NZ617526B2 - Kinase modulation and indications therefor - Google Patents

Abstract

Disclosed is the use of [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (pexidartinib) in the manufacture of a medicament for treating acute myeloid leukaemia (AML) in a subject wherein the subject has an FMS-like tyrosine kinase (Flt3) gene with an internal tandem duplication (ITD) mutation. ne with an internal tandem duplication (ITD) mutation.

Description

KINASE TION AND INDICATIONS THEREFOR FIELD OF THE INVENTION This invention relates to ligands for FMS—like tyrosine kinase 3(Flt3)5 such as abnormally activated Flt3 kinase, and to methods for use thereof. The information provided is intended solely nces cited is to assist the understanding of the reader. None ofthe information provided nor admitted to be prior art to the t invention. Each of the references cited is incorporated herein in its entirety and for any e.

BACKGROUND OF THE INVENTION FLT—3 (FMS-like tyrosine kinase 3) which is also known as FLK-Z (fetal liver kinase 2) and STK~I (Stem cell kinase 1), is a class III RTK structurally related to PDGFR, and colony stimulating factor 1 (CSFI). These RTK contain five immunoglohulin—like domains in the extracellular region and an intracellular tyrosine kinase domain split in two by a specific hydrophilic insertion. The receptor tyrosine kinase Flt3 is expressed in poietic precursor cells, and activation of Flt3 enhances colony—forming capacity ofall hematopoietic lineages. with a kinase Many different mutations of the Flt3 gene can result in the production of Flt3 protein that is abnormally activated, and in such situations these mutant forms of Flt3 can cause malignant transformation of poietic cells in vitro and in vivo. Internal tandem duplications (ITD) and/or insertions and, rarely, deletions in the FLT3-gene are ated in 20—25% of all acute myeloid leukemias (AML). For example, insertion of several amino acids in thejuxtamembrane region of Flt3, often referred to as internal tandem duplication mutations, cause malignant transformation of myeloid cells, and such mutations are present in about 25% of acute myeloid leukemia (AML) cases. The presence of these mutations is associated with decreased survival AML. Mutations at other rcSidues, such as F691 (“gatekeeper”) and D835, have been detected in ts with AML, Point mutations have aiso been observed in the kinase domain of Flt3 in about T36 of AML cases Other types of leukemia, such as c myelomonoeytie leukemia (CMML) Flt3 with activating mutations are an important can also harbor activating mutations of Flt3. Thus 3164317; target for several cancer types (Cancer Cell, (2007), —380; Blood, (2003), WI, Current Pharmaceutical Design , 11:3449—3457).

SUMMARY OF THE INVENTION [0002a] In a first aspect, the t invention provides use of a compound having the formula: or a pharmaceutically able salt or tautomer thereof, in the preparation of a medicament for treating acute myeloid leukaemia (AML) in a subject wherein the subject has an FMS-like tyrosine kinase (Flt3) gene with an internal tandem duplication (ITD) mutation.

The present invention relates to methods of using compounds active on oncogenic Flt3 kinase or Flt3 mutant, such as abnormally activated Flt3 kinase. In one aspect, the present ion provides methods of using compounds of Formula I and all the sub formulas and compounds as described herein that can be used eutically and/or prophylacticallv involving modulation of a Flt3 kinase, such as an oncogenic Fit 3 or Flt3 mutant. In one embodiment, the invention provides a method for treating a subject suffering from or at risk of an oncogenic Flt3 ed disease or condition.

In some embodiments, provided herein is a method of treating Flt3 kinase mediated diseases or conditions in a subject, which comprises administering to the subject at risk or suffering from or having the diseases or conditions a therapeutically effective amount of a compound of a I having the following structure: Ar1 L2 R1 N H Formula I, all salts, prodrugs, tautomers, and isomers f, wherein: X1 is N or CR2, X2 is N or CR6, Y1 is N or CR4, and Y2 is N or CR5, ed, however, that not more than one of X2, Y1 and Y2 is N; L1 is selected from the group consisting of optionally substituted lower ne, -S-, -O-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, and -NR7-; (10966819_1):MGH L2 is selected from the group consisting of a bond, optionally substituted lower alkylene, -(alk)a-S-(alk)b-, -(alk)a-O-(alk)b-, - (alk)a-OC(O)-(alk)b-, -(alk)a-C(O)O-(alk)b-, -(alk)a-OC(S)-(alk)b-, -(alk)a-C(S)O-(alk)b-, -(alk) 9-(alk) 9-(alk) a-C(O)-(alk)b-, -(alk)a-C(S)-(alk)b-, -(alk)a-C(O)NR b-, a-OC(O)NR b-, -(alk)a- OC(S)NR9-(alk)b-, -(alk)a-C(S)NR9-(alk)b-, -(alk)a-S(O)-(alk)b-, -(alk)a-S(O)2-(alk)b-, -(alk)a-S 9-(alk)b-, -(alk)a-NR9-(alk)b-, -(alk)a-NR9C(O)-(alk)b-, -(alk)a-NR9C(S)-(alk)b-, -(alk)a- NR9C(O)NR9-(alk)b-, a-NR9C(S)NR9-(alk)b-, -(alk)a-NR9C(O)O-(alk)b-, -(alk)a-NR9C(S) O-(alk)b-, -(alk)a-NR9S(O)2-(alk)b-, and -(alk)a-NR9S(O)2NR9-(alk)b-, wherein alk is optionally tuted C1-3 alkylene and a and b are independently 0 or 1; (10966819_1):MGH R' is selected from the group consisting of optionally substituted lower alkyl; ally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted hctcroaryl; R2, R4, R5 and R6 are independently selected from the group ting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, ally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl? optionally substituted heteroaryl, -OI—l, -NH1, -N02, -CN, -C(O)OH, -C(S)OH, H2, —C(S)NH2, -S(O)3Nllg, )NH2, -NHC(S)NH3, -NHS(O)ZNI 12, —NR1”R“, -NHR3, —0R3, -SR3, -C(O)R3, -C(S)R3, -S(O)R3, -S(O)gR3, -C(O)OR3, -C(S)OR3, -C(O)NHR3, -C(O)NR3R3, -C(S)NHR3, -C(S)NR3R3, -S(O)2NHR3, -S(O);NR3R3, -NHC(O)R3, -NR3C(O)R3, -NHC(S)R3, -NR3C(S)R3, -NHS(O)3R3, -NR3S(O)2R3, -NHC(O)OR3, -NR3C(O)OH, -N R3C(O)OR3, -NHC(S)OR3, -NR3C(S)OII, S)OR3, -NHC(O)NHR3, —NHC(O)NR3R3, -NR3C(O)NH2, -NR3C(O)NHR3, -NR3C(O)NR3R3, -NHC(S)NHR3, -NHC(S)NR3R3, -NR3C(S)NH;, -NR3C(S)NHR3, -NR3C(S)NR3R3, -NHS(O)2NHR3, -NHS(O)7_NR3R3, -NR3S(VO)ZNH2§ -NR3S(O)3NHR3, and O)2NR3R3; is a 5 or 6 membered optionally substituted heteroarylene having the structure ‘E‘Qigt wherein E :3 indicates the point of attachment of LI and indicates the point of ment of L2, and wherein the indicated N is either =N- or —N=; nisOorl; F and J are both C or one ofF and J is C and the other ofF and J is N; P and Q are independently selected from CR, N, NR, 0 or S; T is selected from CR or N; wherein when n is l% P and J are Ci and P, T and Q are CR, or anyone 01°F: T and Q is N and the other two of P; T and Q are CR: when n is 0 and F and J are both C, then one of P and Q are CR3 N or NR and the other 01°F and Q is C, N, NR, 0 or S} provided both P and Q are not CR, when n is 0, one ofF and J is N and the other ofF and J is C, then one ofP and Q is N and the other of P and Q is CR or both P and Q are CR and R is en or an al substituent as defined herein for optionally tuted heteroarylene that provides a stable compound; R3 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl: provided, however, that no alkene carbon thereof is bound to any -C(O)-, -C('S)-, , —S(O)2-, ~O-, ~S~, or ~N- of any of-OR3, wSRi -C(O)R3, ~C(S)R3, 3. -S(O)2R3, -C(O)OR3, -C(S)OR3, -C(O)NHR3r R3R3, -C(S)NHR3, -C(S)NR”R~‘, -S(O)2NHR3= -S(O)2NR3R3, -NHR3, ~NHC(O)R3, -NR‘C(O)R3, -NHC(S)R3, -NR3C(S)R3, O)3R3, ~N R3S(O)3R3, -NHC(O)OR33 ~NR3C(O)OH, -NR3C(O)OR3, ~NHC(S)OR3, —NR3C(S)OH, -NR3C(S)OR3, -NHC(O)NHR3, ~NHC(O)NR3R3, -NR3C(O)NH2, ~NR3C(O)NHR3, -NR3C(O)NR3R3, ~NHC(S)NHR3, -NHC(S)NR3R£ -NR3C(S)NH2, —NR3C(S)NHR3, -NR3C(S)NR3R3, -NHS(O)2NHR33 -NHS(O)2NR3R3, -NR3S(O)2NH2, -N R38(O)ZNHR3, or -NR38(O)2NR3R3, optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -o-, -s—, or -N- ofany of-ORJ, -518, l, -C(S)R3, -S(O)R3, -S(O)2R3, R3, R3, -C(O)NHR3, ~C(O)NR3R3, -C(S)NHR3, -C(S)NR3R3, -S(O)2NHR3, -S(O)2NR3R3, -NHR3, -NHC(O)R3, -NR3C(O)R3, -NHC(S)R3, ~NR3C(S)R3, -NHS(O)3R3, -NR3S(O)2R3, -NHC(O)OR3, O)OH, -NR3C(O)OR3, -NHC(S)OR3, -NR3C(S)OH, -NR3C(S)OR3, -NHC(O)NHR3, -NHC(O)NR3R3, -NR3C(O)NH2, -N R3C(O)NHR3, -NR3C(O)NR3R3, -NHC(S)NHR3, -NHC(S)NR3R3, -NR3C(S)NH2, -NR3C(S)NHR3, -NR3C(S)NR3R3, -NHS(O)2NHR3, vNHS(O)ENR3R3, -NRJS(O)2NH2, -NR3S(O)2NHR3, or ~NR3S(O)3N R3R3, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally tuted heteroaryl; R7 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)RB, and -S(O)2R8; R8 is selected from the group consisting of optionally tuted lower alkyl, optionally tuted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally tuted heteroaryl; R9 at each occurrence is independently selected from the group consisting of hydrogen, lower .. and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, «Di 1, =NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthiog mono-alkylamino, fluoro substituted mono» alkylarninoy di-alkylamino} fluoro substituted di-alkylamino, and ~NR‘2R‘3, provided, however, that when R9 is substituted lower alkyl, any tution on the alkyl carbon bound to the ,N- of ~7NR9~ is fluoro; R10 and RIi at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to the nitrogen of~NR10R”, optionally substituted lower alkynyL provided, r, that no alkyne carbon thereof is bound to thc nitrogen of ~NR’OR1’3 optionally tuted eycloalkyl, optionally tuted heterocyeloalkyl, optionally substituted arylg and optionally substituted heteroaryl; or R‘0 and R11 together with the nitrogen to which they are attached form a monoeyelic 5-7 membered optionally substituted heteroeycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing aryl; and R12 and R13 combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5—7 membered heterocycloalkyl tuted with one or more substituents selected from the group consisting of fluoro, -OH, NH), lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower , lower alkylthio, and fluoro substituted lower alkylthio.

The Flt3 kinase can be an oncogenic Flt3 kinase or an F16 mutant having one or more ons as described herein. In some ments, the invention provides a method of modulating an Flt3 kinase, which includes administering to a subject a compound of Formula I or any subformulas and any of the compounds as described herein. In certain embodiments, the invention provides a method for inhibiting an Flt3 kinase, which includes contacting the F16 kinase 01‘ a cell containing the Flt3 kinase with a compound of Formula I or any subformulas and any of the compounds as described .

In reference to Formula I, the core structure shown above with X1, X2, Y1 and Y2 as CH and with Ll—Ari-LZ-R' replaced with H is referred to as the “azaindole core.” For that azaindole core, reference to ring atoms or ring ons is as shown in the following structure: in one embodiment of the methods provided herein, nds of Formula I have a structure selected from the foiiowing: wherein L], Ar], L2, R}, R2, R4, R5 and R6 are as defined for Formula I.

In one embodiment of the methods provided herein, X1 and X2 in compounds of Formula I are N or CH. In another embodiment, X], X; and Y1 are N or CH, where in a further embodiment, Y; is CR5 and R5 is other than hydrogen. In another embodiment, X1, X3 and Y; are N or CH, where in a further embodiment Y, is CR4 and R4 is other than hydrogen. In another embodiment, X1, X2 and Y; are CH, where in a further embodiment, Y; is CR5 and R5 is other than hydrogen. In another embodiment, X1, X2 and Y; are CH, where in a fithher embodiment Y, is CR11 and R4 is other than hydrogen.

In one embodiment of the methods provided herein, X1, X1, Y, and Y; in compounds of Formula I are independently CR2, CR6, CR4 and CR5 respectively, one of R4 or R5 is other than hydrogen, preferably where R2 and R6 are hydrogen. In one embodiment, wherein X‘, X2, Y‘ and Y2 are ndently CR2, CR6, CR4 and CR5 respectively, R2, R5 and R6 are hydrogen and R4 is other than hydrogen. In one embodiment, wherein X,, X3, Y, and Y; are independently CR2, CR6, CR4 and CR5 respectively, R2, RL1 and R6 are hydrogen and R5 is other than hydrogen.

In one embodiment of the methods provided herein, in compounds of Formuia I, X: and X: are \ or CH, preferably wherein both X and X; are CH.

In one embodiment ofthe s provided herein, in nds of Formula I, LI is ed from the group consisting , ~03 lower alkylene, -C(O)-, —C(S)—, , ’S(O)2-, and -NR7—, wherein lower ne is optionally substituted with fluoro, and wherein when L2 is ally substituted lower alkylene or comprises optionally substituted C1,} alkylene, the alkylene is optionally tuted with fluoro or lower alkyl. In one embodiment, L3 is selected from the group consisting of ~S», —0—, -C'H2—, «CF23 —C(O)«, , —S(O)-g —S(O)2-, and ~NH~.

In one embodiment of the methods provided herein, in compounds of Formula I, l.2 is selected from the group consisting of a bond, optionally substituted lower alkylene, -O-(alk)b~, —OC(O)-(alk)b—, ~C(O)O—(alk)b—, —OC(S)—(alk)b-, —C(S)O—(alk)b~, -C(O)c(alk)b—, (aik)b—, -C(O)NRgv(alk)b-, —OC(O)NR9—(alk)b—, —OC(S)NR9—(alk)b-, —C(S)NR9«(alk)b-, ~S(O)-(alk)b—, —S(O)2-(alk)b-, S(O)2NRg-(alk)b-, -NR9—(alk)b-, -NR9C(O)—(alk)b—, -NR9C(O)O—(alk)b~: —NR9C(S)—(alk)b—, -NR9C(S)o—(aik)b-, —NR9C(O)NR9~(alk)b-, —NR9C(S)NR9v(aIk)h—, —NRQS(O)z—(alk)h-, and —NR98(O)2NR9—(alk)b—.

Further to any of the above embodiments of the methods ed herein, in Formula when L1 is substituted lower alkylene or when L2 is substituted lower alkylene or comprises substituted C16 alkylene, the alkylcnc is substituted with one or more, ably 1: 2, or 3 substituents selected from the group ting of fluoro, —OH, —NH1, lower alkoxy, lower alkylthio, mono-alkylamino, ylamino, and «NRIZRE, wherein the alkyl chain(s) oflower alkoxy, lower alkylthio, lkylamino or di—alkylamino are optionally substituted with one or more, preferably 1, 2, or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower hio, mono-alkylamino, di—alkylamino, or cycloalkylamino.

In one embodiment ofthe methods provided herein, in the compounds of a I, the variables P, I, Q, T, F and n are selected to provide structures of Ar; selected from the , group consisting of R R R ._..___N MN “N \ / \ N/ \N / R R R R ~35 fl” ”NE/E 5H5 «N S are 5% R “3:? ms ~-; {*7 ~; 07 ~; \7 as? \ ”fire if g and , where each R is independently hydrogen or an ogtionai submituant as defined herein fer optinttafiy tuted heteroaryf.

In one embodiment ofthe methods provided hereirn a campound of Formula I has a structure according to the following sub-generic structure, Formula Ia, R4 L1/Al'1‘L3'R1 l \ R2 R6 N N a Ia all salts, prodrugs, ers, and isomers thereof, wherein L], Ar], R], R2, R4, RS and R6 are as defined for Formula I; L3 is selected from the group consisting ofa bond, optionally substituted lower ne,«O-(alk)b-, —S-(alk)b—, —NR34—(alk)h-, -C(O)-(alk)b—, -C(S)-(alk)b-, -S(O)—(alk)b~, -S(O)g-(alk)h-, -NR”C(O)-(alk)b-, -C(O)NR”—(alk)b-, —S(O)2NR‘4-(alk)b-, —NR”S(O)3-(alk)b-, -NRMC(O)NR”-(alk)b-, -NR”C(S)NR”-(alk)b-, and -NR”S(O)2NRM-(alk)b—; alk is optionally substituted CH ne; b is 0 or 1; and R14 is hydrogen or lower alkyl.

In another embodiment ofthe methods provided herein, in nds ofFormula Ia, R2, R5 and R6 are hydrogen, further wherein R4 is other than hydrogen. In another embodiment, R2, R4 and R6 are hydrogen, further wherein R5 is othcr than hydrogen.

In particular embodiments ofthe methods provided herein, the compound of Formula I has a structure according to the following sub-generic structure, a Ib, R16 / \ n M,N’ /Z\ l lle \V R15 W\N/ N/ Formulalb all salts, prodrugs, tautomers, and isomers thereof, wherein: V and W are independently selected from the group ting ofN and CH; U and Z are independently selected from the group consisting ofN and CR”, provided, however, that not more than one of W, U and Z is N; A is selected from the group consisting of—CR‘ng-, , -C(S)-, —S‘, -S(O)«, -S(O)g-, —NR21-, and —o-; n is 0 or I; F and J are both C or one ofF and J is C and the other ofF and J is N; E and K are selected from C, N, O or S; G is selected from C or N: when n is 1, F and J are C, and E, G and K are C, or any one of E, G and K is N and the other two of E, G and K are C, provided that when E, G or K is N, R13, R17 and R16, respectively, are , when n is 0 and F and J are both C, then one ofE and K is C or N and the other ofE and K is C, N, O or S, provided both E and K are not C, and provided that when both E and K are N, one ofR]5 and R16 is absent, and provided that when one ofE and K are N and the other is O or S, R15 and R16 are absent, when n is 0, one ofF and J is N and the other ofF and J is C, then one ofE and K is N and the other ofE and K is C, or both E and K are C, provided that when E is N, R15 is absent and when K is N, R16 is ; R1 is selected from the group consisting of optionally substituted lower alkyl, ally substituted cycloalkyl, optionally substituted heterocycloalkyl. optionally substituted aryl and optionally substituted heteroaryl; R15 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, -OR22, -SR22 and halogen when E is C, is absent when E is O or S or when n=1 and E is N, and is absent or selected from the group ting of hydrogen and optionally substituted lower alkyl when n20 and E is N; R16 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, -OR22, -SR22 and halogen when K is C, is absent when K is O or S or when n=1 and K is N, and is absent or selected from the group ting of hydrogen and optionally substituted lower alkyl when n=0 and K is N; is selected from the group consisting of hydrogen, optionally substituted lower alkyl, isOREZ, $1233 and halogen when G is C, or is absent when G is N; Re; is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, -OII, -NH3, ~N01, “CN, -NHC(O)NH,, -NHC(S)NH2, )2NH2, -NR24R25, -NHR”, -011”, SR”, -NHC(0)R27’, -NR33C(O)R23, -NHC(S)R33, »NR33C(S)R23, -NHS(0),R3‘, «NR33S(O)3R23, -NHC(O)NHR33, 'NR33C(O)NH2, “NRECCOWHR”, -NHC(0)NR33R2{ -NRZT‘qomRBRRi itxsnkl‘, xNRBCCSWHg, *NRBCtSWHRB, 4NHC(S)NR23R23, -NR23C(S)NR23R32 -NHS(O);NHR33, -NR23S(O)2NH2, -NR23S(O)2NHR35 —NHS(O)3NR23R23, and —NR23S(O)3NR23R23; M is selected from the group consisting of a bond, ~(CR19R20)u-, *(CR19R20)t—C(O)-(CRI9R20)s-, -(CR‘9R20)g-C(S)~(CR‘9R3“ {CR’QREO)E-C(O)O-(CR”R3553 ~(CR’9R20)1~C(S)O-(CR‘9R2°)S-, -(CRlgRgo).~C(O)NRM-(CR'9R3”)5—, ~(CRE9R20)t-C(S)NRzé-(CR‘9R20)S-, R20)t~S(O)-(CR'9R20)5—, -(CR‘yRZO),—S(O)2-(CR”112%, -(CR’9R20)t-S(O)2NR26-(CR19R20)g~, ~(CR‘9R30).-O-(CR19190);,-(CRlgRlo)‘-OC(O)-(CR‘9R20)5-, R2“)l-OC(S)-(CR”R3553 {CR‘ngoxvoctoleéwcCR‘918%-, {CR‘gnwl—oqS)NRZG-(CR‘9R20)S-, -(CR‘9R2°)t-S-(CR”R2“)S-, -(CRI9R20)t-NR26-(CR‘9R2°)5—, {CR‘918°)riNIRZGC(0)-(CR”R20 -(CR’9R2°)t-NR26C(S)-(CR‘“R20)5-, —(CR‘9R2°)t-NR26C(O)O-(CR”R20 -(CR19R2°)‘-NR26C(S)O-(CR‘9R20)S-, -(CR‘9R20)1—NR26C(O)NR26-(CR‘9R3°)S-, ~(CR‘9R20)l-N R26C(S)NR26-(CR19R2°)s-, -(CR'9R3°)t-NR268(O)2—(CR‘9R20)S-, and -(CR‘”Rwy—NRfls(0)2NR36—(CR‘9R2°)s-; wherein R19 and R20 at each occurrence are independently ed from the group consisting of hydrogen, fluoro, -OH, «NHZ, lower alkyl, lower alkoxy, lower alklylthio, mono- alkylamino, di-alkylamino, and ~—NRZ7R28, wherein the alkyl ehain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylaininog or di-alkylamino are optionally substituted with one or more substituents selected from the group ting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and lkylamino; or any two of RI9 and R20 on the same or different carbons combine to form a 3-7 membered monocyclie lkyl or 5-7 ed monoeyelie heteroeycloalkyl and any others of RI9 and R20 are ndently selected from the group consisting of en, fluoro, -OH, NH; lower alkyl, lower alkoxy, lower alklylthio, mono—alkylamino, di-alkylamino, and ~NR‘27R28, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono~all<ylamino, or di~alkylamino are optionally substituted with one or more substituents ed from the group consisting of lluoro, ~OH, -NH2, lower , fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthim mono‘ alkylamino, tii»«all<ylamino, and eyeloalltylaminoE and wherein the monoeyclie eycloalk'yi or monocyclic heterocycloaikyi are optionally substituted with one or more tuents selected from the group consisting ofhalogen, —OI»I, 4&ngg lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono—alkylamino, di-alkylamino: and eyeloalkylamino; R3“ and R22 at each ence are independently hydrogen or optionally substituted lower aikyl; R33 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower li provided, r, that no alkene carbon thereof is bound to any —C(O)-, ~C(S)—, —S(O);-, —O-, —S—, or —N- of any of NHRZS, -OR“, -5183, -NHC(O)R23, ~NR23C(O)R23, —NHC(S)R23, —NRBC(S)RZ£ -antonnu, -NR23S(O);R23, —NHC(O)NHR23, -NR23C(O)NH3, —NR23C(0)NHR23.

—NHC(0)NR23R23, -NR23C(O)NR23R”, -NHC(S)NHR”, (S)NH2, —NR23C(S)NHR33, —NHC(S)NR23R23, «N R33C(S)NR33RZ3, -NHS(O)2NHRZ3, —NR33S(O)2NI~13, —NR23S(O)1NHRZ3, -NHS(O)2NR23R23, or —NRZ3S(0)2NR23R23, optionally tuted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to any —C(O)—, -C(S)—, —S(O)—, -S(O)2-, —o-, -s-, or -N— of any of -NHR23, -ORZ3, -SR23,.

—NHC(O)R23, —NR23C(O)R23, -NHC(S)R23, —NR23C(S)R23, —NHS(O)2R23, —NR23S(O)2RB, -NHC(0)NHR23, -NR23C(O)NH2, -NR33C(0)NHR23, -NHC(O)NR23R23, —NR23C(O)NR23R23, -NHC(S)NHR33, —NR2‘C(S)NH2, —NR23C(S)NHR23, —NHC(S)NR23R23, —NR23C(S)N R2311”, —NHS(O)2NIIR23, —N R238(O)2NH2, —NR23S(0)2NHR23, —NHS(O)2NR23R23, or N R23S(O)2NR23R23, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroary]; R24 and R25 at each ence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, ed, however, that no alkene carbon thereof is bound to the nitrogen of ~NR24R25, ally substituted lower alkynyl, provided, however, that no alkync carbon f is bound to the nitrogen RES substituted cycloalkyl, optionally tuted , ally heterocycloalkyl, optionally tuted aryl, and ally substituted heteroaryl; or R24 and R25 together with the nitrogen to which they are attached form a clic 5-7 membered ally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroary]; R26 at each occurrence is independently selected from the group consisting of en, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, ~OH, ‘NHQ, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio} fluore substituted lower alkylthio, monowalkylaniino, finoro substituted mono» alkylamino, di~alkylamino, linoro substituted disalkylamino’ and ~NR2?R28, provided, however, that when R26 is substituted lower alkyl, any substitution on the lower alkyl carbon bound to the -N- or—NRZG- is fluoro; R37 and R28 combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5»? membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, DH, ~NHZ, lower alkyl, fiuoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio; u is 1—6; t is 0—3; and s is 0-3; ed that when v, w, U and z are CH, n=i, E, F, G, J, and K are C, R”, R16 and R” are H, A is —CH3—, —CH(OH)-, or —C(O)-, and M is —NHCH3—, then R‘ is not phenyl, 4— trifluoromethyl—phenyl, 4-methoxy~phenyl, 4-ehloro—phenyl, 4—fluoro-phenyl, 4— methyl—phenyl, 3—fluoro-phenyl or thiophcn—Z—yl, when V, W, U and Z are CH, n=l, E, F, G, J, and K are C, R”, R26 and R17 are H, and A is -CII;—, then M—R‘ is not CH(CH3)2, when V, W, and U are CH, n=l, E, F, G, J, and K are C, R”, R’6 and R17 are H, A is —CH2—, MRI is —OCH3, and Z is CR”, then Rlg is not thiophcn—3—yl, and when v, w, and U are CH, 11:0, F, J, and K are C, E is N, R15 is CH3, R16 is H, A is , M—R’ is —CH(CH3)3, and z is CR“, then Rlg is not 3-((E)carhoxy- vinyl)phenyl.

In one embodiment ofthe methods provided herein, in compounds of Formula 1b, the variables E, J, K, G, F, n, R”, R16 and R17 are selected to provide structures selected from the grOup consisting of ~% C} ii— €1i>§§~§<¥f§ and R15 - IS , wherein R , Pd6 and R17 are as defined for compounds of Formula “:2 and wherein é indicates the point of allachment of A and 5% indicates the point of attachment of M.

In one embodiment ofthe methods provided herein, in nds of Formula Ib, the variable M is selected from the group consisting of -O-(CR”R20)S-, ~S-(CRF9R20)9-, -OC(O)5(CR19R30)S», —OC(S)»(_’CR’9R30)S-, —OC(O)NR25-(CR’9RZD)E«, -OC(S)NR26—(CR‘9R2”)S~, -C(O)NR26~(CR’9RZO)S-? -C(S)NR36—(CRE9RQO)S—? -S(C))2NR26w(CREgR20)S—, -NR39-(CR‘9R2")S-, (0)~(CR39R29)53 zsimRmthgg -NR36C(O)OK(CR§9R30}§~7 —NR26C(S)o—(CR‘9R3“)S-, -NthqoiNRié-(CR‘9R3O),-, (5)NR26-(CR”180%-, —NR26S(0)3-(CR”’RZO),—, and -NR26$(O)2NR36-(CR”Rmkn In one embodiment ofthe s provided herein, in compounds of Formula Ib, the variable R26 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with I, 2, or 3 substituents selected from the group consisting of fluoro, -OII, -NIIZ, alkoxy, lower alkylthio, mono~alkylamino, di—alkylamino and cycloalkylamino, provided that any substitution on the carbon that is bound to the nitrogen of~ NR26 is fluoro.

In one embodiment ofthe methods provided herein, in nds of Formula Ib, the variable R1 is ed from the group consisting ofoptionally substituted aryl and optionally substituted aryl.

In one embodiment ofthe methods provided herein, in compounds of Formula Ib, the variable Z is N or CH, n is I. ER15 is N or CH, K-Rw is N or CH, and G-Rl7 is N or CH, provided no more than one of ER”, Isl-R") and G-Rl7 is N, In one embodiment, Z is N or CH, n is l, and an”, K—RE6 and GR17 are CH, In one embodiment ofthe s provided , in compounds of Formula lb, the variables V, W and Z are CH, U is CRIS, n is I, ER” is N or CH, K-R16 is N or CH, and G-Rl7 is N or CH, provided no more than one of ER”, K-Rm and G—RE7 is N. In another embodiment, V, W and z are CH, U is CR”, n is 1, and HR”, K-Rm and GR” are CH.

In one embodiment ofthe methods ed herein, in compounds of Formula Ib, the variable Z is N or CH, n is 1, BR”, K-Rm and G-Rl7 are CH, A is —CH;-, M is —NHCH2«, further wherein R1 is optionally substituted . In another embodiment, V, Z, U and W are CH, n is 1, E-RH is N or CH, K—R16 is N or CH, and G-Rl7 is N or CII, provided no more than one of E— R'5,1<.R“S and GR” is N.

In one embodiment of the methods provided , in compounds of Formula Ib, variabie z is N or CH, n is i, as” is N or CH, K—Rgé‘ is N or CH, and on” is N or CH, provided no more than one of ER”, K~RE6 and GR” is N, and RE is phenyl optionaily substituted with one or more substituents selected from the group consisting ofhalogen, —OH, ~NH3, —NOg, «CN, optionally substituted lower alkyl and —OR29, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocyeloalkyl, optionally substituted aryl and optionally substituted heteroaryl, In one embodiment of the methods provided herein, in compounds of Formula Ib, the variables V, Z, U and W are CH, n is 1, BR”, K-R16 and Gan are CH, A is -CH2~, M is - NHCHZ, and Rt is optionally substituted phenyl, further wherein Rx is phenyi optionally substituted with one or more tuents selected from the group consisting of halogen, -OI’I, - NI-Iz, ~N02, «CN, optionally substituted lower alkyl and —OR29, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.

In one embodiment of the methods provided herein, in compounds of Formula Ib, the variables v, w and z are CH, u is CR“, 11 is 1, E—R’i ten16 and G-R” are CH, A is -cn,-, M is -NHCH2, and R1 is ally substituted phenyl, further wherein R1 is phenyl ally substituted with one or more substituents selected from the group consisting of halogen, —OH, - NH}, —N02, -Cl\l, optionally substituted lower alkyl and —OR29, where R29 is selected from the group consisting of ally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heteroeycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.

In one embodiment ofthe methods provided herein, in compounds of Fomiula Ib, when is I, and E, K and G are C, at least one oles, R“S and R‘7 is other than hydrogen. In another embodiment, n is I, one of E, K, and G are N and the other two ofE, K, and G are C and at least one of R”, R,6 and R17 is other than hydrogen. In another embodiment, it is I, E, K and G are C, and at least one of R15, R'6 and R}7 is other than hydrogen.

In one ment ofthe methods ed herein, in nds of Formula lb, n is I, V and W are Clrl, U and Z are independently CR'B, one of E, K, and G are N and the other two of E, K, and G are C and at least one of R”, R16 and R17 is other than hydrogen. In r embodiment, n is l, V and W are CH, U and Z are independently CR“, E, K and G are C, and at least one ofRIS, Rmand R17 is other than hvdro en. . g In one embodiment ofthe methods provided herein, in nds of Formula Ib, n is 1, one ofE, K, and G are N and the other two of E, K, and G are C, at ieast one of R15, R16 and R17 is other than hydrogen, A is «CH3-, M is «NHCHgm, further wherein RE is optionally substituted phenyl. In another embodiment, n is i, E, K, and G are C, at least one of R35, RE6 and R” is other than hydrogen, A is «C1133. M is ~~-NHCH;—, further wherein R5 is optionaiiy substituted phenyl.

In one embodiment ofthe methods provided herein, in compounds of Formula lb, n is l, V, 2:, U and W are CIl, one of [3, K, and G are N and the other two of E, K, and G are C and at least one of R35, R16 and RE7 is other than en, In r embodiment, V, 7, U and Ware CH, E, K and G are C, and at ieast one ofRii, REé and RE7 is other than hydrogen, In one embodiment of the methods provided herein, in compounds of Formula Ib, Z is CR‘S, wherein R18 is other than hydrogen, n is ” is N or CH, HR“ is N or CH and GR” is N or CH. In another ment, Z is CRIS, wherein R'8 is other than hydrogen, n is 1, and ER”, K-R16 and GR” are CH. In another ment, Z is CRIS, n R”3 is other than hydrogen, U is CR'S, V and w are CH, n is l, and ER”, leR‘6 and GR” are CH, further wherein U is CH.

In one embodiment oftlle methods provided herein, in compounds of Formula Ib, Z is CRIB, wherein R18 is other than hydrogen, n is 1, E-R”, K»Rl6 and G-Rl7 are CH, A is -CH2-, M is -NHCH2—, further wherein R1 is ally tuted phenyl. In a further ment, Z is CRIB, n R18 is other than hydrogen, U is CR'R, V and W are CH, n is 1, ER”, K-Rlb and GR” are CH, A is —CH2—, M is —NHCH2—, further wherein R‘ is optionally substituted phenyl. In a further embodiment, Z is CRIS, wherein R18 is other than hydrogen, V, U and W are CH, n is 1, BR”, l<.R‘6 and GR” are CH, A is -CH2-, M is ~NHCH2-, r wherein R‘ is optionally substituted phenyl, In one embodiment of the methods provided herein, in compounds of Formula Ib, U is CR”, wherein R18 is other than hydrogen, n is 1, ER” is N or CH, HR16 is N or CH and GR” is N or CH. In another embodiment, U is Cng, wherein R18 is other than hydrogen, n is 1, and ER”, K-R16 and GR17 are CH1 In another embodiment, U is CR”, wherein R18 is other than hydrogen, Z is CRIS, V and W are CH, n is 1, and ER”, K-R'6 and GR17 are CH, further wherein Z is CH.

In one embodiment ofthe methods provided herein, in compounds of Formula Ib, U is CR”, wherein R‘8 is other than hydrogen, n is 1, BR”, Kit” and GR” are CH, A is -CH;-, M is -, further n R1 is optionally substituted phenyl. In a further embodiment, U is CRIS, wherein R18 is other than hydrogen, Z is CRIB, V and W are CH, n is 1, BR”, K-R“ and GR” are CH, A is -CH2-, M is ~NHCH2-, r wherein R‘ is optionally substituted phenyl. In a further embodiment, U is CRIS, wherein R!8 is other than hydrogen, V, Z and W are CH, n is l, BR”, K-R16 and G»R'7 are CI], A is —CHg-, M is ~NHCH2-, further wherein RI is optionally substituted phenyl, In one embodiment of the methods provided herein, in compounds of Formula Ib, further to any of the above embodiments, R”, R16 and RE7 are independently selected from the group consisting of halogen, wOH, lower alkyl, fluoro substituted lower alkyl, lower , and lluoro substituted lower alkoxy. Further to any of these embodiments R1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, ~OH, -NH2, ~NOZ, ~ CN, optionally substituted lower alkyl and “OR”, where R“9 is selected from the group, , ‘i , ’3 , ‘ ‘ _ . eonsmtlng of optionaiiy substituted lower aikyi, optionally substituted cycloaikyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.

In one embodiment of the methods provided herein, in nds of Formula lb, further to any of the above embodiments, R18 is selected from the group consisting of halogen, -OH, ally substituted lower alkyl and —OR39, where R29 is selected from the group consisting of optionally substituted lower alkyl? optionally substituted eyeloalkyl, optionally substituted heterocycloalkyl, ally tuted aryl and optionally substituted heteroaryl. Further to any of these embodiments, R1 is phenyl optionally su bstitutcd with one or more substituents selected from the group consisting ofhalogen: ~OH, ~NH32 —N03, ~CN, optionally substituted lower alkyl and ~0R29, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lkyl, optionally substituted heterocycloalkyl, optionally substituted my] and optionally substituted heteroaryl.

In another embodiment ofmethods provided herein, in compounds ofFormula Ib, M is a bond and R1 is other than thiophenyl.

In another embodiment ofthe methods provided herein, in compounds ofFormula lb2 Z is N or CR]8 wherein R18 is not hydrogen. Further to this embodiment, as allowed in the description of Formula Ib, E is NR15 or CR”, K is NR” or CR16 and G is CR”, or ations thereof, wherein at least one of R15, R16 and R17 is not hydrogen.

In one embodiment oftlie s provided herein, a compound of Formula I has a structure according to the following sub—generic structure, Formula Ig, R 37 \K1 (3/1)” , FfMa’Cy‘m45)v Aj/J1\ ’4 Formoia lg, all salts, prodrugs, ersi and isomers f, wherein: Z] is selected from the group consisting ofN and CR“; U; is selected from the group consisting ofN and CR”; A; is selected from the group consisting y and 43(0)»; M3 is selected from the group consisting ofa bond, ~NR39~, ~S-, ~O~, ~NR39CH3~, —NR”Cll(R"0)-, solo, -OCH3—, —C(0)NR3"—, ~S(O)gNR39—, -CH2NR39-, —CH(R40)NR3"-, -NR39C(O)-, and (0)2-; n is 0 or 1; v is 0,1, 2 or 3; F1 and J; are both C or one ofFl and J, is C and the other ofF. and J, is N; E1 and K1 are independently selected from C, N, O or S; G. is selected from C or N; wherein when n is 1, F1 and .11 are C, and E, G, and K, are C, or any one 011%, G1 and K1 is N and the other two of Eh 01 and K1 are C, provided that when 13;, G] or K. is N, R36, R37 and R38, respectively, are absent; when n is 0 and F1 and J! are both C, then one of E1 and K; is C or N and the other of E1 and K1 is C, N, O or S, provided both E, and K1 are not C, and provided that when both E] and K] are N, one of R36 and R37 is absent, and provided that when one of E1 and K] are N and the other is O or S, R36 and R37 are absent; when 11 is 0, one of F, and J} is N and the other ofF. and .11 is C, then one of E1 and K1 is N and the other of El and K1 is C, or both El and K1 are C, ed that when E, is N, R36 is absent and when K1 is N, R37 is absent; Cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and aryl; R34 and R35 are independently selected from the group consisting of hydrogen, ~OR‘“, ~SR4', -NHR“, ~NR‘HR‘”, ~NR39C(O)R“, ~NR398(O)2R“, n, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally tuted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower hio, fluoro substituted lower hio, mono— alkylamino, di~alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R34 or R35, or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of-OH, ~NH2, —CN, «N03, -S(O)3NH2, —C(O)NH3, OR“, «SRQ, ,NHR‘”, NR‘QR”, ~NR”(1((3)Rti ~NRwscothi usgobsti halogen, lower alkyl, fluoro substituted lower alkyl, and eyeloalkylamino; R45 at each occurrence is independently selected from the group consisting of OR“, SR“, —NHR‘“, ‘“, -NR39C(0)R“, ~NR3QS(O);R“, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower , fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, ”term“ alkylarnino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and hctcroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R”, or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of~OH, was, as, -5103, -S(O)2NH2, —C(O)NH2, OR“, sn“, ~NHR43, —NR“R“3, —NR39C(0)R42, —NR39S(0)2R43, mobs“, n, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; R36 is ed from the group consisting of hydrogen, n, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when E] is C, is absent when E, is O or S or when n=1 and E, is N, and is absent or selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl when n=0 and E1 is R37 is selected from the group consisting ofhydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when K1 is C, is absent when K] is O or S or when n=1 and K1 is N, and is absent or selected from the group ting ogen, lower alkyl, and fluoro tuted lower alkyl when n=0 and K] is R33 is selected from the group consisting ofhydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when G is C, or is absent when G, is N; R39 at each occurrence is independently hydrogen or lower alkyl; R40 is lower alkyl or fluoro substituted lower alkyl; R41 is selected from the group consisting of lower alkyl, lkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is ally 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, aiyl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R“11 or as tuents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, -NH;, —CN, ‘Nog, NH2, «C(owng, on”, «31142, uNHR“, -NR“3R43, «NR,”C(O)R4?, (O)2R43, $03511“, halogen, lower alkyi, fluoro substituted iower alkyl, and cycloalkylamino; and R"12 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“ ail-(Vlamino , 7 di~alkvlamino, and cwloalkvlamino, and heterocvcioaiks . s If and heteroa , T}’l are t I? optionally substituted with one or more substitucnts selected from the group consisting of halogen, ~CN, lower alkyl, t‘luoro substituted lower alkyl, lower alkoxy and tluoro substituted lower alkoxy.

In one embodiment of methods provided herein> in compounds of Formula Ig, n is 1, Gt and K1 are C, and E is N or C, preferably wherein E is C.

In one embodiment ofthe methods provided herein, in nds of Formula Ig, M3 is selected from the group consisting or-NR39—, —o—, -NR39CIlg-, -NR39CH(R40)-, -SCH2-, pony, -CHZNR39—, -NR39C(O)-, and O)g-, preferably wherein Mr is ~NR39CH3-, —NR39CH(R40)—, song, -OCHg—, or -CH3NR39-.

In one embodiment of the s provided herein, in compounds of Formula Ig, n is l, G; and K1 are C, and E is N or C, preferably wherein E is C, and M3 is selected from the group consisting of —NR39-, —o—, -NR39CH2-, —NR39CH(R‘°)—, sour, , -CH2NR39-, -NR39C(O)-, and 0)2—, ably n M3 is —NR”Cih—, -NR39CH(R4°)—, sorry, , or -CH2NR39-.

In one embodiment ofthe methods provided herein, in compounds of Formula Ig, each R45 is selected from the group consisting of -OH, -NII;, -CN, -NO;, halogen, lower alkyl, fluoro tuted lower alkyl, lower alkoxy, fluoro tuted lower alkoxy, lower thioalkyl, lluoro substitutcd lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1, or 2, also 0 or 1.

In one embodiment ofthe methods provided herein, in compounds of Formula lg, n is l, G and K] are C, and E is N or C, preferably wherein E is C, M3 is selected from the group consisting of -NR”—, —o—, -NR3gCHg~, —NR39CH(R4°)-, song, , -CH2NR39—, -NR39C(O)—, and —NR”3(0)2-, preferably wherein Mi is -NR39CH2—, —NR39CH(R4°)—, song, -OCH2», ~CIIQNR39-, and each R45 is selected from the group consisting of -OH, -N H2, ~CN, -NOg, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower , lower thioelkyl, fiuoro substituted lower thioaikyl, mono-alkylamino, cli—alkylamino and cycloalkylamiuo, preferably wherein v is O, l, or 2, also (i or I.

In one ment ofthe methods provided herein, in compounds of a lg, Z; is CR“, U, is CR”, and R31 and R35 are both hydrogen. In one embodiment, 21 is CR”, U1 is CR”, and R34 and R35 are independently selected from the group consisting of hydrogen, ~OR“, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycioaikyl, aryl and heteroaryl are optioneliy substituted with one or more substituents selected from the group consisting of—OH, -NH2, -CN, ‘Noz, vS(O);NHg, —C(O)NH2, on”, -311”, wins“, —NR42R42, —NR”C(0)R43, -NR393(0)2R"3, -S(O)3R43, n, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, and wherein lower alkyl is optionally substituted with one or more substituents selected from the group ting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, i‘luoro substituted lower alkylthio, mono-alkylamino, di— alkylamino, and cycloalkylamino. In a further embodiment, one of R34 and R35 is hydrogen, and the other of RN and R15 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally tuted with or more substituents selected from the group consisting of -OH, —NH2, -CN, —NO;, -S(O)2NH2, —C(O)NH2, -OR43, -SR”, -NHR42, —NR43R”, ~NR39C(O)R“, -NR”S(O)2R42, —S(O)3R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, and wherein lower alkyl and lower alkoxy are 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, ylamino, and eyeloalkylamino, further wherein the other of R34 and R35 is selected from the group consisting of halogen, lower alkyl, and lower alkoxy, wherein lower alkyl and lower alkoxy are optionally substituted with one or more substituents ed from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, lkylamino, di-alkylamino, and lkylamino.

In one embodiment ofthe methods provided , in nds of Formula lg, each R45 is independently selected from the group consisting of -OH, -NH2, -CN, -NO;, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower lhioalkyl, fluoro tuted lower thioalkyl, monowalkylamino, disalkylamino and cycloalkylamino, preferably wherein v is 0, I, or 2, also 0 or 1, 21 is CR”, U. is CRSS, and R34 and R35 are independently selected from the group ting of hydrogen, ~0R“, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cyeloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more tuents selected from the group consisting of-CJH, -Nlig, «CN, -N02, —S(O)2NH3, -C(O)NH;, -OR‘”, 431%“, NHR”, vNR‘uRQ, annigcgouei newsmiznti stops“, haiogen, iower alkyi, nunm substituted iower aikyi, and eyeioalkylamino, and wherein lower alkyi is optionaily substituted with one or more tuents selected from the group consisting of fluoro, lower aikoxy, fluoro substituted lower , lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di~alkylamino, and cycloalkylamino. In a further embodiment, both of R34 and R35 are hydrogen.

In one embodiment of the methods provided herein, in compounds of Formula lg, each R"5 is selected from the group consisting of 4:111, »NH3, «CN, $4703, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, lluoro substituted lower thioalkyl, mono-alkylamino, di—alkylamino and cycloalkylamino, preferably wherein V is 0, 1, or 2, also 0 or 1, Z} is CR“, U; is CR35, one of R34 and R35 is hydrogen, and the other of R34 and R35 is selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally tuted with one or more substituents ed from the group ting of—OH, —NH2,, ~CN, -NO;, -S(O)3NH;, -C(O)NH2, on“, -SR”, -NHR43, , -NR3°C(O)R“, —NR395(O)2R“, —S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and eyeloalkylamino, and wherein lower alkyl and lower alkoxy are optionally substituted with one or more substiments selected from the group consisting of fluoro, lower alkoxy, fluoro tuted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono—alkylamino, di—alkylamino, and cyeloalkylamino, wherein the other of R34 and R35 is selected from the group consisting of halogen, lower alkyl, lower alkoxy, wherein lower alkyl and lower alkoxy are 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.

In one embodiment ofthe methods provided herein, in compounds ofFonnula lg, n is l, G] and K1 are C, and E is N or C, preferably wherein E is C, M3 is selected from the group consisting of NR”; won —NR39CH2-, —NR”CH(R40)-, -SCH2—, -OCH2-, -CH2NR3”-, -NR39C(O)~, and -NR”S(O)2—, ably wherein M3 is H2-, wNR”CH(R‘“’)., scum -OCH2-, —CH3NR39', each R45 is selected from the group consisting of-OH, ~NH2, —CN, -N03, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, l, or 2, also 0 or I, Z is CR“, U1 is CR”, and R34 and R35 are both hydrogen.

In one embodiment ofthe s ed herein, in compounds ofFonnula lg, n is l, G; and K; are C, and E is N or C, preferably wherein E is C, M 3 is selected from the group consisting ni‘NR9 -ou, -NRSSCHy, -NR39CH(R"G)~, -scnga, floors, 39-t -NR39C(ol-, and wNntfisajiy, ably wherein N13 is writ/tony, aNR”CH(R“)c, serif, eoeuy, or ~CH2NR393 each R45 is selected from the group consisting of ~OH, ~Nl-lg, ~CN, «N03, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono—alkylamino, di—alkylamino and cycloalkylamino, ably wherein v is 0, l. or 2, also 0 or 1, Z] is CR3‘4 and Ui is CR”, and 113‘1 and R35 are independently selected from the group consisting of hydrogen: JDR“, halogen, lower alkyl, eycloalkylt heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heteroeycloalkyl, aryl and heteroaryl are optionally substituted with one or more tuents selected from the group consisting or-on, .erg, cm -Nog, -S(O)3NH2, crowns -OR“, SR“, mun“, -NR‘ER“, -NR”C(0)R43, -NR393(0)2R42, —S(0)2R43, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, and 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. In a further embodiment, one of R34 and R35 is en? and the other of R34 and RSS is selected from the group consisting of halogens lower alkyl, lower alkoxy, alyl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents ed from the group consisting of—Oll, -NH2, -CN, N02, -S(O)2NH2, -C(O)NH2, QR“, -SR“, -NHR“, -NR‘QR‘Q —NR”C(O)R“2, -NR3QS(O)2R42, sroizk”, halogen, lower alkyl, fluoro tuted lower alkyl, and cycloalkylamino, and wherein lower alkyl and lower alkoxy ally substituted with one or more substituents selected from the group consisting of fluoro, lower , fluoro substituted lower , lower alkylthio, fluoro substituted lower alkylthio, lnono-alkylamino, di-alkylamino, and cycloalkylamino, further wherein the other ofR34 and R35 is selected from the group consisting of halogen, lower alkyl, and lower alkoxy, wherein lower alkyl and lower alkoxy are optionally tuted 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, further wherein R34 is hydrogen.

