-benzenesulfυnylamino)-benzoyl]-lH- pyrrolo[2,3-b]pyridin-5-yl}-propiomc acid methyl ester (P-0033):
[0116] To (E)-3- {3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylammo)-benzoyl]-lH- pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester (P-0032, 229 mg , 0.41 mmol, prepared as described in Example 7) was added methanol (15 mL) and tetrahydrofuran (5 mL). The solution was degassed with nitrogen for 5 minutes, followed by the addition of Pdy'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 eluted with ethyl acetate. Solvent was removed to provide an off-white solid (P-0033, 222 mg, 96%). MS (ESl)
Figure imgf000049_0002
Step 2 - Preparation of3-{3-[2, 6-difluoro-3-(4~trifluoromethyl-henzenesulfonylamino}-benzoyl]-lH- pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-0034):
[0117] To 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lH- pyrrolo[2,3-b]pyτidin-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
48
DLMR 329323.5 7 088237
Atty. Dkt. No.: 039363-3550 concentrated to provide an off-white solid (P-0034, 202 ing, 96%). MS (ESI) [M+ir] '=554.0.
Step 3 - Preparation of3-{3-[2, 6-difluorn-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoylJ-lH- pyrrυlo[2,3-b]pyndin-5-yl}-N-ethyl~propionamide (P-0035):
[0118] To 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzo>l]-lH- pyrrolo[2,3-b]pyridin-5-yl} -propionic acid (P-0034, 42 tug. 0.076 mraol) dissolved in tetrahydrofuran (3 HiL) was added a 2,0 M solution of ethylamine in tetrahydrofuran (110 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 eluting solvents removed via lyophilizing to provide a white fluffy solid (P-0035, 13 mg, 30%). MS (ESI) [M+H+]τ= 581.0.
Example 9: Kinase Activity Assays
[0119] Assays for the activity of B-Raf, B-Raf V600E, B-Raf V600EAT529I or c-Raf-1 are known in the art, for example as described 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.
[0120] Representative compounds screened by at least one of the methods described in US Patent Application Serial number 11/473.347, or by similar methods, having IC5O 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), and Id (c-Raf-1).
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-OO 15, P-OO 16, P-0017, P-OO 18, 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-OO33, P-0034, P-0035, P-0036
Table Ib. Representative compounds with activity toward kinase B-Raf V600E with ICw < 10 μM under the test conditions employed.
P-0025. P-0028,
Figure imgf000050_0001
DLMR 329323.5 49 Atty. Dkt. No,: 039363-3550
Table I c. Representative compounds with activity toward kinase B-Raf V600E/T529I with IC501 10 μM under the test conditions employed.
Figure imgf000051_0001
Table 1 d. Representative compounds with activity toward kinase c-Raf-1 with IC50 < 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-OO 13,
P-OO 14, P-OO 15, P-OOl 6, P-OO 17, P-0018, P-OO 19, P-0020, P-0021 , P-0022, P-0023,
P-0025, P-0030. P-0031
Example 10: Efficacy of Compounds in Combination with Standard-of-Care Chemotherapeutic agents in four human cancer cell lines.
[0121] 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, temozolomide, or vinblastine, can be assessed for their effectiveness in killing human tumor cells. Human tumor cell lines, such as A-375 (malignant melanoma), SK-MHL-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.
|0122] 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, Verviers, Belgium) containing 2 mM L-glutamine and supplemented with 10% fetal bovine serum (Ref DEl 4-801 E, 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.
[0123] The cell lines are 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 supernatants of the cell lines and compared to negative and positive controls.
