WO2007002325A1 - Pyrrolo[2,3-b] pyridine derivatives as protein kinase inhibitors - Google Patents

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

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Publication number
WO2007002325A1
WO2007002325A1 PCT/US2006/024361 US2006024361W WO2007002325A1 WO 2007002325 A1 WO2007002325 A1 WO 2007002325A1 US 2006024361 W US2006024361 W US 2006024361W WO 2007002325 A1 WO2007002325 A1 WO 2007002325A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
fluoro
group
lower alkyl
alkylamino
Prior art date
Application number
PCT/US2006/024361
Other languages
English (en)
French (fr)
Inventor
Prahbha N. Ibrahim
Dean R. Artis
Ryan Bremer
Shumeye Mamo
Marika Nespi
Chao Zhang
Jiazhong Zhang
Yong-Liang Zhu
James Tsai
Klaus-Peter Hirth
Gideon Bollag
Wayne Spevak
Hanna Cho
Samuel J. Gillette
Guoxiam Wu
Hongyao Zhu
Shenghua Shi
Original Assignee
Plexxikon, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37033831&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2007002325(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CN2006800303262A priority Critical patent/CN101243084B/zh
Priority to JP2008518402A priority patent/JP5007304B2/ja
Priority to BRPI0611863-1A priority patent/BRPI0611863B1/pt
Priority to NZ565255A priority patent/NZ565255A/en
Priority to KR1020087001659A priority patent/KR101125919B1/ko
Application filed by Plexxikon, Inc. filed Critical Plexxikon, Inc.
Priority to MX2007016463A priority patent/MX2007016463A/es
Publication of WO2007002325A1 publication Critical patent/WO2007002325A1/en
Priority to IL188248A priority patent/IL188248A/en
Priority to ZA2007/11152A priority patent/ZA200711152B/en
Priority to NO20076659A priority patent/NO333913B1/no
Priority to CR20130216A priority patent/CR20130216A/es
Priority to NO2014006C priority patent/NO2014006I1/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

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 INK signal transduction pathway, cell transformation, memory, apoptosis, competitive activity-dependent synapse modification at the neuromuscular synapse, immunological mediation of disease, and calcium regulation.
  • a variety of specific disease states are associated with aberrant regulation of protein kinases. Accordingly, there is a need in the art for additional compounds and methods of use thereof for the modulation of receptor protein kinases in treatment of various diseases.
  • the present invention concerns compounds active on protein kinases in general, including, but not limited to, B-Raf, c-Raf-1, Fms, Jnkl, Jnk2, Jnk3, and/or Kit, including any mutations of these kinases, and the use thereof in treating disease and conditions associated with regulation of the activity of the kinases.
  • the invention concerns compounds of Formula III as described below.
  • the invention provides novel uses of compounds for therapeutic methods involving modulation of protein kinases, as well as novel compounds that can be used for therapeutic methods involving modulation of protein kinases.
  • Formula III all salts, prodrugs, tautomers, and isomers thereof, wherein: Q has a structure selected from the group consisting of
  • ⁇ indicates the attachment point of Q to A of Formula HI;
  • Z 2 is N or CR 12 ;
  • Z 4 is N or CR 14 ;
  • Z 5 is N or CR 15 ;
  • Z 6 is N or CR 16 ;
  • L 2 is selected from the group consisting of -(CR 10 R 11 VNR 21 XCR 10 R 11 V,
  • X is O or S
  • A is selected from the group consisting of -O-, -S-, -CR a R b -, -NR 1 -, -C(O)-, -C(S)-, -S(O)-, and -S(O) 2 -;
  • R a and R b at each occurrence are independently selected from the group consisting of hydrogen, fluoro, -OH, -NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and -NR 8 R 9 , wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-al
  • R a and R b combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
  • R 1 is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)R 7 , -C(S)R 7 , -S(O) 2 R 7 , -C(O)NHR 7 , -C(S)NHR 7 , and -S(O) 2 NHR 7 , wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and -NR 8 R 9 , wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower
  • R 7 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, -OH, -NH 2 , lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and -NR 8 R 9 , provided, however, that any substitution of the alkyl carbon bound to the N of -C(O)NHR 7 , -C(S)NHR 7 or -S(O) 2 NHR 7 is fluoro, wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy
  • R 4 , R 5 , R 6 , R 12 , R 14 , R 15 , R 16 , R 42 , R 43 , R 45 , R 46 and R 47 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -NO 2 , -CR a R b R 26 , and -LR 26 ;
  • L at each occurrence is independently selected from the group consisting of -(alk) a -S-(alk) b -, -(alk) a -O-(alk) b -, -(alk) a -NR 25 -(alk) b -, -(alk) a -C(O)-(alk) b -, -(alk) a -C(S)-(alk) b -, -(alk) a -S(O)-(alk) b -, -(alk) a -S(O) 2 -(alk) b -, -(alk) a -OC(O)-(alk) b -, -(alk) a -C(O)O-(alk) b -, -(alk) a -OC(S)-(alk) b -, -(al
  • R 25 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 26 at each occurrence is independently selected from the group consisting of hydrogen, provided, however, that hydrogen is not bound to any of S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 26 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted lower alkynyl, provided, however, that when R 26 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 10 and R 11 at each occurrence are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, and lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, and cycloalkylamino; or any two of R 10 and R 11 on the same or adjacent carbon atoms combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, and any others of R 10 and R 11 are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, and lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substitute
  • R 17 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl and -OR 18 ;
  • R 31 and R 33 are independently selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;
  • R 36 is selected from the group consisting of substituted methyl, optionally substituted C 2-6 alkyl, optionally substituted lower alkenyl, provided, however, that when R 36 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to the S(O) 2 of S(O) 2 R 36 , optionally substituted lower alkynyl, provided, however, that when R 36 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to the S(O) 2 of S(O) 2 R 36 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and -NR 19 R 20 ;
  • R 19 , R 20 , R 34 , R 35 , R 37 , and R 38 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 19 , R 20 , R 34 , R 35 , R 37 , or R 38 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to the N OfNR 19 R 20 , NR 34 R 35 or NR 37 R 38 , optionally substituted lower alkynyl, provided, however, that when R 19 , R 20 , R 34 , R 35 , R 37 , or R 38 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to the N OfNR 19 R 20 , NR 34 R 35 or NR 37 R 38 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or
  • R 34 and R 35 together with the nitrogen to which they are attached form optionally substituted 5-7 membered heterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl; or
  • R 37 and R 38 together with the nitrogen to which they are attached form optionally substituted 5-7 membered heterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl;
  • R 32 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and -OR 18 ;
  • R 82 is selected from hydrogen or lower alkyl
  • R 18 is hydrogen or optionally substituted lower alkyl; provided, however, that the compound is not 3- ⁇ 3-[2-(tetrahydropyran-2-yloxy)-ethoxy]-benzyl ⁇ - 5-thiophen-3-yl-lH-pyrrolo[2,3-b]pyridine, which has the structure
  • compounds of Formula III have the structure according to the following sub-generic structure Formula Ilia:
  • Formula Ilia all salts, prodrugs, tautomers and isomers thereof, wherein A, L 2 , Z 2 , Z 6 , R 4 , R 5 , R 6 , R 15 , R 17 and R 31 are as defined for Formula III.
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -KR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -
  • R 17 is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro, and R 15 is
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -KR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-
  • R 17 is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro
  • R 15 is selected from the group consisting of hydrogen, hal
  • compounds of Formula III have the structure according to the following sub-generic structure Formula HIb:
  • a 1 is -O-, -CR 40 R 41 -, -C(O)- or -NR 48 -;
  • Z 12 is N or CR 52 ;
  • Z 16 is N or CR 56 ;
  • R 40 and R 41 are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or
  • R 40 and R 41 combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
  • L 3 is selected from the group consisting of -NR 48 -, -S-, -O-, -NR 48 CH(R 49 )-, -SCH(R 49 )-, -OCH(R 49 )-, -C(O)NR 48 -, -S(O) 2 NR 48 -, -CH(R 49 )NR 48 -, -CH(R 49 )O-, -CH(R 49 )S-, -NR 48 C(O)-, and -NR 48 S(O) 2 -;
  • R 53 and R 55 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino or cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro;
  • R 52 and R 56 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • R 49 is selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl
  • Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
  • R 39 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 50 is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino;
  • R 51 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 23 at each occurrence is independently selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 57 , -SR 57 , -NR 48 R 57 , -NR 48 C(O)R 57 , -NR 48 S(O) 2 R 57 , -S(O) 2 R 57 , -C(O)R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , -S(O) 2 NR 48 R 57 , 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 al
  • R 57 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 57 , -SR 57 , -NR 48 R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , or -S(O) 2 NR 48 R 57 is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycl
  • R 58 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, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 58 , -SR 58 , -NR 48 R 58 , -C(O)OR 58 , -C(O)NR 48 R 58 , or -S(O) 2 NR 48 R 58 is fluoro;
  • R 48 at each occurrence is independently hydrogen or lower alkyl; and t is O, 1, 2, or 3.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -, and R 53 and R 55 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • L 3 is -NR 48 CH(R 49 )-, -SCH(R 49 )-, or -OCH(R 49 )-, preferably -OCH(R 49 )-.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -
  • L 3 is -NR 48 CH(R 49 )-, -SCH(R 49 )-, or -OCH(R 49 )-, preferably -OCH(R 49 )-.
  • compounds of Formula IH have the structure according to the following sub-generic structure Formula HIp:
  • a 1 is -O-, -CR 40 R 41 -, -C(O)- or -NR 48 -;
  • Z 22 is N or CR 62 ;
  • Z 26 is N or CR 66 ; r is O, I, or 2;
  • R 40 and R 41 are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or
  • R 40 and R 41 combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
  • R 62 , R 63 , R 65 and R 66 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro;
  • Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
  • R 39 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 50 is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio
  • R 51 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 23 at each occurrence is independently selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 57 , -SR 57 , -NR 48 R 57 , -NR 48 C(O)R 57 , -NR 48 S(O) 2 R 57 , -S(O) 2 R 57 , -C(O)R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , -S(O) 2 NR 48 R 57 , 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 al
  • R 57 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 57 , -SR 57 , -NR 48 R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , or -S(O) 2 NR 48 R 57 is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycl
  • R 58 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, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 58 , -SR 58 , -NR 48 R 58 , -C(O)OR 58 , -C(O)NR 48 R 58 , or -S(O) 2 NR 48 R 58 is fluoro; R 48 at each occurrence is independently hydrogen or lower alkyl; and t is O, 1, 2, or 3.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • A] is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, and R 62 , R 64 , R 65 and R 66 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula III have the structure according to the following sub-generic structure Formula Hie:
  • Formula IIIc all salts, prodrugs, tautomers and isomers thereof, wherein A, s, Z 2 , Z 6 , R 4 , R 5 , R 6 , R 15 , R 17 , and R 32 are as defined for Formula III.