In one embodiment ofthe methods ed herein, a compound of Formula I has a structure according to the following sub-generic structure, a II, Az/D ‘ \ N N Formulall all saltsg prodrugss tautomers, and isomers thereof, wherein; MN M4/Q 1 3% \ / D has a structure selected from the group consisting of QM [N M/QH Q ,N 31 N 021 M7/Q w 5 / / 2%N M5/ 1% \ / 024 033 QM ’ 9 Q52 \ \N N / NxN CPL \ N\Mx a \ 12¢ \ ”Q41 EQ)\M9.‘()51 \ M10'QE1 Q54 064 Q74 QBZ 0102 7 9 9 0112 O\N 0132 1% N//\\M14 '1%\ N IN‘ M 5‘Q 111 / ‘ 0101 1 _, 0124 21; *M16‘Q121 S\N 0152 'EVM ”0131 ' k‘l Q 144 S M15”Q141 in which -3.- indicates the attachment point 0“) to A2 of a ll; A; is selected from the group consisting 9R20-, -C(O)-, —C(S)—, -S-, —S(O)—, ‘S(O)2-, -NR2]-, and -O-, provided? however, that when A2 is NR‘“1 N is not bound to a nitrogen of B is selected from the group consisting, of hydrogen, halogen, optionally substituted lower alkyt optionally substituted cycioaikyl, optionally substituted hetemcyctoalkyi, optionally substituted aryl; optionally substituted hetemaryl, «OH, —Nl{2, —NO;, ~CN, ‘NHC(O)NH2, -NHC(S)NH3~ -NHS(_O)3NH2, ~C(O)NH2§ »C(S)NH2, ~S(O)2NH2, Mum”, NHR”, QR”, -SR”, R23, ~C(S)R23, 23, -S(O)2R23, -C(O)NHR33, —C(O)NR23R23, —C(S)NHR31 -C(S)NR23RZ3, NHR’~3, -S(O)3NR23R23, —NHC(O)R23, —NR“C(O)RB, —NHC(S)R33, -NRZ3Ct(S)R2~1 -Nstthi -NRE3S(O)3R3{ )NHR33, ~NR33C{O)NH3, «NRBQQNHR? ~NHC(O)NRBR”, *NRBctmNRB‘tRfi —NHC(S)NHR22 —NR23C(S)NIIE, —NR33C(S)NHR23, —NHC(S)NR23R33, —NR33C(S)NR23R23, -NHS(0)2NHRZE ~NR23S(O)2NH2§ —NRZ3S(O)3NHR23, —NHS(0)2NR33R21 and -NR”S(O)2NR33RB; M4 is -NR39CH2-, -NR39CH(R“)—, —NR39CIlgCll2—, or «N R39C(0)-; M5, MQSM'LMK)’ MmeH: MI; M13 MM) M15 M15: M17 and Mg are ed from the group consisting ofa bond, -(CR‘9RZ°)U-, —(CR'QRZQ)t-C(O)~(CR19R2°)S-, -(CR39'R2°)¢C(S)~(CR’9R30)s—, —(CRI9R20)1—C(O)O-(CR’9RZ°)s—, —(CR‘9R20)t-C(S)O-(CRI9R2°)s—, —(CR‘9R20)1—C(O)NRlfi—(CR‘9R20)s—, «(CR‘9R30)t-C(S)NRzG—(CngRzuk-g -(CR‘9R2")[—S(O)-(CR’9R2°)S-, R2°)t—S(0)2-(CR‘91120», —(C,R‘9R2°)t—S(O)2NR”—<CR”18”)“ —(CR]9R20)1—0—(CR'9R30)g-, —(CR”R2°)1—OC(O)—(CRI9R20)sv,«(CR19R20)1—OC(S)—(CR’9R2°)s-, ~(CR‘9R20)I—OC(O)Nsz-(CR19R20)S-, R3“).—0C(s)NRZb-(CR‘9R2")S—, —(CR19R20)1—S-(CR19R20 S" _(CRI9R2O)t_NR26_(CRI9R20)s_? —(CR‘9R20)1—NR26C(O)-(CR‘9R2°)s-, —(CRI9R2°)1—NR26C(S)-(CRI9R2°)5—, ~(CRI9R2°)1—NR36C(O)O-(CRI9R20)5-, —(CR’9R20)I—NR26C(S)O~(CR'9R3")S—, —(CR‘9R2”)‘—NR26C(O)NR26—(CRI9R” —(CR’9R2°)t-NR26C(S)NR26-(CR’9RZO)5-, R20),—NR“S(O)2—(CR‘9R2°)5—, and R20)1—NR26S(O)2NR26—(CR19R20)s-; M3 is selected from the group consisting ofa bondg -(CR]9R20)U~, —(CRI9R20)1—C(O)—(CR]9RQG)S-, R20)1—C(S)—(CR'9R2” —(CR’9R2°),—C(O)O—(CR’9R2°)s—, -(CR’9R20)1—C(S)O—(CR'9R20)s-, —(CR’9R2°)I—C(O)NR26—(CR‘9R20)S-, —(CRI9R2D)I—C(S)NR26-(CRIQRZO)“ —(CR’9R20)[—S(O)-(CR’9R20)S—, —(CR’9R20)I—S(O)2—(CR‘9R3”)s-, —(CR‘9R20)t—S(O)2NR26-(CR‘9R20)5—, —(CR19R2°)w—O-(CRl9R20)S—, -(CR’9R20)“,—OC(O)-(CR’9R2°)S—, -(CR’9R2°)w-0C(S)—(CR”R2° —(CR‘9R20)w—OC(O)NR26—(CR”R2553 —(CR’9R20)w-OC(S)NR26—(CR’9R2”)S-, —(CR“’R2”)w—s—(CR‘9R2°)s—, —(CR’9R2°)w—NR26-(CR'9R20)5-, R2°)\t.-NR26C(O)—(CR’9R2°)S-, {CR}9R20)w-NR26C(S)-(CRI9R2°)s-, {CR19R20)w—NR26C(O)O—(CRI9R2°)5-, —(CR’gRgo)“,-NR36C(S)O-(CRI9R2°)S-, -(CRI9R20)w—NR26C(O)NR2"—(CRl9R30)5-, {CRl9RZO)W~NR26C(S)NR36~(CR19R” (CR:9R20)w‘NREGS(O)3-(CR‘9R23)S-, and {CRlQ‘Rm}w«}éR2§S(O)3NR3§,(CR”R3@)S~; QE is aryl or heteroaxylt wherein aryi or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen2 lower alkyl, fluoro substituted lower alkyL ~NHS(O)2R"3, -NHC(_O)R“2 ~NIIR43, *NR43R43, OR“, SR“, S(O)R"3, and —S(O)3R43; Q“, Q”, Q“? Q“, Q“, Q“, Q7: Q5”, Q9: Q”): Qm, Qm, Q13}, and QW are selected from the group consisting of ally tuted lower alkyL optionally substituted cycloalkyl, optionally substituted heteroeyeloalkyl. optionally substituted aryl and optionally tuted lietemaryl; QI2 is fluoro, chloro or —CF;; QH and Q“1 are independently hydrogen, fluoro, ehloro, lower alkyl, or fluoro substituted lower alkyl; Q22, Q“, Q”, Q33, Q43, Q44, Q52, (2542 Q102 and Q104 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro tuted lower alkyl, -NR“RM, OR“, and SR“, provided, however, that at least one of Q22 and Q“, at least one of Q31 and Q”, at least one of Q43 and Q“, at least one of Q52 and Q54? and at least one on102 and Q104 is hydrogen, fluoro, ehloro, lower alkyl or fluoro substituted lower alkyl; Q62, Q74, Q1”, Q1“, Q1”, Q1“, and Q152 are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, 44, -OR44, or —SR44; Q64, Q72, 082, and Q94 are hydrogen, lower alkyl or fluoro substituted lower alkyl; R43 at each occurrence is independently optionally substituted lower alkyl, optionally substituted cycloalkyL optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted hetereoaryl; R39 and R40 are as defined for Formula 1g; each R44 is independently en, lower alkyl or fluoro substituted lower alkyl; w is l, 2, or 3; and R19, R2", R2], R23, R24, R25, R26, 5, t and u are as d for Formula lb.

In certain embodiments ofthe methods provided herein, e.g., the compound is not \hw ’Al ‘ :t‘f \sz Atow/xv3 I! t A am Www ‘\i g 1% hip/{1‘ l O O V/ Of 0 ll } l ’ {kag / N/Au KN”!XL\fi / t N N ’\V/ “N H O 1’ Jr’”\7/NW ~\,/ t \ N‘Q’N \\ 1 SAN/\f/ l E\\ \t‘, '0 \ / \ i \ O i \ H \ Cl ‘ ” ’ r N N N N N N H H H , ,or 8*N’\©\x \ H l Cl In one embodiment of the methods provided , in compounds of Formula II, ,-N M4/Q ‘ it \ / l4 Q13 D has a structure selected from the group consisting of Q Q22 Q52 \ N 11 f M5/Q N\ E \ / ‘N 1;: N x \ N\M ~Q4‘l a \ M10'Q61 074 054 074 , 5 and Q152 ii /S)\M18”Q141\ in which -3“ indicates the attachment point ofD to A; of Formula H; A; is selected from the group consisting of—CR‘9R20-, a0): —C(S)—, s —S(O)~, :S(O)3~, ~NR3l—, and ~05, provided; however, that when A; is NR2}, N is not bound to a nitrogen of D} preferably A; is CH?» or —C(0)~; B is selected from the group consisting of hydrogen, ~CNq 0R“, ~SR“, WEIR“, ~NR41R“? —NR3”C(O)R"L sNRwsgohR“, —C(O)NR39R‘”, mom“; —S(0)2NR39R“, -S(O);R“, halogen. lower alkyl, cycloalkyl, heterocycloalk'yl, 21in 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 alkoxyr lower alkylthiot fluoro tuted tower hio? mono-alkylamino, cibalkylarnirtm eycioalkyi, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl: heterooycloalkyl= aryl, and heteroaryl as B, or as substituents of lower alkyl are ally substituted with one or more substituents selected from the group consisting of —OH? *NHg, -CN, -NOg, -S(O)2NH2, -C(O)NH;, OR“, SR“, -NHR‘3, —NR“R43, —NR”C(O)R4i -NR3gs(0)ZR“, —S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Me is -NR39CHg—, —NR39CH(R"°)—, —NR39CH2CHg-, or ~NR39C(O)—, preferably — or -NHC(O)-; M5, M10, and M13 are selected from the group ting ofa bond, R20)u—, —(CRl9R20)1~C(O)~(CR19R.2°)S-, -(CR‘9R3“)t-C(S)—(CR”R3551, —(CRl9R20)1—C(O)O—(CR‘9R2°)S—, -(CR‘9R2“),—C(S)O-(CR‘9R2°)5-, {CR‘9R30),—C(0)NR2‘1(CR”122%-, —(CRlngo),—C(S)NR26—(CR‘9RZ°)s—, -(CR‘9R2°)t—S(0)—(CR”12255-, RZU),—S(O)2—(CRI9R2°)5—, —(CRlQRZO),—S(O)2NR26—(CR‘9R3°)s—, R2°),—o-(CR‘9R2”)s-, —(CR’9Rg”)t—OC(O)-(CR‘9R2°)S—, —(CR'9R20)t—OC(S)-(CR‘9R20)Ss, —(CRlngo),—OC(O)NR26—(CR’9R2°)5—, R20)1-OC(S)NR26—(CR‘9R2°)3-, —(CR‘9R2°)t—S—(CR‘°R2°)s—, —(CR‘9R2°)t—NR36-(CR‘918m, -(CR’9R2°)I—NR26C(O)—(CR‘9R2°)s—, -(CR‘gRlo),-NR26C(S)-(CR‘9R3°)s-, -(CR‘9R20),—NR26C(O)O-(CR”Rim, —(CR‘9R2°)1-NR26C(S)O—(CR‘9R20)s—, -(CR‘9R20).-NR26C(O)NR26-(CR‘9R20)s-, -(CR‘9RZO),—NR26C(S)NR26-(CR‘9R20)S—, —(CR‘9R2°)[—NR265(O)2—(CR'9R2°)S—, and —(CRlngo),-NR26S(O)2NR26-(CRl9R2°)S—, preferably a bond, -NR32 —s—, —0—, —NR39CH2-, —NR”CH2CH3-, —NR39CH(R““)-, —SCH2—: ~OCH2—, —C(O)NR39—, —S(0)2NR39—, -CH2NR39-, —CH(R“0)NR39—, -NR39C(O)—, —NRSQS(O)2-, more preferably —NR39CH2—, -NR39CH(R4O)— 0r —NR39C(O)—, more preferably —NHCH2—, -NHCH(CH3)— 0r -NHC(O)—; M8 is selected from the group consisting ofa bond, ~(CR‘9R30)U—, -(CRWRZQ),—C(0)-(CR‘9R2“,)S—, -(C'R‘9R2°)f—C(S)—(CR‘9R2°)s—, R20)t—C(O)O-(CR19R20)5-, -(CR’9R2”),—C(S)O—(CR‘9R2°)5-, ~(CR‘9R2°)¢—C(O)NR26-(CR‘9R20)S-, —(CR‘9R30)i—C(S)NR2“-(CR”R‘mxg -(CR‘9R30)t-S(O)—(CRI9R20)5~, —Swh—(CR‘919%», {CR19R30)t~S(O)2NR3“~(CR”R2533 (CR;QR3§)W:O»CCRWR” {CRWkwueoqormR391228)“ ‘)W~0C{S)~(CR”Wage? {CREQREG)W~OC(O)NR26«(CR1gRZQ‘kg {CR19R20)w—OC(S)NR2"—(CR”Rgojses ~(CR39R”)w—S-(CR19REO)S-, _(CRIQRZG)W_NR26_(CRE9R20)S.3 {CR19R20)W~NR26C(O)-(CRIQRZOL‘, -(CR‘9R2°)W-NR25C(S)«(CR’9R20)S—, {CRlng)W—NR26C(O)O-(CRl9R30)§-, -(CR‘9R2§)W-NR36C(S)O~(CR”1853—? {CRl9R3“)WeNR25C(D)NR26~(CR”’R‘j‘ahg {CREQRZQEWNR35C{S;)NR2§r-{CRZngggg «(CRQQREQN’NR25S(O)g»(CRli}REG)S-§ end {CR19R30)w—NRQGS(O)3NREG-(CR‘9R20)S-, preferably a bond, -CH2—, -CH2C(O)-, -S(0)s-, -S(O)2CHg-, ~S(O)2CH(CH3)-, ~S(O);CH;CHg-, -S(O)2NR39-, NR39CH33 -S(O)2NR39CI 1(CH3)-, —S(O)2NR”CH2CH2-, -C(0)—, -C(O)CH3-, -C(O)CH(CH3)-, -C(O)CH2CHg-, -C(0)NR”-, ~C(O)NR39CHZ-, -C(O)NR39CH(CH3)-, and —C(0)NR3"CH2CHZ-, more preferably -C(O)NR39CH2-, -C(O)NR”CH(R4O)- or -C(O)NR39CH3CHg-, more preferably —C(O)NHCI~{2-, -C(fO)NHCH(’CH3)- or —C(O)NHCH;CH3-; Q}, Q“, Q“, Q“, and Q‘41 are aryl or heteroaryl, wherein aryl or heteroalyl are optionally substituted with one or more substituents selected from the group consisting of, «ORM, -SR4‘, -S(O)R“, -S(O)3R”“, MIR“, -NR“R‘“, —NR39C(O)R4‘, -NR3QS(O)2R“. halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more tuents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxyg lower alkylthio, fluoro tuted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryla and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent onI, Q”, Q“, Q“, or Q”), or as a substituent oflower alkyl are optionally substituted with one or more substituents ed from the group consisting of-OH, ~NH2, eCN, N02, -S(O)2NH2, -C(O)NH3, -011“, s11“, , Z, -NR39C(O)R42, -NR39S(O)ZR43, -S(O)2R“, n, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, ably Q], Q”, Q“, Q“, and Q1“ are aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, -NHS(O)2R“, -NHC(O)R‘”, -NHR‘“, -NR“R‘”, -011“ -S(O)2R“; Q12 is , chloro or -CF3; Q13 and Q14 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl; Q”, Q“, Q52 and Q54 are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R‘”, -OR“, and «SRM, provided, however, that at least one of Q22 and Q24 and at least one of Q53 and Q54 is hydrogen, fluoro, chiorou lower aikyl or fluore substituted lower alkyt; Q74 and Q25: are hydrogen, fluorot chloro, lower alkyl, fluoro substituted Iowa alkyl, ~NRHR“, on“, or «312“; Q72 is hydrogen, lower alkyl or fluoro substituted lower alkyl; R”, R40 and R‘” are as defined for Formula lg; each R‘14 is independently hydrogen, lower alkyl or fluoro tuted lower alkyl; and R“: R3: R2: REE s t and u are as defined for Formula lb.

In one embodiment of the methods ed herein, a compound of Formula II has structure according to the following sub—generic structure, Formula Ila, Formula Ila, all salts, prodrugs, tautomers, and isomers thereof, wherein: A3 is ~CH2— or ~C(O)—; Q1a is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more tuents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR4', —NR41R4‘, and —OR‘”; Q5 is hydrogen, —OR43, —CN, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, n cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, —NHR“, —NR“R“, -OR43 and —S(O)2R“; and M4, Q‘z, Q”, Q”, R“, and R43 are as defined for Formula II.

In certain embodiments ofthe methods provided herein, the compound is H H H ./ I” l / o U/‘ o QNVQ/Cl N \d V001 I\\Cl p\CF3 F Nfi it": Nfi NH In one embodiment ofthe methods provided herein, in compounds of Formula, Ila, A3 is ~CI’12— and M4 is —, In one embodiment A3 is ~C(O)— and M; is »NHCH3~. In one embodiment A; is —C(O)— and Mi is ~NI{C(O)~. In one embodiment A is =CH3= and M; is ~NHC(O)x. [0056} In one embodiment of the methods ed herein, in nds of Formula IIa, A; is —CH2~5 M4 is -NHCHg-, o5 is OR“, -CN, cm alkyL fluoro substituted c,_3 alkyl, fluoro, chloro, aryl or heteroaryl} wherein aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl. fluoro substituted lower atkyii -N’Hsi’li ~NR‘3R43, ion“ and stoma“, and of3 and Q” are hydrogen.

In one embodiment ofthe methods provided herein, in nds of Formula Ila, A3 is -C(O)—, Mi is -Ni-ICI-b-, Q5 is on“, «cu, Ci.3 alkyl, fluoro substituted c1.3 alkyl, flthrO, chloro, aryl or heteroaryl, n aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR43, -NR43R43, on43 and -stobR“, and Q13 and Q14 are hydrogen.

In one embodiment ofthe methods provided herein, in compounds of Formula Ila, A3 is -C(O)-, M1 is )—, Q5 is -OR‘“, -CN, ct.3 alkyl, fluoro substituted c,.3 alkyl, nubrb, chloro, aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro tuted lower alkyl, All—IR“, -NR43R$3, —OR43 and —S(O)2R43, and Q13 and Q14 are hydrogen.

In one embodiment ofthe methods provided herein, in compounds of Formula IIa, A3 is —CH;-, M4 is -NHC(O)—. Q5 is -011“, —CN, CH, alkyl, fluoro substituted (31.3 alkyl, fluoro, Cthl‘O, aryl or heteroaryl, wherein aiyl or heteroaryl are optionally substituted with one or more tuents selected from the group ting of halogen, lower alkyL fluoro substituted lower alkyl, —NHR43, -N R43R43, —OR43 and -S(O)2R43, and Q13 and Q!4 are hydrogen.

In one embodiment ofthe methods provided herein, in compounds of Formula Ila, A3 is -CH2- or —C(O)—; Qla is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, —NHR4I, -NR4[R4I, and -OR41; Q5 is hydrogen, -CN, -OR4], fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro tuted lower alkyl, -NHR“, «NR‘HRM, and -OR‘“; M4 is —NR39CH2—, -NR39CH(R40)—. —NR39CH2CH3—, or -NR39C(O)-; Q12 is fluoro, chloro or -cri; and Q13 and Q” are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R41 is as defined for Formula II.

In one embodiment, further to any of the embodiments of the methods provided herein, in Formula Ila above, R43 is R.42 as defined for Formula lg. In one embodiment, r to any of the embodiments ef the methods provided herein, in Formula Ila above} Rd; is R‘12 as defined for Formula lg.

In one embodiment, further to any of the embodiments of the methods provided herein, in Formula Ila above, Qla is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with l or 2 substituents ed from the group consisting of fiuoroi chloro, methyl, methoxy, trifluorometbyl, difluoromethoxy and romethoxy; A; is ~CH3~; Mi is 'NHCI‘Ig“; and Q5 is -CN, fluoro; chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fiuoro substituted lower alkoxy, In one embodiment, further to any of the embodiments of Formula 112: above, Q‘3 is phenyl mono tuted with chloro, preferably at the 4-position; A3 is -CI—I2-; M4 is «NHCHg-g and Q5 is ~CN, fluoro, chloro, methyl, romethyl, y, difluoromethoxy, tritluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen. lower alkyl, tluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. In one embodiment, further to any of the embodiments of Formula Ila, Qla is pyridinyl monosubstituted with methyl; methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position; A3 is —CH;-; M4 is -NHCH2-; Q5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or aryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.

In one embodiment ofthe methods provided herein, in compounds of Formula Ila, A3 is —CH;-; M4 is -NHCH2-; Q1a is phenyl or pyridinyl, n phenyl or pyridinyl are substituted with l or 2 substituents selected from the group ting of fluoro, chloro, , methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy; Q5 is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, —CN, or l—methyl~lH-pyrazoleyl; Q12 is fluoro or ; and Q13 and Q14 are hydrogen. In one embodiment, A3 is -CH2-; M4 is -NHCH2-; Qla is phenyl mono substituted with chloro, preferably at the 4—position, Q5 is en, chloro, methyl, methoxy, or wCN; Q12 is fluoro or chloro; and Q13 and Q14 are hydrogen. In one embodiment, A3 is -CI-I2-; M4 is -NHCH2—; Q121 is pyridinyl monosubstituted with methyl, y, trifluoromethyl, difluoromethoxy or trifluoromethoxy, ably at the 6-position; Q5 is hydrogen, chloro, methyl, methoxy, —CN, or 1—methyl—lH—pyrazole-4—yl; Q12 is fluoro or chloro; and Q13 and QM are hydrogen, In one embodiment of the methods ed herein, wherein the compound of Formula 1121 is a compound selected from the group consisting of: (4~Cbloro=—benzy§}—[5 ‘(5 achloro» l H~pyrroloi2,3~b]pyridin~3 »ylmethyl)»6«fluoro~pyridinQ—ylle amine ), (ti—Chloroabenzy1)-[6-chloro(I olo 2,3«bjpyridin-3 -ylmethyl)-pyridiiiyl]-amine (P-0161), [6-Chloro—5«(l H«pyrrolo[2,3~b]pyridin—3 -ylmethyl)—pyridinn2~yl}(6—trifluoromethyl-pyridin-3— ylmethyi)—amine (P-0174), oro~56(5-chloro~ l H«pyrrolol2,3 fib]pyridin~3 tylmethyij—pyridiné~yll—(6—trifluoromethyL pyridinylmethyl)~amine (P-0176), {6-Chloro[5-( 2 -methyl- 1 H~pyrazolyl)«l olo[2,3—b]pyridin-3 —ylmcthyl]-pyridinyl } - ( 6—trifluoromethyl-pyridin-3 -ylmethyl)-am ine (P-O 1 79), [S-(S-Chloro- l H-pyrrolo[2,3-blpyridin-3 —ylmethyl)~6-1‘luoro-pyridin—Z-ylj-(é-Lrifluoromethylpyridin-3 -ylmetl1yl)-amine (P-0186).J [6—Flu0ro~5—(5 —methoxy~ l H-pyrrolo[2,3 idin-3 -ylmethyl)-pyridin-2—yl]—(6~trifluoromcthyl- pyridin—3 -ylmethyl)-amine (13-0187)‘ [6—Fluoro(l H-pyrrolo[2g3-b]pyridinylmethyl)—pyridin—2—ylj-(6-trifluoromethyl-pyridin-3— ylmethyl)-aminc (P-0188), 3-{2—Chloro[C6—trifluoromethyl-pyridin-3 -ylmethyl)-amino]-pyridin-3 -ylmethyl } -l H— pyrrolo[2,3-b]pyridine-5—carbonitrile 2), [6-Chloro(5—methyl- l H—pleolo[2,3-b]pyridin-3 —ylmethyl)—pyridinyl]-(6—trifluoromethyl- pyridinylmethyl)—amine (P—0233), [6—Chloro(5-methyl-l H-pyrrolo[2,3—b]pyridin-3 —ylmethyl)-pyridin-2~yl]-(6—trifluoromethyl- pyridinylmethyl)—amine (13-0234): [6-Fluor0(1H—pyrrolo[2,3-bjpyridin-3~ylmethyl)-pyridinyl]-(6~meth0xy-pyridin~3—ylmethyl)- amine (P-0378), [5—(5-Chloro- l lI—pyrrolo[2,3 -b]pyridin—3 ~ylmethyl)-6—fluoro-pyridin-2—yl]—(6-methoxy—pyridin—3- ylmethyl)—amine (P—0379), (S-Fluoro-pyridin-3 -ylmethyl)-[6-fluoro-5 -( lH-pyrrolo[2,3-bjpyridin-3~ylmethyl)-pyridinyl]- amine (P-04l4), 3 ~ {2—Fluoro-6—[(5—fluoro-pyridin-3 ~ylmethyl)-amino]-pyridin—3 -ylmethyl}—l olo[2,3- bjpyridine-S-carbonitrile (P—0415) and 3—[6-(4-Chloro—benzylamino)—2-fluoro-pyridin—3 -ylmethyl]— l H-pyrrolo[2,3 -b]pyrid inc—5- carbonitrilc (P—0432), or all salts, gs, tautomers, or s thereof.

In one embodiment ofthe methods provided herein, a compound of Formula II has a structure according to the Following sub~generic structure, a llb, N H ” Q fix/15” A2 \ N N N Formula 11b, all salts, prodrugsy tautomer‘s, and s thereof, wherein: A2 is selected from the group Consisting 00(2ngng -C(O)—, »C(S)-, —s-, -S(O)-, sop“; ngmmo; Q15 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lkyl, optionally tuted heterocycloalkylg optionally substituted aryl, optionally substituted heteroaryl, —OH, NH}, —NOz, -CN, )NH2} -NHC(S)NH1, ~NHS(O)2NH35 -C(O)NH3, ~C(S)NH3, -S(O)3NH2, 253 -NIIR23, 01133, -5112“, —C(O)R23, -C(S)R23, stoma, -S(O)2R23, crowns”, ~C(O)NR23R23, »C(S)NHR23, »C(S)NR33R23, -S(O)2NHR23, —S(0)2NR23R”, -NHC(0)R33, —NR“C(0)R31 —NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR33S(O)2R23, -NHC(O)NHR33, -NR23C(O)N112, -NR23C(0)NHR”, -N HC(O)NR23R23, (O)NR23R23, -NHC(S)NHR23, (S)NH2, _NR23C(S)NHR33, )NR23R23, -NR23C(S)NR23R23, -NHS(O)3NHR23, (O)2NH2, -NRZ3S(O)2NHR23, -NHS(O)2NR“R23, and —NR23S(O)2NR23RZ3; Ms are as defined for Formula , Q”, Q22 and Q24 II; and R“), R20, R“, R23, R24, and R25 are as defined for Formula lb.

In n embodiments of the methods ed herein, the compound is not / Y’SV ml / N N In one embodiment ofthe methods provided herein, in compounds of Formula Ilb, M5 is -(CR‘9R20)FNR26—(CR”Rubs- or ~(CR'9R20)t-NR3°C(O)-(CR‘9R30)5-, preferably -NR26-(CR'9R20)5- or -NR26C(O)—(CR‘9R20)S-, more preferably —NR”CH2-, -NR3QCH(R“”)- or -NR39C(O)-, n R39 is hydrogen or lower alkyl and Rio is lower alkyl or fluoro substituted lower alkyl. In one embodiment, A2 is -CR]9R20- or —C(O)—, preferably -CHg- or -C(O)-. In one embodiment, QH is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloallqzl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyll »NHR23? 233 eORl" and »S(O)3R23 and Q33 is hydrogen, {DRE} QCNt tluoro, ehioro, lower alkyl, fluoro tuted lower alkyl, cyeloalkyl, heteroeyeloalkylg aryl or heteroarylt wherein cycloalkyl? heterocycloalkyl? aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, IOWer alkyl, fluoro substituted lower alkyl, —NI 1R2“: -NR23R23, -OR23 and R33. Further to any of the above embodiments, Q22 and Q24 are independently hydrogen, fluoro, chloro, or -CF3; preferably Q” and QM are hydrogen.

In one embodiment ofthe methods provided herein, in compounds of Formula Ilb, M5 is -(CR‘gnmlt—NRQG—(CR‘9112(1- or -(CR19R20)t~NR35C(O)-(CRmeLg preferably -anétcn‘gnmt- or —NR26C(O)—(CR‘9R2°)a-, more preferably }Ig—, —NR39CH(R‘0)- or -NR39C(0)-, and A2 is -CR”R20- or -C(O)-, preferably -CH3— or -C(O)-. In one embodiment, MS is -(CR‘”Rwy-NRZG—(Cnlgnlot- or «(CR‘9R2O)t-NR36C(O)«(CR‘”R1553 preferably —NR26~(CR"°R20)<- or ~NR26C(O)-(CR‘°R3°)S—, more preferably -NR39CIIz-, -NR39CH(R4°)- or (O)-; A2 is -CR]9R30- or -C(O)«, preferably ~CH2~ or —C(O)~; Q11 is cycloalkyl, hetcrocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterooycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, —NR23R23, —OR23 and -S(O)2R23; and Q15 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, cycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NRZ-‘Rli .OR23 and -S(O)2R23, In one embodiment, M5 is -(CR‘9R20)y—NR26~(CR‘°R20)5- or -(CR'9R20)r-NR26C(O)-(CR‘9R20)5—, preferably _NR26_(CR‘9R2°)S- or -NR26C(O)—(CR‘9RZO)S—, more preferably H3-, —NR39CH(R‘°)- or -NR39C(O)—; A2 is -CR19R20- or , preferably ~CH2- or —C(O)-; OH is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents ed from the group ting of halogen, lower alkyl, fluoro tuted lower alkyl, —NHR23, 23, -OR23 and -S(O)2R23; Q15 '5 hydrogen, -OR23, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro tuted lower alkyly -NHRZ3, —NR23R23, -OR23 and —S(O)2R23; and 023 and Q24 independently hydrogen, tluoro, , or CH, preferably 022 and Q24 are hydrogen.

In one embodiment of the methods provided herein, in compounds of Formula IIb, M5 is -NR39CH2~, -NR39CH(R4O)-y -NR3°CH2CH3—, or -NR39C(O)-; A2 is ~CH3~ or ~C(O)~, preferably {II-lye; Q” is cycloalkyl, oycloalkyh aryl or heteroaryl, n cycloalkyl, heterocycloalkyly aryl or heteroaryl are optionally substituted with one or more substituents selected from the group ting of halogen, lower alkyla fluoro substituted lower alkylg —NHR“, rNRMR“, 43R4E and —S(O)2Rfl; Q15 is hydrogen; -CN, fluoro, chloro> lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterooycloalkyl, aryl or aryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyll fluoro substituted lower alleyt month NR‘“R“, on“ and mS(O)-2R‘”; 032 and Q23 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen, fluoro, chloro, or CE, more preferably both Q22 and Q24 are hydrogen, wherein R41 is as defined for Formula lg.

In one ment of the methods provided herein, in compounds ot'Formula llb, A; is «CH;- or -C(O)—, preferably -CH3-; Q11 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more tuents selected from the group consisting of—OR‘“. —SR“, R“, -S(O)3R“, -NHR““, —NR“R“, -NR39C(O)R“, -NR398(O)2R4‘, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group ting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower hio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lkyl, heterocycloalkyl, aryl, and aryl as a substituent of Q1 ', or as a substituent of lower alkyl are optionally substituted with one or more substituents ed from the group consisting of-OH, -NHZ, -CN, -NOZ, NH2, -C(O)NH3, -OR4Z, —SR“2, -NHR42, —NR42R“, -NR39C(O)R“, -NR39S(O)2R4Z, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q15 is hydrogen, -CN, -OR4‘, SR“, -S(O)R“, -S(O)2R”“, -NHR4‘, -NR‘“R‘”, —NR”C(O)R“, -NR393(O)2R“, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR4‘, -NR“R“, and on”; M5 is a bond, -NR39-, —s—, —o-, -NR39CHz—, -NR39CH2CHg—, —NR39CH(R“°)-, «song, -OCH2-, —C(O)NR3°-, -S(O)2NR39-, —CH2NR”—, —CH(R40)NR39—, —NR39C(O)-, or -NR3QS(O)2—; and Q22, and Q24 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, —NR44R44, -OR44, or —SR44, provided, however, that at least one of Q22 and Q24 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, n R39, R40, R“, and R42 are as defined for Formula Ig, and R44 is defined for Formula ll.

In one ment of the s provided herein, in compounds of Formula Ilb, A; is {fling Q” is aryl or heteroaryi, wherein aryi or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofiluoro, chloro, lower atkyi, fluoro substituted lower alkyl, lower aikoxy, fluoro substituted lower alkoxy, di—alkylamino, and cycloalkyl; Q15 is hydrogen, «CN, tllloro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M5 is —NR39CH2-, -NR39CH2CHz-, ~NR39CH(R40)~; and Q23 and Q24 are independently hydrogen, halogen, lower alkyl, fluoro substituted iower alkyl, lower , or lluoro tuted lower , provided, however} that at least one of Q22 and (324 is en, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of the methods provided herein, which includes Formula IIb above, each occurrence of R?“ is R42 as defined for Formula lg.

In one embodiment ofthe methods provided herein, in compounds ofFormula IIb, M5 is -NHCH2CH2-, 'NHCHg-, —N(CH3)CH2-, or -NHCH(CI13)~, preferably -NHCH2-; A; is -CH2-; QH is cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, wherein phenyl or heteroaryl are optionally tuted with l or 2 tuents ed from the group consisting of n, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, ylamino, and heterocycloalkyl; Q‘5 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro tuted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; and Q22 and Q24 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen, fluoro, chloro, or -CF3, more preferably both Q22 and Q24 are hydrogen.

In one embodiment ofthe s provided herein, in compounds of Formula Ilb, M5 is -NHCH2-; A2 is -CH;—; Q“ is phenyl substituted with l or 2 substituents ed from the group consisting of Iluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q” is hydrogen, -CN, Iluoro, chloro, lower alkyl, fluoro tuted lower alkyl, lower alkoxy, fluoro tuted lower alkoxy, ably hydrogen or chloro; and Q22 and Q24 hydrogen.

In one embodiment ofthe methods provided herein, wherein the compound of Formula IIb is a compound selected from the group consisting of: (4-Chloro-benzyl)-[5-(5-chloro—lH-pyrrolo[2,3-b]pyridinylmethyI)—pyrimidin-2—yl]-amine (P—0260), l5~(_5-Chioro—l Hepyrrolo[2,3-b]pyridin~3 «yilrrsethylflvpyrimidin»2—yl]—(2,6~difiuoro~benzyl§-=an1ine (P-026l), [5—(5-Chloro-l Hupyrrolo[2,3xb]pyridin-3~ylmethyl)-pyrimidin«2~yl]~(2~trifluorotnethyl~benzyl)— amine (P—0262), (2—Chloro~benzyl)—[5-(51chloro-I H-pyrrolo[2,3 -b]pyridin—3 -ylmethyl)-pyrimidin~2—yl]-amine (P-0263), [5»(5-Chloro~l lo[2,3»b]pyridin~3 »ylmethyl)—pyrimidinw2—yl]~(2-fluoro~benzyi)‘arnine (R0264), Ch10r0—1 H—pyrroloflj —bjpyridin—3 ~y1mcthyl)—pyrimidin-2—yl]—(2,4—difluoro—bcnzyl)-amine (P-0265)§ [5-(5—Ch10r0- 1 H-pyrrolo[2,3~b]pyridinylmethyl)—pyrim id inyl]—(4-trifluoroxnethyl-benzyl)— amine (R0266), [5 -(S-Ch10rQ-1 H—pyrrolo[2,3-b]pyridin—3 —ylmethyl)-pyrimidin—Z-yl]-(2,5—difluor0~benzyl)-amine (P-0267), [5-(5—Chlor0-1H—pyrrolo[2,3—b]pyridin-3 -ylmethyl)—pyrimidin-Z—yl]~(3—triflu0romethyl-benzyl)~ amine (P-0268), [5-(5—Ch10ro-1 H-pyrrolo [2,3—b]pyridin—3 -y!methyl)-pyrimidinyl] -(2—flu0r0-5—trifluoromethyl- benzyl)—amine (P—0289), (Z-F luoro-S-trifluoromethyl-benzyl)-[5-( I H-pyrrolo[2,3-b] pyridin-3 -y1methyl)-pyrimidinyl]- amine (P-0291), (2,5—Difluoro—bennrl)—[5—( l H—pyl‘ro10[2,3—h]pyridin—3 —ylmethyl)—pyrimidin—Z—yl]—amine (P—0292), (2-Ch10ro-5 -trifiuoromethyl-benzyD-[S -( l H-pyrr010[2,3-b]pyridin-3 -ylmethyl)-pyrimidiny1]- amine (P-0293)5 (3-Fluor0—S—trifluoromethyl-benzyl)-[5—(1H—pyrrolo[2,3-b]pyridinylmethyl)-pyrimidin—2-yl]— amine (P-0294), (3,5-Diflu0r0-benzyl)—[5—(1H-pyrrolo[2,3-b]pyridin-3—ylmethyl)-pyrimidinyl]-amine 5), (2-Flu0r0-benzyl)-[5—(lH—pyrr010[2,3 -b]pyridin-3 -ylmethy1)-pyrimid in—2—y]]—amine 0), (2-Ch10r0—benzyl)—[5—(lII—pyrrolo[2,3~b]pyridin—3—ylmethyl)-pyrimidin—2—yl]-amine (P-0301), [5-(1H-Pyrrolo[2,3-b]pyridin—3 -y1methyl)-pyrimidin-Z-yl]-(2-trifluoromethyl-benzyl)-amine (P-0302), [5-( l H—Pyrrolo[2,3—b]pyridin—3 —ylmethyl)—pyrimidin—2—y1]-(2—triflu0r0meth0xy—benzyl)-amine oro—Z—fluoro-benzyl)-[5—(1H—pyrrolo[2,3-b]pyridin-3 -ylmethyl)—pyrimidin-Z—yl]—amine (P-0304), (2,4-Dichloro—benzyD-[S-(1H-pyrrolo[2,3~b]pyridin-3 hyl)-pyrimidin—2-yl]-amine 5), (2,4-Diflu0rO-benzyl)—[5 —( 1 H-pyrrolo[2,3 -b]pyriclin-3 -ylmethyl)—py1*imidin—2—yl]-amine (P—0306)3 (4~Chlort:«benzyi)~[5«(I H-pyrmlo[293—h]pyridin-3—yimethyl)-pyrimidin—2~yl]~amine (P-0307); {5M 1 HwaerIOL'ZJabjpyridi{1'3-yimethyl)qpyrimidinéfiii]{44n"fiueremethyi»benzyé}aminc (P~0308), (2—Flu0r0—3utrifluommethyhbenzyl}[S—( I H-pyrrolo[2,343]pyridin-3~yImelhyl)«pyrimidin~2~yi]— amine (P-0309), (2,5—Dich10ro-benzyl)-[5-(1 H—pyrrolo[2,3—b]pyridina3—y1methyD—pyrimidin-Z—yl]—amine (P-0310), (3—Ch10r0—2~flu0ro~benzy1)—[5-(1H-pyrrolo[2,3~b]pyridin—3*ylmethyl)«pyrimidian—yl]—amine ($0311): (2-Difluor0melh0xy—benzyi)~[5-(I H-pyrrolo[2,3-b]pyridin-3 -y|methyl)~pyrimidinyU-am ine (P—0312), ichlor0-benzyl)~[5—(I H—pyrrolo[2,3 idin-3 -yImethyl)-pyrimidin—2-yl]-amine (P~0313), (4-ClflomHuoro-benzyl)-[5—(1H-pyrrolo[2,3 —b]pyridin—3 -yImethyl)-pyrimidiny1]-amine (P-0314), (S-FIuoro-Q—trifluoromethyl-bcnzyi)-[5-( I H-pyrmlo[2,3—b]pyridin-3 -ylmethyl)-pyrimidinylj- amine 03—0315), (2-Ch10r0fluoro-benzyl)-[5-(1H-pyrr010[2,3—b]pyridin—3—y1methyl)-pyrimidinyl]-amine (P—0316), (5-Ch10ro-2~methyl—benzyl)—[5-(1H—pyrr010[2,3-bjpyridiny1methyl)-pyrimidinyl]-amine (5-Flu0r0—2-methyl—benzyl)-[5-( l H-py1T010[2,3-b]pyridin-3 -ylmethyl)-pyrimidin-Z—le—amine 03-0318), (2-Fluorotriflu01‘0methyl-benzyl)-[5-(1 H-pyrro10[2,3—b]pyridinylmethyl)~pyrimidinyi]- amine (P~031 9). (4-Fluorotrifluoromethyl—benzyl)—[5-(1H-pyrrolo[2,3 -h]pyridin—3 -ylmethyl)-pyrimidin—2—yl]— amine 0-0320), [5-(S—Chlor0-1H-pyrrolo[2,3-b]pyridiny1methyl)-pyrimidinyl]-(2—difluoromethoxy-benzyl)- amine 0-0390), [5-(5-Chloro-1H-pyrr010[2,3 -b]py1‘idinylmethyl)—pyrimidin-Z-yl]-(5-flu0roIrifluoromethyl- benzyl)-amine (P-0391), (3 -Ch10r0—2-fluoro-benzyl)—[5—(5-chloro- l I I-pyrrolo[2,3 -b]pyridinylmethyl)—pyrimidinyij- amine 03-0392), [5-(5-Chlor0-1H—pyr1‘010[2,3 idin-3 ~ylmethyl)-pyrimidin—Z—ylj—(Z-fluoro—3 -trifluoromethyl- benzyI)—amine a’~0393), [5-(5-Ch10r0-l H-pyri'olof2,3~bjpyridin—3 —y1methyl)-pyrimidinyl]—(2-flu0r0-4—triflu0r0methy1- benzyi)-amine (P-0394), [5-(5—Chloro»! H—pyrroio[2,3-bjpyridinylmethyl)-pyrimidinyl]-(2,3-difluor0»benzyl)—amine (ZaChim’0-4—fluormbenzyI)~[§«(S~chiom~1H*pyrmlo[2s3»b]pyridinaB«yimethytypyrimidin-E‘yf} amine (R0396)? Chior0- 1 H—pyrrolo[2,3-b]pyridin«3 -ylmethyi)—pyrim idin-2—yl]-(2~trifluoromethcmy—benml)~ amine (P-IMOZ)E (2—Chloro-5~flunr0-benzyl)~[5—( l H-pyrroio[2,3—b]pyridin—3 -yImethyl)-pyrimidin-Zayl]amine (P-0407), (21C};larc-fi~fluor0~benzyi)~[5 ~(5~chler0«§ Hupyrroio{233*b]pyridin—3~yimeihyiypyrimidin«2~yl'§~ amine (13—0408), [5—(S-Chlor0— 1 H—pyrrolo[2,3-b]pyridin~3 —ylmethyi)bpyrimidin—2vyl]-pyridinyimethyl—amine (Pa0416), Ch10r0— I 010[2,3-b]pyridin—S‘ylmethylypyrim idin—2-yl]—(2-pyrrolidinyl-ethyl)- amine (P-0417): Benzyl—[SvG—ChlorO-I H—pyrr010[2,3-b]pyridiii-3 ~ylmcthylj—pyrimidin—2—yl]~amine (’P—0418), Benzyl-[S—(chhlorml H—pyrrol0[2,3vb]pyridin—3 —ylmethyl)—pyrim id in-2—yl]—methyl-am ine (P—04 l9), [5~(5-Ch10r0- 1 H-pyrroio[2,3-b]pyridin—3—ylmethyl)-pyrim idinyI]-(4—trifluoromcthoxy-benzyl)- amine (P—0420), (3-Chloro—benzyl)—[5-(5-chlor0-1H-pyrrolo[2,3—b]pyridin—3-ylmethyl)-pyrimidinyl]—amine (P—0421), [5-(5-Chlor0—1H—pyrrolo[2,3-bjpyridinylmethy|)-pyrimidin—2-yl]-pyridin—3-ylmethyl—amine (P—0422)3 [S—(S-Chloro—l H—pyrrol0[2,3-b]pyridin-3 -ylmethyl)—pyrimidin—2—y1]w(4—fluoro—benzyl)—amine (P-0423), (3-Chloro-benzyl)-[5-(5-Chlor0-1H—pyrrolo[2,3—b]pyridin-3~ylmethyl)—pyrimidin-2—yl]—methyl- amine (P-0424), [5-(5—Chlor0~1H~pyrrolo[2,3-b]pyridin—3—ylmethyl)-pyrimidinyl]—(3,5—diflu0ro-benzyl)-aminc (P—0425), [5-(5-Ch10r0—1H-pyrrolo[2,3-b]pyridin-3—ylmethyl)—pyrimidinv2-yl]-[1-(2—fluor0-phenyl)-e1hyl]— amine (P—0426), [1-(4-Chloro—phenyl)-ethyl]—[5—(5—chloro-1H—pyrrolo[2,3-b]pyridinylmethyl)—pyrimidin-Z—yl]— amine 7), [5—(5-Chloro- 1 H—pyrrolo[2,3-b]pyridin-3 -ylmethyI)—pyrimidin-Z‘yI]-[(S)wI -(4-flu0r0wphenyi)— -amine (P—0428), [S«(5»Chlor0— I H—pyrrol0[2,3-b]pyridinfl—ylmethyl)—pyrimidin—Z—yl]—(6—trifluoromethyl-pyridin-B ylmethyI)-amine (P—0429), (2—Ch10r0~benzy1)—[5~(5~chlor0~ l I I-pyrrolo[2,3=b]pyridin»3 hyl)~pyrimidinm2~yl]—mcthyi~ amine (13-0430)3 [5—(5~ChlorO-I H~pyrrolo[2§3-=b]pyridin-3—ylmethyi)=pyrimidin~2wyf}x(2—methyI-benzyi)'aminc (P—043 I), [5-(5-Ch10r0—1H-pyrroloflfi —b]pyrid iny1mcthyl)-pyrimidin—2-yI]—(2-methoxy-benzyl)-amine (P-0433), [SWCS ~Chl0r0-l H~pyrmlo[2,3 *b]pyridin~3~ylmethyImerimidin«2-yl]~(2-morph0}inx4-yl»cthyl)- amine ($0434): [5-(5—Chioro—1H-pyrrolo[2,3~«b]pyridin-3~ylmethy1)-pyrimidin-2—yl]—cyeiohexylmethyl-amine (P-0435), [5-(5~Chloro— i H«pyrrolo[2,3»b]pyridinylmethy1)-pyrimidin-2—yl]-pyridin-2—ylmethyl—amine (P414136), [2-(4-Chloro-phenyi)-ethyI]-[5-(5~chloro-1H-pyrrolo[223—13]pyridinylmethyl)-pyrimidin-Z—yl]~ amine (P—0437), [5-(5-Chloro—i H-pyrroio[2,3-b]pyridinylmethyl)-pyrimidinyl]-(4-difluoromethoxy—benzyl)— amine (R0438), [5-(5-Chioro—1H-pyrrolo[2,3 ~b]pyridin~3 -yimethyl)-pyrimidinyl]-(4-methoxy-benzyl)—amine (P-0439), [5—(5-Chloro-1H—pyrrolo[2,3 -b]pyridin-3 -ylmethyl)—pyrimidinyl]—(4-methyl-benzyl)-amine [5-(5 —Ch10ro—1H-pyrrolo[2,3 -b]pyrid in-3 ~ylmethy1)—pyrimi di ny1]-(2—methoxy-ethy 1)-amine (P-0441), [5-(5-Chloro-l II-pyrrolo[2,3-b]pyridin—3 hyl)-pyrimidin-2—yl]—(3-fluor0—benzyl)~amine (P—0442), (3 -Chloro—4-fluoro-benzyl)—[5-(5—chloro-1H~pyrrolo[2,3-b]pyridin-3 —y1methyi)-pyrimidin-Z-yl]- amine (P-0443), [5 —(5 —Ch]or0-I H-pyrrolo[2,3 -b]pyridinylmethyl)—py1‘imidinyl]-(2-ethoxy-benzyl)-amine (P-0444), [5-(5-Chloro-1H—pyrrolo[2,3 -b]pyridinylmethyl)-pyrimidinyl]-(4-morpholinyl-benzyl)— amine (P—0445), [S-(S-Chloro- 1 H-pyrrolo[2,3-b]pyridin—3 ~ylmethyl)—pyrimidin-2—y1]—(3 —difluoromethoxy-benzyl)- amine (P-0446), (4-Chlorofluoro‘benzyl)«[5~(5«ch ioro~ l H-pyrrolo[2,3—b]pyridin—3 hyl)—pyrimidin-Z-yl]- amine (P-0447), [5=(5*Chloro- } H-pyrrolo[2,3—b] pyridin—3 hyl)«pyrimidinyl]-[ l —(3-flu0ro-phenyl)-ethyi]- amine (P—0448), and [5«(5~Chloro— 1 oio[2,3—bjpyridin—3 hyi)~pyrimidin~2~yi]~(2~dimethyiamino~benzyh~ amine ($0449); or ail salts} prodrugs, tautomers, or isomers thereof.