50 DLMR 329323.5 Atty Dkt No 039363-3550
[0124] 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 IC53 of each compound to be used for each cell line, the tumor cells arc incubated in a 200 μl final \olume 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, dacarbazme, gefitinib, oxaliplatm, 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 TT, or Formula III, 5-fluorouracil, dacarbdzine or gefitimb, 109 to 104 M for carboplatm, oxaliplatm, or temozolomide, 10 ' ' to 10 s M for pachtaxel or SN-38, and 10 H to 10 10 M for vinblastine Compounds of Formula I Formula II or Formula III are dissolved in DMSO and diluted with culture medium to the desired concentrations 5- fluorouracil (50 mg/ml, Dakota Pharm, I ePlessis Robinson, France), carboplatm (10 mg/ml, Aguettant Lyon, France), and pachtaxel (6 mg/ml, Bristol-Myers Squibb SpΛ, Rueil Malmaison, France), are diluted with culture medium to the desired concentrations Dacarbazme (Sigma, Samt Quentm Fallavier, France) and vinblastine (Lilly France S Λ , Saint Cloud, France) are dissolved m NaCl 0 9% and diluted with culture medium to the desired concentrations ϋefitimb 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) 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) Temozolomide (LKl 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% CO1 At the end of treatments, the cytotoxic activity is evaluated by an MTT assay
[0125] For the MTT assay, at the end of the cells treatment, 20 μl of a 5 mg/ml solution 0 22 μm filtered tetrazohum reagent (MTT, Ref M2128, Sigma) in Phosphate Buffered Saline (PBS, Ref BEl 7-517Q, 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 VICTOR3™ 1420 multilabeled counter (Wallac, PerkmElmer, Courtaboeuf, France)
I0126J The IC5O for each compound on each cell line is determined from the OD measurements ol each sample The dose response inhibition of 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 1 he dose-response curv es are plotted using XLFit 3 (IDBS, United Kingdom) The ICso (drug concentration to obtain 50% inhibition ot cell proliferation) determination values are calculated using
DLMR 329323 5 Atty. Dkt. No.: 039363-3550 the XLFit 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 chetno therapeutic to be used in combination.
[0127] 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-fluorouracil, carboplatin. dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine, based on the IC50 results. The compounds and cells are treated per the IC50 determination described above and assayed by the MTT assay.
[0128] The results are assessed to determine whether the combination is synergistic or antagonistic. The compound interactions are calculated by multiple drug effect analysis and are performed by the median equation principle according to the methodology described by Chou and Talalay (Adv. Enzyme Regul. 19S4, 22: 27-55).
[0129] The combination index (CI) will 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 (Dn, or IC50) 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 , (ZJ)1 (D)2
CI = — • + - <_ + .
(Z)x), (Dx)2 (DJ1(DJ2 where:
(Dx) 1 and (DJ2 in the denominators are the doses (or concentrations) for compound 1 and compound 2 alone which demonstrate x% of inhibition, whereas (D)i and (D)2 in the numerators are doses of both compounds (1 and 2) in combination that also inhibit x% (iso-effective). CI<1 , = 1 , and >1 indicate synergism, additive effect and antagonism, respectively.
[0130] The (Ds)i and (Dx)2 can be calculated from the median-effect equation of Chou et al, (J. Natl. Cancer Inst. 1994, 86: 1517-24):
DLMR 329323.5 Atty Dkt No 039363-3550
Figure imgf000054_0001
\\ here
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{/a/(l-/B)} or Dn, = 10 (i lmercepυ m, and m is the slope of the median-effect plot and /a is the traction oi cells atfccted by the treatment
Each CI will be calculated with CalcuSyn software (Biosoft, UK) from the mean affected fraction at each drug ratio concentration
[0131] Additional examples ot certain methods contemplated by the present invention may be found in 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 11/154,988, U S Pro\ App No 60/682,076, filed May 17, 2005, U S Prov App No 60/682,058, filed May 17, 2005, U S
Figure imgf000054_0002
App No 60/682,063, filed May 17, 2005, U S Prov App No 60'682,05I , 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 11 '435, 381 , filed May 16, 2006, and U S Patent App No 11/473,347, filed June 21, 2006, each of which are hereby incorporated by reference herein in their entireties including all specifications, figures, and tables, and for all purposes
[0132] All patents and other references cited in 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 in its entirety individually
[0133] 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 descnbed 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 will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims
[0134] 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 For example, variations can be made to crystallization or co-cr> stalhzation conditions for Ret and Ret surrogate proteins and/ or various kinase domain sequences can be used
DLMR 329323 5 Atty. Dkt. No.: 039363-3550
Thus, such additional embodiments are within the scope of the present invention and the following claims,
[0135] The invention illustratively described herein suitably may be practiced in the absence of any element 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 terms. 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 variation 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.