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -
  • R 17 is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro, and R 15 is selected from
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-
  • R 17 is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro
  • R 15 is selected from the group consisting of hydrogen, halogen,
  • compounds of Formula III have the structure according to the following sub-generic structure Formula DIn:
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -
  • R 15 is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-
  • R 1S is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy
  • Z 2 is N or CR 12
  • Z 6 is N or CR 16
  • R 12 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy
  • R 5 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and -NR 21 R 22 , wherein R 21 is hydrogen or lower alkyl
  • compounds of Formula III have the structure according to the following sub-generic structure Formula IHo:
  • Formula IHo all salts, prodrugs, tautomers and isomers thereof, wherein A, L 2 , Z 2 , Z 4 , Z 5 , Z 6 , R 4 , R 5 , R 6 , and R 33 are as defined for Formula HI.
  • R 4 and R 6 are hydrogen, A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , and R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycl
  • R 4 and R 6 are hydrogen, A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cyclo
  • R 4 and R 6 are hydrogen, A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy, and R 5 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and NR 21 R 22 , wherein R 21 is hydrogen or lower alkyl, and R 22 is hydrogen, lower alkyl, optionally substituted aryl or
  • compounds of Formula III have the structure according to the following sub-generic structure Formula IHq:
  • a 1 is -O-, -CR 40 R 41 -, -C(O)- or -NR 48 -;
  • Z 12 is N or CR 52 ;
  • Zi 4 is N or CR 54 ;
  • Z 15 is N or CR 55 ;
  • Z 16 is N or CR 56 ;
  • R 40 and R 41 are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or R and R !
  • a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
  • L 3 is selected from the group consisting of -NR 48 -, -S-, -O-, -NR 48 CH(R 49 )-, -SCH(R 49 )-, -OCH(R 49 )-, -C(O)NR 48 -, -S(O) 2 NR 48 -, -CH(R 49 )NR 48 -, -CH(R 49 )O-, -CH(R 49 )S-, -NR 48 C(O)-, and -NR 48 S(O) 2 -;
  • R 54 and R 55 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino or cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro;
  • R 52 and R 56 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • R 49 is selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl
  • Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
  • R 39 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 50 is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino;
  • R 51 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 23 at each occurrence is independently selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 57 , -SR 57 , -NR 48 R 57 , -NR 48 C(O)R 57 , -NR 48 S(O) 2 R 57 , -S(O) 2 R 57 , -C(O)R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , -S(O) 2 NR 48 R 57 , 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 al
  • R 57 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 57 , -SR 57 , -NR 48 R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , or -S(O) 2 NR 48 R 57 is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycl
  • R 58 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, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 58 , -SR 58 , -NR 48 R 58 , -C(O)OR 58 , -C(O)NR 48 R 58 , or -S(O) 2 NR 48 R 58 is fluoro;
  • R 48 at each occurrence is independently hydrogen or lower alkyl; and t is 0, 1, 2, or 3.
  • a 1 is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -, and R 54 and R 55 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • L 3 is -NR 48 CH(R 49 )-, -SCH(R 49 )-, or -OCH(R 49 )-, preferably -OCH(R 49 )-.
  • a 1 is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -CH 2 -
  • L 3 is -NR 48 CH(R 49 )-, -SCH(R 49 )-, or -OCH(R 49 )-, preferably -OCH(R 49 )-.
  • compounds of Formula III have the structure according to the following sub-generic structure Formula Illd:
  • Formula IHd all salts, prodrugs, tautomers and isomers thereof, wherein A, Z 2 , Z 4 , Z 5 , Z 6 , R 4 , R 5 , R 6 , R 10 , R 11 and R 33 are as defined for Formula III, and r is 0, 1, or 2.
  • R 4 and R 6 are hydrogen, A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , and R 12 , R 14 , R ls and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino
  • R 4 and R 6 are hydrogen, A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , R 12 , R 14 , R 1S and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and
  • R 4 and R 6 are hydrogen, A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy, R 10 and R 11 are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, and fluoro substituted lower alkyl, and R 5 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and NR
  • R 22 is hydrogen, lower alkyl, optionally substituted aryl or optionally substituted heteroaryl, and wherein the alkyl chain of R 5 , R 21 or R 22 , when lower alkyl, or the alkyl chain of lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylarnino, di-alkylamino and cycloalkylamino.
  • compounds of Formula III have the structure according to the following sub-generic structure Formula IHe:
  • a 1 is -O-, -CR 40 R 41 -, -C(O)- or -NR 48 -;
  • Z 22 is N or CR 62 ;
  • Z 24 is N or CR 64 ;
  • Z 25 is N or CR 65 ;
  • Z 26 is N or CR 66 ; r is O, I, or 2;
  • R 40 and R 41 are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or
  • R 40 and R 41 combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
  • R 62 , R 64 , R 65 and R 66 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2> lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro;
  • Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
  • R 39 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 50 is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino;
  • R 51 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ;
  • R 23 at each occurrence is independently selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 57 , -SR 57 , -NR 48 R 57 , -NR 48 C(O)R 57 , -NR 48 S(O) 2 R 57 , -S(O) 2 R 57 , -C(O)R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , -S(O) 2 NR 48 R 57 , 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 al
  • R 57 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 57 , -SR 57 , -NR 48 R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , or -S(O) 2 NR 48 R 57 is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycl
  • R 58 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, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 58 , -SR 58 , -NR 48 R 58 , -C(O)OR 58 , -C(O)NR 48 R 58 , or -S(O) 2 NR 48 R 58 is fluoro;
  • R 48 at each occurrence is independently hydrogen or lower alkyl; and t is O, 1, 2, or 3.
  • Aj is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, and R 62 , R 64 , R 65 and R 66 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula III have the structure according to the following sub-generic structure Formula Illf:
  • Formula IIIf all salts, prodrugs, tautomers and isomers thereof, wherein A, Z 2 , Z 4 , Z 5 , Z 6 , X, R 4 , R 5 , R 6 , R 34 , R 35 and R 82 are as defined for Formula III.
  • R 4 and R 6 are hydrogen, A is -0-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , and R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cyclo
  • R 4 and R 6 are hydrogen, A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-, Z 2 is N or CR 12 , Z 4 is N or CR 14 , Z 5 is N or CR 15 , Z 6 is N or CR 16 , R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycl
  • compounds of Formula III have the structure according to the following sub-generic structure Formula IHg:
  • a 1 is -O-, -CR 40 R 41 -, -C(O)- or -NR 48 -;
  • Z 32 is N or CR 72 ;
  • Z 34 is N or CR 74 ;
  • Z 35 is N or CR 75 ;
  • Z 36 is N or CR 76 ;
  • X is O or S;
  • R 48 at each occurrence is independently hydrogen or lower alkyl;
  • R 40 and R l are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or
  • R 40 and R ] combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
  • R 72 , R 74 , R 75 and R 76 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl and lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro;
  • R 67 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)OR 68 , -C(O)
  • R 68 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)OR 68 , -C(O)NR 69 R 68 , -C(S)NR 69 R 68 , -S(O) 2 NR 69 R 68 , -NR 69 C(O)R 68 , -NR 69 C(S)R 68 , -NR 69 S(O) 2 R 68 , -NR 69 C(O)NH 2 , -NR 69 C(O)NR
  • R 69 is hydrogen or optionally substituted lower alkyl
  • R 70 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 82 is hydrogen or lower alkyl.
  • a 1 is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • R 67 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S
  • compounds of Formula III have the structure according to the following sub-generic structure Formula HIh:
  • R 4 and R 6 are hydrogen
  • A is -0-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-
  • R 42 , R 43 , R 45 , R 46 and R 47 are independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO 2 , -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, and cycloalkylamino, further wherein at least one of, at least two of, at least three of, at least four of, or preferably all of R 42 , R 43 , R 45 , R 46 and R 47 are hydrogen.
  • compounds of Formula III have the structure according to the following sub-generic structure Formula ffli:
  • a 1 is -O-, -CR 40 R 41 -, -C(O)- or -NR 48 -;
  • X is O or S
  • R 48 at each occurrence is independently hydrogen or lower alkyl
  • R 40 and R 41 are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or
  • R 40 and R 41 combine to form a 3-7 mer ⁇ bered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
  • R 67 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)OR 68 , -C(O)
  • R 68 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)OR 68 , -C(O)NR 69 R 68 , -C(S)NR 69 R 68 , -S(O) 2 NR 69 R 68 , -NR 69 C(O)R 68 , -NR 69 C(S)R 68 , -NR 69 S(O) 2 R 68 , -NR 69 C(O)NH 2 , -NR 69 C(O)NR
  • R 69 is hydrogen or optionally substituted lower alkyl
  • R 70 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • A] is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, and R 67 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S(O) 2 NR 69 R
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -C(O)-
  • R 67 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and NR 21 R 22 , wherein R 21 is hydrogen or lower alkyl, and R 22 is hydrogen, lower alkyl, optionally substituted aryl or optionally substituted heteroaryl, and wherein the alkyl chain of R 67 , R 21 or R 22 , when lower alkyl, or the alkyl chain of lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkyl
  • a 1 is -C(O)-
  • R 67 is optionally substituted aryl or optionally substituted heteroaryl
  • one of R 60 and R 61 is lower alkyl or fluoro substituted lower alkyl
  • the other of R 60 and R 61 is hydrogen or lower alkyl.
  • compounds of Formula III have the structure according to the following sub-generic structure Formula HIj:
  • Formula IHj all salts, prodrugs, tautomers and isomers thereof, wherein A, R 4 , R 5 , R 6 , R 12 , R 14 , R 15 , R 16 , and R 36 are as defined for Formula III.
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-
  • R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro, preferably where
  • R 4 and R 6 are hydrogen
  • A is -O-, -CR a R b -, -NR 1 -, or -C(O)-, preferably -CH 2 - or -C(O)-
  • R 12 , R 14 , R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the -O- of lower alkoxy is fluoro, preferably where
  • compounds of Formula III have the structure according to the following sub-generic structure Formula ink:
  • a 1 is -O-, -CR 40 R 41 -, -C(O)- or -NR 48 -;
  • R 81 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)
  • R 71 and R 78 are independently selected from the group consisting of hydrogen, halogen, Ci -3 alkyl, and fluoro substituted Ci -3 alkyl;
  • R 77 is selected from the group consisting of substituted methyl, optionally substituted C 2-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and -NR 79 R 80 , wherein methyl is substituted with one or more substituents selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
  • R 68 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)OR 68 , -C(O)NR 69 R 68 , -C(S)NR 69 R 68 , -S(O) 2 NR 69 R 68 , -NR 69 C(O)R 68 , -NR 69 C(S)R 68 , -NR 69 S(O) 2 R 68 , -NR 69 C(O)NH 2 , -NR 69 C(O)NR
  • R 69 is hydrogen or optionally substituted lower alkyl
  • R 79 and R 80 are independently hydrogen or optionally substituted lower alkyl, or R 79 and R 80 combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -C(O)-.
  • Ai is -CR 40 R 41 - or -C(O)-, preferably -CH 2 - or -C(O)-, more preferably -C(O)-, and R 81 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)NR 69 R 68 , -S(O) 2 NR 69 R 68 , -S(O) 2 NR 69 R 68 , -
  • compounds of Formula III have the structure according to the following sub-generic structure Formula IHm:
  • R 81 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)
  • R 83 is selected from the group consisting of hydrogen, fluoro and chloro;
  • R 112 is selected from the group consisting of optionally substituted C 2-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and -NR 79 R 80 ;
  • R 68 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)OR 68 , -C(O)NR 69 R 68 , -C(S)NR 6 V 8 , -S(O) 2 NR 69 R 68 , -NR 69 C(O)R 68 , -NR 69 C(S)R 68 , -NR 69 S(O) 2 R 68 , -NR 69 C(O)NH 2 , -NR 69 C(O)NR 69 R
  • R 69 is selected from the group consisting of hydrogen and optionally substituted lower alkyl
  • R 79 and R 80 are independently hydrogen or optionally substituted lower alkyl, or R 79 and R 80 combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl.