In one embodiment ofthe methods provided herein, a compound of Formula II has structure ing to the following sub-generic structure, Formula 11c? Formula 110, all salts, prodrugs, tautomers, and isomers f, wherein: A4 is selected from the group consisting or—CR‘9R20—, -C(O)-, -C(S)—, —s-, ~S(O)-, -S(O)2-, ‘NRN‘, and ~O-; 025 is selected from the group ting of hydrogen, n, optionally substituted lower alkyl, optionally tuted cycloalkyl, optionally tuted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, eOH, -NH3, -N02, -CN, )NH2, ~NHC(S)NHQ, —NHS(O)2NH2, -C(O)NH2, -C(S)NH3, -S(O)2NH2, -NR24R25, , -OR23, ~SR33, —C(O)R33, -C('S)R23, -S(O)R23, -S(O)2R23, -C(0)NHR”, -C(0)NR23R23, HR23, ~C(S)NR23R23, -S(0)2NHR23, -S(0)2NR23R23, -NHC(0)R23, ~NR23C(O)R23, ~NHC(S)R23, ~NR23C(S)R23, —NHS(O)2RZ3, ~NR238(O)2R23, —NHC(O)NHR23, -NR23C(O)NH2, -NR23C(0)NHR23, ~NHC(O)NR23R23, ~NR23C(O)NR23R23, -NHC(S)NHR”, -NR23C(S)NH2, —NR23C(S)NHR23, -NHC(S)NR23R23, ~NR23C(S)NR23R23, -NHS(0)2NHR23, -N'R23S(0)2NH2, ~NR23S(O)2NHR23, —NHS(O)2NR23R23, and —NR23S(O)2NR23RZ3; Mg, 02], 032 and Q33 are as defined for Formula II; and R”, R20, R“, R”, R“, and R25 are as defined for Fonnula Ib.

In one embodiment ofthe methods provided herein, in compounds of Formula 110, Mr, is R20),-NR25-(CR‘9R20)s~ or —(CR19R20)FNR26C(O)-(CR”R255, preferably —NR26—(CR‘9R3°)S- or -NR2°C(O)—(CR‘9R20)S-, more preferably ~NR39CH2~, —NR39CH(R40)- or eNR39C(O)—, wherein R39 is hydrogen or lower alkyl and R40 is lower alkyl or fluoro substituted lower alkyl. In one embodimenu A4 is ~CRWRZC¥ or eC(O)-, preferably ~CH3— or -C(O)~. In one embodiment, Q33 is aryt or heteroaryl, wherein aryl or heteroaryl are optionaliy substituted with one or more tuents selected from the group consisting of haiogen, lower alkyl, fluoro substituted lower alkyl, -NI-IR33, —NR23R23, —oR-’3 and —S(O)2R23 and Q25 is hydrogen, -OREE, ~CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heteroeycloalkyl, aryl or heteroaryl, n cycloalkyl, heteroeycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen? lower alkyl, fluoro substituted lower alkyl, -NHR23, eNRBR”, -OR23 and R23. Further to any of the above embodiments; Q32 Q33 are independently hydrogen, , chloro, or ~CF3.

In one embodiment of the methods provided herein, in nds of Formula Ilc, Mb is «CR‘”REO),»NR26~(CR‘9R20)S— or -(CR'QRZQ)y-NR2"C(O)-(CR39R20)3—, preferably -NR36—(CR'”R30)S— or -NR26C(O)-(CR‘9R20)s—, more preferably ~NR39CH2-, -NR3°CH(R“)— or -N‘RBQQO}, and A4 is ~CR‘9R9‘O- or -C(O)-, preferably -CH2- or ~C(O)-. in one embodiment, M5 is {CR‘QRZOi—NRZG—(CR‘9R20)5- or {CR19R20)t-NR2°C(O)«(CR19R20)5-, preferably —NR2"-(CR‘9R2°)S— or NR”C(O)-(CR’9R20)S-, more preferably »NR39CH2-, —NR39CH(R4°)— or —NR3"C(0)—; A4 is ~CR19RZO- or -C(O)—, preferably ~CH2« or vC(O)-; Q21 is alyl or heteroaryl, wherein aryl heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of n, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)3R23; and Q25 is hydrogen, -OR23, —CN, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, cycloalkyl, hcterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2RZ3. In one embodiment, M6 is -(CRlgRZO),—NR26-(CR‘9R20)S- -(CR’9R30)t-NR26C(O)-(CR]9R2°)S-, preferably (CR19R20)5- or -NR26C(O)-(CR]9R2°)s-, more preferably H2-, -NR39CH(R40)— or -NR39C(O)-; A4 is —CR’9R20- or -C(O)-, ably -an— or —C(O)-; Q21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with or more tuents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R33, -OR23 and -S(O)3R33; Q25 is hydrogen, -OR23, -CN, fluoro} , lower alkyl, fluoro substituted lower alkyl, lkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR23, -NR23R23, —OR23 and -S(O);R23; and Q32 and Q33 are independently hydrogen, fluoro, chloro, or -CF3.

In one embodiment of the methods proyided herein, in compounds of Formula He: MO is “NR39CH23 ~NR39CH(R4Q)~ or «113930;, ably ~NHCH2-; A4 is ~CH2~ or 41o): preferably «Clip; Q2E is aryl or heteroaryl, wherein aryl or heteroaryl are optionally tuted with one or more substituents selected item the group consisting of halogen, lower alkyl? fluoro substituted lower alkyl, —NHR“, -NRuR'“, on“ and —S(O)2R“; Q25 is hydrogen, , ebloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl? wherein cycloalkyl, heterocyeloalkyl, aryl or heteroaryl are ally substituted with one or more substituents selected from the group consisting of halogen? lower alkyl, fluoro tuted lower alley; -ani‘i ~NR‘5R4‘, on“ and ~S(O)ZR’“; 032 and Q33 are independently hydrogen, l‘luoro, chloro, lower alkyl, or fluoro substituted lower alkyl, ably Q32 and Q33 are independently hydrogen fluoro, ehloro, or -CF;, wherein R“ is as defined for Formula lg.

In one embodiment ofthe methods provided herein, in compounds of Formula NC, A; is CH? or -C(O)-, preferably -Clig-; Q21 is and or heteroaryl, n aryl or heteroaryl optionally tuted with one or more substituents selected from the group consisting of -OR‘“, -SR“, -3(0)R4', -S(O)2R‘“, —NHR“, -NR‘“R“, -NR3°C(O)R‘“, -NR39S(0)2R“, halogen, lower alkyl, cycloalkyl, heteroeycloalkyl, aryI and heteroaryl, wherein lower alkyl is ally substituted with one or more substituents selected from the group ting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower hio, fluoro tuted lower alkylthio, mono‘ alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q“, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, -NH2, -CN, -NOg, -S(O)2NH2, -C(O)NH2, OR“, -SR42, —NHR”, -NR42R42, (0)R42, -NR398(O)3R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q25 is hydrogen, -CN, -OR‘”, -SR‘”, -S(O)R‘“, -S(O)2R‘“, —NHR‘”, _NR‘“R4‘, -NR39C(O)R41, —NR3QS(O)2R41, tluoro, , lower alkyl, fluoro substituted lower alkyl, aryl heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR“R‘“, and -011“, M6 is a bond, -NR”-, —s-, —o-, -NR3"CH2_, H2CH2-, ~NR39CH(R4O)-, sour, -OCH2-, -C(O)NR39—, -S(O)3NR39-, -CH2NR39-, —CH(R4°)NR”—, -NR39C(O)-, -NR398(O)2-; and Q32 and Q33 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or SR“, ed, however, that at least one on32 and Q33 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R39, R40, R41, R42 and R44 are as defined for Formula II.

In one embodiment ofthe methods provided herein, in compounds of Formula ”C, A4 is «CH3; Q21 is aryl or heteroaryl, wherein aiyl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower aikoxy, and fiuoro substituted lower alkoxy; Q' is hydrogen, ~CN, fiuoro, , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fiuoro substituted lower alkoxy; M6 is ~NR39CH3~, "NRSQCHQCHZ‘, or -NR39CH(R4O)-; and Q32 and Q33 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q32 and Q33 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, In one embodiment, further to any of the embodiments of the methods provided herein, which includes Formula IIc above, each occurrence ot‘R‘” is R42 as defined for Formula lg.

In one embodiment ofthe methods provided herein, a compound of Formula II has a structure according to the following sub-generic structure, Formula lld, N?” M7/031 035 RSV/43 \ Q l : Q44 N d Formula Ild, all salts, prodrugs, tautomers, and s thereof, wherein: A5 is selected from the group consisting of—CR’9R20-, -C(O)-, -C(S)-, —s—, —S(O)—, -S(O)2-, -NR“-, and -o-; Q35 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally tuted aryl, optionally substituted aryl, -OH, -NH2, -NO;, -CN, —NHC(O)NH2, - NH2, -NHS(O)2NH2, —C(O)NH2, -C(S)NH2, —S(O)2NH2, 25, -NHR23, -OR23, -511”, -C(O)R23, -C(S)R23, 23, —S(O)2R23, —C(O)NHR23, —C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(())2NIIR23, -S(O)2NR23RZ3, -NHC(O)R23, -NR23C(O)R23, — NHC(S)R23, —NR23C(S)R23, -NHS(O)ZRZ3, (O)2R23, -NHC(O)NHR23, —NRZ3C(O)NI12, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, ~NR23C(S)NH2, -NR23C(S)NHR23, —NHC(S)NR23R23, -NR23C(S)NR23RZ3, -NI-IS(O)2NHR33, -NR33S(O)2NH2, -NR23S(0)2NHR33, -NHS(0)2NR23R”, and -NR23S(O)2NR23R23; Me, Q“, Q43 and Q44 are as defined for Formula II; and R19, R20, R3], R23, R”, and R25 are as defined for Formula lb.

In one embodiment of the methods provided , in compounds of Formula IId, M7 is «(CREQRQGijRZG—(CR19R20)5« or -(CRWR”imagicwj—(CR‘”112%, preferably WN‘R2“«(CR”R3§}; or —NR?*‘C(oj—(CR”R39),-, more preferably eNRii’CILo, ~NR39CH(R“G)e or -NR:WC(())-, wherein R39 is hydrogen or lower alkyl and R48 is lower alkyl or fluoro substituted lower alkyl.

In one embodiment, A5 is -CR’9R20- or -C(O)—, preferably 0r -C(O)-, In one embodiment, Q31 is aryl or aryl, wherein aryl or aryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fiuoro tuted lower alkyl, -NHRB, «12331123,, more?3 and stonnt‘ and Q35 is en, on”, «CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, lieterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heteroeycloalkyl, aryl or aryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, tluoro substituted lower alkyl, «NHRB, -NR23 R23, {)sz and —S(O)3R23. Further to any of the above embodiments, Q43 and Q44 are independently hydrogen, , , or —CF;.

In one embodiment of the methods provided herein, in compounds of Formula lld, M7,. is -(CR“’R3”),-NR26—(CR‘9RZO),— or -(CR‘9R2°)z—NR25C(O)~(CR’9R20)s-, preferably -NR26—(CR‘9R20),— or ~NR26C(O)-(CR‘9R2°)s—, more preferably ~NR39CH2—, -NR3"CH(R4°)- or -NR39C(O)-, and A,- is -CR]9R20- or -C(O)-, preferably -CH2- or ~C(O)e. In one embodiment, M7 is —(CR‘9R3“),—NR2“-(CR‘9R’Z")5- or -(CRi9R2”),-NR25C(0)—(CR19R20)5-, ably -NR3°-(CR”R2°)S- or ~NR26C(O)-(CR’9R2°)s-, more preferably -NR39Cllg-, —NR39CH(R4°)— or —NR39C(O)-; A5 is -CR]9R20— or -C(O)—, preferably ~CH2- or -C(O)-; Q31 is my] or heteroalyl, wherein alyl or heteroaryl are optionally substituted with one or more substituents selected from the group ting of n, lower alkyl, fluoro substituted lower alkyl, 23, ~NRZ3RZ3, ~OR23 and —S(O)2R23; and Q35 is hydrogen, «ORB, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, cycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents ed from the group ting gen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NRZ3R23, ~OR23 and —S(O)2R23. In one embodiment, M7 is —(CR‘9R2”),-NR2°—(CR”RZU),- or -(CR‘9R20),—NRZOC(O)—(CR‘9R2°)s—, preferably (CR“’RZO)S- or -NR26C(O)~(CR‘9R2°)s-, more preferably -NR39CHz—, —N R39CH(R4°)— or ~NR39C(O)-; A5 is -CR”R2°- or , preferably —CH2~ or —C(O)-; Q“ is aryl or heteroaryl, wherein aryl or aryl are optionally substituted with one or more substituents selected from the group consisting gen, lower alkyl, fluoro substituted lower alkyl, ~NHR23, ~NR23R23, on“ and -S(O)2R23; Q35 is hydrogen, on”, -CN, nuoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroalyl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NR23R23, -OR23 and —S(O)2R23; and Q43 and OM are independently hydrogen, fluoro, chloro, or -CF;= In ene ment of the methods previded herein, in compounds of Formula lld, N17 is —NR3§CHs-, ~NR39CH(R48} or coi-, preferably MNHCHze; A5 is -CH2~ or 3(0)”, preferably —CH;—; 03 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR“, ~NR4‘R4‘, ~0R‘H and -S(O)ZR4E; Q35 is hydrogen, -CN, fluoro. chloro. lower alkyl, tluoro substituted lower alkyl, lower alkoxy, fluore substituted lewer alkoxy, cycloalkyl, heteroeyelealkyl, aryl or heteroaryl, wherein eyelealkyl, hetemeyeloalkyl; aryl or hetemaiyl are optionally substituted with one or more substituents selected from the group ting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR“, -NR4lR“, -OR”H and -S(O)2R“; Q43 and Q44 fluoro substituted lower alkyl, are independently hydrogen, fluoro, chloro, lower alkyl, or R“ is as preferably Q43 and Q“u are independently hydrogen, , chloro, or ’CF}, wherein defined for Formula lg.

In one embodiment ofthe methods ed herein, in compounds of Formula 11d, A5 -CH3- or -C(O)—, preferably -CI 13-; Q“ is aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of —OR‘”, «SR‘H, “, -S(O)2R“, -NHR‘“, —NR4‘R4‘, —NR3"C(O)R4‘, —NR3()S(O);R4‘, halogen, lower alkyl, cycloalkyl, cycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro tuted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono— alkylaniino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and aryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q“, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, N02, -S(O)2NH2, -C(O)NH2, -011”, ~SR“, -NHR42, -NR“2R“, -NR39C(0)R“, -NR39$(O)3R42, —S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q35 is hydrogen, -CN, -012“, —SR‘“, -S(O)R“, -S(O)2R‘“, -NHR4‘, —NR‘“R“, -NR39C(O)R41, (O)3R‘H, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR“, —NR“R'“, and OR“; M7 is a bond, —NR39—, —s—, -o—, -NR39CH2-, -NR”CH3CH2-, -NR3°CH(R4°)-, sour, , R”—, —S(O)2NR39-, -CH2NR”—, —CH(R“°)NR39—, -NR39C(O)-, or -NR398(O)Z-; and Q43 and Q44 are independently hydrogen, halogen, lower alkyl, fiuoro substituted lower alkyl, -NR4AR44, -OR44, or SR“, provided, however, that at least one of Q43 and Q44 is R‘12 hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl. wherein R39, R40, R“, and R44 are as defined for Formula II. [0088} In One embodiment of the s provided herein, in compounds of Formula 11d, A5 is (Stir; Q33 is aryl or heteroaryi? wherein any? or heteroaryt are optionalfy substituted with one or lower alkyl, fluoro more substituents selected from the group consisting of fluoro, chloro, substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q35 is hydrogen, *CN, lower fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower , or fluoro substituted alkoxy; M7 is —NR39CH2_, ~NR39CIIZCI-lzg or -‘NR39CH(R‘O)—; and o43 and Q44 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or Home substituted lower , provided, however, that at least one of Q43 and Q44 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of the methods provided herein, which includes Formula lld above, each occurrence ofR41 is R42 as defined for a lg.

In one embodiment of the methods provided herein, a compound of Formula II has a structure according to the following sub—generic structure, a Ile; 045 A6§N\MB~Q“ N d Formula lle, all salts, prodrugs, tautomers, and isomers thereof, wherein: A6 is selected from the group ting of—CRWRZO—, —C(O)—, —C(S)—, -S—, —S(O)—, -S(O)2—, —NR21—, and —0-; Q45 is selected from the group ting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH;, -NOZ, —CN, -NHC(O)NH2, —NHC(S)NH2, —NHS(O)ZNH3, -C(O)NH2, —C(S)NH2, -S(O)2NH2, —NR24R25, —NHR23, on“, SR”, -C(O)R23, -C(S)R23, -S(O)R23, some”, -C(O)NHR23, R23R23, —C(S)NHR23, —C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, —NR”C(0)RZ3, —NHC(S)R23, —NR23C(S)R23, -NHS(O)2R23, —NR23S(O)2R23, —NllC(O)NHR23, —NR23C(O)NH2, —NR23C(0)NHR23, )NR23R23, —NR23C(0)NR33R23, -NHC(S)NHR233 (S)NH2, -NR23C(S)NHR23, )NRBRE3, —NR23C(S)NR23R23, —NIIS(0)2NIIR33, -NRBS(O)2N112, -NR23S(O)2NHR23, —NHS(O)2NR23R23, and -NRBS(O)ZNR23R23; Mg, Q“? Q52 and Q54 are as defined in Formula II; and R29? Rza R21, R33, R24, and R25 are as defined for Formula lb.

] In certain ments of the methods provided herein, the compound is not \ \\ ,o wN fa >:: i \ N Ffi/N \ FAQ fix V/ [1 V \ A»t/S l l " \f l‘ A I ' l \ Ci / /\ 41 il ”’LN [L Ax; C,5 i‘, o H N H W» “ij \ //\‘\ \>:N \ rt >3“ l \ EN x we (Ix r \ ‘ r ,x \ l 2V 1 [W JWNW e . ,.erg; lgk 2 i [I \me/N /- E 5 “kw/2 E \\> 3 0 / g b F fi/é“ g O i f /A, ’ E T\l / I \ M / N \ ,, N K N N H a r v x l \‘3\.. \ "“? Fir \rbl ,i/x/NESfA fit 'x/K‘r/N‘sfwk r’“ \ N/ / x \ , \ 1‘ O l \ i}, 0 RV A» < 1 0 , ,/”\ l an 0 r b \Ni/l’ \Nx’ / ‘N \ ’//l\N/ N N H H H or r r , -N H \ N N k X l \ / l \ O N” N 111 one embodiment ofthe methods provided herein, in compounds of Formula IIe, M3 is -(CR'9R20)t-C(O)NR26-(CR19R20),—, preferably -C(O)NR26—(CR‘9R2°),—, more preferably -C(O)NR39-CR30RSO- or —C(O)NR39-(CR30R8°)2-, wherein R39 is hydrogen or lower alkyl and R30 is hydrogen, lower alkyl or fluoro tuted lower alkyl, preferably en. In one embodiment, A6 is -CRWR2°- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, 23, —OR23 and —S(O)1R23 and Q45 is hydrogen, -OR23, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heteroeyeloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group ting ofhalogen, lower alkyl, fluoro tuted lower alkyl, -NHR23, -NR23R23, —OR23 and -S(O)2R33. Further to any ofthe above embodiments, Q52 and Q54 are independently hydrogen, fluoro, chloro, methyl, or CH.

In one embodiment of the methods provided herein, in compounds of Formula IIe, M8 is R20)t»cro)NR3"—(CR‘9R20),-, preferably —C(O)NR26-(CR19R30)s-, more ably —C(O)NR39~CR30RKO=~ or -C(0)NR”-(CR80R30)T, and A6 is _CR"’R30— or , preferably {Hy or 43(0)», In one embedimenn Mr; is {CR39R30}¢~C(O)NR26»{CRI(”$20,333 preferably eC(O)NR2"=-(CR”R25),e—, more preferably rC(O)NR39—CRSOR8§« er eC(O)NR39—(CRSORSG‘ke; A6 is CRIORQQ or ~C(O)~, preferably —CH2— or —C(O)—; Q41 is aryi or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, rNRmRB, '0ng and -S(O)3R23; and Q45 is hydrogen, 0R”, ~CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkylr cycloalkyl, heteroeyebaikyi, aryi or beremalyl, wherein lkyl, heterecyeiealkyl, aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, «NHRB, -NR23R33, -OR23 and -S(O)3R23. In one embodiment, M8 is —(CR‘gRZO),-C(O)NR36-(CR19R20)5-, preferably -C(0)NR3"—(CR‘9R20),-, more preferably -C(0)NR39-CR30R80- or ~C(O)NR39-(CR30R’“)3-; A6 is -CRI9R20~ or -(:(0)-, preferably (:11;- or ~C(O)~; Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NR23R23, -OR23 and -S(O)3R23; Q45 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, n cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23RZ3, —OR23 and -S(O)2R23; and Q52 and Q54 are independently hydrogen, fluoro, chloro, methyl, or -CF;.

In one embodiment ofthc methods provided herein, in compounds of Formula IIe, M3 is -C(O)NR”-CH2-, -C(O)NR39CH(CH3)-, or -C(O)NR39-(CH3)2~; A6 is «CHZ— or , preferably -CH2-; Q“ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or fluoro substituted more substituents selected from the group ting of halogen, lower alkyl, lower alkyl, -NHR“, -NR“R41, -OR‘“ and -S(O)2R“; Q45 is hydrogen, —CN, fluoro, , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroal-yl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR41, , -OR41 and -S(O)2R‘"; and Q52 and Q54 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q52 and Q54 are indepcndently fluoro, chloro, methyl, or -CF3, n R‘1 is as defined in Formula lg.

In one embodiment ofthe s provided herein, in compounds of a Ile, Ar, is -CH;- or -C(O)-, preferably -CHz-; Q“ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more tuents selected from the group consisting of OR“, -sn“, eS(O)R“, sore“? -NHR“, eNRflR“, -N'R39c:(0)R“, ~NR39S(O)3R“, halogen, lower alkyl, eyeloalkyl, cycloalkyl, aryl and heteroaryl, wherein lower alkyl is ally substituted with ene or more substituents selected from the group consisting of fluoro, lower alkoxy, fiuoro tuted lower alkoxy, lower alkylthio, fluoro tuted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, n cycloalkyl, heterooycloalkyl, aryl, and heteroaryl as a tuent of Q“? or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of «OH, -NHZ, «CN, eNoz, ~S{O)3NH;, Z, ~OR42, err”, Nun”, »NR43R“Z, «Worms? —NRBQS(O)2R42, R“, n, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q45 is hydrogen, -CN, -0R“, -SR“, -S(O)R“, -S(O)2R4', -NHR””, -NR4‘R‘“, -NR39C(O)R41, —NR395(O)2R“, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or aryl, n aryl or heteroaryl are ally substituted with one or more tuents selected from the group ting of n, lower alkyl, lluoro substituted lower alkyl, ~NHR“, —NR"R‘”, and -OR‘“; MS is -C(O)NR39CH2~, -C(O)NR39CH(R40)~, or ~C(O)NR39CH2CHz-; and Q52 and Q54 are independently hydrogen, n, lower alkyl, fluoro substituted lower alkyl, -NR44R44, OR“, or «512“, provided, however, that at least one of Q52 and Q54 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R39, R40, R41, R42 and R44 are as defined for Formula II.

In one embodiment ofthe methods provided herein, in compounds of Formula IIe, A6 is -CH2-; Q“ is aryl or aryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substitutcd lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M8 is «C(O)NR39CH2—, -C(0)NR”CH(R4°)-, or —C(O)NR”CH2CHz-; and Q52 and Q54 are independently en, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q52 and Q54 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of the methods provided herein, which includes Formula IIe above, each occurrence of R4] is R42 as defined for Formula lg.

In one embodiment of the methods provided herein, in compounds ofFormula lle, M3 is -C(O)N[’ICH2-, -C(O)NH—CH(CH3)- or -C(O)NH-(CH2)3-; A5 is —Cl-l2— or -C(O)-, preferably —CH1«; Q“ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with I or 2 substituents selected from the group consisting of' fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen or chloro; and Q53 and Q“;4 are independently hydrogen, fiuoro, chloro, lower alkyi, or fiuoro substituted lower alkyi, preferably Q52 and Q54 are methyl, In one embodiment of the methods provided herein, wherein the compound of a He is a compound is selected from the group consisting of: 3-( l ~Benzylw3 ,5»dimethyl‘ I H~pyrazolylmethyl)—l H-pyrrolo[2,3~b]pyridine (P«0l33), *Dimethyl~4~( l olo[2.3 ridin-3~ylmethyl)—pyrazol— l -yl]- l ~phenyl—ethanone (P~0134), 3 ,5-Dimethyl(1 H-pyrrolo[2,3-b]pyridinv3—ylmethyl)—pyrazole~ 1 xylic acid 4-methoxy- benzylamide 15), 3,5-Dimethyl(l H-pyrrolo[2,3-b]pyridin—3~ylmcthyl)-pyrazolc—1-carboxylic acid 2-chioro~ benzylamide 6), 3‘5'Dimethyl—4-( 1 H-pyrrolo[2,3 -b]pyridinylmethy1)~pyrazole’1-ca.rboxylic acid 2—fluoro- benzylamide (P-0137), 3-[3,5—Dimethyl—I-(5—triflu0romcthyi-furanv2—ylmethyl)-1H—pyrazol—4-ylmcthyl]-l H-pyrr010[2g3- b]pyridine (P-OISS), 3~[3,5-Dimethyl(5 -methy1-isoxazoi-3 hyi)~i H-pyrazol-li-ylmethyl]-l H-pyrrolo[2,3— b]pyridine (P-0139), 3,5-Dimcthyl-4—(1H—pyrrolo[2,3—b]pyridin-3—ylmethyl)-pyrazolec3rboxylic acid 4-Chloro» benzylamide (P-0140), 3,5-Dimethyl-4—(1H-pyrrolo[2,3-b]pyridin-3—ylmcthyl)-pyrazolev1—carb0xylic acid [2-(4-methoxy- )-ethle—amide (P-0141), 3,5—Dimethyl-4—(1H-pyrrolo[2,3-b]pyridin-3—ylmethyl)-pyrazole—i -carb0xylic acid 3—methoxy- benzylamide (P-0142), 3-{3,S—Dimethyl-l -[4—methyl—2'(4vtrifluoromethylnphenyl)-thiazolylmethyl]—1H—pyrazoi—4- ylmethyl}-1H-pyrrolo[2,3—b]pyridine (P-0143), 3-[3,5—Dimethyl(4-methylphenyl-thiazol—S-ylmethyl)-1H—pyrazol—4—ylmethyl]—1H— pyrrolo[2,3-b]pyridine (P—0144), 3,5'Dimcthylv4—(1H—pyrrolo[2,3-b]pyridinylmethyl)-pyrazolecarb0xylic acid 2-methoxy- benzylamidc (P-0145), 3,5—Dimethyl—4—(1H-pyrrolo[2,3-b]pyridinv3vylmethyl)—pyrazole-l-carboxylic acid [2-(2,4- dichloro—phenyl)vethyl]—amide (P-0146), 3,5—Dimethyl-4—(lH-pyrr010[2,3-b]pyridin-3—ylmethyl)-py1‘azole-l-carboxylic acid flu0ro- phenyl)-ethyl]-amide (P-0147), 335-Dimethyl(1H-pyrrolo[2§3vb]pyridin,—3-y1methyl)-pyrazolecarboxylic acid fluoro- phenyl)*cthyl]-amidc (Pu0148), 335—Dimethyl—4~(1H-pyrmlo[2,3ch]pyi‘idin-B;~ylmethyl)-pyrazolc—1~carb0xylic acid {(8} 1 ~phenyiv cthyl)~amide (Pa-0149), 3,5‘Dimcthyl~4w(1H~pyrmi0[2?3’b]pyridinaS‘yimethylypyraznlc-I«carboxyiic acid 0— benzylamide (P-0150), 3,5-Dinmthyl~4=(1Hapyrrolo[2i3—b]pyridinv3-y1methyl)—pyrazolecarb0xylic acid 4»fluor0- benzylamide (P-0151), 3,5-Dimethyln4-(1H~pyrr010[2,3-b]pyridinu3~ylmethyi)—pyrazolc~l—carboxylic acid 4~methyl— bcnzylamide (P«0152)5 3,5—Dimethyi(1H-pyrrolo[2,3—b]pyridin-3—ylmethyl)—pyrazolecarboxylic acid 2-methyl- benzylamide (P-0153), 4-(5—Chioro»lH-pyrrolo[2i3—b]pyridinylmethyl)-3,S-dimethyl-pyrazole-l-carboxylic acid [2-(4~ fluoro«phenyl)-ethyl]—amide (P—0157), 4-(5-Chloro-lH—pyrrolol2,3 -b]pyridinylmethyl)-3,S-dimethyl-pyrazole-l-carboxylic acid 4- fluoro-benzylamide (P~0158), 4-(5-Chloro~llI-pyrrolo[2,3~b]pyridin~3 —ylmethyl)-3,S-dimethyl-pyrazole-1~carboxylic acid 4— chloro-benqlamide 9) and 4-(5-Chloro-1H-pyrrolo[233 -b]pyridinylmethyl)-3,5-dimcthyl—pyrazole- l -carboxylic acid [(3)- l—(4-fluoro-phenyl)-ethylj-amide 0) or all salts, prodrugsg tautomers, or isomers thereof.

In one embodiment of the methods provided herein, a compound of Formula II has a structure according to the following sub-generic structure, a 11f, a Hf, all salts, prodrugs, tautomers, and isomers thereof, wherein: A7, is selected from the group consisting of -CR'ng-, -C(O)-, , -S-, —S(O)-, -S(O)2-, -NR21-, and -O-; Q55 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally tuted aryl, optionally tuted heteroaryl, -OH, -NH3, -N02, -CN, -NHC(O)NII;, -Nncr‘swnb )2NH3, -C(O)Nl{g, ~C(S)NH2, -S(O)3NH2, -NR24R25‘ -NHR23, -0183, 51131 mom”? —C(S)R23, ”, smut”? ~C(O)NHR23, -C(0)NRBRZi “C(S)NHR33, ~C(S)NR23R23, -S(0)2NHR33, -S(O)2NR23R23, ~NHC(Q)R23, ‘NR33C(0)R22 :qusmli ~NR33CT(S)R233 szi pNRfismhRfit -NHC(O)NHK23, «NR23C(O)NH2, NR”C{0)NHRZ§, «N'HC(O)NR:3R23§ ~N’R23C(O)NR23R33, -NHC(S)NHR33, -NR33C(S)NH3, -NR23C(S)NHR23, -NHC(S)NR23R33, -NR23C(S)NR33R23, -NHS(0)2NHR23, —NRHS(O)ZNH;, -NR23S(O)2NHR23, -NHS(O)3NR23R33, and -NR335(0)2NR23R33; Mg, Q51, Q67“, and (26'1 are as defined for Formula II; and Rig, R265 R31; R}3 R343 and R25 are as defined for Formula lb, In one ment of the methods provided herein, in compounds of Formula Hf, Mr; is -(CR‘QRZU),-NR%-(CR‘W“),— or -(CR“’Rl“),-NR2“C(0)-(CR‘9R3“),-, preferably -NR3“-(CR”R20)S- or -NR26C(0)-(CR‘9R30)s—, more preferably -NR39CRSORSO- or -NR39(CR80R80)2-, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A7 is -CR”R2"- or -C(O)-, preferably -CH2— or -C(O)-.

In one embodiment, Q51 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -N R23RZ3, -OR23 and -S(O)3R23 and Q55 is hydrogen, -OR23, -CN, fluoro, , lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heteroeycloalkyl, aryl or heteroaryl, wherein cycloalkyl, cycloalkyl, aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR23, -NR23R33, -OR23 and -S(O)2R23. Further to any ofthe above embodiments, Q62 is en, , chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment ofthe methods ed herein, in compounds of Formula Hf, M9 is _(CR‘9R2”),-NR26-(CR‘9R2°),— or {CR‘9R2°),-NR26C(0)—(CR‘9R20)5—, preferably -NR26-(CR‘9R20)5— or -NR26C(O)-(CR19R20)s-, more ably -NR39CR80R80- or -NR39(CR80R80)2—, and A7 is -CR19R2°- or , preferably -CH2- or -C(O)-. In one embodiment, M9 is {CR”RZO),-NR2“—(CR‘9RZ°),— or —(CR‘9R2°),-NR2°C(0)-(CR‘9R2°),—, preferably (CR‘9R2°),- or —NR36C(O)—(CR‘9R2°),_, more preferably -NR”CR80R3°- or -NR39(CR80R80)2-; A7 is -CR19R20- or -C(O)-, preferably -CH2- or ~C(O)-; Q51 is optionally substituted lower alkyl, aryl or aryl, wherein aryl or heteroaryl are ally substituted with one or more substituents selected from the group consisting of n, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q55 is en, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or aryl are ally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NRZ‘R”, .OR23 and -sr‘olznli In one embodiment, M9 is -(CRI9R2”),—NR25—(CR‘9R20),— or {CRWRZO)¢NR26C(O)«(CR”REL: ably eNR26e(CR”R39),~ bi ,stc‘cmyrcs‘gnmig, more preferably Nietcngfist‘i, e'NR39(CRgGRgQ)g-: A; is -CRWRZQ- or «troy, preferably ’CHE— or »C(O)-; Q51 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NR23R23, —OR23 and —S(O);R23; ()55 is hydrogen, —CN, fluoro, chloro, lower alkyi, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower aikoxy, eyoioalkyl, heterooyeloalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHRB, -NRZ3R23, -OR23 and —S(O 2R5; and Q62 is hydrogen, fluoro, , lower alkyl or fluoro substituted lower alky l.

In one embodiment of the methods provided herein, in compounds of Formula llf, M9 is -NR39CH2- or -NR39-(CH3)2-; A7 is -CH2- or , preferably -CHg-; Q5l is aryl or heteroaryl, wherein atyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro tuted lower alkyl, ~NHR‘”, -NR‘“R‘“, ~ORZll and -S(O)2R‘“; Q55 is hydrogen, ~CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lkyl, heterocycloalkyl, aryl or aryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR4], -NR‘“R“, -OR“ and -S(O)3R“; and Q62 is hydrogen, fluoro, Chloro, lower alkyl or fluoro substituted lower alkyl, wherein R“ is as defined in Formula lg.

In one embodiment ofthe methods provided herein, in nds of Formula Ilf, A7 is nCH2~ or ~C(O)~, preferably «CH2—; Q51 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR“, -511“, -S(0)R‘“, —S(O)2R‘“, , ”, —NR3°C(O)R“, —NR395(O)2R4‘, 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 , lower alkylthio, fluoro substituted lower alkylthio, monoalkylamino , di-alkylamino, lkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q5‘, or as a substituent of lower alkyl are optionally substituted with one or more tuents selected from the group consisting of -OH, -NH2, -CN, —N02, -S(O);NH2, -C(O)NH2, OR“, -SR“, -NHR42, -NR43R42, -NR39C(O)R‘12, —NR3gS(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkyiamino; Q55 is hydrogen, -CN, -0R‘“, -SR‘“, , —S(0)2R“, ~Nl 1R“, —NR“R“, -NR39C(O)R‘“, -NR395(O)3R“, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, aryl or heteroaryl, wherein aryi or heteroaryl are optionally substituted with one or more substituents seiected From the group consisting of haiogen, lower alkyi, fiuoro tuted lower alkyi, ~NHR“, ”NRMR“, and OR“; Mg is a bond, «Nwa, w3», w0, *NREQCHN «NR3§CH2CHZ‘, ~NR3§CH(R4‘3)~, -SCH2—, pour, —C(O)NR39—, —S(0)2NR3"—, -CHZNR”—, -CH(R“)NR3"-, -NR39C(O)—, or ~NR3QS(O)2-; Q62 is hydrogen, fluoro, chloro, iower alkyl, fluoro tuted lower alkyl, -NR44R44, ~0R44, or SR“; and Q64 is hydrogen, lower alkyl, or fiuoro substituted lower alkyl, wherein R39, R40, R“, R42 and R44 are as defined for Formula II.

In one embodiment of the methods provided herein, in compounds of Formula Ilf, A7 is -CH;-; Q5 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more tuents ed from the group ting ot'fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower , and fluoro substituted lower alkoxy; Q55 is en, ~CN, , chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M9 is -NR39CH2-, «NRSQCHQCHE or -NR”CH(R40)-; Q62 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and Q64 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments the methods provided herein, which includes Formula llf above, each occurrence ofR‘” is R42 as defined for Formula Ig.

In one embodiment ofthe methods provided herein, a compound of Formula II has a ure according to the ing sub—generic structure, Formula IIg, N ii Formula Hg, all salts, prodrugs, tautomers, and isomers thereof, A8 is selected from the group ting of—CR‘9R2“-, »C(0)-, C(5)», -5», »S(O)-, -S(O)2-, »NR2‘~, and o, O"5 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH2, —N02, —CN, -NHC(O)NH2, - NHC(S)NH2, —NHS(O)2NH2, -C(O)NH2, ~C(S)NH2, —S(O)ZNI-I2, eNR24R25, ~N‘HR23, won”, -511”, How”, -C(S)R23, -S(O)R23, —S(O)2R“, «C(O)NHR23, -C(o)N {83183, =C(S)NHR23, ~C(S)NR33R?3, «S(O)ZNHRB, -S(O)2NR23R23, iR33, ~NR33C(O)RB, :- NHC{S)R23, C(S)Rii ~NHS(O)2R33, e'NREBStiOhRfi, ~NHC(O)NHR33, eNR23C(O)NH2, eNR,33C(O)NHR23, .NricromRZ‘SRZi ~NR33C(0)NR23R23, -NI~IC(S)NIIR23, -NR23C(S)NH2, —NR23C(S)NHR33, )NR33R23, —NR23C(S)NR23R23, »NHS(O)2NHRZ3, —NR”S(O)2NH3, -NR23S(0)2NHR“, —NHS(0)2NR”R”, and -NR33S(0)2NR23R33; Mis, Q‘s}, Q72, Q74 are as defined for Formula II; and R”: R23 R3, R23, R34, and R32 R“: are as defined for Formula lb, In one embodiment of compounds ofForlnula Hg, M0 is -(CR‘9R30)t—NR26—(CR”RZO)S— or -(CR‘9R20)l—NR36C(0)-(CR‘9R20)S—, preferably -NR36-(CR'9R30)S- or -NR“C(O)-(CR”R20)S-, more preferably —NR39CRSORSO— or -NR39(CRSORSO)2-, wherein R39 is hydrogen or lower alkyl and R30 is hydrogen: lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodimeng Ag is -CR‘9R20— or -C(O)«, preferably ~CH2— or -C(O)-. In one embodiment, Q63 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally tuted with one or more substituents selected from the group ting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, —NR23R23, —OR23 and —S(O)2R23 and Q65 is hydrogen, ~OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, hcterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR23, -NR23R23, —OR23 and —S(O)2R23.

Further to any of the above ments, Q74 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment ofthe methods provided herein, in compounds of Fonnula IIg, Mm is —(CR‘9R30),—NR26-(CR”RZO)S— or ~(CRI9R3”)1-NR26C(O)-(CR'9R2°)s—, preferably —NR26-(CR]9R20)S- or —NR3°C(0)—(CR‘°R3°)S—, more ably CR80R80- or -NR39(CR8°R8°)2-, and AS is ~CR19R20- or —C(O)-, preferably —CH;- or -C(O)-. In one embodiment, M10 is R2°)t-NR2(’—(CR19R2°)S- or —(CRI9R”),—NR26C(O)—(CR'9R2“)5—, preferably -NR2fi—(CR19R2°)5- or -NR26C(O)-(CR‘9R3°)S-, more preferably -NR39CR8°R8°- or —NR39(CR8°R80)2—; A8 is ~CR19RZO- —C(O)—, ably —CH2- or -C(O)—; Q61 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or aryl are optionally tuted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, ~NR23R23, —OR23 and -S(O)2R23; and Q65 is hydrogen, —OR23, -CN, , chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or aryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more tuents selected from the group consisting of halogens lower alkyl, fluoro substituted lower alkyl, —NHR23, -NR23R”, «01123 and -S(O)2R23. In one embodiment, M10 is -(CR19R2°)1«NR26—(CR‘9R2“); ~(CR19R20)t-NR36C(O)-(CR‘9R20)s-, preferably -NR26-(CR‘9R2°)S— or -NR26C(O)«(CR'”R20)53 more preferably ~NR39CR83R80- or CR80RSO)y; A8, is eCRme- or 43(0):, preferably -Crig- eCiO}; Q53 is optionally substituted lower alkyl, aryl or heterodryl, wherein aryl or heteroaryl ally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, nuoro substituted lower alkyl, NHR”, —NR”R23, -OR” and -S(O)2R23; Q65 is hydrogen: «ORB, -CN, fluoro, 3 lower alkyl, fluoro substituted lower alkylt cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, (.J‘! 06 lower alkyl, fluoro substituted lower alkyl, -NHR”, —NR23R23, «OR23 and -S(O)3R33; and Q” is hydrogen, fluoro, chtoro, lower alkyl or fluoro substituted lower alkyl. [0110) In one embodiment ofthe s ed herein, in compounds of Formula 11g, Mm is -NR39CH3- or -NR3°-(CH2)3«; A8 is “CH2- or actor, preferably -CH2-; Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR‘“, —NR41R“, -OR'“ and R41; Q65 is hydrogen, —CN. fluoro. chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluorb substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or aryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR‘“, -NR‘“R‘”, -OR“ and -S(O)2R4'; and Q74 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R4] is as defined for Formula lg.

In one embodiment of the methods provided herein, in compounds of a Hg, A8 is —CH2— or , ably —CH2-; Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR“, -SR‘“, -S(0)R“, —S(O)2R“, -NHR4‘, —NR“R“, 0)R“, —NR”S(O)2R“, n, lower alkyl, cycloalkyl, cycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more tuents 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 aryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q“, or as a substituent oflower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, —N1«lz,-CN, —Nog, -S(O)2NH;, -C(O)NH2, .011“, —SR“, NHR“, —NR"2R“, —NR39C(0)R“, —NR398(O)2R42, -S(O)2R“, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q65 is hydrogen, -CN, 01142-511“, -S(O)R‘”, —S(O)2R“, -NHR“, -NR‘“R‘“, —NR”(:(0)R‘“, —NR”S(O)2R‘”, tluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR“, —NR“R“, and ~OR“; Mm is a bond, -NR3§~, s, o, H2-, ~NR39C‘H3CH23 ~NR3QCH(R‘@)», escrlge ~OCHee, -C(o:lNR39-, stokmwe, «CH3NR3g-, 9)NR39—, —NR3"C(0)-, or ~NRNS(O)2-; Q74 is hydrogen, fluoro, chloro, lower alkyl, fltloro substituted lower alkyl, ‘M, —OR“, or SR“; and Q72 is en, lower alkyl, or fluoro substituted lower alkyl, wherein R39, R40, R“, R42 and l";M are as defined for Formula II. in one embodiment ofthe methods provided herein, in compounds of a llg, AS is —CH;-; Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro tuted lower alkoxy; Q65 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M10 is -NR39CH2-, -NR39CH2CH2-, or —NR”CH(R4°)—; Q74 is hydrogen, fluorog chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and Q72 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment, further to any ofthe ments ofthc methods provided herein, in Formula llg above, each occurrence of R“ is R42 as defined for Formula lg.

In one embodiment ofthe methods provided , in compounds of a llg, Mm is -NHCH2-, A3 is -CH2—, Q“ is phenyl optionally substituted with I or 2 substituents selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, 065 is hydrogen, fluoro, -CN, or l-methyl-pyrazol-Zl-yl, Q72 is lower alkyl or fluoro tuted lower alkyl, and Q74 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, Mm is -NHCH2-, A3 is —, Q“ is 4-fluoro-phenyl, Q65 is en, chloro, —CN, or l—methyl-pyrazolyl, Q72 is methyl or ethyl and Q74 is hydrogen or chloro.

In one embodiment ofthe methods provided herein, the compound of Formula Hg is selected from the group consisting of : [l-Ethyl(1H—pyrrolo[2,3-b]pyridinylmethyl)-l H-pyrazolyl]-(4-fluoro-benzyl)-amine (P—0165), (4-Fluoro-benzyl)—[l—methyl’5-(1H—pyrrolo[2,3-b]pyridin-3 -ylmethyl)- l zol-3 -yl]~amine (P—0169), [5-(5—Chloro-1H-pyrrolo[2,3-b]pyridin—3-ylmethyl)-l—methyl-lH-pyrazolyl]—(4-fluoro-benzyl)v amine (Po0170), (_4~Fluoro»benzyl)~{ l smethyl~5—[Sn( l -methyl-1H—pyrazol«4~yl)— l H»pyrrolo[2,3—b]pyridin-3~ ydmethyl]w i Hapyrazoifi ayi } ~amine (P~0180), (:5~Ciiloro— l H‘pyrrolomfi—b]pyridin~3 ~yl)—[Z—ethyL5~(4~fluorowbenzylamino)~2H—pyrazoi-3 ~yl]~ mcthanone (P—0184), [5 -(5 -Chloro- l H-pyrro lo [2,3—b]pyridiiiylmethyl} l —l H—pyrazol—3 4~fluoro-benzyl)~ amine (P—OISS), 3~[S-(4-Fluoro—benzylaminoyZ~methyl~2H~pyrazoL3 -ylmethyl]~l H«pyrrolo[2,3 ~b]pyridine-5~ earbonitrile (@0191), (3-Chloro-benzyl)-[5—(5-chloro—lH~pyrrolo[2,3«b]pyridin~3~ylmethyl)~1—methyl-l H-pyrazolyi]— amine 0-0410); [5—(5—Chloro—1H—pyrrolo[2,3—b]pyridin-3 hyl)- l l— l H—pyrazol—3 2,5—ditluoro« benzyl)-amine 1) and [5—(5 -Chloro~ l H«pyrrolo[2,3 -b] pyridin—3 —ylmethyl)- l l—l H—pyrazol~3 ~yl]-(2—fluoro—benzyl)— amine (P~[l413), or all salts? gs, tautomers, or isomers thereof.

In one embodiment ofthe methods provided herein, a compound of Formula I] has a ure according to the following sub—generic structure, Formula Ilh, Ag’<\ k _. 71 Q75 N M11 Q l \ N/ {fill Formula IIh, all salts, prodrugs, tautomers, and isomers thereof, wherein: A9 is selected from the group consisting of—CR‘9R2°—, -C(O)—, —C(S)—, —s—, , —S(O)2—, —NR2}-, and —O—; Q75 is selected from the group ting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl} optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH2, —N02, —CN, —NHC(O)NH2, —NHC(S)NH2, —NHS(O)2NH2, —C(O)NH2, -C(S)NH2, -S(O)2NH2, —NR24R25, —NIIR23, —OR23, s12”, -C(O)R23, -C(S)RZ3, -S(O)R23, —S(O)2R23, HR23, —C(O)NR23R33, —C(S)NHR23, —C(S)NR23RZ3, -S(O)2NHR23, —S(O)2NR23R23, —NHC(O)R23, —NR”C(O)R”, —NHC(S)RZ3, —NR23C(S)R23, —NI~IS(O)2R23, —NRZ3S(O)2R23, —NHC(O)NHR23, ~NR33C(O)NH2, -NR23C(O)NHR23, )NR”R33, -NR23C(0)NR33R23, ~NHC(S)NHR23, -NR73C(S)NH;, —NR33C(S)NHR3‘, -NHC(S)NR33R23, —NR23C(S)NR33RB, eNHsthHRZi ~NR23S(O)2NH3, —NR333(0)3NHR33, ~NHS(O)2NR23R23, and ‘N RZ3S(O)3N RBRZB; M; g; Q“: and Q53 are as defined for Formula II; and R12 R20, R21? R23, R24, and R25 are as defined For Formula, lb.

In one embodiment ofthe methods provided herein, in compounds of Formula llh, M“ is «(CR’QR20)¢NR36~(CR‘”ka or {CR‘”REU').«NR3§C{O)~(CR‘9R20)S~, preferably —NR26~(CR39R20)5~ or ~NR§6C(O)~(CR39R:’O)S—s mere preferably eNR39CR_SOR80- nr xNR39(CRSBR30)y, wherein R39 is hydrogen or lower alkyl and R‘q‘0 is hydrogen, lower alkyl or fluoro substituted lower alkyl, ably hydrogen. In one embodiment, A9 is -CR'9RZG— or —C(O)—, preferably —CIlg— or —C(O)u.

In one embodiment, (f1 is optionally substituted lower alkyl? aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected f1 om the group consisting of halolgen lower alkyl fluoro substituted lower alkyl, -l\lHR‘3 —NR‘3R“ —OR23 and —S(O)2R23 and Q75 is hydrogen, —OR““, -CN, fluoro, , lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, n cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NR23R23, —OR23 and —S(O)ZR33.