[0136] 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.
[0137] 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.
[0138] Thus, additional embodiments are within the scope of the invention and within the following claims.
DLMR 329323.5

Claims

US2007/088237Atty. Dkt. No,: 039363-3550CLAIMS
What is claimed is:
I. A compound having the chemical structure of Formula I,
Figure imgf000056_0001
all salts, prodrugs, tautomers and isomers thereof, 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)2NII2, -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, -NR5C(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)NR8R', 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, -OR*, -SR9, -NR8R9, -NRSC(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, -NIIS(O)2NH2, -OR7, -SR7. -NRSR7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR*C(0)R", -NR8C(S)R7, -NR5S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R^, -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. -OR , -NR R ', cycloalkyl. heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, helerocycloalkyl. aryl, and heteroaryl as R" or as substituents of low er 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, -NRSR9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9. -S(O)2NR14R",
DLMR 329323.5 7 088237 Atty. Dkt. No,: 039363-3550
-C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylainino;
R is selected from the group consisting of hydrogen, fluoro and chloro;
R1 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-alky lamino, 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, -NO;, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NRHC(O)Rg, -NR3S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylainino;
R8 at each occurrence is independently hydrogen or lower alkyl; and
R1 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 wherein 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, provided, however, the compound is not
Figure imgf000057_0001
DLMR 329323.5 56 Atty. Dkt. No.: 039363-3550
Figure imgf000058_0001
2. The compound of Claim 1, wherein:
R1 is selected from the group consisting of hydrogen, -CN, -OR7,
Figure imgf000058_0002
-NR8R7, -NR8C(O)R\ -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NRSR7, -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 aikoxy, 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 aikyl 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, -NRV, -NR5C(O)R9, -NR8S(O)3R9, -S(O)2R", -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9. halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
DLMR 329323 5 57 Atty. Dkt. No. : 039363-3550
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 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-alkyiamino, di- alkyl amino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R" or as a substituent of lower alkyl arc optionally substituted with one or more substituents selected from the group consisting of -OH, -NH?, -CN, -NO2, -S(O)3NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR51S(O)2R5, -S(O)2R", -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
3. The compound of Claim 2, 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
R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7.
4. The compound of Claim 3, wherein:
R1 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 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,
5. The compound of Claim 1 , wherein the compound is selected from the group consisting of
4-Butoxy-N-[3-(5 -chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyI)-2,4-difluoro-phenyl]- benzenesulfonatnide,
N-fS^S-Chloro-lH-pyrroloP^-bjpyridine-S-carbonyD^^-difluoro-phenylJ^-pyrazol-l -yl- benzenesulfonamide,
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
N-[3-(5-Chloro-l H-pyrrolo[2,3-b]p\τidine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy- benzenesulfonamidc,
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-lII-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl- beozenesulfonamide ,
N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-lH-p>τrolo[2.3-b]ρyridine-3-carbonyl]-ρhenyl}-4- isopropyl-benzenesulfbnamide,
N-{2,4-Difluoro-3-[5-(4-methyl-lH-imida7.ol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-ρhenyI} -
4-isopropyl-benzenesulfonamide,
4-Diπuoromethoxy-N-{2,4-difluoro-3-[5-(l-methyl-l H-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-3- carbonyl]-phenyl} -benzenesulfonamide,
N- {2,4-Difluoro-3-[5-(l-mcthyl-lII-pyrazol-4-yl)-l H-pyiτolo[2,3-b]pyridine-3-carbonyl]-phenyU-4- propyl -bcnzenesulfonamide,
N- {2,4-Difluoro-3-[5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-phcnyl}-4- isopropyl-benzenesulfonamide,
N- {2,4-Dif]uoro-3-[5-(5-methyl-lH-imidazol-2-yl)-lII-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-
4-propyl-benzenesulfonamide,
N-{2,4-Difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-l H-pyiτolo[2,3-b]pyridine-3-carbonyl]-phenyl} -
4-trifluoromcthyl-benzenesulfonaroide,
N-{2,4-Difluoro-3-[5-(l -methyl- lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-ρhenyl} -
4-propyl-benzenesulfonamide,
N-{3-[5-(l ,5-Dimethyl-l H-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- phenyl} ^-propyl-bcnzcncsulfonamide,
N-[2,4-Difluoro-3-(5-methyl-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl- benzenesulfonamide,
N-[3-(5-Cyano-lII-ρyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl- benzenesulfonamide,
(E)-3- -|3-[2)6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lII-pyrrolo[2,3- b]pyridin-5-yl} -acrylic acid methyl ester,
3- {3-[2)6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-bcnzoyl]-l H-pyrrolo[2,3-b]pyridin-
5-yl}-propionic acid methyl ester,
3- {3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoylJ-lH-pyrrolo[2,3-b]pyridin-
5 -yl} -propionic acid.