  • R 81 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 68 , -SR 68 , -NR 69 R 68 , -C(O)R 68 , -C(S)R 68 , -C(O)NR 69 R 68 , -S(O) 2 NR 69 R 68 , -NR 69 C(O)R 68 , -NR 69 S(O) 2 R 68 , -S(O)R 68 , and -S(O) 2 R 68 ,
  • the present invention includes compounds that are useful as intermediates in the preparation of compounds of Formula III, the compounds having a structure selected from the group consisting of Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, and Formula IX as follows:
  • Z 2 , Z 4 , Z 5 , Z 6 , L 2 , X, s, R 15 , R 17 , R 31 , R 32 , R 33 , R 37 , R 38 , R 42 , R 43 , R 45 , R 46 , and R 47 are as defined for Formula III;
  • R 108 is selected from the group consisting of -C(O)R 84 , -CH 2 I, -CH 2 Cl, -CH 2 Br, -CH 2 OH, and -CH 2 OS(O) 2 R 109 ;
  • R 109 is selected from the group consisting of lower alkyl and aryl
  • R 84 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl;
  • R 85 is selected from the group consisting of hydrogen, a nitrogen protecting group, -S(O) 2 R 87 , -C(O)NR 88 R 89 , and -C(S)NR 88 R 89 ;
  • R 86 is selected from the group consisting of hydrogen, lower alkyl, and a nitrogen protecting group
  • R 87 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 87 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to S(O) 2 , optionally substituted lower alkynyl, provided, however, that when R 87 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to S(O) 2 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and -NR 90 R 91 ; and
  • R 88 , R 89 , R 90 and R 91 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 88 and R 89 together with the nitrogen to which they are attached form optionally substituted 5-7 membered lieterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl.
  • R 108 is -C(O)R 84 , preferably wherein R 84 is hydrogen.
  • Z 2 is N or CR 12
  • Z 4 is N or CR 14
  • Z 5 is N or CR 15
  • Z 6 is N or CR 16 and R 12 , R 14 , R 15 , R 16 , R 17 , R 42 , R 43 , R 45 , R 46 and R 47 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula IV have the structure according to the following sub-generic structure Formula IVa:
  • R 84 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl;
  • R 92 , R 93 , R 95 , and R 96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • L 4 is selected from the group consisting of -NR 48 -, -S-, -O-, -NR 48 CH(R 49 )-, -SCH(R 49 )-, -OCH(R 49 )-, -C(O)NR 48 -, -S(O) 2 NR 48 -, -CH(R 49 )NR 48 -, -CH(R 49 )O-, -CH(R 49 )S-, -NR 48 C(O)-, and -NR 48 S(O) 2 -;
  • Cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
  • R 97 at each occurrence is independently selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 57 , -SR 57 , -NR 48 R 57 , -NR 48 C(O)R 57 , -NR 48 S(O) 2 R 57 , -S(O) 2 R 57 , -C(O)R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , -S(O) 2 NR 48 R 57 , 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
  • R 49 is selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl
  • R 57 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 57 , -SR 57 , -NR 48 R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , or -S(O) 2 NR 48 R 57 is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycl
  • R 58 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, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 58 , -SR 58 , -NR 48 R 58 , -C(O)OR 58 , -C(O)NR 48 R 58 , or -S(O) 2 NR 48 R 58 is fluoro;
  • R 48 at each occurrence is independently hydrogen or lower alkyl; and u is O, 1, 2, or 3.
  • R 92 , R 93 , R 95 and R 96 are hydrogen. In some embodiments, at least two of R 92 , R 93 , R 95 and R 96 are hydrogen, L 4 is -NR 48 CH(R 49 )-, -SCH(R 49 )-, or -OCH(R 49 )-, preferably L 4 is -OCH 2 -, Cy is aryl or heteroaryl, and each R 97 is independently selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula IV have the structure according to the following sub-generic structure Formula IVb:
  • At least two of R 92 , R 93 , R 95 and R 96 are hydrogen. In some embodiments, at least two of R 92 , R 93 , R 95 and R 96 are hydrogen, Cy is aryl or heteroaryl, and each R 97 is independently selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula V have the structure according to the following sub-generic structure Formula Va:
  • R 84 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl;
  • R 92 , R 93 , R 95 , and R 96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • R 98 is selected from the group consisting of hydrogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; and s is 0, 1, or 2;
  • compounds of Formula VI have the structure according to the following sub-generic structure Formula Via:
  • R 84 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl
  • R 92 , R 94 , R 95 , and R 96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • L 4 is selected from the group consisting of -NR 48 -, -S-, -O-, -NR 48 CH(R 49 )-, -SCH(R 49 )-, -OCH(R 49 )-, -C(O)NR 48 -, -S(O) 2 NR 48 -, -CH(R 49 )NR 48 -, -CH(R 49 )O-, -CH(R 49 )S-, -NR 48 C(O)-, and -NR 48 S(O) 2 -;
  • Cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
  • R 97 at each occurrence is independently selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -C(O)OH, -S(O) 2 NH 2 , -C(O)NH 2 , -OR 57 , -SR 57 , -NR 48 R 57 , -NR 48 C(O)R 57 , -NR 48 S(O) 2 R 57 , -S(O) 2 R 57 , -C(O)R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , -S(O) 2 NR 48 R 57 , 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
  • R 49 is selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl
  • R 57 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 57 , -SR 57 , -NR 48 R 57 , -C(O)OR 57 , -C(O)NR 48 R 57 , or -S(O) 2 NR 48 R 57 is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycl
  • R 58 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, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of -OR 58 , -SR 58 , -NR 48 R 58 , -C(O)OR 58 , -C(O)NR 48 R 58 , or
  • R 58 is fluoro
  • R 48 at each occurrence is independently hydrogen or lower alkyl; and u is 0, 1, 2 or 3.
  • R 92 , R 94 , R 95 and R 96 are hydrogen.
  • at least two of R 92 , R 94 , R 95 and R 96 are hydrogen
  • L 4 is -NR 48 CH(R 49 )-, -SCH(R 49 )-, or -OCH(R 49 )-, preferably L 4 is -OCH 2 -
  • Cy is aryl or heteroaryl
  • each R 97 is independently selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula VI have the structure according to the following sub-generic structure Formula VIb:
  • At least two of R 92 , R 94 , R 95 and R 96 are hydrogen. In some embodiments, at least two of R 92 , R 94 , R 95 and R 96 are hydrogen, Cy is aryl or heteroaryl, and each R 97 is independently selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula VII have the structure according to the following sub-generic structure Formula Vila:
  • R 84 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl;
  • R 92 , R 94 , R 95 , and R 96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • R 99 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, and -NR 79 R 80 ; and
  • R 79 and R 80 are independently hydrogen or optionally substituted lower alkyl, or R 79 and R so combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl.
  • one of R 92 and R 96 is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy, and the other of R 92 and R 96 is selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; in further embodiments, one of R 92 and R 96 is hydrogen, fluoro or chloro, and the other of R 92 and R 96 is fluoro or chloro; in further embodiments, R 92 is fluoro and R 96 is hydrogen, fluoro, or chloro; in further embodiments, R 92 and R 96 are both fluoro.
  • R 94 and R 95 are hydrogen; in further embodiments, one of R 92 and R 96 is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy and the other of R 92 and R 96 is selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; in further embodiments, one of R 92 and R 96 is selected from hydrogen, fluoro or chloro and the other of R 92 and R 96 is selected from fluoro or chloro; in further embodiments, R 92 is fluoro and R 96 is selected from hydrogen, fluoro, or chloro; in further embodiments, R 92 and R 96 are both fluoro.
  • compounds of Formula VII have the structure according to the following sub-generic structure Formula VIIb:
  • R 84 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl;
  • R 92 , R 94 , R 95 , and R 96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • R 82 is hydrogen or lower alkyl; one of R 100 and R 101 is lower alkyl, fluoro substituted lower alkyl, or -(CH 2 V 2 R 70 , and the other of
  • R 100 and R 101 is hydrogen or lower alkyl; or R 100 and R 101 together with the nitrogen to which they are attached form optionally substituted 5-7 membered heterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl; and R 70 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • At least two of R 92 , R 94 , R 95 and R 96 are hydrogen. In some embodiments, at least two of R 92 , R 94 , R 95 and R 96 are hydrogen, and R 70 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • compounds of Formula VDI have the structure according to the following sub-generic structure Formula Villa:
  • R 84 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl;
  • R 102 , R 103 , R 105 , R 106 , and R 107 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • one of R 100 and R 101 is lower alkyl, fluoro substituted lower alkyl, or -(CH 2 V 2 R 70 and the other of
  • R 100 and R 101 is hydrogen or lower alkyl; or R 100 and R 101 together with the nitrogen to which they are attached form optionally substituted
  • R 70 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • At least two, also at least three, also at least four, or all of R 102 , R 103 , R 105 , R 106 , and R 107 are hydrogen. In some embodiments, at least two, also at least three, also at least four, or all of R 102 , R 103 , R 105 , R 106 , and R 107 are hydrogen, and R 70 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fiuoro substituted lower alkyl, lower alkoxy, and fiuoro substituted lower alkoxy.
  • compounds of Formula IX have the structure according to the following sub-generic structure Formula DCa:
  • R s4 is selected from the group consisting of hydrogen, lower alkoxy, -OH, and -Cl;
  • R 92 , R 95 , and R 96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fiuoro substituted lower alkoxy;
  • R 98 is selected from the group consisting of hydrogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; and s is O, 1, or 2.
  • R 84 is hydrogen
  • 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; 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 present invention: -NR-CH 2 -NR-, -0-CH 2 -NR-, -S-CH 2 -NR-, -NR-CH 2 -O-, -0-CH 2 -O-, -S-CH 2 -O-, -NR-CH 2 -S-, -0-CH 2 -S-, -S-CH
  • the invention provides 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 Formula III.
  • treat refers to the administration of material, e.g., compound of Formula HI, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated.
  • protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a protein kinase affects the development and/or course of the disease or condition, and/or in which modulation of the protein kinase alters the development, course, and/or symptoms of the disease or condition.
  • a protein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit, e.g. wherein treatment with protein kinase inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the method involves administering to the subject an effective amount of a compound of Formula III in combination with one or more other therapies for the disease or condition.
  • the invention provides methods for treating a Raf protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of a compound of Formula III.
  • Raf protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a Raf kinase, including any mutations thereof, affects the development and/or course of the disease or condition, and/or in which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease or condition.
  • the Raf protein kinase includes, but is not limited to, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1.
  • the Raf protein kinase is B-Raf mutation V600E.
  • the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E mutant B-Raf.