In one embodiment of the methods provided herein, in compounds of Formula Ilh M1] is —(CR'9RRoy—NR26(CR‘9R20)Sor —_(CR'9R2°)t—NR26C(O)(CR'9R2°)S , preferably NR26—(CR'9R20)5 or NR“6C(O)(CR'9R0)3 , more preferably——oNR39CR80RS°r—NR”(CR80R3°)2—, and A9 -CRR20— or -C(O)— preferably C112- or —C(O)-. In one ment M1, is (CR‘9R20)tNRZ6(CR'gR20)5-0or 20)1—NR26C(O)(CRIQRZOL , preferably NR26(CR'9R2°)S or —NR~C(O)(CR‘9R20)5 more preferably NR39CR30R30—or-NR39(CR8°R8°)2-; , A9IS —.oCR‘9R20 —C(O)— preferably CH2— or —C(O)—; Q71 is ally substituted lower alkyl, aryl or heteroaryl whelein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen lower alkyl, fluoro substituted lower alkyl, -l\lHR“3,—l\lR23R23 —OR23 and R23‘ , and Q75 is hydlogen N, fluoro, chloro, lower alkyl fluoro substituted lower alkyl, cycloalk’yl, heterocycloalkyl , aryl or heteroaryl, wherein cycloalkyl, eycloalkyl, aryl or aryl are optionally substituted With one or more substituents selected from the group consisting of halogen lower alkyl. fluoro substituted lower alkyl -NHR“3, -NR23R2‘ -OR” and S(.O)2R23 {0119] In one embodiment ofthe methods provided herein in compounds of a llh, M” is —NR39CH2— or1le19(-CHgb- A9is -CH;— or —C(O)—, preferably -Cng— Q“ is aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen lower alkyl, fluoro substituted lower alkyl ~NHR4‘ —NR“R“, 43R4 andS(0)3R‘”,5Q is hydrogen «CN fluoro. chloro iowei alkyl, fluoro tuted lower aikyllower aikoxy, fluoro substituted lower alkoxy, eveeloalkyLheterocycloalk},l arylo heteroaryl, wherein cycloalkyl, heterocycloalkyl, aiyl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, —NHR‘“, -NR“R“: -OR“ and —S(O)3R4l, wherein R’” is as defined for Formula lg.

In one embodiment of the methods provided , in compounds of Formula IIh, A9 is -CH;- or ) preferably -CH3~; Q?I is aryl or aryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR“; sn‘”, -S(O)R‘“, some: —NHR‘”, ~NR4‘R“, -NR39C(0)R“, -NR3QS(O)2R“, n, lower alkyl, cycloalkyl, cycloalkyl, aryl and aryl, 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 tuted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryh and heteroaryl as a substituent of Q“, or as a tuent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NHQ, -CN, N02, -S(O)3NH2, H2, on“, SR“, NHR‘”, —NR“R“, —NR”C(O)R4{ -NR3DS(O)3R43, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q75 is hydrogen, -CN, on“, sn“, -S(O)R“, —S(O)2R“, -NHR‘”, —NR‘“R“, -NR39C(O)R4', -NR393(O)ER“, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are ally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl2 fluoro substituted lower alkyl, -NHR“, —NR4’R“, and -OR‘”; Mll is a bond, —NR39—, ——.s —o—, -NR39CH2-, -NR39CH2CH2-, -NR39CH(R"0)—, sorry, -OCH2-, —C(0)NR3°—, -S(O)2NR3°-, ~CH2NR39-, —CH(R40)NR39—, -NR39C(O)-, -NR398(O)2—; and Q82 is hydrogen, lower alkyl, or fluoro substituted lower alkyl, wherein R39, R40, R“, R“12 and R‘44 are as defined for Formula II.

In one embodiment of the methods provided , in compounds of Formula IIh, A9 is ~CH2—; Q71 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group ting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q75 is hydrogen, ~CN, fluoro, chloro: lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; Mn is —NR39CHg-, -NR”CHZCHl-, 0r H(R4O)—; and Q82 is hydrogen, lower alkyl, fluoro substituted lower alkyl. [0122} In one embodiment, further to any of the embodiments of the methods provided herein, in Formula Ilh above? each occurrence of R4; is Rfl2 as defined for Formula lg. [0123} In one embodiment of the methods provided herein, a compound of Formula II has ure according to the following sub-generic structure, Formula lli, 065 Miz‘QB1 \ l I \ N N a Hi, all salts, prodrugs, tautomers, and isomers thereof, wherein: Am is selected from the group consisting 9R20-, -C(O)-, -C(S)-, -S-, —S(O)-, -S(O)2—, , and -O-; Q85 is ed from the group consisting ofhydrogen, halogen, optionally substituted lower alkyl, optionally substituted lkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, ally tuted heteroaryl, -OH, —NH2, -N02, -CN, -NHC(O)NH2, - NHC(S)NH2, -NHS(O)ZNH2, -C(O)NHZ, -C(S)NH2, -S(O)2NH1, —NR“R”, -NHR23, -011”, -SR23, -C(0)R23, —C(S)R“, -S(O)R23, -S(O)2R23. -C(O)NHR23, -C(0)NR2~‘R23, -C(S)NHR23, -C(S)NR23R23, -S(O)3NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR13C(0)R21- NHC(S)R23, -NR23C(S)R23, -NHS(O)3R23, (0)2R“, -NHC(O)NHR23, -NRZ3C(O)NH3, -NR33C(O)NHR23, -NHC(O)NR23R33, -NR23C(O)NR23R23, -NHC(S)NHRZ3, (S)NH2, —NR“C(S)NHR33, -NHC(S)N R2311”, —NR23C(S)NR23R23, -NHS(O)2NHR23, —NR23S(0)2NH2, —NR23S(O)ZNHR”, -NHS(O)2NR33RZ3, and —NR23S(O)2NR“R”; M12, Q3], and Q94 are as defined for Formula II; and R”, R2”, R2}, R23, R24, and R25 are as defined for a Ib.

In one embodiment ofthe methods provided herein, in compounds ofFormula IIi, M12 is -(CR‘9R3°)t-N R26«(CR'9R20)S- or -(CR'9R2”)l-NR26C(O)-(CR'9R20)S-, preferably -NR26-(CR”R20)S- or -NR2"C(O)-(CR’9R20)S-, more preferably -NR39CR3“R"“- or -NR39(CR80R8°)2-, n R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, Am is -CR19R20- or -C(O)-, preferably CHE- or —C(O}—.

In one embodiment, Q81 is optionally tuted lower alkyl, aryl or heteroaryl: wherein aryl heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyi, fluoro substituted lower silky}; eNHRZS’, ~NR33RZ3, eOR” ~S(O);R33 and QR5 is hydrogen, ~OR33, eCN, fiuorog chlorofi lower aikyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloaIkyl, heteroeycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyla ~NIIR23, ~NR23R23, OR23 (0);th In one embodiment ofthe methods provided herein, in compounds of Formula IIi, M12 is -(CR‘9R20)l-NR26—(CR‘9R29)5- or R30)t—NR26C(O)-(CR‘9R20)5-, ably —NR26-(CR'9R30),— or -NR26C(O)-(CR'9R20)S-, more preferably ~NR39CR80R80- or —NR39(CR80R80)2-, and Am is -CRE9REU- or ~C(O)—, preferably -CHg- or -C(O)-, In one embodiment, M32 is R33)t-NR26-(CR”R30)S- or -(CR'9R2°)t-NR26C(O)-(CR'9R2°)s-, preferably -NR36—(CR‘9R2°),- or -NR26C(O)-(CR'9R2°),—, more preferably R80R80- or -N R39(CR80R80)g-; A10 is —CR"’R2°— or —C(O)-, ably -CHg- or —C(O)-; QBI is optionally substituted lower alkyl, aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyi, -NHR?3, -NR23R23, -OR23 and —S(O)2R23; and Q85 is hydrogen, -ORZ3, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group ting ofhalogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, 23, on23 and -S(O)2R23.

In one embodiment ofthe methods provided herein, in compounds of Formula IIi, M12 is -NR39CH2- or -NR39—(CII;)2~; Am is ~CH2- or -C(O)-, preferably -CH2-; Q81 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selccted from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR4', -NR“R“, -OR'“ and —S(:O)2Rm; Q85 is hydrogen, -CN, fluoro, , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower , cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted IOWer alkyl, -NHR“, 4‘, -OR“ and -S(O)2R4', wherein R“ is as defined for Formula lg.

In one embodiment ofthe methods ed herein, in compounds of Formula IIi, Am is -CHZ~ or , preferably ~CH3—; 081 is aryl or heteroaryl, wherein aryl or heteroalyl are optionally substituted with one or more substituents selected from the group ting of OR“, -511“, sails“, R“, Min“, eNR‘i‘R“! eNR39C(Q)R“, —NR3QS(O)2R“, halogen. inwer alkyia cycioalkyl, heterocycloalkyl, aryi and beteroaryi, wherein lower alkyl is optionaiiy substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower hio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl‘ and heteroaryl, wherein cycloalkyl, heterocycloallcylg aryl, and heteroaryi as a substituent of Q“, or as a substituent of lower alkyl are optionally substituted with one or more substitucnts selected from the group consisting of OH, «NH;;,, ~ "N, No «SCOXgNlh, «C(03NH2, (anti en“, »NHR“2, eNR‘3R4i eN'R3§C(O)R“3, —NR395(0)2R43, smut”, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloaikylamino; Q35 is hydrogen, ~CN, on“, sa“, -S(O)R‘“, sauna“, -NHR‘“, ~NR4‘R“, (O)R4I, ~NR39$(0)3R41, fluoro, ohloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryi are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR“, -NR‘”R“, and DR“; M12 is a bond, -NR39—, -s-, —o—, -NR39CHg-, —NR39CH2CH2-, -NR”CH(R40)—, sour, berry, —C(0)NR39—, -S(O)3NR39-, -CH2NR39-, -CH(R“”)NR39—, -NR39C(O)«, -NR39$(O)3-; and Q94 is en, lower alkyl, or fluoro substituted lower alkyl, n R39, R40, R41, R42 and RAM are as defined for Formula II.

In one embodiment ofthe methods provided herein, in compounds of Formula IIi, A10 is -CH2-; Q81 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting o, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted IOWer alkoxy; Q85 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M13 is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R4O)-; and Q94 is en, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of the methods provided herein, in Formula IIi above, each occurrence of R“ is R42 as defined for a lg.

In one embodiment ofthe s provided herein, a compound of Formula II has a structure ing to the following sub-generic structure, Formula IIj, Formula Ilj, all salts, prodrugs, tautomers, and isomers thereof, A” is selected from the group ting ofCRme», ~C(Q)—, «(XS)», 45(0), and story; Q95 is selected from the group consisting of hydrogen, halogens optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OI~I, -\lH2, -NO;g -CN, vNHC(O)NH2, -NHC(S)NH3, “NHS(O)2NH3, -C(O)NH2, «C(S)NH3, ~S(O)3NH2, -NR2“R25, -NHR23, -OR”, sax: worms”, ZT’, ~S(O)R33, swim”, ~C(O)NHR33, ~C(O)NR33R23, asylum”, -C(S}NR33'R22 ~S(O)311HR33,—S(O)2NR33R33, «mommy, “NR23C(O)R23, —NHC(S)R1‘, —NR23C(S)R23, ~NHS(O)2R23, -NR33S(O)2R33, —NHC(o)NHR23, (O)NH2, -NRZ3C(O)NHRZ3, —NHC(0)NR33R23, -NR33C(0)NR23R33, -NHC(S)NHR33, (S)Nlia, -NR23C(S)NHR23, -NHC(S)NR23R”, -NR23C(S)NR23R23, —NHS(0)2NHR33, -NR33S(0)2NH2, —NR23S(O)2NHR23, -NHS(O)1NR23R21 and -NR23S(O)3NR33R33; MB, 09}, Q102 and Q1” are as defined for Formula II; and R19, R20, R23, R34, and R25 are as defined for Formula 1b.

In one embodiment ofthe methods provided herein, in compounds of Formula IIj, M13 is -(CR'9R20)t-NR26-(CR'°R20)S— or -(CR'9R2°)t-NR26C(O)-(CR‘9R20)S-, ably -NR26—(CR‘9R20),- or (0)-(CR'9R2”),-, more preferably —NR39CR3°R“°— or CR““R8°)2—, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A” is -CR'9R20- or -C(O)-, ably -CH2— or -C(O)—.

In one embodiment, Q91 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR33, Z3, -OR23 and -S(O)2R23 and Q95 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heteroeycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, 23, —OR23 and -S(O)2R23. Further to any ofthe above embodiments, Q]02 and Q]04 are independently hydrogen, fluoro, chloro, methyl, or -CF;.

In one embodiment ofthe methods provided herein, in compounds of Formula le, M13 is R20),—NR2“—(CR”R20)5- or -(CR'9R20),-NR26C(O)-(CR'9R20),-, preferably -NR26-(CR”R2°)5- or (O)—(CR'9RZO),-, more preferably -NR39CR80RS°— or CR8°R80)3-, and All is —CR'9R20— or —C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M13 is ’Rl")l—NR26—(CR'9R2°),— or —(CR‘9R20)t-NR26C(O)-(CR”R2553 preferably -NR26-(CR'9R20),— or -NR26C(O)-(CR‘9RZQ)S~, more preferably RSDR8°e or -NR39(CR30R80)2-; AH is 3‘£ or ~C(,'O)=—, preferably ~CH1~ or ~C(O)-; QgI is optionally substituted lower alkyl, aryl or heteroaryi, wherein aryl or heteroaryi are optionally substituted with one or more tuents selected from the group consisting of halogen, Iower alley!g fluoro substituted lower alkyl, NHRB, —NR2’3R23, ~OR23 and ~S(O)2R23; and Q95 is hydrogen, DR”, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, eyeloalkyl, heteroeycloalkyl, aryl or heteroaryl, wherein eycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, NHREE —NR33R21 «OR33 and aloha“. In one embodiment, M£3 is {CRWRESVNRZélCR”Rislse or 2“)i—NR26C(ol—(CR‘9R30),—, preferably —NR36-(CR‘9R“‘),— or —NR26C(O)-(CR19Rgo)g—, more preferably -NR”CRSUR50— or -NR3°(CR30R“)2_; A” is —CR”R20- or -C(O)—, preferably -CH2- —C(O)—; Q” is optionally tuted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of n, lower alkyl, nuoro substituted lower alkyl, -NHR”, —NR23R23, on” and —S(O)2RB; Q95 is hydrogen, —OR23, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl. fluoro substituted lower alkyl, ~NHR23, 33, -OR23 and -S(O)2R23; and Q102 and Q104 are independently hydrogen, fluoro, chloro, methyl, or CH.

In one embodiment ofthe methods provided herein, in compounds of Formula Hj, M13 is —NR39CH2— or —NR39—(CH2)2—, A“ is -CH2— or -C(O)-, preferably —CH2—; Q91 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more tuents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR‘“, -NR‘“R“, -OR41 and -S(O)2R4l; Q95 is hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, lower , fluoro substituted lower alkoxy, cycloalkyl, heteroeycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocyeloalkyl, aryl or lieteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, —NHR4I, —NR‘”R“, -OR41 and —S(O)2R4I; and Q102 and Q104 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, ably Q102 and Q104 are independently hydrogen, fluoro, , methyl, or ~CF3, wherein R41 is as defined for Formula lg.

In one ment ofthe methods provided herein, in compounds ofFormula Hj. A” is 'CHZ- or -C(O‘-, preferably —CH2—; Q91 is aryl or heteroaryl, wherein aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of —OR‘“, -SR‘“, —S(O)R“, —S(O)2R“, NHR“, -NR4‘R‘“, —NR”C(O)R“, —NR39S(0)2R‘“, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxyi fluoro substituted lower alkoxy} lower alkylthio, fluoro substituted lower alkylthio, mono~ alkyiamino, di—alkylamino, lkyl, heterocycioalkyi, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q9}, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group ting of —OH, -NH2, -CN, ~N03, ~S(O)2NH2, crown), -on‘”, SR”, -NHR”’2, -NR“2R42, (O)R“, —l\lR3QS(O)gR432 -S(O)3R43, halogen, lower alkyl, fiuoro substituted lower alkyl, and cycloaikyiamino; Q95 is hydrogen, ~CN, -oR“, -SR‘“, sols“, stops“, -NHR“, ~NR4ER“, —NR”C(0)R‘”, —NR”S(O)2R“, nuoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhaiogen, lower alkyl, fluoro substituted lower alkyl, -NHR“, ~NR4’R4‘, and -OR“; M13 is a bond, —NR39~, -s-, —o—, -NR39CHg—, —NR39C‘H3CH2-, -NR39CH(R4”)-, sour, —OCHg-, -C(O)NR3"-, -S(O)3NR39-, -CH2NRW-, -CH(R40)NR”—, —NR39C(0)-, -NR3QS(O)2-; and sz and Q104 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, —NR4‘1R44, -OR”M, or 611“, provided, however, that at least one of Q102 and Q104 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R39, R40, R“, R42 and R44 are as defined for Formula II.

In one embodiment ofthe methods provided herein, in compounds of Formula Ilj, A” is —CH2-; Q91 is aryl or heteroalyl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q95 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, lower alkoxy, or fluoro substituted lower ; M13 is —NR39CH2—, -NR39CIIZCH2—, or -NR39CH(R40)—; and Q102 and Q104 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower , provided, however, that at least one of Q102 and Q1051 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment, further to any of the ments ofthe methods provided herein, in Formula IIj above, each ence ofR‘“ is R42 as defined for Formula lg.

In one embodiment ofthe methods provided herein, a compound of Formula II has a structure according to the following sub-generic structure, Formula Hk, Formula llk, all salts, gs, tautomers, and isomers f. wherein: A13 is selected from the group consisting of -CR‘9R30—, —C(O)—, -C(S)-, —S(O)-, and -S(O)3-; Q105 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lkyl, optionally tuted heterocyeloalkyl, optionally substituted aryl, optionally substituted heteroaryl, «OH, —NH;, ~N02, ~CN, )NH3, NH2, eNHS(O)3NH3, weiomnz, “C(swng, ~S(O)3NH3. —NR34R25, NPR”, OR”. SR”, -C(O)R23, -C(S)R33, —S(O)R23, -S(O)2R23, -C(O)NHR23, -C(0)NR”R”, -C(S)NI 11133, ~C(S)NR23R23, -S(O)2NHR23, ~S(O)ZNR23R23, —NHC(0)R”, -NR23C(O)R23, —NHC(S)R23, —NR23C(S)R33, -NHS(0)2R23, -NR23S(0)2R23, -NHC(0)NHR”, —NR23C(0)NH2, (O)NHR23, -N HC(O)NR23R23, (O)NRBR23, -NHC(S)NHR”, -NR23C(S)NH2, -NR”C(5)NHR33, —NHC(S)NRZ3R23, -NR33C(S)NR23RB, -NHS(O)2NHRZ3, -NR233(0)3NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R33, and —NR23S(O)2NR23R23; MM, Qm, and Q112 are as defined for Formula II; and R”, R20, R23, R24, and R25 are as defined for Formula 1b.

In one embodiment ofthe methods provided herein, in compounds of Formula IIk, MM is —(CR‘9R2”),-NR26-(CR‘9R20)5— or -(CR'9R2°)t-NR26C(O)-(CR19R2°)s-, preferably -NR26—(CR]9R2°)S- or -NR26C(O)-(CR]9R20)Sr, more preferably —NR”CR“OR”— or -NR39(CR8°R8°)2-, wherein R” is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro tuted lower alkyl, preferably hydrogen. In one embodiment, A12 is —CR‘9R20— or , preferably -CH2— or .

In one ment, Q1m is optionally substituted lower alkyl, aryl or heteroaryl, n aryl or heteroaryl are ally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, —NR23R23, -OR23 and -S(O)2R23 and Q105 is hydrogen, —ORZ3, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, uNRBRB, -OR23 and —S(O)2R23. Further to any of the above embodiments, QI '2 is hydrogen, fluoro, , lower alkyl or fluoro substituted lower alkyl.

In one ment ofthe methods provided herein, in compounds ofForrnula IIk, MM is -(CR’9R2”),-NR26—(CR‘9R2°)S— or -(CR'9R20),-NR26C(0)—(CR‘9R2°)S—, preferably (CR“’R20),~ 0r -NR26C(O)—(CR]9R2°)s—, more preferably -NR39CR30RSQ- or -NR39(CRRORBO)2-, and A]; is ~CR‘9R30— or -C(O)-, preferably non? or ‘C(0)—. In one embodiment, MM is {CRmex-NRZé-«(CR‘9R30)g« 02‘{CR19R20){~NR25C(O)*(CRI9R23)3‘, ably —NR2‘*—(CR”RZG),— or r'oyrcnitnmle, more preferably «NRSQCRSORm» or «Nnigmnmnm‘ygm; Ara is ”CRinge or ”(3(0): preferably «CHZ- or 43:0}; QEm is optionaily substituted lower alkyl, aryl or heteroaryl, wherein any} or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, tower alkyl, fluoro substituted lower alkyl, ~NHR23, -NR23R23, ~OR33 and -S(O)2R23; and Q105 is hydrogen, OR”, -CN, fluom, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein eycloalkyly, heterocycioaikyi, aryi or aryl are optimlalIy substituted with One or more substituents ed from the group consisting ot‘halogeni lower alkyl, fluoro substituted lower alkyl, -NHR23, $118311”, -0sz and -S(O)2R23. In one embodiment, MN is -(CR‘9R20)t-NR2°-(CR”RZO)S- -(CR‘Wot-NR36C(0)—(CR‘9R3°)s—, preferably -NR35-(CR‘9R20)S- or (O)-(CR‘9R20)s-, more preferably ~NR39CR80R80~ or -NR”(CR5°R80)2-; A,2 is —CR‘°R”— or am, preferably 4:11;.

-C(O)~; Q10" is optionally substituted lower alkyl, aryl or heteroalyl, wherein aryl or heteroaryl optionally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, ~OR23 and -S(O)3R23; Q105 is hydrogen, ~0R23, -CN, fluoro, ehloro. lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heteroeycloalkyl, aryl or heteroaryl, n cycloalkyl, heteroeycloalkyl, aryl or aryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, MIR”, -NRZ3R23, .01123 and -S(O)2RZ3; and Q112 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment ofthe methods provided herein, in compounds of Formula llk, MM is ~NR39CH2- or (CH2)2-; A12 is —CH;- or -C(O)-, preferably -CH2-; 0“” is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR“, -NR4]R4’, -OR41 and -S(O)2R41; Q‘05 is en, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or aryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, ~NHR“, -NR‘“R“, -OR41 and -S(O);R“; and Qm is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R4] is as defined for Formula lg.

In one embodiment ofthe methods provided , in compounds ofFormula IIk, A12 -CH3- or -C(O)-, preferably -Cl-[;-; Q“)1 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more tuents selected from the group consisting of—OR“, -511“, stone“, ~S(O)2R‘“, —NHR“, -NR“R“, —NR‘WC(O)R“, _NR39S(0)2R‘“, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxyl fluoro substituted lower alkoxyg lower alkylthioi fluoro tuted lower alkyllhio, monoe rninos tli~all<ylamim cycloalkyl, eyeloalkyl, aryl, and heteroaryl, wherein eyeloalkyl, heterocyeloalkyl, aryl, and heteroaryl as a substitucnt ot’Qm, or as a tuent oflower alkyl are optionally tuted with one or more substituents selected from the group consisting of—OH, -NH3, -CN, —Noz, -S(obNH2, -C(O)NH2, on“, -SR“, -NHR“, ~NR42R“, (O)R42, eNR3QS(O)gR“3, R‘2, halogen, lower alkyl, fluoro substituted lower alkyl, and cy‘eioelkylamino; oEOE is hydrogen, -CN, on“, use“, oops“, stow“, NHR“, NRJER“, —NR39C(O)R“, -NR395(O)2R“, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR‘”, -NR“R“, and OR“; M14 is a bond, -NR‘°-, ~5., -o-, -NR”CH3—, -NR”CH3CHz-, -NR”CI~I(R4")-, sour, bony, -C(0)NR”-, -S(O)3N R393 —CH;NR39—, -CH(R“G)NR”-, —NR39C(O)-, or -NR398(O)3-; and Q1 E2 is hydrogen, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, ~NR44R44, OR“, or SR“, wherein R3”, R40, R“, R‘12 and R44 are as defined for Formula II.

In one embodiment ofthe s provided herein, in nds of Formula lIk, A12 is -CH3—; Q‘m is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or lower alkyl, fluoro more substituents selected from the group consisting of fluoro, chloro, substituted lower alkyl, lower alkoxy, and fluoro substituted lower ; Q105 is hydrogen, —CN, Iluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M14 is -NR39CH3-, H2CH3-, or —NR39CH(R40)-; and Q112 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments of the methods provided herein, in Formula IIk above, each occurrence of R‘“ is R42 as defined for Formula Ig.

In one embodiment ofthe methods provided herein, a compound of Formula II has a structure ing to the following sub—generic ure, Formula IIm, 0115 AHVM .0111 m0124 / a IIm, all salts, gs, tautomers, and isomers thereof, wherein: A13 is selected from the group consisting oi'»CRmR20~, -C(O)-, “C(S); -S-, —S(O)-, -S(O)2-, ~NR21—, and -O-; 0335 is selected from the groep consisting of en, halogen, optionally substituted lower alkyi, optionally substituted cycloalkyi, optionally substituted heteroeycloalkyl, optionally substituted aryl, optionally substituted heteroaryi, OH, ~NH3, ~N02, -CN, —NHC(O)N’H2, —NHC(S)NH2, ~NHS(O)2NH2, -C(O)NH2, -C(S)NH2, ~S(O)3NH2, -NR2“R35, NHR”, -018“, SR”, -C(Q)R23, -C(S)R23, -S(O)R23, R23, -C(O)NHR23, -C(O)NR23R23, ~C(S)NHR23, R23R23, —S(O);3NHRB, “5(0)2NR23R23, -NHC(O)RB, «NR33C(0)R”, ~NHC(5)R33, ”NR23C{S)R23, «NHSCOhRZ‘, =NR3iS{Q)gR23, -NHC(O)NHR”, ~NR13C(O)NH3, -NR23C(O)NHR23, )NRl3RZ3, —NR23C(O)NRBR33, -NHC(S)NHR23, —NR”C(S)NH3, —NR23C(S)N11R23, -NHC(S)NR23R33, —NR33C(S)NR33R33, —NHS(O)2NHR23, -NR23S(O)2NH -NR2:‘S(O)ZNHR23, -NHS(O)2NRBRZ3, and -NR23S(O);;NR23R23; Mrs, Q”, and Q|24 are as defined for Fonnula ll; and R19, R20, R”, R23, R24, and R25 are as defined for Formula Ib.

In one embodiment ofthe methods provided , in compounds of Formula llm, Mrs is -(CR‘9R30),-NR26-(CR‘9R2“),— 0r -(CR‘9R30),-NR26C(O)-(CR19R20)5—, preferably —NR26—(CR‘9R20),- or ~NR39(CR80R80)2-, wherein R” is or -NR26C(O)-(CR’9R2°)s-, more preferably —NR”CR3°R3°- hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A13 is -CR‘9R20- or —C(O)-, preferably -CH3- or —C(O)-.

In one embodiment, Q‘11 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaiyl are optionally substituted with one or more substituents selected from the group -OR23 and consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -S(O)2R23 and Q”5 is en, -ORZ3, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, n cycloalkyl, heteroeycloalkyl, aryl or heteroaryl are ally substituted with one or more tuents selected from the group -OR23 and consisting of halogen, lower alkyl, lluoro substituted lower alkyl, -NHR23, —NR23R23, -S(O)2R23. Further to any of the above ments, Q‘24 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl. [0146| In one embodiment ofthe methods provided herein, in compounds of Formula Ilm, M15 is -(CR‘9R20)t-NR26-(CR‘9R20)3- or —(CR‘gRZOy—anéqoymk‘9R2“),—, ably —NR2"-(CR‘“’R2“),— or -NR39(CR8°R8°)2-, and A13 is or —NR26C(0)—(CR‘9R20),—, more preferably R80R“— - or -C(O)—, preferably -CH2- 0r -C(O)—. In one embodiment, M,5 is -(CR‘9R20)t-NR26-(CR‘9R20)5- or -(CR‘9RZ°)t-NR36C(O)-(CR‘9R20)s-, preferably -NR26—(CR‘9R20)5- or -NR3°(CRROR8°)2—; A13 is —CR”R2D« or -NR26C(O)-(CR' 9113‘}, more preferably —NR39CR80R3°— or -C(O)-, preferably -CH2— or -C(O)-; QI is ally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkylF fluoro substituted lower alkyl, eNHRLX‘g, NRBRB, DR23 and —S(()}2R23; and QE ‘5 is hydrogen, 0112:}, ~CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, eycloalkyl, heteroeyeloalkyl, aryl or aryl, wherein cycloalkyl, heterooycloalkyl, aryl or aryl are optionally substituted with one or more substituents selected from the group ting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, «NRERB, 01133 and ~S(O)3R:'3. In one embodiment, M15 is -(CRWREQyNRzé-(CRWRZQ),— or {CR1§R26)§~NR3“C{O)K(CRE9REQ),-, preferably —NR25«(CRWRZG),~ or -Nazt’cljor(cn‘glz29),x, mere preferably -NR39CR30R80- or ~NR39(CkxaR3“)2—; A13 is -CRWRm- or —C(O)-, preferably —Cllg- or -C(O)—; Ql is optionally substituted lower alkyl, aryl or aryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, —NR23RZ3, —OR23 and —S(O)3R23; Q1 is hydrogen, ~0RZ3, —CN, lluoro, ehloro, lower alkyl, fluoro substituted lower alkyl, eyeloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, , —NR23R23, vOR23 and —S(O)2R23; and Q124 is hydrogen, fluoro, ehloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment ofthe methods provided herein, in compounds of Formula llm, M15 is ~NR39CH2- or (CH2)2—; A13 is —CH3- or —C(O)—, preferably —CHg—; Q1” is aryl or aryl, wherein aryl or heteroalyl are optionally substituted with one or more substituents selected from the group consisting of halogen. lower alkyl, fluoro substituted lower alkyl, —NHR‘“, -NR“R‘“, ~OR‘“ and —S(O)2R“; Q“5 is hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or aryl are optionally substituted with of halogen, lower alkyl, fluoro one or more substituents ed from the group consisting tuted lower alkyl, , -NR42R42, —OR42 and -S(O)3R42; and Q124 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R41 is as defined for Formula lg.

In one embodiment ofthe methods provided herein, in compounds of Formula Hm, A13 is —CH2— or -C(O)—, preferably —CH2—; Q1 is aryl or heteroaryl, wherein aryl or alyl are optionally substituted with one or more substituents selected from the group consisting of —OR‘“, SR“, -S(0)R‘“, -S(O)3R‘“, —NHR4‘, -NR‘”R“, -NR39C(O)R“, O)2R4‘, halogen, lower alkyl, cycloalkyl, eycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents sclccted from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, monos alkylamino, di—alkylamino, cycloalkyl, heteroeycloalkyl, alyl, and l‘leteroaryl, wherein cycloalkyl, heteroeyeloalkyli aryl, and lietemasyl as a substituent ot‘Q m, or as a substituent of lower alkyl are optionally substituted with one or more substituents seieeted from the group consisting of «OH, -NHgi ~CN, N02, «5(0)»! H2, -C(O)NH3, 4:311“, -SR“, —NHR"‘E -Natzati megawatt, (0)2R‘3, -S(O)2R“i halogen, lower alkyl, fluoro substituted lower alkyl, and lkylamino; Q‘ ‘5 is hydrogen, -CN, ~OR‘", ~SR“, —S(O)R‘”, -S(O)2R“? NHR“, -NR“R‘“, «NR39C(O)R“, «NRSQS(O)2R“, , chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally tuted with one or more substituents selected fiem the group ting ot‘haiogen. lower aikyl, fluoro substituted lower alkyl? “NHR‘”, -NR‘”R‘“, and -OR‘”; M15 is a bond, , --,s —o—, —NR39CH2—, -NR39CH2CH3—, _NR3”CH(R“)-, -SCH2-, ocnr, -C(O)NR39—, —S(O)2NR39-, —CH2NR39-, -CH(R‘°)NR39-, -NR39C(O)-, or (O)2-; and Q124 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —NR44R44, -OR44, or SR“, wherein R39, R40, R“, R42 and R4“1 are as defined for Formula II.

In one embodiment of the s provided herein, in compounds of a llm, AB is -CH3~; Q1” is aryl or heteroaryi, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q115 is hydrogen, -CN, l'luoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M15 is -NR39CH3-, -NR39CH2CH2-, or -NR39CH(R4°)-; and Q‘24 is hydrogen, , chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro tuted lower alkoxy.

In one embodiment, further to any of the embodiments ofthe methods provided herein, in a Hm above, each occurrence of R“ is R42 as defined for Formula lg.

In one embodiment of the s provided , a compound of Formula II has a structure according to the following neric structure, Formula IIn, 0132 A1‘12\)\N/ Formula IIn, all salts, prodrugs, tautomers, and isomers thereof, wherein: A14 is selected from the group consisting of —CR]9R20-, —C(O)-, -C(S)—, —S-, —S(O)-, -S(O)2-, —NR2]-, and -O—; Q125 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, ally substituted heterearyl, ~OH, WNHE, N03,, -CN, ‘NHC(O)NIlg, S)NH3, «NHS(O)2NH3, ~C(O)NH2, —C(S)NH2, wsagging, *Nnitnii -NHR23, “one“, SR12»C(O)R33; —C(S)R23, -S(o)R3i «50331123, -C(O)NHR23, —C(O)NRZ3R23, —C(S)NHR”, -C(S)NR23R33, -S(0)2NHR33, —S(O)2NR23R23, -NHC(O)R23, —NR33C(O)R23, -NHC(S)R23, -NR33C(S)R33, -NHS(O)2R23, -NR”S(O);R23, —NHC(O)NHR23, ~NR33C(O)NH2, snnficcownnfl, —NIIC(O)NR33R”, -'NR230(0)NRZ3R23, -NHC(5)NHRZ{ -NRZ3C(S)NH2, WNR23CCSJNHRE3, —NHC(san33R33, wNR23C(S)NR23R23, O);NIIR33, -NR23S(O)2NH2, —NR3-‘S(0)2NHR33, eNHS(O)3NRZ‘lR”, and —NR235(0)2NR”R33; M16, Q12], and Q132 are as defined for Formula II; and R”, R20, R21, R23, R24, and R25 are as defined for Formula lb.

In one embodiment ofthe methods provided herein, in nds of Formula Iln, M16 is —(CR‘9R2°)t—NR26-(CR’9R20)5~ or R20),«NR36C(0)—(CR‘9180),, preferably —NR26—(CR19R20),— or —NR26C(O)-(CR19R20)S-, more preferably —NR39CR80R30- or CR80R30)2—, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A14 is -CR‘9R2°— or , preferably —CH2- or —C(O)-.

In one embodiment, Q121 is optionally substituted lower alkyl, aryl or heteroaryl, n alyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NR23R23, —OR23 and R23 and Qllj is en, —OR23, —CN, fluoro, , lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heteroeyeloalkyl, aryl or heteroaryl, wherein cyeloalkyl, heteroeyeloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro tuted lower alkyl, —NHR23, —\IR23R13, —OR23 and —S O)2R23. r to any ofthe above embodiments, Q132 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment ofthe methods provided herein, in compounds of Formula IIn, M”, is R2°)t-NR26—(CR’9R20),— or -(CR‘9R20),—NR26C(O)—(CR‘9R20)5-, preferably -NR26—(CR’9R20),— or —NR26C(O)—(CR'9R20),—, more preferably -NR39CR8°RSO— or CR80R30)2—, and A14 is —CRI9R2°— or -C(O)—, preferably —CH2- or -C(O)-. In one embodiment, M16 is —(CR‘QRZO),—NR26—(CR‘9R2°),— or -(CRl9R20)t-NR26C(O)-(CR‘9R20),—, preferably —NR25-(CR‘9R20)S— or —NR36C(O)—(CR‘9R20 more preferably ~NR39CR80R3°« or -NR39(CR8°R80)2—; A14 is —CR”R2"— or —C(O)-, preferably —CH2— or —C(O)-', Q121 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NRZIR23, eORB and »S(O)2R13; and C2125 is hydrogen, ORB, CN fluoro, ehloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heteroeyeloalkyl, aryl or heteroaryl, wherein eycioalkyi, heteroeyeloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -N HRZS, -NRBR23, —OR23 and —S(O)2R23. In one embodiment, M16 is {CR}QRZOL—NRZé-(CRWRZO); or -(CRI9R20)t-NR26C(O)-(CR‘9R2”),~, preferably (CR‘9R7‘°),» or «NR35C(O)~(CR‘9R2°)S-, more preferably ~NR39CR¥UR80— or aNR39(CR8°RgQ)g—; A14 is —CR”R3‘¥“- or —C(O)—, preferably ~CH2- or ~C(O)e; Qm is optionally substituted lower alkyli aryl or heteroaryl, n aryl or heteroalyl are optionally tuted with one or more substituents selected from the group ting of halogen, lower alkyl, fluoro tuted lower alkyl, Allan”, -NR23R23, DR” and some; Q‘25 is hydrogen, -OR33, ~CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or aryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, -NR23R23, -OR23 and -S(O)3R23; and Q132 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of the methods provided herein, in compounds of Formula Iln, M16 is -NR39CH2- or -NR39-(CH2)2-; A14 is -CH2- or —C(O)-, ably -CH2-; Qm is optionally substituted lower alkyl, aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro tuted lower alkyl, , -NR42R42, -OR42 and —S(O)2R42; Q225 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro tuted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR4I, —NR'“R'H, —OR41 and -S(O)3R4I; and Q132 is hydrogen, fluoro, chloro, lower alkyl or lluoro substituted lower alkyl, wherein R“ is as defined for Formula lg.

In one embodiment ofthe methods ed herein, in compounds of Formula Iln, A14 is -CIIg- or -C(O)-, preferably -CH2-; Q121 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of ~OR‘“, —SR4’, -S(0)R“, -S(O)2R“, -NHR‘”, —NR4’R4‘, -NR39C(O)R’“, -NR398(O)2R‘“, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and aryl, 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 tuted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, 'otryla and heteroaryl as a substitucnt of Qm, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, Bung, -CN, N02, ;NH2, ~C(C))NH2, on”, SR”, Nun”, ~NR42RQ, Numeromtz, -NR395(O)3R4Z, —S(O)2R42, halogen, lower alkyl, fluoro tuted lower alkyl, and lkylamino; Q225 is en, cm on", -SR‘”, -S(0)R“”, ~S(O)2R“, ~NHR‘”, -NR‘”R‘”, -NR39C(O)R“, -NR3QS(O)2R“, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or aryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR“, serum“, and “on“; Mm is a bond, we“, s, «on ”Nrawcuge NRE‘tchnze NRWCIICR‘W)», sorry, bony, —C(0)NR”-, —S(O)2NR39—, —CH2NR39—, -CH(R”)NR3"-, -NR39C(O)—, or -NR”S(O)3—; and Q132 is hydrogen, tluoro, chloro, lower alkyl, fluoro tuted lower alkyl, —NR44R“, ~OR44, or SR“, wherein R39, R40, R“, R!12 and RM are as defined for Formula II.

In one embodiment ofthe methods provided herein, in compounds of Formula Iln, AM is 'CHg—; Qm is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q125 is hydrogen, vCN, fluoro, , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro tuted lower alkoxy; M16 is -NR39CH2-, H2CH2—, or —NR39CH(R40)-; and Q132 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments of the methods ed herein, in Formula [In above, each occurrence of R41 is R42 as defined for Formula lg.

In one embodiment ofthe methods provided herein, a compound of Formula II has a structure according to the following neric structure, Formula 110, 0135 \\M17“Ql:31 m0144 N/ N a 110, all salts, prodrugs, ers, and isomers thereof, wherein: A15 is selected from the group consisting of —CR‘9R20—, -C(O)-, —C(S)—, —S-, -S(O)—, —S(O)2—, -NR2]-, and -O-; Q135 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally tuted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, ally substituted heteroaryl, —OH, —Nl-Ig, -’NO;, —CN, -NHC(O)NH2, -NHC(S)NH3, -NHS(O)3NH2, «C(O)NH:, ‘C(S)NH2, gNH2, »NR24R25, «NHRB, 4312*, SR“, 3mm”: -C(S)R23, »S(O)R33, “3(0),,183, -C(o)NHR31 R23R23, crswufi. _C(S)NR23RB, *S(O)2NHR23, —S(O)3NR23R33, dNHCt’OjRB, —NR33C(O)R33, NHC(S)R23, »NR23C(S)R33, ~NHS(O)2R23, «NRESS(O)2R23, «NHC(O)NHR23, —NR23C(O)NH2, -NR23C(O)NHR23, -NHC(0)NR“RZ’, -NR33C(O)NR23R23, —NHC(S)NHR33, —NR23C(S)NH2, ~NR23C(S)NHR23, ~N’HC(S)NR23R23, —NR33C(S)NRZ*R31 );NHRZ3, -NR23$(O)2NH3, -NR233(O)3NHR23, “NHS(O);NR23R33, and ~NR33$(D)2NR13R33; Mn, Qm, and QW are as defined for Formula II; and R”, R20, RN, R23, R24, and R25 are as defined for Formula lb.

In one embodiment ofthe methods provided herein, in compounds ot‘Formula Ho, Mia is -(CR‘9R20),—NR2°-(CR‘9R20),— or {CR‘9R2‘)),-NRZ"C(O)«(CR‘9R2“),-, ably (CR'9R20),— or —NR360(0)-(CR’9R20)s-, more preferably -NR39CR8°RSO- or -NR39(CR8°R8°)2-, wherein R3” is hydrogen or lower alkyl and R30 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A15 is -CR19R20- or -C(O)-, ably -CH3- or -C(O)-.

In one embodiment, Qm is optionally substituted lower alkyl, aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23 and Q135 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein eycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, —NR23R23, ~OR23 and —S(O)2R23. Further to any ofthe above embodiments, Q44 is en, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment of the methods provided herein, in compounds of Formula 110, Mn is -(CR‘91120),—lxll{26—(CR19R20)s- or {CR}9R20)t-NR26C(O)-(CR‘9R20)S-, preferably —NR26-(CR‘9R20),- or -NR26C(O)-(CR‘9R2O),-, more preferably -NR39CR80R8°-, -NR39(CRB°RBO)2-, and A15 is -CR‘9R2°- or -C(O)-, ably -CH2- or -C(O)-. In one embodiment, M17 is —(CR‘9R30),-NR26-(CR‘9R20)5- or R20),-NR26C(0)—(CR‘9R2“),—, preferably -NR26-(CR‘9R20)5- or -NR2“C(O)—(CR‘9R20),—, more preferably -NR39CRSOR8°-, -NR39(CR8°R80)z-; A15 is —CR“’RZO- or -C(O)-, preferably -CH2- or ; Q131 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -N HRZJ, -NR23R23, -OR23 and -S(O)2R23; and Q135 is hydrogen, —OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lkyl, eyeloalkyl, aryl or heteroaryl, wherein lkyl, heteroeycloalkyl, aryi or heteroaryl are optionaliy substituted with one or more substituents selected from the group consisting of halogen? lower alkyl, fiuoro substituted lower alkyl, wNH'REi «NRERB, coal" and -S(O)2R23. in one embodiment, Mp; is -(CR‘twat-NRMCR”1130),- or ~(CR‘9R2{3)t~NR36C(C))~(CR}nglsa, preferabiy eNRM-(CKWRZOL— or -NR26C(O)-(CR”R20),-, more preferably R8"RSD-, —NR\‘9(CRXOR3°)2-; A15 is -CR‘9RZU- or ~C(O)-, preferably ~CH3- or —C(O)-; Q131 is optionally tuted lower alkyl, aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fiuoro substituted lower alkylt «NHRZS, ~NR23R23, «OR23 and R23, Q£35 is hydrogen, {IRE}? eCN, fluoro, chioro, iower alkyl, fluoro substituted lower alkyl, cycloalkyl, cycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR33, —NR23R23, —OR23 and —S(O)2R23; and QM4 is hydrogen, fluoro, , lower alkyl, or fluoro substituted lower alkyl.

In one embodiment ofthe methods provided herein, in compounds of Formula 110, M17. is —NR39CH2— or -NR39—(CH2)2-; A15 is -CH2— or —C(O)~, preferably -CH2—; Q81 is aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR42, ~NR42R42, —OR42 and -S(O)2R42; Q'35 is hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, n cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR4], -NR‘”R4', —OR‘“ and —S(O)2R‘”; and Q144 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R41 is as defined for Formula lg.

In one embodiment ofthe methods provided herein, in compounds of a Ho, A15 is -CH3— or , preferably —CHz—; Q‘31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR“, .512“, -S(O)R‘“, -S(O)2R“, -NHR“, -NR‘“R‘“, ~NR39C(O)R‘“, —NR398(O)2R4‘, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally tuted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower , lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, cycloalkyl, aryl, and heteroaryl as a substituent of Q“, or as a substituent oflower alkyl are optionally substituted with one or more substituents selected from the group consisting of OH, —NH2, CN -Nog, —S(O)2NH2, ~C(O)NH2, -OR“, -512“, NHR“, —NR”R‘“, -NR39C(O)R42, —NRBQS(O);R42, R42, halogen, lower alkyl, fluoro substituted lower alkyl, and eyeloalkylamino; QE35 is hydrogen, -C.N, on“, on“, “, sang“, *NHR“, -NR“R4‘, uNR‘igC(O)RAE, aNRfiSijOkR“, fluoro? chioro, lower alkyl, fluoro substituted lower alkyl, aryi or aryl, wherein aryl or aryl are optionally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, , —NR‘”R“, and —OR’“; M15 is a bond, -NR39-, —s—, -o—, —NR39CHg—, —NR39CH2CH2—, —NR”CII(R4°)—, sorry, Deny, -C(C))NR39‘, —S(0)2NR‘”-, 39-, -CH(R‘”)NR39—, _NR39C(0)-, or CNR3QS(O)2~; and QM is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, ~NRMR“, OR“, or -SR“, wherein R39, R“: R“, R42 and R“ are as defined ror Formula IL In one embodiment ofthe methods provided herein, in compounds of Formula 110, A15 is -CH2-; Qm is aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more tuents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q 115‘is hydrogen, ~CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M.5 is ~NR“9CH2-, -NR3°CH2CH2-, or —NR39CH(R“0)—; and 0““ is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments 0fthe methods provided herein, in Formula IIo above, each occurrence of R41 is R!12 as defined for Formula lg.

In one embodiment of the methods provided herein, a compound of Formula II has a structure according to the following sub-generic structure, Formula IIp, Q152 A15 bN 0145 SxMw'Qm m\\ N Formula IIp, all salts, prodrugs, tautomers, and isomers thereof, wherein: A16 is selected from the group consisting 0f—CR19R20-, -C(O)-, -C(S)-, ~S-, —S(O)-, -S(O)3—, , and -O—; Q145 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aryl, -OH, -NH3, -N03, -CN, ~NHC(O)NH;, - NHC(S)NHZ, -NHS(O);NH2, -C(O)NH2, -C(S)NH2, -S(O)3NH2, 44112411”, -NHR23, -011”, -3183, —C(O)R23, {(5)113 mom”, R2:‘, -C(O)NHRZ3, -C(O)NR23R”, -C(S)NHR23, -C(S)NRBR23, NHR23, —S(O)2NR23R23, —NHC(O)R23, ~NR23C(O)R23, a NHC(S)R?3, ~NR23C(S)R23, ~NHS(O)2R23, (0)2R21 -NHC(O)NHR33, rown; a R23C(O)N‘IIR33, -Nuorowaeazi ~NRZ3C(O)NR23R33, ~NHC(S)NHR23, *NR23C(S)NHZ, v-NRBQSWHRB, —NHC(5)NR23R33, -NRZ3C(S)NR23R2{ )3NHR§3, nNRz‘S(O)2NH2, -NR33S(o)zNHR23, izNR33R33, and (O)2NR33R23; M18, Q14], and Q“72 are as defined for Formula II; and R”, R20, R2], R23, R24, and R25 are as defined for Formula lb, in certain embodiments of the s provided herein, the compound is not O (‘N >~N ] \ SXNAQH p C: r\ \ /S/\\\N/\©\H or / ' N N x N N or H In one embodiment oFthe methods provided herein, in compounds of Formula llp, M18 is —(CR‘9R2”)i—NR26~(CR‘9RZO)S— or -(CR'ORZOL-NR26C(O)-(CR‘9R20)S-, preferably -NR26-(CR'9R30)5— or -NR26C(0)-(CR‘9R2°),-, more ably -NR39CR80R80— or —NR39(CR8°R80)2-, wherein R39 is hydrogen or lower alkyl and RS0 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one ment, A16 is —CR19R20- or -C(O)-, preferably -CI~I2- or -C(O)-.