3- {3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-lH-pyrrolo[2,3-b]pyπdin-
5-yl} -N-ethyl-propionamide; and all salts, prodrugs, tautomers. and isomers thereof.
59
DLMR 329323 5 Atty. Dkt. No.: 039363-3550
6. A compound having the chemical structure of Formula II
Figure imgf000061_0001
all salts, prodrugs, tautomers and isomers thereof, wherein:
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkcnyl, 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)NH ,, -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, -NRSR7, -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, -SRg, -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;
R2d 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)2NR5R7, -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, -NR8R', 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)NH2, -OR9, -SR9, -NRSR9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NRSR9, halogen, lower alkyl, fluoro substituted lower alkyl, and cy cloa lkyl amino ; R3 is selected from the group consisting of hydrogen, fluoro and chloro;
60 DLMR 329323 5 Atty. Dkt. No.: 039363-3550
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 alkyllhio, 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, -OR", -SR9, -NR8R", -NR8C(O)R0,. -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R"', -C(O)R9, -C(O)NR5R9, 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 wherein heterocycloalkyl and heteroaryl arc 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, provided, however, the compound is
Figure imgf000062_0001
DLMR 329323.5 61 Atty. Dkt. No.: 039363-3550
Figure imgf000063_0001
7. The compound of Claim 6, wherein:
R1 is selected from the group consisting of hydrogen, -CN, -OR/, -SR7, -NR8R7, -NR8C(O)R", -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NRSR7, -S(O)R7, -S(O)2R", 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
R23 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 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 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)2R9, -S(O)2NR3R0, -C(O)R9. -C(O)NR8R9, halogen, lower alkyl. fluoro substituted lower alkyl. and cycloalkylamino.
DLMR 329323 5 Atty. Dkt. No.: 039363-3550
8. The compound of Claim 7, wherein:
R1 is hydrogen, -CN, -NR8R7, -OR1, -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, -OR" and -S(O)2R7, and
R2a is -CN, fluoro, chloro, lower alkyl, iluoro substituted lower alkyl, -NR8R", -OR' or -S(O)2R7.
9. The compound of Claim 8, wherein:
R1 is hydrogen, -CN, tluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2^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
R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
10. The compound of Claim 6, wherein the compound is selected from the group consisting of:
3-[3-(5-Chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid,
N-[3-(5-Chloro-lII-pyrrolo[2,3-b]pyridinc-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy- benzenesulfonamide,
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-l H-imidazol-2-yl)-lH-pyiτolo[2,3-b]pyridine-3- carbonylj-phenyl} -benzenesulfonamide; and all salts, prodrugs, tautomers, and isomers thereof.
11. A compound having the chemical structure of Formula III,
Figure imgf000064_0001
all salts, prodrugs, tautomers and isomers thereof,
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH1, -CN, -NO2, -C(O)OH.