  • a Raf protein kinase mediated disease or condition includes a disease or condition for which Raf inhibition provides a therapeutic benefit, e.g. wherein treatment with Raf inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the method involves administering to the subject an effective amount of a compound of Formula III in combination with one or more other therapies for the disease or condition.
  • the invention provides methods for treating a Fms 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 Formula HI.
  • Fms protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a Fms protein kinase, including any mutations thereof, affects the development and/or course of the disease or condition, and/or in which modulation of Fms alters the development, course, and/or symptoms of the disease or condition.
  • a Fms mediated disease or condition includes a disease or condition for which Fms inhibition provides a therapeutic benefit, e.g. wherein treatment with Fms inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the method involves administering to the subject an effective amount of a compound of Formula III in combination with one or more other therapies for the disease or condition.
  • the invention provides methods for treating a Kit 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 Formula III.
  • Kit mediated disease or condition refers to a disease or condition in which the biological function of a Kit protein kinase, including any mutation thereof, affects the development and/or course of the disease or condition, and/or in which modulation of Kit alters the development, course, and/or symptoms of the disease or condition.
  • a Kit mediated disease or condition includes a disease or condition for which Kit inhibition provides a therapeutic benefit, e.g.
  • Kit inhibitors including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the method involves administering to the subject an effective amount of a compound of Formula III in combination with one or more other therapies for the disease or condition.
  • the invention provides methods for treating a Jnk 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 Formula III.
  • Jnk mediated disease or condition refers to a disease or condition in which the biological function of a Jnk kinase, e.g. Jnkl, Jnk2, Jnk3, or any mutation thereof, affects the development and/or course of the disease or condition, and/or in which modulation of the Jnk kinase alters the development, course, and/or symptoms of the disease or condition.
  • a Jnk mediated disease or condition includes a disease or condition for which Jnk inhibition provides a therapeutic benefit, e.g. wherein treatment with Jnk inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the method involves administering to the subject an effective amount of a compound of Formula III in combination with one or more other therapies for the disease or condition.
  • the Jnk protein kinase includes, but is not limited to, Jnkl, Jnk2, or Jnk3.
  • a compound of the invention 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 kinase activity assay.
  • a compound of Formula m will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to at least one kinase selected from the group consisting of B-Raf, c-Raf-1, Fms, JrM, Jnk2, Jnk3, and Kit, and any mutations thereof.
  • a compound of Formula III will have an IC 5O of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to at least one kinase selected from the group consisting of B-Raf, B-Raf V600E mutant, c-Raf-1, Fms, Jnkl, Jnk2, Jnk3, and Kit, preferably B-Raf, B-Raf V600E mutant or c-Raf-1.
  • a compound of 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 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 B-Raf, c-Raf-1, or B-Raf V600E mutant.
  • a compound of Formula III will selectively inhibit one Raf kinase relative to one or more other Raf kinases.
  • the compound of Formula III will selectively inhibit a mutation of the Raf kinase relative to the wild type kinase, for example B-Raf V600E relative to wild type B-Raf.
  • a compound of Formula III is an inhibitor of a Fms 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 Fms kinase activity assay.
  • a compound of Formula III will selectively inhibit Fms kinase relative to Kit kinase.
  • a compound of Formula III is an inhibitor of a Kit 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 Kit kinase activity assay.
  • a compound of Formula III is an inhibitor of a Jnk 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 Jnk kinase activity assay.
  • a compound of Formula JJI is an inhibitor of a Jnkl 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 Jnkl kinase activity assay.
  • a compound of Formula III is an inhibitor of a Jnk2 kinase and has an IC 5 O of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 iiM as determined in a generally accepted Jnk2 kinase activity assay.
  • a compound of Formula III is an inhibitor of a Jnk3 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 Jnk3 kinase activity assay.
  • a compound of Formula III will selectively inhibit one Jnk kinase relative to one or more other Jnk kinases, such as selectively inhibiting Jnk 1 relative to Jnk 2 and/or Jnk3, selectively inhibiting Jnk2 relative to Jnk3 and/or Jnkl, or selectively inhibiting Jnk3 relative to Jnkl and/or Jnk 2.
  • a compound of the invention will inhibit the effects of a mutation of the kinase, including, but not limited to, a mutation that is related to a disease state, such as a cancer.
  • a mutation that is related to a disease state such as a cancer.
  • B-Raf V600E mutant is present in a high percentage of some cancers, such as melanoma, and compounds of the invention will inhibit the kinase activity of this mutant.
  • a compound of the invention may selectively inhibit one kinase relative to one or more other kinases, where preferably inhibition is selective with respect to any of the other kinases, whether a kinase discussed herein, or other kinases.
  • the compound may selectively inhibit the effects of a mutation of the kinase relative to the wild type kinase, for example B-Raf V600E relative to wild type B-Raf.
  • the compound may selectively inhibit Fms relative to Kit.
  • IC 50 for the one kinase may be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold, also 50-fold, or at least about 100-fold less than the IC 50 for any of the other kinases as determined in a generally accepted kinase activity assay.
  • the invention provides 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 a compound of Formula III.
  • the invention provides methods for treating a disease or condition mediated by a protein kinase selected from the group consisting of B-Raf, c-Raf-1, Fms, Jnkl, Jnk2, Jnk3, and Kit, and any mutations thereof, by administering to the subject an effective amount of a composition including a compound of Formula III.
  • a protein kinase selected from the group consisting of B-Raf, c-Raf-1, Fms, Jnkl, Jnk2, Jnk3, and Kit, and any mutations thereof.
  • the invention provides methods for treating a disease or condition mediated by B-Raf, c-Raf-1 , or B-Raf V600E by administering to the subject an effective amount of a composition including a compound of Formula IJJ.
  • the invention provides methods for treating a disease or condition mediated by B-Raf, c-Raf-1, or B-Raf V600E by administering to the subject an effective amount of a composition including a compound of Formula III in combination with one or more other suitable therapies for treating the disease or condition.
  • the invention provides methods for treating a cancer mediated by B-Raf V600E mutant by administering to the subject an effective amount of a composition including a compound of 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 or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of a compound of 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 a compound of Formula HI, 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.
  • the invention provides compositions that include a therapeutically effective amount of a compound of Formula III and at least one pharmaceutically acceptable carrier, excipient, and/or diluent.
  • the composition can include a plurality of different pharmacologically active compounds, which can include a plurality of compounds of Formula III.
  • kits that include a composition as described herein.
  • the composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the composition is approved by the U.S.
  • the composition is approved for administration to a mammal, e.g., a human, for a protein kinase mediated disease or condition;
  • the invention kit includes written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a protein kinase-mediated disease or condition; and the composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.
  • the disease or condition is, for example without limitation, selected from the group consisting of neurologic diseases such as ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, and Huntington's disease; neoplastic diseases and associated complications, including chemotherapy-induced hypoxia, gastrointestinal stromal tumors (GISTs), prostate tumors, mast cell tumors (including canine mast cell tumors), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g.
  • neurologic diseases such as ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer'
  • carcinomas e.g. lung, breast, pancreatic, renal, female genital tract, carcinoma in situ
  • lymphoma e.g. histiocytic lymphoma
  • neurofibromatosis including Schwann cell neoplasia
  • myelodysplastic syndrome leukemia, tumor angiogenesis, and cancers of the thyroid, liver, bone, skin, brain, pancreas, lung (e.g. small cell lung cancer), breast, colon, prostate, testes and ovary
  • pain of neuropathic or inflammatory origin including acute pain, chronic pain, and migraine
  • cardiovascular diseases including heart failure, cardiac hypertrophy, thrombosis (e.g.
  • thrombotic microangiopathy syndromes thrombotic microangiopathy syndromes
  • atherosclerosis reperfusion injury and ischemia
  • ischemia e.g. cerebrovascular ischemia, liver ischemia
  • inflammation including, but not limited to, polycystic kidney disease (PKD), 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, vascular restenosis, fibrotic disorders, hypereosinophilia, CNS inflammation, pancreatitis, nephritis, atopic dermatitis, and
  • compounds of Formula IH can be used in the preparation of a medicament for the treatment of a B-Raf-mediated disease or condition, selected from the group consisting of neurologic diseases such as ischemic stroke, 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. lung, breast, pancreatic, renal), lymphoma (e.g. histiocytic lymphoma) and cancer of the thyroid, lung (e.g.
  • a B-Raf-mediated disease or condition selected from the group consisting of neurologic diseases such as ischemic stroke, 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. lung,
  • liver small cell lung cancer
  • breast breast
  • ovary and colon neurofibromatosis
  • myelodysplastic syndrome myelodysplastic syndrome
  • leukemia a tumor angiogenesis
  • pain of neuropathic or inflammatory origin including acute pain, chronic pain, and migraine
  • cardiovascular diseases including heart failure, cardiac hypertrophy, thrombosis (e.g.
  • thrombotic microangiopathy syndromes thrombotic microangiopathy syndromes
  • atherosclerosis reperfusion injury
  • inflammation including, but not limited to, psoriasis, polycystic kidney disease (PKD), arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, f ⁇ brotic disorders, rheumatoid arthritis, inflammatory bowel disease (EBD); immunodeficiency diseases, organ transplant rejection, graft versus host disease; renal or prostatic diseases including diabetic nephropathy, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, obesity; infection, including, but not limited to Helicobacter pylori and Influenza virus, fever, sepsis; pulmonary diseases including chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases such as Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome
  • compounds of Formula III can be used in the preparation of a medicament for the treatment of a c-Raf-1 -mediated disease or condition selected from the group consisting of colorectal, ovarian, lung and renal cell carcinoma, acute myeloid leukemia, myelodysplastic syndromes, tumor angiogenesis, and neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma.
  • compounds of Formula III can be used in the preparation of a medicament for the treatment of a Fms-mediated disease or condition selected from the group consisting of immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), Wegener's granulomatosis, and transplant rejection, inflammatory diseases including Chronic Obstructive Pulmonary Disease (COPD), emphysema, and atherosclerosis, metabolic disorders, including insulin resistance, hyperglycemia, and lipolysis, disorders of bone structure or mineralization, including osteoporosis, increased risk of fracture, hypercalcemia, and bone metastases, kidney diseases, including nephritis (e.g.
  • glomerulonephritis including interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications, and hypertrophy and cancers, including multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia (CML), breast cancer, and ovarian cancer.
  • CML chronic myeloid leukemia
  • compounds of Formula in can be used in the preparation of a medicament for the treatment of a Jnk-mediated disease or condition selected from the group consisting of Metabolic diseases including type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, and hepatic steatosis; cardiovascular diseases such as atherosclerosis, ischemia (e.g.
  • renal diseases such as chronic renal failure
  • neoplastic diseases and associated complications including chemotherapy- induced hypoxia, prostate tumors, myeloid leukemia and cancers of the liver, bone, skin, brain, pancreas, lung breast, colon, prostate and ovary
  • transplant rejection pain of neuropathic or inflammatory origin including acute and chronic pain
  • inflammatory and autoimmune diseases including age-related macular degeneration, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, psoriasis, scleroderma, chronic thyroiditis
  • Grave's disease myasthenia gravis, and multiple sclerosis, and inflammation in other organs including CNS inflammation, pancreatitis, nephritis, atopic dermatitis, and hepatitis
  • airway inflammatory diseases such
  • compounds of Formula III can be used in the preparation of a medicament for the treatment of a Jnkl -mediated disease or condition selected from the group consisting of type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity and hepatic steatosis.