In one embodiment, Q”! is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting ofhalogcn, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23RZ3, -OR23 and -S(O)2R23 and QMS is hydrogen, —OR23, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl3 n cycloaikyl, heterocyeloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NllR23, Z3, -OR23 and -S O)2R23. Further to any ofthe above embodiments, Q]52 is hydrogen, fluoro, chloro, lower alk or fluoro substituted lower alkyl, In one embodiment ofthe methods provided herein, in compounds of Formula Hp, M13 is -(CR'9R20)t-NR36-(CR'QRZOL- or R2”),-NR26C(O)-(CR'9R2”)S—, preferably (CR‘9R20)S- or —NR“C(0)—(CR‘9RZO)S-, more preferably -NR39CR8”R8°— or -NR39(CRR°R8”)2-, and A,6 is ~ or —C(O)—, preferably ~CH2- or -C(O)~. In one embodiment, Mix is -(CR‘9R2”)r-NR2"-(CR”R3°)S— or -(CR‘9R20)t-NR26C(O)—(CR‘9R20)§—, preferably -NR2"’-(CR‘9R2“)S» or -NR26C(O)-(CR'9R20)S-, more ably -NR39CR8"R"“- or -NR3"(CR"”R"°)2-; A,6 is 20— or -C(O)-, preferably -CH3- or -C(O)-; QM is optionally substituted lower alkyl, aryl or aryl, wherein aryl or heteroaryl are ally tuted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, «NI-IR”? »NR23R23 ~OR23 and eS(O)3R23; and Q345 is hydrogen, ~0R23, JEN, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, cycloalkyli heterocycloaikyl, aryi or heteroaryl, wherein eycioaikyi, lieterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -;\lHR23, -NR23R33, on” and -S(O)2R23. In one embodiment, M18 is -(CR‘QRZOi—anércw9R30)5- br- ~(CR‘"R2”)l—NR2‘5C(O)~(CR‘ng)S-, preferably (CRE9RZG); or ~NR26C(O)—(CRI9RZO);, more preferably «NR39CRSGR30- or —NR39(CR80R39)3«; As is ~CR‘9R251 or -cro}, preferably ~CH2» or -C(O)-; QW is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionaliy tuted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, *NRBRB, -OR23 and AS(O)2R23; Ql‘15 is hydrogen, —OR23, -CN, fluoro, chioro, lower alkyi, fluoro substituted lower aikyl, lkyl, heteroeycioalkyl, aryl or heteroaryl, whcrcin cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR23, ~NR23R23, -OR23 and -S(O)2R23; and Q152 is hydrogen, , chloro, lowcr alkyl, or fluoro substituted lower alkyl.

In one embodiment of the methods provided herein, in compounds of Formula IIp, M13 is H2- or -NR39-(CH2)2-; A16 is -CH2— or , preferably -CH2-; QMl is aryl or heteroaryl, wherein aryl or hctcroaryl are ally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NHR41, ~NR41R“, -OR‘” and —S(O)2R‘“; QMj is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lowcr alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, n cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR4], -NR‘”R41, -OR‘” and -S(O)3R4l; and Q”2 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R41 is as defined for Formula lg.

In one embodiment ofthe methods provided herein, in compounds of Formula IIp, A16 is -CHg- or —C(O)-, preferably -CH3-; Q141 is aryl or heteroaryl, n aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of -OR4], -SR‘“, -S(O)R‘”, -S(O)2R“, -NHR“, -NR‘”R‘”, -NR39C(0)R“, -NR393(O)2R’“, halogens, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with onc 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-aikylamino, cycloalkyl, cyeloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q14], or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of—OII, aNHg, .«:N, No NH3, ~C(Q)NH2, on“: sat”, ~NHRfl, :NRHR‘Q, “Nawcromfl, vNR39$(O)gR42, —S(O)2R42, haiogen, lower alkyi, fiuoro substituted lower alkyl, and cycloalkylamino; QMS is hydrogen, -CN, -011“, sa“, “, stow“, -NHR“, —NR4‘R“, -NRWC(O)R‘”, -NR3QS(O)2R“, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents ed from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, »NR“R“, and DR“; Mtg is a bond, ‘NR393 43,) -o‘, EM, -NRWCHECHZN, weafi‘crttiei’y, -scug—, -OCH3-, -C(0)NR39-, -S(0),NR3"-, 39-, —CH(R40)NR”—, —NR3“‘C(0)—, or -NR3QS(O)3-; and Q152 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR“R44, OR“, or «SRM, wherein R39, R40, R“, R42 and R“ are as defined for a II.

In one embodiment of the methods provided herein, in compounds of a llp, A16 is -CH2'; Qm is aryl or heteroaryl, wherein aryl or heteroaryl are optionally tuted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, tluoro substituted lower alkyl, lower alkoxy, and lluoro substituted lower alkoxy; Q"15 is hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M18 is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R40)—; and Q152 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower .

In one embodiment, further to any of the embodiments of the methods provided herein, in Formula Ilp above, each occurrence of R'“ is R42 as defined for a lg. ln one embodiment of the methods provided herein, in compounds of Formula Hp, M13 is -NH-CH2- or —NH-(CH2)2-, preferably r; A16 is -CH2- or -C(O)-, preferably -C‘H2-; Q'“ is aryl or heteroaryl, wherein aryl or aryl are optionally substituted with l or 2 substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, and heterocycloalkyl; Qm is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, -CN, or chloro; and QI52 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen or , more ably chloro.

In one embodiment of the methods provided herein, the compound of a Ih is selected from the group consisting of [4—Chloro(l H-pyrrolo[2,3-b]pyridinylmethyl)-thiazolyl]-(4-fluoro-benzyl)-amine (P-0156), [4-Ethyl-5—(lH-pyrrolo[2,3—b]pyridin-3—ylmethyl)—thiazol-2—yl]-(4-fluoro-benzyl)—amine (P-0162), oro~benzyl)—[4~methyI( l Hapyrrolo[2,3—b]pyridin-3 ~ylmethyl)~thiazol—2—yl]~amine (P-0163), [4-Chloro—5—t' l Hepryrrolo[2,3—b]pyridim3~y§methyl)«thiazoloZ-yl]~pyridin~3 ~ylmethyl~amine (P~0164), [4-Chloro—5—(1lI-pyrrolo[2,3-b]pyridin-3~ylmetliyl)-thiazolyl]-pyridinv2-ylmethyl-amine (P—0167), [4-Chloro-5—( l H-pyrrolo[2,3-b]pyrid inylmethyl)-thiazol~2-yl]-pyridin—4—ylmethyl-amine (P~0168), [4—Chloro»5~( l H~pyrrolo[2,t3~b]pyridin-3~ylmethyl)«thiazol~2-yl]-(6~methyl—pyridiii—Z—ylmethyl)— amine (P-0171); [4-Chlor0~5-(1H-pyrroloLZJ~b]pyridiny]methyl)—thiazolyl]—(1,S-dimethyHH-pyrazol yimethyl)«amine (P-017‘2), [Kl-Chloro-S‘UH-pyrrolo[2,3-b]pyridinyImethy1)-thiazo1y1]-(6-trifluoromethpryridin-B- yI)—amine (P—0173), [4~Chlor0—5-(1H-pyrro10[2$3-b]pyridin-3«ylmethyl)-thiazo1—2—yl]-(2,5-dimethyl-2lI-pyrazoI-S— ylmelhyl)-amine(P-0175), [2-(4-Fluoro-benzylamino)-thiazol~5~yl]-( ] H-py11‘010[2:3-b]pyridin-3~yl)-meth anone (P-0177), {2»[(4~Chlor0=benzyl)-methyl—amino]—thiazol-S-yl}-(1H—pyrrolo[2,3-bjpyridin-3 -yl)~methanone (P-0178), [4-Chloro-5 10r0-1 H-pyrr010[2:3-b]pyridinylmethyl)-thiazol-Z-yl]-thiazolylmethyl- amine (P-0189), [4-Ch10r0-5—(5-ch]0r0- 1 H-pyrrolo[2,3-b] n-3 -ylmethy1)-thiazol-Z—yl]-(6—meth0xy-pyridin-3 - ylmethyl)-amine (P-0190), Benzyl-[4-chlor0(5-chlor0—1H-pyrr010[2,3-b]pyridin—3 -ylmethyl)-thiazolyl]—amine (P-0192), [4—Chlor0(5—chlor0- I olo[2,3 -b]pyridin-3 -ylmethyl)-thiazol-Z-yl]—(3 -mcthoxy-benzyl)- amine (P-0193), (4-Chloro-benzyl)-lV4-chlor0-5—(5-chlor0—l H-pyrr010[:2,3-b]pyridin-3 -ylmethy1)-thiazol-Z-yl]- amine (P-0194), [4-Chlor0(5-ch10r0-1H-pyrrolo[2,3-b]pyridin-3 -y1methyl)-thiazol-Z-yl]-(4-fluoro-benzyl)- amine (P-0195), [’4-Ch10r0(5-ch10r0-1 H-pyrro10[2,3-b]pyridiny1methyl)-thiazol-Z-yl]~(2,4-dimethyl-thiazol ylmethyl)-amine 6), [4-Chlor0-S~(5~chlor0—1H-pyrrolo[2,3-b]pyridinylmethyl)—lhiazo1yl]-(2-ethyl—5-methyl-3 H- imidazolylmethyl)-amine (P—0197), [4-Ch101‘0(5-ch10r0-1 H-pyrr010[2,3~b]pyridin—3 -ylmethyl)-thiazol—Z-yl]-(2-ethyl~2H-pyrazol ylmethyl)—amine (P201818), [4-Ch10r0(5—chi0r0-1 H—pyrr010[2,3 «bprridin-i’y -ylmethyl)~thiazol—2-yl]-(6-methoxy-pyridin-E- ylmethyl)~amine (P-0199)e [4‘ChI01‘0-5=(5ach30m~E H~pyrr0i0[2,3»b3pyridin«3 «ylmethyD‘th£2120i==2~yl]«(3wfiuor0‘pyridin»4_ ylmethyl)’aminc (PaOZUO), [4~Ch10r0—5-(5-chloro~ 1 olo[2?3—b]pyridin—3 «ylmethyIJ—thiazoI—2~yl]~(2-methyl-thiazoI—4v ylmelhyI)-amine (P-0201), [4’Ch10ro(5—chlor0-lH-pyrroIo[2,3~b]pyridin~3‘yhncthy1)~thiazol-E—yi]~(4-methyl—thiazo1—5- ylmethyI)—amine (P—0202), [4-Chi0re-5—(5-shloro- i H~pyrr0§0§233wb]pyridin13«yimethyi)~thiaz01w2—yi]w(5 »ch10mwpyridin~2~ yimethyl)-amine (P-0203), [4-ChiOI‘O-5 -( I H-pyrrolo[2,3-b]pyridin—3 —ylmethyl)-thiazolyl]-(2,4-dimethyl-thiazoI-S— ylmelhyl)-amine (P-0204), [4«Ch10r0-5 ‘(1 I‘I-pyrr010[2,3-b]pyridinylmethyl)-1hiazolyi]-(2-ethylmethyi-3H-imidazol- 4-ylmethy1)-amine (P—0205), [4-Clilor0(l H-pyrrolo[2,3—b]pyridinylmethyl)-thiazolyl]-(5-fluoro-pyridin-2«ylmethyl)- amine (P-0206), [4-Chloro—5-( 1 H-pyrrolo[2,3 -b]pyridin-3 -ylmethyl)-thiazolyl]-(5~methoxy-pyridin-3 -ylmethyl)- amine (P-0207), oro( l H-pyrr010[2,3 -b] pyridin-3 -ylmethyl)-thiazolyl]-(4,5-dimethyl—thiophen-Z— ylmetliyl)-an1ine (P-0208), or0(l H-pyrrolo[2,3 -b]pyridin-3 -ylmethyD—thiazol-Z-yl]-(2,5-d imethyl-thiophen-3 - yl)-amine (P-0209), [4—Chloro-5 -(5-chloro- l H-pyrrolo[2,3-b]pyridin-3 -ylmethyI)-1hiazolyl]-(5-fluoro-pyridin-3 - ylmethyD-amine (P-0231), 10r0(5-chlor0-l H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-thiazolyl]-pyridin—3 -ylmcthy!- amine (P-0236), [4-Chlor0(5-chloro-l H—pyrrolo[2,3—b]pyridin-3 -ylmethyl)-thiazolyl]-pyridinylmelhyl- amine (P-0237), [4-Chlor0(5 -chlor0-I H-pyrr010[2,3-b]pyridin-3 hyl)-thiazolyl]-(3 -chloro-pyridin ylmethyl)—amine (P-0238), [4-Ch10ro(5-chloro-1H-pyrrolo[2,3 -b]pyridin—3 -ylmethyl)-thiazol~2-yl]—(1-cthyl- lH-pyrazol ylmethyl)-amine (P-0239), oro—5—(5-Chloro—l H~pyrrolo[2,3 -b] pyrid inylmethyl)-thiazol-Z-yl]-(5-fluoro-pyrid in ylmethyi)-amine (P-0240), [4-Cliloro(5-chlor0-1H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-thiaZOlyl]-(5-methoxy—pyridin-3 - ylmcthyl)-amine (P-0241), [4—Cliloro(5-clilor0-I H-pyrrolo[2,3—b]pyridin—3 hyl)-thia20I—2-yi]~(6-trifluoromelhyl- pyridin-3~yImethyI)~amine (P~0242)f {4‘Chlom»5~{5~chloro‘ l H~pyrroio[2:3‘bjpyridiné‘:uyimethyl)—thiazeE~2-yi]a(2~chlem-6~fiuor0~ benzyl)—amine (13—0243), [4-Chior0-5—(5—chior0-I H-pyrroi0[293-b]pyridinw3 »yimethyl)»thiazolx’l—ylyphcnethyl-amine (R0244), [4-Chior0(5-chlor0-1 H-pyrrolo[2,3-b]pyridin—3 hyl)-thiazoI-2~yl]-(2,4adiflu0r0—benzyl)- amine (P—0245)3 [4»Chlom»5~(5‘ch inm— l Hapyrmlof233JD]pyridinyimethythEamiaZ-yILQfiuom-benzyi} amine (P-0246), [4-Chloro—5—(5—chloro- l H—pyrrolo[2,3—b]pyridin—3 -ylmethyl)-thiazol~2-yl]-(2—meth0xy-pyridin—3- ylmethyl)—amine (P412471, (2-Chloro—benzyl)-[4—chloro~5—(5—chloro— l H—pyrrolo[2,3—b]pyridin—3-ylmethyl)—thiazol—2—yl]— amine (P—0248), [4~Chlor0-5—(5—chloro-1H~pyrrolo[2,3—b]pyridin—3—ylmethyl)—thiazol—2—yl]-(2—methyl~benzyl)* amine (P—0249), [4—Chloro—5—(5—chloro—lII-pyrrolo[233—b]pyridin—3 —ylmethyl)-thiazol—2—yl]—(2-chlorofluor0— benq’lyamine (F0250), [4—Chloro-5—(5—chloro—lH—pyrrolo[2,3-b]pyridin-3—ylmethyl)-thiazol-2—yl]-(3-fluoro—pyridin—2— ylmethyl)—amine (P-0251), [4-Chloro—5—(5—chloro—1H—pyrrolo[2,3—b]pyridin—3—ylmethyl)-thiazol—2—yl]~(6—morpholin—4—yl— pyridin-Z—ylmethyl)-amine (P-0252), [4—Chloro—5—(5—chloro—l H—pyrrolo[2,3—b]pyridin-3—ylmethyl)—thiazol—2—yl]—(3,5—dichloro—pyridin—4— ylmethyl)—amine (P—0253), oro—5 —(5 o—l olo[2,3-b]pyridin-3 -ylmethyl)—thiazo1-2.—yl]—(2—trifluoromethyl— benzyl)—amine (P-0254), [4—Chloro—5-(5—chlorO—l H—pyrrolo[2,3—b]pyridin—3-ylmethyl)—thiazol—2-yl]—(6—methyl—pyridin—2— ylmethyl)—amine (P-0255) and [5-(5—Chlor0—l H—pyrrolo[2,3—b] pyridin—3 —ylmethyl)—thiazol—2—yl]—(4-fluoro—benzyl)-amine (P—0290), or all salts, prodrugs, tautomers, or isomers thereof.

In one embodiment ofthe methods ed herein, a compound of Formula I has a structure according to the following sub—generic structure, Formula III, / H .1 ”x \ N R83 l \ R52 N N Formula [I], all saltsi gs, tautomers, or isomers thereof; L4 is -CH;-, -CH2CH2-g -CH(R“°)-_, -C(0)-g or —C(O)NH-; R8I is selected from the group consisting of hydrogen, “OR“, ~CN§ fluoro, chloro, lower alkylg fluom substituted lower alkyl, cycloalkyl, heterocycloalkylg aryl and hetemaiyl, wherein cycloalkyl, heterocycloaikyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, ~NHR‘“§ »NR“R“, -0R“ and -S(O)2R“; R82 is selected from the group consisting of hydrogen, CH alkyl, fluoro substituted Cg_3alkyl, OH, CH alkoxy, and fluoro tuted CL; ; R83 is cyeloalkyl, heteroaryl, or R92 . . ‘3— indicates the attachment. . in which point of R83 to L; of Formula II], wherein heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR“, -NR“R“, ~OR4’ and -S(0)2R‘“; R92, R93, R94, R95, and R96 are independently selected from the group ting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, ~NHS(O)3R“, —NHC(O)R“K —NHR“, —NR“R4’, on“ and —S(O)2R“; and R40 and R“ are as defined for Formula lg.

In certain embodiments of'the methods provided herein, the compound is not In one embodiment ofthe methods provided herein, in compounds ofFormula Ill, L4 is -CH2-, -CH2CH2-, 3)— or -C(O)—, R81 is hydrogen, fiuoro, chloro, —CN, lower alkyl, fiuoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower , R32 is hydrogen, R83 is R92 , wherein R9"), R93, R94, R95, and R96 are independently hydrogen, fluoro, chloro, lower alkyl, fiuoro substituted lower alkyl, lower alkoxy, or fluoro tuted lower alkoxy, provided, however, that when R94 is fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fiuoro substituted lower alkoxy, at least one of R92, R93, R95, and R96 is fluoro, ehloro, Eower alkyl, lluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower aikcxy; In one embodiment ofthe methods provided herein, in compounds ofFormula Ill, L4 is —CH;-, -CH2CHg-, —CH(CH3)- or , R“ is hydrogen, fiuoro, chloro, —CN, methyl, or methoxy, 3 1 R93 preferably hydrogen, chloro, ~CN, or methyl, R8“ is en, RS“ . 7 R92 wherein R9“, R”, R94, R95, and R96 are independently hydrogen, fluoro, chloro, methyl, ethyl, romethyl, methoxy, ethoxy, difluoromelhoxy or trifluoromethoxy, preferably hydrogen, chloro, methyl, trifluoromcthyl, methoxy, ethoxy, or oromethoxy, provided, however, that when R94 is fluoro, , , ethyl, trifluoromethyl, methoxy. ethoxy, difluoromcthoxy or trifluoromethoxy, at least one of R92, R93, R95, and R96 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In one embodiment ofthe methods provided herein, in compounds ofFormula Ill, L4 is ~CH;-, R8! is fluoro, chloro, -CN, methyl, or methoxy, preferably chloro, ~CN, or methyl, Rs2 is ‘ fi hydrogen, R83 is R92 wherein Rg4 1s hydrogen and Rg‘, R93, R95, and R96 are' independently hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, cthoxy, romethoxy or trifluoromethoxy.

In one embodiment ofthe methods provided herein, in compounds of Formula Ill, L4 is CH2, -Cnlcnm , or -CH(CH3)—, preferably ~CH3- or -C(0)-, R81 is hydrogen, flouro, R82 n R93 is en. R83 is Rg‘ wherein R92 is fluoro, chloro, , ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or oromethoxy, preferably fluoro, chloro, methyl, or trifluoromethyl, and R93, R94, R95, and R96 are independently en, fluoro, chloro, methyl, romethyl, methoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro.

In one embodiment, L4 is £142-, {:03}, or —CH(CH3)-, R’“ is hydrogen, R82 is hydrogen, R92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or triflueromethoxy, ably fluoro, methyl, or trifluoromethyl, and R93, R94, R95, and R95 are hydrogen, In one embodiment, L; is —CH;~, -C(O)-, or »CH(CH;)~*, R3} is hydrogen, R82 is hydrogen, R92 is , chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl, R94, R95, and R96 are hydrogen, and R93 is fluoro, chloro, methyl, ethyl, trifluoromcthyl, methoxy, ethoxy, difluommethoxy, or trifluoromethoxy, preferably fluore, chlore, mmethyl er methoxy, more preferably fluoror In one embodiment, L4 is -CH2-, —C(O)-, or -CH(CH3)-, R“ is hydrogen, R82 is hydrogen, R93 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluorornethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifiuoromethyl, R93, R95, and R96 are hydrogen, and R94 is lluoro, ehloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or tritluoromethoxy, preferably fluoro, chloro, methyl or trifluoromethyl, more preferably fluoro. In one embodiment, L4 is -CH2CHZ— or —C(O)—, R81 is hydrogen, R82 is hydrogen, R92, R95, and R96 are hydrogen, R93 is hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen, fluoro, , methyl, trifluoromethyl, methoxy, or trifluoromcthoxy, more preferably fluoro, chloro, trifluoromethyl or methoxy, and R94 is hydrogen, fluoro, or , provided, r, that when L4 is -C(O)- and R94 is fluoro or ehloro, Ry3 is not hydrogen. In one embodiment, L4 is -CH2CH2-, R81 is hydrogen, RE2 is hydrogen, R92, R94, R95, and R96 are hydrogen, and R93 is hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro. In one embodiment, L4 is —C(O)-, R81 is hydrogen, R82 is en, R92, R95, and R96 are hydrogen, R93 is fluoro, chloro, , ethyl, trifluoroniethyl, rnethoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, ably fluoro, chloro, trifluoromethyl or methoxy, and R94 is hydrogen, fluoro, or chloro.

In one embodiment ofthe methods provided herein, in compounds of Formula III, R83 is pyrrolidine, line, pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazol, or benzimidazole, wherein R83 is optionally substituted with one or more substituents independently selected from the group ting of halogen, lower alkyl, fluoro substituted lower alkyl, cyeloalkylamino, -NHR41, 41, ~OR4] and -S(O)2R4l, preferably wherein R83 is optionally substituted with l or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino, more preferably fluoro, chloro, methyl, oromethyl, methoxy or line.

In one embodiment ofthc methods provided herein, in compounds of a III, L4 is -CH2-, —CH;CH2~, —CH(CH3)- or —C(O)—, preferably -CH2-, -CH2CH3~, or —C(O)-, R“ is hydrogen, , chioro, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, Chlore, methyl or ~CN, R32 is en, and R83 is pyrrelidine, morpholine, pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazole, or benzimidazole, wherein R83 is optionally substituted with I or 2 substituents ndently ed from fiuoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower , fluoro substituted lower , or cycloalkylamino, preferably fluoro, chloro, methyl, trifluoromcthyl, methoxy or morpholine.

In one embodiment of the methods ed herein, in compounds of Fomiula III, L4 is ‘CHZ or —C(O)—. In another embodiment of the methods provided herein, in nds of Formula III, R81 is selected from the group consisting of hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro tuted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy. In yet another embodiment ot‘the methods provided herein, in compounds of Formula III, R82 is hydrogen. In still another embodiment ofthe methods provided herein, in compounds of Formula III, R83 is nitrogen containing aryl, wherein nitrogen ning heteroaryl is ally substituted with one or two substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR‘”, —NR“R“, on“ and stow“. In another embodiment ofthe methods provided herein, in compounds of Formula III, R“ at each occurrence is lower alkyl or lkyl, wherein lower alkyl is optionally substituted with one or more fluoro.

In some embodiments of the methods provided herein, in nds of Formula III, L4 is -CH2 or -C(O)-; R“ is selected from the group consisting of en, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; R32 is hydrogen; R83 is, nitrogen containing heteroaryl, wherein nitrogen containing heteroaryl is optionally substituted with one or two substituents selected from the group ting of halogen, lower alkyl, fluoro substituted lower alkyl, eycloalkylamino, «NHR‘H, -NR“R41, —OR‘11 and R41; and R4] at each occurrence is lower alkyl or cycloalkyl, n lower alkyl is optionally substituted with one or more fluoro.

In one embodiment of the methods provided herein, in compounds of Formula III, the compound is selected from the group consisting of: Pyridin-3 -ylmethyl-[5-(I H—pyrrolo[2,3-b]pyridin—3—ylmethyl)~pyridin—2—yl]—amine (P-0094), (S-Methyl-isoxazolylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridinylmethyl)—pyridin-2—yl]—amine (P-0095), (2—Pyrrolidin— l -yl-ethyl)—[5—(1H—pyrrolo[2,3—b]pyridin—3-ylmethyl)—pyridinyl]—amine 03-0096), [1—(4-Methanesulfonyl-phenyl)-ethyl]—[5-( I H-pyrrolo[2,3-b] pyridin—3—ylmethyl)-pyridinyl]— amine 7), {24Morph0linv4~yl-ethyl)—[5—(I H-pyrroio[2,3~b]pyridin«3~yImethyl)~pyridin~2~yI]—amine (P-0099), 3,4~Dichlorovl\3~[5~{ E 'H»pyrroto[2,3~h]pyridinw3'ylmethyt)»pyridin~2*yl]—henzamidc O), 2*Chloro~4»t‘luoro—N*[5—( I H-pyrrolo[2,3~b]pyridin—3-ylmethyl)—pyridin—Znyl]-benzamide (P-O 101), 2,S-Dimethyl—2H—pyrazole-3—carboxylic acid [5-(1H-pyrroIo[2,3-h]pyridin—3—yImethyl)~pyridin yl]—amide (P-OlOZ), Thiophene-B—carboxylic acid [5-(1H—pyrrolo[2,3~b]pyridin=3=ylmethyl)-pyridin-2~yl]—amide (P~0103), 2-Methoxy~N—[5 —( t HupyrroIo[2,3«b]pyridin~3~ylmethyi)«pyridin-Z—yl]~isonicotinamide (P-0104), N-[5-( 1 H—Pyrrolo[2,3—b]pyridin—3 -y1methyI)—pyridin—2—yl]-isonicotinamide (P-OlOS), Pyrazine—E—carboxylic acid [5—(1H—pyrrolo[2,3—bjpyridin-3—ylmethy1)—pyridi11yl]—amide (P-0106), Pyridinecarb0xylic acid [5-(1 H—pyrrol 0[2,3—b]pyridin—3 —y1methyI)—pyridin—2—yi]—amide (P-0107), 6-MethyI-N—[5—(1H-pyrrolo[2:3—b]pyridir1—3—y1methyl)—pyridin-2—yl]—nicotinamide 8), 4-FIum‘o-34116tl1yI—N—[5 -( 1 H—pyrrolo[2,3—b]pyridin—3 hyI)-pyridin—2—yl]~benzamide (P-0109), -Methyl—pyrazine-Z—carboxylic acid [5 -( 1 H»pyrrolo[2,3~b]pyridin—3 hyl)—pyridin-Z—yI]- amide (P—Ol 10), 3-Chloro-N-[5-(1H—pyrrolo[233-b]pyridiny1methyl)—pyridi11—2-yI]-benzamide (P-01 1 1), 4—Fluoro—N-[5-(1H-pyrroIo[2,3—b]pyridin—3—yImethyl)—pyridin-2—yl]—3—trifluoromethyl-benzamide (P-01 12), N-[5—( 1H—Pyrrolo[2,3 -b]pyridin-3 -ylmethyl)—pyridin—2—yl]-3 —trifluoromethoxy-benzamide (P-01 13), N-[5—(1H—Pyrrolo[2,3—b]pyridin-3—ylmethyI)—pyridin—Z—yl]—3 -trifluoromethyl—benzamide (P—0114), 3—Chloro-4—fluoro—N—[5-(1H-pyrrolo[2,3-b]pyridin—3—ylmelhyl)—pyridin-2—yl]—benzamide (P-Ol 15), 3,4—Difluoro—N—[5—( 1 H—pyrrolo[2,3-b]pyridin-3—ylmethyI)-pyridin—2—y1]—benzamide (P-Ol 16), 2—Chloro—N—[5-(1H-pyrrolo[2,3—b]pyridin-3—y1methyl)—pyridin-2—yl]—benzamide (P-01 l7), ro—Z—methyl-N-[S—( 1H—pyrrolo[2,3—b]pyrid in-3 -ylmethyl)—pyridin—Z—y1]—benzamide (P—Ol 18), Z-Fluoro-N-[5—( 1 H—pyrrolo[2,3—b]pyridin—3—ylmethyi)—pyridin—2-yI]—benzamide (P—01 l9), 3-Metl1oxy—N-[5—(1H-pyrrolo[2,3—b]pyridin—3 -ylmelhyl)-pyridin—2—yl]—benzamide (P-0120), 3-Fluoro«N-[5-(1H-pyrrolo[2,3—b]pyridin—3 ~ylmethyD—pyridin—2—yl]—benzamide (P-0121), 3—MethyI—N—[5—(1H—pyrrolo[2,3—b]pyridin—3—ylmethyl)~pyridinyl]—bcnzamide (P—0122), 2-Ch10r0—N—[5—(1H—pyrr010[2,3—b]pyridin—3-ylmethyI)-pyridin—2-y1]—isonicotinamide (P-0123), ((R)— 1 ~Phenyl-ethyI)-[5-( l H-pyrrolo[2,3—b]pyridin—3 =yImethyl)~pyridin—2—yl]—amine (P-0125), (3 -M0rph01in~4*yi—benzy])-[5-( I H-pyrroio[2,3-b]pyridin-3—ylmethyi)-pyridin»2vy1]—amine (13—0126), [1~(2-Fluero~p§’leny1)xethyIHS—‘fI H-pyrrsio{2?3~b]pyridinw3aylmethy1)3pyridina2~yij~amine (Ii-0127)! [2‘(3~F1u0r0~phenyl)-ethyI]—[5—( I H—pyrrolof2,3—b]pyridin—3 «ylmethyl)~pyridin-2~ylj-amine (P-0128), (3—Chlor0-benzyl)-[5-(1H-pyrroIo[2,3—b]pyridin-3 ~yImethyl)—pyridin—Z'yl]«amine 9), (I~MethyI—1H’imida201—4‘ylmethyl}f5—( 1H-pyrrolo[2,3 ‘idin~3~ylmethy1)—pyridin-2—yl]— amine (P~0130), \O L») (LS-DimethyI-lH-pyrazol-B-ylmfithyl)-[5—(]H-pyrr010[2,3«b]pyridin~3-ylmethyl)-pyridin—2-yl]- amine (P-0131), [5—(5 -Chi0ro«l H-pyrrolo[2,3 -b}pyridin-3 -ylmethyl)—pyridin-2—yl]—(6—trifluoromethyl-pyridin-3 - yhnethyl)—a_mine (P-0181), [5-(1H-Pyrrolo[2,3-b]pyridin~3~yimcthyl)-pyridin-Z-yl]-(6-trifluoromethyl-pyridin~3-ylmethy[)— amine (P-0182), loro~pyridinylmethyl)—[5-(1H-pyrro10[2,3-b]pyridin—3 —ylmethyl)-pyridin-2~yl}amine (P—0183), oro~6-fluoro—benzyl)»f5—( 1 H—pyrrolo{2,3 «b]pyridin~3—ylmethy1)-pyridiny1]—aminc (P—0210), Phcncthyl-[5-(1H-pyrrolo[2,3 -b]pyridin-3 hyl)-pyridinyl]—an1ine (P-0211), (2,4-Difluoro—benzy])-[5-(1H-pyrrolo[2,3-b]pyridin-3—ylmethyl)-pyridinyl'j-aminc (P—0212), (Z-FluorO-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-pyrid inyl]-amine (P—0213), (3-Bromo—pyridinylmethyl)—[5-(1I~{-pyn'olo[2,3-b]pyridin-3 -ylmethyl)-pyridin-Z-yl]-amine (P-0214), (2-Methoxy—pyridin-3 -ylmethyl)—[5—(1H-pyrrolo[2,3 -b]pyridin-3 -ylmethyl)-pyridinyi]-amine (P—0215), (2-Chlor0-benzyl)-[5-(1H-pyrrolo[2,3-bjpyridin—3 -ylmcthyl)-pyridin-Z-yl]-amine (P—0216), (2-Methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-pyrid inyl]-amine (P-02 l7), (1 -Methyl-]H-benzoimidazol-Z-ylmethyl)-[5-(1H-pyrro10[2,3-b]pyridin-3 -ylmethyl)-pyridin yl]—aminc (P—0218), (6-Methoxy-pyridin-3 —ylmethyl)-[5-( 1 H-pyn‘olo[2,3-b]pyridin-3 -ylmethyl)—pyridinyl]-aminc (P-0219), (1H-Benzoimidazol—2~ylmethyl)—[5—(1II~pyrrolo[2,3-b]pyridinylmethyl)-pyridinyl]-amine (P—0220), or0«4~flu0r0-benzyl)-[5-( l olo[2,3 -b]pyridin-3 -ylmethyl)-pyridiny1]-amine (P—0221), (S‘Methoxy—pyrid in—3-ylmethyl)- [5 -(1H-pyrro!0[2,3—b]pyridin—3 —ylmcthyl)—pyrid I]-amine (P-0222L {3‘Fiu0rwpyrid En»4~y§ methyi)’[5~={ i H~pyrrcaia[2,3 »b]pyridinfl —ylmethyi)°pyridin»~2-y1]«am§ne (P—0223), (6-Methoxyepyridiny1methyl)—[5—( 1 prrrolo[2,3Ab]pyridin—3 -y1methyl)~pyridin—2~yij~aminc (P-0224), 0r0-2»trifluoromethyl-benzyl)v[5-(1 I1~pyrr010[2,3—b]pyridin-3~y1methy1)—pyridin-2—yl]~ amine (P-OZZS)S [5-.(1H—Pyzmlo[2,3~b]pyridin~3~y§methyi)—pyridin~2—yi]{2amfluoromethyiabenzyfyamine (P—0226), (3,5 ~Dichloro—pyridin—4—ylmethyI)—[5-(, l 010[2,3—bjpyridin—3—yimethyl )«pyridin—2—yl]—amine (P—0227), (6«Morph01in«4—yl—pyridin-Z—ylmethyD—[S—(1 H—pyrrolo[2,3—b]pyridin—3—ylmethyl)-pyridin—2—y1]— amine (P~0228), (3—Flu0ro-pyridin-2—ylmethy1)-[5—(1H—pyrrolo[2,3—b]pyridin—3 -y1methyl)—pyridin—2—yl]—amine (P-0229), (5-Fluoro—pyridin-3 —ylmethyl)-[5 —( IH-pyrrolo[2,3~b]pyridinylmethyl)—pyridin‘2—yl]—amine (P—0230), (3-CIiloro-pyridiiiylmethyl)-[5-(5—chloro- I H—pyn'olo[2,3-b]pyridin—3 —ylmethyl)—pyridin—2-yl]- amine (P-023S), 3—{6-[(3 —Chlor0-pyridin—4—ylmethyl)-amino]-pyridin—3 —ylmethyl } — l H—pyrrolo[2,3-b]pyridine—5— carbonitrile (P-0256), 3—[6-(4—Ch10r0—benzylamino)—pyridin—3—ylmethyl]-1H—pyrrol0[2,3-b]pyridinccarbonitrile (P-0257), Propane- I nic acid (2,4—difluoro—3 —{[5-(l H—pyrrolo[2,3 idin—3 -ylmethyl)—pyridin-2— ylamino]—methyl}-phenyl)—amide (P-0258), Propane— 1—sulfonic acid (3 -{[S—(S-chloro—1H—pyrrolo[2,3 —b]pyridin—3—ylmethyl )-pyridin 0]-methyl}-2,4—difluoro—phenyl)-amide (P-0259), 3—[6~(4—Trifluoromethyl—benzylamino)-pyridin-3 —ylmethyl]— l olo[2,3 —b]pyridine—S— itrile (P—0269), [5—(5 —Chloro- 1 H-pyrrolo [2,3—b]pyridin—3—ylmethyl)—pyridin—2—yl]—(2—fluor0-benzyl)—aminc (P-0270), 3 —[6-(2-Fluoro-benzylamino)-pyridin~3 —ylmethyl]-I H-pyrrolo[2,3-b]pyrid ine-S-carbonitrile (P—0271), (2-FIuor0—benzyl)—[5—(5—methyl— I H—pyrrolo[2,3 —b]pyridiii—3~ylmethyl)—pyridinyl]—amine 72), 3— { 6-[(6-Trifluoromethyl-pyridin-3 —ylmethyl)—amino]—pyridin»3 ~ylmethyi}~111~pynoio[2,3~ b]pyridine—S-carbonitrile CP—0273), 3~[6»(2:TriflHammethylubénzylamine)—pyridin~3-ylmethy E} E H»pyrr0}o[233‘b1pyridineé , carbonitrile (P~0274)§ [5-(5—Chloro— ] H~pyrrolo[2,3~b]pyridin-3 ~ylmethyl)«pyridi11—2-yl]-{2—trifluoromethyl-bcnzyl)a amine (P~0275), [5-(5-MethyL i H—pyrmlo[2,3—bjpyridin-3 -ylmethyl)—pyridin—2—yl]~(2—trifluormnethyl—benzyD- amine (19-0276), 3 -=[6»(2,6~Di enzyiamineypyridin~3~y1methy§} E H~pyrr0£o[2,3‘b]pyridine—5-carb0nitri1e (11.0277), [5»(S—Ch10r0— l oi0[2,3«b]pyridin—3-ylmethyl)-pyridin—2-yl]-(2,6-diflu0r0-benzyl)~aminc (P-0278), (EL-Chlom-benzyl)~[S-(5-methyl-1 H-pyrrolo[2,3-b]pyridinyImethyl)-pyridinyi]-amine (2-Chloro-benzyl)-[S—(5~chloro—1H-pyrrolo[2,3wb]pyridin~3-ylmethyl)-pyridinyl]~amine (P-0280), 3~[6-(2-Chlor0-bcnzylamin0)-pyridin-3~ylmethy1]-1H-pyrrolo[2,3-b]pyridine03rbonitrile (30281), (6-Meth0xy—pyridinylmethyl)-[S-(5—methyl-1H-pyrrolo[2,3-b]pyridin-3 -y1methyl)-pyridin-2— yl]-amine a’-0282), [5—(5~Chloro-l H—pyrrolo[2$3 ~b] pyridin-3 -ylmethyl)-pyridin-2~yl]-(6-methoxy-pyridin ylmethyl)-amine (P-0283), 3-{ 6-[(6-Methoxy-pyridiny|methyl)-ami110]-pyridin-3 -ylmethyl}- l H-pyrrolo[273—b] pyridine carbonitrile (P-0284), (2-Methoxy-pyridin-3 -ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3—b]pyridin-3—ylmethyl)-pyridin yI]-amine (P-0285), [5—(5-Chloro-1H-pyrrolo[2,3-bjpyridin-3~ylmcthyl)-pyridinyl]-(2-methoxy-pyridin—3 - ylmethyl)-amine (P-0286), 3 -{6-[(2-Meth0xy-pyridin-3 ~ylmethyl)-amino]-pyridin-3 -ylmethyl}-1H-pyrrolo[2,3-b]pyridine—5— carbonitrile 7), (2-Eth0xy-benzyl)—[5 —( 1 H—pyrrolo[2,3—b]pyridin—3 ~ylmethyl)-pyridinyl]—aminc (P-0288), (2,5-Difluoro-benzyl)—[5-(1H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-pyridinyl]-amine (P—0296), (2,5-Diflu0ro-benzyl)-[5—(5—methyl—1H-pyrrol0[2,3-b]pyridin-3 -ylmethyl)-pyridinyl]-amine (P—0297), [S-(S-Chloro— l H-pyrrolo[2§3 -b]pyridinylmethyl)-pyridinyl]~(2,5—diflu0r0~benzyl)~amine (P-0298), 3—[6-(2‘5-Difluore-benzylamino)-pyridin=3-ylmcthyl]==1H«pyrr010[2,3~b]pyridinccarbonitrile (P—0299), 2~Trifium‘omefimxynbenzyiami110)~pyridin~3 ~ylmethy§]~ 1 H»pyrr010[2,3»b]pyridi118 carbenitri k: 1), [5-(1H—PyrrolO[2,3-b]pyridin-3 -yimethy3)—pyridin-2»yl]-(2—trifiuor0meth0xy—benzyfj-amine (13-0322), 3~[6-(2-Eth0xy—benzylaminO)-pyridin-3 -ylmethy[]—f H—pyn‘o10[2,3~b]pyridine—S-carbonitrile [5-(S«Chi0m— I H-pyrmiem} -mpyridinw’}«ylmethyl)=pyridin~2~y£}n(5=~fiuom~pyridinw3fimethyb— amine (P-0324), [5—(S-Fluoro-1 H~pyrrolo[2,3 -b]pyridinylmethy|)-pyridinyI]-(2-irifluor0methyl-benql)- amine (P-0325)§ [5~(5—Melhoxy-1H-pyrr010[2,3-b]pyridin-3 -y1methyl)-pyridin-2—y1}—(2~triflu0r0methyl—benzyl} amine (P-0326), (2-Chloro—benzyI)—[5-(5-fluoro- l H-pyrrolo[2,3-bjpyridin—3 -ylmethyl)~pyridin-2—yl]-amine (P-0327), (2-Ch10r0-benA/l)-[5-(5-methoxy-1 H-pyrrolo[2,3-b]pyridin-3—ylmethyl)~pyridiny1]-amine (P~=0328), (2,5-Difluor0- benql)—[5-(5-flu0ro-I H-pyrroio[2,3-b]pyridin«3 -y1methy1)—pyridinyl]-amine (2,5-Diflu0r0—benzyl)-[5—(5-mcth0xy-1H—pyrr010[2,3-b]pyridinylmethyl)-pyridin—2-yl]-amine (P-0330), [S-(S-Fluom-l H-pyrr010[2,3-b]pyridiny]methy1)-pyridin-2—y1]-(6-methoxy-pyridin-3 -ylmethyl)- amine (P-0331), (6—Methoxy-pyridin-3—y1methyl)-[5-(5-methoxy—J H-pyrr010[2,3—b]pyridin—3-y1methyl)-pyridin yl]-amine (P—0332), (2,6—Difluoro—benzy])-[5-(5 -flu0r0-JII-pyrr010[2,3—b]pyridiny1methyl)-pyridinyl]-amine (P-0333), ifluoro-benzyl}[S-(S-methoxy-JH-pyrr010[2,3-b]pyridin-3 -y1methyl)-pyridiny1]—amine (P—0334), (2-Methoxyvbenzyl)-[5-(lH—pyrrolo[2,3—b]pyridiny1mcthyl)-pyridin—2-yl]-amine (P-0336), 3-[6-(2-Meth0xy—benzylamin0)—pyridin-3 —y1methy]]- 1 olo[2,3-b]pyridine-S—carbonitrile (P—0337), [5-(5-Ch10r0—JH—pyrr010[2,3 —b]pyridin~3 ~y1methyl)e-pyridin»2-y1]—(2-difluoromelhoxy-benzyl)- amine (P-0338), 3»[6-(24)ifluoromethoxy-benzylamino)—pyridin-3 -y1methyl]- l H-pyrr010[2,3 -b]pyridine-5— carbonitrilc (P903259), (236~Diflu0re-benzyl)~[5v(1vayrr010[2,3»~b]pyridinaB —ylmethyl)‘pyridin~2syi]-amine (P4840): ('2;6-Difltmrwbenzyiyfi thyia§ H—pyrmioflfi«10]pyridin~3—y1methyi)~pyridin~2—yt]amine (P-0341), (2,4-Dichloro~benzyi)~[5-( 1H-pyrro10[2,3~b]pyridin‘3 ~y1mcthyl)*pyridin—2-y1]-amine (P413412), oro-benzyl)-[S-(1H-pyrrolo[2,3—b]pyridin—3—y1methyI)-pyridiny1]-amine 3), oro~4~triflu0r0methyLbenzyl)—[5~(I H-pyrro]o[2,3-b]pyridin-3 -ylmethyl)—pyridinyl} amine (P-0344), (4»Chior0~2—flu0r0»benzyl)=[5~( 1 Hapyrmlofifi ~b}pyridin~3 ~ylmethy1)-pyridin—2~yiJ-aminc (P—0345), (3—Fluoro—S—trifluoromethyl—benzyl)—[5-(1H~pyrmlo[2?3-b]pyridin-3 —ylmelhy1)-pyridinyl]- amine (P-0346), (2-Morpholin—4uy1-pyridin—3 hyl)—[5—(l H—pyrr010[2,3-b]pyridinylmethyl)—pyridin-2~yl]- amine (P-0347), (4—Chlor0-3 ~trifluoromethyl-benzyl)-[5-( l H-pyrrolo[2,3~bjpyridin~3 -ylmethyl)~pyridinyl]- amine (P—(l348), (2—Chlorotrifluoromethyl—benzyl)-[5-(1H—pyrrolo[2,3—b]pyridin-3—ylmethyl)—pyridin—2-yl]- amine (E0349), (Z-Fluoro—S-trifluoromethyl—benzyl)—[5-( l H—pyrrolo[2,3-b]pyridin—3—ylmethyl)-pyridin—2—yl]- amine (P-0350), (2,3-Dichloro-benzyl)—[5-( l H—pyrrolo[2,3—b]pyridin—3—ylmethyl)—pyridin—2—yl]—amine (P-0351), (2-F1u0r0meth0xy—benzyl)—[5—( lH-pyrrolo[2,3—b]pyridinylmeth_vl)—pyridin—2-yl]-amine (P—0352), DimethyI-(S— { [5—( i H-pyrrolo[2,3—b]pyridin—3-y1methyl)-pyridin—2—ylamino]—methyl } -pyrimidin—2- yl)-amine 3), (3—Chloro—2—fluoro—benzyl)—[5—( lH—pyrrolo[2,3-b]pyridin-3—y1methyl)—pyridin—2-yl]—amine (P-0354), (5-Fluoro—pyridin-2—ylmethyl)-[5 —(l H—pyrrolo[2,3-b]pyridin—3—ylmethyl)-pyridin—2-yl]—amine ifluoro—benzyl)-[5—(IH—pyrrolo[2,3-b]pyridiii-3—ylmethy1)-pyridin—2-yl]-amine 6), (2—Propoxy-benzyl)—[5~(1H—pyrrolo[2,3-b]pyridin—3—ylmethyl)—pyridin-2—yl]—amine (P-0357), (Z-Morpholin-4—yl—benzy1)-[5-(1H—pyrro10[2,3-b]pyridin—3-y1methyl)—pyridin-2—yl]—aminc (P-0358), 0r0methoxy—bcnzyl)—[5—(l H-pyrr010[2,3—b]pyridin—3 ~yImethyl)—pyridin-2—yl]—amine (P-0359), (2mFluoro-6~trifluoromelhyl—benzyi)—[5-(1H—pyrr010[2,3—b]pyridin—3—ylmethyl)-pyridin—2—yl]- amine (150360), [2—(2~M0rph0Ein~4~yi—eth0xy)-benzyl]u[5—(1H=pyrrolo[2,3~bjpyridiii-3=ylmethyi)‘pyridin—Z-yl} amine (P418631), {2,34}fiuamvbenzyi)»[5‘( i H~pyrroio[2,3~ij]pyridin~3-ylmethyl)—pyridin~2'y1]»amine (I’=0362), (2-Chl0r0-3 «trifluoromethyl~benzyl)—[5—( I H-pyrr010[2,3—b]pyridin~3~ylmethyl)-pyridin—2-yl]‘ amine (P-0363), (2—Chlore—5—fluor0~ben7yl)-[5—( } H-pyrrolo[2:3—b]pyridin-3 —y1methyl)«pyridin~2~yl]-aminc (13—0364), (2»Fiu0ma3»trifluoromethyiabenzyi)~[S«( E H‘pyrmlai233»b]pyridin«~3~ylmethyE)-p)*ridin«2«yl]— amine (P—-03v65)2 (5 -Flu0ro~2-methoxy—bcnzyl}[5-( 1 H—pyrr010[2,3-b]pyridin-3 -y[Inefhyl)-pyridiI1yI]-amine (2-Difluoromethoxy-benzyl)-[5—(1H-pyrroi0[2:3-b]pyridin-3 -y1methyl)-pyridin-Z-yihimine (P—0367)5 (2-Fluor0methyl—benzyl)-[5-(1H-pyrrolo[2,3-b]pyridiny}methyl)-pyridinyl]~amine (P-0368), [2-(3 -Dimethylamino-propoxy)-benzyl]-[5—(I H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-pyridinyl]- amine (P~0369), (2,6-Dimelh0xy-pyridin-3 -ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-pyridinyl] - amine 0), (Z-Fluoro-S-methoxy-benzyl)-[S-(1H-pyrrolo[2,3-bjpyridinylmethyl)-pyridinyl]-amine (P-0371), uor0mefhyl-benzyl)-[5-(I H-pyrrolo[2,3-b]pyridinylmethyl)-pyridinyl]-amine (P—0372), (3 -Chloro-S-flu0r0-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridinylmethyl)-pyridin-Z-ylj-aminc (P-0373), (6-Cyclopentyloxy-pyridin-3 -ylmcthyl)-[5 -( l H-pyrrolo[2,3-b]pyridin»3 -y| methyl)-pyridinyl]- amine (P-0374), (5-Flu0r0—2-trifluoromelhyl-benzyl)-[5-( lH—pyrr010[2,3-b]pyridin-3 hyl)-pyridinyl]‘ amine (P—0375), [5-(1H-Pyrrolo[2,3~b]pyridin~3-ylmethyl)-pyridinyl]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3 - ylmethyl]—amine (P—0376), Propane-1~sulfonic acid (2-fluoro—3-{[5-(1H-pyrrol0[2,3 idillylmelhyl)—pyridin ylamin0]-methyl} -phenyl)-amide (F0377), (2,5-Dichlor0-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)—pyridinn2-yl]-aminc (P—0380), din-S-yimethyl-[5m(lH=~pyrr0lo[2,3ab]pyridinu3~yImethyl)-pyridinyI]—amine (P—0381), (S-ChlorO-E-fluoro—benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin~3~ylmethyl)-pyridinyl]-amine (P-0382), {E—Ethyi~b€l12yi)w[5«(i H-pyrmiafifiiflpyridinn}xylmethy1):»pyridin‘2uyijflmine (P433833), 2,2-Dimethyi-=N—(3t{ [5-( i vayrmkcflfi~bipyridinn3 «ylmethybapyridinv2«yiamino]~melhyf} ‘ pyridin~2~yl)-pr0pionamide (R0384): Melhyi-(3-{[S-(1H-pyrr010[2,3-b]pyridin-3 —y1methyl)-pyridinylamin0]-methyi } -pyridiny1)- amine (P-0385), Methyl—(S- {[5~( 1 H-pyrroioflfi‘bprridir1~3«yimethyl)~pyridin~2—ylamin0J—mcthyl} vpyrimidin—2» y§)—amine (110386)? (2~Chloro-4—methanesulfonyl-benzyl}[5-(1H-pyrrolo[2=3-b]pyridinylmethyl)-pyridin~2-yl]- amine (P—0387). {5-[1-(1H-Pyrrolo[2,3 idin-3—yl)—ethyl]—pyridin-Z-yl } »(4—trifluoromethyl~benzyl)—amine (P- 0388), (5~Fluoromethyl-benzyl)—[5-(1H-pyrroIo[2,3-b]pyridin—3 -ylmethyl)—pyridinyl]-amine 9-0397), Dimethyl-(3 -{[5-(1H—pyrrol o[2,3-b]pyridin~3-ylmethyl)-pyridinylamino]-methyl}-pyridinyl)-an1ine (P-0399), (5-Chlor0-pyridin~3 ~ylmethyl)~[5~(l pryrrolo{2,3—b]pyridin—3 —ylmcthyl)-pyridinylj-amine (P-0400), (2-Mcthoxy-pyrimidin-S-ylmethyl)-[5-(1lil-pyrrolo[2,3-b]pyridinylmethyl)-pyridinyl]-amine (P-0401), [S-(S-Chloro- l H-pyrrolo[2,3-b]pyridinylmethyl)-pyridinyl]-[6-(2,2,2-trifluoro-ethoxy)~ pyridin-3 -ylmethyl]-amine (P-0409) and l—(3 —Fluoro-phenyl)~3v [S—(l olo[2,3-b]pyridinylmethyl)-pyridin-2—yl]—urea 2), or all salts, prodrugs, tautomers, or isomers thereof.