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
-S(O)2NH2. -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH1, -OR", -SR7, -NRV, -C(O)R\ -C(S)R7. -C(O)OR7, -C(O)NRV, -C(S)NR8R", -S(O)2NRV, -NR8C(O)R7, -NRSC(S)R", -NR5S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR^C(S)NH2, -NR8C(S)NR8R', -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R', and -S(O)2R", 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, -OR', -NR V, -C(O)OR7, -C(O)NR8R', cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, hctcrocycloalkyl. 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, -NR3R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R5, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
Rλ is selected from the group consisting of hydrogen, fluoro and chloro;
R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, hctcrocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH;, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NRV, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NII2, -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, -NR8R', 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)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-alkylammo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, arvl, 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, -NIL, -CN, -NO2, -S(O)2NH2. -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9. -NR8S(O)2R9, -S(O)2R9, -S(O)2NRV, -C(O)R9. -C(O)NR8R", halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; R8 at each occurrence is independently hydrogen or lower alkyl; and
64
DLMR 329323 5 Atty. Dkt. No.: 039363-3550
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, provided, however, the compound is not
Figure imgf000066_0001
Figure imgf000066_0002
DLMR 329323.5 65 Atty. Dkt. No.: 039363-3550
12. The compound of Claim 1 1, wherein:
R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SRT, -NR V. -NR8C(O)R", -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R", -S(O)R7, -S(O)2R7, halogen, lower alk\ l, 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)R5, -NR8S(O)2R*. -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, -NRSC(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, 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, -NH:, -CN, -NO2, -S(O)2NH2, -C(O)NII2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R", -S(O)2R*, -S(O)2NR8R", -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
13. The compound of Claim 12, 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, -NRgR7, -OR7 and -S(O),R\ and
R6 is heteroaryl optionally substituted with one or more of -CN. fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
Figure imgf000067_0001
-OR7 or -S(OJ2R7.
DLMR 329323.5 Atty. Dkt. No.: 039363-3550
14. The compound of Claim 13, wherein:
R1 is hydrogen, -CN, fluoro. cliloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2^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, monα-alkylamino, 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.
15. The compound of Claim 1 1 , wherein the compound is selected from the group consisting of:
Benzo[b]thiophenc-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl] -amide.
5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3- carbonyl)-2,4-difluoro-phenyl]-amide,
5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-l H-pyrrαlo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide,
2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenylj-amide,
5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenylj-amide,
Bcnzothiazole-6-sulfonic acid [3-(5-chloro-lH-pyrrolot2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]-amide, l -Methyl-3-trifluoromethyl-lH-pyrazole-4-sulfonic acid [3-(5-chloro-l H-pyrrolo[2.3-b]pyridine-3- carbonyl)-2,4-difluoro-phenyl]-amide,
Benzo[l ,2,5]thiadiazoe-5 -sulfonic acid [3-(5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenylj-amide,
5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-lH-p>rrrolo[2,3-b]pyridine-3-carbonyI)-2.4- difluorn-phenyl]-amide,
5-Mcthyl-thiophene-2-suIfonic acid f3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]-amide,
1 -Methyl- l H-pyrazole-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]-amide,
Pyridine-2-suIfonic acid [2,4-difluoro-3-(5-methoxy-l H-pyτrolo[2,3-b]pyridine-3-carbonyl)-phenyI]~
rn DLMR 329323 5 Atty. Dkt. No,: 039363-3550 amide; and all salts, prodrugs, tautomers, and isomers thereof,
16. A composition comprising: a pharmaceutically acceptable carrier; and a compound according Io any of Claims 1-15.
17. A method for treating a subject suffering from 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 1-15 or a composition of Claim 16.
18. The method of Claim 17, wherein the compound or composition is approved for administration to a human.
19. The method of Claim 18, wherein the disease or condition is 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 pain, 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- faciocutancous 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, ncmahnc myopathy, myotubtilar myopathy, periodic paralysis and metabolic diseases of muscle,
20. A kit comprising a compound according to any of Claims 1-15 or a composition according to Claim 16,
21. The kit of Claim 20, 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,
DLMR 329323,5 68 Atty. Diet. No.: 039363-3550 lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, phcochromocytoma, 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, repcrfusion 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.
69
DLMR 329323.5
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WO2008079903A1 (en) 2008-07-03
US20080167338A1 (en) 2008-07-10
EP2097414A1 (en) 2009-09-09
TW200845975A (en) 2008-12-01
RU2009122436A (en) 2011-01-27
UA98629C2 (en) 2012-06-11
KR20090095654A (en) 2009-09-09
MX2009006162A (en) 2009-06-19
CA2673000A1 (en) 2008-07-03
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ECSP099444A (en) 2009-07-31
UY30816A1 (en) 2008-07-31
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BRPI0722088A2 (en) 2016-03-22
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US7863289B2 (en) 2011-01-04

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