  • compounds of Formula III can be used in the preparation of a medicament for the treatment of a Jnk2-mediated disease or condition, such as atherosclerosis.
  • compounds of Formula III can be used in the preparation of a medicament for the treatment of a Jnk3 -mediated disease or condition selected from the group consisting of inflammatory diseases including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, psoriasis and multiple sclerosis, airway inflammatory diseases such as asthma, allergy, pulmonary fibrosis, and chronic obstructive pulmonary disease, and inflammation in other organs, such as CNS inflammation, pancreatitis, nephritis, and hepatitis; neurologic diseases such as stroke, cerebrovascular ischemia, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease; and neoplastic diseases such as prostate tumors and myeloid leukemia.
  • autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic
  • compounds of Formula IH can be used in the preparation of a medicament for the treatment of a Kit-mediated disease or condition selected from the group consisting of malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.
  • malignancies including mast cell tumors, small cell
  • Halogen refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
  • Thiol refers to the group -SH.
  • Lower alkyl alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl.
  • the straight chain or branched alkyl group is attached at any available point to produce a stable compound.
  • a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.
  • a “substituted lower alkyl” denotes lower alkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)R 0 , -C(S)R 0
  • substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula III, attached at any available atom to produce a stable compound.
  • fluoro substituted lower alkyl denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms.
  • substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -OR (e.g. alkoxy), -SR (e.g.
  • 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 ring atom) excludes substituents that would result in any O, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkyl carbon bound to any O, S, or N of the moiety.
  • C 2-6 alkyl denotes lower alkyl containing 2-6 carbon atoms.
  • a “substituted C 2-6 alkyl” denotes optionally substituted lower alkyl containing 2-6 carbon atoms.
  • a “substituted methyl” denotes methyl that is independently substituted, unless indicated otherwise, with 1, 2, or 3 substituents, wherein the substituents are selected as per optionally substituted lower alkyl.
  • Ci -3 alkylene refers to a divalent alkane-derived radical containing 1-3 carbon atoms, straight chain or branched, from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms.
  • Ci -3 alkylene includes methylene -CH 2 -, ethylene -CH 2 CH 2 -, propylene -CH 2 CH 2 CH 2 -, and isopropylene -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-.
  • C 1-3 alkylene substituted with one or more substituents indicates Ci -3 alkylene that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents as indicated, attached at any available atom to produce a stable compound.
  • Lower alkenyl alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
  • a "substituted lower alkenyl” denotes lower alkenyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)R 0
  • substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula III, attached at any available atom to produce a stable compound.
  • fluoro substituted lower alkenyl denotes a lower alkenyl group substituted with one or more fluoro atoms, where preferably the lower alkenyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms.
  • 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, -C(O)R, and the like
  • substitution of the moiety is such that any -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -0-, -S-, or N thereof (except where N is a heteroaryl ring 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, -NHR, -C(O)NHR, and the like
  • substitution of the alkenyl R group is such that substitution of the alkenyl carbon bound to any O, S, or N of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkenyl carbon bound to any O, S, or N of the moiety.
  • 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, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)R 0 , -C(S)R
  • substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula III, attached at any available atom to produce a stable compound.
  • fluoro substituted lower alkynyl denotes a lower alkynyl group substituted with one or more fluoro atoms, where preferably the lower alkynyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms.
  • substitutions are attached at any available atom to produce a stable compound
  • substitution of alkynyl groups are such that -F, -C(O)-, -C(S)-, -C(NH)-, -S(O)-, -S(O) 2 -, -O-, -S-, or N (except where N is a heteroaryl ring atom) are not bound to an alkyne carbon thereof.
  • alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like
  • substitution of the moiety is such that any -C(O)-, -C(S)-,-S(O)-, -S(O) 2 -, -0-, -S-, or N thereof (except where N is a heteroaryl ring atom) are not bound to an alkyne carbon of the alkynyl substituent or R group.
  • alkynyl is a substituent of another moiety or an R group of a moiety such as -OR 1 -NHR, -C(O)]SlHR, 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 within an alkynyl group, whether saturated or part of the carbon to carbon triple bond.
  • alkyne carbon refers to a carbon within an alkynyl group that is part of a carbon to carbon triple bond.
  • Cycloalkyl refers to saturated or unsaturated, non-aromatic monocyclic, bicycHc or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • a “substituted cycloalkyl” is a cycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O
  • Heterocycloalkyl refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e.
  • the ring carbon is a carbonyl group, such as lactones and lactams.
  • the point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained.
  • heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl.
  • a “substituted heterocycloalkyl” is a heterocycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)R
  • Aryl alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members.
  • a "substituted aryl” is an aryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0 , -C(O)R 0 ,
  • Heteroaryl alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl.
  • Nitrogen containing heteroaryl 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, wherein the substituents are selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR 0 , -SR 0 , -OC(O)R 0 , -OC(S)R 0
  • R 0 , R p , R c , R d , R e , R f and R g as used in the description of optional substituents for alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are defined as follows:
  • each R 0 , R p , and R° are independently selected from the group consisting of R d , R e , R f , and R g , or R p and R c combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -NO 2 , -CN, -OH, -NH 2 , -OR U , -SR U , -NHR U , -NR U R U , -R x , and -R y ;
  • each R d is independently lower alkyl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -0C(0)R k , -OC(S)R k , -C(0)R k , -C(S)R k , -C(0)0R ⁇ -C(S)OR k , -S(O)R k , -
  • each R e is independently lower alkenyl, wherein lower alkenyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -0C(0)R k , -OC(S)R k , -C(O)R k , -C(S)R k , -C(0)0R ⁇ -C(S)OR k , -S(O)R k
  • each R f is independently lower alkynyl, wherein lower alkynyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -OC(O)R k , -OC(S)R k , -C(0)R k , -C(S)R k , -C(O)OR k , -C(S)OR k , -S(
  • each R g is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R k , -SR k , -0C(0)R k , -OC(S)R
  • R k , R m , and R" at each occurrence are independently selected from the group consisting of R h , R 1 , and R J , or R m and R n combine with the nitrogen to which they are attached form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -NO 2 , -CN, -OH, -NH 2 , OR U , -SR U , -NHR U , -NR U R U , -R x , and -R y ;
  • each R h is independently lower alkyl optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -0R r , -SR r , -OC(O)R r , -OC(S)R r , -C(0)R r , -C(S)R r , -C(0)0R r , -C(S)OR r , -S(O)R r , -S(O)
  • each R 1 is independently selected from the group consisting of lower alkenyl and lower alkynyl, wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH 5 -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR', -SR', -OC(O)R', -OC(S)R', -C(O)R', -C(O)R', -C(S)R'
  • each R j is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)OH, -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)NH 2 , -OR', -SR', -OC(O)R', -OC(S)R', -C(O
  • each R', R s , and R 1 at each occurrence are independently selected from the group consisting of lower alkyl, C 3-6 alkenyl, C 3-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of-R y , fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the lower alkyl carbon bound to any O, S, or N, of -OR r , -SR r , -C(O)OR r , -C(S)OR r , -C(
  • 6 alkenyl or C 3-6 alkynyl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -R y , fiuoro, lower alkyl, fiuoro substituted lower alkyl, lower alkoxy, fiuoro substituted lower alkoxy, lower alkylthio, fiuoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the C 3-6 alkenyl or C 3-6 alkynyl carbon bound to any O, S, or N, of -0R r , -SR r , -C(O)OR r , -C(S)OR r , -C(O)NHR r , -C(S)NHR r , -C(0)NR r R r , -C(S)NR
  • each R u is independently selected from the group consisting of lower alkyl, C 3-6 alkenyl, C 3-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of-R y , fiuoro, -OH, -NH 2 , lower alkoxy, fiuoro substituted lower alkoxy, lower alkylthio, fiuoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the lower alkyl carbon bound to the O of -OR U , S of -SR U , or N of -NHR U is fiuoro or -R y , and wherein C 3-6 alkenyl or C 3-6 alkynyl
  • each R x is selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -R y , fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -R y , fluoro, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkyl
  • each R y is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.
  • all occurrences of optionally substituted lower alkyl, optionally substituted C 2-6 alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, -NO 2 , -CN, -0R la , -SR la , -NR la R la , -OC(O)R la , -OC(S)R la , -C(0)R la , -C(S)R Ia , -C(O)OR !a , -C(S)OR la , -C(0)NR la R Ia , -C(S)NR la R la , -S(O) 2 NR la R la , -C(NH)NR 13 R 1 ⁇ -NR la C(0)R la , -NR la C(S)R la , -NR la S(0)
  • all occurrences of optionally substituted lower alkyl, optionally substituted C 2-6 alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, -CN, -0R la , -SR la , -NR la R la , -C(O)R la , -C(S)R la , -C(O)OR la , -C(O)NR la R la , -C(S)NR la R la , -S(O) 2 NR la R la , -NR la C(O)R la , -NR la C(S)R la , -NR la S(O) 2 R la , -S(O)R la , -S(O) 2 R la , cycloalkyl, heterocycloalkyl, aryl and
  • “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 III, including descriptions of substituted cycloalkyl, cycloheteroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound.
  • substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents.
  • fluoro substituted lower alkoxy denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkoxy are attached at any available atom to produce a stable compound, substitution of alkoxy is such that O, S, or N (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy O.
  • alkoxy is described as a substituent of another moiety
  • the alkoxy oxygen is not bound to a carbon atom that is bound to an O, S, or N of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.
  • Lower alkylthio denotes the group -SR aa , where R aa is lower alkyl.
  • Substituted lower alkylthio denotes lower alkylthio in which R aa is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula III, including descriptions of substituted cycloalkyl, cycloheteroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound.
  • substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents.
  • fluoro substituted lower alkylthio denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkylthio are attached at any available atom to produce a stable compound, substitution of alkylthio is such that O, S, or N (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkylthio S.
  • 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 0C , where R bb and R cc are independently lower alkyl.
  • Cycloalkylamino denotes the group -NR dd R ee , where R dd and R ee combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with lower alkyl.
  • Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine.
  • a "nitrogen protecting group” is a chemical group covalently bound to a nitrogen atom of a compound that is used to protect the nitrogen from reaction during a synthetic step.
  • the nitrogen protecting group may be added to a compound and removed in a subsequent step by methods known to those of skill in the art.
  • 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 or veterinary practitioner to avoid administration of the material to a subject, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles.
  • the term "therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, and/or to prolong the survival of the subject being treated.
  • the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase.
  • a biological activity associated with a particular biomolecule such as a protein kinase.
  • an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity of the biomolecule, such as an enzyme.
  • Such activity is typically indicated in terms of an inhibitory concentration (IC 50 ) or excitation concentration (EC 50 ) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.
  • IC 50 inhibitory concentration
  • EC 50 excitation concentration
  • the term "contacting" means that the compound(s) are caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction between the compound and other specified material can occur.
  • the present invention concerns compounds of Formula HI and all sub-generic formulae thereof including compounds of Formula IIIa-m and all sub-generic formulae thereof, including all salts, prodrugs, tautomers, and isomers, 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 B-Raf, c-Raf-1, Fms, Jnkl, Jnk2, Jnk3, Kit, and any mutations of these kinases, and the use of such compounds in the treatment of diseases or conditions.