In one embodiment ofthe methods provided herein, the compound is: (4~Chloro—benzyl)—[6v(1H-pyrrolo[2,3-b]pyridin-3 —ylmethyl)-pyridazin-3 -yl]-a1nine (P-0092), (4-Morpholinylmethyl-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin—3 —ylmethyl)—pyridinyl]-amine (P-0093), (ZvMethoxy—ethyl)-[5-(1H-pyrrolo[2,3-b]pyridinylmethyl)-pyridinyl]-amine (P—0098), [4-Chloro-l -ethyl-S -( l H-pyrrolo[2,3-blpyridin—3 -ylmethyl)—1H-pyrazol—3 —yl]—[1-(4-fluoro- phenyl)-meth-(E)—ylidene]-amine (P-0166) or ( (2,2-Difluoro-bcnzo[l ,3]di0xolylmethyl)- [5-( l H-pyrrolo[2,3 —b]pyridinylmethyl)-pyridin-2— yl]-amine (P-0398); or all salts, prodrugsj tautomers, or isomers f.

In one embodiment of the methods provided herein, the compound is selected from: 3"(6463112Butoxypyridénfi~ylmethyl)—lH—pyrrolo[2,3-bjpyridine (P‘0020), 3-(6~l\»leth0xy~pyridin«3~ylmethyl)=4=~thi0phene3 ~ylnl H-pyrroloflfiwbEpyridine 22), {6~Isobutylaminmpyridin‘3—yl)-{E H‘pyrrolo[2}3~b}pyridin—3 ethanol (1350029): [@(Cyclopropylmethyl-amino)-pyridin-3 ~ylj-( l H—pyrrolo[2,3-b]pyridin-3 ethanol (P-0034), [6-(Cyclohexylmethyl-amino)-pyridin-3 ~yl]—( l H—pyrrolo[2,3~b]pyridin—3-yl)—methanol 5), ( l H-Pyrrolo[2,3~b]pyridin~3~yl)—[6—(4—triFluoromethyl-benzylamino)vpyridinw3syl]~methanol (P-0036), {6-{4-Chlero»benzylamintijiupyridinKS-ylla(1H-pyrrolo[2,3-b]pyridin«3~yl)-methanol (P0037), (4-Chloro-bcnzyl)- { S— [methoxy-(l H-pyrrolo[2,3~b]pyridin-3 ethyl]-pyridinyl } -amine (P—0039), (4-Chlorotrifluoromethyl-benzyl)-{5-[methoxy-(1H-pyrrolo[2,3 -b]pyridin-3 -yl)-methyl]- pyridin-2wyl} -amine 0), (4~Chlor0~benzyl)— { 5-[methoxy-(5~pyridin~3~yl~ I I l—pyrrolo[2,3~b]pyridin-3 -yl)-methyl]-pyrid in ine (P-0041), [6—(4-Ch loro~benzylamino)methyl-pyrid in-3 -yl]v(1H-pyrrolo[2,3-b]pyridinyl)-methanol (P—0046), [2,6-Bis-(4-chloro-benzylamino)epyridin~3«yl]-(1H-pyrrolo[2,3 -b]pyridin-3 ethanone (P-0049), and 3-(2—Ethylsulfanyl-4,6-dimcthyl-pyrimidin-S-ylmethyl)-l H-pyrrolo[2,3-b]pyridine (P-0052), or all salts, prodrugs, ers, or isomers thereof. ln certain embodiments of the methods provided herein, in above nds, compounds are excluded where N (except where N is a heteroaryl ring atom), O, or S is bound to a carbon that is also bound to N (except where N is a heteroaryl ring atom), O, or S, except where the carbon forms a double bond with one ofthe heteroatoms, such as in an amide, carboxylic acid, and the like; or where N (except where N is a aryl ring atom), O, C(S), C(O), or 8(0)n (n is 0-2) is bound to an alkene carbon ofan alkenyl group or bound to an alkyne carbon of an alkynyl group; accordingly, in n embodiments compounds which e linkages such as the following are excluded from the present invention: -NR-CH2-NR-, -O-CH2-NR-, ~S-CH2-NR-, ~NR-CHg-O-, ~O-CH2-O-, -S-Cl~l2-O~,—NR-CH2-S-, —O-CH2-S-, —S-CH;-S-, -NR-CH=CH-:, -CH=CH-NR-, -NR-CEC-, -CEC-NR~, ~O-CH=CH—, ~CH:CH-O-, -O-CEC-, -CEC-O-, -S(O)0CH:CH-, -CH=CH-S(O)0~2-, —S(O)oCEC-, -CEC-S(O)0»2-, —C(O)—CH=CH—, -CH:CH-C(O)-, -CEC-C(O)-, or -C(O)-CEC-, CH=CH-, -CH=CH-C(S)-, -CEC-C(S)-, 0r -C(S)-CEC-.

In reference to compounds in the methods provided herein, specification ofa compound or group of compounds includes pharmaceutically acceptable salts of such compound(s), prodrugt’s’), and all stereoisomers, unless clearly indicated to the contrary, In reference to compounds of a II, unless ciearly indicated to the contrary, it is tood that such reference includes compounds of Formulae lla, llb, llc, lId, 11c, Hf, Hg, Ilh, lli, IIj, llk, Hm, Iln, and Up, and all sub—embodiments thereof.

In another , the invention provides methods for treating a mutant FIB-mediated Fla-mediated disease or condition in an animal subject (eg. a mammal such as a human, other primates, sports animalst animais of commercial interest such as came, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Flt3 activity (eg. kinase activity). Invention methods involve administering to the subject suffering from or at risk of a Flt3 —mediated e or condition an effective amount ofa compound of Formula II or Formula III, and all sub—embodiments thereof. In one embodiment, the Flt3 mediated disease is selected from the group consisting of acute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic leukemia; acute lymphocytic leukemia, acute lymphoblastic leukemia, d sarcoma; T~cell type acute lymphocytic leukemia (T-ALL); B cell type acute lymphocytic leukemia (B—ALL); c myelomonocytic leukemia (CMML); myelodysplastic syndrome; myeloproliferative disorders; other proliferative ers. including, but not limiting to, cancer; autoimmune disorders; and skin disorders, such as psoriasis and atopic itis. In another embodiment, the Flt3 mediated disease is selected from axonal degeneration, acute transverse myelitis, amyotrophic lateral sclerosis, infantile spinal muscular atrophy,juvenile spinal muscular atrophy, Creutzfeldt—Jakob disease, subacute sclerosing panencephalitis, organ rejection, bone marrow lant rejection, non—myeloablative bone marrow transplant rejection, ankylosing spondylitis, aplastic anemia, Behcet’s disease, graft— versus—host e, Graves' disease, autoimmune hemolytic anemia, r’s granulomatosis, hyper lgE syndrome, idiopathic thrombocytopenia purpura, or Myasthenia gravis.

In a related aspect, compounds of Formula II or Formula 111, and all sub—embodiments thereof, can be used in the preparation ofa medicament for the treatment ofa Flt3 —mediated or a mutant FIB—mediated e or condition selected from the group ting ofmalignancies, ing, but not limited to, acute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic leukemia; acute cytic leukemia, acute lymphoblastic leukemia, myeloid sarcoma; T—cell type acute lymphocytic leukemia ); B—cell type acute lymphocytic leukemia (B—ALL); chronic myelomonocytic leukemia (CMML); myelodysplastic syndrome; myeloproliferative disorders; other proliferative disorders, ing, but not limiting to, ; autoimmune disorders; and skin ers, such as psoriasis and atopic dermatitis In a further aspect, the invention provides s for treating a Flt3 —mediated or a mutant Flt3-mediated disease or condition in an animal subject (eg. a mammal such as a human, other primates, SpOI‘tS animals, animals of cial interest such as cattle, farm animals such as berscs, or pets such as dogs and cats), eg, a disease or condition characterized by abnormal F113 activity (e. g. kinase activity). Invention s involve administering to the subject suffering from or at risk of a Flt3 mediated e or condition an effective amount of compound of Formula II or Formula III, and all sub—embodiments f. In one embodiment, the Flt3 mediated or mutant Flt3-mediatcd disease is selected from the group consisting of acute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelceytie leukemia; acute lymphocytic leukemia, acute lymphoblastic leukemia, myeloid sarcoma; T~cell type acute cytic leukemia (‘l‘—ALL); B—ccll type acute lymphocytic leukemia (IS-ALL); chronic myelomonocytic ia ; myelodysplastic syndrome; roliferative disorders; other proliferative disorders, including, but not ng to, cancer; autoimmune disorders; and skin disorders, such as sis and atopic dermatitis.

In a d aspect, compounds of Formula II or Formula III, and all sub—embodiments thereof, can be used in the preparation ofa medicament for the treatment of a FIB-mediated or a mutant F lt3—mediated disease or condition selected from the group consisting of acute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic leukemia; acute lymphocytic leukemia, acute lymphoblastic leukemia, myeloid sarcoma; T-cell type acute lymphocytic leukemia (T-ALL); B—cell type acute lymphocytic leukemia (B-ALL); chronic myelomonocytic leukemia (CMML); myelodysplastic syndrome; myeloproliferative disorders; other proliferative disorders, including, but not limiting to, cancer; autoimmune ers; and skin disorders, such as psoriasis and atopic dermatitis.

In a further , the invention provides methods for treating a ediated or a mutant ediated e or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of cial interest such as cattle, farm s such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Flt3 activity (e.g. kinase activity), Invention methods involve administering to the subject suffering from or at risk ofa ediatedor a mutant FIG-mediated disease or condition an effective amount of compound of Formula 1, Formula la, Formula lb, or Fomiula lg, and all sub- embodiments thereof. In one embodiment, the Flt3 mediated disease is selected from the group consisting of acute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic leukemia; acute lymphocytic leukemia, acute lymphoblastic leukemia, myeloid sarcoma; T-cell type acute lymphocytic leukemia ); B-cell type acute lymphocytic leukemia ); chronic myelomonocytic leukemia (CMML); myelodysplastic syndrome; myeloproliferative disorders; other proliferative disorders, including, but not limiting to, cancer; autoimmune disorders; and skin disorders, such as psoriasis and atopic dermatitis.

In a d aspect, compounds of Formula 1, Formula Ia, Formula lb, or Formula lg, and all sub-embodiments thereof, can be used in the preparation of a medicament for the treatment of a FIB-mediated or a mutant FIB-mediated disease or condition selected from the group consisting of acute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic leukemia; acute lymphocytic leukemia, acute lyrnphoblastic leukemia, myeloid a; T-cell type acute lymphocytic leukemia (BALL); B~eeil type acute lymphocytic leukemia (BALL); chronic myelomonocytic leukemia (CMML); myelodyspiastie me; myeloproliferative disorders; other proliferative disorders, including, but not limiting to, cancer; mune disorders; and skin ers, such as psoriasis and atopic dermatitis.

In a further aspect, the ion provides methods for treating, in an animal subject (eg. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and eats), a disease or condition mediated by oncogenic Flt3, e.g., a disease or condition characterized by al Flt3 activity (eg. kinase activity). Invention methods involve administering to the subject suffering from or at risk ofa e or condition mediated by Flt3 an effective amount of compound of Formula II or Formula III, and all sub-embodiments thereof. In one embodiment, the condition mediated by Flt3 is selected from the group consisting ofacute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic ia; acute lymphocytic leukemia, acute lymphoblastic leukemia, myeloid a; T—cell type acute lymphocytic leukemia (T-ALL); B-cell type acute lymphocytic leukemia (B-ALL); chronic myelomonocytic leukemia (CMML); myelodysplastic syndrome; myeloproliferative disorders; other proliferative disorders, including, but not limiting to, cancer; autoimmune disorders; and skin ers, such as psoriasis and atopic dermatitis.

In a related aspect, compounds of Formula II or Formula III, and all sub-embodiments thereof, can be used in the ation ofa medicament for the treatment ofa FIB—mediated or a mutant FIG-mediated disease or condition selected from the group consisting of acute myeloic leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic leukemia; acute lymphocytic leukemia, acute lymphoblastic leukemia, d sarcoma; T-cell type acute lymphocytic leukemia (T—ALL); B-cell type acute lymphocytic ia (B-ALL); c myelomonocytic ia, (CMML); myelodysplastic syndrome; myeloproliferative disorders; other proliferative disorders, including, but not limiting to, cancer; autoimmune disorders; and skin ers, such as psoriasis and atopic dermatitis. [0198} In particular embodiments, the compound has an ICSO of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay. In certain embodiments, the seieetivity of the compound is such that the compound is at least 2—foid, Smfold, 10~foid, or lOt‘Jgfold more active on oncogenic or mutant Flt3 than wild type Flt3. In certain embodiments, the selectivity of the compound is such that the compound is at least 2—fold, 5—fold, 10—fold, 0r lOO—fold more active oncogenic Flt3 than wild type Flt3. In certain embodiments, the selectivity ofthe nd is such that the nd is at least 2«fold, 5-fold, 10-fold, or IOU—fold more active on nic Flt3 than wild type Flt3, In certain embodiments, the compound has in combination each g of activity (eg. ICSO) andz'or ivity as specified in this paragraph.

In particular embodiments, the compound has an IC50 of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 uM as determined in a generally accepted kinase activity assay for F16 kinase activity. In certain embodiments, the selectivity ofthe compound is such that the compound is at least 2-fold, 5-fold, 10~fold, or 100~fold more active on oncogenic Flt3 than on wild type Flt3.

In particular embodiments, the compound has an ICSO of less than l00 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for F1t3 kinase ty, and further has an IC50 of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase ty.

] An onal aspect of this invention relates to compositions that include a therapeutically effective amount ofa compound of Formula II or Formula IIIand all sub— embodiments thereof and at least one pharmaceutically acceptable r, excipient, and/or diluent, including combinations of any two or more compounds of Formula II or Formula III. The composition can further include one or more different pharmacologically active nds, which can include one or more compounds of Formula I (including Formula Ia, Ib, and Ig, and all sub- embodiments thereof), Formula II or Formula III.

In one aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount ofa ition including a compound of Formula II or Formula III, in combination with one or more other therapies or medical procedures effective in treating the cancer. Other therapies or medical procedures e suitable ncer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hermia heating, bone marrow or stem cell transplant). In one aspect, the one or more suitable anticancer ies or medical procedures is selected from treatment with a chemotherapeutic agent (eg. herapeutic drug), ion treatment (eg. x—ray, «pray, or electron, proton, neutron, or a particle beam), hyperthermia heating (eg. microwave, ultrasound. radiofrequency ablation), Vaccine therapy (eg. AFP gene hepatoeellular carcinoma e, AFP adenoviral vector vaccine, ALE-858, allogcneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines), gene therapy (cg. AdSCMV-p53 , adenovector encoding MDA7, adenovirus 5«tumor necrosis factor alpha), photodynamic therapy (eg. aminolevulinic acid, motexafin lutetium), surgery, and bone marrow and stem cell transplantation.

In one aspect, the invention es a method of treating a cancer by administering to the subject an effective amount of a composition including a compound of Formula II or Formula III, in combination with one or more suitable chemotherapeutic agents. In one aspect, the one or more suitable chemotherapeutic agents is ed from an ting agent, including, but not limited to, adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, azine, estramustine, fotemustine, fam, ifosfainide, improsulfan, irofulven, ine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; an antibiotic, including, but not limited to, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, inenogaril, mitomycin, initoxantrone, neocarzinostatin, pentostatin, and plicamycin; an antimetabolite, ing, but not d to, azacitidine, capecitabine, cladribine, clofarabinc, cylarabine, decitabine, floxuridine, fludarabine, 5~fluor0uracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and lrimetrexate; an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; a hormone or e antagonist, ing, but not limited to, ozole, androgens, buserelin, diethylstilbestrol, excmestane, de, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including, but not limited to, DJ—927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; a retinoid, including, but not limited to, alitrctinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid, ing, but not limited to, etoposide, rringtonine, sidc, stine, vincristine, vindesine, and vinorelbine; an antiangiogenic agent, including, but not limited to, Ali—941 (GW786034, Neovastat), ABT-S 10, 2~methoxyestradiol, lenalidomide, and thalidomide; a omerase inhibitor, including, but not limited to, amsacrine, edotecarin, an, irinotecan (also active metabolite SN—38 (7-ethyl-l,O-hydroxyscamptothecin)), rubitecan, topotecan, and 9*a1nin0camptothecin; a kinase inhibitor, including, but not limited to, erlotinib, ib, ridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, ABE-788, AG- 01373 6, AMG 706, AMN107, EMS-354825, EMS-599626, UCN-Ol (7»hydroxystaurosporine), veinurafenib, dabrafenib and vatalanib; a targeted signal transduction inhibitor including, but not limited to bortezomib, geldanamycin, and rapamycin; a biological response modifier, including, but not limited to, imiquimod, interferoma, and interleukinQ; and other chemotherapeutics, including, but not limited to 3—AP (3-amino-2—carboxyaldehyde thiosemicarbazone), aminoglutethimide, asparaginase, btyostatin—l, cilengitide, E7389, ilone, procarbazine, sulindac, temsirolimus, tipifamib, Preferably, the method of treating a cancer involves administering to the subject an effective amount of a composition of Formula II, Formula III or a EV in combination with a chemotherapeutic agent selected from 5~flt](3i'ottt‘acil, carboplatin, dacarbazine, getitinib, latin, axel, SN-3 8, temozolomide, vinblastine, bevacizumab, cetuximab, or erlotinib. In another embodiment, the chemotherapeutic agent is a Mek tor. Exemplary Mek inhibitors include, but are not limited to, AS703026, 1112136244 (Selumetinib), AZD8330, BIX 02188, CI—1040 (P0184352), GSK1120212 4057), PD0325901, PD318088, PD98059. RDEAI 19(BAY 869766), TAR—733 and UOI26—EtOH.

In r aspect, the invention provides a method of treating or prophylaxis ofa disease or ion in a mammal, by stering to the mammal a therapeutically effective amount of a compound of Formula II or Formula III, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug. The compound can be alone or can be part ofa composition.

In another aspect, the present invention also provides a method for modulating F lt3 activity by contacting a Flt3 or a mutant Flt3 with administering an effective amount of a compound of Formula I, Formula Ia, Formula Ib, a Ig, Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, a IIe, Formula 111‘, Formula 11g, Formula Ilh, a IIi, Formula IIj, Formula IIk, a IIm, Formula IIn, Formula IIo, Formula Up, or Formula III and all sub-embodiments thereof and all the compounds described . The compound is preferably provided at a level sufficient to modulate the activity of the Flt3 by at least 10%, more preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater than 90%. In many embodiments, the compound will be at a concentration of about 1 uM, 100 11M, or 1 mM, or in a range of 1—100 nM, 100—500 nM, 500—1000 nM, 1-100 uM, 100—500 11M, or 500—1000 11M. In some embodiments, the contacting is carried out in vitro. In other embodiments, the contacting is carried out in viva.

Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims.

ED DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein the feliowing definitiens apply: “Halo” and “halogen” refer to all halogens, that is, chlorn (Cl), fluoro (F), bromo (Br), or iedo (I).

“Hydroxyl” and “hydroxy” refer to the group —OH. [0210; “Thief” 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. In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1-6, 1—4, or 1—2, carbon atoms, such as methyl, ethyl. propyl, isopropyl, butyl, t- butyl, and the like. "Optionally substituted lower alkyl" s lower alkyl that is independently substituted, unless indicated otherwise, with one or more, ably l, 2, 3, 4 or 5, also 1, 2, or 3 tuents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group ting of -F, -OH, -NH;, -N03, -CN, ~C(O)OH, ll, -C(O)Nllz, -C(S)NH2, NH2, )NH3, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NHZ, -OR", -SR“, -OC(O)R’“‘, -OC(S)R”, -C(O)R”, -C(S)R“, -C(O)OR"‘, -C(S)ORa, -S(O)R“, -S(O)2Ra, -C(O)NHR‘“, -C(S)NHR3, -C(O)NRaRa, -C(S)NR3R“, NHR”, NR”R3, -C(NH)NHRE‘, -C(NH)NRbR°, -NHC(O)R"’, -NHC(S)R“, -NR“C(O)R”, -NRZC(S)Ra, )2R”, -NR"S(O)2R“, -NHC(O)NHR‘], -NHC(S)NHR3, -NR“C(O)NH2, -NR"‘C(S)NH3, -NRaC(O)NlrlRa, -NR3C(S)NHR3, -NHC(O)NR3RZ, -NHC(S)NR3R3, -NR”C(O)NR”RB, S)NRaRa, -NHS(O)2NHRZ, -N’RaS(O)2NH2, —NRaS(O)2NHR”, -NHS(O)2NR"‘R", -NRaS(O)2NR“R“, -Nl~lRa, -NRaRa, -R°, -Rf, and -Rg. Further, possible substitutions e subsets of these substitutions, such as are indicated herein, for example, in the description ofcompounds of Formula I (including Formulae la, lb, lg and all bodiments thereof), attached at any available atom to produce a stable nd. For example “fluoro substituted lower alkyl” denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with l, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -OR, —NHR, -C(O)NHR, and the like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any —O-, -S-, or -N- of the moiety (except Where -N- is a heteroaryl 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.

”Lower alkylene” refers to a divalent alkane«derived l containing l~6 carbon atoms, straight chain or branched, from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms, Examples of lower alkylene include, but are not limited to, methylene _CH2—, ethylene - CHZCH2—, ene -CH2CH3CH2-, isopropylene ~CH(CH3)CH-, and the like. "Optionally substituted lower alkylene" denotes lower alkylene that is independently tuted, unless indicated otherwise. with one or more, preferably 1, 2, 3, 4 or 5, also I, 2, or 3 substituents, attached at any available atom te produce a stable cempeund, wherein the substituents are selected from the group consisting of—F; ~OH, ~NH3, -NO;, -CN, H, -C(S)OH, -C(O)NH;, —C(S)NH3, -S(O)2Nng -NHC(O)NH;, -NHC(S)NlIg, -NHS(O);NH3, -C(NH)NH3, -OR“, -SR3, -OC(O)Ra5 -OC(S)R"‘, ‘C(O)Ra, -C(S)R”, Ra, -C(S)ORa, -S(O)Ra, R3, -C(O)NHR3, -C(S)NHRaa -C(O)NR3R3, -C(S)NR“Ra, —S(O)2NHR“, -S(O)2NR3R3, -C(NH)NHR“, -C(NH)NRbR°, -\iHC(O)Ra, -NHC(S)R3, -NRBC(O)R3, -NRaC(S)R“, -NHS(O);R3, -NRaS(O)2R”, -NHC(O)NHR“, -NHC(S)NHRa, mNRaC(O)NHRa, -NR“C(O)NH2, -NRaC(S)NHg, -NRaC(S)NHRa, ~NHC(O)NR“Ra, -NHC(S)NR3R“, -NR“C(O)NR“R3, -NR“C(S)NR“R3, -NHS(O)2NHR3, -NRaS(O)3NH2, -NR“S(O)3NHR“, —NHS(O)2NR3R3, -NR“S(O)2NRaR3, -NHR“, -NRaRa, —Re, ~Rf, and ng, or two substituents on any one carbon or a tuent on each of any two carbons in the alkylene chain mayjoin to form a 3-7 membered monocyclic cycloalkyl or 5—7 mcmbered monocyclic heterocycloalkyl wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, and cycloalkylamino.

“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, l, and the like. "Substituted lower l” denotes lowcr alkcnyl 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 ting of -F, -OH, -NH;, -NO;, -CN, -C(O)OII, -C(S)OH, —C(O)NH2, -C(S)NH3, -S(O)2NH2, )NH2, —NHC(S)NH2, )2NH2, NH2, -OR“, -SR“, -OC(O)R”, R“, -C(O)Ra, ~C(S)R“, -C(O)ORa, -C(S)OR”, -S(O)Ra, -S(O)2Ra, -C(O)NHR3, -C(S)NHR3, -C(O)NRaRa, -C(S)NR”R“, —S(O)2NHR“, -S(O)3NR3R”, NHR“, -C(NH)NRbR°, -NHC(O)R", -NHC(S)R“, -NR“C(O)R"> «NR3C(S)R3, ~NHS(O)3R”, “NR“S(013R“, —NHC(O)NHR“, *NHC(S)NHRa, -NR“C(O)NH2, ”NR“C(S)NHg, ~NRT£O)NHR35 ~NR3C(S)NHRa, ~NHC(O)NRaRa, ~NHC(S)NR”R3, —NR3C(O)NRRR“, -NR3C(S)NR3R3, vNHS(O)2NHRac “NRaS(O)2NH33 O)2NHR3, —NHS{O)3NR3R“, ~NRaS(O)2NRaRa, =NHR3, 11a, “Rd, ‘Rf, and -Rg. Funher, possible substitutions include subsets of these substitutions, such as are ted herein, for example, in the description of compounds of Formula 1 (including ae Ia, Ib, lg and all bodiments thereot), attached at any available atom to produce a stable compound. For example “Iluoro substituted lower alkenyi” denotes a lower alkenyl group substituted with one or more fiuoro atoms, where ably the lower alkenyl is substituted with I, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that tutions are attached at any available atom to produce a stable compound, substitution of alkenyl groups are such that -F, —C(O)-, -C(S)-, - )-, -S(O)-, -S(O)3-, —O—, -S-, or —N— (except where ~N- is a heteroaryl ring atom), are not bound to an alkene carbon thereof. Further, where alkenyl is a substituent of another moiety or an R group ofa 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)3«, -O-, -S-, or —N- thereof (except where —N- is a heteroaryl ring atom) are not bound to an alkenc carbon of the alkenyl substituent or R group. Further, where alkenyl is a substituent of r moiety or an R group of a moiety such as -OR, —NHR, -C(O)NHR, and the like, substitution ofthe alkenyl R group is such that substitution of the alkenyl carbon bound to any -O—, -S-, or «N- ofthe moiety (except where -N- is a heteroaiyl ring atom) excludes substituents that would result in any -O-, —S-, or -N- ofthe substituent (except whcre -N- is a heteroaryl ring atom) being bound to the l carbon bound to any «0-, -S-, or -N- ofthe 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 ofa carbon to carbon double bond.

“Lower alkynyl” alone or in combination means a ht or ed hydrocarbon containing 2-6 carbon atoms (unless specifically ) containing at least one, preferably one, carbon to carbon triple bond. Examples of alkynyl groups e ethynyl, propynyl, butynyl, and the like. "Substituted lower l" s lower l that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also I, 2, or 3 tuents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NH2, -N02, -CN, -C(O)OH, -C(S)OH, —C(O)NH2, —C(S)NH2, -S(O)3NH2, -NHC(O)NH2, ~NHC(S)NH2, -NI'IS(O)2NH2, -C(NH)NH2, ~ORa, ~SRa, -OC(O)Ra, -OC(S)R3, -C(O)Ra, a, -C(O)OR3, -C(S)ORa, -S(O)R“, —S(O)2R", -C(O)NHRB, -C(S)NHRa, —C(O)NRaRa, ~C(S)NR3R“, -S(O)2NHR“, —S(O)2NR3R“, -C(NH)NHR"‘, -C(NH)NRbRC, —NHC(O)R", ~NHC(S)RB, —NRaC(O)Ra, -NR"C(S)RE‘, -NHS(O)2R", -NRaS(O)3R3, —NHC(O)NHR“, —NHC(S)NHRB, -NR3C(O)NH1, «NR3C(:S)NH3, -NR“C(O)NHR“, —NRBC(S)NHR“, -NHC(O)NRaRa, ~NHC(S)NR3RS, O)NR“R“, =NR“C(S)NRaRa, —NHS(O)2NHR3, ~N’RQS(Q)2NH2, —NRaS(O)3Nl'{R”, -NHS{O)3NR”R*‘, aNRaS(O)3NRaR“, —NHR3, vNRE‘Ra, 41“, Re, and R? Further, possible tutions include subsets e substituticns, such as are indicated herein, fer example, in the description of compounds of Formula I (including Formulae Ia, Ib, Ig and all sub— embodiments thereof), attached at any available atom to produce a stable compound. For example “fluoro substituted lower alkynyl” denotes a lower alkynyl group substituted with one or more flucro atoms, where preferably the lower alkynyl is substituted with l, 2, 3, 4 0r 5 fluero atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, substitution of alkynyl groups are such that -F, -C(O)-, -C(S)-, -C(NH)-, «S(O)-, -S(O)2-, —O-, -S-, or -N- (except where -N- is a heteroaryl ring atom), are not bound to an alkyne carbon f, r, where alkynyl is a substituent of another moiety or an R group of a moiety such as —OR, NHR, -C(O)R, and the like, substitution of the moiety is such that any -C(O)-, -C(S)~,-S(O)—, -S(O)2-, -O-, -S—, or «N» thereof (except where ~N- is a heteroaryl ring atom) are not bound to an alkyne carbon of the alkynyl tuent or R group. r, where alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, ~NHR, - R, and the like, substitution of the alkynyl R group is such that substitution of the alkynyl carbon bound to any -O«, -S-, or —N- ofthe moiety t where -N- is a heteroaryl ring atom) excludes substituents that would result in any -O-, —S-, or -N— ofthe substituent (except where -N- is a heteroaryl ring atom) being bound to the alkynyl carbon bound to any 0-, -S-, or -N- ofthe moiety. An “alkynyl carbon” refers to any carbon within an alkynyl group, whether saturated or part of the carbon to carbon triple bond. An “alkyne carbon” refers to a carbon within an alkynyl group that is part ofa carbon to carbon triple bond, "Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. "Cycloalkylene" is a divalent lkyl. A "substituted cycloalkyl" is a cycloalkyl that is independently tuted, 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 e a stable nd, wherein the tuents are selected from the group consisting of halogen, -OH, -NH2, -NOZ, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR“, -SR3, -OC(O)R3, —OC(S)Ra, —C(O)R”, -C(S)R“, -C(O)ORa, —C(S)ORa, a, -S(O)2Ra, HRa, -C(S)NHR3, R“R", -C(S)NR“R“, -S(O)2NHR", ~S(O)2NR“R"', -C(NH)NHRa, -C(NH)NRbR°, )RE‘, )R3, -NRaC(O)Ra, ~NRaC(S)Ra, -NHS(O)2R3, —NR”S(O)2R”, -NHC(O)NHR3, -NHC(S)NHR“, -NR“C(O)NH3, -NR“C(S)NH2, -NR3C(O)NHR3, -NR“C(S)NHR“, -NHC(O)NR“R3, -NHC(S)NR“R“, -NRaC(O)NRaRa, -NR3C(S)NR3R3, -NHS(O)2NHR3, ~NRaS(O)3NHg, -NRast‘omHRa, -anmpuaaai ‘NRaS(O)3NR§Ra, ~NHR3, -NR“R”, Rd, 4%: «R2 and -11? ”Substituted cycioalkylene“ is a divalent substituted cycloalkyl.

“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. Heterocycloalkyi is also intended to include compounds in which ll]. one ofthc ring s is oxo substituted, i.e. the ring carbon is a carbonyl group, such as lactones and lactams. The point of attachment of the heterocycloaikyl ring is at a carbon or nitrogen atom such that a stable ring is retained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyirolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. "Heterocycloalkylene" is a divalent heterooycloalkyl. A "substituted heterocycloalkyl" is a heterocycloalkyl that is independently substituted, unless indicated otherwise, with one or more, ably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —OH, -NH2, N02, —CN, —C(O)OH, II, -C(O)NH2, —C(S)NH2, -S(O)2NH2, )NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, —OR”, —SR“, -OC(O)R“, -OC(S)R“, -C(O)R“, -C(S)R“, —C(O)OR“, -C(S)OR“, -S(O)Ra, —S(O)2R“, -C(O)NHR"’, -C(S)NHR“, -C(O)NR“R”, -C(S)NR"R“, -S(O)2NHRa, —S(O)2NRaR“, -C(NH)NHR", —C(NH)NRbR°, -NHC(O)R“, -NHC(S)R", -NR3C(O)R3, -NR3C(S)R"’, )2R“, -NR"S(O)2R“, -NHC(O)NHR“, —NHC(S)NIIR3, -NR“C(O)NH2, —NR“C(S)NH2, -NR“C(O)NHR“, -NR“C(S)NHR”, —NHC(O)NR3R3, )NR“R“, -NR“C(O)NR“R“, -NRaC(S)NR“Ra, - NHS(O)2NHR3, -NRaS(O)2NH2, -NR“S(O)ZNHR3, —NHS(O)2NR3R3, —NR“S(O)2NR“R“, —NHR“, —NR“Ra, —Rd, -R°, —Rf, and —Rg. "Substituted heterocycloalkylene" is a divalent substituted heterocycloalkyl.

“Aryl” alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5—7, more preferably 5-6, ring members. “Arylene” is a divalent aryl. A "substituted aryl” is an aryl that is independently substituted, unless indicated othcrwise, with or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any ble atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, -OH, —NH2, -NOZ, -CN, -C(O)OH, H, —C(O)NH2, -C(S)NH2, -S(O)2N112, -NHC(O)NH2, -NHC(S)NH2, «NHS(O)2NH3, -C(NH)NH2, —ORa, -SR3, -OC(O)R3, —OC(S)R“, —C(O)R“, —C(S)Ra, -C(O)OR“, —C(S)OR”, -S(O)R“, R", -C(O)NHR", -C(S)NHR”, —C(O)NR3R3, -C(S)NR3R3, -S(O)2NHR“‘, —S(O);NRBR“, —C(N H)NHR3, )NRbR°, —NHC(O)R"‘, ~NHC(S)R3, «NRaC(O)Ra, «NR3C(S)Ra, -NHS(O);R3, ~NRaS(O)3Ra, )NHR3, »NHC(S)N11Ra, ’NRaC{D)NH3, ‘NR3C(S)NH2, “NR3C(O)NHR”, ~NR"C(S)NHR3, ~NHC(O)NR3R3, ~NHC(S)NRaRa, ~NR3C(Q)NRaR“, ~NR3C(S)NRaRa, ~NIIS(O);NHRa, —NRaS(O)2NH2, —NRaS(O)2NHRa, —NHS(O)2NR3R3, «NRaS(/O)2NR3R3, -NHR3, —NR“R“, —Rd, —RC, —Rf, and -Rg. A "substituted e" is a divalent substituted aryl.

“Heteroaryl” alone or in ation refers to a clic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic ic group having 8 to £0 atoms, containing one or more, preferably [—4, more preferably 1-3, even more preferably l~2, heteroatoms independently ed from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as suliinyl, sulfonyl and N-oxide ofa tertiary ring nitrogen. A carbon or nitrogen atom is the point ofattachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, nyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, dinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, and indolyl. “Nitrogen containing heteroaryl” refers to aryl wherein any heteroatoms are N. “Heteroaiylene” is a divalent heteroaryl. A "substituted heteroaryl” is a heteroaryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also I, 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;, —N02, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, —C(S)NH2, -S(O)2NH2, —NHC(O)NH2, vNHC(S)NH3, —NHS(O)2NH2, -C(NH)NI 13, —OR“, -SR“, R“, R“, -C(O)Ra, -C(S)Ra, -C(O)OR“, -C(S)ORa, -S(O)Ra, —S(O)2R“, —C(O)NHR“, -C(S)NHRa, -C(O)NR“R"‘, R”RH, -S(O);NHRa, NR3R", -C(NH)NHR", -C(NH)NRbR°, -NHC(O)R“, -NHC(S)R“, O)Ra, -NRaC(S)R3, -NHS(O)2R3, -NRaS(O)2R“, —NHC(O)NHR“, -NHC(S)NHR8, -NRaC(O)NH2, -NRaC(S)NH2, O)NHR“, -NR“C(S)NHR“, -NHC(O)NRaRa, -NHC(S)NRaRa, -NRaC(O)NRaR3, -NRaC(S)NRaR“, -NHS(O)2NHR“, -NRaS(O)2NH2, -NR“S(O)2NHR“, —NHS(O)2NR“Ra, -NR“S(O)2NR“R“, -NHR"‘, -NR“R“, -Rd, -Re, -Rf, and -Rg.

“Substituted arylene” is a divalent substituted heteroaryl.

The variables Ra, Rb, R”, —Rd, -Re, -Rf and -RE as used in the description of optional substituents for alkyl, alkylene, alkenyl, alkynyl, lkyl, heterocycloalkyl, aryl and heteroaryl are defined as follows: each R“, R”, and RC are independently selected from the group consisting of -Rd, —Re, -Rf, and —Rg, or Rb and Rf 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 cycloalkyl or 5 or ? membered nitrogen containing heteroaryl are ally substituted with one or more, ably l, 2;. 35, 4 or ‘57 aiso 1: 2, or 3 tuents selected from the group consisting of halogen, -NO;, ‘CNt ~OH, NHE, —OR“, ~SR“, ~NHR”, *NR,“R“} —R*, and ~Ry; each —Rd is independently lower alkyl, wherein lower alkyl is optionally tuted with one or more: preferably 1, 2, 3, 4 or 5, also I, 2 or 3 substituents selected from the group consisting of fluoro, OH, NH}, N03, -CN, ‘C(O)OII, ~C(S)OH3 ~C(O)NH2, ~C’(S)NH2, ~S(O)3NH2, ~NHC(O)NH3, “NHC(S)NH3, wNustoigNug, ~C(NH)NH3, oak, asak, -OC(O)RE ‘oqsmi 410)ng —C(S)Rk, —C(0)OR‘: -C(S)0Rk, —S(O)Rk, —S(O)2Rk, -C(O)NHR", —C(S)NHRk, —C(O)NRkRk, »C(’S)NR"’R", -S(O)3NHR"’, -S(0)3NRkRk, -C(NH)NHR“, —C(NH)NR”‘R“, —NHC(O)Rk, -NHC(S)R“, -NRkC(O)R’: S)Rk, ~NHS(O)ng, —NRkS(O)2Rk, )NIIR", —N1~1C(S)NHR': —NRkC(O)NH2, —NR"C(S)NH2, —NRkC(O)NHRk, -NR“C(S)NHR", —NHC(0)NR“R", -NHC(S)NRkRk, —N RkC(O)NRkRk, —NR“C(S)NR*R", —NHS(O)2NHR", -NRkS(O)2NH2, —NRkS(O)ZNHRk, —NHS(O)2NRkRk, O)gNRkRk, ~NHRk, —NR“R“, —R‘, and .115 each vRe is independently lower alkenyl, wherein lower alkenyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, -Nog, —CN, —C(O)OH, H, —C(O)NH2, —C(S)NH2, —S(O)3NH2, -NHC(O)NH2, )NH3, —NIIS(O)3NH2, —C(NH)NH2, -OR“, -SRk, —OC(O)R“, —OC(S)R“, -C(O)Rk, —C(S)R", -C(O)ORk, -C(S)ORk. —S(O)Rk, -S(O)2Rk, —C(O)NHRk, —C(S)NIIR}‘, —C(O)NR"R", —C(S)NRkRk, —S(O)2NHRk, NR“R", NHRk, —C(NH)NR"‘R“, )Rk, )R“, -NRkC(O)Rk, ~NRkC(S)Rk, —NHS(O)2Rk, -NRkS(O)2Rk, —NHC(O)NHRk, —NHC(S)NHRk, —NR"C(O)NH2, ~NR"C(S)NH2, —NRkC(O)NHRk, —NR"C(S)NHR“, ~NHC(O)NRkRk, —NHC(S)NR"R", —NRkC(O)NRkRk, —NRkC(S)NRkRk, —NHS(O)2NHR1‘, -NR"S(O)2NH2, -NR"S(O)2NHR", —NHS(O)2NRkRk, —NRkS(O)2NR"R", —NHR“, -NRkR“, —Rh, and -RJ; each —Rfis independently lower alkynyl, wherein lower alkynyl is optionally substituted with or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, -Noz, —CN, —C(O)OH, —C(S)OH, —C(O)NH2, —C(S)NH2, —S(O)2NH2, —NHC(O)NH2, -NHC(S)NH2, )2NH2, —C(NH)NH2, —OR", —SR“, -OC(O)Rk, R“, —C(O)Rk, —C(S)Rk, —C(O)OR", —C(S)ORk, —S(O)R", ~S(O)3Rk, —C(O)NHR“, —C(S)NHR", »C(O)NR"R“', —C(S)NRkRk, —S(O)2NIIR“, -S(0)2NR“R“, —C(NH)NHR“, —C(NH)NR‘”R“, —NHC(O)Rk, -NHC(S)R", —NR"C(O)R", —NRkC(S)Rk, -NHS(O)2R", O)2Rk, —NHC(0)NHRk, -NHC(S)NHRk, -NR“C(O)NH;, —NR"C(S)NH2, —NR“C(O)NHR“, -NR“C(S)NHR“, —NHC(O)NRkRk, )NRkRk, O)NRkRk, -NR“C(S)NR“R“, -NHS(O)2NHR", -NR"S(O)2NH2, ~NRks<jokNHRE —NHS(O)2NRkRk, O)2NRkRk, -NIIR‘1 —NRkRk, -R': and -R3; each MR3 is independently ed 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 I, 2 or 3 substituents selected from the group consisting of halogen, «OH: »NH;,, -N02§ —CN, -C(O)OH, —C(S)OHg -C(O)NH3§ H3, nS(O)2NH2, «Nnciij'Hg, 9NHC(S)NHQ§ wreiswhixnb, —C(NH)NH3, aoni ~sn‘i —OC(O)R‘2 —OC(S)R", —C(O)R", ~C(S)R", —C(O)OR“, -C(S)0Rk, k, —S(O)2Rk, -C(O)NHR“, -C(S)NHRk, —C(O)NR“R*, -C(S)NR"R“} —S(O);NHR“, -S(0)2NRkRk, —C(NH)NIHIR", NR"‘R”, -NHC(O)R‘“, -NHC(S)R‘1 -NR“C(0)R“, —NRkC(S)Rk, -NHS(O)2R", -NRkS(O)3Rk, —NHC(O)NIIRk, ~NHC(S)NIIR", —NR"C(O)NH;, —NRkC(S)NH3, -NRkC(0)NHRE —NR“C(S)NHR", _NHC(O)NR"R“, ~NHC(S)NRI‘Rk, —NRkC(O)NRkRk, —NR*’C(S)NR“R*, )3NHR", —NRkS(O)2NH2, —NRkS(O)2NHRk, -NHS(O)2NR“R“, -NRkS(O)gNRkRk, —NHR", -NRKR“, —R“, —R‘, and ‘R’; wherein ng R'", and R" at each occurrence are independently selected from the group consisting of—Rh, —R', and —RJ, or Rm and RH combine with the nitrogen to which they are attached form a 5—7 membered helerocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5—7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing aryl are ally substituted with one or more, ably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -NOZ, -CN, ~OH, —NH2, OR“, —SR”, —NHR”, —NR”R”, —Rx, and —R’V; wherein each —Rh is independently lower alkyl optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, —NO;, —CN, —C(O)OH, —C(S)OH, —C(O)NH2, —C(S)NH2, —S(O)2NHZ, —NHC(O)NH2, —NHC(S)NH3, —NHS(O)2NHZ, —C(NH)NH2, —ORr, —SR', —OC(O)R", —OC(S)Rr, —C(O)R’, —C(S)Rr, Rr, —C(S)ORr, —S(O)Rr, —S(O)2Rr, -C(O)NHRr, —C(S)NHRr, —C(O)NRrRr, —C(S)NRrR‘, —S(O)2NHR’, —S(O)2NRrRr, —C(NH)NHRr, —C(NH)NRSR‘, —NHC(O)Rr, —NHC(S)Rr, —NR'C(O)R’, —NRrC(S)Rrg )2R‘, —NR'S(O)2RZ —NHC(O)NHR", —NHC(S)NHRr, —NR'C(O)NH2, —N’RrC(S)NH2, —NRrC(O)NHRr, —NRrC(S)NHRr, —NIIC(O)NR’R‘, —NHC(S)NR'R’, —N RrC(O)NRrR’, —NRrC(S)NRrRr, —NHS(O)3NHR’, vNRrS(O)2NH2, —NR‘S(O)ZNHRr, —NHS(O)3NRFR', —NRrS(O)2NRrRi, —NHRr, -NRrRr, -R‘, and —Rl; wherein each —R‘ is ndently selected from the group consisting of lower aikenyl and lower alkynyi. wherein lower alkenyl or lower l are optionally substituted with one or more, pre’fcrabiy 15 2, 3., 4 or 53 aise l, 2 er 3 substituents seiected frcm the group consisting of fluoro, ‘QH: *NHb ~N023 -CN, »C(O)C)H, Hg H2, -C(S)Nl~lg, ¢S(iO);NHzr »NHC(O)NH;, )NH3, ~NilS(O)gNHg, «C(NHNNV'Hg: -ORr, —SR‘, -OC(O)R’, —OC(S)R‘, —C(O)Rr, r9 -C(O)OR‘, -C(S)ORr, -S(O)Rr, —S(O)2Rr, 11Rr, ~C(S)NHRZ —C(O)NRrR', -C(S)NRrRr, —S(O)2NHR', —S(O)2NRrRr, NHRZ —C(NH)NRSR‘, )R’, ~NHC(S)R‘A, -NR'C(O)R', ~NR‘C(S)R”, ~NHS(O)3R‘, -NR'S(O)2R‘, QNHCtiCDWHR‘, ~NHC(S)NHR2 ~NR‘C(O)N H33 -NRYC(S)NIlg, ’NRIC(0)NHR: ~NR‘C(S)NHR", -NHC(0)NR‘R1 )NR’R’, O)NR’”R', -NRrC(S)NR‘R’, -NHS(O)2NHR’, -NR‘S(O)2NH3, —NR’S(O)2NHR", -NI-IS(O)2NR‘R‘, —NR'S(0)2NRrR: -NHR’, -NR'R: and _R~i; wherein each ~Rl is independently selected from the group consisting of cycloalkyl2 heterocycloaikyl, aryl, and aryl, 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 ting of halogen, —OH, ~NH23 -NO;, «CN, -C(O)OH,, ~C(S)OH, -C(O)NH3, ~C(S)NH2, —S(O)3NIIZ, ~NHC(O)NH3, -NHC(S)NH2, —NHS(O)2NH2, —C(NH)NH2, -OR', —SR', —OC(O)R’, ~OC(S)Rr, —C(O)R', —C(S)R’, -C(O)OR', —C(S)OR’, —S(O)R', —S(O)2R', HR’, -C(S)NHR', -C(O)NR’R', —C(S)NR'R', NHR', -S(O)3NR’R’, —C(NH)NI'IR', —C(NH)NRSR‘, )R', -NHC(S)R’, -NR‘C(O)R’, -NR’C(S)R’, -NHS(O)2R’, ~NR’S(O)2R', —NHC(O)NHR1 -NHC(S)NHR’, —NR'C(O)NH2, -NRFC(S)NH2, -NR'C(O)NHR’, -NR‘C(S)NHR', -NHC(O)NR’R’, —NHC(S)NR'R’, —NR’C(O)NR’R', -NR‘C(S)NR’R“, ~NHS(O)2NHR’, -NR’S(O)2NH2, -NR‘S(O)2NHR‘, —NHS(O)2NRrR', ~NR’S(O)2NR'R', -NHR’, —NR'R', cycloalkylamino, and —R"; wherein each R', R3, and RI at each occurrence are ndently selected from the group consisting oflower alkyl, CM alkenyl, CM l, cycloalkyl, heterocycloalkyl, aryl and aryl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of—Ry, fluoro, -OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided that any tution of the lower alkyl carbon bound to any —O—, —S—, or ‘N-, of -OR', ~SR', -C(O)OR’, ~C(S)OR’, —C(O)NHR', —C(S)NHR', -C(O)NR’R', —C(S)NR'R', —S(O)3NHRr, -S(O)2NR'R'§ —C(NH)NHR', -NRrC(O)Rr, —NR‘C(S)RZ -NR'S(O)2R’, -NHC(O)NHR’, )NHR‘, -NR’C(O)NH2, —NR’C(S)NH;, -NR’C(O)NHR', S)NHRY, —NHC(O)NRrR’, —NHC(S)NR‘R‘, O)NR'RF, -NR’C(S)NR‘R', ~NHS(O);NI IR’, -NR"S(O)2NH2; O)2NHR’; —NHS(O)2NR’R', -NR’S(O);NR’R‘, -NHR', or JV’RrRr is selected from the group consisting of fluoro and MR); and wherein (33-5 alkenyl or (33.6 alkynyl are optionally substituted with one or more preferably l, 2: 3, 4 or , also is 2, or 3 substituents selected from the group consisting owayg fluorog lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono—alkylamino, di—alkylamino, and cycloalkylamino, provided that any substitution of the C345 alkenyl or CM alkynyl carbon bound to any «Oat ”8—, or ~N~, oilOR’, ~SR‘, R', —C(S)0Rrg -C(O)NHR', ~C{S)NHR2 “C(OjNRrR’S —C(S)NRrRr, VS(O)2NHR‘, wS(O)3NRFR2 —C(NII)NHR1 ‘ 1 16 )R', S)R', -NR’S(O)3R‘, —NHC(O)NHR': ~NHC(S)NHRF, ~NR‘C(O)NH2, ~NR'C(S)NH2, O)NHR', -NR’C(S)NHRZ -NHC(O)NRIR', -NI’IC(S)NR’R', -NR‘C(O)NR‘R', -NR'C(S)NR'Rr, -NHS(O)2NHR’, -NR'S(O)2NH2, -NRFS(O)gNHRr, ~NHS(O)2NR’R‘, -NRrS(O)2NR‘R', ~NHR‘, or «NR’Rr is ed from the group consisting of fluoro, lower alkyl, fluoro substituted lower alkyl, or ~R’, and n 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, ‘NHZ, -N02, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkyl amino, di-alkyl amino, and lkylamino, or RS and Rt 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, -N02, -CN, -OH, -NH2, OR", -SR”, -NHR“, -NR"R”, -R‘, and ~R”; wherein each Ru is independently selected from the group consisting of lower alkyl, CM alkenyl, CH, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and aryl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -—Ry, fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower hio, mono- alkylamino, ylamino, and lkylamino, provided that any substitution of the lower alkyl carbon bound to the -O- of-—OR”, -S- of—SR", or -N- of ~NHR” is fluoro or -Ry, and n C34 alkenyl or C34 alkynyl are optionally substituted with one or more, ably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of ~R”, fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, tluoro substituted lower alkoxy, lower hio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, provided that any substitution ofthe CM alkenyl or C34; alkynyl carbon bound to the -O— of »»»0R“, -8— of ~SR”, or ~N~ of~NHR” is fluoro, lower alkyl, fluoro substituted lower alkyl, or ~R£ and wherein cycloalkyl. heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also I, 2, or 3 substituents selected from the group consisting of halogen, ~0H, -NH2, -NO;, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthios fluoro substituted lower alkylthio, mono- alkyl amino, (ii-alkyl amino, and cycloalkylamino; wherein each ~R" 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 ting of~Ry, fluoro, «OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono—alkyl amino, di—alkyl amino, and cycloalkylamino, and wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also I, 2, or 3 substituents selected from the group consisting 0f 41”, fluoro, —OH, -NH;, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower hio, fluoro substituted lower alkylthio, lkyl amino, di—alkyl amino, and cycloalkylamino; wherein each ~R” is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl, and heteroaryl, n cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are ally substituted with one or more, preferably 1, 2, 3, 4 0r 5, also 1, 2, or 3 substituents selected from the group consisting of n, -OH, -NH;, -NO;, —CN, lower alkyl, fluoro tuted lower alkyl, lower , fluoro substituted lower , lower alkylthio, fluoro substituted lower hio, mono-alkyl amino, yl amino, and cycloalkylamino.