  • Protein kinases play key roles in propagating biochemical signals in diverse biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions including, for example without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases and conditions. As such, kinases represent important control points for small molecule therapeutic intervention. Specific target protein kinases contemplated by the present invention follow:
  • B-Raf Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogene homolog Bl) is a 84.4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol: BRAF).
  • the mature protein comprises RBD (i.e., Ras binding domain), Cl (i.e., protein kinase C conserved region 1) and STK (i.e., serine/threonine kinase) domains.
  • Target kinase B-Raf includes any mutations of B-Raf, such as Val ⁇ 600> to Glu ⁇ 600> (V600E) mutant.
  • Indications for modulation of B-Raf activity, including B-Raf V600E activity, for the treatment of pathologic states include, but are not limited to, neurologic diseases such as ischemic stroke, 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. lung, breast, pancreatic, renal), lymphoma (e.g. histiocytic lymphoma) and cancer of the thyroid, lung (e.g.
  • neurologic diseases such as ischemic stroke, 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. lung, breast, pancreatic, renal), lymphoma (e.g. his
  • liver small cell lung cancer
  • breast breast
  • ovary and colon neurofibromatosis
  • myelodysplastic syndrome myelodysplastic syndrome
  • leukemia a tumor angiogenesis
  • pain of neuropathic or inflammatory origin including acute pain, chronic pain, and migraine
  • cardiovascular diseases including heart failure, cardiac hypertrophy, thrombosis (e.g.
  • thrombotic microangiopathy syndromes thrombotic microangiopathy syndromes
  • atherosclerosis reperfusion injury
  • inflammation including, but not limited to, psoriasis, polycystic kidney disease (PKD), arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, organ transplant rejection, graft versus host disease; renal or prostatic diseases including diabetic nephropathy, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, obesity; infection, including, but not limited to Helicobacter pylori and Influenza virus, fever, sepsis; pulmonary diseases including chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases such as Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), leopard
  • 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 the mitochondria by BCL2 (i.e., oncogene B-cell leukemia 2) which is a regulator of apoptotic cell death. Active c-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1 phosphorylates BAD (i.e., BCL2-binding protein).
  • BAD i.e., BCL2-binding protein
  • c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lung and renal cell carcinoma. C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood 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, CurrPharm Des 2002, 8(25):2243- 8).
  • Raf-1 activators may be useful as treatment for neuroendocrine tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17(2):139-42).
  • Fms Target kinase Fms (i.e., feline McDonough sarcoma) is a member of the family of genes originally isolated from the Susan McDonough strain of feline sarcoma viruses. Fms is a transmembrane tyrosine kinase of 108.0 kDa coded by chromosome 5q33.2-q33.3 (symbol: CSFlR). The structure of the transmembrane receptor Fms comprises two Ig-like domains, a IgC2-like domain, two additional Ig-like domains, a TM domain, and the TK domain.
  • c-fins have been associated with a number of different types of diseases. Fms has been associated with immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), Wegener's granulomatosis, and transplant rejection, inflammatory diseases including Chronic Obstructive Pulmonary Disease (COPD), emphysema, and atherosclerosis, metabolic disorders, including insulin resistance, hyperglycemia, and lipolysis, disorders of bone structure or mineralization, including osteoporosis, increased risk of fracture, hypercalcemia, and bone metastases, kidney diseases, including nephritis (e.g.
  • glomerulonephritis including interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications, and hypertrophy and cancers, including multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia (CML), breast cancer, and ovarian cancer.
  • CML chronic myeloid leukemia
  • Jnkl Target Jnkl (i.e., c-Jun kinase 1) is a 48.3 kDa serine/threonine kinase encoded by chromosome 1OqI 1.22 (symbol: MAPK8), also known as mitogen-activated protein kinase 8.
  • MAPK8 mitogen-activated protein kinase 8
  • Jnkl is a mitogen-activated protein kinase (i.e., MAPK) which form a family of serine-threonine protein kinases that participate in a major signaling system by which cells transduce extracellular stimuli into intracellular responses. Jnkl is implicated in type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity and hepatic steatosis.
  • Jnk2 Target kinase Jnk2 (i.e., c-Jun kinase 2) is 48.1 kDa serine/threonine kinase encoded by chromosome 5q35 (symbol: MAPK9). Jnk2 is implicated in atherosclerosis.
  • Jnk3 Target kinase Jnk3 (i.e., c-Jun kinase 3) is 52.6 kDa serine/threonine kinase encoded by chromosome 4q21-q22 (symbol: MAPKlO).
  • Jnk3 inhibitors are potential therapeutics for the treatment of Inflammatory diseases including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, psoriasis and multiple sclerosis, airway inflammatory diseases such as asthma, allergy, pulmonary fibrosis, and chronic obstructive pulmonary disease, and inflammation in other organs, such as CNS inflammation, pancreatitis, nephritis, and hepatitis; neurologic diseases such as stroke, cerebrovascular ischemia, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease; and neoplastic diseases such as prostate tumors and myeloid leukemia.
  • autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, ps
  • Kit Target kinase Kit (i.e., feline Hardy-Zuckerman 4 sarcoma viral oncogene) is a 109.9 kDa transmembrane tyrosine kinase encoded by chromosome 4ql2 (symbol: KIT).
  • Receptor protein tyrosine kinases RPTKs regulate key signal transduction cascades that control cellular growth and proliferation.
  • the Stem Cell Factor (SCF) receptor Kit is a type III transmembrane RPTK that includes five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment. Kit plays an important role in the development of melanocytes, mast, germ, and hematopoietic cells.
  • IG immunoglobulin
  • Kit Aberrant expression and/or activation of Kit has been implicated in a variety of pathologic states.
  • Kit has been associated with mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.
  • GISTs gastrointestinal stromal tumors
  • 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 of kinases.
  • assays mentioned in the Examples below, one of ordinary skill in the art will know of other assays that can be utilized and can modify an assay for a particular application. For example, numerous papers concerning kinases describe assays that can be used.
  • preferred compounds of the present invention i.e., compounds of Formula m
  • preferred compounds of the present invention will have an IC 50 or EC 50 of less than 10 ⁇ M, also less than 1 ⁇ M, also less than 100 nM, also less than 10 nM or less than 1 nM.
  • invention compounds contemplated herein are described with reference to both generic formulae and specific compounds.
  • invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (e.g., carboxylic acid esters), solvated forms, different crystal forms or polymorphs, and active metabolites.
  • some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms.
  • compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. enantiomers or diastereomers).
  • stereoisomers i.e., essentially free of other stereoisomers
  • racemates i.e., essentially free of other stereoisomers
  • stereoisomers include geometric isomers, such as cis- or trans- orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms are included within the formulae provided herein.
  • a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess ("e.e.") or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e.).
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compound is present in optically pure form.
  • the addition may occur at either of the double bond-linked atoms.
  • the present invention includes both such regioisomers.
  • the formulae are intended to cover solvated as well as unsolvated forms of the identified structures.
  • the indicated structures include both hydrated and non-hydrated forms.
  • Other examples of solvates include the structures in combination with a suitable solvent such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts.
  • Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • a common example or a prodrug is an alkyl ester of a carboxylic acid.
  • further examples include, without limitation, an amide or carbamate derivative at the 1 -position nitrogen of the azaindole core.
  • bioprecursor prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs.
  • bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • the formation of active drug compound involves a metabolic process or reaction that is one of the follow types:
  • Oxidative reactions are exemplified without limitation to reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon- carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, as well as other oxidative reactions.
  • Reductive reactions are exemplified without limitation to reactions such as reduction of carbonyl functionalities, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of nitrogen-containing function groups, and other reduction reactions.
  • Reactions without change in the oxidation state are exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improves uptake and/or localized delivery to a site(s) of action.
  • a transport moiety e.g., that improves uptake and/or localized delivery to a site(s) of action.
  • the linkage between the drug moiety and the transport moiety is a covalent bond
  • the prodrug is inactive or less active than the drug compound
  • the prodrug and any release transport moiety are acceptably non-toxic.
  • the transport moiety is intended to enhance uptake
  • the release of the transport moiety should be rapid.
  • it is desirable to utilize a moiety that provides slow release e.g., certain polymers or other moieties, such as cyclodextrins.
  • carrier prodrugs are often advantageous for orally administered drugs.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.
  • Metabolites e.g., active metabolites overlap with prodrugs as described above, e.g., bioprecursor prodrugs.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chern 40:2011-2016; Shan et al., JPharm Sd 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra.
  • Compounds can be formulated as or be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered.
  • the preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect.
  • Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate,/?-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate,/?-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, j ⁇ -toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, j ⁇ -toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • Such salts can be prepared using the appropriate corresponding bases.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous- alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • a salt can be prepared by reacting the free base and acid in an organic solvent.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid
  • an inorganic acid such as hydrochloric acid, hydrobromic
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • Further examples of pharmaceutically acceptable salts of compounds of Formula I include, without limitation, the mono-sodium and bis-potassium salts thereof.
  • the pharmaceutically acceptable salt of the different compounds may be present as a complex.
  • complexes include 8-chlorotheophylline complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes.
  • the 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.
  • Suitable dosage forms depend upon the use or the route of administration, for example, oral, transdermal, transmucosal, inhalant or by injection (parenteral). Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein).
  • Carriers or excipients can be used to produce compositions.
  • the carriers or excipients can be chosen to facilitate administration of the compound.
  • Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents.
  • physiologically compatible solvents include sterile solutions of water for injection (WFI), saline solution, and dextrose.
  • WFI water for injection
  • the compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalant. Oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • compounds of the invention may be formulated as dry powder or a suitable solution, suspension, or aerosol.
  • Powders and solutions may be formulated with suitable additives known in the art.
  • powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts.
  • suitable powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts.
  • Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like.
  • the compounds of the invention may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratroprium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single or double stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.
  • corticosteroids such as
  • compositions for oral use can be obtained, for example, by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
  • disintegrating agents may be added, such as the cross — linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • injection parenteral administration
  • the compounds of the invention are formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • physiologically compatible buffers or solutions such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Administration can also be by transmucosal, topical, or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays or suppositories (rectal or vaginal).
  • the topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers known in the art.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than Ci 2 ).
  • the preferred carriers are those in which the active ingredient is soluble.
  • Emulsif ⁇ ers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount solvent (e.g., an oil), is admixed.
  • transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
  • a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • a dose will be between about 0.01 and 50 mg/kg, preferably 0.1 and 20 mg/kg of the subject being treated. Multiple doses may be used.
  • the mass spectrometry result indicated for a compound may have more than one value due to the isotope distribution of an atom in the molecule, such as a compound having a bromo or chloro substituent.
  • Example 1 Synthesis of propane-1-sulfonic acid [3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3- carbonyl)-2,4-difluoro-phenyl]-amide P-0773 and related compounds.
  • Step 1 Preparation of3-amino-2,6-difluoro-benzoic acid benzyl ester (43): [0180] To 2,4-difluoro-phenylamine (42, 5.11 mL, 50.7 mmol) in tetrahydrofuran (250 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) slowly.