“Lower alkoxy” denotes the group ~ORZ, where R2 is lower alkyl. "Substituted lower alkoxy” s lower alkoxy in which R2 is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description ofcompounds of Formula 1 (including Formulae la, 1b, lg and all sub-embodiments thereof), including descriptions of substituted cycloalkyl, cycloheteroalkyl, aryl and heteroaryl, attached at any available atom to e a stable compound. Preferably, substitution of lower alkoxy is with l, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkoxy” denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with l, 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 «0—, —S-, or ~N~ (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy '0‘. Further, where alkoxy is described as a substituent of another moiety, the alkoxy oxygen is not bound to a carbon atom that is bound to an —O-, —S-, or «N- of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety. [0221} “Lower alkylthio” denotes the group wSR“, where R33 is lower alkyl, “Substituted lower alkyithio” denotes lower alkylthio in which R“ is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula 1 (including Formulae la, lb, lg and all sub-embodiments thereof), including descriptions of substituted cycloalkyl, cycloheteroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound. Preferably, tution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkylthio” denotes lower hio in which the lower alkyl is tuted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with l, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkylthio are attached at any available atom to produce a stable compound, substitution of alkylthio is such that —O—, —S—, or ~N— (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkylthio —S-. Further, where alkylthio is described as a substituent of another moiety, the alkylthio sulfur is not bound to a carbon atom that is bound to an ~O—, —S—, or ~N- of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.

“Amino” or “amine” denotes the group ~Nllg. “Mono—alkylamino” s the group —NHRbb where Rbb is lower alkyl. “Di—alkylamino” denotes the group wNRbbRcc, where Rbb and Rcc are independently lower alkyl. “Cycloalkylamino” s the group —NRddRee, where Rdd and Ree combine with the nitrogen to form a 5—7 membered heterocycloalkyl, where the heteroeycloalkyl may contain an additional heteroatom within the ring, such as —O—, —N—, or ~S—, and may also be further substituted with lower alkyl. es of5—7 membered heteroeycloalkyl include, but are not limited to, pipcridine, piperazine, 4—methylpiperazine, morpholine, and thiomorpholine. While it is understood that when mono—alkylamino, di—alkylamino, or cycloalkylamino are substituents on other moieties that are attached at any available atom to produce a stable compound, the nitrogen of mono—alkylamino, di—alkylamino, or lkylamino as substituents is not bound to a carbon atom that is bound to an ~-O—, —S~, or —N- ofthe other moiety.

As used herein, the term Flt3 mediated disease or condition refers to a disease condition in which the biological function of Fit": affects the development and/or course of the disease or condition, and/or in which modulation of Flt3 alters the development, course, and/or symptomst These mutations ate the intrinsic tyrosine kinase activity ofthe receptor to different degrees and are models for the effect of modulation of Flt3 activity. A Flt3 mediated disease or ion es a disease or condition for which Flt3 inhibition provides a therapeutic benefit, eg. wherein treatment with Flt3inhibitors, including compounds bed herein, provides a therapeutic benefit to the subject ing from or at risk ofthe disease or condition.

As used herein, the term flt3 mediated disease or condition refers to a disease or condition in which the biological function of flt3 affects the pment and/or course ofthe disease or condition, and/or in which modulation of I18 alters the development, course, and/or symptoms, As used , the term “composition” refers to a fonnulation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceuticaliy active compound and at least one pharmaceutically acceptable carrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid stration ofthe material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For e, it is commonly required that such a al be essentially sterile, e.g., for injectibles.

In the present context, the terms “therapeutically effective” and "effective " indicate that the matcrials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical ion, and/or to prolong the survival ofthe subject being d.

Reference to particular amino acid residues in human Flt3 polypeptide is defined by the numbering corresponding to the F1t3 sequence in GenBank NP~004I 10.2 (SEQ ID N021).

Reference to particular nucleotide positions in a nucleotide sequence encoding all or a portion of Flt3 is defined by the numbering corresponding to the sequence provided in GenBank NMN44l 19 (SEQ ID NO:2).

The terms “Flt3” mean an enzymatically active kinase that contains a portion with greater than 90% amino acid sequence identity to amino acid residues including the ATP binding site of full-length F1t3 (e.g., human Flt3, e.g., the sequence NPw004l10.2 ID NO: 1), for a maximal , SEQ ent over an equal length segment; or that contains a portion with grcatcr than 90% amino acid sequence ty to at least 200 contiguous amino acids of native F113 and retains kinase activity. Preferably the sequence identity is at least 95, 7, 98, 99, or even 100%. Preferably the specified level of sequence ty is over a sequence at least l00~500, at least 200400, or at least 300 contiguous amino acid residues in length, Unless ted to the contrary, the term includes rcfcrcnce to wild—type c— Flt3, c variants, and mutated forms (e.g., having activating mutations).

The terms "Flt3 =mediated diseases or disorders." shall include es associated with implicating Flt3 ty, for example, the overactiviiy of Fit3, and ions that accompany with these diseases. The term "overactivity ofFlt3 " refers to either 1) F16 expression in cells which normally do not express Flt3; 2) Flt3 sion by cells which normally do not eXpress v; 3) increased Flt3 expression leading to unwanted cell proliferation; or 4) mutations leading constitutive activation of Fit}. Examples of " Flt3 ~mediated diseases or disorders" include disorders resulting from over stimulation of Flt3 or from abnormally high amount of Flt3 activity, due to abnormally high amount of Flt3 or mutations in Flt3. It is known that overactivity ofFlt3 has been implicated in the enesis ofa number of diseases, including inflammatory and autoimmune diseases, cell proliferativc disorders, neoplastic disorders and cancers as described herein.

The term " Flt3 —ITD allelic ratio" refers to the percentage of tumor DNA alleles harboring the Flt3-ITD mutation normalized to the percent blast cells in a patient sample. In embodiment2 a low Flt3—ITD allelic ratio is Where less than 25% alized tumor DNA alleles is a Flt3-ITD allele. In n embodiments, an intermediate Flt3—ITD allelic ratio is where between 25% and 50% ofnormalizcd tumor DNA alleles is a Flt3-ITD allele. In certain embodiments, a high Flt3-lTD c ratio is where greater than 50% ofnormalized tumor DNA alleles is a Flt3-ITD allele.

The "Flt3/ITD mutation-containing cells" include any ofcells having tandem ation mutation absent in healthy humans in a region of exons 14 to 15 in ajuxtamembrane region of Flt3, that is, cells highly expressing mRNA derived from the mutation, cells having increased Flt3- derived growth s caused by the mutation, cells highly expressing the mutant Flt3 protein, etc.

The "Flt3/lTD mutation-containing cancerous cells" include any of cancerous cells having tandem duplication on absent in healthy humans in a region of exons 14 to 15 in membrane region ofFlt3, that is, cancerous cells highly expressing mRNA derived fiom the mutation, cancerous cells having increased Flt3 -derivcd growth signals caused by the mutation, cancerous cells highly expressing the mutant Flt3 protein, etc. The "Flt3/ITD mutation-containing leukemic cells” include any ofleukemic cells having tandem duplication mutation absent in healthy humans in a region of exons 14 to l5 in ajuxtamcmbrane region of‘Flt33 that is, ic cells highly sing mRNA derived from the mutation, leukemic cells having increased FIB-derived growth signals caused by the mutation, leukemic cells highly expressing the mutant Flt} protein, etc As used herein, the terms “ligand” and “modulator" are used equivalently to refer to nd that changes (Lea, increases or decreases) the activity ofa target biomolecule, rag, an enzyme such as a kinase or l lly a ligand or modulator will be a small molecule: where “small molecule” refers to a compound with a molecular weight of 1500 daltons or less, or ably 1000 daltens or less, 800 daltons or less, or 600 daltons or less.

The terms "modulate", ”modulation" and the like refer to the ability of a compound to increase or decrease the function and/or expression of Flt3, where such function may include transcription regulatory ty and/or protein~binding. Modulation may occur in vitro or in viva.

Modulation, as described herein, includes the inhibition, antagonism, partial antagonism, tion, agonism or partial agonism of a function or characteristic ated with Flt3, either directly or indirectly, and/or the upregulation or downregulation of the expression of Flt3, either directly or indirectly. In a preferred embodiment, the modulation is direct Inhibitors or antagonists are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, inhibit, delay activation, inactivate, desensitize, or downregulate signal uction. Activators or ts are compounds that, e.g., bind to, ate, increase, open, activate, facilitate, enhance activation, activate, sensitize or upregulate signal transduction. The ability of a compound to inhibit the function ofFlt3 can be demonstrated in a biochemical assay, e.g., binding assay, or a cell—based assay.

In the context of compounds binding to a target, the term “greater y” indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, i.e., with a lower dissociation constant. In particular embodiments, the greater y is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or —fold greater affinity.

Also in the context of compounds binding to a biomolecular target, the term er city” indicates that a compound binds to a specified target to a r extent than to another ecule or biomolecules that may be present under relevant binding conditions, where binding to such other biomolecules produces a different biological activity than binding to the specified target. Typically, the specificity is with reference to a d set ofother biomolecules, e.g., in the ease of Flt3, other tyrosine kinases or even other type of enzymes. In particular embodiments, the greater specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or lOOO-fold greater specificity.

As used herein in connection with binding compounds or ligands, the term “specific for Flt3 kinase”, fic for Flt3”, and terms oflike import mean that a particular nd binds Fit3 to a statisticaily greater extent than to other kinases that may be present in a particular sample, Also, where biological activity other than binding is indicated, the term “specific for Flt3” tes that a particular compound has greater biological effect associated with binding Flt3 than to other tyrosine kinases, cg, kinase activity inhibition. Preferably, the specificity is also with respect to other biomolecules (not limited to tyrosine kinases) that may be present in a particular sample. The term “specific for Flt3 kinase”, “specific for Flt3”, and terms of like import mean that a particular nd binds to Fit? to a tically greater extent than to other kinases that be present in a particular sample. Also, where biological activity other than binding is indicated, the term “specific for Flt3” indicates that a particular compound has greater biological effect associated with binding Flt3than to other tyrosine kinases, e.g., kinase ty inhibition.

Preferably, the specificity is also with t to other biomoleeules (not limited to tyrosine kinases) that may be present in a particular . [0238} As used herein in connection with test compounds, binding compounds, and modulators (ligands), the term “synthesizing” and like terms means chemical synthesis from one or more precursor materials.

By “assaying” is meant the creation of experimental conditions and the gathering of data regarding a particular result ofthe experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate. A nd or ligand can be assayed based on its ability to bind to a particular target molecule or molecules.

The term "first line cancer y" refers to therapy administered to a subject as an initial regimen to reduce the number of cancer cells. First line therapy is also referred to as induction therapy, primary therapy and primary treatment. Commonly administered first—line therapy for AML is cytarabine—based therapy in which cytarabine is administered Often in combination with one or more agents selected from ubicin, idarubicin, doxorubicin, mitoxantrone, rnib, anine or gemluzumab ozogamicin. Common ns used in cytarabine—based therapy include the "7 + 3" or "5 + 2" therapy comprising administration ofcytarabine with anthracycline such as daunorubicin or idarubicin. Another first-line therapy is clofarabine-based y in which clofarabine is administered, often in combination with an anthracycline such as ubicin, idarubicin or doxorubicin. Other first-line therapy for AML are etoposide-based y in which etoposide is administered, Often in combination with mitoxantrone, and ally, with cytarabine. Another first— line therapy for AML (for subtype M3, also called acute promyelocytic leukemia) is all-trans-retinoic acid (ATRA). It is recognized that what is considered ”first line therapy" by those of ordinary skill in the art will continue to evolve as new anti-cancer agents are developed and tested in the clinics. A summary of the currently accepted approaches to first time treatment is described in NCCN Clinical Practice Guidelines in Oncology for acute myeloid Eeukemia and the NC] guideiines on acute myeloid leukemia treatment (see, eg, http:/i'\narw.cancer.gov/cancertopicsx’pdq/trcatment/adultAML/HealthProfessional/pagef). [0241 [ The term "second line cancer y" refers to a cancer ent that is administered a subject who does not respond to first line therapy, that is, often first line therapy is stered or who has a recurrence of cancer after being in remission, In n embodiments, second line therapy that may be administered includes a repeat of the initial successful cancer therapy, which may be any of the treatments described under "first line cancer therapy". In certain embodiments, second line therapy is the administration of gemtuzumab ozogamicin. In certain embodiments, investigational drugs may also be stered as second line therapy in a clinical trial setting. A summary of the currently accepted approaches to second line treatment is described in the NCCN Clinical Practice Guidelines in Oncology for acute myeloid leukemia and the NCI guidelines acute d ia treatment (see, eg, http://www.cancer.gov/cancertopies/pdq/treatment/adultAML/HealthProfessional/pageS).

The tenn "refractory" refers to wherein a subject fails to respond or is otherwise ant to cancer therapy or treatment. The cancer therapy may be first-line, second-line or any subsequently administered treatment. In certain embodiments, refractory refers to a condition where a subject fails to achieve complete remission after two induction attempts. A t may be refractory due to a cancer cell’s intrinsic resistance to a particular therapy, or the subject may be refractory due to an ed resistance that develops during the course of a particular therapy As used herein, the term “modulating” or ate” refers to an effect of altering biological activity, especially a ical activity associated with a particular biomoleeule such as Flt3.. For e, an agonist or antagonist of a particular biomolecule modulates the activity of that ecule, eg, an enzyme.

In the t of the use, testing, or screening of compounds that are or may be modulators, the term “contacting” means that the compound(s) are caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction between the nd and other ied material can occur.

As used herein in connection with amino acid or nucleic acid sequence, the term “isolate” indicates that the sequence is separated from at least a portion of the amino acid and/or nucleic acid sequences with which it would normally be associated.

In connection with amino acid or nucleic sequences, the term “purified” indicates that the particular molecule constitutes a significantly greater proportion of the biomolecules in a composition than in a prior composition, tag, in a cell culture. The greater tion can be 2— folda 5~fold, iO-fold or more greater.

I. General In one aspect, the present invention concerns compounds ofFormula 1; Formula Ia, Formula Ib, Formula Ig, Formula II, Formula Ila, Formula IIb, Formula IIc, Formula IId, Formula IIe, a IIf, Formula Hg, Formula IIh, Formula IIi, Formula IIj, Formula Ilk, Formula Hm, Formula Iln, Formula 110, Formula IIp, or Formula III, all bodimcnts thereof, compounds P—0001-P-0449, and any compounds as described , that are useful as inhibitors of an oncogenic Flt3 or a Flt3 mutant, and the use ofthc compounds in treating a subject suffering from diseases that are mediated by a mutated Flt3 kinasc.

FLT3 kinasc is a tyrosine kinase receptor involved in the tion and stimulation cellular proliferation. See e.g., and et al., Blood 100: 1532-42 (2002). The FLT3 kinase is a member of the class Ill receptor tyrosine kinase (RTKIII) receptor family and belongs to the same subfamily of tyrosine kinases as c-kit, c-fms, and the platelet-derived growth factor . and .beta. receptors. See e.g., Lyman et al., FLT3 Ligand in THE CYTOKINE HANDBOOK (Thomson el al., eds. 4th Ed.) (2003). The FLT3 kinasc has fivc immunoglobulin-like domains in its extracellular region as well as an insert region of 75-100 amino acids in the middle ofits cytoplasmic domain. FLT3 kinasc is activated upon the binding of the FLT3 ligand, which causes or dimerization. zation of the FLT3 kinase by FLT3 ligand activates the intracellular kinase activity as well as a cascade ofdownstream substrates including Stat5, Ras, atidylinositolkinasc (PI3K), mma., Erk2, Akt, MAPK, SHC, SHPZ, and SHIP.

See e.g., Rosnet et al., Acta Haematol. 95: 218 (I996); Hayakawa et al., Oncogene 19: 624 (2000); Mizuki et al., Blood 96: 3907 (2000); and Gilliand et al., Curr. Opin. Hematol. 9: 274-81 (2002).

Both membranc«b0und and soluble FLT3 ligand bind, dimerize, and subsequently activate the FLT3 kinase.

In normal cells, immature poietic cells, typically CD34+ cells, ta, gonads, and brain express FLT3 kinase. See, e.g., Rosnet, et al., Blood 82: 9 (1993); Small et al., Proc. Natl. Acad. Sci. USA. 91: 459-63 (1994); and Rosnet et al.,, Leukemia 10; 23 848 (1996).

However. efficient stimulation of proliferation via FLT} kinasc typically requires other hematopoietic growth factors or interleukins. FLT3 kinase also plays a critical role in immune function through its regulation ofdendritic cell proliferation and differentiation. See e.g., McKenna et al., Blood 95: 3489-97 (2000).

Numerous hematologic malignancies express FLT3 kinase, the most prominent of which is AML. See e.g., Yokota et al., Leukemia 1 1: 1605-09 (1997). Other FLT3 expressing malignancies include B~precursor cell acute Iymphoblastic leukemias, myeloriysplastic leukemiasa T—ceii acute lymphoblastic leukemias, and chronic myelogenous leukemias.

See e.g., Rasko et al., Leukemia 9: 2058-66 (1995).

FLT3 kinase mutations ated with hematologic malignancies are activating mutations. In other words, the FLT3 kinasc is constitutively activated without the need for binding and dimerization by FLT3 ligand, and therefore stimulates the celi to grow continuously.

Several studies have identified tors of FLT3 kinase activity that also t kinase activity of related receptors, e.g., VEGF receptor (VEGFR), PDGF receptor ), and kit or kinases. See e.g., Mendel et al., Clin. Canccr Res. 9: 327-37 ; O’Farrell et al., Blood 101: 3597-605 (2003); and Sun et al., J. Med. Chem. 46: 1116-19 (2003).

Such compounds effectively inhibit FLT3 kinase-mediated orylation, cytokine production, cellular proliferation, resulting in the induction of apoptosis. Sec e.g., Spiekermann et al., Blood 101: 1494-1504 (2003). Moreover, such compounds have potent antitumor ty in vitro and in vivo.

In some embodiments, the oncogenic Flt3 or Flt3 mutant is encoded by a Flt3 gene with an internal tandem duplication (ITD) on in thejuxtamembrane as bed in US. Patent No. 6,846,630, which is herein incorporated by reference. In certain embodiments, the oncogenic Flt3 or Flt3 mutant encoded by flt3 with ITD mutations has one or more mutations at residues F691, D835, Y842 or combinations thereof. In some embodiments, the oncogenic Flt3 or Flt3 mutant has one or more mutations are selected from F691L, D835V/Y, H or combinations thereof.

In some embodiments, the subject has an Flt3 gene mutation encoding an Flt3 mutant having an amino acid substitution at residues F691, D835, Y842 or combinations thereof. In certain instances, the amino acid substitution is selected from F691L, D835V/Y, Y842C/H combinations thereof.

In some embodiments, the invention provides a method ofinhibiting an oncogenic Flt3 or a mutant Flt3. The method includes contacting the Flt3 kinase with a compound as described herein. In some embodiments, the oncogenic Flt3 or Flt3 mutant is encoded by an F lt3 gene having an [TD mutation. In some ments, the oncogenic Fifi or Flt3 mutant encoded by Flt3 gene with an ITD mutation has one or more mutations at residues F691, D835, Y842 or combinations thereof. In some embodiments, the oncogenic F It3 or F16 mutant has one or more mutations are selected from F691 L, D835V/Y, Y842C/H or combinations thereof. logic cancers, also known as hematologic or poietic malignancies, are cancers of the biood or bone marrow; incindin leukemia and l m homat Acute mveloP cnous J g leukemia (AML) is a clonal poietic stem cell leukemia that represents about 90% of all acute ias in adults with an incidence of3.9 per i00,000 (See e.g., Lowenberg et al., N. Eng. .1. Med. 341: 1051-62 (1999) and Lopesde Menezes, et al, Ciin. Cancer Res. (2005), ll(l4):5281— 5291). While chemotherapy can result in complete remissions, the long term disease-free survival rate for AML is about 14% with about 7,400 deaths from AML each year in the United States.

Approximately 70% of AML blasts express wild type FLT3 and about 25% to about 35% express FLT3 kinase receptor ons which result in constitutively active FLT3.

Two types of activating mutations have been identified, in AML ts: internal tandem duplications (I'l‘Ds) and point mutation in the activating loop of the kinase domain. FLT3—ITD mutations in AML patients is indicative ofa poor sis for survival, and in patients who are in remission, FLT3- ITD mutations are the most significant factor adversely affecting relapse rate with 64% of patients having the mutation relapsing Within 5 years (see Current Pharmaceutical Design (2005), 1 113449- 3457. The prognostic significance of FLT3 mutations in clinical studies suggests that FLT3 plays a driving role in AML and may be ary for the development and maintenance ofthe disease.

Mixed Lineage Leukemia (MLL) e translocations of some 1 1 band q23 (l lq23) and occur in approximately 80% ofinfant hematological malignancies and 10% of adult acute leukemias. Although certain I lq23 translocation have been shown to be ial immortalization of hematopoietic progenitors in vitro, a secondary genotoxic event is ed to develop leukemia. There is a strong concordance between FLT3 and MLL fusion gene expression, and the most consistently overexpressed gene in MLL is FLT3. Moreover, it has been shown that activated FLT3 together with MLL fusion gene expression induces acute leukemia with a short latency period (see Ono, et al., J. of al Investigation (2005), l 15:919—929). Therefore, it is believed that Fl.T3 signally is involved in the development and maintenance ofMLL (see Armstrong, et al., Cancer Cell (2003), 3:173—183).

The FLT3—ITD mutation is also present in about 3% of cases ofadult myelodysplastic syndrome and some cases of acute cytic leukemia (ALL) (Current Pharmaceutical Design , 11:3449-3457).

FLT3 has been shown to be a client protein of Hsp90, and l7AAG, a benzoquinone ein antibiotic that inhibits Hsp90 activity, has been shown to disrupts the association of Flt3 with Hsp90. The growth of leukemia cell that express either wild type FLT3 or FLT3~ITD mutations was found to be inhibited by treatment with l7”AAG (Yao, et al., Clinical Cancer Research (2003), 9:44 83—4493).

The compounds as described herein are useful for the treatment or prevention of haematoiogicai malignancies, including, but not limiting to, acute c leukemia (AML); mixed lineage leukemia (MLL); acute promyelocytic leukemia; acute lymphocytic leukemia, acute lymphoblastic leukemia, myeloid sarcoma; T—cell type acute lymphocytic leukemia (T—ALL); B— cell type acute lymphocytic leukemia (B—ALL); chronic myelomonocytic leukemia (CMML); myelodysplastic syndrome; myeloproliferative disorders; other proliferative disorders, including? but not limiting to, cancer; autoimmune disorders; and skin disorders, such as psoriasis and atopic dermatitis.

II. Binding Assays The methods of the present invention can involve assays that are able to detect the g of compounds to a target molecule. Such binding is at a statistically significant level, preferably with a nce level of at least 90%, more ably at least 95, 97, 98, 99% or greater confidence level that the assay signal ents binding to the target molecule, 1'. a, is distinguished from ound. Preferably controls are used to distinguish target binding from non-specific binding. A large variety of assays indicative of binding are known for different target types and can be used for this invention.

Binding compounds can be characterized by their effect on the activity of the target molecule. Thus, a “low activity” compound has an inhibitory concentration (ICSO) or ive concentration (ECSO) of greater than 1 pM under standard conditions. By “very low activity” is meant an ICSO or ECjU of above 100 uM under standard conditions. By “extremely low activity” is meant an ICSO or ECSO ofabove 1 mM under rd conditions. By “moderate activity” is meant an ICSO or ECSO of 200 nM to 1 pM under standard conditions. By ately high activity” is meant an ICSO or EC50 of 1 nM to 200 nM. By “high ty” is meant an IC50 or EC50 of below 1 nM under standard conditions. The [€50 or ECSO is defined as the concentration of compound at which 50% ofthe activity ofthe target le (e.g. enzyme or other protein) activity being measured is lost or gained relative to the range of activity observed when no compound is present.

Activity can be measured using methods known to those of ordinary skill in the art, e.g., by measuring any able product or signal produced by occurrence of an enzymatic reaction, or other activity by a protein being measured, By “background signal" in reference to a binding assay is meant the signal that is recorded under standard conditions for the particular assay in the e of a test compound, molecular scaffold, or ligand that binds to the target molecule. Persons of ordinary skill in the art will realize that accepted methods exist and are widely available for determining background signal.

By ard deviation” is meant the square root of the ce. The variance is a measure of how spread out a distribution is. It is computed as the average squared deviation of each number from its mean. For example, for the s 1, 2, and 3, the mean is 2 and the variance is: 02: (1-2)3+g2-2)2+g3—2)2 20.667.

Surface Plasmon Resonance Binding ters can be measured using surface n resonance, for example, with a BIAcore'JD chip (Biacore, Japan) coated with immobilized binding components. Surface plasmon resonance is used to characterize the microscopic association and dissociation constants of reaction between an st or other ligand directed t target molecules. Such methods are generally described in the following references which are incorporated herein by reference. Vely F. et al., (2000) BlAcore® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology. 121 :3 13-21; Liparoto et al., (1999) Biosensor analysis of the eukin-2 or complex, Journal of Molecular Recognition. 12:316-21; Lipschultz et al., (2000) mental design for analysis of complex cs using surface plasmon resonance, Methods. 20(3):310-8; Malmqvist., (1999) BlACORE: an affinity biosensor system for characterization ofbiomolecular interactions, Biochemical Society Transactions 27:33 5—40; Alfthan, (1998) Surface plasmon nce biosensors as a tool in antibody engineering, Biosensors & Bioeleclronics. 13:653-63; Fivash et al., (1998) BIAcore for macromolecular interaction, Current Opinion in Biotechnology. 9:97—101; Price et al.; (1998) Summary report on the ISOBM TD—4 Workshop: analysis of 56 onal antibodies against the MUCl mucin. Tumour Biology 19 Suppl 1:1-20; Malmqvist et a1, (1997) ecular interaction analysis: affinity biosensor technologies for functional analysis ofproteins, Current Opinion in Chemical Biology. 12378-83; O’Shannessy et al., (1996) Interpretation of deviations from pseudo-first-order kinetic behavior in the terization of ligand binding by biosensor technology, Analytical Biochemistry. 236:275—83; Malmborg et 31., (1995) BIAcore as a tool in antibody engineering, Journal of Immunological Methods. 183:7-13; Van Regenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in Biologicai Standardization, 83:143-51; and O’Shannessy, (1994) Determination of kinetic rate and equilibrium binding constants for macromolecuiar interactions: a critique ofthe surface n resonance literature, Current Opinions in Biotechnology. 5:654]: BlAcore® uses the l properties of surface piasmon resonance (SPR) to detect alterations in protein concentration bound to a dextran matrix lying on the surface of a gold/glass sensor chip interface, a dextran biosensor . In brief, proteins are covalently bound to the dextran matrix at a known concentration and a ligand for the protein is injected through the dextran matrix. Near infrared light, directed onto the opposite side of the sensor chip surface is reflected and also induces an evanescent wave in the gold film, which in turn, causes an intensity dip in the reflected light at a particular angle known as the nce angle. If the refractive index of the sensor chip surface is altered (eg. by ligand g to the bound protein) a shift occurs in the resonance angle. This angle shift can be measured and is expressed as resonance units (RUs) such that 1000 RUs is equivalent to a change in surface protein concentration of 1 ng/mmz. These changes are displayed with respect to time along the y~axis of a sensorgram, which depicts the ation and dissociation of any biological reaction.

High Throughput Screening (HTS) Assays HTS typically uses automated assays to search through large s of compounds for a desired activity. Typically HTS assays are used to find new drugs by screening for chemicals that act on a particular enzyme or molecule. For example, ifa chemical inactivates an enzyme it might prove to be effective in preventing a process in a cell which causes a disease. High throughput methods enable chers to assay thousands ofdiffercnt chemicals against each target molecule very quickly using robotic handling systems and automated analysis of results.

As used herein, “high throughput screening” or “HTS” refers to the rapid in vitro screening of large numbers of compounds (libraries); generally tens to hundreds of thousands of compounds, using robotic screening assays. Ultra high—throughput Screening (uHTS) generally refers to the high—throughput screening accelerated to greater than 100,000 tests per day.

To achieve high—throughput screening, it is advantageous to house samples on a multicontainer carrier or platform. A ontainer carrier facilitates measuring reactions of a plurality of candidate compounds simultaneously. well microplates may be used as the r. Such multi—well microplates, and methods for their use in numerous assays: are both known in the art and cially available.

Screening assays may include controls for es of calibration and confirmation of proper manipulation of the components of the assay. Blank wells that contain all of the reactants but no member of the chemical library are usualiy included. As another example, a known inhibitor (or activator) of an enzyme for which tors are sought, can be incubated with one sample of the assay, and the resulting se (or increase) in the enzyme activity used as a ator or control. It will be appreciated that modulators can also be combined with the enzyme activators or inhibitors to find modulators which inhibit the enzyme activation or repression that is otherwise caused by the presence of the known the enzyme modulator.

Measuring tic and Binding Reactions During Screening Assays Techniques for measuring the progression of enzymatic and binding reactions, e.g., in multicontainer carriers, are known in the art and include, but are not limited to, the ing.

Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxides, as described in Gordon, A. J. and Ford, R. A., (1972) The Chemist's Companion: A Handbook Of Practical Data.

Techniques, And References, John Wiley and Sons, N.Y., Page 43 7.

Fluorescence spectrometry may be used to monitor the generation of reaction products.

Fluorescence methodology is generally more ive than the absorption methodology. The use of fluorescent probes is well known to those skilled in the art. For s, see Bashford et al., (1987) Spectrophotometry and Spectrofluorometrv: A Practical Approach, pp. 91—1 14, IRL Press Ltd; and Bell, (1981) Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press.

In spectrofluorometric methods, enzymes are exposed to substrates that change their intrinsic fluorescence when processed by the target enzyme. Typically, the substrate is orescent and is converted to a fluorophore through one or more reactions. As a non—limiting example, SMase activity can be detected using the Amplex® Red reagent (Molecular , Eugene, OR). In ordcr to mcasurc sphingomyclinase activity using Amplex® Red, the ing reactions occur. First, SMase hydrolyzes sphingomyelin to yield ceramide and phosphorylcholine.

Second, alkaline phosphatase hydrolyzes phosphorylcholine to yield choline. Third, e is oxidized by e oxidase to betaine. Finally, H202, in the presence of horseradish peroxidase, reacts with Amplex® Red to produce the fluorescent product, Resorufin, and the signal therefrom is detected using spectrofluorometry.

Fluorescence polarization (FF) is based on a decrease in the speed of molecular rotation ofa fluorophore that occurs upon binding to a larger molecule, such as a receptor protein, allowing for zed fluorescent emission by the bound ligand. FF is empirically determined by measuring the vertical and ntal components of fluorophore emission following excitation with plane zed light. Polarized emission is increased when the molecular on of a fluorophore is reduced. A fluorophore produces a larger polarized signal when it is bound to a larger molecule (Le. a receptor), slowing lar rotation of the lluorophore. The magnitude of the polarized signal relates quantitatively to the extent of fluorescent ligand g. Accordingly, zation of the “bound” signal depends on maintenance of high affinity binding.

FF is a homogeneous technology and reactions are very rapid, taking seconds to minutes to reach equilibrium. The reagents are stable, and large batches may be prcpared, ing in high reproducibility. Because of these properties, F? has proven to be highly automatable, often performed with a single incubation with a , premixed, tracer—receptor reagent. For a review. see Owickiet al., (1997), Application of Fluorescence zation Assays in High—Throughput Screening, Genetic Engineering News, 17:27.

FF is particularly desirable since its readout is independent of the emission intensity (Checovich, W. J., et al., (1995) Nature 375:254-256; Dandliker, W. B., et al., (1981) Methods in Enzymology 743528) and is thus insensitive to the presence of colored compounds that quench fluorescence emission. FF and FRET (see below) are well—suited for identifying compounds that block interactions between sphingolipid receptors and their ligands. See, for example, Parker et al., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor—ligand—binding and /phosphatase assays, J Biomol Screen 5:77—88.

Fluorophores derived from sphingolipids that may be used in FF assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and one ceramide flurophores. These are, respectively, N-(4,4—difluoro-S,7—dimethyl-4—bora-3a,4a—diaza—s— indacene- 3—pentanoyl)sphingosyl phosphocholine (BODIPY® FL ingomyelin); N-(4,4- difluoro-5,7—dimethyl—4—bora-3a,4a—diaza—s—indacene- canoyl)sphingosyl phosphocholine (BODIPY® FL hingomyelin); and —difluoro—5,7—dimethyl—4-bora—3a,4a—diaza—s— indacene- 3-pentanoyl)sphingosine (BODIPY® FL C5-ceramide). US. Patent No. 4,150,949, oassay for gentamicin), discloses fluorescein—labelled gentamicins, including fluoresceinthiocarbanyl gentamicin. Additional fluorophores may be prepared using methods well known to the skilled artisan.

Exemplary —and—polarized cence readers include the POLARION® fluorescence polarization system (Tecan AG, I’Iombrechtikon, Switzerland). l multiwell plate readers for other assays are ble, such as the VERSAMAX® reader and the SPECTRAMAXOD multiwell plate spectrophotometer (both from Molecular Devices).

Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interaction and has been described. See, e.g., Helm et al., (1996) Curr. Biol. 6:178-182; Mitra et al... (1996) Gene 373:13n17; and Selvin et al., (1995) Meth. Enzymol. 246500—345. FRET detects the transfer ef energy between two fluorescent substances in close proximity, having known excitation and emission ngths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in ity, such as when a protein specifically interacts with a target molecule, the resonance energy can be transferred from one excited molecule to the other. As a result, the emission spectrum of the sample shifts, which can be measured by a eter, such as a fMAX ell fluorometer (Molecular Devices, Sunnyvale Calif.) Scintillation proximity assay (SPA) is a particularly useful assay for detecting an interaction with the target le. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al., (1997) J. Lipid Res. 38:2365—2373; Kalil et al., (1996) Anal.

Biochem. 243282—783; Undenfriend et al., (1987) Anal. Biochem. 161:494—500). See also US.

Patent Nos. 4,626,513 and 4,568,649, and European Patent No. 0,154,734. One commercially available system uses FLASHPLATE® scintillant—coated plates (NEN Life Science ts, Boston, MA).

The target molecule can be bound to the scintillator plates by a variety of well known means. Scintillant plates are available that are derivatized to bind to fusion proteins such as GST, His6 or Flag fusion proteins. Where the target molecule is a protein complex or a multimer, one protein or subunit can be attached to the plate first, then the other components of the complex added later under binding conditions, ing in a bound complex.

In a typical SPA assay, the gene products in the expression pool will have been radiolabeled and added to the wells, and allowed to interact with the solid phase, which is the immobilized target molecule and llant coating in the wells. The assay can be measured immediately or allowed to reach equilibrium. Either way, when a radiolabel becomes sufficiently close to the scintillant coating, it produces a signal detectable by a device such as a TOPCOUNT NXT® microplate scintillation counter (Packard BioScience C0,, Meriden Conn). If a radiolabeled expression product binds to the target molecule, the radiolabel remains in proximity to the scintillant long enough to produce a detectable signal.

In contrast, the d proteins that do not bind to the target molecule, or bind only briefly, will not remain near the llant long enough to produce a signal above background.

Any time spent near the scintillant caused by random an motion will also not result in a significant amount of signal. se, residual unincorporated radiolabel used during the expression step may be present, but will not generate significant signal because it will be in solution rather than interacting with the target le. These non—binding interactions will therefore cause a certain level of background signal that can be mathematically removed. If too many signais are ed, salt or other modifiers can be added directly to the assay plates until the desired specificity is obtained (Nichols et aL, (1998) Anal. Biochem. 257:112»119).

III. Kinase Activity Assays A number of different assays for kinase activity can be utilized for assaying for active modulators and/or ining specificity of a tor for a particular kinase or group or kinases. In addition to the assay mentioned in the Examples beiow, 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 described assays that can be used.

Additional alternative assays can employ binding inations. For example, this sort of assay can be formatted either in a fluorescence resonance energy er (FRED , or using an creen (amplified luminescent ity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phospho-specilie antibody. lV. Alternative Compound Forms or Derivatives (a) s, Prodrugs, and Active Metabolites Compounds contemplated herein are described with nce to both generic formulae and specific compounds. In addition, the invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention. These include, for example, ers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (e.g. ylic acid esters), solvated forms, different crystal forms or polymorphs, and active metabolites. (b) Tautomers, Stereoisomers, Regioisomers, and Solvated Forms It is understood that some compounds may t tautomerism. In such cases, the formulae provided herein expressly depict only one ofthe possible tautomeric forms It is therefore to be understood that the formulae provided herein are intended to represent any tautomeric form ofthe depicted compounds and are not to be limited merely to the specific tautomeric form depicted by the drawings of the formulae. se, some ofthe 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 l orientation of the atoms. For example, compounds may be optical stereoisomers, which contain one or more chiral s, and therefore, may exist in two or more stereoisomeric forms (eg. enantiomers or diastereomers), Thus, such compounds may be present as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, andg’or mixtures of enantiomers andior diastereomers, As another example. stereoisomers include geometric isomers, such as 615- or trans— orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, tes and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all sueh steroisomeric forms are included within the formulae provided herein.

In some embodiments, a chiral compound of the present invention is in a form that contains at least 80% ofa single isomer (60% enantiomeric excess (“ea”) 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% ee. or d.e.), or 99% (98% e.e. or d.e.). As generally understood by those skilled in the art, 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 omerically pure. In some embodiments, the compound is present in optically pure form.

For compounds in which synthesis es on ofa single group at a double bond, particularly a carbon-carbon double bond, the addition may occur at either of the double bond- linked atoms. For such compounds, the present invention includes both such regioisomers.

Additionally, the formulae are intended to cover solvated as well as unsolvated forms of the identified structures. For example, 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. (c) Prodrugs and Metabolites In addition to the present ae and compounds described herein, the invention also includes prodru gs (generally pharmaceutically acceptable gs), active lic derivatives (active metabolites), and their pharmaceutically acceptable salts.

Prodrugs are compounds or ceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound. Prodrugs include, without limitation, esters, amidcs, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is ve, or less active than the active compound, but may provide one or more of ageous handling, administration, and/or lic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated tically to yield the active nd, or a compound which, upon further chemical on, yields the active compound.

In this context. a common example of a prodrug is an alkyl ester of a carboxylic acid.

Relative to compounds of Formula I, Formula Ia, Formula lb, Formula lg, Formula II, Formula IIa, a Ill), Formula llc, Formula Ild, Formula IIe, Fonnula IIf, Formula IIg, a llh, Formula Ili, Formula llj, Formula llk, Formula llm, Formula lln, Formula 110, Formula Ilp, or Fonnula 111, further examples include, t limitation, an amide or carbamate derivative at the pyrrole nitrogen (i.e. Ni) ofthe azaindole core.

As described in IhfiilflégfiifiéQXMSZQLCDJQ Chemistry, Ch. 31—32 (Ed. h, Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non~ exclusive ries, bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug nd, 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 lic products should have acceptably low toxicity. Typically, the formation of active drug compound involves a metabolic process or reaction that is one of the follow types: Oxidative reactions: Oxidative reactions are ified without limitation to reactions such as oxidation of alcohol, yl, and acid functionalities, ylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, ion of aromatic carbon atoms, ion of carbon— carbon double bonds, oxidation of nitrogen—containing onal 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: ive 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 functional groups, and other reduction reactions.

Reactions without change in the oxidation state: Reactions without change in the state of oxidation are exemplified without limitation to reactions such as hydrolysis ofesters and others, 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 ort moiety, eg, that es uptake andj’or localized ry to a ) of action. Desirably for such a carrier prodrug, 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. For prodrugs where the transport moiety is intended to e uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow reiease, cg, certain poiymers or other es, such as cyclotlextrins.

(See, eg, Cheng et al., US. Patent Publ. No. 2004/0077595, App. Ser. No. 10/656,838, incorporated herein by reference.) Such 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 pecificity, decreased toxicity and adverse ons, and/or improvement in drug formulation (e.g. stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, ilieity can be increased by esterification of hydroxyl groups with lipophilie carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.

Prodrugs may proceed from g 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 lites, overlap with gs as described above, e_g., bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body ofa subject. Of these, active metabolites are such pharmacologically active derivative nds. For prodrugs, thc prodrug compound is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound may be either an active compound or may be an inactive prOdrug.

Prodrugs and active lites may be identified using routine techniques known in the art. See, e.g., Bertolini et al., 1997, J. Med. Chem, 1-2016; Shan et al., 1997, JPharm Sci 86(7):756-757; Bagshawe, 1995, Drug Dev. Res, —230; Wermuth, supra. (d) Pharmaceutically acceptable salts Compounds can be ated as or be in the form of ceutically acceptable salts.

Contemplated pharmaceuticaliy acceptable salt forms include, t limitation, mono, bis. tris, tetrakis, and so on. ceutically 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 t preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and sing 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, p~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, p—toluenesulfonic acid, cyclohexylsulfamic acid, c acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, nolamine, lamine, t—butylamine, ethylenediamine, ine, ne, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional , such as carboxylic acid or phenol are present. For example, see Remington’s Pharmaceutical Sciences, 19‘h ed., Mack hing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the ase form ofa compound can be dissolved in a suitable t, such as an aqueous or aqueous—alcohol solution containing the appropriate acid and then isolated by evaporating the solution. In another example, a salt can be prepared by reacting the free base and acid in an organic solvent.

Thus, for example, ifthe particular compound is a base, the d pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment ofthe 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, or the like. rly, if the particular compound is an acid, the desired pharmaceuticaily 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. Illustrative es of suitable salts include organic salts derived from amino acids, such as L~glycine, ne, and L—arginine, ammonia, primary, ary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and nic salts d from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and m.

The pharmaceutically acceptable salt of the different compounds may be present as a complex. Examples of complexes include 8—chlorotheophylline x (analogous to, eg, dimenhydrinate: diphenhydramine rotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes.

Unless specified to the contrary. specification ofa nd herein includes pharmaceutically acceptable salts of such compound. (e) rphic forms In the ease of agents that are solids, it is understood by those skilled in the art that the nds and salts may exist in different l or polymorphic forms, all of which are intended to be within the scope ofthe present invention and specified fonnulae.

V. Administration The methods and compounds will typically be used in therapy for human subjects.

However, they may also be used to treat similar or cal tions in other animal subjects.

In this context, the terms ct,” “animal subject,” and the like refer to human and non~human vertebrates, e.g. mammals, such as man primates, sports and commercial animals, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines.

Suitable dosage forms, in pait, depend upon the use or the route of administration, for example, oral, transdermal, transmueosal, 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 ofPharmacy, 21“ edition, Lippineott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein).

Compounds ofthe present invention (Le. Formula 1, Formula Ia, Formula lb, Formula lg, Formula II, Formula Ila, Formula IIb, Formula IIc, Formula Ild, Formula He, Formula 11f, Formula lIg, Formula IIh, Formula Ili, Formula Ilj, Formula llk, Formula Ilm, a Iln, Formula Ho, Formula Up, or Formula III, and all sub-embodiments disclosed herein) can be formulated as pharmaceutically acceptable salts. rs or excipients can be used to produce compositions. The rs or excipients can be chosen to facilitate stration ofthe nd Examples of carriers include calcium ate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and logically compatible solvents. Examples of physiologically compatible solvents include sterile ons of water for injection (WFI), saline solution, and dextrose.

The compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalant.

In some embodiments, oral administration is preferred. For oral administration, for e, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.

For inhalants, compounds of the invention may be formulated as dry powder or a le solution, suspension, or aerosol. Powders and solutions may be formulated with suitable additives known in the art. For example, 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 propionate, beclomethasone dipropionate, inolone acetonide, budesonide, and mometasone furoate', beta agonists such as albuterol, salmeterol, and erol; anticholinergic agents such as ipratropium bromide or tiotropium; vasodilators such as treprostinal and iloprost; s such as DNAase; eutic proteins; immunoglobulin antibodies; an ucleotide, 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 ; and sodium cromoglycate.

Pharmaceutical preparations for oral use can be obtained, for e, 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 cxcipients 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, ypropylmethyl-cellulose, sodium carboxymethylccllulose (CMC), and/or nylpyrrolidonc (PVP: povidone). It‘desired, disintegrating agents may be added, such as the eross~linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly- vinylpyrrolidone, carbopol gcl, hylene 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. In soft es, the active nds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid n, or liquid polyethylene glycols (PEGS). In addition. stabilizers may be added.

Alternatively, injection (parenteral administration) may be used, eg, intramuscular, intravenous, intraperitoneal, and/or subcutaneous. For injection, 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. In addition, the compounds may be formulated in solid form and redissolved or suspended ately prior to use. Lyophilized forms can also be produced.

Administration can also be by transmucosal, topical, transdermal, or nt means. For transmucosal, l or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such pcnctrants are generally known in the art, and include, for e, for transmucosal stration, bile salts and fusidic acid tives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for e, may be h nasal sprays or suppositories (rectal or vaginal).

The topical compositions of this invention are formulated ably 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 pctrolatum (White soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C”). The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be ed as well as agents impaiting color or fragrance, if desired.

Creams for l application are preferably formulated from a mixture of mineral oil, self- emulsi zing beeswax and water in which mixture the active ingredient, dissolved in a small amount solvent (eg, an oil), is admixed. Additionally, stration by transdermal means may comprise a transdermal patch or ng such as a bandage impregnated with an active ingredient and optionaliy one or more carriers or ts known in the art. To be administered in the form of a transderrnal delivery system, the dosage administration will, of course, be uous rather than intermittent throughout the dosage regimen.

The amounts of various nds to be administered can be determined by standard procedures taking into account factors such as the compound ICm, the biological half—life ofthe compound, the age, size, and weight of the subject, and the indication being treated. The importance of these and other factors are well known to those of ordinaiy skill in the art.

Generally, 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 compounds of the invention may also be used in combination with other therapies for ng the same disease. Such combination use includes administration ofthe compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies. in some embodiments, dosage may be modified for one or more of the compounds ofthe invention or other eutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by s well known to those of ordinary skill in the art.