  • l,2-Bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol) dissolved in tetrahydrofuran (40.0 mL) was added to the reaction slowly.
  • n-butyllithium (1.60 M in hexane, 31.9 mL, 51.0 mmol) was added slowly to the reaction.
  • the reaction was stirred at -78 0 C for 30 minutes and then allowed to warm to room temperature over 40 minutes.
  • the reaction was cooled to -78 0 C, followed by addition of n-butyllithium (1.60 M in hexane, 35.1 mL, 56.2 mmol) slowly.
  • Step 2 Preparation of 2, 6-difluoro-3-(propane-l-sulfonylamino)-benzoic acid benzyl ester (44): [0181] To 3-amino-2,6-difluoro-benzoic acid benzyl ester (43, 6.00 g, 22.8 mmol) in methylene chloride (150 mL) was added pyridine (2.76 mL, 34.2 mmol) and propane-1-sulfonyl chloride (3.80 mL, 33.8 mmol). The reaction was stirred at room temperature overnight. Then the reaction was poured into water, and extracted with ethyl acetate.
  • Step 3 Preparation of2,6-difluoro-3-(propane-l-sulfonylamino)-benzoic acid (45): [0182] To 2,6-difluoro-3-(propane-l-sulfonylamino)-benzoic acid benzyl ester (44, 2.0 g, mmol) in methanol (30 mL) was added 20% palladium hydroxide on carbon (100 mg). The reaction was stirred under hydrogen at 1 atm for 15 minutes. The reaction was filtrated and concentrated to give white solid 45 that was used in the next step.
  • Step 4 Preparation of2,6-difluoro-3-(propane-l-sulfonylamino)-benzoyl chloride (46): [0183] To 2,6-difluoro-3-(propane-l-sulfonylamino)-benzoic acid (45, 1.50 g, 5.4 mmol) was added toluene (7.0 mL) and thionyl chloride (15.0 mL, 0.21 mmol). The reaction was heated to reflux for 3 hours. The reaction was concentrated to give crude compound that was used in the next step.
  • Example 2 Synthesis of Propane-1-sulfonic acid [3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3- carbonyl)-2-fluoro-phenyl]-amide P-0955 and related compounds.
  • Step 1 Preparation ofi-Amino-6-chloro-2-fluoro-benzoic acid benzyl ester (48): [0190] To 4-chloro-2-fluoro-phenylamine (47, 6.30 mL, 57.0 mmol) in tetrahydrofuran (300 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (2.500 M in hexane, 24.4 mL) slowly.
  • Step 2 Preparation of6-chloro-2-fluoro-3-(propane-l-sulfonylamino)-henzoic acid benzyl ester (49):
  • Step 3 Preparation of6-chloro-2-fluoro-3-(propane-l-$idfonylamino)-benzoic acid (115): [0192] To 6-chloro-2-fluoro-3 -(propane- 1 -sulfonylamino)-benzoic acid benzyl ester (49, 6.00 g, 15.6 mmol) in tetrahydrofuran (100 mL) was added 1.0 M aqueous potassium hydroxide (100 mL). The reaction was heated to reflux overnight. The reaction was poured into water, acidified to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtrated and concentrated to give a white solid 115 (3.95 g, 85.8%).
  • Step 5 Preparation of2-fluoro-3-(propane-l-sulfonylamino)-benzoyl chloride (51): [0194] To 2-fluoro -3-(propane-l -sulfonylamino)-benzoic acid (50, 1.17 g, 4.5 mmol) was added thionyl chloride (10.0 mL). The reaction was heated to reflux for 3 hours. The reaction was concentrated to give crude compound 51 that was used in the next step.
  • Example 3 Propane-l-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine- 3-carbonyI)-phenyI]-amide P-0088 and related compounds.
  • Compound P-0088 was synthesized in one step from propane-l-sulfonic acid [3-(5-bromo- lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide P-0773 by Suzuki coupling ((Muyaura and Suzuki, Chem. Rev. 1995, 95:2457) as shown in Scheme 15.
  • Step 2 Preparation of3-diben ⁇ ylamino-2,6-difluoro-benzaldehyde (53): [0202] To dibenzyl-(2,4-difluoro-phenyl)-amine (52, 4.30 g, 13.9 mmol) in tetrahydrofuran (60 niL), under an atmosphere of nitrogen, cooled in a -78 0 C acetone/dry ice bath, was added n- butyllithium (2.50 M in hexane, 6.1 niL, 15.3 mmol) slowly.
  • Step 3 Preparation of(3-dibenzylamino-2,6-difluoro ⁇ phenyl)-(5-pyridin-3-yl-lH-pyrrolo[2,3- b]pyridin-3-yl)-methanol (54):
  • Step 4 Preparation of (3-dibenzylamino-2, 6-difluoro-phenyl)-(5-pyridin-3-yl-lH-pyrrolo[2, 3- b]pyridin-3-yl)-methanone (55) :
  • Step 5 Preparation of (3-dibenzylamino-2, 6-difluoro-phenyl)-(5-pyridin-3-yl-l-triisopropylsilanyl- lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone (56):
  • Step 6 Preparation of(3-amino-2, 6-difluom-phenyl)-(5-pyridin-3-yl-l ⁇ triisopropylsilanyl-lH ⁇ pyrrolo[2, 3-bjpyridin-3-yl)-methanone (57):
  • Step 7 Preparation ofN-[2,4-difluoro-3-(5-pyridin-3-yl-l-triisopropylsilanyl-lH-pyrrolo[2,3- h]pyridine-3-carbonyl)-phenyl]-ethanesulfonamide (58):
  • Step 8 Preparation ofN-[2,4-difluoro-3-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)- phenylj-ethanesulfonamide (P-0728):
  • Step 1 Preparation of propane-2-sulfonic acid (2,4-difluoro-phenyl)-amide (59): [0210] To 2,4-difluoro-phenylamine (42, 4.0 mL, 40.0 mmol) in methylene chloride (50 mL) were added pyridine (3.37 mL, 42.3 mmol), propane-2-sulfonyl chloride (6.00 g, 42.3 mmol) and dimethylaminopyridine (0.20 g, 1.64 mmol) under an atmosphere of nitrogen. The reaction was stirred at 45 °C overnight. The reaction was poured into water and extracted with ethyl acetate.
  • Step 2 Preparation of propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (60): [0211] To propane-2-sulfonic acid (2,4-difluoro-phenyl)-amide (59, 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).
  • Piperidine-1 -sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b] ⁇ yridine-3-carbonyl)-2,4-difluoro- phenyl]-amide (P-1020),
  • Butane-1 -sulfonic acid [3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- amide (P-1263),
  • Butane-1 -sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- amide (P-1265),
  • Example 6 Synthesis of propane-1-sulfonic acid [2,4-difhioro-3-(5-phenylamino-lH- pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-aniide P-0848 and related compounds.
  • Step 1 Preparation qf5-bromo-l-triisopropylsilanyI-lH-pyrrolo[2,3-b]pyridine (68): [0221] To 5-bromo-7-azaindole (67, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0 mmol) and trriisopropylsilyl chloride ( 2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate.
  • Step 2 Preparation of5-phenyl ⁇ (l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-5-yl)-amine (69): [0222] To 5-bromo-l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (68, 0.10 g, 0.3 mmol) in toluene (5 mL) were added aniline (0.04 mL, 0.42 mmol), sodium tert-b ⁇ toxid ⁇ (0.15 g, 1.56 mmol), tris(dibenzyllideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol) and (S) -(-)-2,2'- bis(diphenylphosphino)-l,l '-binaphthyl (6.3 mg, 0.01 mmol).
  • Step 3 Preparation ofphenyl-(-lH-pyrrolo[2,3-b]pyridine-5-yl) ⁇ amine (70): [0223] To 5-phenyl-(l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-5-yl)-amine (69, 0.14 g, mmol) in tetrahydrofuran (3.0 mL) was added tetra-n-butylammonium fluoride (0.197 g, 0.76 mmol). The reaction was stirred for 1 hour at room temperature.
  • Step 4 Preparation of propane- 1 -sulfonic acid ⁇ 2,4-difluoro-3-[hydroxy-(5-phenylamino-lH- pyrrolo[2, 3-bJpyridin-3-yl)-methylJ-phenyl ⁇ -amide (71):
  • Example 7 Synthesis of propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 73.
  • Step 1 Preparation of Propane- 1 -sulfonic acid (2,4-difluoro-phenyl)-amide (72): [0229] To 2,4-difluoro-phenylamine (42, 3.0 mL, 29.8 mmol) in tetrahydrofuran (50 niL) were added triethylamine (9.13 mL, 65.5 mmol) and propane- 1-sulfonyl chloride (2.90 mL, 25.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the compound (72, 2.0 g, 28%) that was used in the next step.
  • Step 2 Preparation of propane-1 -sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (73): [0230] To propane-1 -sulfonic acid (2,4-difluoro-phenyl)-amide (72, 1.5 g, 6.38 mmol) in tetrahydrofuran (10 mL) under an atmosphere of nitrogen, cooled in a -78 0 C acetone/dry ice bath was added lithium diisopropylamide (0.80 M in tetrahydrofuran, 24 mL, freshly prepared from n- butyllithium and diisopropylamine).
  • N,N-dimethyl-formamide (542 ⁇ L, 7.018 mmol) was added dropwise to the reaction.
  • the reaction was stirred for 30 minutes at -78 0 C and then allowed to warm to room temperature for 40 minutes.
  • the reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5 % ethyl acetate in hexane to give a light yellow solid (73, 300 mg, 18 %).
  • MS(ESI)[M- H + ] " 262.3.
  • Example 8 Synthesis of propane-1-sulfonic acid [3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3- carbonyl)-phenyl]-amide P-1116.
  • Step 1 Preparation of3-(propane-l-sulfonylamino)-benzoic acid ethyl ester (75): [0232] To 3-amino-benzoic acid ethyl ester (74, 5.0 g, 0.030 mol) in methylene chloride (30.0 mL) were added pyridine (3.67 mL, 0.045 mol) and propane- 1-sulfonyl chloride (3.75 mL, 33.0 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (75, 6.0 g, 74.1%).
  • Step 3 Preparation of3-(propane-l-sulfonylamino)-benzoyl chloride (77): [0234] A solution of 3 -(propane- l-sulfonylamino)-benzoic acid (76, 1.20 g, 4.93 mmol) in thionyl chloride was heated to reflux for 3.0 hours. Evaporation of the solvent gave compound 77 as white solid that was used for the next step.
  • Step 1 Preparation 5-chloro-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (79): [0237] To 5-bromo-l-triisopropylsilyl-7-azaindole (68, 1.60 g, 4.53 mmol, prepared as described in Example 6) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at -78 0 C, was added tert- butyllithium (1.70 M in hexane, 6.12 mL). The reaction was stirred for 1 hour, followed by addition of hexachloroethane (1.29 g, 5.43 mmol).
  • Step 1 Preparation of2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)- methyl] -phenol (P-0009):
  • Example 11 Synthesis of N-[2,4-difluoro-3-(lH-pyrrolo[2,3-b]pyridine-3-carbonyl) phenyl]-3- methoxy-benzenesulf onamide P-0971.
  • Step 1 Preparation ofN-(2,4-difluoro-phenyl)-3-methoxy-benzenesulfonamide (91): [0245] To 2,4-difluoro-phenylamine(42, 0.44 niL, 4.4 mmol) in methylene chloride (10.0 niL), under an atmosphere of nitrogen, were added pyridine (1.00 mL, 12.4 mmol) and 3-methoxy- benzenesulfonyl chloride (1.00 g, 4.84 mmol). After 12 hours, the reaction was poured into cold 1 M HCl and extracted with ethyl acetate.
  • Step 2 Preparation ofN- ⁇ 2,4-difluoro-3-[hydroxy-(l-triisopropylsilanyl-lH-pyrrolo[2 > 3-b]pyridin- 3-yl)-methyl]-phenyl ⁇ 3-methoxy-benzenesulfonamide (92):
  • Step 3 Preparation of N- ⁇ 2,4-difluoro-3-[hydroxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)methyl] -phenyl ⁇ - 3-methoxy ⁇ benzenesulfonamide (93) :
  • Step 2 Preparation ofl-trii$opropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (96): [0252] To lH-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (95, 4.05 g, 27.71 mmol) in tetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil, 1.5 g, 38 mmol) and trriisopropylsilyl chloride (8.0 mL, 38 mmol) under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate.
  • Step 1 Preparation of2-(l-triisopropylsilanyl-lH-pyrrolo[2,3 ⁇ b]pyridin-5-yl)-propan-2-ol (97): [0254] To 5-bromo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (68, 2.0 g, 5.66 mmol, prepared as described in Example 6) in tetrahydrofuran (20.0 mL), cooled in a -78 0 C acetone/dry ice bath, under an atmosphere of nitrogen, was added tert-butyllithium (1.7 M in tetrahydrofuran, 7.3 mL, 12 mmol) dropwise.
  • tert-butyllithium 1.7 M in tetrahydrofuran, 7.3 mL, 12 mmol
  • Step 1 Preparation of 5-Methyl-l-triisopropylsilanyl-lH-pyrrolo [2, 3-b] pyridine (100): [0258] To PdCl 2 (dppf) (0.04 g, 0.05 mmol) in toluene (10.0 mL) under an atmosphere of nitrogen were added 5-bromo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (68, 0.3 g, 0.8 mmol, prepared as described in Example 6, 1.0 mL in toluene) and methylmagnesium bromide (1.0 M in tetrahydrofuran, 3.0 mL, 3.0 mmol).
  • Example 15 Synthesis of l-[2,4-difluoro-3-(5-pyridin-3-yI-lH-pyrrolo[2,3-b]pyridine-3- carbonyl) ⁇ phenyI]-3-propyl-urea P-0774 and related compounds.
  • Step 1 Preparation ofl- ⁇ 2,4-difluoro-3 ⁇ [hydroxy-(5-pyridin-3-yl-lH-pyrrolo[2,3b]py ⁇ din-3-yl)- methyl]-phenyl ⁇ -3-propyl-urea (103):
  • Step 2 Preparation ofl-[2,4-difluoro-3 ⁇ (5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)- phenylJ-3-propyl-urea (P-0774):
  • Morpholine-4-carboxylic acid [2,4-difluoro-3 -(5 -methoxy- 1 H-pyrrolo[2,3 -b]pyridine-3 - carbonyl)-phenyl]-amide (P-1894), l-Butyl-3-[2,4-difluoro-3-(lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-l-ethyl-urea (P-1983), l-Butyl-3-[2,4-difluoro-3-(5-methoxy-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-l-ethyl- urea (P-1994), and
  • the intermediate product of Step 1 of Scheme 30 can alternatively be reacted under reducing conditions to provide analogous compounds in which the carbonyl linker of the 3 -position of azaindole to the phenyl ring is methylene.
  • the product of Step 1 is a mixture of the hydroxyl and methoxy methyl linker of the 3 -position, which may be carried through the reduction Step as the mixture or may be isolated as either the hydroxyl or methoxy for use in this reaction.
  • Step 1 Preparation ofl-Butyl-3-[2,4-difluoro-3-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- phenylj-urea (P-1571):
  • Morpholine-4-carboxylic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro- phenyl]-amide (P-1595), l-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-3-(2,2,2-trifluoro- ethyl)-urea (P-1601), l-Cyclopentyl-3- ⁇ 2 ) 4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3- ylmethyl]-phenyl ⁇ -urea (P-1615), l-Butyl-3-[3-(5-chloro-lH-pyrrolo[2 ) 3-b]pyridin-3-yl
  • R can be H or CH 3 , where the compound was either a mixture of the two, or either of the isolated compounds wherein R is H or R is CH 3 .
  • Column 1 provides the compound number and column 5 the observed mass.
  • Example 18 Synthesis of 3-(4-(4-chlorobenzyIoxy)-3-methoxybenzyl)-lH-pyrrolo[2,3- b]pyridine P-1247.
  • Step 2 Preparation of3-((4-(4-chlorobenzyloxy)-3-methoxyphenyl)(methoxy)methyl)-lH- pyrrolo [2, 3 -bj pyridine (107):
  • Example 19 Synthesis of Propane-1-sulfonic acid [3-(5-bromo-lH-pyrroIo[2,3-b]pyridine-3- carbonyl)-2-fluoro-phenyl] -amide P-0955 and related compounds.
  • Step 1 Preparation ofi-Amino- ⁇ -chloro-l-fluoro-benzoic acid benzyl ester (48): [0282] To 4-chloro-2-fluoro-phenylamine (47, 6.30 mL, 57.0 mmol) in tetrahydrofuran (300 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) was added slowly.
  • benzyl chloroforrnate (10.0 mL, 70.0 mmol) was added to the reaction.
  • the reaction mixture was stirred at -78 0 C overnight followed by addition of water (80 mL) and concentrated hydrochloric acid (25 mL).
  • the reaction was allowed to warm to room temperature for 2 hours.
  • the organic layer was separated.
  • the aqueous layer was basified with potassium carbonate and extracted with ethyl acetate.
  • the organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 2 Preparation of6-chloro-2-fluoro ⁇ 3-(propane-l-sulfonylamino)-benzoic acid benzyl ester (49):
  • Step 3 Preparation of6-chloro-2-fl ⁇ oro ⁇ 3-(propane-l-sulfonylamino)-benzoic acid (115): [0284] To 6-chloro-2-fluoro-3-(propane-l-sulfonylamino)-benzoic acid benzyl ester (49, 6.00 g, 15.6 mmol) in tetrahydrofuran (100 mL) was added 1.0 M aqueous potassium hydroxide (100 mL). The reaction was heated to reflux overnight. The reaction was poured into water, acidified to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid 115 (3.95 g, 85.8%).
  • Step 5 Preparation of2-fluoro-3-(propane-l-sulfonylamino)-henzoic acid methyl ester (501): [0286] To a 2-fluoro-3 -(propane- l-sulfonylamino)-benzoic acid (50, 5.05 g, 0.0193 mol) in methylene chloride (100 mL) was added N,N-dimethylformamide (0.075 mL, 0.97 mmol) under an atmosphere of nitrogen. The reaction was cooled with ice/water, followed by slow addition of Oxalyl chloride (2.00 M of in methylene chloride, 10.8 mL, 21.6 mmol).
  • reaction mixture was stirred at room temperature for 3.0 hours.
  • the reaction was cooled with ice/water, followed by addition of methanol (36.0 mL, 0.89 mol) slowly.
  • the reaction was stirred at room temperature overnight.
  • the reaction was concentrate and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a crude white solid 4.Og.
  • Step 6 Preparation of Propane- 1 -sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (502): [0287] To 2-fluoro-3-(propane-l-sulfonylamino)-benzoic acid methyl ester (501, 3.80 g, 13.8 mmol) in tetrahydrofuran (133 mL) was added lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 20.0 mL, 20.0 mmol) under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g OfNaSO 4 -IOH 2 O. After 12 hours, the reaction was filtered, concentrated and purified with silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (502, 3.0 g, 87.9%).
  • Step 7 Preparation of propane- J -sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (503): [0288] To propane-1 -sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (502, 0.20 g, 0.81 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.377 g, 0.89 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered.
  • Step 8 Preparation of Propane-1 -sulfonic acid ⁇ 3-[(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)- hydroxy-methyl]-2-fluoro-phenyl ⁇ -amide (504):
  • Step 1 Preparation of(E)-3-3-[2,6-difluoro-3-(propane-l -sulfonylamino)-benzoyl] ⁇ lH-pyrrolo [2,3-b]pyridin-5-yl-acrylic acid m ethyl ester (505):
  • the reaction was stirred at 140 0 C overnight, then poured into water, acidified with water and extracted with ethyl acetate. To the filtrate in methylene chloride (5.0 mL) was added l,8-diazabicyclo[5.4,0]undec-7-ene (0.50 mL, 3.3 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a light yellow oil that was used directly in the next step.
  • Step 2 Preparation of3-3-[2,6-difluoro-3-(propane-l-sulfonylamino)-benzoyl]-lH-pyrrolo[2,3 - b]pyridin-5-yl-acrylic acid (P-1269):
  • Step 3 3-3-[2,6-difluoro-3-(propane-l-sulfonylamino)-benzoyl]-lH-pyrrolo[2,3 -bJpyridin-5-yl- propionic acid (P-1270):
  • Example 21 Synthesis of thiophene-2-sulfonic acid (2,4-difluoro-3-formyI-phenyI)-amide 508.
  • the reaction was stirred at -78 0 C for 20 minutes and then allowed to warm to room temperature over 60 minutes.
  • the reaction was cooled to -78 0 C, followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, ethyl chloroformate (6.69 mL, 70.0 mmol) was added to the reaction.
  • the reaction mixture was stirred at -78 0 C overnight followed by addition of water (80 mL) and concentrated hydrochloric acid (25 mL). The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate.
  • Step 2 Preparation of2,6-difluoro-3-(thiophene-2-sulfonylamino)-benzoic acid ethyl ester (510): [0300] To 3-amino-2,4-difluoro-benzoic acid ethyl ester (509, 1.20 g, 5.93 mmol) in methylene chloride (28 mL) was added pyridine (0.52 mL, 6.4 mmol) and thio ⁇ hene-2-sulfonyl chloride (0.97 g, 5.38 mmol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate.
  • Step 4 Preparation of thiophene-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (512): [0302] To thiophene-2-sulfonic acid (2,4-difluoro-3-hydroxymethyl-phenyl)-amide (511, 0.46 g, 1.52 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.71g, 1.67 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered.
  • Step 2 Preparation of4-[Hydroxy-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-indole-l- carboxylic acid butylamide (520):
  • Step 3 Preparation of4-(5-Pyridin-3-yl ⁇ lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-l-carboxylic acid butylamide (P-1486):
  • Step 2 of Scheme 41 can alternatively be reacted to form the corresponding compounds with methylene linker at the 3 position of the azaindole.
  • P-1656 was prepared from 4-[Hydroxy-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-indole-l-carboxylic acid butylamide 520 as shown in Scheme 41a.
  • Step 1 Preparation of4-(5-pyridin-3-yl-lH-pyrrolof2,3-bJpyridin-3'-ylmethyl)-indole-l-carboxylic acid butylamide (P-1656):
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