It is understood that use in ation includes use with other therapies, drugs, l procedures etc., where the other therapy or procedure may be administered at different times (e.g. within a short time, such as Within hours (e.g. l, 2, 3, 4-24 hours), or Within a longer time (e.g. 1—2 days, 2—4 days, 4—7 days, 1-4 weeks)) than a compound of the present invention, or at the same time as a compound of the invention. Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound ofthe invention administered within a short time or longer time before or after the other therapy or procedure. In some embodiments, the present invention es for delivery of compounds of the invention and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration. The use in combination for any route of administration includes dciivcry of compounds of the invention and one or more other drug therapeutics delivered by the same route of administration together in any formuiation, including ations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered. In one aspect, the other drug therapy may be co- administered with one or more compounds of the invention. Use in ation by co- stration includes administration of conformulations or formulations of chemicallyjoined nds, or administration of two or more compounds in separate fonnuiations within a short time of each other (cg. within an hour, 2 hours, 3 hours, up to 24 hours), administered by the same or different routes. Co-administration of separate formulations includes covadministration by delivery via one device, for example the same inhalant device, the same syringe, etc, or administration from separate deviees within a short time of each other. Co-fonnulations of compounds of the invention and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are d such that they are chemically joined, yet still maintain their biological activity. Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in viva, ting the two active components.

In certain embodiments, the patient is 60 years or older and relapsed after a first line cancer therapy. In certain embodiments, the t is 18 years or older and is relapsed or tory after a second line cancer y. In certain embodiments, the patient is 60 years or older and is primary refractory to a first line cancer therapy. In certain embodiments, the patient is 70 years or older and is previously untreated. In certain embodiments, the patient is 70 years or oldcr and is ineligible and/or unlikely to benefit from cancer therapy.

In certain embodiments, the therapeutically ive amount used in the methods provided herein is at least 10 mg per day. In certain ments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500 mg per dosage. In other embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg per day or more. In certain embodiments, the compound is administered uously.

In certain embodiments, provided herein is a method for treating a diseases or condition mediated by Flt3 or oncogenic Flt3 by stering to a mammal having a disease or condition at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 300, 900, 1000, 1200, 1300, 1400, 3,500, 3600, l700, 1.800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg per day ofa compound cf any 0f formulas I, la, lb, lg, Ila to Ilk, Ilm to Up and III or any of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof, and wherein the compound is administered on an empty stomach.

In certain embodiments, the disease or condition in the methods provided herein is cancer, In certain embodiments, the e or ccndition in the s previdcd herein is a solid tumor. In yet another embodiment, the disease or condition in the methods ed herein is a blood—home tumor. In yet another embodiment, the disease or condition is leukemia. In n embodiments, the leukemia is acute myeloid leukemia. In certain embodiments, the leukemia is acute lymphocytic leukemia. In still another embodiment, the leukemia is a refractory or drug resistant leukemia.

In certain embodiments, the drug resistant leukemia is drug resistant acute myeloid leukemia. In certain embodiments, the mammal having the drug resistant acute myeloid leukemia has an activating FLT3 mutation. In still another embodiment, the drug resistant acute myeloid leukemia has a FLT3 internal tandem duplication (ITD) mutation.

Each method provided herein may further comprise administering a second therapeutic agent. In certain embodiments, the second therapeutic agent is an anticancer agent. In certain embodiments, the second therapeutic agent is a protein kinase tor; In certain embodiments, a tyrosine kinase inhibitor; and in yet another embodiment, a second FLT3 kinase inhibitor, ing, but not limiting t0, Sunitinib, Cediranib, XL—184 free base (Cabozantinib, Ponatinib (AP24534), FHA—665752, Dovitinib S, CIIIR—258), AC220 (Quizartinib), TG101209 , KW—2449, AEE788 (NVP—AEE788), MP—470 (Amuvatinib), TSU—68 (SU6668, Orantinib, ENMD—2076, Vatalanib dihydrochloride (PTK787) and Tandutinib (MLNSIS).

VII. Manipulation of Flt3 Techniques for the manipulation of nucleic acids, such as, e.g., subcloning, labeling probes (e.g. random—primer labeling using Klenow polymerase, nick translation, cation), sequencing, hybridization and the like are well disclosed in the scientific and patent literature, see, e.g., Sambrook, ed., Molecular Cloning: a Laboratory Manual (2nd ed.), Vols. 1—3, Cold Spring Harbor tory, ; Current Protocols in Molecular y, Ausubel, ed. John Wiley & Sons, Inc., New York (1997); Laboratory Techniques in Biochemistry and Molccular Biology: Hybridization With c Acid , Part 1. Theory and Nucleic Acid Preparation, Tijssen, ed.

Elsevier, NY. (1993), [0334} Nucleic acid ces can be amplified as ary for further use using cation methods. such as PCR, isothermal methodst rolling circle methods, etc. are well known to the skilled artisan. See, eg, Saiki, “Amplification of Genomic DNA” in PCR ols, Innis et al., Eds, Academic Press, San Diego, CA 1990, pp 13-20; Wharam et al., c Acids Res. 2001 Jun l;29(l I):E54~E54; Hafner et al., Biotechniques 2001 Apr;30(4):852—6, 858. 860 passim; Zhong et al., Biotechniques 2001 .upr;30(4):852—6, 858, 860 passim, Nucleic acids, vectors, capsids, polypeptides, and the like can be analyzed and quantified by any ofa number of general means well known to those of skill in the art. These include, e.g., analytical biochemical methods such as NMR, spectrophotometry, radiography, electrophoresis, capillary electrophoresis, high performance liquid chromatography (1 IPLC), thin layer chromatography (TLC), and hyperdiffusion chromatography, various immunological methods, e. g. fluid or gel precipitin reactions, immunodiffusion, immuno-electrophoresis, radioimmunoassays (RIAs), enzyme-linked immunosorbent assays (ELISAs), immuno-fluorescent assays, Southern is, Northern analysis, dot—blot analysis, gel electrophoresis (cg. SDS«PAGE), nucleic acid or target or signal amplification methods, radiolabeling, scintillation counting, and affinity chromatography.

Obtaining and manipulating nucleic acids used to practice the methods ofthe invention can be performed by g from genomic samples, and, if desired, screening and re-cloning inserts isolated or amplified from, e.g., c clones or cDNA . Sources of nucleic acid used in the methods ofthe invention include genomic or cDNA libraries contained in, e.g., mammalian artificial chromosomes , see, e.g., US. Patent Nos. 5,721,118; 6,025,155; human ial chromosomes, see, e.g., Rosenfeld (1997) Nat. Genet. 15:333-335; yeast artificial chromosomes (YAC); bacterial ial chromosomes (BAC); Pl artificial chromosomes, see, e.g., Woon (1998) Genomics 502306-316; Pl-derived vectors , see, e.g., Kern (1997) Biotechniques -124; cosmids, recombinant viruses, phages or ds.

The nucleic acids used to ce the methods ofthe invention can be operatively linked to a promoter. A promoter can be one motif or an array of nucleic acid control sequences which direct transcription ofa nucleic acid. A promoter can include necessary nucleic acid sequences near the start site of transcription, such as, in the case ofa polymerase 11 type promoter, a TATA element. A promoter also optionally includes distal enhancer or sor elements which can be located as much as several thousand base pairs from the start site of transcription. A "constitutive" promoter is a promoter which is active under most nmental and developmental conditions.

An "inducible“ promoter is a promoter which is under environmental or developmental regulation.

A “tissue specific” promoter is active in certain tissue types of an organism, but not in other tissue types From the same organism. The term ”operabiy linker ” refers to a functional linkage between a nucleic acid expression control ce (such as a promoter, or array oftranscription factor binding sites) and a second c acid sequence, wherein the expression control ce directs transcription ofthe nucleic acid corresponding to the second sequence. [[0338] The nucleic acids used to practice the methods ofthe invention can also be provided in expression vectors and eioning vehicles, e.g., sequences ng the polypeptides used to practice the methods of the invention. sion vectors and cloning vehicles used to practice the methods ofthe invention can comprise viral particles, baculovirus, phage, plasmids, phagemids, cosmids, s, bacterial artificial chromosomes, viral DNA (e.g. ia, irus, foul pox virus, pseudorabies and derivatives of SV40), Pl—bascd artificial chromosomes, yeast plasmids, yeast artificial chromosomes, and any other vectors specific for specific hosts of interest (such as bacillus, Aspergillus and yeast). Vectors used to practice the methods of the invention can include somal, non~chromosomal and synthetic DNA sequences. Large numbers of suitable s are known to those of skill in the an, and are cially available.

The nucleic acids used to practice the methods of the invention can be cloned, if desired, into any ofa variety ofvectors using routine molecular biological methods; methods for cloning in vitro amplified nucleic acids are disclosed, e.g., US. Pat. No. 5,426,039. To facilitate cloning of amplified sequences, restriction enzyme sites can be “built into” a PCR primer pair. s may be introduced into a genome or into the cytoplasm or a nucleus of a cell and expressed by a variety of conventional techniques, well described in the scientific and patent literature. See, e.g., Roberts (1987) Nature 328:731; Schneider (1995) Protein Expr. Purif. 6435210; Sambrook, Tijssen or l. The vectors can be isolated from natural s, obtained from such sources as ATCC or GenBank libraries, or ed by tic or recombinant methods. For example, the nucleic acids used to ce the methods of the ion can be expressed in expression cassettes, vectors or viruses which are stably or ently expressed in cells (e.g. episomal expression systems). ion markers can be incorporated into expression cassettes and vectors to confer a selectable phenotype on transformed cells and sequences. For example, selection markers can code for episomal nance and replication such that integration into the host genome is not required.

In one aspect, the nucleic acids used to ce the methods of the invention are administered in viva For in situ expression of the peptides or polypeptides used to practice the methods ofthe invention. The nucleic acids can be administered as “naked DNA” (see, e.g., US.

Patent No. 5,580,859) or in the form of an expression vector, cg, a recombinant virus. The nucleic acids can be administered by any route, including perix or intra—tumoraliy, as described below. Vectors administered in Viva can be derived from virai genomes, including recombinantly modified enveloped or non-enveloped DNA and RNA viruses, preferably selected from baculoviridiae, parvoviridiae, picornoviridiae, herpesveridiae, poxviridae, adenoviridiae, or picornnaviridiae. Chimeric vectors may also be employed which exploit advantageous merits of each of the parent vector properties (Sec cg, Feng (1997) Nature Biotechnology 151866-870).

Such viral genomes may be d by recombinant DNA techniques to include the nucleic acids used to practice the methods of the invention; and may be further engineered to be replication deficient, conditionally replicating or replication competent. In alternative aspects, vectors are derived from the adenoviral (cg. replication etent vectors derived from the human adenovirus genome, see, eg, US. Patent Nos. 6,096,718; 6,110,453; 6,113,913; 5,631,236); adeno~associated viral and retroviral genomes. Retroviral s can include those based upon murine ia virus (MuLV), gibbon ape leukemia virus , Simian Immuno deficiency vims (SIV), human immuno deficiency virus (HIV), and combinations thereof; see, e.g., US.

PatentNos. 6,117,681; 6,107,478; 5,658,775; 5,449,614; her (1992) J. Virol. 66:2731- 2739; Johann (1992) J. Viral. 66:1635-1640). associated virus (AAV)-based vectors can be used to transduce cells with target nucleic acids, e.g., in the in vilro production of nucleic acids and peptides, and in in vivo and ex vivo gene therapy procedures; sec, c.g., US. Patent Nos. 6,110,456; 935; Okada (1996) Gene Ther. 3:957-964.

The present invention also s to use of fusion proteins, and nucleic acids encoding them. A polypeptide used to practice the s of the invention can be fused to a heterologous peptide or polypeptide, such as N-terminal identification peptides which impart desired characteristics, such as increased stability or simplified purification. Peptides and polypeptides used to practice the methods of the ion can also be synthesized and expressed as fusion proteins with one or more additional domains linked thereto for, e.g., producing a more immunogenic e, to more readily isolate a recombinantly synthesized peptide, to identify and isolate antibodies and antibody-expressing B cells, and the like. Detection and purification facilitating domains e, e.g., metal chelating peptides such as polyhistidine tracts and histidine—tryptophan modules that allow purification on immobilized metals, protein A domains that allow purification on immobilized globulin, and the domain utilized in the FLAGS extension/affinity purification system (lmmunex Corp, Seattle WA). The ion ofa eleavable linker sequences such as Factor Xa or enterokinase (Invitrogen, San Diego CA) between a purification domain and the motif-comprising peptide or polypeptide to facilitate purification. For example, an expression vector can include an epitope~encoding nucleic acid sequence linked to six histidine residues ed by a thioredoxin and an enterokinase ge site (see e.g., Williams (1995) Biochemistry 34:1787‘1797; Dobeli (1998) Protein Expr. Purif. 12:404—414). The histidine residues facilitate detection and purification while the enterokinase cleavage site es a means for purifying the epitope from the remainder efthe fusion protein. In ene aspect, a nucleic acid encoding a polypeptide used to practice the methods of the invention is assembled in appropriate phase with a leader ce capable of directing secretion ofthe translated polypeptide or fragment thereof. Technology pertaining to vectors encoding fusion proteins and application of fusion proteins are well disclosed in the scientific and patent literature, see e.g., Kroll (1993) DNA Cell. Bioii 12:44153, The nucleic acids and polypeptides used to practice the s of the invention can be bound to a solid support, e.g., for use in screening and diagnostic methods. Solid supports can include, e.g., membranes (eg. nitrocellulose or nylon), a microtiter dish (eg. PVC. polypropylene, or polystyrene), a test tube (glass or piastic), a dip stick (e.g. glass, PVC, polypropylene, polystyrene, latex and the like), a microfuge tube, or a glass, silica, plastic, ic or polymer head or other substrate such as paper. One solid support uses a metal (eg. cobalt or nickel)— comprising column which binds with specificity to a histidine tag engineered onto a peptide.

Adhesion of molecules to a solid support can be direct (i.e., the molecule contacts the solid support) or indirect (a ”linker" is bound to the support and the molecule of interest binds to this linker). Molecules can be immobilized either covalently (e.g. utilizing single reactive thiol groups of ne residues (see, e.g., Colliuod (1993) Bioconjugate Chem. 42528-536) or non- covalently but specifically (e.g. via immobilized antibodies (see, e.g., Schuhmann (1991) Adv.

Mater. 3:388—391; Lu (1995) Anal. Chem. 67:83—87; the biotin/strcpavidin system (see, e.g., Iwane (1997) Biophys. Biochem. Res. Comm. 230276-80); metal chelating, e.g., Langmuir-Blodgett films (see, e.g., Ng (1995) Langmuir 11:4048—55); metal-chelating self-assembled yers (see, e.g., Sigal (1996) Anal. Chem. 68:490—497) for binding of polyhistidine fusions.

Indirect binding can be achieved using a variety of linkers which are commercially ble. The reactive ends can be any ofa variety of functionalities including, but not limited to: amino reacting ends such as N—hydroxysuccinimide (NHS) active esters, imidoesters, aldehydes, epoxides, sulfonyl halides, isocyanate, isothiocyanate, and ryl s; and thiol reacting ends such as l disulfides, maleimides, thiophthalimides, and active halogens. The heterobifunctional crosslinking reagents have two ent reactive ends, e.g., an amino-reactive end and a thiol—reactive end, while homobifunctional ts have two similar reactive ends, e. g., bismaleimidohexane (BMH) which permits the cross—linking of dryl-containing compounds. The spacer can be of varying length and be aliphatic or aromatic. Examples of commercially available homobifunctional linking reagents include, but are not limited to, the imidoesters such as dimethyl adipimidate dihydrochloride (DMA); dimethyl pimelimidate dihydrochloride (UMP); and dimethyl midate ochloride (DMS). Heterobifunctional ts inciude commercialiy available active halogenNHS active esters coupiing agents such as Nwsuccinimidyl bromoacetate and N-succinimidyl (4«iodoacetyi)aminobenzoate (SIAB) and the uccinimidyl derivatives such as sulfosuccinimidyl(4—i0doacetyl)aminobenzoate (sulfo—SIAB) (Pierce). Another group of coupling agents is the heterobifunctional and thiol cleavable agents such as N~succinimidyl 3~(2~pyridyidithio)propionate (SPDP) (Pierce Chemicals, Rockford, IL).

Antibodies can also be used for binding polypeptides and peptides used to practice the methods of the invention to a solid support. This can be done directly by binding peptide-specific antibodies to the column or it can be done by creating fusion protein chimeras comprising motif~ containing peptides linked to, e.g., a known epitope (eg. a tag (eg. FLAG, myc) or an appropriate immunoglobulin constant domain sequence (an “immunoadhesin,” see, e.g., Capon (1989) Nature 377:525-531 (1989).

Nucleic acids or polypeptides used to practice the methods of the invention can be immobilized to or applied to an array. Arrays can be used to screen for or monitor ies of compositions (e.g. small molecules, antibodies, nucleic acids, etc.) for their y to bind to or modulate the activity of a nucleic acid or a polypeptide uscd to practice the methods of the invention. For example, in one aspect of the invention, a monitored parameter is transcript expression ofa gene comprising a c acid used to practice the methods ofthe invention. One or more, or all the transcripts ofa cell can be measured by hybridization ofa sample comprising transcripts ofthe cell, or nucleic acids representative of or mentary to transcripts ofa cell, by hybridization to immobilized nucleic acids on an array, or “biochip.” By using an “array” of c acids on a microchip, some or all ofthe transcripts ofa cell can be simultaneously quantified. Alternatively, arrays comprising genomic nucleic acid can also be used to determine the pe of a newly engineered strain made by the methods of the invention. Polypeptide arrays” can also be used to simultaneously fy a plurality ofproteins.

The terms “array” or “microarray” or “biochip” or “chip” as used herein is a plurality of target elements, each target element comprising a defined amount of one or more polypeptides (including antibodies) or nucleic acids immobilized onto a defined area ofa substrate surface. In practicing the methods of the invention, any known array and/or method of making and using arrays can be incorporated in whole or in part, or variations thereof, as disclosed, for example, in US. Patent Nos. 6,277,628; 6,277,489; 6,261,776; 6,258,606; 6,054,270; 695; 6,045,996; 6,022,963; 440; 5,965,452; 5,959,098; 5,856,174; 5,830,645; 5,770,456; 957; ,556,752; 5,143,854; 5,807,522; 5,800,992; 5,744,305; 5,700,637; 752; 5,434,049; see also, cg, WO 99251773; WO 99/09217; WO 97/46313; WO 96/17958; see also, cg, Johnston (1998) Curr. Bioi. 8le Z’i‘Ri74; Schummer (1997) Biotechniques 23:1087-1092; Kent (E997) Biotechniques 23:120-124; s~Toldo (1997) Genes, Chromosomes & Cancer 20399407; Bowtell (1999) Nature Genetics Supp. 21 . See also hed US. patent ation Nos. 20010018642; 20010019827; 20010016322; 20010014449; 20010014448; 20010012537; 20010008765.

Host Cells and Transformed Cells The invention also provides a transformed cell comprising a nucleic acid sequence used to practice the methods ofthe invention, eg, a sequence encoding a polypeptide used to practice the methods of the invention, or a vector used to practice the methods of the invention. The host cell may be any ofthe host cells familiar to those skilled in the art, including prokaryotic cells, otic cells, such as bacterial cells, fungal cells, yeast cells, mammalian cells, insect cells, or plant cells. Exemplary bacterial cells include E. coli, Streptomyces, Bacillus subtilis, Salmonella gmhimurium and various species within the genera Pseudamonas, Streptomyces, and Staphylococcus. Exemplary insect cells include Drosoplzila S2 and Spodoptera Sf9. Exemplary animal cells e CHO, COS or Bowes ma or any mouse or human cell line. The selection of an appropriate host is within the abilities ofthose skilled in the art.

Vectors may be introduced into the host cells using any ofa variety oftechniques, including transformation, transfection, transduction, viral ion, gene guns, or Ti«mediated gene er. Particular methods include calcium phosphate transfection, DEAEDextran ed transfection, lipofection, or electroporation.

Engineered host cells can be cultured in conventional nt media modified as appropriate for activating promoters, ing transfomiants or amplifying the genes used to practice the methods of the invention. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell y, the selected promoter may be induced by appropriate means (e.g. temperature shift or chemical induction) and the cells may be cultured for an additional period to allow them to produce the desired polypeptide or fragment thereof.

Cells can be harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract is retained for further purification. Microbial cells employed for expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, tion, ical disruption, or use of cell lysing agents. Such methods are well known to those skilled in the art, The expressed polypeptide or fragment can be recovered and purified from inant cell cultures by methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, mceiiulose chromatography, hydrophobic ction tography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Protein refolding steps can be used, as necessary, in completing configuration ofthe polypeptide. if desired, high performance liquid chromatography (HPLC) can be employed for final purification steps.

Various mammalian cell culture systems can also be employed to express recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts and other cell lines capable of expressing proteins from a compatible vector, such as the C127, 3T3, CHO. HeLa and BHK cell lines.

The constructs in host cells can be used in a conventional manner to produce the gene product encoded by the recombinant sequence. Depending upon the host employed in a recombinant production ure, the polypeptides produced by host cells containing the vector may be glycosylated or may be non-glycosylated. Polypeptides used to practice the methods of the invention may or may not also include an initial methionine amino acid residue.

Cell—free translation systems can also be employed to produce a polypeptide used to practice the methods of the invention. Cell-free translation systems can use mRNAs transcribed from a DNA construct sing a promoter operably linked to a nucleic acid encoding the polypeptide or fragment thereof. In some s, the DNA construct may be ized prior to ting an in vitro transcription reaction. The transcribed mRNA is then incubated with an appropriate cell-free translation extract, such as a rabbit locyte extract, to produce the d polypeptide or fragment thereof.

The expression s can contain one or more selectable marker genes to e a phenotypic trait for selection of transformed host cells such as dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, or such as tetracycline or llin resistance in E. coli.

For transient expression in mammalian cells, cDNA encoding a polypeptide of interest may be incorporated into a mammalian expression vector, eg. pcDNAl, which is available commercially from Invitrogen ation (San Diego, Calif., U.S.A.; catalogue number V490- ). This is a multifunctional 4.2 kb plasmid vector designed for cDNA expression in eukalyotic systems, and cDNA is in prokaryotcs, incorporated on the vector are the CMV promoter and enhancerr splice segment and polyadenylation signal? an SV40 and Polyoma virus origin of replication; and Ml 3 origin to rescue single strand DNA for sequencing and mutagenesis, Sp6 and T7 RNA promoters for the production of sense and anti-sense RNA transcripts and a Col [El-like high copy plasmid origin. A polylinker is d riately downstream of the CMV er (and 3‘ of the T7 promoter).

The cDNA insert may be first released from the above phagemid incorporated at appropriate restriction sites in the pcDNAI polylinker, Sequencing across thejunctions may be performed to confirm proper insert orientation in pcDNAI. The resulting plasmid may then be introduced for transient expression into a selected mammalian cell host, for example, the — derived, fibroblast like cells of the COS-l lineage (available from the American Type Culture Collection, Rockville, Md. as ATCC CRL l650).

For ent expression ofthe protein-encoding DNA, for example, COS-1 cells may be transfected with approximately 8 ug DNA per 106 COS cells, by ediated DNA transfection and treated with chloroquine according to the procedures described by Sambrook et a], Molecular Cloning: A Laboratory Manual, 1989, Cold Spring Harbor Laboratory Press, Cold Spring Harbor NY, pp. 16.30-16.37. An exemplary method is as follows. Briefly, COS-1 cells are plated at a density of5 x 106 dish and then grown for 24 hours in PBS-supplemented lfl medium. Medium is then removed and cells are washed in PBS and then in medium.

A transfection solution containing DEAE dextran (0.4 mg/ml), 100 pM chloroquine, 10% NuSerum, DNA (0.4 mg/ml) in DMEM/F12 medium is then applied on the cells 10 ml volume.

After incubation for 3 hours at 37 0C. cells are washed in PBS and medium asjust described and then shocked for 1 minute with 10% DMSO in DMEM/Flfl medium. Cells are allowed to grow for 2-3 days in 10% PBS-supplemented medium, and at the end ofincubation dishes are placed on ice, washed with ice cold PBS and then removed by scraping. Cells are then harvested by centrifugation at 1000 rpm for 10 minutes and the cellular pellet is frozen in liquid en, for subsequent use in protein sion. Northern blot analysis ofa thawed aliquot of frozen cells may be used to confirm expression of receptor-encoding cDNA in cells under storage.

In a like manner, stably transfected cell lines can also prepared, for example, using two different cell types as host: CHO K1 and CH0 ProS. To construct these cell lines, cDNA coding for the relevant protein may be incorporated into the mammalian expression vector pRC/CMV (Invitrogen), which enables stable expression. Insertion at this site places the cDNA under the expression control of the cytomegalovirus promoter and upstream of the poiyadenylation site and terminator of the bovine growth hormone gene, and into a vector background sing the neomycin resistance gene (driven by the SV40 early promoter) as selectable .

An exemplary protecel to introduce plasmids ucted as described above is as fellows. The host CHO cells are first seeded at a density of 5x105 in 10% upplemented MEM . After growth for 24 hours, fresh medium is added to the plates and three hours later, the cells are transfected using the calcium phosphate-DNA cipitation procedure (Sambrook et al, supra). Briefly, 3 pg of DNA is mixed and incubated with buffered calcium solution for 10 minutes at room temperature. An equal volume of buffered phosphate solution is added and the suspension is ted for 15 minutes at room temperature. Next, the incubated suspensien is applied (:0 the cells fer A hoursg retrieved and cells were shocked with medium containing 15% glycerol. Three minutes later, cells are washed with medium and ted for 24 hours at normal growth conditions. Cells resistant to neomycin are selected in 10% FBS- supplemented alpha—MEM medium containing G418 (1 mg/ml). Individual colonies of G418- resistant cells are isolated about 2—3 weeks later, clonally selected and then propagated for assay pllI'pOSES.

EXAMPLES Examples d to the present invention are described below. In most cases, alternative techniques can be used. The examples are ed to be illustrative and are not limiting or restrictive to the scope of the invention.

Example 1: Synthesis The synthesis ofthe nds bed herein was bed in PCT Patent publication N05,: WO 64255; ; and US Patent Application Publication No.: US 2009/0076046. A person of skill in the art is readily capable of preparing all the compounds described herein and those encompassed by the generic formulas 1, la, Ib, 1g, 11a to 11k, 11m to 11p and 11] using the procedures described in the above~mentioned patent applications.

Example 2: Binding Assays g assays can be performed in a variety ofways, including a variety of ways known in the art. For example, as indicated above, binding assays can be performed using fluorescence resonance energy transfer (FRET) , or using an AlphaSereen.

Alternatively, any method which can measure binding ofa ligand to the ATvainding site can be used. For example, a fluorescent ligand can be used. When bound Flt3, the emitted fluorescence is polarized. Once displaced by inhibitor binding, the polarization decreases.

Determination ofngg for compounds by competitive binding assays. (Note that K1 is the dissociation constant for inhibitor g; KD is the dissociation constant for substrate binding.) For this system, the lCSQ, inhibitor binding constant and substrate binding constant can be elated according to the following Formula; K1: ICSO . 1+ [L*]/KD When using radiolabeled substrate, the 1C5C. ~ K; when there is a small amount of labeled substrate.

Example 3: Cell-based assays of Flt3-ITD kinase activity The FLT3 inhibitors may also be assesscd using MV1 1 cells are a human biphenotypic B—myelomonocytic leukemia derived cell line that harbor an activated FLT3 allele with an internal tandem duplication (ITD) which is frequently observed in human acute myelocytic leukemia. MV- 4—1 1 cells (ATCC catalog # CRL—9591). This cell line proliferation is dependent on the FLT3~ ITD activity. Inhibitors of FLT3 kinase activity reduce or eliminate the FLT3-ITD oncogenic signaling, resulting in reduced cell proliferation. This inhibition is measured as a function of compound concentration to assess IC50 values. MVl 1 cells were seeded at l x 104 cells per well ofa 96 well cell culture plate in 50 ul of cell culture medium of lMDM (Invitrogen catalog #12440) supplemented with 10 % FBS (Sigma catalog #12306C). Compounds were dissolved in DMSO at a concentration of 1 mM and were serially diluted 1:3 for a total of eight points and added to the cells to final concentrations of 10, 3.3, 1.1, 0.37, 0.12, 0.041, 0.014 and 0.0046 uM in 100 pl cell culture medium (final concentration 0.2% DMSO). Cells were also treated with staurosporine as a positive control. The cells were incubated at 37 0C, 5% CD; for three days. ter~Glo Buffer ga Cell Viability Assay catalog #G7573) and ate were equilibrated to room temperature, and enzyme/substrate inant Firefly Luciferase/Beetle Luciferin was tituted. The cell plates were equilibrated to room temperature for 30 minutes, then lysed by addition of an lent volume of the Celltiter—Glo Reagent. The plate was mixed for 2 minutes on a plate shaker to lyse the cells, then incubated for 10 minutes at room temperature. The plates were read on a Victor Wallac II using Luminescence protocol modified to read 0. ls per well. The luminescence reading assesses the ATP content, which correlates ly with cell number such that the reading as a function of compound concentration was used to determine the IC50 value.

This cell based assay was also used to assess inhibition of TD phosphorylation in MV—4—l 1 cells. Samples were prepared with compounds as described for the growth inhibition assay only MV—4—ll cells were seeded at 2 x 10‘6 cells per well in a 96 Well Flat Clear Bottom Black Polystyrene Poly—D~Lysine Coated Microplate (Coming #3667). Cells were incubated for 1 hour at 37 9C with the compounds as described above, and then the cuiture medium was removed by aspiration and the ceils were lysed by addition of30 ul lysis buffer (25 mM Tris HCi pH 7.5, 150 mM NaCl, 5 mM EDTA. 1% Triton X100. 5 mM NaF, 1 mM date, 10 mM Beta— glycerophosphate: no EDTA (Boehringer-Roche catatalog #1873580) and placed on ice for 30 minutes. A 15 ul aliquot ofthe lysate was taken and assayed ing to Cell Signaling Technology ELISA ol (catalog #7206) PathScan® Phospho-FLT3 (Tyr59l) Sandwich ELISA Kit by diluting the aliquot with 85 n1 dilution buffer in the assay plate, incubating for 2 hours at room temperature and washing the plate 4 times with wash buffer. ion antibody (100 pl) was added to the plate and samples incubated for 1 hour at room temperature, then washed 4 times with wash buffer. HRP anti-rabbit antibody (100 ill) was added and samples incubated for 30 minutes at room temperature, then washed 4 times with wash . Stabilized chromogen (100 pl) was added and samples incubated for 15-25 minutes at room temperature, then washed 4 times with wash buffer. Stop on (100 pl) was added and the samples read on a Wallae Victor reader at 450 nm. The absorbanee was plotted against the compound tration and the ICso concentration was determined.

Example 4. Exemplary Flt3 biochemical assay protocol In order to determine the effect of compounds on FLT3 catalytic activity, kinase assays using recombinant enzymes and AlphaSereenTM technology has been established. When the kinases are catalytically active, they phosphorylates a biotinylated peptide substrate on tyrosine residues. Using AlphaScreenTM technology, the y of the compounds to affect the catalytic activity ofthe kinases can be measured quantitatively. The peptide substrate is immobilized by the AlphaScreenTM Streptavidin Donor beads and, upon phosphorylation by a tyrosine kinasc, can bind to AlphaScreenTM hosphotyrosine (PY20) Acceptor beads. Upon excitation of these beads with laser light at 680 nm, singlet oxygen is produced. This singlet oxygen is rapidly quenched, unless the AlphaScreenTM Anti-Phosphotyrosinc (PYZO) Acceptor beads are in close proximity, in which case a ity signal can be ed at 580 nm. In the presence of tic activity, there is a very strong proximity signal. Selective kinase inhibitors affect a decrease in this proximity signal h a se in tyrosine phosphorylation of the peptide substrate.

Assa {Buffer Sto Meteetion Buffer mM Hepes pH 7.5, mM Hepes pH 7.5 mM MnClz mM MnC12 mM MgClz mM Mng 0.01% Tween-20 0.01% Tween-20 0.3% BSA 1 mM DTT 1 mM DTT 100 mM EDTA Recombinant Enzymes En me Commercial Source 7 7 , 7 7 77 Invitrogen #PVS 182 Substrate Poly (Glu4-Tyr) Peptide, biotin conjugate [Biotin-GG(EEEEY)}OEE] UBI/Millipore #12-440 Finai concentration230 nM ine Triphesphate (AT?) Sigma #A-3377 Final concentration for ICSO determination: 100 MM Detection Reagent AlphaScreenTM Phosphotyrosine (PYZO) Assay Kit Perkin-Elmer #6760601M Final concentration=10 ug/ml Protocol 1C5 0 Dilute compounds in DMSO to 20X final concentration.

Add 1 pl of compound to each Well of384 well white reaction plate (Coming .

Mix enzymc and Poly (Glu4-Tyr) Peptide ate at 1.33X final concentration in assay buffer.

Mix ATP at 5X final concentration in assay .

Add 15 uL enzyme/substrate mixture to the reaction plate.

Add 4 uL of ATP to the reaction plate. Centrifuge ] minute, shake to mix, and incubate as follows: Reaction Assay temperature Reaction time FLT3 Room temperature I 60 minutes Mix Streptavidin Donor beads at 6X final concentration in Stop/Detection buffer.

Add 5 uL Streptavidin Donor beads to the reaction plate. Centrifuge 1 minute, shake to mix, and incubate at room temperature for 20 minutes.

Mix Anti-Phosphotyrosine (PY20) Acceptor beads at 6X final concentration in Stop/Detection buffer.

Add 5 pL Anti-Phosphotyrosine (PYZO) beads to the reaction plate. fuge 1 minute, shake to mix, and incubate at room temperature for 60 minutes.

Read plate on Wallac EnVisionTM 2103 Multilabel Reader.

The following Table provides Flt3 mical assay data of certain compounds.

{Compound No._r 1 FLT3 IC50 (11M) P0232 ,,,___:,9,1,_,W, P-0332 < 0.1 P-0282 < 0.1 P-0283 < 0.1 _2P4-027_0, __ WW: 0-1 P-0372 < 0.1 P-0442 < 0.1 P-0399 < 0.1 _,,__.P_-9,3_2_9. < 0.1 P-0383 < 1 P-0433 < 1 P-0428 < 1 3 P-0284 < 1 fl __,,, P0324 < 1 P-0427 < 1 P—0408 < 1 ___££3_89~L___,fmlm___m P-0385 < 1 P0415 < 1 P—0330 < 1 00391 < H ,,,,,,,,,,,, P-0333 < 10 Compounds P0001, P0002, P0003, P0004, P0005, P0006, P0007, P-0008, P0009, P0010, P0011, P0012, P0013, P0014, P0015, P0016, P0017, P0018, P0020, P0022, P0024, P0025, P0026, P0027, P0028, P0029, P0030, P0031, P0032, P0033, P0035, P- 0036, P0037, P003 8, P0039, P0040, P0041, P0046, P0049, P0052, P0053, P0054, P 0055, P0056, P0057, P0050, P0059, P0060, P0061, P0062, P0063, P0064, P0005, P0066, P0069, P0071, P0072, P0073, P0074, P0075, P0078, P0082, P0092, P0093, P0094, P0095, P0096, P0097, P0098, P0099, P0100, P0101, P0102, P0103, P0104, P0105, P0107, P0103, P0109, P—0111,P-0112, P0113, P0114, P0115, P0116, P0118, P0120, P0121, P0122, P0123, P0125, P0126, P0127, P0128, P0129, P0131, P0132, P-0138, P0143, P0144, P0145, P0148, P0154, P0156, P0157, P0159, P0161, P0163, P0170, P0121, P0173, P0174, P0176, P0177, P0179, P0180, P0181, P0182, P0136, P0167, P-0188, P-0190, P—0192, P—0193, P-0194, P—0195, P-0197, P-0199, P—0201, P-0203, P—0205, P-0206, 13-0208, P—02l 1, P-02l2, P-0213, P—02l4, P-0215, 19—0216, P—0217, P-0218, , P-0221, P-0222, P—0224, P-0225, , P—0228, P-0234, P—0237, 13—0239, P-0‘240, , P-0243, P-0244, P—0245, P—0246, , , P-OZSS, P-0257, 13-0258, P-0259, P-0260, P—0262, , P-0264, P-0265, P-0266, Pv0267, P-0268, P—0269, P—0270, P—027l, P—0272, , , P~0275, P-0276, P-0277, P—0278, P-0279, P-0280, P—0281, P-0282, P-0283, P-0284, P-0285, P—0286, P-0287, P-0288, P—0289, P-0290, P-029l, 13—0294, P-0297, P—0298, P-030], P-0302, , P-0305, P-0306, P-0307, P-0308, P-0309, P—03ll, P03 12, P-03 l3, , P-0316, P—0319, 13-0320, 19-0321, P—0322, P-0323, P-0324, P—0325, P-0326, P-0327, P~0328, P-0329, P—0330, P—033l, P-0332, P—0334, P-0336, P-0337, P-0338, P-0339, P—0340, P—034l, P-0342, , P-0344, P-0345, P-0346, , P—0348, P—0350, P-0351, P-0352, , P-0355, P-0356, P—0357, P-0358, P—0359, P—036l, P-0362, P—0363, 13-0365, P-0366, P—0367, , P-0369, P—0370, P-037l, P-0372, P—0373, P-0375, P—0376, P-0377, P-037S, P—03 79, P-0382, P—0383, P—0385, P-0387, P—0390, 13—0392, P-0393, P—0394, P-0395, P-0396, P-0402, P-0404, P-0406, P—0407, P—0408, P-0409, and P-04l2 had ICSO of less than 1 uM in the Flt3assays described above in Example 3_ In viva model system testing For in viva testing, a suitable animal model system can be ed for use. For example, for multiple scerosis, the rodent mental allergic encephalomyelitis (EAE) is commently used. This system is nown, and is described, for example, in Steinman, 1996, Cell 85:299— 302 and Secor et al., 2000, J Exp. Med 5:813—82l, which are incorporated herein by reference in their entireties.

Similarly, other model systems can be selected and used in the present invention.

Example 5. Inhibition of the proliferation of the human FLT3—ITD+ AML cell lines Compounds ofFormula I, Formula Ia, Formula lb, Formula lg, a II, a lla, Formula Hb, Formula He, Formula Hd, Formula He, Formula Hf, Formula Hg, Formula Hh, Formula Hi, Formula Hj, Formula 11k, Formula Hm, a lln, Formula Ho, Formuia Ilp, or Formula HI, all sub~embodiments thereof, compounds p,0001-p-0449: and any compounds as described herein were found to inhibited the proliferation of the human FLT3~ITD+ AML cell lines MV4;1 l and Molml4 with a 50% inhibitory concentration (ICSO) in the submicromolar range (~0.l-0.25 uM). The compounds as described herein inhibited phosphorylation of FLTB-ITD with a dose response r to the growth inhibition range.

Example 6. Inhibition of FLT3—ITD mutant isoforms Compounds of a I, a Ia, Formula lb, Formula lg, Formula II, a lla, Formula lib, a lIc, Formula Ild, Formula 116, Formula llf, Formula llg, Formula llh, Formula Hi, Formula llj, a llk, Formula IIm, Formula Iln, Formula [[0, Formula llp, or Formula [11, all bodiments thereof, compounds P~0001—P‘0449, and any compounds as described herein were found toinhibit the eration of BaF3 cells transformed with FLT3-[TD and AC220—resistant FLT3—ITD mutant isoforms F691L, D835V/Y, and Y842C/H. The compounds as bed herein inhibited the proliferation of Ba/F3WLT3—ITD cells at submicromolar concentrations. Encouragingly, The compounds as described herein retained activity against cells sing the ally—relevant F691L gatekeeper mutation at a similar concentration, although all other AC220—resistant mutations evaluated conferred substantial cross— resistance to The nds as described herein. .

Example 7. FLT3 inhibitor for AML therapy A ed plasma inhibitory assay was med by incubating Molm 14 cells in either normal donor or AML patient plasma spiked with increasing concentrations of compounds of Formula 1, Formula Ia, Formula lb, Formula lg, Formula II, Formula Ila, Formula llb, Formula llc, Formula lld, Formula lle, Formula llf, Formula Ilg, Formula llh, Formula lIi, Formula llj, Formula llk, Formula llm, Formula lln, Formula 110, Formula Up, or Formula 111, all sub— embodiments thereof, compounds P—OOOl—P—0449, and any compounds as described herein as well as unmanipulated, steady—state plasma samples from the solid tumor. Using phospho-specific flow cytometry to evaluate Fl,,T3 signaling through the downstream protein ribosomal S6, we observed near—maximal reductions in phospho-Sfi in both normal and AML patient plasma containing 310 uM the compounds as described herein as well as plasma samples obtained from the solid tumor trial.

All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, inciuding any tabies and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually, One skilled in the art would readily appreciate that the present invention is well d to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances, and compositions described herein as presently entative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit ofthe invention. For example, variations can be made to provide additional compounds of Formulae I, II or III, and all sub-embodiments thereof, and/or various methods of administration can be used. Thus, such onal embodiments are within the scope ofthe present ion and the following claims.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed . The terms and sions which have been employed are used as terms ofdeseription and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions f, but it is recognized that various modifications are possible within the scope ofthe invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by red embodiments and optional features, modification and variation of the concepts herein sed may be resorted to by those skilled in the art, and that such modifications and variations are ered to be within the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the alt will recognize that the invention is also thereby described in terms of any dual member or subgroup of members ofthe Markush group or other group.

Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are bed by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the bed invention.

Thus, additional embodiments are within the scope of the invention and within the ing claims.

SEQUENCE LISTING SEQ ID NO:1 SequenceP€P_004ll(l2 DGGQLPLLVVFSAMIFGT I”I1eQELPVIhfi7‘INh<NND SSVGKSSSYPHVSESPEDLGCALREQSSGTVYEAAAVEVDV ASITLQVLVDAPGNIS CLWVFKHSSLNCQPHFDLQNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSI RNTLLYTLRRPYFRKMENQDALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEE KVLHELFGTDIRCCARNELGRECTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVH VNHGFGLTWELENKAL EEGNYFEMSTYSTNRTMIRILFAFVSSVRRNDTGYYTCSSSK HPSQSALVTIVEKGFINATNSSEDYEIDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPC EQKGLDNGYSISKFCNHKHQPGEYIFHAENDDAQFTKMFTLNIRRKPQVLAEASASQA SCFSDGYPLPSWTWKKCSDKSPNCTEEITEGVWNRKANRKVFGQWVSSSTLNMSEAIK GFLVKCCAYNSLGTSCETILLNSPGPFPFIQDNISFYATIGVCLLFIVVLTLLICHKY KKQFRYESQLQMVQVTGSSDNEYFYVDFREYEYDLKWEFPRENLEFGKVLGSGAFGKV MNATAYGISKTGVSIQVAVKMLKEKADSSEREALMSELKMMTQLGSHENIVNLLGACT LIFEYCCYGDLLNYLRSKREKFHRTWTEIFKEHNFSFYPTFQSHPNSSMPGS REVQIHPDSDQISGLHGNSFHSEDEIEYENQKRLEEEEDLNVLTFEDLLCFAYQVAKG MEFLEFKSCVHRDLAARNVLVTHGKVVKICDFGLARDIMSDSNYVVRGNARLPVKWMA PESLFEGIYTIKSDVWSYGILLWEIFSLGVNPYPGIPVDANFYKLIQNCFKMDQPFYA TEEIYIIMQSCWAFDSRKRPSFPNLTSFLGCQLADAEEAMYQNVDGRVSECPHTYQNR MDLGLLSPQAQVEDS SEQ ID NO:2 Sequence NM__44119 1 acctgcagcg cgaggcgcgc cgctccaggc ggcatcgcag ggctgggccg gcgcggcctg 61 gggaccccgg gctccggagg ccatgccggc gttggcgcgc ggcc agctgccgct 121 gcthttgtt ttttctgcaa tgatatttqg taca aatcaagat: tgcctqtqat 181 caagtgtgtt ttaatcaatc ataagaacaa tgattcatca gtggggaagt catcatcata 241 tcccatggta tcagaatccc acct cgggtgtgcg ttgagacccc agagctcagg 301 gacagtgtac gaagctgccg ctgtggaagt ggatgtatct gcttccatca cactgcaagt 361 gctggtcgac gccccaggga acatttcctg tchnggtc tLtaagcaca gctccctgaa 421 ttgccagcca gat: tacaaaacag aggagttgtt tccatggtca :tttgaaaat 481 gacagaaacc caagctgqag aatacctact ttttattcag agtgaagcta ccaattacac EéI gttt agta taagaaatac cctgstttac acattaagaa &m O (‘2 d” (T C13 f“ s”? t 631 acgccctggt g {)1 IQa U3 s g tic flm \Q p k1} F} {"2 m2 m ('1‘ ; C?“ CS”, I“; {‘3 w m w m D ‘Q m m m HQ FT 1') (”J m «11 0 Hr m ('1 , aticacaggg w} p) w 1 0 LC}Qm H m N m m - tgctt :atga N tQ \Q Ng0 (“T kg m Q n \J w H* aafgcaccag gctgttcaca W Ww m S atecaaactc: w in F4 tatttcttaa agtaggggaa ccctt tgga‘ Ldaggtgcaa m)\9 O H gattcgggct caccugggaa ttagaaaa:a aagcactcga ox %a :gagtaccta :tcaecaaac agaastatga tacggattetC I.” C) m {.4 tggcaagaaa cgacacen( a tactacactt :tCCtC t M Q aaagcatccc catcgtgqaa aagggaitta taaatgctac aagt atatgaagag ttttqttttt ctgtcaggtt taaagcccac gaccttctct cgaaaatcat gtga gcaaaagggt cttgataacg atccaagttt tgcaatcaLfi agcaccagcc aggagaatat atattccatg tgatgcccaa tttaccaaaa :g:tcacgct gaatataaqa aggaaacctc aagtgctcgc agaagcatcg cgccctqttt thqqatqga tacccattac catcttqqac ctqqaagaaq aqtctcccaa ctqcacagaa gagatcacag aaggagtctg gaatagaaag aagtgtttgg acagtgggtg tcgagcagta ctctaaacat gagtgaagcc tcctggtcaa gtgctgtgca tacaattccc tuggcacatc ttgtgagacg actctccagg ccccttccct LtcaLccaag acaacatctc attctatgca acaattggtg ttLchtCCt cttcattgtc accc tgctaatttg tcacaagtac aaaaagcaat ttaggtatga aagccagcta cagatggtac aggtgaccgg ctcctcagat aatgagtact tctacgttga tttcagagaa :atqaatatq atctcaaatq qqagtttcca aatt taqaqtttqq gaaggtacta ggatcaggtg cttttggaaa agtgatgaac gcaacagctt atgqaattag caaaacagga gtctcaatcc ccgt gctg aaagaaaaag gctc tgaaagagag gcactcatgt cagaactcaa gatgatgacc cagctgggaa gccacgagaa tattgtgaac ctgctggggg cgtgcacact gtcagqacca atttacttga titttgaata ctgttgctat ggtgatcttc tcaactatct aagaagtaaa agagaaaaat ttcacaggac ttggacagag attttcaagg aacacaattt cagtttttac cccactttcc aatcacatcc aaattccaqc qqtt caaqaqaaqt tcagatacac ccggactcgg tctc tcat gggaattcat ttcactctqa agatgaaatt gaaa accaaaaaag gctggaagaa gact tgaatgtgct tacatttgaa gatcttcttt gctttgcata tcaagttgcc atgg aatttctgga atttaagtcg caca gagacctggc cgccaggaac gtgcttgtca cccacgggaa gaag atatgtgact ttggattggc tcgagatatc atgagtgatt ccaactatgt tgtcaggggc aatgcccgtc tgcctgtaaa atggatggcc cccgaaagcc tgtttgaagg catctacacc attaagagtg atgtctggtc atatggaata ttactgtggg aaatcttctc tgtg aat0cttacc ctggcattcc gqttgatgct aacttctaca aactgattca aaatggattt aaaatggatc agccatttta tgctacagaa taca tgca atcctgctgg gcttttgact caaggaaacg gccatccttc cctaatttga cttcgttttt aggatgtcag ctggcagatg cagaagaagc gatgtatcag aatgtggatg gccgtgtttc ggaatgtcct cacacctacc aaaacaggcg acctttragc agagagatgg actctctccg caggctcagg tcgaagattc gtagaggaac aatttagttt ctatccctaa caggctgtag tat:at:&a: ttcaaaggqa éficttiéttg itscctgaag gctaaggéga agcta8tatg Ab cagctattta gtgatapatt H :attgaatta tttacatggt ,3 Ln L: @032 km: gtg {"3 acccatag HH £41 m C} M agatacgwxkL} LL} w W 1” L52 {T Li.) H“ w (2 £3i y 3661 tgtcacagcc taagatttct gcaacaacag gggtt gqqqqaaqtt tataatgaa: 3721 aggtgttcta ccataaagag taatacatca cac: :tggcggcct tcccagactc 3781 aqgg:cagtc agaagtaaca tggaggatta gt a taaagttact cttgtcccca 3841 caaaaaaa

Claims (8)

CLAIMS 1.:

1. Use of a compound having the formula: or a ceutically acceptable salt or tautomer thereof, in the preparation of a medicament for treating acute myeloid leukaemia (AML) in a subject wherein the subject has an ke tyrosine kinase (Flt3) gene with an internal tandem duplication (ITD) mutation.

2. The use of claim 1, wherein the Flt3 gene of the subject further has a F691L mutation.

3. The use of claim 1, wherein the AML is refractory or drug resistant.

4. The use of any one of claims 1-3, wherein the subject is a human.

5. The use of any one of claims 1-4, wherein the compound is formulated into oral dosage form.

6. The use of any one of claims 1-5, wherein the nd is in formulated into tablet form.

7. The use of any one of claims 1-5, wherein the nd is formulated into a capsule form.

8. The use of any one of claims 1-7, wherein the compound is in a hydrochloride salt form.